Acute toxicity and primary irritancy of alkylalkanolamines.

PubMed

Ballantyne, B; Leung, H W

1996-12-01

The acute handling hazards of several alkylalkanolamines were determined by investigating their potential acute toxicity and primary irritancy. Materials studied were N-methylethanolamine (MEA), N, N, -dimethylethanolamine (DMEA), N, N, -dimethylisopropanolamine (DMIPA), N-methyldiethanolamine (MDEA), and tertbutyldiethanolamine (BDEA). All these alkylalkanolamines were of comparable acute peroral toxicity in the rat (LD50 range 1.48-2.83 ml/kg). By 24 h occluded epicutaneous contact in the rabbit, MEA, DMEA and DMIPA were of moderate acute percutaneous toxicity (LD50 range 1.13-2.0 ml/kg), MDEA was of slight acute percutaneous toxicity (LD50 male 9.85 ml/kg, female 10.90 ml/kg), and BDEA of intermediate toxicity (LD50 6.4 ml/kg). Due to differences in vapor pressure the acute vapor exposure toxicity of the alkylalkanolamines to rats varied; MEA, MDEA and BDEA were of a low order of acute toxicity, and DMIPA was moderately toxic with an LT50 of 3.2 h for a saturated vapor atmosphere exposure. A 4 h-LC50 (rat combined sex) of 1461 ppm was determined for DMEA. All alkylalkanolamines studied, except MDEA, were moderately to markedly irritating and caused variable degrees of skin corrosivity; MDEA caused only transient minor skin irritation. In accord with the skin irritancy results, the eye irritancy from 0.005 ml MEA, DMEA, DMIPA and BDEA was severe, and that from MDEA was slight. Exposure to these compounds has implications for occupational health procedures.

Dose-volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.

PubMed

Kim, Tae Hyun; Cho, Kwan Ho; Pyo, Hong Ryull; Lee, Jin Soo; Han, Ji Youn; Zo, Jae Ill; Lee, Jong Mog; Hong, Eun Kyoung; Choi, Il Ju; Park, Sung Yong; Shin, Kyung Hwan; Kim, Dae Yong; Kim, Joo Young

2005-07-15

To retrospectively evaluate which dose-volumetric parameters are associated with the risk of > or = Grade 3 acute esophageal toxicity (AET) in lung cancer patients treated with three-dimensional conformal radiotherapy (3D-CRT). One hundred twenty-four lung cancer patients treated curatively with 3D-CRT were retrospectively analyzed. All patients received conventionally fractionated radiotherapy (RT) with median dose of 60 Gy (range, 54-66 Gy) delivered in 30 fractions (range, 27-33 fractions). Thirty-one patients underwent curative surgery before RT. Ninety-two patients received chemotherapy (induction, 18; concurrent +/- induction, 74). Acute esophageal toxicity was scored by Radiation Therapy Oncology Group criteria. The parameters analyzed included sex; age; Karnofsky performance score; weight loss; surgery; concurrent chemotherapy; the percentages of organ volume receiving > or =20 Gy (V20), > or =30 Gy (V30), > or =40 Gy (V40), > or =50 Gy (V50), > or =55 Gy (V55), > or = 58 Gy (V58), > or =60 Gy (V60), and > or =63 Gy (V63); the percent and absolute length of the esophagus irradiated; the maximum and mean dose to the esophagus; and normal tissue complication probability. Of the 124 patients, 15 patients (12.1%) had Grade 3 AET, and 1 (0.8%) patient had Grade 4 AET. There was no fatal Grade 5 AET. In univariate and multivariate logistic regression analyses, concurrent chemotherapy and V60 were significantly associated with the development of severe (> or = Grade 3) AET (p < 0.05). Severe AET was observed in 15 of 74 patients (20.3%) who received concurrent chemotherapy, and in 1 of 50 patients (2.0%) who did not (p = 0.002). Severe AET was observed in 5 of 87 patients (5.7%) with V60 < or = 30% and in 11 of 37 patients (29.7%) with V60 > 30% (p < 0.001). Among 50 patients who did not receive concurrent chemotherapy, severe AET was observed in 0 of 43 patients (0%) with V60 < or = 30% and in 1 of 7 patients (14.2%) with V60 > 30% (p = 0.140). Among 74 patients

Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Musah, Sadiatu; Schlueter, Connie F.; Humphrey, Da

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbitsmore » were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. - Highlights: • A novel rabbit model of chlorine-induced lung disease was

Comparative lung toxicity of engineered nanomaterials utilizing in vitro, ex vivo and in vivo approaches.

PubMed

Kim, Yong Ho; Boykin, Elizabeth; Stevens, Tina; Lavrich, Katelyn; Gilmour, M Ian

2014-11-26

Although engineered nanomaterials (ENM) are currently regulated either in the context of a new chemical, or as a new use of an existing chemical, hazard assessment is still to a large extent reliant on information from historical toxicity studies of the parent compound, and may not take into account special properties related to the small size and high surface area of ENM. While it is important to properly screen and predict the potential toxicity of ENM, there is also concern that current toxicity tests will require even heavier use of experimental animals, and reliable alternatives should be developed and validated. Here we assessed the comparative respiratory toxicity of ENM in three different methods which employed in vivo, in vitro and ex vivo toxicity testing approaches. Toxicity of five ENM (SiO2 (10), CeO2 (23), CeO2 (88), TiO2 (10), and TiO2 (200); parentheses indicate average ENM diameter in nm) were tested in this study. CD-1 mice were exposed to the ENM by oropharyngeal aspiration at a dose of 100 μg. Mouse lung tissue slices and alveolar macrophages were also exposed to the ENM at concentrations of 22-132 and 3.1-100 μg/mL, respectively. Biomarkers of lung injury and inflammation were assessed at 4 and/or 24 hr post-exposure. Small-sized ENM (SiO2 (10), CeO2 (23), but not TiO2 (10)) significantly elicited pro-inflammatory responses in mice (in vivo), suggesting that the observed toxicity in the lungs was dependent on size and chemical composition. Similarly, SiO2 (10) and/or CeO2 (23) were also more toxic in the lung tissue slices (ex vivo) and alveolar macrophages (in vitro) compared to other ENM. A similar pattern of inflammatory response (e.g., interleukin-6) was observed in both ex vivo and in vitro when a dose metric based on cell surface area (μg/cm(2)), but not culture medium volume (μg/mL) was employed. Exposure to ENM induced acute lung inflammatory effects in a size- and chemical composition-dependent manner. The cell culture and lung

Fingerprint of Lung Fluid Ultrafine Particles, a Novel Marker of Acute Lung Inflammation.

PubMed

Bar-Shai, Amir; Alcalay, Yifat; Sagiv, Adi; Rotem, Michal; Feigelson, Sara W; Alon, Ronen; Fireman, Elizabeth

2015-01-01

Acute lung inflammation can be monitored by various biochemical readouts of bronchoalveolar lavage fluid (BALF). To analyze the BALF content of ultrafine particles (UFP; <100 nm) as an inflammatory biomarker in early diagnosis of acute and chronic lung diseases. Mice were exposed to different stress conditions and inflammatory insults (acute lipopolysaccharide inhalation, tobacco smoke and lethal dose of total body irradiation, i.e. 950 rad). After centrifugation, the cellular pellet was assessed while cytokines and ultrafine particles were measured in the soluble fraction of the BALF. A characteristic UFP distribution with a D50 (i.e. the dimension of the 50th UFP percentile) was shared by all tested mouse strains in the BALF of resting lungs. All tested inflammatory insults similarly shifted this size distribution, resulting in a unique UFP fingerprint with an averaged D50 of 58.6 nm, compared with the mean UFP D50 of 23.7 nm for resting BALF (p < 0.0001). This UFP profile was highly reproducible and independent of the intensity or duration of the inflammatory trigger. It returned to baseline after resolution of the inflammation. Neither total body irradiation nor induction of acute cough induced this fingerprint. The UFP fingerprint in the BALF of resting and inflamed lungs can serve as a binary biomarker of healthy and acutely inflamed lungs. This marker can be used as a novel readout for the onset of inflammatory lung diseases and for complete lung recovery from different insults.

Acute and delayed toxicity of gemcitabine administered during isolated lung perfusion: a preclinical dose-escalation study in pigs.

PubMed

Pagès, Pierre-Benoit; Derangere, Valentin; Bouchot, Olivier; Magnin, Guy; Charon-Barra, Céline; Lokiec, François; Ghiringhelli, François; Bernard, Alain

2015-08-01

Colorectal cancer is the third most commonly diagnosed cancer worldwide, with up to 25% of patients presenting with metastases at the time of diagnosis. Despite pulmonary metastasectomy many patients go on to develop pulmonary recurrence, which might be linked to the presence of lung micrometastases. In this setting, the adjuvant administration of high-dose chemotherapy by isolated lung perfusion (ILP) has shown encouraging results. However, the tolerance to and efficacy of modern gemcitabine (GEM)-based chemotherapy regimens during adjuvant ILP remain unknown. We conducted a dose-escalating preclinical study to evaluate the immediate and delayed toxicity of GEM in a pig model to define dose-limiting toxicity (DLT) and maximum tolerated concentration. Twenty-three pigs were given increasing concentrations of GEM during ILP, and were awakened at the end of the procedure. The concentrations of GEM were 40, 80, 160, 320, 640 and 1280 µg/ml. Serum and lung samples were taken to measure GEM concentrations. Pulmonary damage was evaluated by histological examination and cleaved caspase-3 detection. Immediate and delayed (1 month) toxicity were recorded. All of the animals underwent successful ILP with GEM. No systemic leak was observed. The three pigs that received a concentration of GEM of 1280 µg/ml died of hypoxia after lung recirculation at the end of the procedure. Eleven pigs survived for 1 month. Major lung toxicity was observed for the concentration of GEM of 640 µg/ml, both at the end of the procedure and after 1 month. DLT was defined at the concentration of 640 µg/ml and the maximum tolerated dose (MTD) was defined at the concentration of 320 µg/ml. ILP with GEM is a safe and reproducible technique in this large-animal model, which includes 1 month of survival. The MTD in this pig model was a concentration of GEM of 320 µg/ml. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All

Role of Nrf2 and Autophagy in Acute Lung Injury

PubMed Central

Rojo de la Vega, Montserrat; Dodson, Matthew; Gross, Christine; Manzour, Heidi; Lantz, R. Clark; Chapman, Eli; Wang, Ting; Black, Stephen M.; Garcia, Joe G.N.; Zhang, Donna D.

2016-01-01

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS. PMID:27313980

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

PubMed Central

Schmiegelow, Kjeld; Müller, Klaus; Mogensen, Signe Sloth; Mogensen, Pernille Rudebeck; Wolthers, Benjamin Ole; Stoltze, Ulrik Kristoffer; Tuckuviene, Ruta; Frandsen, Thomas

2017-01-01

During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs. PMID:28413626

Classification of baseline toxicants for QSAR predictions to replace fish acute toxicity studies.

PubMed

Nendza, Monika; Müller, Martin; Wenzel, Andrea

2017-03-22

Fish acute toxicity studies are required for environmental hazard and risk assessment of chemicals by national and international legislations such as REACH, the regulations of plant protection products and biocidal products, or the GHS (globally harmonised system) for classification and labelling of chemicals. Alternative methods like QSARs (quantitative structure-activity relationships) can replace many ecotoxicity tests. However, complete substitution of in vivo animal tests by in silico methods may not be realistic. For the so-called baseline toxicants, it is possible to predict the fish acute toxicity with sufficient accuracy from log K ow and, hence, valid QSARs can replace in vivo testing. In contrast, excess toxicants and chemicals not reliably classified as baseline toxicants require further in silico, in vitro or in vivo assessments. Thus, the critical task is to discriminate between baseline and excess toxicants. For fish acute toxicity, we derived a scheme based on structural alerts and physicochemical property thresholds to classify chemicals as either baseline toxicants (=predictable by QSARs) or as potential excess toxicants (=not predictable by baseline QSARs). The step-wise approach identifies baseline toxicants (true negatives) in a precautionary way to avoid false negative predictions. Therefore, a certain fraction of false positives can be tolerated, i.e. baseline toxicants without specific effects that may be tested instead of predicted. Application of the classification scheme to a new heterogeneous dataset for diverse fish species results in 40% baseline toxicants, 24% excess toxicants and 36% compounds not classified. Thus, we can conclude that replacing about half of the fish acute toxicity tests by QSAR predictions is realistic to be achieved in the short-term. The long-term goals are classification criteria also for further groups of toxicants and to replace as many in vivo fish acute toxicity tests as possible with valid QSAR

Evaluating the Performance of the Pediatric Acute Lung Injury Consensus Conference Definition of Acute Respiratory Distress Syndrome.

PubMed

Parvathaneni, Kaushik; Belani, Sanjay; Leung, Dennis; Newth, Christopher J L; Khemani, Robinder G

2017-01-01

The Pediatric Acute Lung Injury Consensus Conference has developed a pediatric-specific definition of acute respiratory distress syndrome, which is a significant departure from both the Berlin and American European Consensus Conference definitions. We sought to test the external validity and potential impact of the Pediatric Acute Lung Injury Consensus Conference definition by comparing the number of cases of acute respiratory distress syndrome and mortality rates among children admitted to a multidisciplinary PICU when classified by Pediatric Acute Lung Injury Consensus Conference, Berlin, and American European Consensus Conference criteria. Retrospective cohort study. Tertiary care, university-affiliated PICU. All patients admitted between March 2009 and April 2013 who met inclusion criteria for acute respiratory distress syndrome. None. Of 4,764 patients admitted to the ICU, 278 (5.8%) met Pediatric Acute Lung Injury Consensus Conference pediatric acute respiratory distress syndrome criteria with a mortality rate of 22.7%. One hundred forty-three (32.2% mortality) met Berlin criteria, and 134 (30.6% mortality) met American European Consensus Conference criteria. All patients who met American European Consensus Conference criteria and 141 (98.6%) patients who met Berlin criteria also met Pediatric Acute Lung Injury Consensus Conference criteria. The 137 patients who met Pediatric Acute Lung Injury Consensus Conference but not Berlin criteria had an overall mortality rate of 13.1%, but 29 had severe acute respiratory distress syndrome with 31.0% mortality. At acute respiratory distress syndrome onset, there was minimal difference in mortality between mild or moderate acute respiratory distress syndrome by both Berlin (32.4% vs 25.0%, respectively) and Pediatric Acute Lung Injury Consensus Conference (16.7% vs 18.6%, respectively) criteria, but higher mortality for severe acute respiratory distress syndrome (Berlin, 43.6%; Pediatric Acute Lung Injury Consensus

The acute toxicity of inhaled beryllium metal in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haley, P.J.; Finch, G.L.; Hoover, M.D.

1990-01-01

The authors exposed rats once by nose only for 50 min to a mean concentration of 800 [mu]g/m[sup 3] of beryllium metal to characterize the acute toxic effects within the lung. Histological changes within the lung and enzyme changes within bronchoalveolar lavage (BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and 171 days postexposure (dpe). Beryllium metal-exposed rats developed acute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolar fibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesions were replaced by minimal interstitial and intraalveolar fibrosis. Necrotizing inflammation was observed again at 59 dpe which progressed tomore » chronic-active inflammation by 115 dpe. Low numbers of diffusely distributed lymphocytes were also present but they were not associated with granulomas as is observed in beryllium-induced disease in man. Lymphocytes were not elevated in BAL samples collected from beryllium-exposed rats at any time after exposure. Lactate dehydrogenase (LDH), [beta]-glucuronidase, and protein levels were elevated in BAL fluid from 3 through 14 dpe but returned to near normal levels by 31 dpe. LDH increased once again at 59 dpe and remained elevated at 171 dpe. [beta]-Glucuronidase and protein levels were slightly, but not significantly, elevated from 31 through 171 dpe.« less

Induced hypernatraemia is protective in acute lung injury.

PubMed

Bihari, Shailesh; Dixon, Dani-Louise; Lawrence, Mark D; Bersten, Andrew D

2016-06-15

Sucrose induced hyperosmolarity is lung protective but the safety of administering hyperosmolar sucrose in patients is unknown. Hypertonic saline is commonly used to produce hyperosmolarity aimed at reducing intra cranial pressure in patients with intracranial pathology. Therefore we studied the protective effects of 20% saline in a lipopolysaccharide lung injury rat model. 20% saline was also compared with other commonly used fluids. Following lipopolysaccharide-induced acute lung injury, male Sprague Dawley rats received either 20% hypertonic saline, 0.9% saline, 4% albumin, 20% albumin, 5% glucose or 20% albumin with 5% glucose, i.v. During 2h of non-injurious mechanical ventilation parameters of acute lung injury were assessed. Hypertonic saline resulted in hypernatraemia (160 (1) mmol/l, mean (SD)) maintained through 2h of ventilation, and in amelioration of lung oedema, myeloperoxidase, bronchoalveolar cell infiltrate, total soluble protein and inflammatory cytokines, and lung histological injury score, compared with positive control and all other fluids (p ≤ 0.001). Lung physiology was maintained (conserved PaO2, elastance), associated with preservation of alveolar surfactant (p ≤ 0.0001). Independent of fluid or sodium load, induced hypernatraemia is lung protective in lipopolysaccharide-induced acute lung injury. Copyright © 2016 Elsevier B.V. All rights reserved.

Extensive review of fish embryo acute toxicities for the prediction of GHS acute systemic toxicity categories.

PubMed

Scholz, Stefan; Ortmann, Julia; Klüver, Nils; Léonard, Marc

2014-08-01

Distribution and marketing of chemicals require appropriate labelling of health, physical and environmental hazards according to the United Nations global harmonisation system (GHS). Labelling for (human) acute toxicity categories is based on experimental findings usually obtained by oral, dermal or inhalative exposure of rodents. There is a strong societal demand for replacing animal experiments conducted for safety assessment of chemicals. Fish embryos are considered as alternative to animal testing and are proposed as predictive model both for environmental and human health effects. Therefore, we tested whether LC50s of the fish embryo acute toxicity test would allow effectively predicting of acute mammalian toxicity categories. A database of published fish embryo LC50 containing 641 compounds was established. For these compounds corresponding rat oral LD50 were identified resulting in 364 compounds for which both fish embryo LC50 and rat LD50 was available. Only a weak correlation of fish embryo LC50 and rat oral LD50 was obtained. Fish embryos were also not able to effectively predict GHS oral acute toxicity categories. We concluded that due to fundamental exposure protocol differences (single oral dose versus water-borne exposure) a reverse dosimetry approach is needed to explore the predictive capacity of fish embryos. Copyright © 2014 Elsevier Inc. All rights reserved.

Acute aquatic toxicity of biodiesel fuels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wright, B.; Haws, R.; Little, D.

1995-12-31

This study develops data on the acute aquatic toxicity of selected biodiesel fuels which may become subject to environmental effects test regulations under the US Toxic Substances Control Act (TSCA). The test substances are Rape Methyl Ester (RME), Rape Ethyl Ester (REE), Methyl Soyate (MS), a biodiesel mixture of 20% REE and 80% Diesel, a biodiesel mixture of 50% REE and diesel, and a reference substance of Phillips D-2 Reference Diesel. The test procedure follows the Daphnid Acute Toxicity Test outlined in 40 CFR {section} 797.1300 of the TSCA regulations. Daphnia Magna are exposed to the test substance in amore » flow-through system consisting of a mixing chamber, a proportional diluter, and duplicate test chambers. Novel system modifications are described that accommodate the testing of oil-based test substances with Daphnia. The acute aquatic toxicity is estimated by an EC50, an effective concentration producing immobility in 50% of the test specimen.« less

Acute Lung Injury and Persistent Small Airway Disease in a Rabbit Model of Chlorine Inhalation

PubMed Central

Musah, Sadiatu; Schlueter, Connie F.; Humphrey, David M.; Powell, Karen S.; Roberts, Andrew M.; Hoyle, Gary W.

2016-01-01

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure-volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. PMID:27913141

Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation.

PubMed

Musah, Sadiatu; Schlueter, Connie F; Humphrey, David M; Powell, Karen S; Roberts, Andrew M; Hoyle, Gary W

2017-01-15

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24h after exposure to 800ppm chlorine for 4min to study acute effects or up to 7days after exposure to 400ppm for 8min to study longer term effects. Acute effects observed 6 or 24h after inhalation of 800ppm chlorine for 4min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400ppm chlorine for 8min, rabbits exhibited mild hypoxemia, increased area of pressure-volume loops, and airway hyperreactivity. Lung histology 7days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute Esophagus Toxicity in Lung Cancer Patients After Intensity Modulated Radiation Therapy and Concurrent Chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kwint, Margriet; Uyterlinde, Wilma; Nijkamp, Jasper

2012-10-01

Purpose: The purpose of this study was to investigate the dose-effect relation between acute esophageal toxicity (AET) and the dose-volume parameters of the esophagus after intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for patients with non-small cell lung cancer (NSCLC). Patients and Methods: One hundred thirty-nine patients with inoperable NSCLC treated with IMRT and concurrent chemotherapy were prospectively analyzed. The fractionation scheme was 66 Gy in 24 fractions. All patients received concurrently a daily dose of cisplatin (6 mg/m Superscript-Two ). Maximum AET was scored according to Common Toxicity Criteria 3.0. Dose-volume parameters V5 to V70, D{sub mean} andmore » D{sub max} of the esophagus were calculated. A logistic regression analysis was performed to analyze the dose-effect relation between these parameters and grade {>=}2 and grade {>=}3 AET. The outcome was compared with the clinically used esophagus V35 prediction model for grade {>=}2 after radical 3-dimensional conformal radiation therapy (3DCRT) treatment. Results: In our patient group, 9% did not experience AET, and 31% experienced grade 1 AET, 38% grade 2 AET, and 22% grade 3 AET. The incidence of grade 2 and grade 3 AET was not different from that in patients treated with CCRT using 3DCRT. The V50 turned out to be the most significant dosimetric predictor for grade {>=}3 AET (P=.012). The derived V50 model was shown to predict grade {>=}2 AET significantly better than the clinical V35 model (P<.001). Conclusions: For NSCLC patients treated with IMRT and concurrent chemotherapy, the V50 was identified as most accurate predictor of grade {>=}3 AET. There was no difference in the incidence of grade {>=}2 AET between 3DCRT and IMRT in patients treated with concurrent chemoradiation therapy.« less

Lung lavage with oxygenated perfluorochemical liquid in acute lung injury.

PubMed

Richman, P S; Wolfson, M R; Shaffer, T H

1993-05-01

To investigate the effects of lung lavage with oxygenated liquid perfluorochemical on gas exchange, lung mechanics, and cardiac function in animals with acute lung injury. Prospective, randomized, controlled trial. Animal laboratory. Eight adult cats (2 to 4 kg, random sex). Two insults were combined to cause lung injury: oleic acid infusion and saline whole-lung wash. Animals were assigned to either the control or treatment group which consisted of a perfluorochemical liquid (Rimar 101) lavage. Perfluorochemical liquid lavage was performed three times at hourly intervals after lung injury. Three other cats with identical injury but no perfluorochemical liquid lavage served as control animals. All cats were ventilated with an FIO2 of 0.95 and positive end-expiratory pressure of 2 cm H2O continuously. Arterial blood gas tensions and pH, dynamic pulmonary compliance were measured at 15-min intervals. Cardiac index was assessed hourly, and lung fluid was collected after each of the three perfluorochemical liquid lavages. Arterial oxygen tension and pulmonary compliance deteriorated abruptly after lung injury in all cats, and improved significantly (p < .001, two-way analysis of variance) 15 mins after perfluorochemical liquid lavage. These parameters gradually returned to their baseline over 60 mins. Arterial blood pressure and cardiac index decreased after injury in all cats, and were not significantly changed after perfluorochemical liquid lavage. Hemorrhagic fluid was recovered from distal airways by perfluorochemical liquid lavage, despite prior suctioning of the airway. Perfluorochemical liquid lavage removes pulmonary edema fluid and improves gas exchange and the mechanical properties of the lung, after acute severe lung injury.

Surfactant for Pediatric Acute Lung Injury

PubMed Central

Willson, Douglas F.; Chess, Patricia R.; Notter, Robert H.

2008-01-01

Synopsis This article reviews exogenous surfactant therapy and its use in mitigating acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in infants, children, and adults. Biophysical and animal research documenting surfactant dysfunction in ALI/ARDS is described, and the scientific rationale for treatment with exogenous surfactant is discussed. Major emphasis is on reviewing clinical studies of surfactant therapy in pediatric and adult patients with ALI/ARDS. Particular advantages from surfactant therapy in direct pulmonary forms of these syndromes are described. Also discussed are additional factors affecting the efficacy of exogenous surfactants in ALI/ARDS, including the multifaceted pathology of inflammatory lung injury, the effectiveness of surfactant delivery in injured lungs, and composition-based activity differences among clinical exogenous surfactant preparations. PMID:18501754

Type XVIII collagen degradation products in acute lung injury

PubMed Central

Perkins, Gavin D; Nathani, Nazim; Richter, Alex G; Park, Daniel; Shyamsundar, Murali; Heljasvaara, Ritva; Pihlajaniemi, Taina; Manji, Mav; Tunnicliffe, W; McAuley, Danny; Gao, Fang; Thickett, David R

2009-01-01

Introduction In acute lung injury, repair of the damaged alveolar-capillary barrier is an essential part of recovery. Endostatin is a 20 to 28 kDa proteolytic fragment of the basement membrane collagen XVIII, which has been shown to inhibit angiogenesis via action on endothelial cells. We hypothesised that endostatin may have a role in inhibiting lung repair in patients with lung injury. The aims of the study were to determine if endostatin is elevated in the plasma/bronchoalveolar lavage fluid of patients with acute lung injury and ascertain whether the levels reflect the severity of injury and alveolar inflammation, and to assess if endostatin changes occur early after the injurious lung stimuli of one lung ventilation and lipopolysaccharide (LPS) challenge. Methods Endostatin was measured by ELISA and western blotting. Results Endostatin is elevated within the plasma and bronchoalveolar lavage fluid of patients with acute lung injury. Lavage endostatin reflected the degree of alveolar neutrophilia and the extent of the loss of protein selectivity of the alveolar-capillary barrier. Plasma levels of endostatin correlated with the severity of physiological derangement. Western blotting confirmed elevated type XVIII collagen precursor levels in the plasma and lavage and multiple endostatin-like fragments in the lavage of patients. One lung ventilation and LPS challenge rapidly induce increases in lung endostatin levels. Conclusions Endostatin may adversely affect both alveolar barrier endothelial and epithelial cells, so its presence within both the circulation and the lung may have a pathophysiological role in acute lung injury that warrants further evaluation. PMID:19358707

Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders*

PubMed Central

Calfee, Carolyn S.; Eisner, Mark D.; Ware, Lorraine B.; Thompson, B. Taylor; Parsons, Polly E.; Wheeler, Arthur P.; Korpak, Anna; Matthay, Michael A.

2009-01-01

Objective Patients with trauma-associated acute lung injury have better outcomes than patients with other clinical risks for lung injury, but the mechanisms behind these improved outcomes are unclear. We sought to compare the clinical and biological features of patients with trauma-associated lung injury with those of patients with other risks for lung injury and to determine whether the improved outcomes of trauma patients reflect their baseline health status or less severe lung injury, or both. Design, Setting, and Patients Analysis of clinical and biological data from 1,451 patients enrolled in two large randomized, controlled trials of ventilator management in acute lung injury. Measurements and Main Results Compared with patients with other clinical risks for lung injury, trauma patients were younger and generally less acutely and chronically ill. Even after adjusting for these baseline differences, trauma patients had significantly lower plasma levels of intercellular adhesion molecule-1, von Willebrand factor antigen, surfactant protein-D, and soluble tumor necrosis factor receptor-1, which are biomarkers of lung epithelial and endothelial injury previously found to be prognostic in acute lung injury. In contrast, markers of acute inflammation, except for interleukin-6, and disordered coagulation were similar in trauma and nontrauma patients. Trauma-associated lung injury patients had a significantly lower odds of death at 90 days, even after adjusting for baseline clinical factors including age, gender, ethnicity, comorbidities, and severity of illness (odds ratio, 0.44; 95% confidence interval, 0.24 – 0.82; p = .01). Conclusions Patients with trauma-associated lung injury are less acutely and chronically ill than other lung injury patients; however, these baseline clinical differences do not adequately explain their improved outcomes. Instead, the better outcomes of the trauma population may be explained, in part, by less severe lung epithelial and

Beryllium metal I. experimental results on acute oral toxicity, local skin and eye effects, and genotoxicity.

PubMed

Strupp, Christian

2011-01-01

The toxicity of soluble metal compounds is often different from that of the parent metal. Since no reliable data on acute toxicity, local effects, and mutagenicity of beryllium metal have ever been generated, beryllium metal powder was tested according to the respective Organisation for Economical Co-Operation and Development (OECD) guidelines. Acute oral toxicity of beryllium metal was investigated in rats and local effects on skin and eye in rabbits. Skin-sensitizing properties were investigated in guinea pigs (maximization method). Basic knowledge about systemic bioavailability is important for the design of genotoxicity tests on poorly soluble substances. Therefore, it was necessary to experimentally compare the capacities of beryllium chloride and beryllium metal to form ions under simulated human lung conditions. Solubility of beryllium metal in artificial lung fluid was low, while solubility in artificial lysosomal fluid was moderate. Beryllium chloride dissolution kinetics were largely different, and thus, metal extracts were used in the in vitro genotoxicity tests. Genotoxicity was investigated in vitro in a bacterial reverse mutagenicity assay, a mammalian cell gene mutation assay, a mammalian cell chromosome aberration assay, and an unscheduled DNA synthesis (UDS) assay. In addition, cell transformation was tested in a Syrian hamster embryo cell assay, and potential inhibition of DNA repair was tested by modification of the UDS assay. Beryllium metal was found not to be mutagenic or clastogenic based on the experimental in vitro results. Furthermore, treatment with beryllium metal extracts did not induce DNA repair synthesis, indicative of no DNA-damaging potential of beryllium metal. A cell-transforming potential and a tendency to inhibit DNA repair when the cell is severely damaged by an external stimulus were observed. Beryllium metal was also found not to be a skin or eye irritant, not to be a skin sensitizer, and not to have relevant acute oral

Pathophysiology of pulmonary hypertension in acute lung injury

PubMed Central

Price, Laura C.; McAuley, Danny F.; Marino, Philip S.; Finney, Simon J.; Griffiths, Mark J.

2012-01-01

Acute lung injury (ALI) and acute respiratory distress syndrome are characterized by protein rich alveolar edema, reduced lung compliance, and acute severe hypoxemia. A degree of pulmonary hypertension (PH) is also characteristic, higher levels of which are associated with increased morbidity and mortality. The increase in right ventricular (RV) afterload causes RV dysfunction and failure in some patients, with associated adverse effects on oxygen delivery. Although the introduction of lung protective ventilation strategies has probably reduced the severity of PH in ALI, a recent invasive hemodynamic analysis suggests that even in the modern era, its presence remains clinically important. We therefore sought to summarize current knowledge of the pathophysiology of PH in ALI. PMID:22246001

Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study.

PubMed

Needham, Dale M; Colantuoni, Elizabeth; Mendez-Tellez, Pedro A; Dinglas, Victor D; Sevransky, Jonathan E; Dennison Himmelfarb, Cheryl R; Desai, Sanjay V; Shanholtz, Carl; Brower, Roy G; Pronovost, Peter J

2012-04-05

To evaluate the association of volume limited and pressure limited (lung protective) mechanical ventilation with two year survival in patients with acute lung injury. Prospective cohort study. 13 intensive care units at four hospitals in Baltimore, Maryland, USA. 485 consecutive mechanically ventilated patients with acute lung injury. Two year survival after onset of acute lung injury. 485 patients contributed data for 6240 eligible ventilator settings, as measured twice daily (median of eight eligible ventilator settings per patient; 41% of which adhered to lung protective ventilation). Of these patients, 311 (64%) died within two years. After adjusting for the total duration of ventilation and other relevant covariates, each additional ventilator setting adherent to lung protective ventilation was associated with a 3% decrease in the risk of mortality over two years (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). Compared with no adherence, the estimated absolute risk reduction in two year mortality for a prototypical patient with 50% adherence to lung protective ventilation was 4.0% (0.8% to 7.2%, P=0.012) and with 100% adherence was 7.8% (1.6% to 14.0%, P=0.011). Lung protective mechanical ventilation was associated with a substantial long term survival benefit for patients with acute lung injury. Greater use of lung protective ventilation in routine clinical practice could reduce long term mortality in patients with acute lung injury. Clinicaltrials.gov NCT00300248.

Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury.

PubMed

Aggarwal, Saurabh; Lam, Adam; Bolisetty, Subhashini; Carlisle, Matthew A; Traylor, Amie; Agarwal, Anupam; Matalon, Sadis

2016-01-10

Exposure to irritant gases, such as bromine (Br2), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br2 upregulates the heme degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br2 toxicity. C57BL/6 mice were exposed to Br2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3 μg/gm body weight), or saline. Twenty-four hours postexposure, saline-treated mice had elevated total heme in bronchoalveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet-to-dry weight ratios, and decreased airway hyperreactivity to methacholine), and reduced mortality. In addition, Br2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1-/-) compared to wild-type controls, while transgenic mice overexpressing the human HO-1 gene (hHO-1) showed significant protection. This is the first study delineating the role of heme in ALI caused by Br2. The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI.

Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

PubMed

Shah, Dilip; Romero, Freddy; Guo, Zhi; Sun, Jianxin; Li, Jonathan; Kallen, Caleb B; Naik, Ulhas P; Summer, Ross

2017-08-01

Obesity is a significant risk factor for acute respiratory distress syndrome. The mechanisms underlying this association are unknown. We recently showed that diet-induced obese mice exhibit pulmonary vascular endothelial dysfunction, which is associated with enhanced susceptibility to LPS-induced acute lung injury. Here, we demonstrate that lung endothelial dysfunction in diet-induced obese mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins, including protein kinase R-like ER kinase, inositol-requiring enzyme α, and activating transcription factor 6, in whole lung and in primary lung endothelial cells isolated from diet-induced obese mice. Furthermore, we found that primary lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of diet-induced obese mice, including an increase in expression of endothelial adhesion molecules and a decrease in expression of endothelial cell-cell junctional proteins. Similar changes were observed in lung endothelial cells and in whole-lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation, indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-phenylbutyric acid, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in diet-induced obese mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium, leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the ER of pulmonary endothelial cells might protect against acute respiratory distress syndrome in obese

Esophagus and Contralateral Lung-Sparing IMRT for Locally Advanced Lung Cancer in the Community Hospital Setting.

PubMed

Kao, Johnny; Pettit, Jeffrey; Zahid, Soombal; Gold, Kenneth D; Palatt, Terry

2015-01-01

The optimal technique for performing lung IMRT remains poorly defined. We hypothesize that improved dose distributions associated with normal tissue-sparing IMRT can allow safe dose escalation resulting in decreased acute and late toxicity. We performed a retrospective analysis of 82 consecutive lung cancer patients treated with curative intent from 1/10 to 9/14. From 1/10 to 4/12, 44 patients were treated with the community standard of three-dimensional conformal radiotherapy or IMRT without specific esophagus or contralateral lung constraints (standard RT). From 5/12 to 9/14, 38 patients were treated with normal tissue-sparing IMRT with selective sparing of contralateral lung and esophagus. The study endpoints were dosimetry, toxicity, and overall survival. Despite higher mean prescribed radiation doses in the normal tissue-sparing IMRT cohort (64.5 vs. 60.8 Gy, p = 0.04), patients treated with normal tissue-sparing IMRT had significantly lower lung V20, V10, V5, mean lung, esophageal V60, and mean esophagus doses compared to patients treated with standard RT (p ≤ 0.001). Patients in the normal tissue-sparing IMRT group had reduced acute grade ≥3 esophagitis (0 vs. 11%, p < 0.001), acute grade ≥2 weight loss (2 vs. 16%, p = 0.04), and late grade ≥2 pneumonitis (7 vs. 21%, p = 0.02). The 2-year overall survival was 52% with normal tissue-sparing IMRT arm compared to 28% for standard RT (p = 0.015). These data provide proof of principle that suboptimal radiation dose distributions are associated with significant acute and late lung and esophageal toxicity that may result in hospitalization or even premature mortality. Strict attention to contralateral lung and esophageal dose-volume constraints are feasible in the community hospital setting without sacrificing disease control.

Acute oral toxicity test of chemical compounds in silkworms.

PubMed

Usui, Kimihito; Nishida, Satoshi; Sugita, Takuya; Ueki, Takuro; Matsumoto, Yasuhiko; Okumura, Hidenobu; Sekimizu, Kazuhisa

2016-02-01

This study performed an acute oral toxicity test of 59 compounds in silkworms. These compounds are listed in OECD guidelines as standard substances for a cytotoxicity test, and median lethal dose (LD(50)) werecalculated for each compound. Acute oral LD(50) values in mammals are listed in OECD guidelines and acute oral LD(50) values in silkworms were determined in this study. R(2) for the correlation between LD(50) values in mammals and LD(50) values in silkworms was 0.66. In addition, the acute oral toxicity test in silkworms was performed by two different facilities, and test results from the facilities were highly reproducible. These findings suggest that an acute oral toxicity test in silkworms is a useful way to evaluate the toxicity of compounds in mammals.

Albendazole Induced Recurrent Acute Toxic Hepatitis: A Case Report.

PubMed

Bilgic, Yilmaz; Yilmaz, Cengiz; Cagin, Yasir Furkan; Atayan, Yahya; Karadag, Nese; Harputluoglu, Murat Muhsin Muhip

2017-01-01

Drug induced acute toxic hepatitis can be idiosyncratic. Albendazole, a widely used broad spectrum antiparasitic drug is generally accepted as a safe drug. It may cause asymptomatic transient liver enzyme abnormalities but acute toxic hepatitis is very rare. Case Report : Herein, we present the case of 47 year old woman with recurrent acute toxic hepatitis after a single intake of albendazole in 2010 and 2014. The patient was presented with symptoms and findings of anorexia, vomiting and jaundice. For diagnosis, other acute hepatitis etiologies were excluded. Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated and found to be 10, which meant highly probable drug hepatotoxicity. Within 2 months, all pathological findings came to normal. There are a few reported cases of albendazole induced toxic hepatitis, but at adults, there is no known recurrent acute toxic hepatitis due to albendazole at this certainty according to RUCAM score. Physicians should be aware of this rare and potentially fatal adverse effect of albendazole. © Acta Gastro-Enterologica Belgica.

Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study

PubMed Central

Colantuoni, Elizabeth; Mendez-Tellez, Pedro A; Dinglas, Victor D; Sevransky, Jonathan E; Dennison Himmelfarb, Cheryl R; Desai, Sanjay V; Shanholtz, Carl; Brower, Roy G; Pronovost, Peter J

2012-01-01

Objective To evaluate the association of volume limited and pressure limited (lung protective) mechanical ventilation with two year survival in patients with acute lung injury. Design Prospective cohort study. Setting 13 intensive care units at four hospitals in Baltimore, Maryland, USA. Participants 485 consecutive mechanically ventilated patients with acute lung injury. Main outcome measure Two year survival after onset of acute lung injury. Results 485 patients contributed data for 6240 eligible ventilator settings, as measured twice daily (median of eight eligible ventilator settings per patient; 41% of which adhered to lung protective ventilation). Of these patients, 311 (64%) died within two years. After adjusting for the total duration of ventilation and other relevant covariates, each additional ventilator setting adherent to lung protective ventilation was associated with a 3% decrease in the risk of mortality over two years (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). Compared with no adherence, the estimated absolute risk reduction in two year mortality for a prototypical patient with 50% adherence to lung protective ventilation was 4.0% (0.8% to 7.2%, P=0.012) and with 100% adherence was 7.8% (1.6% to 14.0%, P=0.011). Conclusions Lung protective mechanical ventilation was associated with a substantial long term survival benefit for patients with acute lung injury. Greater use of lung protective ventilation in routine clinical practice could reduce long term mortality in patients with acute lung injury. Trial registration Clinicaltrials.gov NCT00300248. PMID:22491953

Functional genomics of chlorine-induced acute lung injury in mice.

PubMed

Leikauf, George D; Pope-Varsalona, Hannah; Concel, Vincent J; Liu, Pengyuan; Bein, Kiflai; Brant, Kelly A; Dopico, Richard A; Di, Y Peter; Jang, An-Soo; Dietsch, Maggie; Medvedovic, Mario; Li, Qian; Vuga, Louis J; Kaminski, Naftali; You, Ming; Prows, Daniel R

2010-07-01

Acute lung injury can be induced indirectly (e.g., sepsis) or directly (e.g., chlorine inhalation). Because treatment is still limited to supportive measures, mortality remains high ( approximately 74,500 deaths/yr). In the past, accidental (railroad derailments) and intentional (Iraq terrorism) chlorine exposures have led to deaths and hospitalizations from acute lung injury. To better understand the molecular events controlling chlorine-induced acute lung injury, we have developed a functional genomics approach using inbred mice strains. Various mouse strains were exposed to chlorine (45 ppm x 24 h) and survival was monitored. The most divergent strains varied by more than threefold in mean survival time, supporting the likelihood of an underlying genetic basis of susceptibility. These divergent strains are excellent models for additional genetic analysis to identify critical candidate genes controlling chlorine-induced acute lung injury. Gene-targeted mice then could be used to test the functional significance of susceptibility candidate genes, which could be valuable in revealing novel insights into the biology of acute lung injury.

Apigenin Attenuates Inflammation in Experimentally Induced Acute Pancreatitis-Associated Lung Injury.

PubMed

Basios, Neofitos; Lampropoulos, Pavlos; Papalois, Apostolos; Lambropoulou, Maria; Pitiakoudis, Michael K; Kotini, Athanasia; Simopoulos, Constantinos; Tsaroucha, Alexandra K

2016-06-01

Acute pancreatitis is associated with acute lung injury. The aim of the present study is to evaluate alterations of lungs in an experimental model of acute pancreatitis (AP) following both bilio-pancreatic duct obstruction close to the duodenum. Acute pancreatitis is a common disease with significant mortality. This situation makes the need of finding protective factors for the lung parenchyma, imperative. In the present study there is an effort to clarify the role of apigenin, a substance which is well known for its antioxidant and anti-inflammatory effects, on lung injury, following acute pancreatitis in rats. In the present study, 126 male Wistar-type rats 3-4 months old and 220-350 g weight were used. At time 0 we randomly assigned the following groups: Group Sham: Rats were subjected to virtual surgery. Group Control: Rats were subjected to surgery for induction of acute pancreatitis. Group Apigenin: Rats were subjected to surgery for induction of acute pancreatitis and enteral feeding with apigenin. Immunochemistry for TNF-α and IL-6 as well as MPO activity were measured at predetermined time intervals 6, 12, 24, 48, and 72 h, in order to evaluate architectural disturbances of the lung tissue. From the pathological reports we realized that comparing the control group with the apigenin group, there is an improvement of lung tissue damage following apigenin administration, with statistical significance. Apigenin reduces most histopathological alterations of the pulmonary tissue, reduces MPO and TNF-α activity at 48 hours and, furthermore, reduces IL-6 activity at 72 hours post-administration. Oral Apigenin administration in rats, following experimental induced acute pancreatitis, seems to be protective on the lung tissue. Apigenin administration to humans could potentially ameliorate acute lung injuries. However, special caution is required for humans' use, as more detailed studies are needed.

Mutagenicity and Lung Toxicity of Smoldering vs. Flaming Emissions from Various Biomass Fuels: Implications for Health Effects from Wildland Fires.

PubMed

Kim, Yong Ho; Warren, Sarah H; Krantz, Q Todd; King, Charly; Jaskot, Richard; Preston, William T; George, Barbara J; Hays, Michael D; Landis, Matthew S; Higuchi, Mark; DeMarini, David M; Gilmour, M Ian

2018-01-24

The increasing size and frequency of wildland fires are leading to greater potential for cardiopulmonary disease and cancer in exposed populations; however, little is known about how the types of fuel and combustion phases affect these adverse outcomes. We evaluated the mutagenicity and lung toxicity of particulate matter (PM) from flaming vs. smoldering phases of five biomass fuels, and compared results by equal mass or emission factors (EFs) derived from amount of fuel consumed. A quartz-tube furnace coupled to a multistage cryotrap was employed to collect smoke condensate from flaming and smoldering combustion of red oak, peat, pine needles, pine, and eucalyptus. Samples were analyzed chemically and assessed for acute lung toxicity in mice and mutagenicity in Salmonella . The average combustion efficiency was 73 and 98% for the smoldering and flaming phases, respectively. On an equal mass basis, PM from eucalyptus and peat burned under flaming conditions induced significant lung toxicity potencies (neutrophil/mass of PM) compared to smoldering PM, whereas high levels of mutagenicity potencies were observed for flaming pine and peat PM compared to smoldering PM. When effects were adjusted for EF, the smoldering eucalyptus PM had the highest lung toxicity EF (neutrophil/mass of fuel burned), whereas smoldering pine and pine needles had the highest mutagenicity EF. These latter values were approximately 5, 10, and 30 times greater than those reported for open burning of agricultural plastic, woodburning cookstoves, and some municipal waste combustors, respectively. PM from different fuels and combustion phases have appreciable differences in lung toxic and mutagenic potency, and on a mass basis, flaming samples are more active, whereas smoldering samples have greater effect when EFs are taken into account. Knowledge of the differential toxicity of biomass emissions will contribute to more accurate hazard assessment of biomass smoke exposures. https://doi.org/10

Contribution of neutrophils to acute lung injury.

PubMed

Grommes, Jochen; Soehnlein, Oliver

2011-01-01

Treatment of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain unsolved problems of intensive care medicine. ALI/ARDS are characterized by lung edema due to increased permeability of the alveolar-capillary barrier and subsequent impairment of arterial oxygenation. Lung edema, endothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and broncheoalveolar space. Hence, activation and recruitment of neutrophils are regarded to play a key role in progression of ALI/ARDS. Neutrophils are the first cells to be recruited to the site of inflammation and have a potent antimicrobial armour that includes oxidants, proteinases and cationic peptides. Under pathological circumstances, however, unregulated release of these microbicidal compounds into the extracellular space paradoxically can damage host tissues. This review focuses on the mechanisms of neutrophil recruitment into the lung and on the contribution of neutrophils to tissue damage in ALI.

Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury

PubMed Central

Aggarwal, Saurabh; Lam, Adam; Bolisetty, Subhashini; Carlisle, Matthew A.; Traylor, Amie; Agarwal, Anupam

2016-01-01

Abstract Aims: Exposure to irritant gases, such as bromine (Br2), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br2 upregulates the heme degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br2 toxicity. Results: C57BL/6 mice were exposed to Br2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3 μg/gm body weight), or saline. Twenty-four hours postexposure, saline-treated mice had elevated total heme in bronchoalveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet-to-dry weight ratios, and decreased airway hyperreactivity to methacholine), and reduced mortality. In addition, Br2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1−/−) compared to wild-type controls, while transgenic mice overexpressing the human HO-1 gene (hHO-1) showed significant protection. Innovation: This is the first study delineating the role of heme in ALI caused by Br2. Conclusion: The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI. Antioxid. Redox Signal. 24, 99–112. PMID:26376667

Complement Inhibition Alleviates Paraquat-Induced Acute Lung Injury

PubMed Central

Sun, Shihui; Wang, Hanbin; Zhao, Guangyu; An, Yingbo; Guo, Yan; Du, Lanying; Song, Hongbin; Qiao, Fei; Yu, Hong; Wu, Xiaohong; Atkinson, Carl; Jiang, Shibo; Tomlinson, Stephen

2011-01-01

The widely used herbicide, paraquat (PQ), is highly toxic and claims thousands of lives from both accidental and voluntary ingestion. The pathological mechanisms of PQ poisoning–induced acute lung injury (ALI) are not well understood, and the role of complement in PQ-induced ALI has not been elucidated. We developed and characterized a mouse model of PQ-induced ALI and studied the role of complement in the pathogenesis of PQ poisoning. Intraperitoneal administration of PQ caused dose- and time-dependent lung damage and mortality, with associated inflammatory response. Within 24 hours of PQ-induced ALI, there was significantly increased expression of the complement proteins, C1q and C3, in the lung. Expression of the anaphylatoxin receptors, C3aR and C5aR, was also increased. Compared with wild-type mice, C3-deficient mice survived significantly longer and displayed significantly reduced lung inflammation and pathology after PQ treatment. Similar reductions in PQ-induced inflammation, pathology, and mortality were recorded in mice treated with the C3 inhibitors, CR2-Crry, and alternative pathway specific CR2-fH. A similar therapeutic effect was also observed by treatment with either C3a receptor antagonist or a blocking C5a receptor monoclonal antibody. Together, these studies indicate that PQ-induced ALI is mediated through receptor signaling by the C3a and C5a complement activation products that are generated via the alternative complement pathway, and that complement inhibition may be an effective clinical intervention for postexposure treatment of PQ-induced ALI. PMID:21421909

Stem cells in sepsis and acute lung injury.

PubMed

Cribbs, Sushma K; Matthay, Michael A; Martin, Greg S

2010-12-01

Sepsis and acute lung injury continue to be major causes of morbidity and mortality worldwide despite advances in our understanding of pathophysiology and the discovery of new management strategies. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the potential use of endogenous adult tissue-derived stem cells in sepsis and acute lung injury as prognostic markers and also as exogenous cell-based therapy. A directed systematic search of the medical literature using PubMed and OVID, with particular emphasis on the time period after 2002, was done to evaluate topics related to 1) the epidemiology and pathophysiology of sepsis and acute lung injury; and 2) the definition, characterization, and potential use of stem cells in these diseases. DATA SYNTHESIS AND FINDINGS: When available, preferential consideration was given to prospective nonrandomized clinical and preclinical studies. Stem cells have shown significant promise in the field of critical care both for 1) prognostic value and 2) treatment strategies. Although several recent studies have identified the potential benefit of stem cells in sepsis and acute lung injury, further investigations are needed to more completely understand stem cells and their potential prognostic and therapeutic value.

Mesenchymal stem cells for acute lung injury: Preclinical evidence

PubMed Central

Matthay, Michael A.; Goolaerts, Arnaud; Howard, James P.; Lee, Jae Woo

2013-01-01

Several experimental studies have suggested that mesenchymal stem cells may have value for the treatment of clinical disorders, including myocardial infarction, diabetes, acute renal failure, sepsis, and acute lung injury. In preclinical studies, mesenchymal stem cells have been effective in reducing lung injury from endotoxin, live bacteria, bleomycin, and hyperoxia. In some studies, the cultured medium from mesenchymal stem cells has been as effective as the mesenchymal stem cells themselves. Several paracrine mediators that can mediate the effect of mesenchymal stem cells have been identified, including interleukin-10, interleukin-1ra, keratinocyte growth factor, and prostaglandin E2. Further preclinical studies are needed, as is planning for clinical trials for acute lung injury. PMID:21164399

Spontaneously regulated vs. controlled ventilation of acute lung injury/acute respiratory distress syndrome.

PubMed

Marini, John J

2011-02-01

To present an updated discussion of those aspects of controlled positive pressure breathing and retained spontaneous regulation of breathing that impact the management of patients whose tissue oxygenation is compromised by acute lung injury. The recent introduction of ventilation techniques geared toward integrating natural breathing rhythms into even the earliest phase of acute respiratory distress syndrome support (e.g., airway pressure release, proportional assist ventilation, and neurally adjusted ventilatory assist), has stimulated a burst of new investigations. Optimizing gas exchange, avoiding lung injury, and preserving respiratory muscle strength and endurance are vital therapeutic objectives for managing acute lung injury. Accordingly, comparing the physiology and consequences of breathing patterns that preserve and eliminate breathing effort has been a theme of persisting investigative interest throughout the several decades over which it has been possible to sustain cardiopulmonary life support outside the operating theater.

Dual pancreas- and lung-targeting therapy for local and systemic complications of acute pancreatitis mediated by a phenolic propanediamine moiety.

PubMed

Li, Jianbo; Zhang, Jinjie; Fu, Yao; Sun, Xun; Gong, Tao; Jiang, Jinghui; Zhang, Zhirong

2015-08-28

To inhibit both the local and systemic complications with acute pancreatitis, an effective therapy requires a drug delivery system that can efficiently overcome the blood-pancreas barrier while achieving lung-specific accumulation. Here, we report the first dual pancreas- and lung-targeting therapeutic strategy mediated by a phenolic propanediamine moiety for the treatment of acute pancreatitis. Using the proposed dual-targeting ligand, an anti-inflammatory compound Rhein has been tailored to preferentially accumulate in the pancreas and lungs with rapid distribution kinetics, excellent tissue-penetrating properties and minimum toxicity. Accordingly, the drug-ligand conjugate remarkably downregulated the proinflammatory cytokines in the target organs thus effectively inhibiting local pancreatic and systemic inflammation in rats. The dual-specific targeting therapeutic strategy may help pave the way for targeted drug delivery to treat complicated inflammatory diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nambiar, Madhusoodana P.; Gordon, Richard K.; Rezk, Peter E.

2007-03-15

To develop therapeutics against lung injury and respiratory toxicity following nerve agent VX exposure, we evaluated the protective efficacy of a number of potential pulmonary therapeutics. Guinea pigs were exposed to 27.03 mg/m{sup 3} of VX or saline using a microinstillation inhalation exposure technique for 4 min and then the toxicity was assessed. Exposure to this dose of VX resulted in a 24-h survival rate of 52%. There was a significant increase in bronchoalveolar lavage (BAL) protein, total cell number, and cell death. Surprisingly, direct pulmonary treatment with surfactant, liquivent, N-acetylcysteine, dexamethasone, or anti-sense syk oligonucleotides 2 min post-exposure didmore » not significantly increase the survival rate of VX-exposed guinea pigs. Further blocking the nostrils, airway, and bronchioles, VX-induced viscous mucous secretions were exacerbated by these aerosolized treatments. To overcome these events, we developed a strategy to protect the animals by treatment with atropine. Atropine inhibits muscarinic stimulation and markedly reduces the copious airway secretion following nerve agent exposure. Indeed, post-exposure treatment with atropine methyl bromide, which does not cross the blood-brain barrier, resulted in 100% survival of VX-exposed animals. Bronchoalveolar lavage from VX-exposed and atropine-treated animals exhibited lower protein levels, cell number, and cell death compared to VX-exposed controls, indicating less lung injury. When pulmonary therapeutics were combined with atropine, significant protection to VX-exposure was observed. These results indicate that combinations of pulmonary therapeutics with atropine or drugs that inhibit mucous secretion are important for the treatment of respiratory toxicity and lung injury following VX exposure.« less

Severe acute interstitial lung disease in a patient with anaplastic lymphoma kinase rearrangement-positive non-small cell lung cancer treated with alectinib.

PubMed

Yamamoto, Yuzo; Okamoto, Isamu; Otsubo, Kohei; Iwama, Eiji; Hamada, Naoki; Harada, Taishi; Takayama, Koichi; Nakanishi, Yoichi

2015-10-01

Alectinib, the second generation anaplastic lymphoma kinase (ALK) inhibitor, has significant potency in patients with ALK rearrangement positive non-small cell lung cancer (NSCLC), and its toxicity is generally well tolerable. We report a patient who developed severe acute interstitial lung disease after alectinib treatment. An 86-year-old woman with stage IV lung adenocarcinoma positive for rearrangement of ALK gene was treated with alectinib. On the 215th day after initiation of alectinib administration, she was admitted to our hospital with the symptom of progressive dyspnea. Computed tomography (CT) revealed diffuse ground glass opacities and consolidations in both lungs, and analysis of bronchoalveolar lavage fluid revealed pronounced lymphocytosis. There was no evidence of infection or other specific causes of her condition, and she was therefore diagnosed with interstitial lung disease induced by alectinib. Her CT findings and respiratory condition improved after steroid pulse therapy. As far as we are aware, this is the first reported case of alectinib-induced severe interstitial lung disease (ILD). We should be aware of the possibility of such a severe adverse event and should therefore carefully monitor patients treated with this drug.

Acute and subacute pulmonary toxicity caused by a single intratracheal instillation of colloidal silver nanoparticles in mice: pathobiological changes and metallothionein responses.

PubMed

Kaewamatawong, Theerayuth; Banlunara, Wijit; Maneewattanapinyo, Pattwat; Thammachareon, Chuchaat; Ekgasit, Sanong

2014-01-01

To study the acute and subacute pulmonary toxicity of colloidal silver nanoparticles (Ag-NPs), 0 or 100 ppm of Ag-NPs were instilled intratracheally in mice. Cellular and biochemical parameters in bronchoalveolar lavage fluid (BALF) and histological alterations were determined 1, 3, 7, 15, and 30 days after instillation. Ag-NPs induced moderate pulmonary inflammation and injury on BALF indices during the acute period; however, these changes gradually regressed in a time-dependent manner. Concomitant histopathological and laminin immunohistochemical findings generally correlated to BALF data. Superoxide dismutase and metallothionein expression occurred in particle-laden macrophages and alveolar epithelial cells, which correlated to lung lesions in mice treated with Ag-NPs. These findings suggest that instillation of Ag-NPs causes transient moderate acute lung inflammation and tissue damage. Oxidative stress may underlie the induction of injury to lung tissue. Moreover, the expression of metallothionein in tissues indicated the protective response to exposure to Ag-NPs.

Derivation of occupational exposure levels (OELs) of low-toxicity isometric biopersistent particles: How can the kinetic lung overload paradigm be used for improved inhalation toxicity study design and OEL-derivation?

PubMed

Pauluhn, Jürgen

2014-12-20

Convincing evidence suggests that poorly soluble low-toxicity particles (PSP) exert two unifying major modes of action (MoA), in which one appears to be deposition-related acute, whilst the other is retention-related and occurs with particle accumulation in the lung and associated persistent inflammation. Either MoA has its study- and cumulative dose-specific adverse outcome and metric. Modeling procedures were applied to better understand as to which extent protocol variables may predetermine any specific outcome of study. The results from modeled and empirical studies served as basis to derive OELs from modeled and empirically confirmed directions. This analysis demonstrates that the accumulated retained particle displacement volume was the most prominent unifying denominator linking the pulmonary retained volumetric particle dose to inflammogenicity and toxicity. However, conventional study design may not always be appropriate to unequivocally discriminate the surface thermodynamics-related acute adversity from the cumulative retention volume-related chronic adversity. Thus, in the absence of kinetically designed studies, it may become increasingly challenging to differentiate substance-specific deposition-related acute effects from the more chronic retained cumulative dose-related effects. It is concluded that the degree of dissolution of particles in the pulmonary environment seems to be generally underestimated with the possibility to attribute to toxicity due to decreased particle size and associated changes in thermodynamics and kinetics of dissolution. Accordingly, acute deposition-related outcomes become an important secondary variable within the pulmonary microenvironment. In turn, lung-overload related chronic adversities seem to be better described by the particle volume metric. This analysis supports the concept that 'self-validating', hypothesis-based computational study design delivers the highest level of unifying information required for the risk

Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takeda, Ken; Nemoto, Kenji; Saito, Haruo

2005-07-01

Purpose: To evaluate the factors associated with acute esophagitis in lung cancer patients treated with thoracic radiotherapy. Methods and Materials: We examined 35 patients with non-small-cell lung cancer (n = 27, 77%) and small-cell lung cancer (n = 8, 23%) treated with thoracic radiotherapy between February 2003 and November 2004. The median patient age was 70 years (range, 50-83 years). The disease stage was Stage I in 2 patients (6%), Stage II in 1 (3%), Stage IIIa in 10 (28%), Stage IIIb in 9 (26%), and Stage IV in 9 (26%); 4 patients (11%) had recurrent disease after surgery. Amore » median dose of 60 Gy (range, 50-67 Gy) was given to the isocenter and delivered in single daily fractions of 1.8 or 2 Gy. With heterogeneity corrections, the median given dose to the isocenter was 60.3 Gy (range, 49.9-67.2 Gy). Of the 35 patients, 30 (86%) received concurrent chemotherapy consisting of a platinum agent, cisplatin or carboplatin, combined with paclitaxel in 18 patients (52%), irinotecan hydrochloride in 7 (20%), vincristine sulfate and etoposide in 2 (5%), vinorelbine ditartrate in 1 (3%), etoposide in 1 (3%), and docetaxel in 1 patient (3%). Three of these patients underwent induction therapy with cisplatin and irinotecan hydrochloride, administered before thoracic radiotherapy, and concurrent chemotherapy. Esophageal toxicity was graded according to the Radiation Therapy Oncology Group criteria. The following factors were analyzed with respect to their association with Grade 1 or worse esophagitis by univariate and multivariate analyses: age, gender, concurrent chemotherapy, chemotherapeutic agents, maximal esophageal dose, mean esophageal dose, and percentage of esophageal volume receiving >10 to >65 Gy in 5-Gy increments. Results: Of the 35 patients, 25 (71%) developed acute esophagitis, with Grade 1 in 20 (57%) and Grade 2 in 5 (14%). None of the patients had Grade 3 or worse toxicity. The most significant correlation was between esophagitis and percentage

Inhalation of substance P and thiorphan: acute toxicity and effects on respiration in conscious guinea pigs.

PubMed

Koch, B L; Edvinsson, A A; Koskinen, L O

1999-01-01

Substance P is a tachykinin and a biologically active neuropeptide. The peptide produces salivation, neuronal excitation, vasodilatation, increased vascular permeability and contraction of smooth muscles in the respiratory tract. The study was designed to evaluate the acute effects in guinea pigs of inhaled aerosolized Substance P (SP). Apart from the acute toxic effect of the peptide, the distribution in different organs was also investigated. The acute inhalation toxicity of SP (LC50, 15 min) when co-administrated with the neutral endopeptidase inhibitor thiorphan was 368 microg m(-3). The peptide caused an increase in respiratory rate proceeding a decrease in tidal volume. As the exposure proceeded, a decrease in both respiratory rate and further decreases in tidal volume were observed until either the animal died or the exposure was terminated. The decreases in respiratory rate and tidal volume were probably due to bronchoconstriction caused by SP. Eighteen per cent of the inhaled amount of radioactive SP was retained in the body, and the highest concentrations of radioactivity were found in the kidney, lung and liver. Substance P in combination with thiorphan administered as an aerosol is extremely toxic and highly potent. Exposure to the substance at extremely low air concentrations may result in incapacitation in humans.

Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands.

PubMed

Procházková, Jiřina; Strapáčová, Simona; Svržková, Lucie; Andrysík, Zdeněk; Hýžďalová, Martina; Hrubá, Eva; Pěnčíková, Kateřina; Líbalová, Helena; Topinka, Jan; Kléma, Jiří; Espinosa, Joaquín M; Vondráček, Jan; Machala, Miroslav

2018-08-01

Exposure to persistent ligands of aryl hydrocarbon receptor (AhR) has been found to cause lung cancer in experimental animals, and lung adenocarcinomas are often associated with enhanced AhR expression and aberrant AhR activation. In order to better understand the action of toxic AhR ligands in lung epithelial cells, we performed global gene expression profiling and analyze TCDD-induced changes in A549 transcriptome, both sensitive and non-sensitive to CH223191 co-treatment. Comparison of our data with results from previously reported microarray and ChIP-seq experiments enabled us to identify candidate genes, which expression status reflects exposure of lung cancer cells to TCDD, and to predict processes, pathways (e.g. ER stress, Wnt/β-cat, IFNɣ, EGFR/Erbb1), putative TFs (e.g. STAT, AP1, E2F1, TCF4), which may be implicated in adaptive response of lung cells to TCDD-induced AhR activation. Importantly, TCDD-like expression fingerprint of selected genes was observed also in A549 cells exposed acutely to both toxic (benzo[a]pyrene, benzo[k]fluoranthene) and endogenous AhR ligands (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester and 6-formylindolo[3,2-b]carbazole). Overall, our results suggest novel cellular candidates, which could help to improve monitoring of AhR-dependent transcriptional activity during acute exposure of lung cells to distinct types of environmental pollutants. Copyright © 2018 Elsevier B.V. All rights reserved.

Acute aquatic toxicity and biodegradation potential of biodiesel fuels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haws, R.A.; Zhang, X.; Marshall, E.A.

1995-12-31

Recent studies on the biodegradation potential and aquatic toxicity of biodiesel fuels are reviewed. Biodegradation data were obtained using the shaker flask method observing the appearance of CO{sub 2} and by observing the disappearance of test substance with gas chromatography. Additional BOD{sub 5} and COD data were obtained. The results indicate the ready biodegradability of biodiesel fuels as well as the enhanced co-metabolic biodegradation of biodiesel and petroleum diesel fuel mixtures. The study examined reference diesel, neat soy oil, neat rape oil, and the methyl and ethyl esters of these vegetable oils as well as various fuel blends. Acute toxicitymore » tests on biodiesel fuels and blends were performed using Oncorhynchus mykiss (Rainbow Trout) in a static non-renewal system and in a proportional dilution flow replacement system. The study is intended to develop data on the acute aquatic toxicity of biodiesel fuels and blends under US EPA Good Laboratory Practice Standards. The test procedure is designed from the guidelines outlined in Methods for Measuring the Acute Toxicity of Effluents and Receiving Waters to Freshwater and Marine Organisms and the Fish Acute Aquatic Toxicity Test guideline used to develop aquatic toxicity data for substances subject to environmental effects test regulations under TSCA. The acute aquatic toxicity is estimated by an LC50, a lethal concentration effecting mortality in 50% of the test population.« less

Open lung approach vs acute respiratory distress syndrome network ventilation in experimental acute lung injury.

PubMed

Spieth, P M; Güldner, A; Carvalho, A R; Kasper, M; Pelosi, P; Uhlig, S; Koch, T; Gama de Abreu, M

2011-09-01

Setting and strategies of mechanical ventilation with positive end-expiratory pressure (PEEP) in acute lung injury (ALI) remains controversial. This study compares the effects between lung-protective mechanical ventilation according to the Acute Respiratory Distress Syndrome Network recommendations (ARDSnet) and the open lung approach (OLA) on pulmonary function and inflammatory response. Eighteen juvenile pigs were anaesthetized, mechanically ventilated, and instrumented. ALI was induced by surfactant washout. Animals were randomly assigned to mechanical ventilation according to the ARDSnet protocol or the OLA (n=9 per group). Gas exchange, haemodynamics, pulmonary blood flow (PBF) distribution, and respiratory mechanics were measured at intervals and the lungs were removed after 6 h of mechanical ventilation for further analysis. PEEP and mean airway pressure were higher in the OLA than in the ARDSnet group [15 cmH(2)O, range 14-18 cmH(2)O, compared with 12 cmH(2)O; 20.5 (sd 2.3) compared with 18 (1.4) cmH(2)O by the end of the experiment, respectively], and OLA was associated with improved oxygenation compared with the ARDSnet group after 6 h. OLA showed more alveolar overdistension, especially in gravitationally non-dependent regions, while the ARDSnet group was associated with more intra-alveolar haemorrhage. Inflammatory mediators and markers of lung parenchymal stress did not differ significantly between groups. The PBF shifted from ventral to dorsal during OLA compared with ARDSnet protocol [-0.02 (-0.09 to -0.01) compared with -0.08 (-0.12 to -0.06), dorsal-ventral gradients after 6 h, respectively]. According to the OLA, mechanical ventilation improved oxygenation and redistributed pulmonary perfusion when compared with the ARDSnet protocol, without differences in lung inflammatory response.

Pulmonary toxicity of simulated lunar and Martian dusts in mice: II. Biomarkers of acute responses after intratracheal instillation

NASA Technical Reports Server (NTRS)

Lam, Chiu-Wing; James, John T.; Latch, Judith N.; Hamilton, Raymond F Jr; Holian, Andrij

2002-01-01

Volcanic ashes from Arizona and Hawaii, with chemical and mineral properties similar to those of lunar and Martian soils, respectively, are used by the National Aeronautics and Space Administration (NASA) to simulate lunar and Martian environments for instrument tests. NASA needs toxicity data on these volcanic soils to assess health risks from potential exposures of workers in facilities where these soil simulants are used. In this study we investigated the acute effects of lunar soil simulant (LSS) and Martian soil simulant (MSS), as a complement to a histopathological study assessing their subchronic effects (Lam et al., 2002). Fine dust of LSS, MSS, TiO(2), or quartz suspended in saline was intratracheally instilled into C57Bl/6J mice (4/group) in single doses of 0.1 mg/mouse or 1 mg/mouse. The mice were euthanized 4 or 24 h after the dust treatment, and bronchoalveolar lavage fluid (BALF) was obtained. Statistically significant lower cell viability and higher total protein concentration in the BALF were seen only in mice treated with the high dose of quartz for 4 h and with the high dose of MSS or quartz for 24 h, compared to mice treated only with saline. A significant increase in the percentage of neutrophils was not observed with any dust-treated group at 4 h after the instillation, but was observed after 24 h in all the dust-treated groups. This observation indicates that these dusts were not acutely toxic and the effects were gradual; it took some time for neutrophils to be recruited into and accumulate significantly in the lung. A statistically significant increase in apoptosis of lavaged macrophages from mice 4 h after treatment was found only in the high-dose silica group. The overall results of this study on the acute effects of these dusts in the lung indicate that LSS is slightly more toxic than TiO(2), and that MSS is comparable to quartz. These results were consistent with the subchronic histopathological findings in that the order of severity of

Acute Oral Toxicity Up-And-Down-Procedure

EPA Pesticide Factsheets

The Up-and-Down Procedure is an alternative acute toxicity test that provides a way to determine the toxicity of chemicals with fewer test animals by using sequential dosing steps. Find out about this test procedure.

Acute recreational drug toxicity

PubMed Central

Liakoni, Evangelia; Yates, Christopher; Dines, Alison M.; Dargan, Paul I.; Heyerdahl, Fridtjof; Hovda, Knut Erik; Wood, David M.; Eyer, Florian; Liechti, Matthias E.

2018-01-01

Abstract The aim of the study was to compare self-reported and analytically confirmed substance use in cases of acute recreational drug toxicity. We performed a retrospective analysis of emergency department presentations of acute recreational drug toxicity over 2 years (October 2013 to September 2015) within the European Drug Emergencies Network Plus project. Among the 10,956 cases of acute recreational drug toxicity during the study period, 831 could be included. Between the self-reported substance use and the toxicological results, the highest agreement was found for heroin (86.1%) and cocaine (74.1%), whereas inhalants, poppers, and magic mushrooms were self-reported but not analytically detected. Cathinones and other new psychoactive substances (NPS) could be detected using additional analytical methods. Among cases with both immunoassay (IA) and confirmation with mass spectrometry (MS), the results were consistent for methadone (100%) and cocaine (95.5%) and less consistent for amphetamines (81.8%). In cases with a positive IA for amphetamines (n = 54), MS confirmed the presence of 3,4-methylenedioxymethamphetamine (MDMA), amphetamine, methamphetamine, and NPS in 37, 20, 10, and 6 cases, respectively, also revealing use of more than 1 substance in some cases. MS yielded positive results in 21 cases with a negative IA for amphetamines, including amphetamine, MDMA, methamphetamine, and NPS, in 14, 7, 2, and 2 cases, respectively. In conclusion, the highest agreement was found between self-reports and analytical findings for heroin and cocaine. The diagnosis of NPS use was mainly based on self-report. The IAs accurately identified methadone and cocaine, and MS had advantages for the detection of NPS and amphetamine derivatives. PMID:29384873

Acute native lung hyperinflation is not associated with poor outcomes after single lung transplant for emphysema.

PubMed

Weill, D; Torres, F; Hodges, T N; Olmos, J J; Zamora, M R

1999-11-01

Single-lung transplantation for emphysema may be complicated by acute native lung hyperinflation (ANLH) with hemodynamic and ventilatory compromise. Some groups advocate the routine use of independent lung ventilation, double-lung transplant, or right-lung transplant with or without contralateral lung volume reduction surgery in high-risk patients. The goal of this study was to determine the incidence of ANLH and identify its potential predictors. We reviewed 51 consecutive single-lung transplants for emphysema. Symptomatic ANLH was defined as mediastinal shift and diaphragmatic flattening on chest x-ray with hemodynamic or respiratory failure requiring cardiopressor agents or independent lung ventilation. Preoperative and postoperative physiologic and hemodynamic data were analyzed from both recipients and donors. Sixteen patients developed radiographic ANLH; 8 were symptomatic, 2 severely so. We could not identify high-risk patients before transplant by pulmonary function tests, predicted donor total lung capacity (TLC)/actual recipient TLC ratio, pulmonary artery pressures, or the side transplanted. There was a trend toward an increased incidence of symptomatic ANLH in patients with bullous emphysema on chest computed tomography, but this was accounted for primarily by patients with alpha1-antitrypsin deficiency (4/13 vs 4/38 with chronic obstructive pulmonary disease, P = 0.10). No patient required cardiopulmonary bypass or inhaled nitric oxide intraoperatively. Patients with acute native lung hyperinflation did not have increased reperfusion edema as measured by chest x-ray score or PaO2/F(I)O2 ratio. Compared to patients without ANLH, symptomatic patients had longer ventilator times (64.9+/-14.6 hours vs 40.4+/-3.9, P = 0.02, ANOVA) and longer lengths of stay (19.3+/-2.1 days vs 13.7+/-1.3, P = 0.07), but 30-day survival was 100%. Two symptomatic patients required independent lung ventilation or inhaled nitric oxide; the others were managed with decreased

Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

PubMed Central

Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E.; Padera, Robert F.; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D’Agostino, Emmanuel; Goldberg, Hilary J.; Perrella, Mark A.; Forteza, Rosanna Malbran; Rosas, Ivan O.; Visner, Gary; El-Chemaly, Souheil

2015-01-01

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma.

PubMed

Bradley, Jeffrey; Graham, Mary V; Winter, Kathryn; Purdy, James A; Komaki, Ritsuko; Roa, Wilson H; Ryu, Janice K; Bosch, Walter; Emami, Bahman

2005-02-01

To evaluate prospectively the acute and late morbidities from a multiinstitutional three-dimensional radiotherapy dose-escalation study for inoperable non-small-cell lung cancer. A total of 179 patients were enrolled in a Phase I-II three-dimensional radiotherapy dose-escalation trial. Of the 179 patients, 177 were eligible. The use of concurrent chemotherapy was not allowed. Twenty-five patients received neoadjuvant chemotherapy. Patients were stratified at escalating radiation dose levels depending on the percentage of the total lung volume that received >20 Gy with the treatment plan (V(20)). Patients with a V(20) <25% (Group 1) received 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, and 90.3 Gy in 42 fractions, successively. Patients with a V(20) of 25-36% (Group 2) received doses of 70.9 Gy and 77.4 Gy, successively. The treatment arm for patients with a V(20) > or =37% (Group 3) closed early secondary to poor accrual (2 patients) and the perception of excessive risk for the development of pneumonitis. Toxicities occurring or persisting beyond 90 days after the start of radiotherapy were scored as late toxicities. The estimated toxicity rates were calculated on the basis of the cumulative incidence method. The following acute Grade 3 or worse toxicities were observed for Group 1: 70.9 Gy (1 case of weight loss), 77.4 Gy (nausea and hematologic toxicity in 1 case each), 83.8 Gy (1 case of hematologic toxicity), and 90.3 Gy (3 cases of lung toxicity). The following acute Grade 3 or worse toxicities were observed for Group 2: none at 70.9 Gy and 2 cases of lung toxicity at 77.4 Gy. No patients developed acute Grade 3 or worse esophageal toxicity. The estimated rate of Grade 3 or worse late lung toxicity at 18 months was 7%, 16%, 0%, and 13% for Group 1 patients receiving 70.9, 77.4, 83.8, or 90.3 Gy, respectively. Group 2 patients had an estimated late lung toxicity rate of 15% at 18 months for both 70.9 and 77.4 Gy. The prognostic

OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS

PubMed Central

SEPEHR, REYHANEH; AUDI, SAID H.; MALEKI, SEPIDEH; STANISZEWSKI, KEVIN; EIS, ANNIE L.; KONDURI, GIRIJA G.; RANJI, MAHSA

2014-01-01

Reactive oxygen species (ROS) have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI) in adults and bronchopulmonary dysplasia (BPD) in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD), referred to as NADH redox ratio (NADH RR) has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS) exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2) pups, hyperoxic (90% O2) pups, pups treated with LPS (normoxic + LPS), and pups treated with LPS and hyperoxia (hyperoxic + LPS). Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure. PMID:24672581

Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome

PubMed Central

Raghavendran, Krishnan; Pryhuber, Gloria S.; Chess, Patricia R.; Davidson, Bruce A.; Knight, Paul R.; Notter, Robert H.

2009-01-01

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article. PMID:18691048

Mean esophageal radiation dose is predictive of the grade of acute esophagitis in lung cancer patients treated with concurrent radiotherapy and chemotherapy.

PubMed

Ozgen, Aytul; Hayran, Mutlu; Kahraman, Fatih

2012-11-01

The intention of this research was to define the predictive factors for acute esophagitis (AE) in lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy. The data for 72 lung cancer patients treated with concurrent chemoradiotherapy between 2008 and 2010 were prospectively evaluated. Mean lung dose, mean dose of esophagus, volume of esophagus irradiated and percentage of esophagus volume treated were analysed according to esophagitis grades. The mean esophageal dose was associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P < 0.001). However, the mean lung dose and the volume of esophagus irradiated were not associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P = 0.50 and P = 0.41, respectively). The mean radiation dose received by the esophagus was found to be highly correlated with the duration of Grade 2 esophagitis (Spearman test, r = 0.82, P < 0.001). The mean dose of esophagus ≥28 Gy showed statistical significance with respect to AE Grade 2 or worse (receiver operating characteristic curve analysis, 95% CI, 0.929-1.014). In conclusion, the mean esophageal dose was significantly associated with a risk of esophageal toxicity in patients with lung cancer treated with concurrent radiotherapy and chemotherapy.

Mean esophageal radiation dose is predictive of the grade of acute esophagitis in lung cancer patients treated with concurrent radiotherapy and chemotherapy

PubMed Central

Ozgen, Aytul; Hayran, Mutlu; Kahraman, Fatih

2012-01-01

The intention of this research was to define the predictive factors for acute esophagitis (AE) in lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy. The data for 72 lung cancer patients treated with concurrent chemoradiotherapy between 2008 and 2010 were prospectively evaluated. Mean lung dose, mean dose of esophagus, volume of esophagus irradiated and percentage of esophagus volume treated were analysed according to esophagitis grades. The mean esophageal dose was associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P < 0.001). However, the mean lung dose and the volume of esophagus irradiated were not associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P = 0.50 and P = 0.41, respectively). The mean radiation dose received by the esophagus was found to be highly correlated with the duration of Grade 2 esophagitis (Spearman test, r = 0.82, P < 0.001). The mean dose of esophagus ≥28 Gy showed statistical significance with respect to AE Grade 2 or worse (receiver operating characteristic curve analysis, 95% CI, 0.929–1.014). In conclusion, the mean esophageal dose was significantly associated with a risk of esophageal toxicity in patients with lung cancer treated with concurrent radiotherapy and chemotherapy. PMID:22915782

Low level laser therapy reduces acute lung inflammation without impairing lung function.

PubMed

Cury, Vivian; de Lima, Thais Martins; Prado, Carla Maximo; Pinheiro, Nathalia; Ariga, Suely K K; Barbeiro, Denise F; Moretti, Ana I; Souza, Heraldo P

2016-12-01

Acute lung injury is a condition characterized by exacerbate inflammatory reaction in distal airways and lung dysfunction. Here we investigate the treatment of acute lung injury (ALI) by low level laser therapy (LLLT), an effective therapy used for the treatment of patients with inflammatory disorders or traumatic injuries, due to its ability to reduce inflammation and promote tissue regeneration. However, studies in internal viscera remains unclear. C57BL/6 mice were treated with intratracheal lipopolysaccharide (LPS) (5 mg/kg) or phosphate buffer saline (PBS). Six hours after instillation, two groups were irradiated with laser at 660 nm and radiant exposure of 10 J/cm 2 . Intratracheal LPS inoculation induced a marked increase in the number of inflammatory cells in perivascular and alveolar spaces. There was also an increase in the expression and secretion of cytokines (TNF-α, IL-1β, IL-6,) and chemokine (MCP-1). The LLLT application induced a significant decrease in both inflammatory cells influx and inflammatory mediators secretion. These effects did not affect lung mechanical properties, since no change was observed in tissue resistance or elastance. In conclusion LLLT is able to reduce inflammatory reaction in lungs exposed to LPS without affecting the pulmonary function and recovery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Acute toxicity of some nerve agents and pesticides in rats.

PubMed

Misik, Jan; Pavlikova, Ruzena; Cabal, Jiri; Kuca, Kamil

2015-01-01

Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and patchy. Therefore, there is a need for integrated summary comparing acute toxicity of organophosphates using different administration routes in the same animal model with the same methodology. Based on original data, a summary of in vivo acute toxicity of selected V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon (POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. Male Wistar rats were exposed to organophosphates in several administration routes (i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal dose (LD50, mg kg(-1)) 2, 4, and 24 hours post exposure. V-agents were the most toxic presented with LD50 ranged from 0.0082 mg kg(-1) (VX, i.m.) to 1.402 mg kg(-1) (Russian VX, p.o.), followed by G-agents (LD50 = 0.069 mg kg(-1)/soman, i.m./ - 117.9 mg kg(-1)/sarin, p.c./), organophosphate POX and DFP (LD50 = 0.321 mg kg(-1)/POX, i.m./ - 420 mg kg(-1)/DFP, p.c./). Generally, i.m. administration was the most toxic throughout all tested agents and ways of administration (LD50 = 0.0082 mg kg(-1)/VX/ - 1.399 mg kg(-1)/DFP/) whereas p.c. way was responsible for lowest acute toxicity (LD50 = 0.085 mg kg(-1)/VX/ - 420 mg kg(-1)/DFP/). The acute toxicity of selected organophosphorus compounds is summarized throughout this study. Although the data assessed in rats are rather illustrative prediction for human, it presents a valuable contribution, indicating the toxic potential and harmfulness of organophosphates.

Predictive acute toxicity tests with pesticides.

PubMed

Brown, V K

1983-01-01

By definition pesticides are biocidal products and this implies a probability that pesticides may be acutely toxic to species other than the designated target species. The ways in which pesticides are manufactured, formulated, packaged, distributed and used necessitates a potential for the exposure of non-target species although the technology exists to minimize adventitious exposure. The occurrence of deliberate exposure of non-target species due to the misuse of pesticides is known to happen. The array of predictive acute toxicity tests carried out on pesticides and involving the use of laboratory animals can be justified as providing data on which hazard assessment can be based. This paper addresses the justification and rationale of this statement.

Punica granatum L. Leaf Extract Attenuates Lung Inflammation in Mice with Acute Lung Injury

PubMed Central

Pinheiro, Aruanã Joaquim Matheus Costa Rodrigues; Gonçalves, Jaciara Sá; Dourado, Ádylla Wilenna Alves; de Sousa, Eduardo Martins; Brito, Natilene Mesquita; Silva, Lanna Karinny; Batista, Marisa Cristina Aranha; de Sá, Joicy Cortez; Monteiro, Cinara Regina Aragão Vieira; Fernandes, Elizabeth Soares; Campbell, Lee Ann; Zago, Patrícia Maria Wiziack

2018-01-01

The hydroalcoholic extract of Punica granatum (pomegranate) leaves was previously demonstrated to be anti-inflammatory in a rat model of lipopolysaccharide- (LPS-) induced acute peritonitis. Here, we investigated the anti-inflammatory effects of the ethyl acetate fraction obtained from the pomegranate leaf hydroalcoholic extract (EAFPg) on the LPS-induced acute lung injury (ALI) mouse model. Male Swiss mice received either EAFPg at different doses or dexamethasone (per os) prior to LPS intranasal instillation. Vehicle-treated mice were used as controls. Animals were culled at 4 h after LPS challenge, and the bronchoalveolar lavage fluid (BALF) and lung samples were collected for analysis. EAFPg and kaempferol effects on NO and cytokine production by LPS-stimulated RAW 264.7 macrophages were also investigated. Pretreatment with EAFPg (100–300 mg/kg) markedly reduced cell accumulation (specially neutrophils) and collagen deposition in the lungs of ALI mice. The same animals presented with reduced lung and BALF TNF-α and IL-1β expression in comparison with vehicle controls (p < 0.05). Additionally, incubation with either EAFPg or kaempferol (100 μg/ml) reduced NO production and cytokine gene expression in cultured LPS-treated RAW 264.7 macrophages. Overall, these results demonstrate that the prophylactic treatment with EAFPg attenuates acute lung inflammation. We suggest this fraction may be useful in treating ALI. PMID:29675437

Acute Toxicity of Tributyltins and Tributyltin Leachates from Marine Antibiofouling Paints.

DTIC Science & Technology

1982-09-10

RO-0184 224 ACUTE TOXICITY OF TRIBUTYLTINS AND TRIBUTYLTIN i/I LEACHATES FROM MARINE ANTIBIOFOULING PAINTS(U) CALIFORNIA UNIV OAKLAND NAVAL...Classification) (U) ACUTE TOXICITY OF TRIBUTYLTINS AND TRIBUTYLTIN LEACHATES FROM MARINE ANTIBIOFOULING PAINTS 12, PERSO A UHR Laugin, Koy"., Linden, Olof and...xins causing acute toxicity or two amphipou species at concentrations as low as 10 g/L . Orchestia traskiana was exposed to bis ( tributyltin ) oxide

Acute and subacute toxicity of Schinus terebinthifolius bark extract.

PubMed

Lima, L B; Vasconcelos, C F B; Maranhão, H M L; Leite, V R; Ferreira, P A; Andrade, B A; Araújo, E L; Xavier, H S; Lafayette, S S L; Wanderley, A G

2009-12-10

Schinus terebinthifolius Raddi (Anacardiaceae) has long been used in traditional Brazilian medicine, especially to treat inflammatory and haemostatic diseases. The objective of this study was to evaluate the acute and subacute toxicity (45 days) of Schinus terebinthifolius via the oral route in Wistar rats of both sexes. For the acute toxicity test, the dried extract of Schinus terebinthifolius bark was administered in doses from 0.625 to 5.0 g/kg (n=5/group/sex) and in the subacute toxicity test the following doses were used: 0.25, 0.625 and 1.5625 g/kg/day (n=13/group/sex), for 45 consecutive days. In the acute toxicity test, Schinus terebinthifolius did not produce any toxic signs or deaths. The subacute treatment with Schinus terebinthifolius did not alter either the body weight gain or the food and water consumption. The hematological and biochemical analysis did not show significant differences in any of the parameters examined in female or male groups, except in two male groups, in which the treatment with Schinus terebinthifolius (0.25 and 0.625 g/kg) induced an increase of mean corpuscular volume values (2.9 and 2.6%, respectively). These variations are within the physiological limits described for the specie and does not have clinical relevance. The acute and subacute administration of the dried extract of Schinus terebinthifolius bark did not produced toxic effects in Wistar rats.

Comparison of Toxicity Between Intensity-Modulated Radiotherapy and 3-Dimensional Conformal Radiotherapy for Locally Advanced Non-small-cell Lung Cancer.

PubMed

Ling, Diane C; Hess, Clayton B; Chen, Allen M; Daly, Megan E

2016-01-01

The role of intensity-modulated radiotherapy (IMRT) in reducing treatment-related toxicity for locally advanced non-small-cell lung cancer (NSCLC) remains incompletely defined. We compared acute toxicity and oncologic outcomes in a large cohort of patients treated with IMRT or 3-dimensional conformal radiotherapy (3-DCRT), with or without elective nodal irradiation (ENI). A single-institution retrospective review was performed evaluating 145 consecutive patients with histologically confirmed stage III NSCLC treated with definitive chemoradiotherapy. Sixty-five (44.8%) were treated with 3-DCRT using ENI, 43 (30.0%) with 3-DCRT using involved-field radiotherapy (IFRT), and 37 (25.5%) with IMRT using IFRT. All patients received concurrent chemotherapy. Comparison of acute toxicities by treatment technique (IMRT vs. 3-DCRT) and extent of nodal irradiation (3-DCRT-IFRT vs. 3-DCRT-ENI) was performed for grade 2 or higher esophagitis or pneumonitis, number of acute hospitalizations, incidence of opioid requirement, percutaneous endoscopic gastrostomy utilization, and percentage weight loss during treatment. Local control and overall survival were analyzed by the Kaplan-Meier method. We identified no significant differences in any measures of acute toxicity by treatment technique or extent of nodal irradiation. There was a trend toward lower rates of grade 2 or higher pneumonitis among IMRT patients compared to 3-DCRT patients (5.4% vs. 23.0%; P = .065). Local control and overall survival were similar between cohorts. Acute and subacute toxicities were similar for patients treated with IMRT and with 3-DCRT with or without ENI, with a nonsignificant trend toward a reduction in pneumonitis with IMRT. Larger studies are needed to better define which patients will benefit from IMRT. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of olanzapine pretreatment on acute cocaine toxicity in mice.

PubMed

Heard, Kennon J; Cleveland, Nathan R; Krier, Shay

2009-07-01

Acute cocaine poisoning causes neuroexcitation and can be fatal. The toxic effects of cocaine can be attenuated by antagonists of serotonin, muscarinic cholinergic, and dopamine receptors. Olanzapine, an atypical antipsychotic medication, is an antagonist of these receptors. The objective of this study is to evaluate the efficacy of olanzapine pretreatment for attenuation of acute cocaine toxicity using a mouse model. Eighty male CF-1 mice were randomly assigned to olanzapine (1 mg/kg) or placebo pretreatment. Fifteen minutes later, all animals received 103 mg/kg intraperitoneal cocaine. Overall mortality was 11% for olanzapine-treated animals and 45% for placebo. Olanzapine also appeared to alter the characteristics of seizures due to cocaine. In this model of acute cocaine toxicity, olanzapine pretreatment attenuated acute cocaine toxicity. Olanzapine should be evaluated further as a potential treatment for acute cocaine poisoning.

Pleural effusion in patients with acute lung injury: a CT scan study.

PubMed

Chiumello, Davide; Marino, Antonella; Cressoni, Massimo; Mietto, Cristina; Berto, Virna; Gallazzi, Elisabetta; Chiurazzi, Chiara; Lazzerini, Marco; Cadringher, Paolo; Quintel, Michael; Gattinoni, Luciano

2013-04-01

Pleural effusion is a frequent finding in patients with acute respiratory distress syndrome. To assess the effects of pleural effusion in patients with acute lung injury on lung volume, respiratory mechanics, gas exchange, lung recruitability, and response to positive end-expiratory pressure. A total of 129 acute lung injury or acute respiratory distress syndrome patients, 68 analyzed retrospectively and 61 prospectively, studied at two University Hospitals. Whole-lung CT was performed during two breath-holding pressures (5 and 45 cm H2O). Two levels of positive end-expiratory pressure (5 and 15 cm H2O) were randomly applied. Pleural effusion volume was determined on each CT scan section; respiratory system mechanics, gas exchange, and hemodynamics were measured at 5 and 15 cm H2O positive end-expiratory pressure. In 60 patients, elastances of lung and chest wall were computed, and lung and chest wall displacements were estimated. Patients were divided into higher and lower pleural effusion groups according to the median value (287 mL). Patients with higher pleural effusion were older (62±16 yr vs. 54±17 yr, p<0.01) with a lower minute ventilation (8.8±2.2 L/min vs. 10.1±2.9 L/min, p<0.01) and respiratory rate (16±5 bpm vs. 19±6 bpm, p<0.01) than those with lower pleural effusion. Both at 5 and 15 cm H2O of positive end-expiratory pressure PaO2/FIO2, respiratory system elastance, lung weight, normally aerated tissue, collapsed tissue, and lung and chest wall elastances were similar between the two groups. The thoracic cage expansion (405±172 mL vs. 80±87 mL, p<0.0001, for higher pleural effusion group vs. lower pleural effusion group) was greater than the estimated lung compression (178±124 mL vs. 23±29 mL, p<0.0001 for higher pleural effusion group vs. lower pleural effusion group, respectively). Pleural effusion in acute lung injury or acute respiratory distress syndrome patients is of modest entity and leads to a greater chest wall expansion than lung

Fish embryo toxicity test: identification of compounds with weak toxicity and analysis of behavioral effects to improve prediction of acute toxicity for neurotoxic compounds.

PubMed

Klüver, Nils; König, Maria; Ortmann, Julia; Massei, Riccardo; Paschke, Albrecht; Kühne, Ralph; Scholz, Stefan

2015-06-02

The fish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, but concerns have been raised for its predictivity given that a few compounds have been shown to exhibit a weak acute toxicity in the fish embryo. In order to better define the applicability domain and improve the predictive capacity of the fish embryo test, we performed a systematic analysis of existing fish embryo and acute fish toxicity data. A correlation analysis of a total of 153 compounds identified 28 compounds with a weaker or no toxicity in the fish embryo test. Eleven of these compounds exhibited a neurotoxic mode of action. We selected a subset of eight compounds with weaker or no embryo toxicity (cyanazine, picloram, aldicarb, azinphos-methyl, dieldrin, diquat dibromide, endosulfan, and esfenvalerate) to study toxicokinetics and a neurotoxic mode of action as potential reasons for the deviating fish embryo toxicity. Published fish embryo LC50 values were confirmed by experimental analysis of zebrafish embryo LC50 according to OECD guideline 236. Except for diquat dibromide, internal concentration analysis did not indicate a potential relation of the low sensitivity of fish embryos to a limited uptake of the compounds. Analysis of locomotor activity of diquat dibromide and the neurotoxic compounds in 98 hpf embryos (exposed for 96 h) indicated a specific effect on behavior (embryonic movement) for the neurotoxic compounds. The EC50s of behavior for neurotoxic compounds were close to the acute fish toxicity LC50. Our data provided the first evidence that the applicability domain of the fish embryo test (LC50s determination) may exclude neurotoxic compounds. However, neurotoxic compounds could be identified by changes in embryonic locomotion. Although a quantitative prediction of acute fish toxicity LC50 using behavioral assays in fish embryos may not yet be possible, the identification of neurotoxicity could trigger the conduction of a conventional fish

Effects of Shuang Wuzhen Tong Capsule on acute toxicity of mice caused by swelling and auricular dimethylbenzene

NASA Astrophysics Data System (ADS)

Hao, Shaojun; Sun, Youshu; Guo, Junyi; Chen, Weiliang; Wang, Hongyu; Sun, Jianhua; Guan, Zhijiang; Zhang, Zhengchen; Wang, Fang

2018-04-01

To observe the effect of Shuang Wuzhen Tong Capsule on acute toxicity of mice caused by swelling and auricular dimethylbenzene. 40 rats, weighing 18 ˜ 22G, half male and half female. Shuang Wuzhen Tong Capsule maximum concentration maximum volume to mice for 1 days by gavage for 1 times, for 7 consecutive days, to observe the situation of animal death, the maximum tolerance; the other 50 mice, were divided into 5 groups, were fed with Shuang Wuzhen Tong capsule suspension, Jingfukang granule suspension and the same volume 0.5%CMC. No death in 7 days. After death animal autopsy, heart, liver, spleen, lung, kidney, brain, stomach, intestine and no important organ obvious bleeding, hyperemia and edema, exudation, ulcer, perforation, pleural, peritoneal, pericardial cavity without effusion. Shuang Wuzhen Tong Capsule group and Jingfukang granule group could obviously reduce the xylene induced swelling of mouse ear, ear swelling degree decreased significantly (P<0.01). Shuang Wuzhen Tong Capsule has no obvious acute toxicity, anti-inflammatory effects.

Acute and sub-chronic toxicity studies of honokiol microemulsion.

PubMed

Zhang, Qianqian; Li, Jianguo; Zhang, Wei; An, Quan; Wen, Jianhua; Wang, Aiping; Jin, Hongtao; Chen, Shizhong

2015-04-01

The purpose of this study was to investigate the acute and sub-chronic toxicity of honokiol microemulsion. In the acute toxicity tests, the mice were intravenously injected graded doses of honokiol microemulsion and were observed for toxic symptoms and mortality daily for 14 days. In the sub-chronic toxicity study, rats were injected honokiol microemulsion at doses of 100, 500, 2500 μg/kg body weight (BW) for 30 days. After 30 days treatment and 14 days recovery, the rats were sacrificed for hematological, biochemical and histological examination. In the acute toxicity tests, the estimated median lethal dosage (LD50) was 50.5mg/kg body weight in mice. In the sub-chronic toxicity tests, the non-toxic reaction dose was 500 μg/kg body weight. In each treatment group, degeneration or/and necrosis in vascular endothelial cells and structure change of vessel wall can be observed in the injection site (cauda vein) of a few animals while there were no changes in the vessels of other organs. The overall findings of this study indicate that the honokiol microemulsion is non-toxic up to 500 μg/kg body weight, and it has irritation to the vascular of the injection site which should be paid attention to in clinical medication. Copyright © 2015. Published by Elsevier Inc.

Open Lung Approach for the Acute Respiratory Distress Syndrome: A Pilot, Randomized Controlled Trial.

PubMed

Kacmarek, Robert M; Villar, Jesús; Sulemanji, Demet; Montiel, Raquel; Ferrando, Carlos; Blanco, Jesús; Koh, Younsuck; Soler, Juan Alfonso; Martínez, Domingo; Hernández, Marianela; Tucci, Mauro; Borges, Joao Batista; Lubillo, Santiago; Santos, Arnoldo; Araujo, Juan B; Amato, Marcelo B P; Suárez-Sipmann, Fernando

2016-01-01

The open lung approach is a mechanical ventilation strategy involving lung recruitment and a decremental positive end-expiratory pressure trial. We compared the Acute Respiratory Distress Syndrome network protocol using low levels of positive end-expiratory pressure with open lung approach resulting in moderate to high levels of positive end-expiratory pressure for the management of established moderate/severe acute respiratory distress syndrome. A prospective, multicenter, pilot, randomized controlled trial. A network of 20 multidisciplinary ICUs. Patients meeting the American-European Consensus Conference definition for acute respiratory distress syndrome were considered for the study. At 12-36 hours after acute respiratory distress syndrome onset, patients were assessed under standardized ventilator settings (FIO2≥0.5, positive end-expiratory pressure ≥10 cm H2O). If Pao2/FIO2 ratio remained less than or equal to 200 mm Hg, patients were randomized to open lung approach or Acute Respiratory Distress Syndrome network protocol. All patients were ventilated with a tidal volume of 4 to 8 ml/kg predicted body weight. From 1,874 screened patients with acute respiratory distress syndrome, 200 were randomized: 99 to open lung approach and 101 to Acute Respiratory Distress Syndrome network protocol. Main outcome measures were 60-day and ICU mortalities, and ventilator-free days. Mortality at day-60 (29% open lung approach vs. 33% Acute Respiratory Distress Syndrome Network protocol, p = 0.18, log rank test), ICU mortality (25% open lung approach vs. 30% Acute Respiratory Distress Syndrome network protocol, p = 0.53 Fisher's exact test), and ventilator-free days (8 [0-20] open lung approach vs. 7 [0-20] d Acute Respiratory Distress Syndrome network protocol, p = 0.53 Wilcoxon rank test) were not significantly different. Airway driving pressure (plateau pressure - positive end-expiratory pressure) and PaO2/FIO2 improved significantly at 24, 48 and 72 hours in patients

40 CFR 799.9135 - TSCA acute inhalation toxicity with histopathology.

Code of Federal Regulations, 2013 CFR

2013-07-01

... TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9135 TSCA acute inhalation toxicity with... Substances Control Act (TSCA). In the assessment and evaluation of the potential human health effects of chemical substances, it is appropriate to test for acute inhalation toxic effects. The goals of this test...

40 CFR 799.9135 - TSCA acute inhalation toxicity with histopathology.

Code of Federal Regulations, 2012 CFR

2012-07-01

... TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9135 TSCA acute inhalation toxicity with... Substances Control Act (TSCA). In the assessment and evaluation of the potential human health effects of chemical substances, it is appropriate to test for acute inhalation toxic effects. The goals of this test...

40 CFR 799.9135 - TSCA acute inhalation toxicity with histopathology.

Code of Federal Regulations, 2014 CFR

2014-07-01

... TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9135 TSCA acute inhalation toxicity with... Substances Control Act (TSCA). In the assessment and evaluation of the potential human health effects of chemical substances, it is appropriate to test for acute inhalation toxic effects. The goals of this test...

Acute respiratory toxicity following inhalation exposure to soman in guinea pigs.

PubMed

Perkins, Michael W; Pierre, Zdenka; Rezk, Peter; Sabnekar, Praveena; Kabra, Kareem; Chanda, Soma; Oguntayo, Samuel; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

2010-06-01

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m(3) concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m(3) soman survived, while animals exposed to 841, and 1121 mg/m(3) resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt(50) for soman determined by probit analysis was 827.2mg/m(3). A majority of the animals that died at 1121 mg/m(3) developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs. (c) 2010 Elsevier Inc. All rights reserved.

Diabetes, insulin, and development of acute lung injury

PubMed Central

Honiden, Shyoko; Gong, Michelle N.

2009-01-01

Objectives Recently, many studies have investigated the immunomodulatory effects of insulin and glucose control in critical illness. This review examines evidence regarding the relationship between diabetes and the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), reviews studies of lung injury related to glycemic and nonglycemic metabolic features of diabetes, and examines the effect of diabetic therapies. Data Sources and Study Selection A MEDLINE/PubMed search from inception to August 1, 2008, was conducted using the search terms acute lung injury, acute respiratory distress syndrome, hyperglycemia, diabetes mellitus, insulin, hydroxymethylglutaryl-CoA reductase inhibitors (statins), angiotensin-converting enzyme inhibitor, and peroxisome proliferator-activated receptors, including combinations of these terms. Bibliographies of retrieved articles were manually reviewed. Data Extraction and Synthesis Available studies were critically reviewed, and data were extracted with special attention to the human and animal studies that explored a) diabetes and ALI; b) hyperglycemia and ALI; c) metabolic nonhyperglycemic features of diabetes and ALI; and d) diabetic therapies and ALI. Conclusions Clinical and experimental data indicate that diabetes is protective against the development of ALI/ARDS. The pathways involved are complex and likely include effects of hyperglycemia on the inflammatory response, metabolic abnormalities in diabetes, and the interactions of therapeutic agents given to diabetic patients. Multidisciplinary, multifaceted studies, involving both animal models and clinical and molecular epidemiology techniques, are essential. PMID:19531947

Lung recruitment manoeuvres are effective in regaining lung volume and oxygenation after open endotracheal suctioning in acute respiratory distress syndrome

PubMed Central

Dyhr, Thomas; Bonde, Jan; Larsson, Anders

2003-01-01

Introduction Lung collapse is a contributory factor in the hypoxaemia that is observed after open endotracheal suctioning (ETS) in patients with acute lung injury and acute respiratory distress syndrome. Lung recruitment (LR) manoeuvres may be effective in rapidly regaining lung volume and improving oxygenation after ETS. Materials and method A prospective, randomized, controlled study was conducted in a 15-bed general intensive care unit at a university hospital. Eight consecutive mechanically ventilated patients with acute lung injury or acute respiratory distress syndrome were included. One of two suctioning procedures was performed in each patient. In the first procedure, ETS was performed followed by LR manoeuvre and reconnection to the ventilator with positive end-expiratory pressure set at 1 cmH2O above the lower inflexion point, and after 60 min another ETS (but without LR manoeuvre) was performed followed by reconnection to the ventilator with similar positive end-expiratory pressure; the second procedure was the same as the first but conducted in reverse order. Before (baseline) and over 25 min following each ETS procedure, partial arterial oxygen tension (PaO2) and end-expiratory lung volume were measured. Results After ETS, PaO2 decreased by 4.3(0.9–9.7)kPa (median and range; P < 0.005). After LR manoeuvre, PaO2 recovered to baseline. Without LR manoeuvre, PaO2 was reduced (P = 0.05) until 7 min after ETS. With LR manoeuvre end-expiratory lung volume was unchanged after ETS, whereas without LR manoeuvre end-expiratory lung volume was still reduced (approximately 10%) at 5 and 15 min after ETS (P = 0.01). Discussion A LR manoeuvre immediately following ETS was, as an adjunct to positive end-expiratory pressure, effective in rapidly counteracting the deterioration in PaO2 and lung volume caused by open ETS in ventilator-treated patients with acute lung injury or acute respiratory distress syndrome. PMID:12617741

Acute cardiopulmonary toxicity of inhaled aldehydes: role of TRPA1

PubMed Central

Conklin, Daniel J.

2016-01-01

Inhalation of high-level volatile aldehydes, as present in smoke from wildfires and in tobacco smoke, is associated with both acute and chronic cardiopulmonary morbidity and mortality, but the underlying mechanisms are unclear. The transient receptor potential ankyrin 1 (TRPA1) protein forms a cation channel (irritant receptor) that mediates tobacco smoke–induced airway and lung injury, yet the role of TRPA1 in the cardiovascular toxicity of aldehyde exposure is unclear. Physiologically, airway-located TRPA1 activation triggers an irritant response (e.g., coughing and “respiratory braking”) that alters the rate and depth of breathing to reduce exposure. Acrolein (2-propenal), a volatile, unsaturated aldehyde, activates TRPA1. Acrolein was used as a chemical weapon in World War I and is present at high levels in wildfires and tobacco smoke. Acrolein is thought to contribute to pulmonary and cardiovascular injury caused by tobacco smoke exposure, although the role of TRPA1 in cardiovascular toxicity is unclear. This mini-review addresses this gap in our knowledge by exploring literature and recent data indicating a connection between TRPA1 and cardiovascular as well as pulmonary injury due to inhaled aldehydes. PMID:27152448

Regulation of alveolar macrophage death in acute lung inflammation.

PubMed

Fan, Erica K Y; Fan, Jie

2018-03-27

Acute lung injury (ALI) and its severe form, known as acute respiratory distress syndrome (ARDS), are caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis, trauma, and major surgery. The reciprocal influences between pulmonary and systemic inflammation augments the inflammatory process in the lung and promotes the development of ALI. Emerging evidence has revealed that alveolar macrophage (AM) death plays important roles in the progression of lung inflammation through its influence on other immune cell populations in the lung. Cell death and tissue inflammation form a positive feedback cycle, ultimately leading to exaggerated inflammation and development of disease. Pharmacological manipulation of AM death signals may serve as a logical therapeutic strategy for ALI/ARDS. This review will focus on recent advances in the regulation and underlying mechanisms of AM death as well as the influence of AM death on the development of ALI.

Acute and Subacute Toxicity Evaluation of Corn Silk Extract

PubMed Central

Ha, Ae Wha; Kang, Hyeon Jung; Kim, Sun Lim; Kim, Myung Hwan

2018-01-01

Many studies have reported therapeutic efficacy of corn silk extract. However, research on its toxicity and safe dose range is limited. Thus, the objective of this study was to determine the acute and subacute toxicity of corn silk extract in ICR mice. To determine acute toxicity, corn silk extract containing high levels of maysin was orally administered to mice at a dose of 0 or 2,000 mg/kg. Clinical symptoms, mortality, and body weight changes were recorded for 14 days. To determine subacute toxicity, corn silk extract was orally administered to mice over a 4-week period, and then body weight, water and food consumption, and organ weight were determined. In addition, urine and serum analyses were performed. In the acute toxicity study, no death or abnormal symptoms was observed in all treatment groups during the study period. Body weights did not show any significant change compared to those of the control group. Lethal dose of corn silk extract was estimated to be more than 2,000 mg/kg. In the 4-week subacute toxicity study, there was no corn silk extract related toxic effect on body weight, water intake, food consumption, urine parameters, clinical chemistry, or organ weight. Histopathological examination showed no abnormality related to the administration of corn silk extract at 500 mg/kg. The maximum non-toxic dose of corn silk extract containing high levels of maysin was found to be more than 500 mg/kg. PMID:29662850

Acute and Subacute Toxicity Evaluation of Corn Silk Extract.

PubMed

Ha, Ae Wha; Kang, Hyeon Jung; Kim, Sun Lim; Kim, Myung Hwan; Kim, Woo Kyoung

2018-03-01

Many studies have reported therapeutic efficacy of corn silk extract. However, research on its toxicity and safe dose range is limited. Thus, the objective of this study was to determine the acute and subacute toxicity of corn silk extract in ICR mice. To determine acute toxicity, corn silk extract containing high levels of maysin was orally administered to mice at a dose of 0 or 2,000 mg/kg. Clinical symptoms, mortality, and body weight changes were recorded for 14 days. To determine subacute toxicity, corn silk extract was orally administered to mice over a 4-week period, and then body weight, water and food consumption, and organ weight were determined. In addition, urine and serum analyses were performed. In the acute toxicity study, no death or abnormal symptoms was observed in all treatment groups during the study period. Body weights did not show any significant change compared to those of the control group. Lethal dose of corn silk extract was estimated to be more than 2,000 mg/kg. In the 4-week subacute toxicity study, there was no corn silk extract related toxic effect on body weight, water intake, food consumption, urine parameters, clinical chemistry, or organ weight. Histopathological examination showed no abnormality related to the administration of corn silk extract at 500 mg/kg. The maximum non-toxic dose of corn silk extract containing high levels of maysin was found to be more than 500 mg/kg.

Emerging toxicities in the treatment of non-small cell lung cancer: ocular disorders.

PubMed

Agustoni, Francesco; Platania, Marco; Vitali, Milena; Zilembo, Nicoletta; Haspinger, Eva; Sinno, Valentina; Gallucci, Rosaria; de Braud, Filippo; Garassino, Marina Chiara

2014-02-01

The treatment of advanced disease (stage IIIb and IV) of non-small cell lung cancer (NSCLC) is based on systemic treatment with platinum-based chemotherapy or biological compounds depending on the disease molecular profile. In the last few years, intensive investigational efforts in anticancer therapy have led to the registration of new active chemotherapeutic agents, combination regimens, and biological drugs, expanding choices for customizing individual treatment. However, the introduction of new drugs in the clinical setting has led to several new toxicities, creating some difficulties in daily management. Among these, ocular toxicity is generally overlooked as more common toxicities such as myelosuppression, stomatitis, diarrhea, vomiting, "hand-foot syndrome", and neurological alterations attract greater attention. Ophthalmic complications from cytotoxic chemotherapeutics are rare, transient, and of mild/moderate intensity but irreversible acute disorders are possible. The best way to prevent potential irreversible visual complications is an awareness of the potential for ocular toxicity because dose reductions or early drug cessation can prevent serious ocular complications in the majority of cases. However, given the novelty of many therapeutic agents and the complexity of ocular pathology, oncologists may be unfamiliar with these adverse effects of anticancer therapy. Although toxicities from chemotherapy are generally intense but short lasting, toxicities related to targeted drugs are often milder but longer lasting and can persist throughout treatment. Here we review the principal clinical presentations of ocular toxicity arising from chemotherapy [1-3], target therapies [4], and newly developed drugs and provide some recommendations for monitoring and management of ocular toxicity. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Diagnostic value of plasma and bronchoalveolar lavage samples in acute lung allograft rejection: differential cytology.

PubMed

Speck, Nicole E; Schuurmans, Macé M; Murer, Christian; Benden, Christian; Huber, Lars C

2016-06-21

Diagnosis of acute lung allograft rejection is currently based on transbronchial lung biopsies. Additional methods to detect acute allograft dysfunction derived from plasma and bronchoalveolar lavage samples might facilitate diagnosis and ultimately improve allograft survival. This review article gives an overview of the cell profiles of bronchoalveolar lavage and plasma samples during acute lung allograft rejection. The value of these cells and changes within the pattern of differential cytology to support the diagnosis of acute lung allograft rejection is discussed. Current findings on the topic are highlighted and trends for future research are identified.

Acute and chronic toxicity studies with monochlorobenzene in rainbow trout

USGS Publications Warehouse

Dahlich, G.M.; Larson, R.E.; Gingerich, W.H.

1982-01-01

The toxicity of monochlorobenzene (CB) was investigated in rainbow trout following acute intraperitoneal (i.p.) administration and chronic exposure via the water in a continuously flowing system for 15 or 30 days. In the acute study overt toxicity and hepatotoxicity were monitored over a 96-h time period. Variables measured to assess toxicity included weight changes, liver weight to body weight ratios, behavioral changes, alanine aminotransferase activity (GPT), sulfobromophthalein (BSP) retention, total plasma protein concentration and liver histopathology. In the chronic study the same measures of toxicity were followed as well as food consumption and alkaline phosphatase (AP) activity. Upon acute i.p. exposure the toxicant (9.8 mmol/kg) caused behavioral changes in the fish which were consistent with the known anesthetic properties of CB in mammals. Elevations in BSP retention and GPT activity, and histopathology indicated that CB was hepatotoxic in fish. The LC50 of CB in trout exposed via the water for 96 h was 4.7 mg/l. Chronic exposure of trout to 2 or 3 mg/l CB resulted in similar behavioral changes as seen in the acute study. Liver toxicity was evident from elevations in GPT activity. BSP retention and AP activity appeared to be affected by the nutritional status of the trout as much as by the CB treatment. After 30 days of exposure to 3 mg/l CB, trout appeared to have developed some tolerance to the toxic effects.

Targeting Transfusion-Related Acute Lung Injury: The Journey From Basic Science to Novel Therapies.

PubMed

Semple, John W; McVey, Mark J; Kim, Michael; Rebetz, Johan; Kuebler, Wolfgang M; Kapur, Rick

2018-05-01

Transfusion-related acute lung injury is characterized by the onset of respiratory distress and acute lung injury following blood transfusion, but its pathogenesis remains poorly understood. Generally, a two-hit model is presumed to underlie transfusion-related acute lung injury with the first hit being risk factors present in the transfused patient (such as inflammation), whereas the second hit is conveyed by factors in the transfused donor blood (such as antileukocyte antibodies). At least 80% of transfusion-related acute lung injury cases are related to the presence of donor antibodies such as antihuman leukocyte or antihuman neutrophil antibodies. The remaining cases may be related to nonantibody-mediated factors such as biolipids or components related to storage and ageing of the transfused blood cells. At present, transfusion-related acute lung injury is the leading cause of transfusion-related fatalities and no specific therapy is clinically available. In this article, we critically appraise and discuss recent preclinical (bench) insights related to transfusion-related acute lung injury pathogenesis and their therapeutic potential for future use at the patients' bedside in order to combat this devastating and possibly fatal complication of transfusion. We searched the PubMed database (until August 22, 2017). Using terms: "Transfusion-related acute lung injury," "TRALI," "TRALI and therapy," "TRALI pathogenesis." English-written articles focusing on transfusion-related acute lung injury pathogenesis, with potential therapeutic implications, were extracted. We have identified potential therapeutic approaches based on the literature. We propose that the most promising therapeutic strategies to explore are interleukin-10 therapy, down-modulating C-reactive protein levels, targeting reactive oxygen species, or blocking the interleukin-8 receptors; all focused on the transfused recipient. In the long-run, it may perhaps also be advantageous to explore other

Mechanisms of decreased intestinal epithelial proliferation and increased apoptosis in murine acute lung injury.

PubMed

Husain, Kareem D; Stromberg, Paul E; Woolsey, Cheryl A; Turnbull, Isaiah R; Dunne, W Michael; Javadi, Pardis; Buchman, Timothy G; Karl, Irene E; Hotchkiss, Richard S; Coopersmith, Craig M

2005-10-01

The aim of this study was to determine the effects of acute lung injury on the gut epithelium and examine mechanisms underlying changes in crypt proliferation and apoptosis. The relationship between severity and timing of lung injury to intestinal pathology was also examined. Randomized, controlled study. University research laboratory. Genetically inbred mice. Following induction of acute lung injury, gut epithelial proliferation and apoptosis were assessed in a) C3H/HeN wild-type and C3H/HeJ mice, which lack functional Toll-like receptor 4 (n = 17); b) C57Bl/6 mice that received monoclonal anti-tumor necrosis factor-alpha or control antibody (n = 22); and c) C57Bl/6 wild-type and transgenic mice that overexpress Bcl-2 in their gut epithelium (n = 21). Intestinal epithelial proliferation and death were also examined in animals with differing degrees of lung inflammation (n = 24) as well as in a time course analysis following a fixed injury (n = 18). Acute lung injury caused decreased proliferation and increased apoptosis in crypt epithelial cells in all animals studied. C3H/HeJ mice had higher levels of proliferation than C3H/HeN animals without additional changes in apoptosis. Anti-tumor necrosis factor-alpha antibody had no effect on gut epithelial proliferation or death. Overexpression of Bcl-2 did not change proliferation despite decreasing gut apoptosis. Proliferation and apoptosis were not correlated to severity of lung injury, as gut alterations were lost in mice with more severe acute lung injury. Changes in both gut epithelial proliferation and death were apparent within 12 hrs, but proliferation was decreased 36 hrs following acute lung injury while apoptosis returned to normal. Acute lung injury causes disparate effects on crypt proliferation and apoptosis, which occur, at least in part, through differing mechanisms involving Toll-like receptor 4 and Bcl-2. Severity of lung injury does not correlate with perturbations in proliferation or death in the

Vildagliptin-induced acute lung injury: a case report.

PubMed

Ohara, Nobumasa; Kaneko, Masanori; Sato, Kazuhiro; Maruyama, Ryoko; Furukawa, Tomoyasu; Tanaka, Junta; Kaneko, Kenzo; Kamoi, Kyuzi

2016-08-12

Dipeptidyl peptidase-4 inhibitors are a class of oral hypoglycemic drugs and are used widely to treat type 2 diabetes mellitus in many countries. Adverse effects include nasopharyngitis, headache, elevated serum pancreatic enzymes, and gastrointestinal symptoms. In addition, a few cases of interstitial pneumonia associated with their use have been reported in the Japanese literature. Here we describe a patient who developed drug-induced acute lung injury shortly after the administration of the dipeptidyl peptidase-4 inhibitor vildagliptin. A 38-year-old Japanese woman with diabetes mellitus developed acute respiratory failure 1 day after administration of vildagliptin. Chest computed tomography revealed nonsegmental ground-glass opacities in her lungs. There was no evidence of bacterial pneumonia or any other cause of her respiratory manifestations. After discontinuation of vildagliptin, she recovered fully from her respiratory disorder. She received insulin therapy for her diabetes mellitus, and her subsequent clinical course has been uneventful. The period of drug exposure in previously reported cases of patients with drug-induced interstitial pneumonia caused by dipeptidyl peptidase-4 inhibitor varied from several days to over 6 months. In the present case, our patient developed interstitial pneumonia only 1 day after the administration of vildagliptin. The precise mechanism of her vildagliptin-induced lung injury remains uncertain, but physicians should consider that dipeptidyl peptidase-4 inhibitor-induced lung injury, although rare, may appear acutely, even within days after administration of this drug.

Acute Toxicity Study of Zerumbone-Loaded Nanostructured Lipid Carrier on BALB/c Mice Model

PubMed Central

Rahman, Heshu Sulaiman; Rasedee, Abdullah; Othman, Hemn Hassan; Chartrand, Max Stanley; Namvar, Farideh; Abdul Samad, Nozlena; Andas, Reena Joys; Ng, Kuan Beng; How, Chee Wun

2014-01-01

Zerumbone- (ZER-) loaded nanostructure lipid carrier (NLC) (ZER-NLC) prepared for its antileukemia effect in vitro was evaluated for its toxicological effects by observing changes in the liver, kidney, spleen, lung, heart, and brain tissues, serum biochemical parameters, total haemogram, and bone marrow stem cells. The acute toxicity study for ZER-NLC was conducted by orally treating BALB/c mice with a single dose with either water, olive oil, ZER, NLC, or ZER-NLC for 14 days. The animals were observed for clinical and behavioral abnormalities, toxicological symptoms, feed consumption, and gross appearance. The liver, kidney, heart, lung, spleen, and brain tissues were assessed histologically. Total haemogram was counted by hemocytometry and microhematocrit reader. Bone marrow examination in terms of cellular morphology was done by Wright staining with bone marrow smear. Furthermore, serum biochemical parameters were determined spectrophotometrically. Grossly all treated mice, their investigated tissues, serum biochemical parameters, total haemogram, and bone marrow were normal. At oral doses of 100 and 200 mg/kg ZER-NLC there was no sign of toxicity or mortality in BALB/c mice. This study suggests that the 50% lethal dose (LD50) of ZER-NLC is higher than 200 mg/kg, thus, safe by oral administration. PMID:25276798

Acute toxicity study of zerumbone-loaded nanostructured lipid carrier on BALB/c mice model.

PubMed

Rahman, Heshu Sulaiman; Rasedee, Abdullah; Othman, Hemn Hassan; Chartrand, Max Stanley; Namvar, Farideh; Yeap, Swee Keong; Abdul Samad, Nozlena; Andas, Reena Joys; Muhammad Nadzri, Nabilah; Anasamy, Theebaa; Ng, Kuan Beng; How, Chee Wun

2014-01-01

Zerumbone- (ZER-) loaded nanostructure lipid carrier (NLC) (ZER-NLC) prepared for its antileukemia effect in vitro was evaluated for its toxicological effects by observing changes in the liver, kidney, spleen, lung, heart, and brain tissues, serum biochemical parameters, total haemogram, and bone marrow stem cells. The acute toxicity study for ZER-NLC was conducted by orally treating BALB/c mice with a single dose with either water, olive oil, ZER, NLC, or ZER-NLC for 14 days. The animals were observed for clinical and behavioral abnormalities, toxicological symptoms, feed consumption, and gross appearance. The liver, kidney, heart, lung, spleen, and brain tissues were assessed histologically. Total haemogram was counted by hemocytometry and microhematocrit reader. Bone marrow examination in terms of cellular morphology was done by Wright staining with bone marrow smear. Furthermore, serum biochemical parameters were determined spectrophotometrically. Grossly all treated mice, their investigated tissues, serum biochemical parameters, total haemogram, and bone marrow were normal. At oral doses of 100 and 200 mg/kg ZER-NLC there was no sign of toxicity or mortality in BALB/c mice. This study suggests that the 50% lethal dose (LD50) of ZER-NLC is higher than 200 mg/kg, thus, safe by oral administration.

Acute toxicity and effects analysis of endosulfan sulfate to freshwater fish species.

PubMed

Carriger, John F; Hoang, Tham C; Rand, Gary M; Gardinali, Piero R; Castro, Joffre

2011-02-01

Endosulfan sulfate is a persistent environmental metabolite of endosulfan, an organochlorine insecticide-acaricide presently registered by the United States Environmental Protection Agency. There is, however, limited acute fish toxicity data for endosulfan sulfate. This study determines the acute toxicity (LC₅₀s and LC₁₀s) of endosulfan sulfate to three inland Florida native fish species (mosquitofish [Gambusia affinis]; least killifish [Heterandria formosa]; and sailfin mollies [Poecilia latipinna]) as well as fathead minnows (Pimephales promelas). Ninety-six-h acute toxicity tests were conducted with each fish species under flow-through conditions. For all of the above-mentioned fish species, 96-h LC₅₀ estimates ranged from 2.1 to 3.5 μg/L endosulfan sulfate. The 96-h LC₁₀ estimates ranged from 0.8 to 2.1 μg/L endosulfan sulfate. Of all of the fish tested, the least killifish appeared to be the most sensitive to endosulfan sulfate exposure. The above-mentioned data were combined with previous acute toxicity data for endosulfan sulfate and freshwater fish for an effects analysis. The effects analysis estimated hazardous concentrations expected to exceed 5, 10, and 50% of the fish species' acute LC₅₀ or LC₁₀ values (HC₅, HC₁₀, and HC₅₀). The endosulfan sulfate freshwater-fish acute tests were also compared with the available freshwater-fish acute toxicity data for technical endosulfan. Technical endosulfan is a mixture of α- and β-endosulfan. The LC₅₀s had a wider range for technical endosulfan, and their distribution produced a lower HC₁₀ than for endosulfan sulfate. The number of freshwater-fish LC₅₀s for endosulfan sulfate is much smaller than the number available for technical endosulfan, reflecting priorities in examining the toxicity of the parent compounds of pesticides. The toxicity test results and effects analyses provided acute effect values for endosulfan sulfate and freshwater fish that might be applied

Comparison of lung protective ventilation strategies in a rabbit model of acute lung injury.

PubMed

Rotta, A T; Gunnarsson, B; Fuhrman, B P; Hernan, L J; Steinhorn, D M

2001-11-01

To determine the impact of different protective and nonprotective mechanical ventilation strategies on the degree of pulmonary inflammation, oxidative damage, and hemodynamic stability in a saline lavage model of acute lung injury. A prospective, randomized, controlled, in vivo animal laboratory study. Animal research facility of a health sciences university. Forty-six New Zealand White rabbits. Mature rabbits were instrumented with a tracheostomy and vascular catheters. Lavage-injured rabbits were randomized to receive conventional ventilation with either a) low peak end-expiratory pressure (PEEP; tidal volume of 10 mL/kg, PEEP of 2 cm H2O); b) high PEEP (tidal volume of 10 mL/kg, PEEP of 10 cm H2O); c) low tidal volume with PEEP above Pflex (open lung strategy, tidal volume of 6 mL/kg, PEEP set 2 cm H2O > Pflex); or d) high-frequency oscillatory ventilation. Animals were ventilated for 4 hrs. Lung lavage fluid and tissue samples were obtained immediately after animals were killed. Lung lavage fluid was assayed for measurements of total protein, elastase activity, tumor necrosis factor-alpha, and malondialdehyde. Lung tissue homogenates were assayed for measurements of myeloperoxidase activity and malondialdehyde. The need for inotropic support was recorded. Animals that received a lung protective strategy (open lung or high-frequency oscillatory ventilation) exhibited more favorable oxygenation and lung mechanics compared with the low PEEP and high PEEP groups. Animals ventilated by a lung protective strategy also showed attenuation of inflammation (reduced tracheal fluid protein, tracheal fluid elastase, tracheal fluid tumor necrosis factor-alpha, and pulmonary leukostasis). Animals treated with high-frequency oscillatory ventilation had attenuated oxidative injury to the lung and greater hemodynamic stability compared with the other experimental groups. Both lung protective strategies were associated with improved oxygenation, attenuated inflammation, and

Targeting Extracellular Histones with Novel RNA Biodrugs for the Treatment of Acute Lung Injury

DTIC Science & Technology

2017-10-01

inactivate) circulating histones and prevent the morbidity and mortality associated with multiple organ dysfunction/ acute respiratory distress syndrome ...patients. 15. SUBJECT TERMS Acute lung injury (ALI), acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome , extracellular...are acute lung injury (ALI) from smoke/chlorine gas inhalation, burns, radiation , influenza and severe infection. Only recently have investigators

Performance of an automated electronic acute lung injury screening system in intensive care unit patients.

PubMed

Koenig, Helen C; Finkel, Barbara B; Khalsa, Satjeet S; Lanken, Paul N; Prasad, Meeta; Urbani, Richard; Fuchs, Barry D

2011-01-01

Lung protective ventilation reduces mortality in patients with acute lung injury, but underrecognition of acute lung injury has limited its use. We recently validated an automated electronic acute lung injury surveillance system in patients with major trauma in a single intensive care unit. In this study, we assessed the system's performance as a prospective acute lung injury screening tool in a diverse population of intensive care unit patients. Patients were screened prospectively for acute lung injury over 21 wks by the automated system and by an experienced research coordinator who manually screened subjects for enrollment in Acute Respiratory Distress Syndrome Clinical Trials Network (ARDSNet) trials. Performance of the automated system was assessed by comparing its results with the manual screening process. Discordant results were adjudicated blindly by two physician reviewers. In addition, a sensitivity analysis using a range of assumptions was conducted to better estimate the system's performance. The Hospital of the University of Pennsylvania, an academic medical center and ARDSNet center (1994-2006). Intubated patients in medical and surgical intensive care units. None. Of 1270 patients screened, 84 were identified with acute lung injury (incidence of 6.6%). The automated screening system had a sensitivity of 97.6% (95% confidence interval, 96.8-98.4%) and a specificity of 97.6% (95% confidence interval, 96.8-98.4%). The manual screening algorithm had a sensitivity of 57.1% (95% confidence interval, 54.5-59.8%) and a specificity of 99.7% (95% confidence interval, 99.4-100%). Sensitivity analysis demonstrated a range for sensitivity of 75.0-97.6% of the automated system under varying assumptions. Under all assumptions, the automated system demonstrated higher sensitivity than and comparable specificity to the manual screening method. An automated electronic system identified patients with acute lung injury with high sensitivity and specificity in diverse

Management of normal tissue toxicity associated with chemoradiation (primary skin, esophagus, and lung).

PubMed

Yazbeck, Victor Y; Villaruz, Liza; Haley, Marsha; Socinski, Mark A

2013-01-01

Nearly one quarter of patients with lung cancer present with locally advanced disease where concurrent chemoradiotherapy is the current standard of care for patients with good performance status. Cisplatin-based concurrent chemoradiotherapy consistently showed an improvement in survival compared with sequential chemoradiotherapy, at the expense of an increase in the toxicity profile. Over the past decades, several encouraging biomarkers such as transforming growth factor-beta and radioprotective agents such as amifostine were studied but without reaching approval for patient care. We reviewed the prevalence and risk factors for different adverse effects associated with the combined chemoradiotherapy modality, especially dermatitis, mucositis, esophagitis, and pneumonitis. These adverse effects can further be divided into acute, subacute, and chronic. Dermatitis is usually rare and responds well to topical steroids and usual skin care. Acute esophagitis occurs in 30% of patients and is treated with proton pump inhibitors, promotility agents, local anesthetic, and dietary changes. Radiation pneumonitis is a subacute complication seen in 15% of patients and is usually managed with steroids. Chronic adverse effects such as radiation fibrosis and esophageal stricture occur approximately 6 months after completion of radiation therapy and are usually permanent. In this review, complications of chemoradiotherapy for patients with locally advanced lung cancer are delineated, and approaches to their management are described. Given that treatment interruption is associated with a worse outcome, patients are aggressively treated with a curative intent. Therefore, planning for treatment adverse effects improves patient tolerance, compliance, and outcome.

Mechanisms of alveolar fibrosis after acute lung injury.

PubMed

Marinelli, W A; Henke, C A; Harmon, K R; Hertz, M I; Bitterman, P B

1990-12-01

In patients who die after severe acute lung injury, a dramatic fibroproliferative response occurs within the alveolar air space, interstitium, and microvessels. Profound shunt physiology, dead space ventilation, and pulmonary hypertension are the physiologic consequences of this fibroproliferative response. The anatomic pattern of the response is unique within each alveolar compartment. For example, the air space is obliterated by granulation tissue, with replicating mesenchymal cells, their connective tissue products, and an expanding network of intra-alveolar capillaries. In contrast, the vascular fibroproliferative response is dominated by mesenchymal cell replication and connective tissue deposition within the walls of microvessels. Despite the unique anatomic features of these fibroproliferative processes, the regulatory signals involved are likely to be similar. Although our current understanding of the signals regulating the fibroproliferative response to acute lung injury is limited, inferences can be made from in vitro studies of mesenchymal cell behavior and several better understood fibroproliferative processes, including wound healing and chronic fibrotic lung diseases. As clinicians, our future ability to enhance effective lung repair will likely utilize therapeutic strategies specifically targeted to the signals that regulate the fibroproliferative process within the alveolar microenvironment.

In vivo anti-psoriatic activity, biodistribution, sub-acute and sub-chronic toxicity studies of orally administered methotrexate loaded chitin nanogel in comparison with methotrexate tablet.

PubMed

Panonnummal, Rajitha; Jayakumar, R; Anjaneyan, Gopikrishnan; Sabitha, M

2018-04-15

The anti-psoriatic efficacy of orally administered methotrexate loaded chitin nanogel (MCNG) was evaluated (two doses- 2.715 mg/kg and 5.143 mg/kg) and compared against orally administered methotrexate tablet MTX (5.143 mg/kg). MCNG at both dose levels of 2.715 mg/kg and 5.143 mg/kg exhibited significant anti-psoriatic activity which is very much comparable with MTX, caused normalization of histological features and inflammatory score associated with induced psoriasis. Biodistribution studies revealed the presence of drug in serum and in vital organs at all the three cases with highest amount in MCNG at 5.143 mg/kg dose, followed by MTX tablet and are lowest in MCNG at 2.715 mg/kg dose. MCNG at the highest dose of 5.143 mg/kg caused liver, lung and kidney toxicities on sub acute toxicity studies and MTX tablet was found to be toxic on liver and lung on sub chronic toxicity studies. MCNG 2.715 mg/kg was found to be safe on both sub acute and sub chronic administrations, suggesting that it can provide sufficient serum and tissue level of methotrexate necessary to clear psoriatic lesions, without inducing systemic toxicity and expected to be a better alternative for orally administered conventional methotrexate tablet for patients who need systemic medications for psoriasis. Copyright © 2018. Published by Elsevier B.V.

Acute toxicity and associated mechanisms of four strobilurins in algae.

PubMed

Liu, Xiaoxu; Wang, Yu; Chen, Hao; Zhang, Junli; Wang, Chengju; Li, Xuefeng; Pang, Sen

2018-06-01

Strobilurins have been reported highly toxic to non-target aquatic organisms but few illustrated how they cause toxic effects on algae. This study investigated the acute toxicity of Kresoxim-methy (KRE), Pyraclostrobin (PYR), Trifloxystrobin (TRI) and Picoxystrobin (PIC) on two algae and their toxicity mechanisms. Four strobilurins showed lower toxic effects on Chlorella pyrenoidsa but higher on Chlorella vulgaris. bc1 complex activities in C. vulgaris were significantly inhibited by all strobilurins, suggesting bc 1 complex might be the target of strobilurin toxicity in algae. Moreover, SOD, CAT and POD activities were significantly up-regulated by all doses of KRE, PYR and PIC. In contrast, low concentrations of TRI stimulated SOD and POD activities but highest concentration significantly inhibited those activities. Comet assays showed damaged DNA in C. vulgaris by four strobulirins, suggesting their potential genotoxic threats to algae. The results illustrated acute toxicity by strobulirins on algae and their possible toxicity mechanisms. Copyright © 2018 Elsevier B.V. All rights reserved.

Accuracy of Chronic Aquatic Toxicity Estimates Determined from Acute Toxicity Data and Two Time–Response Models.

EPA Science Inventory

Traditionally, chronic toxicity in aquatic organisms and wildlife has been determined from either toxicity test data, acute to chronic ratios, or application of safety factors. A more recent alternative approach has been to estimate chronic toxicity by modeling the time course of...

Comparative acute toxicity of shale and petroleum derived distillates.

PubMed

Clark, C R; Ferguson, P W; Katchen, M A; Dennis, M W; Craig, D K

1989-12-01

In anticipation of the commercialization of its shale oil retorting and upgrading process, Unocal Corp. conducted a testing program aimed at better defining potential health impacts of a shale industry. Acute toxicity studies using rats and rabbits compared the effects of naphtha, Jet-A, JP-4, diesel and "residual" distillate fractions of both petroleum derived crude oils and hydrotreated shale oil. No differences in the acute oral (greater than 5 g/kg LD50) and dermal (greater than 2 g/kg LD50) toxicities were noted between the shale and petroleum derived distillates and none of the samples were more than mildly irritating to the eyes. Shale and petroleum products caused similar degrees of mild to moderate skin irritation. None of the materials produced sensitization reactions. The LC50 after acute inhalation exposure to Jet-A, shale naphtha, (greater than 5 mg/L) and JP-4 distillate fractions of petroleum and shale oils was greater than 5 mg/L. The LC50 of petroleum naphtha (greater than 4.8 mg/L) and raw shale oil (greater than 3.95 mg/L) also indicated low toxicity. Results demonstrate that shale oil products are of low acute toxicity, mild to moderately irritating and similar to their petroleum counterparts. The results further demonstrate that hydrotreatment reduces the irritancy of raw shale oil.

[Low dose volume histogram analysis of the lungs in prediction of acute radiation pneumonitis in patients with esophageal cancer treated with three-dimensional conformal radiotherapy].

PubMed

Shen, Wen-bin; Zhu, Shu-chai; Gao, Hong-mei; Li, You-mei; Liu, Zhi-kun; Li, Juan; Su, Jing-wei; Wan, Jun

2013-01-01

To investigate the predictive value of low dose volume of the lung on acute radiation pneumonitis (RP) in patients with esophageal cancer treated with three-dimensional conformal radiotherapy (3D-CRT) only, and to analyze the relation of comprehensive parameters of the dose-volume V5, V20 and mean lung dose (MLD) with acute RP. Two hundred and twenty-two patients with esophageal cancer treated by 3D-CRT have been followed up. The V5-V30 and MLD were calculated from the dose-volume histogram system. The clinical factors and treatment parameters were collected and analyzed. The acute RP was evaluated according to the RTOG toxicity criteria. The acute RP of grade 1, 2, 3 and 4 were observed in 68 (30.6%), 40 (18.0%), 8 (3.6%) and 1 (0.5%) cases, respectively. The univariate analysis of measurement data:The primary tumor length, radiation fields, MLD and lung V5-V30 had a significant relationship with the acute RP. The magnitude of the number of radiation fields, the volume of GTV, MLD and Lung V5-V30 had a significant difference in whether the ≥ grade 1 and ≥ grade 2 acute RP developed or not. Binary logistic regression analysis showed that MLD, Lung V5, V20 and V25 were independent risk factors of ≥ grade 1 acute RP, and the radiation fields, MLD and Lung V5 were independent risk factors of ≥ grade 2 acute RP. The ≥ grade 1 and ≥ grade 2 acute RP were significantly decreased when MLD less than 14 Gy, V5 and V20 were less than 60% and 28%,respectively. When the V20 ≤ 28%, the acute RP was significantly decreased in V5 ≤ 60% group. When the MLD was ≤ 14 Gy, the ≥ 1 grade acute RP was significantly decreased in the V5 ≤ 60% group. When the MLD was >14 Gy, the ≥ grade 2 acute RP was significantly decreased in the V5 ≤ 60% group. The low dose volume of the lung is effective in predicting radiation pneumonitis in patients with esophageal cancer treated with 3D-CRT only. The comprehensive parameters combined with V5, V20 and MLD may increase the

Is the fish embryo toxicity test (FET) with the zebrafish (Danio rerio) a potential alternative for the fish acute toxicity test?

PubMed

Lammer, E; Carr, G J; Wendler, K; Rawlings, J M; Belanger, S E; Braunbeck, Th

2009-03-01

The fish acute toxicity test is a mandatory component in the base set of data requirements for ecotoxicity testing. The fish acute toxicity test is not compatible with most current animal welfare legislation because mortality is the primary endpoint and it is often hypothesized that fish suffer distress and perhaps pain. Animal alternative considerations have also been incorporated into new European REACH regulations through strong advocacy for the reduction of testing with live animals. One of the most promising alternative approaches to classical acute fish toxicity testing with live fish is the fish embryo toxicity (FET) test. The FET has been a mandatory component in routine whole effluent testing in Germany since 2005 and has already been standardized at the international level. In order to analyze the applicability of the FET also in chemical testing, a comparative re-evaluation of both fish and fish embryo toxicity data was carried out for a total of 143 substances, and statistical approaches were developed to evaluate the correlation between fish and fish embryo toxicity data. Results confirm that fish embryo tests are neither better nor worse than acute fish toxicity tests and provide strong scientific support for the FET as a surrogate for the acute fish toxicity test.

The outcomes of children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference.

PubMed

Quasney, Michael W; López-Fernández, Yolanda M; Santschi, Miriam; Watson, R Scott

2015-06-01

To provide additional details and evidence behind the recommendations for outcomes assessment of patients with pediatric acute respiratory distress syndrome from the Pediatric Acute Lung Injury Consensus Conference. Consensus conference of experts in pediatric acute lung injury. A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The outcomes subgroup comprised four experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was used. The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, seven of which related to outcomes after pediatric acute respiratory distress syndrome. All seven recommendations had strong agreement. Children with acute respiratory distress syndrome continue to have a high mortality, specifically, in relation to certain comorbidities and etiologies related to pediatric acute respiratory distress syndrome. Comorbid conditions, such as an immunocompromised state, increase the risk of mortality even further. Likewise, certain etiologies, such as non-pulmonary sepsis, also place children at a higher risk of mortality. Significant long-term effects were reported in adult survivors of acute respiratory distress syndrome: diminished lung function and exercise tolerance, reduced quality of life, and diminished neurocognitive function. Little knowledge of long-term outcomes exists in children who survive pediatric acute respiratory distress syndrome. Characterization of the longer term consequences of pediatric acute respiratory distress syndrome in children is vital to help identify opportunities for improved therapeutic and rehabilitative strategies that will lessen the long-term burden of pediatric acute

Toxicity of Lunar Dust in Lungs Assessed by Examining Biomarkers in Exposed Mice

NASA Technical Reports Server (NTRS)

Lam, C.-W.; James, J. T.; Zeidler-Erdely, P. C.; Castranova, V.; Young, S. H.; Quan, C. L.; Khan-Mayberry, N.; Taylor, L. A.

2009-01-01

NASA plans to build an outpost on the Moon for prolonged human habitation and research. The lunar surface is covered by a layer of soil, of which the finest portion is highly reactive dust. NASA has invited NIOSH to collaboratively investigate the toxicity of lunar dust. Dust samples of respirable sizes were aerodynamically isolated from two lunar soil samples of different maturities (cosmic exposure ages) collected during the Apollo 16 mission. The lunar dust samples, titanium dioxide, or quartz, suspended in normal saline or in Survanta (a bovine lung surfactant), were given to groups of 5 mice (C-57 male) by intrapharyngeal aspiration at 1, 0.3, or 0.1 mg/mouse. The mice were euthanized 7 or 30 days later, and their lungs were lavaged to assess the toxicity biomarkers in bronchioalveolar lavage fluids. The acellular fractions were assayed for total proteins, lactate dehydrogenase activities, and cytokines; the cellular portions were assessed for total cell counts and cell differentials. Results from the high-dose groups showed that lunar dust, suspended in saline, was more toxic than TiO 2, but less toxic than quartz. Lunar dust particles aggregate and settle out rapidly in water or saline, but not in Survanta. Lunar dust suspended in Survanta manifested greater toxicity than lunar dust in saline. The increase in toxicity presumably was due to that Survanta gave a better particle dispersion in the lungs. The two lunar dust samples showed similar toxicity. The overall results showed that lunar dust is more toxic than TiO 2 but less toxic than quartz.

Model-based approach for quantitative estimates of skin, heart, and lung toxicity risk for left-side photon and proton irradiation after breast-conserving surgery.

PubMed

Tommasino, Francesco; Durante, Marco; D'Avino, Vittoria; Liuzzi, Raffaele; Conson, Manuel; Farace, Paolo; Palma, Giuseppe; Schwarz, Marco; Cella, Laura; Pacelli, Roberto

2017-05-01

Proton beam therapy represents a promising modality for left-side breast cancer (BC) treatment, but concerns have been raised about skin toxicity and poor cosmesis. The aim of this study is to apply skin normal tissue complication probability (NTCP) model for intensity modulated proton therapy (IMPT) optimization in left-side BC. Ten left-side BC patients undergoing photon irradiation after breast-conserving surgery were randomly selected from our clinical database. Intensity modulated photon (IMRT) and IMPT plans were calculated with iso-tumor-coverage criteria and according to RTOG 1005 guidelines. Proton plans were computed with and without skin optimization. Published NTCP models were employed to estimate the risk of different toxicity endpoints for skin, lung, heart and its substructures. Acute skin NTCP evaluation suggests a lower toxicity level with IMPT compared to IMRT when the skin is included in proton optimization strategy (0.1% versus 1.7%, p < 0.001). Dosimetric results show that, with the same level of tumor coverage, IMPT attains significant heart and lung dose sparing compared with IMRT. By NTCP model-based analysis, an overall reduction in the cardiopulmonary toxicity risk prediction can be observed for all IMPT compared to IMRT plans: the relative risk reduction from protons varies between 0.1 and 0.7 depending on the considered toxicity endpoint. Our analysis suggests that IMPT might be safely applied without increasing the risk of severe acute radiation induced skin toxicity. The quantitative risk estimates also support the potential clinical benefits of IMPT for left-side BC irradiation due to lower risk of cardiac and pulmonary morbidity. The applied approach might be relevant on the long term for the setup of cost-effectiveness evaluation strategies based on NTCP predictions.

Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

PubMed Central

Kawakami, Takao; Nagasaka, Keiko; Takami, Sachiko; Wada, Kazuya; Tu, Hsiao-Kun; Otsuji, Makiko; Kyono, Yutaka; Dobashi, Tae; Komatsu, Yasuhiko; Kihara, Makoto; Akimoto, Shingo; Peers, Ian S.; South, Marie C.; Higenbottam, Tim; Fukuoka, Masahiro; Nakata, Koichiro; Ohe, Yuichiro; Kudoh, Shoji; Clausen, Ib Groth; Nishimura, Toshihide; Marko-Varga, György; Kato, Harubumi

2011-01-01

Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control. PMID:21799770

Acute Exacerbation in Interstitial Lung Disease

PubMed Central

Leuschner, Gabriela; Behr, Jürgen

2017-01-01

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has been defined as an acute, clinically significant deterioration that develops within less than 1 month without obvious clinical cause like fluid overload, left heart failure, or pulmonary embolism. Pathophysiologically, damage of the alveoli is the predominant feature of AE-IPF which manifests histopathologically as diffuse alveolar damage and radiologically as diffuse, bilateral ground-glass opacification on high-resolution computed tomography. A growing body of literature now focuses on acute exacerbations of interstitial lung disease (AE-ILD) other than idiopathic pulmonary fibrosis. Based on a shared pathophysiology it is generally accepted that AE-ILD can affect all patients with interstitial lung disease (ILD) but apparently occurs more frequently in patients with an underlying usual interstitial pneumonia pattern. The etiology of AE-ILD is not fully understood, but there are distinct risk factors and triggers like infection, mechanical stress, and microaspiration. In general, AE-ILD has a poor prognosis and is associated with a high mortality within 6–12 months. Although there is a lack of evidence based data, in clinical practice, AE-ILD is often treated with a high dose corticosteroid therapy and antibiotics. This article aims to provide a summary of the clinical features, diagnosis, management, and prognosis of AE-ILD as well as an update on the current developments in the field. PMID:29109947

Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity.

PubMed

Zhang, Qi; Pan, Jing; North, Paula E; Yang, Shoua; Lubet, Ronald A; Wang, Yian; You, Ming

2012-05-01

3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer.

CMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantation.

PubMed

Roux, Antoine; Mourin, Gisèle; Fastenackels, Solène; Almeida, Jorge R; Iglesias, Maria Candela; Boyd, Anders; Gostick, Emma; Larsen, Martin; Price, David A; Sacre, Karim; Douek, Daniel C; Autran, Brigitte; Picard, Clément; Miranda, Sandra de; Sauce, Delphine; Stern, Marc; Appay, Victor

2013-07-01

Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection. Copyright © 2013 Elsevier Inc. All rights reserved.

In vitro cytotoxicity testing of 30 reference chemicals to predict acute human and animal toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barile, F.A.; Arjun, S.; Borges, L.

1991-03-11

This study was conducted in cooperation with the Scandinavian Society of Cell Toxicology, as part of the Multicenter Evaluation for In Vitro Cytotoxicity (MEIC), and was designed to develop an in vitro model for predicting acute human and animal toxicity. The technique relies on the ability of cultured transformed rat lung epithelial cells (L2) to incorporate radiolabled amino acids into newly synthesized proteins in the absence or presence of increasing doses of the test chemical, during a 24-hr incubation. IC50 values were extrapolated from the dose-response curves after linear regression analysis. Human toxic blood concentrations estimated from rodent LD50 valuesmore » suggest that our experimental IC50's are in close correlation with the former. Validation of the data by the MEIC committee shows that our IC50 values predicted human lethal dosage as efficient as rodent LD50's. It is anticipated that this and related procedures may supplement or replace currently used animal protocols for predicting human toxicity.« less

OECD validation study to assess intra- and inter-laboratory reproducibility of the zebrafish embryo toxicity test for acute aquatic toxicity testing.

PubMed

Busquet, François; Strecker, Ruben; Rawlings, Jane M; Belanger, Scott E; Braunbeck, Thomas; Carr, Gregory J; Cenijn, Peter; Fochtman, Przemyslaw; Gourmelon, Anne; Hübler, Nicole; Kleensang, André; Knöbel, Melanie; Kussatz, Carola; Legler, Juliette; Lillicrap, Adam; Martínez-Jerónimo, Fernando; Polleichtner, Christian; Rzodeczko, Helena; Salinas, Edward; Schneider, Katharina E; Scholz, Stefan; van den Brandhof, Evert-Jan; van der Ven, Leo T M; Walter-Rohde, Susanne; Weigt, Stefan; Witters, Hilda; Halder, Marlies

2014-08-01

The OECD validation study of the zebrafish embryo acute toxicity test (ZFET) for acute aquatic toxicity testing evaluated the ZFET reproducibility by testing 20 chemicals at 5 different concentrations in 3 independent runs in at least 3 laboratories. Stock solutions and test concentrations were analytically confirmed for 11 chemicals. Newly fertilised zebrafish eggs (20/concentration and control) were exposed for 96h to chemicals. Four apical endpoints were recorded daily as indicators of acute lethality: coagulation of the embryo, lack of somite formation, non-detachment of the tail bud from the yolk sac and lack of heartbeat. Results (LC50 values for 48/96h exposure) show that the ZFET is a robust method with a good intra- and inter-laboratory reproducibility (CV<30%) for most chemicals and laboratories. The reproducibility was lower (CV>30%) for some very toxic or volatile chemicals, and chemicals tested close to their limit of solubility. The ZFET is now available as OECD Test Guideline 236. Considering the high predictive capacity of the ZFET demonstrated by Belanger et al. (2013) in their retrospective analysis of acute fish toxicity and fish embryo acute toxicity data, the ZFET is ready to be considered for acute fish toxicity for regulatory purposes. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Respiratory infections and acute lung injury in systemic illness.

PubMed

Skerrett, S J; Niederman, M S; Fein, A M

1989-12-01

syndrome and identified how it may lead to lung injury, usually by indirect means, through activation of inflammatory mediators that are carried to the lung via the vasculature. Although it is frequently impossible to predict which specific patient with systemic sepsis will develop acute lung injury, the current state of knowledge does permit us to identify high-risk individuals. Surprisingly, clinical assessment rather than biochemical testing is the best predictor of the development of acute lung injury. Patients with severe injury, profound shock and multiple systemic insults are most prone to acute lung injury in the presence of systemic sepsis.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of high airway pressure and dynamic strain on ventilator-induced lung injury in a heterogeneous acute lung injury model.

PubMed

Jain, Sumeet V; Kollisch-Singule, Michaela; Satalin, Joshua; Searles, Quinn; Dombert, Luke; Abdel-Razek, Osama; Yepuri, Natesh; Leonard, Antony; Gruessner, Angelika; Andrews, Penny; Fazal, Fabeha; Meng, Qinghe; Wang, Guirong; Gatto, Louis A; Habashi, Nader M; Nieman, Gary F

2017-12-01

Acute respiratory distress syndrome causes a heterogeneous lung injury with normal and acutely injured lung tissue in the same lung. Improperly adjusted mechanical ventilation can exacerbate ARDS causing a secondary ventilator-induced lung injury (VILI). We hypothesized that a peak airway pressure of 40 cmH 2 O (static strain) alone would not cause additional injury in either the normal or acutely injured lung tissue unless combined with high tidal volume (dynamic strain). Pigs were anesthetized, and heterogeneous acute lung injury (ALI) was created by Tween instillation via a bronchoscope to both diaphragmatic lung lobes. Tissue in all other lobes was normal. Airway pressure release ventilation was used to precisely regulate time and pressure at both inspiration and expiration. Animals were separated into two groups: (1) over-distension + high dynamic strain (OD + H DS , n = 6) and (2) over-distension + low dynamic strain (OD + L DS , n = 6). OD was caused by setting the inspiratory pressure at 40 cmH 2 O and dynamic strain was modified by changing the expiratory duration, which varied the tidal volume. Animals were ventilated for 6 h recording hemodynamics, lung function, and inflammatory mediators followed by an extensive necropsy. In normal tissue (N T ), OD + L DS caused minimal histologic damage and a significant reduction in BALF total protein (p < 0.05) and MMP-9 activity (p < 0.05), as compared with OD + H DS . In acutely injured tissue (ALI T ), OD + L DS resulted in reduced histologic injury and pulmonary edema (p < 0.05), as compared with OD + H DS . Both N T and ALI T are resistant to VILI caused by OD alone, but when combined with a H DS , significant tissue injury develops.

The role of innate immunity in acute allograft rejection after lung transplantation.

PubMed

Palmer, Scott M; Burch, Lauranell H; Davis, R Duane; Herczyk, Walter F; Howell, David N; Reinsmoen, Nancy L; Schwartz, David A

2003-09-15

Although innate immunity is crucial to pulmonary host defense and can initiate immune and inflammatory responses independent of adaptive immunity, it remains unstudied in the context of transplant rejection. To investigate the role of innate immunity in the development of allograft rejection, we assessed the impact of two functional polymorphisms in the toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness on the development of acute rejection after human lung transplantation. Patients and donors were screened for the TLR4 Asp299Gly and Thr399Ile polymorphisms by polymerase chain reaction using sequence-specific primers. The rate of acute rejection at 6 months was significantly reduced in recipients, but not in donors, with the Asp299Gly or Thr399Ile alleles as compared with wild type (29 vs. 56%, respectively, p = 0.05). This association was confirmed in Cox proportional hazards and multivariate logistic regression models. Our results suggest activation of innate immunity in lung transplant recipients through TLR4 contributes to the development acute rejection after lung transplantation. Therapies directed at inhibition of innate immune responses mediated by TLR4 may represent a novel and effective means to prevent acute rejection after lung transplantation.

Nrf2-dependent protection against acute sodium arsenite toxicity in zebrafish

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fuse, Yuji; Nguyen, Vu Thanh; Kobayashi, Makoto, E

Transcription factor Nrf2 induces a number of detoxifying enzymes and antioxidant proteins to confer protection against the toxic effects of a diverse range of chemicals including inorganic arsenicals. Although a number of studies using cultured cells have demonstrated that Nrf2 has a cell-protective function against acute and high-dose arsenic toxicity, there is no clear in vivo evidence of this effect. In the present study, we genetically investigated the protective role of Nrf2 against acute sodium arsenite toxicity using the zebrafish Nrf2 mutant, nrf2a{sup fh318}. After treatment with 1 mM sodium arsenite, the survival of nrf2a{sup fh318} larvae was significantly shortermore » than that of wild-type siblings, suggesting that Nrf2 protected the zebrafish larvae against high-dose arsenite exposure. To understand the molecular basis of the Nrf2-dependent protection, we analyzed the gene expression profiles after arsenite exposure, and found that the genes involved in the antioxidative function (prdx1 and gclc), arsenic metabolism (gstp1) and xenobiotic elimination (abcc2) were induced in an Nrf2-dependent manner. Furthermore, pre-treatment with sulforaphane, a well-known Nrf2 activator improved the survival of zebrafish larvae after arsenic exposure. Based on these results, we concluded that Nrf2 plays a fundamental and conserved role in protection against acute sodium arsenite toxicity. - Highlights: • The role of Nrf2 under arsenite exposure was valuated using zebrafish. • Nrf2 mutant zebrafish was highly sensitive to acute arsenic toxicity. • Nrf2 induced anti-arsenic genes in response to arsenite. • Sulforaphane attenuated arsenic toxicity through Nrf2 activation. • Nrf2 system plays an important role in the defense against acute arsenic toxicity.« less

Outcomes of stereotactic body radiotherapy (SBRT) treatment of multiple synchronous and recurrent lung nodules.

PubMed

Owen, Dawn; Olivier, Kenneth R; Mayo, Charles S; Miller, Robert C; Nelson, Kathryn; Bauer, Heather; Brown, Paul D; Park, Sean S; Ma, Daniel J; Garces, Yolanda I

2015-02-18

Stereotactic body radiotherapy (SBRT) is evolving into a standard of care for unresectable lung nodules. Local control has been shown to be in excess of 90% at 3 years. However, some patients present with synchronous lung nodules in the ipsilateral or contralateral lobe or metasynchronous disease. In these cases, patients may receive multiple courses of lung SBRT or a single course for synchronous nodules. The toxicity of such treatment is currently unknown. Between 2006 and 2012, 63 subjects with 128 metasynchronous and synchronous lung nodules were treated at the Mayo Clinic with SBRT. Demographic patient data and dosimetric data regarding SBRT treatments were collected. Acute toxicity (defined as toxicity < 90 days) and late toxicity (defined as toxicity > = 90 days) were reported and graded as per standardized CTCAE 4.0 criteria. Local control, progression free survival and overall survival were also described. The median age of patients treated was 73 years. Sixty five percent were primary or recurrent lung cancers with the remainder metastatic lung nodules of varying histologies. Of 63 patients, 18 had prior high dose external beam radiation to the mediastinum or chest. Dose and fractionation varied but the most common prescriptions were 48 Gy/4 fractions, 54 Gy/3 fractions, and 50 Gy/5 fractions. Only 6 patients demonstrated local recurrence. With a median follow up of 12.6 months, median SBRT specific overall survival and progression free survival were 35.7 months and 10.7 months respectively. Fifty one percent (32/63 patients) experienced acute toxicity, predominantly grade 1 and 2 fatigue. One patient developed acute grade 3 radiation pneumonitis at 75 days. Forty six percent (29/63 patients) developed late effects. Most were grade 1 dyspnea. There was one patient with grade 5 pneumonitis. Multiple courses of SBRT and SBRT delivery after external beam radiotherapy appear to be feasible and safe. Most toxicity was grade 1 and 2 but the risk was

Assessment of N-acetylcysteine as a therapy for phosgene-induced acute lung injury.

PubMed

Rendell, Rachel; Fairhall, Sarah; Graham, Stuart; Rutter, Steve; Auton, Philippa; Smith, Adam; Perrott, Rosi; Jugg, Bronwen

2018-06-15

The toxic industrial chemical (TIC 1 ) phosgene remains an important chemical intermediate in many industrial processes. Inhalation of phosgene can cause an acute lung injury (ALI) which, in severe cases may result in death. There are currently no effective pharmacological therapies or evidence-based treatment guidelines for managing exposed individuals. N-acetylcysteine (NAC) is a commercially available drug licensed in the UK and elsewhere for the treatment of paracetamol (acetaminophen) overdose. It has a number of mechanisms of action which may provide therapeutic benefit for the treatment of phosgene-induced ALI. It has previously been shown to provide therapeutic efficacy against the lung damaging effects of sulfur mustard vapour exposure, when given by the inhaled route, in the pig (Jugg et al., 2013). Our research objective was to determine whether inhaled NAC might also be therapeutic for other chemicals, in this case, phosgene. This study has demonstrated that multiple nebulised doses, administered from 30 min after exposure of terminally anaesthetised pigs to phosgene, is not an effective therapy when administered at the times and doses employed in this study. There remains no pharmacological treatment for phosgene-induced lung injury. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

[Acute toxicity analysis performance of CellSense biosensor with E. coli].

PubMed

Wang, Xue-Jiang; Wang, Hong; Zhao, Jian-Fu; Xia, Si-Qing; Zhao, Hong-Ning

2009-04-15

E. coli microbial electrodes for CellSense biosensor were prepared by polycarbonate membrane immobilization process, and their performance for heavy metals and toxic organic compounds acute toxicity determination were studied. The results showed that when E. coli was in logarithmic and stationary phase, the CellSense biosensor with E. coli showed good performance in heavy metal ions and organic pollutants acute toxicity analysis, when E. coli was in its decline phase, the stability and sensitivity of the CellSense biosensor was poor. The EC50 values of Hg2+, Cu2+, Zn2+, o-chlorophenol (2-CP) and p-nitrophenol (4-NP) detected by CellSense biosensor with E. coli were 0.6, 3.1, 5.8, 180 and 94 microg/mL, respectively. The immobilized E. coli electrodes could still suit for acute toxicity assessment after 2 months storage at 4 degrees C.

Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy.

PubMed

Singh, Anurag K; Lockett, Mary Ann; Bradley, Jeffrey D

2003-02-01

To evaluate the incidence and clinical/dosimetric predictors of acute and late Radiation Therapy Oncology Group Grade 3-5 esophageal toxicity in patients with non-small-cell lung cancer (NSCLC) treated with definitive three-dimensional conformal radiotherapy (3D-CRT). We retrospectively reviewed the charts of 207 consecutive patients with NSCLC who were treated with high-dose, definitive 3D-CRT between March 1991 and December 1998. This population consisted of 107 men and 100 women. The median age was 67 years (range 31-90). The following patient and treatment parameters were studied: age, gender, race, performance status, sequential chemotherapy, concurrent chemotherapy, presence of subcarinal nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy. All doses are reported without heterogeneity corrections. The median prescription dose to the isocenter in this population was 70 Gy (range 60-74) delivered in 2-Gy daily fractions. All patients were treated once daily. Acute and late esophageal toxicities were graded by Radiation Therapy Oncology Group criteria. Patient and clinical/dosimetric factors were coded and correlated with acute and late Grade 3-5 esophageal toxicity using univariate and multivariate regression analyses. Of 207 patients, 16 (8%) developed acute (10 patients) or late (13 patients) Grade 3-5 esophageal toxicity. Seven patients had both acute and late Grade 3-5 esophageal toxicity. One patient died (Grade 5 esophageal toxicity) of late esophageal perforation. Concurrent chemotherapy, maximal point dose to the esophagus >58 Gy, and a mean dose to the entire esophagus >34 Gy were significantly associated with a risk of Grade 3-5 esophageal toxicity on univariate analysis. Concurrent chemotherapy and maximal point dose to the esophagus >58 Gy retained significance on multivariate analysis. Of 207 patients, 53 (26%) received concurrent

Toxic Inhalational Injury-Associated Interstitial Lung Disease in Children

PubMed Central

Lee, Eun; Seo, Ju-Hee; Kim, Hyung Young; Yu, Jinho; Jhang, Won-Kyoung; Park, Seong-Jong; Kwon, Ji-Won; Kim, Byoung-Ju; Do, Kyung-Hyun; Cho, Young Ah; Kim, Sun-A; Jang, Se Jin

2013-01-01

Interstitial lung disease in children (chILD) is a group of disorders characterized by lung inflammation and interstitial fibrosis. In the past recent years, we noted an outbreak of child in Korea, which is possibly associated with inhalation toxicity. Here, we report a series of cases involving toxic inhalational injury-associated chILD with bronchiolitis obliterans pattern in Korean children. This study included 16 pediatric patients confirmed by lung biopsy and chest computed tomography, between February 2006 and May 2011 at Asan Medical Center Children's Hospital. The most common presenting symptoms were cough and dyspnea. The median age at presentation was 26 months (range: 12-47 months), with high mortality (44%). Histopathological analysis showed bronchiolar destruction and centrilobular distribution of alveolar destruction by inflammatory and fibroproliferative process with subpleural sparing. Chest computed tomography showed ground-glass opacities and consolidation in the early phase and diffuse centrilobular nodular opacity in the late phase. Air leak with severe respiratory difficulty was associated with poor prognosis. Although respiratory chemicals such as humidifier disinfectants were strongly considered as a cause of this disease, further studies are needed to understand the etiology and pathophysiology of the disease to improve the prognosis and allow early diagnosis and treatment. PMID:23772158

Safety assessment of hydroethanolic rambutan rind extract: acute and sub-chronic toxicity studies.

PubMed

Thinkratok, Aree; Suwannaprapha, Parin; Srisawat, Rungrudee

2014-10-01

This study evaluated the safety of rambutan rind extract (RRE) in male Wistar rats. While acute toxicity was evaluated by feeding the rats with single doses of RRE (1000, 2000, 3000, 4000, and 5000 mg/kg) and its sub-chronic toxicity was observed in rats orally administered with RRE (500, 1000, and 2000 mg/kg) daily for 30 days. In acute toxicity study, the LD50 was found to be greater than 5000 mg/kg of RRE. In sub-chronic toxicity study, no mortality and sign of toxicity was found up to 1000 mg/kg/day of RRE. At 2000 mg/kg/day dose, the mortality rate was 12.5%. Significant decreases in body weight gain and food consumption were found in both acute and sub-chronic toxicity studies. In acute toxicity study, all the studied doses of RRE did not alter serum levels of triglyceride (TG), aspartate aminotransferase (AST) andalanine aminotransferase (ALT). In sub-chronic toxicity study, all studied doses of RRE significantly decreased plasma levels of TG and blood urea nitrogen, but did not alter plasma levels of AST and ALT. TC levels did not show any significant change in both the studies. The obtained results provide basic information for in vivo experimental studies of the pharmacological potentiality of RRE.

Acute toxicity value extrapolation with fish and aquatic invertebrates

USGS Publications Warehouse

Buckler, Denny R.; Mayer, Foster L.; Ellersieck, Mark R.; Asfaw, Amha

2005-01-01

Assessment of risk posed by an environmental contaminant to an aquatic community requires estimation of both its magnitude of occurrence (exposure) and its ability to cause harm (effects). Our ability to estimate effects is often hindered by limited toxicological information. As a result, resource managers and environmental regulators are often faced with the need to extrapolate across taxonomic groups in order to protect the more sensitive members of the aquatic community. The goals of this effort were to 1) compile and organize an extensive body of acute toxicity data, 2) characterize the distribution of toxicant sensitivity across taxa and species, and 3) evaluate the utility of toxicity extrapolation methods based upon sensitivity relations among species and chemicals. Although the analysis encompassed a wide range of toxicants and species, pesticides and freshwater fish and invertebrates were emphasized as a reflection of available data. Although it is obviously desirable to have high-quality acute toxicity values for as many species as possible, the results of this effort allow for better use of available information for predicting the sensitivity of untested species to environmental contaminants. A software program entitled “Ecological Risk Analysis” (ERA) was developed that predicts toxicity values for sensitive members of the aquatic community using species sensitivity distributions. Of several methods evaluated, the ERA program used with minimum data sets comprising acute toxicity values for rainbow trout, bluegill, daphnia, and mysids provided the most satisfactory predictions with the least amount of data. However, if predictions must be made using data for a single species, the most satisfactory results were obtained with extrapolation factors developed for rainbow trout (0.412), bluegill (0.331), or scud (0.041). Although many specific exceptions occur, our results also support the conventional wisdom that invertebrates are generally more

Effect of Ergothioneine on Acute Lung Injury and Inflammation in Cytokine Insufflated Rats

PubMed Central

Repine, John E.; Elkins, Nancy D.

2012-01-01

Objective The Acute Respiratory Distress Syndrome (ARDS), the most severe form of Acute Lung Injury (ALI), is a highly-fatal, diffuse non-cardiogenic edematous lung disorder. The pathogenesis of ARDS is unknown but lung inflammation and lung oxidative stress are likely contributing factors. Since no specific pharmacologic intervention exists for ARDS, our objective was to determine the effect of treatment with ergothioneine---a safe agent with multiple anti-inflammatory and antioxidant properties on the development of lung injury and inflammation in rats insufflated with cytokines found in lung lavages of ARDS patients. Method Sprague-Dawley rats (3-10/group) were given 15 mg/kg or 150 mg/kg L-ergothioneine intravenously 1 hour before or 18 hours after cytokine (IL-1 and IFNγ) insufflation. Lung injury (lavage LDH levels) and lung inflammation (lavage neutrophil numbers) were measured 24 hours after cytokine insufflation. Results Ergothioneine pre- and post- treatment generally decreased lung injury and lung inflammation in cytokine insufflated rats. Conclusion Ergothioneine should be considered for additional testing as a potential therapy for treating and preventing ARDS. PMID:22197759

Treatment of acute lung injury by targeting MG53-mediated cell membrane repair

PubMed Central

Lieber, Gissela; Nishi, Miyuki; Yan, Rosalie; Wang, Zhen; Yao, Yonggang; Li, Yu; Whitson, Bryan A.; Duann, Pu; Li, Haichang; Zhou, Xinyu; Zhu, Hua; Takeshima, Hiroshi; Hunter, John C.; McLeod, Robbie L.; Weisleder, Noah; Zeng, Chunyu; Ma, Jianjie

2014-01-01

Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischemia-reperfusion and over-ventilation induced injury to the lung when compared with wild type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases. PMID:25034454

Acute Exacerbations and Lung Function Loss in Smokers with and without Chronic Obstructive Pulmonary Disease.

PubMed

Dransfield, Mark T; Kunisaki, Ken M; Strand, Matthew J; Anzueto, Antonio; Bhatt, Surya P; Bowler, Russell P; Criner, Gerard J; Curtis, Jeffrey L; Hanania, Nicola A; Nath, Hrudaya; Putcha, Nirupama; Roark, Sarah E; Wan, Emily S; Washko, George R; Wells, J Michael; Wendt, Christine H; Make, Barry J

2017-02-01

Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown. To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up. We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV 1 decline based on reported exacerbations or acute respiratory events. In subjects with COPD, exacerbations were associated with excess FEV 1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV 1 decline. Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease

Emodin ameliorates acute lung injury induced by severe acute pancreatitis through the up-regulated expressions of AQP1 and AQP5 in lung.

PubMed

Xu, Junfeng; Huang, Bo; Wang, Yu; Tong, Caiyu; Xie, Peng; Fan, Rong; Gao, Zhenming

2016-11-01

The present study investigates the ameliorating effects of emodin on acute lung injury (ALI) induced by severe acute pancreatitis (SAP). An ALI rat model was constructed by sodium ursodeoxycholate and they were divided into four groups: SHAM, ALI, emodin and dexamethasone (DEX) (n=24 per group). Blood samples and lung tissues were collected 6, 12 and 24 hours after the induction of SAP-associated ALI. Lung wet/dry ratio, blood gases, serum amylase and tumor necrosis factor-α (TNF-α) were measured at each time point. The expressions of AQP1 and AQP5 in lung tissue were detected by immunohistochemical staining, western blotting and real-time PCR. As the results show, there were no statistical differences in the levels of serum amylase, lung wet/dry ratio, blood gases indexes, serum TNF-α and pathological changes between emodin and DEX groups. However, significant differences were observed when compared with the ALI group. AQP1 and AQP5 expressions were significantly increased and lung oedemas were alleviated with the treatment of emodin and DEX. The expressions of AQP1 and AQP5 were significantly decreased in SAP-associated ALI rats. Emodin up-regulated the expression of AQP1 and AQP5, it could reduce pulmonary oedema and ameliorate SAP-induced ALI. Regulations on AQP1 and AQP5 expression had a great value in clinical application. © 2016 John Wiley & Sons Australia, Ltd.

DETERMINANTS OF VARIABILITY IN ACUTE TO CHRONIC TOXICITY RATIOS IN AQUATIC INVERTEBRATES AND FISH

EPA Science Inventory

Variability in acute to chronic ratios (ACRs; LC50/chronic value) has been a continuing interest in aquatic toxicology because of the reliance on ACRs to estimate chronic toxicity for chemicals and species with known acute toxicity but limited or no information on sublethal toxic...

Safety and Tolerability of SBRT after High-Dose External Beam Radiation to the Lung

PubMed Central

Owen, Dawn; Olivier, Kenneth R.; Song, Limin; Mayo, Charles S.; Miller, Robert C.; Nelson, Kathryn; Bauer, Heather; Brown, Paul D.; Park, Sean S.; Ma, Daniel J.; Garces, Yolanda I.

2015-01-01

Purpose: Stereotactic body radiotherapy (SBRT) is commonly used to treat unresectable lung nodules. Given its relative safety and effective local control, SBRT has also been used to treat recurrent lung nodules after high-dose external beam radiation (EBRT) to the lung. The toxicity of such treatment is unknown. Methods and Materials: Between 2006 and 2012, 18 subjects at the Mayo Clinic with 27 recurrent lung nodules were treated with SBRT after receiving EBRT to the lung. Median local control, overall survival, and progression-free survival (PFS) were described. Acute toxicity and late toxicity (defined as toxicity ≥ and >90 days, respectively) were reported and graded as per standardized CTCAE 4.0 criteria. Results: The median age of patients treated was 68 years. Fifteen patients had recurrent lung cancer as their primary histology. Twelve patients received ≥60 Gy of conventional EBRT prior to SBRT. SBRT dose and fractionation varied; the most common prescriptions were 48 Gy/4, 54 Gy/3, and 50 Gy/5 fractions. Only four patients had SBRT planning target volumes (PTVs) that overlapped more than 50% of their prior EBRT PTV. Two patients developed local recurrence following SBRT. With a median follow up of 21.2 months, median SBRT-specific overall survival and PFS were 21.7 and 12.3 months, respectively. No grade ≥3 acute or late toxicities were noted. Conclusion: Stereotactic body radiotherapy may be a good salvage option for select patients with recurrent lung nodules following definitive EBRT to the chest. Toxicity is minimal and local control is excellent. PMID:25642416

Amniotic fluid stem cells from EGFP transgenic mice attenuate hyperoxia-induced acute lung injury.

PubMed

Wen, Shih-Tao; Chen, Wei; Chen, Hsiao-Ling; Lai, Cheng-Wei; Yen, Chih-Ching; Lee, Kun-Hsiung; Wu, Shinn-Chih; Chen, Chuan-Mu

2013-01-01

High concentrations of oxygen aggravate the severity of lung injury in patients requiring mechanical ventilation. Although mesenchymal stem cells have been shown to effectively attenuate various injured tissues, there is limited information regarding a role for amniotic fluid stem cells (AFSCs) in treating acute lung injury. We hypothesized that intravenous delivery of AFSCs would attenuate lung injury in an experimental model of hyperoxia-induced lung injury. AFSCs were isolated from EGFP transgenic mice. The in vitro differentiation, surface markers, and migration of the AFSCs were assessed by specific staining, flow cytometry, and a co-culture system, respectively. The in vivo therapeutic potential of AFSCs was evaluated in a model of acute hyperoxia-induced lung injury in mice. The administration of AFSCs significantly reduced the hyperoxia-induced pulmonary inflammation, as reflected by significant reductions in lung wet/dry ratio, neutrophil counts, and the level of apoptosis, as well as reducing the levels of inflammatory cytokine (IL-1β, IL-6, and TNF-α) and early-stage fibrosis in lung tissues. Moreover, EGFP-expressing AFSCs were detected and engrafted into a peripheral lung epithelial cell lineage by fluorescence microscopy and DAPI stain. Intravenous administration of AFSCs may offer a new therapeutic strategy for acute lung injury (ALI), for which efficient treatments are currently unavailable.

The acute toxicity of local anesthetics.

PubMed

Mather, Laurence E

2010-11-01

Systemic toxicity, usually from overdose or intravascular dose, is feared because it mainly affects the heart and brain, and may be acutely life-threatening. Pharmacological studies of local anesthetic toxicity have largely been reviewed primarily relating to the evaluation of ropivacaine and levobupivacaine during the past decade. This review/opinion focuses more on the principles and concepts underlying the main models used, from chemical pharmacological and pharmacokinetic perspectives. Research models required to produce pivotal toxicity data are discussed. The potencies for neural blockade and systemic toxicity are associated across virtually all models, with some deviations through molecular stereochemistry. These models show that all local anesthetics can produce direct cardiovascular system toxicity and CNS excitotoxicity that may further affect the cardiovascular system response. Whereas the longer-acting local anesthetics are more likely to cause cardiac death by malignant arrhythmias, the shorter-acting agents are more likely to cause cardiac contraction failure. In most models, equi-anesthetic doses of ropivacaine and levobupivacaine are less likely to produce serious toxicity than bupivacaine. Of the various models, this reviewer favors a whole-body large animal preparation because of the comprehensive data collection possible. The conscious sheep preparation has contributed more than any other, and may be regarded as the de facto 'standard' experimental model for concurrent study of local anesthetic toxicity ± pharmacokinetics, using experimental designs that can reproduce the toxicity seen in clinical accidents.

Adoptive transfer of acute lung injury.

PubMed

Moxley, M A; Baird, T L; Corbett, J A

2000-11-01

In this study, we describe a novel adoptive transfer protocol to study acute lung injury in the rat. We show that bronchoalveolar lavage (BAL) cells isolated from rats 5 h after intratracheal administration of lipopolysaccharide (LPS) induce a lung injury when transferred to normal control recipient rats. This lung injury is characterized by increased alveolar-arterial oxygen difference and extravasation of Evans blue dye (EBD) into lungs of recipient rats. Recipient rats receiving similar numbers of donor cells isolated from healthy rats do not show adverse changes in the alveolar-arterial oxygen difference or in extravasation of EBD. The adoptive transfer-induced lung injury is associated with increased numbers of neutrophils in the BAL, the levels of which are similar to the numbers observed in BAL cells isolated from rats treated for 5 h with LPS. As an indicator of BAL cell activation, donor BAL cell inducible nitric oxide synthase (iNOS) expression was compared with BAL cell iNOS expression 48 h after adoptive transfer. BAL cells isolated 5 h after LPS administration expressed iNOS immediately after isolation. In contrast, BAL cells isolated 48 h after adoptive transfer did not express iNOS immediately after isolation but expressed iNOS following a 24-h ex vivo culture. These findings indicate that the activation state of donor BAL cells differs from BAL cells isolated 48 h after adoptive transfer, suggesting that donor BAL cells may stimulate migration of new inflammatory cells into the recipient rats lungs.

PREDICTING CHRONIC TOXICITY OF CHEMICALS TO FISHES FROM ACUTE TOXICITY TEST DATA: CONCEPT AND LINEAR REGRESSION

EPA Science Inventory

A comprehensive approach to predicting chronic toxicity from acute.toxicity data was developed in which simultaneous consideration is given to concentration, degree of response, and time course of effect. onsistent endpoint (lethality) and degree of response (O%) were used to com...

Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

PubMed Central

Gralinski, Lisa E.; Bankhead, Armand; Jeng, Sophia; Menachery, Vineet D.; Proll, Sean; Belisle, Sarah E.; Matzke, Melissa; Webb-Robertson, Bobbie-Jo M.; Luna, Maria L.; Shukla, Anil K.; Ferris, Martin T.; Bolles, Meagan; Chang, Jean; Aicher, Lauri; Waters, Katrina M.; Smith, Richard D.; Metz, Thomas O.; Law, G. Lynn; Katze, Michael G.; McWeeney, Shannon; Baric, Ralph S.

2013-01-01

ABSTRACT Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. PMID:23919993

Study on acute toxicity of compound coggygria oral liquid

NASA Astrophysics Data System (ADS)

Su, Feng; Wen, Zhonghua; Sun, Jianhua; Hao, Shaojun; Xie, Guoqi; Li, Xianyu; Zhang, Zhengchen

2018-04-01

To observe the effect of compound oral liquid on acute toxicity of mice cotinus coggygria. Forty mice were randomly divided into two groups: compound Cotinus coggygria oral solution group and blank control group, 20 rats in each group, half male and half female. The mice fasted for 12 hours. Coggygria oral liquid concentrated solution. In the blank control group, normal saline was administered at the maximum volume of 0.4ml/10 g. The mice were given normal diet for 4 consecutive times in 1st, each time at intervals of 6 hours. On the day of administration, the mice in each group were observed continuously after administration and after administration. Observe continuously for 3 hours, observe every hour thereafter. Fast on the 13th day 12 hours, weigh the mice on the 14th day, then kill the mice, dissect the mice. During the observation period of 14 days after administration, there was no death in mice. The activity of mice decreased slightly after initial administration, decreased after the second and third administration, and generally returned to normal after 2h of administration. No abnormalities of heart, liver, spleen, lung, kidney, stomach, brain and so on were observed. Conclusion: the oral toxicity of compound Cotinus coggygria is very small. In 1st, the mice did not die, and the cumulative maximum tolerance dose was 320ml/kg per day, which was 320 times of the clinical dosage.

[Lung Abscess with Acute Empyema Which Improved after Performing by Video Assissted Thoracic Surgery( Including Pneumonotomy and Lung Abscess Drainage);Report of a Case].

PubMed

Gabe, Atsushi; Nagamine, Naoji

2017-05-01

We herein report the case of a patient demonstrating a lung abscess with acute empyema which improved after performing pnemumonotomy and lung abscess drainage. A 60-year-old male was referred to our hospital to receive treatment for a lung abscess with acute empyema. At surgery, the lung parenchyma was slightly torn with pus leakage. After drainage of lung abscess by enlarging the injured part, curettage in the thoracic cavity and decortication were performed. The postoperative course was uneventful. Direct drainage of an abscess into the thoracic cavity is thought to be a choice for the treatment of lung abscesses.

Acute Toxicity Grade 3 and 4 After Irradiation in Children and Adolescents: Results From the IPPARCA Collaboration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pixberg, Caroline; Koch, Raphael; Eich, Hans Theodor, E-mail: Hans.Eich@ukmuenster.de

Purpose: In the context of oncologic therapy for children, radiation therapy is frequently indicated. This study identified the frequency of and reasons for the development of high-grade acute toxicity and possible sequelae. Materials and Methods: Irradiated children have been prospectively documented since 2001 in the Registry for the Evaluation of Side Effects After Radiation in Childhood and Adolescence (RiSK) database in Germany and since 2008 in the registry for radiation therapy toxicity (RADTOX) in Sweden. Data were collected using standardized, published forms. Toxicity classification was based on Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Results: Asmore » of June 2013, 1500 children have been recruited into the RiSK database and 485 into the RADTOX registry leading to an analysis population of 1359 patients (age range 0-18). A total of 18.9% (n=257) of all investigated patients developed high-grade acute toxicity (grades 3/4). High-grade toxicity of the bone marrow was documented for 63.8% (n=201) of those patients, oral mucositis for 7.6% (n=24), and dermatitis for 7.6% (n=24). Patients with high-grade acute toxicity received concomitant chemotherapy more frequently (56%) than patients with no or lower acute toxicity (31.5%). In multivariate analyses, concomitant chemotherapy, diagnosis of Ewing sarcoma, and total radiation dose showed a statistically noticeable effect (P≤.05) on acute toxicity, whereas age, concomitant chemotherapy, Hodgkin lymphoma, Ewing sarcoma, total radiation dose, and acute toxicity influenced the time until maximal late toxicity. Conclusions: Generally, high-grade acute toxicity after irradiation in children and adolescence occurs in a moderate proportion of patients (18.9%). As anticipated, the probability of acute toxicity appeared to depend on the prescribed dose as well as concomitant chemotherapy. The occurrence of chronic toxicity correlates with the prior

THE 5-LIPOXYGENASE PATHWAY IS REQUIRED FOR ACUTE LUNG INJURY FOLLOWING HEMORRHAGIC SHOCK

PubMed Central

Eun, John C.; Moore, Ernest E.; Mauchley, David C.; Johnson, Chris A.; Meng, Xianzhong; Banerjee, Anirban; Wohlauer, Max V.; Zarini, Simona; Gijón, Miguel A.; Murphy, Robert C.

2012-01-01

The cellular and biochemical mechanisms leading to acute lung injury and subsequent multiple organ failure are only partially understood. In order to study the potential role of eicosanoids, particularly leukotrienes, as possible mediators of acute lung injury, we used a murine experimental model of acute lung injury induced by hemorrhagic shock after blood removal via cardiac puncture. Neutrophil sequestration as shown by immunofluorescence, and protein leakage into the alveolar space, were measured as markers of injury. We used liquid chromatography coupled to tandem mass spectrometry to unequivocally identify several eicosanoids in the bronchoalveolar lavage fluid of experimental animals. MK886, a specific inhibitor of the 5-lipoxygenase pathway, as well as transgenic mice deficient in 5-lipoxygenase, were used to determine the role of this enzymatic pathway in this model. Leukotriene B4 and leukotriene C4 were consistently elevated in shock-treated mice compared to sham-treated mice. MK886 attenuated neutrophil infiltration and protein extravasation induced by hemorrhagic shock. 5-lipoxygenase-deficient mice showed reduced neutrophil infiltration and protein extravasation after shock treatment, indicating greatly reduced lung injury. These results support the hypothesis that 5-lipoxygenase, most likely through the generation of leukotrienes, plays an important role in the pathogenesis of acute lung injury induced by hemorrhagic shock in mice. This pathway could represent a new target for pharmacological intervention to reduce lung damage following severe primary injury. PMID:22392149

Acute Vilazodone Toxicity in a Pediatric Patient.

PubMed

Acker, Emily C; Sinclair, Elizabeth A; Beardsley, Andrew L; Ahmed, Sheikh S; Froberg, Blake A

2015-09-01

Vilazodone is a selective serotonin reuptake inhibitor and 5HT1A agonist recently approved to treat depression in adults. To date, there are minimal data available regarding the expected course and treatment of acute vilazodone ingestions. We report a case of a previously healthy 19-month-old girl who presented after an acute ingestion of an estimated 37 mg/kg vilazodone. She was taken to an outside emergency department approximately 1 h after an unwitnessed ingestion. Initially, the patient was noted to have decreased responsiveness, sluggish but reactive pupils, altered mental status, and reported seizure activity. She was given intravenous lorazepam for seizure control, intubated, and transferred to a pediatric tertiary care facility, where she continued to show signs of serotonin toxicity and received treatment with benzodiazepines and cyproheptadine. Despite vilazodone's long half-life and the large amount ingested, the patient was extubated within 10 h of presentation, had returned to baseline mental status by 22 h, and was discharged home approximately 57 h after ingestion. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Accidental ingestions are common in the pediatric population. Emergency physicians need to be aware of the signs and symptoms of acute medication toxicities, the expected clinical course, and the necessary supportive measures used to treat these patients. Because vilazodone is a recently approved medication, there is little experience with acute vilazodone ingestions. This report considerably increases the understanding of vilazodone's effects in the setting of an acute ingestion. Copyright © 2015 Elsevier Inc. All rights reserved.

Acute and chronic toxicity of boron to a variety of freshwater organisms.

PubMed

Soucek, David J; Dickinson, Amy; Koch, Brian T

2011-08-01

Boron enters the aquatic environment from various sources, including weathering of borates, sewage effluents, coal combustion, use of cleaning compounds, and agrochemicals. The present study was designed to generate data on acute and chronic boron toxicity in support of an update of water quality standards in Illinois, USA. We examined the acute toxicity of boron to eight different freshwater organisms including a fish, an insect, two crustaceans, and four bivalve mollusks. To our knowledge, this is the first study to present data on the toxicity of boron to freshwater mollusks. We also sought to clarify whether hardness or pH affect boron toxicity to aquatic life, and to quantify chronic effect levels in two freshwater species. Sensitivity among the various species ranged widely, with the fathead minnow (Pimephales promelas) being the most sensitive. Neither pH nor hardness had a consistent effect on acute boron toxicity to two crustaceans (Ceriodaphnia dubia and Hyalella azteca), but we observed evidence that chloride reduces boron toxicity to H. azteca. The fathead minnow, while more acutely sensitive than the other species, had a lower acute to chronic ratio than did H. azteca, which had reduced reproduction at 13 mg/L. While we do not know the extent to which the eight tested species represent the range of sensitivities of native but untested species in Illinois, the current water quality standard for Illinois (1 mg/L) is conservative with regard to the native species tested thus far. Copyright © 2011 SETAC.

Development of an acute toxicity test with the tropical marine amphipod Parhyale hawaiensis.

PubMed

Artal, Mariana Coletty; Dos Santos, Amanda; Henry, Theodore Burdick; Umbuzeiro, Gisela de Aragão

2018-03-01

There is a lack of suitable tropical marine species for ecotoxicity tests. An attractive model organism for ecotoxicology is the marine amphipod Parhyale hawaiensis, which is already a model for genetic and developmental studies. This species is widespread, can tolerate changes in salinity, is easy to handle and is representative of circumtropical regions. The aim of this work was to describe standardized procedures for laboratory husbandry, define conditions for acute toxicity tests, and to provide acute toxicity test results for some reference toxicants. Culturing conditions for the organism in the laboratory were established in reconstituted seawater (30 ± 2 salinity), 24 ± 2 °C, photoperiod 12/12 h light/dark. Acute toxicity test procedures were developed for 96 h-exposure time, and organisms at ages <7 days. The miniaturized version of the test, based on 96-well microplates and 200 µL of exposure media provided consistent results compared to larger exposure volumes (80-mL vials protocol). Acute toxicity of Ag, Cd, Cu, Zn and ammonia determined for P. hawaiensis were consistent to previous results for other marine amphipods. We conclude that P. hawaiensis can be successfully cultured in standardized conditions and be effectively used in acute toxicity testing. Further development and use of this model will enable standardized and reproducible ecotoxicology investigations in understudied and vulnerable tropical marine ecosystems.

An evaluation of acute toxicity of colloidal silver nanoparticles.

PubMed

Maneewattanapinyo, Pattwat; Banlunara, Wijit; Thammacharoen, Chuchaat; Ekgasit, Sanong; Kaewamatawong, Theerayuth

2011-11-01

Tests for acute oral toxicity, eye irritation, corrosion and dermal toxicity of colloidal silver nanoparticles (AgNPs) were conducted in laboratory animals following OECD guidelines. Oral administration of AgNPs at a limited dose of 5,000 mg/kg produced neither mortality nor acute toxic signs throughout the observation period. Percentage of body weight gain of the mice showed no significant difference between control and treatment groups. In the hematological analysis, there was no significant difference between mice treated with AgNPs and controls. Blood chemistry analysis also showed no differences in any of the parameter examined. There was neither any gross lesion nor histopathological change observed in various organs. The results indicated that the LD(50) of colloidal AgNPs is greater than 5,000 mg/kg body weight. In acute eye irritation and corrosion study, no mortality and toxic signs were observed when various doses of colloidal AgNPs were instilled in guinea pig eyes during 72 hr observation period. However, the instillation of AgNPs at 5,000 ppm produced transient eye irritation during early 24 hr observation time. No any gross abnormality was noted in the skins of the guinea pigs exposed to various doses of colloidal AgNPs. In addition, no significant AgNPs exposure relating to dermal tissue changes was observed microscopically. In summary, these findings of all toxicity tests in this study suggest that colloidal AgNPs could be relatively safe when administered to oral, eye and skin of the animal models for short periods of time.

Potential Application of Viral Empty Capsids for the Treatment of Acute Lung Injury/Acute Respiratory Distress Syndrome

DTIC Science & Technology

2016-07-01

Particles (VLPs). The rationale is based on the beneficial effect of SV40 VLPs on an Acute Kidney Injury (AKI) model in mice, previously demonstrated...signaling which, as was demonstrated, protect mice kidneys from apoptosis, necrosis and consequent damage induced by a toxic (mercury) insult, increasing...recombinant VP1, without any genetic material. Using a mouse model for toxic Acute Kidney Injury (AKI), we demonstrated that systemic

Imbalanced immune responses involving inflammatory molecules and immune-related pathways in the lung of acute and subchronic arsenic-exposed mice.

PubMed

Li, Jinlong; Zhao, Lu; Zhang, Yang; Li, Wei; Duan, Xiaoxu; Chen, Jinli; Guo, Yuanyuan; Yang, Shan; Sun, Guifan; Li, Bing

2017-11-01

Inorganic arsenic has been claimed to increase the risk of pulmonary diseases through ingestion, as opposed to inhalation, which makes it a unique and intriguing environmental toxicant. However, the immunotoxic effects of lung, one of the targets of arsenic exposure, have not been extensively investigated in vivo. In the present study, we first confirmed that 2.5, 5 and 10mg/kg NaAsO 2 orally for 24h dose-dependently triggered the infiltration of neutrophils, lymphocytes and macrophages in BALF. Not only the transcription activity, but also the secretion of proinflammatory cytokines IL-1β, IL-6 and TNF-α were consistently raised in the lung and BALF of acute arsenic-exposed mice. Acute oral administration of NaAsO 2 also raised pulmonary MPO activity and mRNA levels of chemokine Mip-2 and Mcp-1. Meanwhile, obvious histopathological damages with inflammatory cells infiltration and erythrocyte aggregation around the capillaries were verified in the lung of mice drank arsenic-rich water freely for 3 months. Furthermore, we affirmed notable disturbance of CD4 + T-cell differentiation in the lung of acute arsenic-exposed mice, as demonstrated by up-regulated mRNA levels of regulator Gata3 and cytokine Il-4 of Th2, enhanced Foxp3 and Il-10 of Treg, down-regulated T-bet and Ifn-γ of Th1, as well as lessened Ror-γt and Il-23 of Th17. However, impressive elevation of cytokine Ifn-γ and Il-23, as well as moderate enhancement of Il-4 and Il-10 were found in the lung by subchronic arsenic administration. Finally, our present study demonstrated that both a single and sustained arsenic exposure prominently increased the expression of immune-related p38, JNK, ERK1/2 and NF-κB proteins in the lung tissue. While disrupting the pulmonary redox homeostasis by increasing MDA levels, exhausting GSH and impaired enzyme activities of CAT and GSH-Px, antioxidant regulator NRF2 and its downstream targets HO-1 and GSTO1/2 were also up-regulated by both acute and subchronic arsenic

Alternative approaches for identifying acute systemic toxicity: Moving from research to regulatory testing.

PubMed

Hamm, Jon; Sullivan, Kristie; Clippinger, Amy J; Strickland, Judy; Bell, Shannon; Bhhatarai, Barun; Blaauboer, Bas; Casey, Warren; Dorman, David; Forsby, Anna; Garcia-Reyero, Natàlia; Gehen, Sean; Graepel, Rabea; Hotchkiss, Jon; Lowit, Anna; Matheson, Joanna; Reaves, Elissa; Scarano, Louis; Sprankle, Catherine; Tunkel, Jay; Wilson, Dan; Xia, Menghang; Zhu, Hao; Allen, David

2017-06-01

Acute systemic toxicity testing provides the basis for hazard labeling and risk management of chemicals. A number of international efforts have been directed at identifying non-animal alternatives for in vivo acute systemic toxicity tests. A September 2015 workshop, Alternative Approaches for Identifying Acute Systemic Toxicity: Moving from Research to Regulatory Testing, reviewed the state-of-the-science of non-animal alternatives for this testing and explored ways to facilitate implementation of alternatives. Workshop attendees included representatives from international regulatory agencies, academia, nongovernmental organizations, and industry. Resources identified as necessary for meaningful progress in implementing alternatives included compiling and making available high-quality reference data, training on use and interpretation of in vitro and in silico approaches, and global harmonization of testing requirements. Attendees particularly noted the need to characterize variability in reference data to evaluate new approaches. They also noted the importance of understanding the mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Workshop breakout groups explored different approaches to reducing or replacing animal use for acute toxicity testing, with each group crafting a roadmap and strategy to accomplish near-term progress. The workshop steering committee has organized efforts to implement the recommendations of the workshop participants. Copyright © 2017 Elsevier Ltd. All rights reserved.

Alternative Approaches for Identifying Acute Systemic Toxicity: Moving from Research to Regulatory Testing

PubMed Central

Hamm, Jon; Sullivan, Kristie; Clippinger, Amy J.; Strickland, Judy; Bell, Shannon; Bhhatarai, Barun; Blaauboer, Bas; Casey, Warren; Dorman, David; Forsby, Anna; Garcia-Reyero, Natàlia; Gehen, Sean; Graepel, Rabea; Hotchkiss, Jon; Lowit, Anna; Matheson, Joanna; Reaves, Elissa; Scarano, Louis; Sprankle, Catherine; Tunkel, Jay; Wilson, Dan; Xia, Menghang; Zhu, Hao; Allen, David

2017-01-01

Acute systemic toxicity testing provides the basis for hazard labeling and risk management of chemicals. A number of international efforts have been directed at identifying non-animal alternatives for in vivo acute systemic toxicity tests. A September 2015 workshop, Alternative Approaches for Identifying Acute Systemic Toxicity: Moving from Research to Regulatory Testing, reviewed the state-of-the-science of non-animal alternatives for this testing and explored ways to facilitate implementation of alternatives. Workshop attendees included representatives from international regulatory agencies, academia, nongovernmental organizations, and industry. Resources identified as necessary for meaningful progress in implementing alternatives included compiling and making available high-quality reference data, training on use and interpretation of in vitro and in silico approaches, and global harmonization of testing requirements. Attendees particularly noted the need to characterize variability in reference data to evaluate new approaches. They also noted the importance of understanding the mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Workshop breakout groups explored different approaches to reducing or replacing animal use for acute toxicity testing, with each group crafting a roadmap and strategy to accomplish near-term progress. The workshop steering committee has organized efforts to implement the recommendations of the workshop participants. PMID:28069485

[The influnence of dachengqi tang on acute lung injury and intra abdominal hypertension in rats with acute pancreatitis].

PubMed

Wan, Mei-Hua; Li, Juan; Tang, Wen-Fu; Gong, Han-Lin; Chen, Guang-Yuan; Xue, Ping; Zhao, Xian-Lin; Xia, Qing

2011-09-01

To test the hypothesis "lung and large intestine are interior exteriorly related" through investgating into the effect of Dacheng qi tang (DCQT) on intra abdominal hypertension (IAH) and acute lung injury (ALI) in rats with acute pancreatitis. Male SD rats were randomly divided into three groups with ten rats for each group: rats with sham-operations (SO); rats with acute necrosis pancreatitis (ANP); rats with ANP plus DCQT treatment. ANP was induced by retrograde infusion of 5% taurocholic acid into pancreatic duct. Two hours after operations, 10 mL/kg of normal saline was orally adminstered to the rats in both SO and ANP groups, whereas 10 mL/kg DCQT was adminstered to the rats in the treatment group. Aterial blood, pancreas and lung tissues were collected for biomarkers and histopathology 24 hours after operations. Intra-abdominal pressure and intestinal propulsion rate were also measured. RESULTS; DCQT treatment reduced intra-abdominal pressure and improved intestinal propulsion rate compared with those treated with saline (P < 0.05). The ANP rats treated with DCQT had lower wet to dry weight ratio, and milder myeloperoxidase activity and histopathology changes in pancreas and lung than those treated with saline (P < 0.05). Higher pressure of oxygen (PO2) was found in the rats treated with DCQT, while no difference in PCO2 was found between the DCQT and ANP groups (P > 0.05). Only two rats in the ANP group died. DCQT can effectively relieve IAH and cure ALI at the same time in rats with acute pancreatitis. The result provides evidence to support the hypothesis "lung and large intestine are interior exteriorly related".

SU-E-J-149: Establishing the Relationship Between Pre-Treatment Lung Ventilation, Dose, and Toxicity Outcome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mistry, N; D'Souza, W; Sornsen de Koste, J

2014-06-01

Purpose: Recently, there has been an interest in incorporating functional information in treatment planning especially in thoracic tumors. The rationale is that healthy lung regions need to be spared from radiation if possible to help achieve better control on toxicity. However, it is still unclear whether high functioning regions need to be spared or have more capacity to deal with the excessive radiation as compared to the compromised regions of the lung. Our goal with this work is to establish the tools by which we can establish a relationship between pre-treatment lung function, dose, and radiographic outcomes of lung toxicity.more » Methods: Treatment planning was performed using a single phase of a 4DCT scan, and follow-up anatomical CT scans were performed every 3 months for most patients. In this study, we developed the pipeline of tools needed to analyze such a large dataset, while trying to establish a relationship between function, dose, and outcome. Pre-treatment lung function was evaluated using a recently published technique that evaluates Fractional Regional Ventilation (FRV). All images including the FRV map and the individual follow-up anatomical CT images were all spatially matched to the planning CT using a diffusion based Demons image registration algorithm. Change in HU value was used as a metric to capture the effects of lung toxicity. To validate the findings, a radiologist evaluated the follow-up anatomical CT images and scored lung toxicity. Results: Initial experience in 1 patient shows a relationship between the pre-treatment lung function, dose and toxicity outcome. The results are also correlated to the findings by the radiologist who was blinded to the analysis or dose. Conclusion: The pipeline we have established to study this enables future studies in large retrospective studies. However, the tools are dependent on the fidelity of 4DCT reconstruction for accurate evaluation of regional ventilation. Patent Pending for the technique

Effects of Physalis peruviana L on Toxicity and Lung Cancer Induction by Nicotine Derived Nitrosamine Ketone in Rats.

PubMed

El-Kenawy, Ayman El-Meghawry; Elshama, Said Said; Osman, Hosam-Eldin Hussein

2015-01-01

Nicotine-derived nitrosamine ketone (NNK) is considered a key tobacco smoke carcinogen inducing lung tumors. Physalis peruviana L (harankash) is considered one plant with marked health benefits. This study aimed to evaluate Physalis peruviana L effect on the toxic effect of NNK induced lung cancer in the rats by using pulmonary histopathological, immunohistochemical and DNA flow cytometric analyses. Sixty adult male rats were divided into four groups, each consisting of fifteen animals. The first group received saline, the second received two successive toxic doses of NNK only while the third received two successive toxic doses of NNK with a single daily dose of Physalis peruviana L. The fourth group received a single daily dose of Physalis peruviana L only. Toxic doses of NNK induced hyperplasia and adenocarcinoma in the lung and positive immunoreactivity for Ki-67 and p53 staining with disturbance of the lung DNA content. Administration of Physalis peruviana L with NNK led to a mild pulmonary hyperplasia and weak expression of Ki-67 and p53 with an improvement in the lung DNA content. Physalis peruviana L may protect against NNK induced lung carcinogenesis due to its antioxidant and anti-proliferative effects.

Mesenchymal Stem Cells From Bone Marrow, Adipose Tissue, and Lung Tissue Differentially Mitigate Lung and Distal Organ Damage in Experimental Acute Respiratory Distress Syndrome.

PubMed

Silva, Johnatas D; Lopes-Pacheco, Miquéias; Paz, Ana H R; Cruz, Fernanda F; Melo, Elga B; de Oliveira, Milena V; Xisto, Débora G; Capelozzi, Vera L; Morales, Marcelo M; Pelosi, Paolo; Cirne-Lima, Elizabeth; Rocco, Patricia R M

2018-02-01

Mesenchymal stem cells-based therapies have shown promising effects in experimental acute respiratory distress syndrome. Different mesenchymal stem cells sources may result in diverse effects in respiratory diseases; however, there is no information regarding the best source of mesenchymal stem cells to treat pulmonary acute respiratory distress syndrome. We tested the hypothesis that mesenchymal stem cells derived from bone marrow, adipose tissue, and lung tissue would lead to different beneficial effects on lung and distal organ damage in experimental pulmonary acute respiratory distress syndrome. Animal study and primary cell culture. Laboratory investigation. Seventy-five Wistar rats. Wistar rats received saline (control) or Escherichia coli lipopolysaccharide (acute respiratory distress syndrome) intratracheally. On day 2, acute respiratory distress syndrome animals were further randomized to receive saline or bone marrow, adipose tissue, or lung tissue mesenchymal stem cells (1 × 10 cells) IV. Lung mechanics, histology, and protein levels of inflammatory mediators and growth factors were analyzed 5 days after mesenchymal stem cells administration. RAW 264.7 cells (a macrophage cell line) were incubated with lipopolysaccharide followed by coculture or not with bone marrow, adipose tissue, and lung tissue mesenchymal stem cells (10 cells/mL medium). Regardless of mesenchymal stem cells source, cells administration improved lung function and reduced alveolar collapse, tissue cellularity, collagen, and elastic fiber content in lung tissue, as well as decreased apoptotic cell counts in liver. Bone marrow and adipose tissue mesenchymal stem cells administration also reduced levels of tumor necrosis factor-α, interleukin-1β, keratinocyte-derived chemokine, transforming growth factor-β, and vascular endothelial growth factor, as well as apoptotic cell counts in lung and kidney, while increasing expression of keratinocyte growth factor in lung tissue

Mesenchymal Stem Cell Derived Secretome and Extracellular Vesicles for Acute Lung Injury and Other Inflammatory Lung Diseases

PubMed Central

Monsel, Antoine; Zhu, Ying-gang; Gudapati, Varun; Lim, Hyungsun; Lee, Jae W.

2017-01-01

Introduction Acute respiratory distress syndrome is a major cause of respiratory failure in critically ill patients. Despite extensive research into its pathophysiology, mortality remains high. No effective pharmacotherapy exists. Based largely on numerous preclinical studies, administration of mesenchymal stem or stromal cell (MSC) as a therapeutic for acute lung injury holds great promise, and clinical trials are currently underway. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, remains unresolved. Accumulating evidence now suggest that novel cell-free therapies including MSC-derived conditioned medium and extracellular vesicles released from MSCs might constitute compelling alternatives. Areas covered The current review summarizes the preclinical studies testing MSC conditioned medium and/or MSC extracellular vesicles as treatment for acute lung injury and other inflammatory lung diseases. Expert opinion While certain logistical obstacles limit the clinical applications of MSC conditioned medium such as the volume required for treatment, the therapeutic application of MSC extracellular vesicles remains promising, primarily due to ability of extracellular vesicles to maintain the functional phenotype of the parent cell. However, utilization of MSC extracellular vesicles will require large-scale production and standardization concerning identification, characterization and quantification. PMID:27011289

A Challenging Case of Acute Mercury Toxicity

PubMed Central

Alghoula, Faysal; Holewinski, Christopher

2018-01-01

Background Mercury exists in multiple forms: elemental, organic, and inorganic. Its toxic manifestations depend on the type and magnitude of exposure. The role of colonoscopic decompression in acute mercury toxicity is still unclear. We present a case of acute elemental mercury toxicity secondary to mercury ingestion, which markedly improved with colonoscopic decompression. Clinical Case A 54-year-old male presented to the ED five days after ingesting five ounces (148 cubic centimeters) of elemental mercury. Examination was only significant for a distended abdomen. Labs showed elevated serum and urine mercury levels. An abdominal radiograph showed radiopaque material throughout the colon. Succimer and laxatives were initiated. The patient had recurrent bowel movements, and serial radiographs showed interval decrease of mercury in the descending colon with interval increase in the cecum and ascending colon. Colonoscopic decompression was done successfully. The colon was evacuated, and a repeat radiograph showed decreased hyperdense material in the colon. Three months later, a repeat radiograph showed no hyperdense material in the colon. Conclusion Ingested elemental mercury can be retained in the colon. Although there are no established guidelines for colonoscopic decompression, our patient showed significant improvement. We believe further studies on this subject are needed to guide management practices. PMID:29559996

Zebrafish (Danio rerio) Models To Assess Acute, Developmental, And Neurodevelopmental Toxicity

EPA Science Inventory

Zebrafish (Danio rerio) acute, developmental, and neurodevelopmental model systems have been developed to assess both known and unknown environmental contaminants. Developmental toxicity is assessed using death and dysmorphology as endpoints, whereas neurodevelopmental toxicity ...

Prevalidation of an Acute Inhalation Toxicity Test Using the EpiAirway In Vitro Human Airway Model.

PubMed

Jackson, George R; Maione, Anna G; Klausner, Mitchell; Hayden, Patrick J

2018-06-01

Introduction: Knowledge of acute inhalation toxicity potential is important for establishing safe use of chemicals and consumer products. Inhalation toxicity testing and classification procedures currently accepted within worldwide government regulatory systems rely primarily on tests conducted in animals. The goal of the current work was to develop and prevalidate a nonanimal ( in vitro ) test for determining acute inhalation toxicity using the EpiAirway™ in vitro human airway model as a potential alternative for currently accepted animal tests. Materials and Methods: The in vitro test method exposes EpiAirway tissues to test chemicals for 3 hours, followed by measurement of tissue viability as the test endpoint. Fifty-nine chemicals covering a broad range of toxicity classes, chemical structures, and physical properties were evaluated. The in vitro toxicity data were utilized to establish a prediction model to classify the chemicals into categories corresponding to the currently accepted Globally Harmonized System (GHS) and the Environmental Protection Agency (EPA) system. Results: The EpiAirway prediction model identified in vivo rat-based GHS Acute Inhalation Toxicity Category 1-2 and EPA Acute Inhalation Toxicity Category I-II chemicals with 100% sensitivity and specificity of 43.1% and 50.0%, for GHS and EPA acute inhalation toxicity systems, respectively. The sensitivity and specificity of the EpiAirway prediction model for identifying GHS specific target organ toxicity-single exposure (STOT-SE) Category 1 human toxicants were 75.0% and 56.5%, respectively. Corrosivity and electrophilic and oxidative reactivity appear to be the predominant mechanisms of toxicity for the most highly toxic chemicals. Conclusions: These results indicate that the EpiAirway test is a promising alternative to the currently accepted animal tests for acute inhalation toxicity.

Consensus Modeling of Oral Rat Acute Toxicity

EPA Science Inventory

An acute toxicity dataset (oral rat LD50) with about 7400 compounds was compiled from the ChemIDplus database. This dataset was divided into a modeling set and a prediction set. The compounds in the prediction set were selected so that they were present in the modeling set used...

Targeting Extracellular Histones with Novel RNA Bio drugs for the Treatment of Acute Lung Injury

DTIC Science & Technology

2017-10-01

organ involved in MODS is the lung (referred to as acute respiratory distress syndrome or ARDS). Trauma, smoke inhalation, burns, radiation , severe...and mortality associated with multiple organ dysfunction/ acute respiratory distress syndrome (MODS/ARDS) and ALI that can be easily delivered in combat...MODS, the risk of death is 40%. The most common organ involved in MODS is the lungs (referred to as acute respiratory distress syndrome or ARDS

An interspecies correlation model to predict acute dermal toxicity of plant protection products to terrestrial life stages of amphibians using fish acute toxicity and bioconcentration data.

PubMed

Weltje, Lennart; Janz, Philipp; Sowig, Peter

2017-12-01

This paper presents a model to predict acute dermal toxicity of plant protection products (PPPs) to terrestrial amphibian life stages from (regulatory) fish data. By combining existing concepts, including interspecies correlation estimation (ICE), allometric relations, lethal body burden (LBB) and bioconcentration modelling, an equation was derived that predicts the amphibian median lethal dermal dose (LD 50 ) from standard acute toxicity values (96-h LC 50 ) for fish and bioconcentration factors (BCF) in fish. Where possible, fish BCF values were corrected to 5% lipid, and to parent compound. Then, BCF values were adjusted to an exposure duration of 96 h, in case steady state took longer to be achieved. The derived correlation equation is based on 32 LD 50 values from acute dermal toxicity experiments with 15 different species of anuran amphibians, comprising 15 different PPPs. The developed ICE model can be used in a screening approach to estimate the acute risk to amphibian terrestrial life stages from dermal exposures to PPPs with organic active substances. This has the potential to reduce unnecessary testing of vertebrates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus.

PubMed

Schmiegelow, Kjeld; Attarbaschi, Andishe; Barzilai, Shlomit; Escherich, Gabriele; Frandsen, Thomas Leth; Halsey, Christina; Hough, Rachael; Jeha, Sima; Kato, Motohiro; Liang, Der-Cherng; Mikkelsen, Torben Stamm; Möricke, Anja; Niinimäki, Riitta; Piette, Caroline; Putti, Maria Caterina; Raetz, Elizabeth; Silverman, Lewis B; Skinner, Roderick; Tuckuviene, Ruta; van der Sluis, Inge; Zapotocka, Ester

2016-06-01

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lung toxicities of core–shell nanoparticles composed of carbon, cobalt, and silica

PubMed Central

Al Samri, Mohammed T; Silva, Rafael; Almarzooqi, Saeeda; Albawardi, Alia; Othman, Aws Rashad Diab; Al Hanjeri, Ruqayya SMS; Al Dawaar, Shaikha KM; Tariq, Saeed; Souid, Abdul-Kader; Asefa, Tewodros

2013-01-01

We present here comparative assessments of murine lung toxicity (biocompatibility) after in vitro and in vivo exposures to carbon (C–SiO2-etched), carbon–silica (C–SiO2), carbon–cobalt–silica (C–Co–SiO2), and carbon–cobalt oxide–silica (C–Co3O4–SiO2) nanoparticles. These nanoparticles have potential applications in clinical medicine and bioimaging, and thus their possible adverse events require thorough investigation. The primary aim of this work was to explore whether the nanoparticles are biocompatible with pneumatocyte bioenergetics (cellular respiration and adenosine triphosphate content). Other objectives included assessments of caspase activity, lung structure, and cellular organelles. Pneumatocyte bioenergetics of murine lung remained preserved after treatment with C–SiO2-etched or C–SiO2 nanoparticles. C–SiO2-etched nanoparticles, however, increased caspase activity and altered lung structure more than C–SiO2 did. Consistent with the known mitochondrial toxicity of cobalt, both C–Co–SiO2 and C–Co3O4–SiO2 impaired lung tissue bioenergetics. C–Co–SiO2, however, increased caspase activity and altered lung structure more than C–Co3O4–SiO2. The results indicate that silica shell is essential for biocompatibility. Furthermore, cobalt oxide is the preferred phase over the zerovalent Co(0) phase to impart biocompatibility to cobalt-based nanoparticles. PMID:23658487

Prone positioning ventilation for treatment of acute lung injury and acute respiratory distress syndrome.

PubMed

Lan, Mei-juan; He, Xiao-di

2009-08-01

Patients who are diagnosed with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) usually have ventilation-perfusion mismatch, severe decrease in lung capacity, and gas exchange abnormalities. Health care workers have implemented various strategies in an attempt to compensate for these pathological alterations. By rotating patients with ALI/ARDS between the supine and prone position, it is possible to achieve a significant improvement in PaO2/FiO2, decrease shunting and therefore improve oxygenation without use of expensive, invasive and experimental procedures. Prone positioning is a safe and effective way to improve ventilation when conventional strategies fail to initiate a patient response. Because a specific cure for ARDS is not available, the goal is to support the patients with therapies that cause the least amount of injury while the lungs have an opportunity to heal. Based on current data, a trial of prone positioning ventilation should be offered to the patients who have ALI/ARDS in the early course of the disease. Published studies exhibit substantial heterogeneity in clinical results, suggesting that an adequately sized study optimizing the duration of proning ventilation strategy is warranted to enable definitive conclusions to be drawn.

Local Control and Toxicity in a Large Cohort of Central Lung Tumors Treated With Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Modh, Ankit; Rimner, Andreas; Williams, Eric

2014-12-01

Purpose: Stereotactic body radiation therapy (SBRT) in central lung tumors has been associated with higher rates of severe toxicity. We sought to evaluate toxicity and local control in a large cohort and to identify predictive dosimetric parameters. Methods and Materials: We identified patients who received SBRT for central tumors according to either of 2 definitions. Local failure (LF) was estimated using a competing risks model, and multivariate analysis (MVA) was used to assess factors associated with LF. We reviewed patient toxicity and applied Cox proportional hazard analysis and log-rank tests to assess whether dose-volume metrics of normal structures correlated with pulmonarymore » toxicity. Results: One hundred twenty-five patients received SBRT for non-small cell lung cancer (n=103) or metastatic lesions (n=22), using intensity modulated radiation therapy. The most common dose was 45 Gy in 5 fractions. Median follow-up was 17.4 months. Incidence of toxicity ≥ grade 3 was 8.0%, including 5.6% pulmonary toxicity. Sixteen patients (12.8%) experienced esophageal toxicity ≥ grade 2, including 50% of patients in whom PTV overlapped the esophagus. There were 2 treatment-related deaths. Among patients receiving biologically effective dose (BED) ≥80 Gy (n=108), 2-year LF was 21%. On MVA, gross tumor volume (GTV) was significantly associated with LF. None of the studied dose-volume metrics of the lungs, heart, proximal bronchial tree (PBT), or 2 cm expansion of the PBT (“no-fly-zone” [NFZ]) correlated with pulmonary toxicity ≥grade 2. There were no differences in pulmonary toxicity between central tumors located inside the NFZ and those outside the NFZ but with planning target volume (PTV) intersecting the mediastinum. Conclusions: Using moderate doses, SBRT for central lung tumors achieves acceptable local control with low rates of severe toxicity. Dosimetric analysis showed no significant correlation between dose to the lungs, heart, or NFZ

Acute toxicity of diphacinone in Northern bobwhite: Effects on survival and blood clotting

USGS Publications Warehouse

Rattner, Barnett A.; Horak, Katherine E.; Warner, Sarah E.; Johnston, John J.

2010-01-01

The anticoagulant rodenticide diphacinone was slightly toxic (acute oral LD50 2014 mg/kg) to Northern bobwhite (Colinus virginianus) in a 14-day acute toxicity trial. Precise and sensitive assays of blood clotting (prothrombin time, Russell?s Viper venom time, and thrombin clotting time) were adapted for use in quail, and this combination of assays is recommended to measure the effects of anticoagulant rodenticides. A single oral sublethal dose of diphacinone (434 mg/kg body weight) prolonged clotting time at 48 h post-dose compared to controls. At 783 mg/kg (approximate LD02), clotting time was prolonged at both 24 and 48 h post-dose. Prolongation of in vitro clotting time reflects impaired coagulation complex activity, and was detected before overt signs of toxicity were apparent at the greatest dosages (2868 and 3666 mg/kg) in the acute toxicity trial. These clotting time assays and toxicity data will assist in the development of a pharmacodynamic model to predict toxicity, and also facilitate rodenticide hazard and risk assessments in avian species.

Acute toxicity and chemical evaluation of coking wastewater under biological and advanced physicochemical treatment processes.

PubMed

Dehua, Ma; Cong, Liu; Xiaobiao, Zhu; Rui, Liu; Lujun, Chen

2016-09-01

This study investigated the changes of toxic compounds in coking wastewater with biological treatment (anaerobic reactor, anoxic reactor and aerobic-membrane bioreactor, A1/A2/O-MBR) and advanced physicochemical treatment (Fenton oxidation and activated carbon adsorption) stages. As the biological treatment stages preceding, the inhibition effect of coking wastewater on the luminescence of Vibrio qinghaiensis sp. Nov. Q67 decreased. Toxic units (TU) of coking wastewater were removed by A1/A2/O-MBR treatment process, however approximately 30 % TU remained in the biologically treated effluent. There is a tendency that fewer and fewer residual organic compounds could exert equal acute toxicity during the biological treatment stages. Activated carbon adsorption further removed toxic pollutants of biologically treated effluent but the Fenton effluent increased acute toxicity. The composition of coking wastewater during the treatment was evaluated using the three-dimensional fluorescence spectra, gas chromatography-mass spectrometry (GC-MS). The organic compounds with high polarity were the main cause of acute toxicity in the coking wastewater. Aromatic protein-like matters in the coking wastewater with low biodegradability and high toxicity contributed mostly to the remaining acute toxicity of the biologically treated effluents. Chlorine generated from the oxidation process was responsible for the acute toxicity increase after Fenton oxidation. Therefore, the incorporation of appropriate advanced physicochemical treatment process, e.g., activated carbon adsorption, should be implemented following biological treatment processes to meet the stricter discharge standards and be safer to the environment.

The acute toxicity of major ion salts to Ceriodaphnia dubia: III. Mathematical models for mixture toxicity

EPA Science Inventory

Based on previous research on the acute toxicity of major ions (Na+, K+, Ca2+, Mg2+, Cl, SO42, and HCO3/CO32) to C. dubia, two mathematical models were developed for predicting the LC50 for any ion mixture, excluding those dominated by K toxicity. One model addresses a mechanism...

Prevalidation of an Acute Inhalation Toxicity Test Using the EpiAirway In Vitro Human Airway Model

PubMed Central

Jackson, George R.; Maione, Anna G.; Klausner, Mitchell

2018-01-01

Abstract Introduction: Knowledge of acute inhalation toxicity potential is important for establishing safe use of chemicals and consumer products. Inhalation toxicity testing and classification procedures currently accepted within worldwide government regulatory systems rely primarily on tests conducted in animals. The goal of the current work was to develop and prevalidate a nonanimal (in vitro) test for determining acute inhalation toxicity using the EpiAirway™ in vitro human airway model as a potential alternative for currently accepted animal tests. Materials and Methods: The in vitro test method exposes EpiAirway tissues to test chemicals for 3 hours, followed by measurement of tissue viability as the test endpoint. Fifty-nine chemicals covering a broad range of toxicity classes, chemical structures, and physical properties were evaluated. The in vitro toxicity data were utilized to establish a prediction model to classify the chemicals into categories corresponding to the currently accepted Globally Harmonized System (GHS) and the Environmental Protection Agency (EPA) system. Results: The EpiAirway prediction model identified in vivo rat-based GHS Acute Inhalation Toxicity Category 1–2 and EPA Acute Inhalation Toxicity Category I–II chemicals with 100% sensitivity and specificity of 43.1% and 50.0%, for GHS and EPA acute inhalation toxicity systems, respectively. The sensitivity and specificity of the EpiAirway prediction model for identifying GHS specific target organ toxicity-single exposure (STOT-SE) Category 1 human toxicants were 75.0% and 56.5%, respectively. Corrosivity and electrophilic and oxidative reactivity appear to be the predominant mechanisms of toxicity for the most highly toxic chemicals. Conclusions: These results indicate that the EpiAirway test is a promising alternative to the currently accepted animal tests for acute inhalation toxicity. PMID:29904643

Acute oral toxicity and biodistribution study of zinc-aluminium-levodopa nanocomposite

NASA Astrophysics Data System (ADS)

Kura, Aminu Umar; Saifullah, Bullo; Cheah, Pike-See; Hussein, Mohd Zobir; Azmi, Norazrina; Fakurazi, Sharida

2015-03-01

Layered double hydroxide (LDH) is an inorganic-organic nano-layered material that harbours drug between its two-layered sheets, forming a sandwich-like structure. It is attracting a great deal of attention as an alternative drug delivery (nanodelivery) system in the field of pharmacology due to their relative low toxic potential. The production of these nanodelivery systems, aimed at improving human health through decrease toxicity, targeted delivery of the active compound to areas of interest with sustained release ability. In this study, we administered zinc-aluminium-LDH-levodopa nanocomposite (ZAL) and zinc-aluminium nanocomposite (ZA) to Sprague Dawley rats to evaluate for acute oral toxicity following OECD guidelines. The oral administration of ZAL and ZA at a limit dose of 2,000 mg/kg produced neither mortality nor acute toxic signs throughout 14 days of the observation. The percentage of body weight gain of the animals showed no significant difference between control and treatment groups. Animal from the two treated groups gained weight continuously over the study period, which was shown to be significantly higher than the weight at the beginning of the study ( P < 0.05). Biochemical analysis of animal serum showed no significant difference between rats treated with ZAL, ZA and controls. There was no gross lesion or histopathological changes observed in vital organs of the rats. The results suggested that ZAL and ZA at 2,000 mg/kg body weight in rats do not induce acute toxicity in the animals. Elemental analysis of tissues of treated animals demonstrated the wider distribution of the nanocomposite including the brain. In summary, findings of acute toxicity tests in this study suggest that zinc-aluminium nanocomposite intercalated with and the un-intercalated were safe when administered orally in animal models for short periods of time. It also highlighted the potential distribution ability of Tween-80 coated nanocomposite after oral administration.

ACUTE BEHAVIORAL TOXICITY OF SULFOLANE: INFLUENCE OF HYPOTHERMIA

EPA Science Inventory

Sulfolane is a solvent which produces hypothermia and decreased oxygen consumption following acute exposure. In the present experiment, the author investigated effects of sulfolane on a behavioral measure of toxicity at ambient temperatures which would either prevent or facilitat...

Effects of budesonide on the lung functions, inflammation and apoptosis in a saline-lavage model of acute lung injury.

PubMed

Mokra, D; Kosutova, P; Balentova, S; Adamkov, M; Mikolka, P; Mokry, J; Antosova, M; Calkovska, A

2016-12-01

Diffuse alveolar injury, edema, and inflammation are fundamental signs of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Whereas the systemic administration of corticosteroids previously led to controversial results, this study evaluated if corticosteroids given intratracheally may improve lung functions and reduce edema formation, migration of cells into the lung and their activation in experimentally-induced ALI. In oxygen-ventilated rabbits, ALI was induced by repetitive saline lung lavage, until PaO2 decreased to < 26.7 kPa in FiO 2 1.0. Then, one group of animals was treated with corticosteroid budesonide (Pulmicort susp inh, AstraZeneca; 0.25 mg/kg) given intratracheally by means of inpulsion regime of high-frequency jet ventilation, while another group was non-treated, and both groups were oxygen-ventilated for following 5 hours. Another group of animals served as healthy controls. After sacrifice of animals, left lung was saline-lavaged and protein content was measured and cells in the lavage fluid were determined microscopically. Right lung tissue was used for estimation of edema formation (expressed as wet/dry weight ratio), for histomorphological investigation, immunohistochemical determination of apoptosis of lung cells, and for determination of markers of inflammation and lung injury (IL-1β, IL-6, IL-8, TNF-α, IFNγ, esRAGE, caspase-3) by ELISA methods. Levels of several cytokines were estimated also in plasma. Repetitive lung lavage worsened gas exchange, induced lung injury, inflammation and lung edema and increased apoptosis of lung epithelial cells. Budesonide reduced lung edema, cell infiltration into the lung and apoptosis of epithelial cells and decreased concentrations of proinflammatory markers in the lung and blood. These changes resulted in improved ventilation. Concluding, curative intratracheal treatment with budesonide alleviated lung injury, inflammation, apoptosis of lung epithelial cells and lung edema and

Study on acute toxicity of amoxicillin wastewater to Zebrafish

NASA Astrophysics Data System (ADS)

Xie, Weifang; Shen, Hongyan

2017-12-01

The main research in this paper is to obtain the effect of pharmaceutical wastewater on the acute toxicity of Zebrafish. The experimental method of exposure is used in this research. Experiments were carried out with different groups of pharmaceutical wastewater. Zebrafish was cultivated in a five liter fish tank. In the experiment, according to mortality, initially a 96h preliminary test was carried out at exposure concentrations to determine if the amoxicillin wastewater was toxic and to define the concentration range (24h LC100, 96h LC0) to be employed in the definitive tests. Based on the half lethal concentration of Zebrafish, the acute toxicity of amoxicillin wastewater to Zebrafish was calculated and the toxicity grade of wastewater was determined. In the experiment, the Zebrafish was exposed with amoxicillin wastewater during 96h. The 24h, 48h, 72h and 96h LC50 of amoxicillin wastewater on the Zebrafish were 63.10%, 53.70%, 41.69% and 40.74%, respectively. At 96h, the test time is the longest, and the value of LC50 is the smallest. In the observation period of 96 hours, the LC50 of amoxicillin wastewater were in the range of 40% ~ 60% and the value of Tua is 1 ~ 2. It indicates amoxicillin wastewater is low toxic wastewater when the experimental time is shorter than 48h, amoxicillin wastewater is moderate toxicity wastewater when the experimental time is higher than 48h. According to the experimental data, with the exposure time and the volume percentage of amoxicillin wastewater increases, the mortality rate of Zebrafish is gradually increased and the toxicity of amoxicillin wastewater increases. It indicates that the toxicity of amoxicillin wastewater is the biggest and the effect of wastewater on Zebrafish is greatest. In some ways, the toxicity of amoxicillin wastewater can be affected by the test time.

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement.

PubMed

Ali, Rashid; Ali, Raisuddin; Jaimini, Abhinav; Nishad, Dhruv Kumar; Mittal, Gaurav; Chaurasia, Om Prakash; Kumar, Raj; Bhatnagar, Aseem; Singh, Shashi Bala

2012-01-01

Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). In vivo toxicity studies were performed in male balb 'C' mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement.

Early pulmonary toxicity following lung stereotactic body radiation therapy delivered in consecutive daily fractions.

PubMed

Stauder, Michael C; Macdonald, O Kenneth; Olivier, Kenneth R; Call, Jason A; Lafata, Kyle; Mayo, Charles S; Miller, Robert C; Brown, Paul D; Bauer, Heather J; Garces, Yolanda I

2011-05-01

Identify the incidence of early pulmonary toxicity in a cohort of patients treated with lung stereotactic body radiation therapy (SBRT) on consecutive treatment days. A total of 88 lesions in 84 patients were treated with SBRT in consecutive daily fractions (Fx) for medically inoperable non-small cell lung cancer or metastasis. The incidence of pneumonitis was evaluated and graded according to the NCI CTCAE v3.0. With a median follow-up of 15.8 months (range 2.5-28.6), the median age at SBRT was 71.8 years (range 23.8-87.8). 47 lesions were centrally located and 41 were peripheral. Most central lesions were treated with 48Gy in 4 Fx, and most peripheral lesions with 54Gy in 3 Fx. The incidence of grade ≥ 2 pneumonitis was 12.5% in all patients treated, and 14.3% among the subset of patients treated with 54Gy in 3 Fx. A total of two grade 3 toxicities were seen as one grade 5 toxicity in a patient treated for recurrence after pneumonectomy. Treating both central and peripheral lung lesions with SBRT in consecutive daily fractions in this cohort was well tolerated and did not cause excessive early pulmonary toxicity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Non-animal Replacements for Acute Toxicity Testing.

PubMed

Barker-Treasure, Carol; Coll, Kevin; Belot, Nathalie; Longmore, Chris; Bygrave, Karl; Avey, Suzanne; Clothier, Richard

2015-07-01

Current approaches to predicting adverse effects in humans from acute toxic exposure to cosmetic ingredients still heavily necessitate the use of animals under EU legislation, particularly in the context of the REACH system, when cosmetic ingredients are also destined for use in other industries. These include the LD50 test, the Up-and-Down Procedure and the Fixed Dose Procedure, which are regarded as having notable scientific deficiencies and low transferability to humans. By expanding on previous in vitro tests, such as the animal cell-based 3T3 Neutral Red Uptake (NRU) assay, this project aims to develop a truly animal-free predictive test for the acute toxicity of cosmetic ingredients in humans, by using human-derived cells and a prediction model that does not rely on animal data. The project, funded by Innovate UK, will incorporate the NRU assay with human dermal fibroblasts in animal product-free culture, to generate an in vitro protocol that can be validated as an accepted replacement for the currently available in vivo tests. To date, the project has successfully completed an assessment of the robustness and reproducibility of the method, by using sodium lauryl sulphate (SLS) as a positive control, and displaying analogous results to those of the original studies with mouse 3T3 cells. Currently, the testing of five known ingredients from key groups (a surfactant, a preservative, a fragrance, a colour and an emulsifier) is under way. The testing consists of initial range-finding runs followed by three valid runs of a main experiment with the appropriate concentration ranges, to generate IC50 values. Expanded blind trials of 20 ingredients will follow. Early results indicate that this human cell-based test holds the potential to replace aspects of in vivo animal acute toxicity testing, particularly with reference to cosmetic ingredients. 2015 FRAME.

Acute respiratory distress syndrome and acute lung injury.

PubMed

Dushianthan, A; Grocott, M P W; Postle, A D; Cusack, R

2011-09-01

Acute respiratory distress syndrome (ARDS) is a life threatening respiratory failure due to lung injury from a variety of precipitants. Pathologically ARDS is characterised by diffuse alveolar damage, alveolar capillary leakage, and protein rich pulmonary oedema leading to the clinical manifestation of poor lung compliance, severe hypoxaemia, and bilateral infiltrates on chest radiograph. Several aetiological factors associated with the development of ARDS are identified with sepsis, pneumonia, and trauma with multiple transfusions accounting for most cases. Despite the absence of a robust diagnostic definition, extensive epidemiological investigations suggest ARDS remains a significant health burden with substantial morbidity and mortality. Improvements in outcome following ARDS over the past decade are in part due to improved strategies of mechanical ventilation and advanced support of other failing organs. Optimal treatment involves judicious fluid management, protective lung ventilation with low tidal volumes and moderate positive end expiratory pressure, multi-organ support, and treatment where possible of the underlying cause. Moreover, advances in general supportive measures such as appropriate antimicrobial therapy, early enteral nutrition, prophylaxis against venous thromboembolism and gastrointestinal ulceration are likely contributory reasons for the improved outcomes. Although therapies such as corticosteroids, nitric oxide, prostacyclins, exogenous surfactants, ketoconazole and antioxidants have shown promising clinical effects in animal models, these have failed to translate positively in human studies. Most recently, clinical trials with β2 agonists aiding alveolar fluid clearance and immunonutrition with omega-3 fatty acids have also provided disappointing results. Despite these negative studies, mortality seems to be in decline due to advances in overall patient care. Future directions of research are likely to concentrate on identifying potential

Curcumin alone and in combination with augmentin protects against pulmonary inflammation and acute lung injury generated during Klebsiella pneumoniae B5055-induced lung infection in BALB/c mice.

PubMed

Bansal, Shruti; Chhibber, Sanjay

2010-04-01

Acute lung injuries due to acute lung infections remain a major cause of mortality. Thus a combination of an antibiotic and a compound with immunomodulatory and anti-inflammatory activities can help to overcome acute lung infection-induced injuries. Curcumin derived from the rhizome of turmeric has been used for decades and it exhibits anti-inflammatory, anti-carcinogenic, immunomodulatory properties by downregulation of various inflammatory mediators. Keeping these properties in mind, we investigated the anti-inflammatory properties of curcumin in a mouse model of acute inflammation by introducing Klebsiella pneumoniae B5055 into BALB/c mice via the intranasal route. Intranasal instillation of bacteria in this mouse model of acute pneumonia-induced inflammation resulted in a significant increase in neutrophil infiltration in the lungs along with increased production of various inflammatory mediators [i.e. malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), tumour necrosis factor (TNF)-alpha] in the lung tissue. The animals that received curcumin alone orally or in combination with augmentin, 15 days prior to bacterial instillation into the lungs via the intranasal route, showed a significant (P <0.05) decrease in neutrophil influx into the lungs and a significant (P <0.05) decrease in the production of MDA, NO, MPO activity and TNF-alpha levels. Augmentin treatment alone did not decrease the MDA, MPO, NO and TNF-alpha levels significantly (P >0.05) as compared to the control group. We therefore conclude that curcumin ameliorates lung inflammation induced by K. pneumoniae B5055 without significantly (P <0.05) decreasing the bacterial load in the lung tissue whereas augmentin takes care of bacterial proliferation. Hence, curcumin can be used as an adjunct therapy along with antibiotics as an anti-inflammatory or an immunomodulatory agent in the case of acute lung infection.

Saving two birds with one stone: using active substance avian acute toxicity data to predict formulated plant protection product toxicity.

PubMed

Maynard, Samuel K; Edwards, Peter; Wheeler, James R

2014-07-01

Environmental safety assessments for exposure of birds require the provision of acute avian toxicity data for both the pesticidal active substance and formulated products. As an example, testing on the formulated product is waived in Europe using an assessment of data for the constituent active substance(s). This is often not the case globally, because some countries require acute toxicity tests with every formulated product, thereby triggering animal welfare concerns through unnecessary testing. A database of 383 formulated products was compiled from acute toxicity studies conducted with northern bobwhite (Colinus virginianus) or Japanese quail (Coturnix japonica) (unpublished regulatory literature). Of the 383 formulated products studied, 159 contained only active substances considered functionally nontoxic (median lethal dose [LD50] > highest dose tested). Of these, 97% had formulated product LD50 values of >2000 mg formulated product/kg (limit dose), indicating that no new information was obtained in the formulated product study. Furthermore, defined (point estimated) LD50 values for formulated products were compared with LD50 values predicted from toxicity of the active substance(s). This demonstrated that predicted LD50 values were within 2-fold and 5-fold of the measured formulated product LD50 values in 90% and 98% of cases, respectively. This analysis demonstrates that avian acute toxicity testing of formulated products is largely unnecessary and should not be routinely required to assess avian acute toxicity. In particular, when active substances are known to be functionally nontoxic, further formulated product testing adds no further information and unnecessarily increases bird usage in testing. A further analysis highlights the fact that significant reductions (61% in this dataset) could be achieved by using a sequential testing design (Organisation for Economic Co-operation and Development test guideline 223), as opposed to established single

ACUTE TOXICITY OF PARA-NONYLPHENOL TO SALTWATER ANIMALS

EPA Science Inventory

?para-Nonylphenol (PNP), a mixture of alkylphenols used in producing nonionic surfactants, is distributed widely in surface waters and aquatic sediments, where it can affect saltwater species. This article describes a database for acute toxicity of PNP derived for calculating a n...

Acute and chronic toxicity assessment of benzylpenicillin G residue in heat-treated animal food products.

PubMed

Cui, Cheng; Zhang, Xiang; Wang, Yang; Lu, Shiying; Lu, Huijun; Hui, Qi; Ahmad, Waqas; Cai, Yan; Liu, Xilin; Liu, Lingjiu; Shi, Fengfeng; Liu, Yanyan; Zhao, Ke; Zhai, FeiFei; Xiang, Yangzhen; Hu, Pan; Li, Yansong; Ren, Honglin; Jin, Ningyi; Liu, Zengshan

2018-07-01

The current level of penicillin use and its persisting residue in livestock is potentially concerning; the toxicity of penicillin residue in heat-treated animal food products (HAFP) is yet to be elucidated. In this study, the acute and chronic toxicity of benzylpenicillin G (BPG) residue in HAFP was investigated in a mouse model. The calculated LD 50 of BPG heated to cooking temperature (BPHCT) was 933.04 mg kg -1 [b.w.] intraperitoneally corresponding to 3.75 times lower than its prototype. Mice fed on the experimental diet containing heat-treated beef with high BPG levels for 6 months displayed a reduction in body weight and altered serum values indicating for liver and renal function. Further, the organ ratios of intestinal and spleen were increased. Histopathological changes were observed in the liver, lung and parenchyma testis tissue. BPHCT residue induced sperm aberration and micronucleated polychromatic erythrocytes formation. Present results indicate that prolonged exposure of BPHCT at higher residue levels might have an impact on public health. Importantly the toxic concentrations of BPHCT are relatively high compared with levels that would result from the degradation of antibiotic residues in meat from animals that have received a therapeutic dose of BPG. Copyright © 2018 Elsevier Ltd. All rights reserved.

Acute Toxicity and Cytotoxicity of Pereskia aculeata, a Highly Nutritious Cactaceae Plant.

PubMed

Silva, Debora O; Seifert, Mauricio; Nora, Fabiana R; Bobrowski, Vera L; Freitag, Rogerio A; Kucera, Heidi R; Nora, Leonardo; Gaikwad, Nilesh W

2017-04-01

Pereskia aculeata is a Cactaceae plant with valuable nutritional properties, including terrific amounts of protein, minerals, vitamins, and fiber. However, P. aculeata is reported to contain antinutrients and alkaloids in its leaves. In addition, in a study on growth and development, Wistar rats fed with P. aculeata and casein as protein source grew less than the control group (fed with casein only). Therefore, in this study, we evaluated, for the first time, the oral acute toxicity of P. aculeata in rats and also the cytotoxicity behavior of the plant on lettuce seeds. The acute toxicity research was carried out using dried P. aculeata ethanolic extract, in three different doses, administered by gavage to 24 female Wistar rats. The rats were then examined for signs of toxicity, food intake, body weight, and fecal excretion fluctuations, as well as histopathological alterations, using eight different body tissues. The acute toxicity study did not show any difference among the groups in either clinical evaluation or histopathological analyses. For the cytotoxicity study, dried P. aculeata ethanolic extract was applied on lettuce seeds in five different concentrations. These seeds were evaluated for germination, root and shoot length, and mitotic index. The results show that P. aculeata extract affects lettuce root and shoot growth, but not germination or mitotic index. In conclusion, the acute toxicity on rats and the cytogenotoxicity on lettuce of P. aculeata are neglectable, validating the potential of this plant to be used as a functional food.

Three dimensional quantitative structure-toxicity relationship modeling and prediction of acute toxicity for organic contaminants to algae.

PubMed

Jin, Xiangqin; Jin, Minghao; Sheng, Lianxi

2014-08-01

Although numerous chemicals have been identified to have significant toxicological effect on aquatic organisms, there is still lack of a reliable, high-throughput approach to evaluate, screen and monitor the presence of organic contaminants in aquatic system. In the current study, we proposed a synthetic pipeline to automatically model and predict the acute toxicity of chemicals to algae. In the procedure, a new alignment-free three dimensional (3D) structure characterization method was described and, with this method, several 3D-quantitative structure-toxicity relationship (3D-QSTR) models were developed, from which two were found to exhibit strong internal fitting ability and high external predictive power. The best model was established by Gaussian process (GP), which was further employed to perform extrapolation on a random compound library consisting of 1014 virtually generated substituted benzenes. It was found that (i) substitution number can only exert slight influence on chemical׳s toxicity, but low-substituted benzenes seem to have higher toxicity than those of high-substituted entities, and (ii) benzenes substituted by nitro group and halogens exhibit high acute toxicity as compared to other substituents such as methyl and carboxyl groups. Subsequently, several promising candidates suggested by computational prediction were assayed by using a standard algal growth inhibition test. Consequently, four substituted benzenes, namely 2,3-dinitrophenol, 2-chloro-4-nitroaniline, 1,2,3-trinitrobenzene and 3-bromophenol, were determined to have high acute toxicity to Scenedesmus obliquus, with their EC50 values of 2.5±0.8, 10.5±2.1, 1.4±0.2 and 42.7±5.4μmol/L, respectively. Copyright © 2014 Elsevier Ltd. All rights reserved.

Active Oxygen Metabolites and Thromboxane in Phorbol Myristate Acetate Toxicity to the Isolated, Perfused Rat Lung.

NASA Astrophysics Data System (ADS)

Carpenter, Laurie Jean

When administered intravenously or intratracheally to rats, rabbits and sheep, phorbol myristate acetate (PMA) produces changes in lung morphology and function are similar to those seen in humans with the adult respiratory distress syndrome (ARDS). Therefore, it is thought that information about the mechanism of ARDS development can be gained from experiments using PMA-treated animals. Currently, the mechanisms by which PMA causes pneumotoxicity are unknown. Results from other studies in rabbits and in isolated, perfused rabbit lungs suggest that PMA-induced lung injury is mediated by active oxygen species from neutrophils (PMN), whereas studies in sheep and rats suggest that PMN are not required for the toxic response. The role of PMN, active oxygen metabolites and thromboxane (TxA_2) in PMA-induced injury to isolated, perfused rat lungs (IPLs) was examined in this thesis. To determine whether PMN were required for PMA to produce toxicity to the IPL, lungs were perfused for 30 min with buffer containing various concentrations of PMA (in the presence or absence of PMN). When concentrations >=q57 ng/ml were added to medium devoid of added PMN, perfusion pressure and lung weight increased. When a concentration of PMA (14-28 ng/ml) that did not by itself cause lungs to accumulate fluid was added to the perfusion medium containing PMN (1 x 10 ^8), perfusion pressure increased, and lungs accumulated fluid. These results indicate that high concentrations of PMA produce lung injury which is independent of PMN, whereas injury induced by lower concentrations is PMN-dependent. To examine whether active oxygen species were involved in mediating lung injury induced by PMA and PMN, lungs were coperfused with the oxygen radical scavengers SOD and/or catalase. Coperfusion with either or both of these enzymes totally protected lungs against injury caused by PMN and PMA. These results suggest that active oxygen species (the hydroxyl radical in particular), mediate lung injury in

Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.

PubMed

Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

2015-02-01

We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

Critique on the use of the standardized avian acute oral toxicity test for first generation anticoagulant rodenticides

USGS Publications Warehouse

Vyas, Nimish B.; Rattner, Barnett A.

2012-01-01

Avian risk assessments for rodenticides are often driven by the results of standardized acute oral toxicity tests without regards to a toxicant's mode of action and time course of adverse effects. First generation anticoagulant rodenticides (FGARs) generally require multiple feedings over several days to achieve a threshold concentration in tissue and cause adverse effects. This exposure regimen is much different than that used in the standardized acute oral toxicity test methodology. Median lethal dose values derived from standardized acute oral toxicity tests underestimate the environmental hazard and risk of FGARs. Caution is warranted when FGAR toxicity, physiological effects, and pharmacokinetics derived from standardized acute oral toxicity testing are used for forensic confirmation of the cause of death in avian mortality incidents and when characterizing FGARs' risks to free-ranging birds.

Integrating microRNAs into a system biology approach to acute lung injury.

PubMed

Zhou, Tong; Garcia, Joe G N; Zhang, Wei

2011-04-01

Acute lung injury (ALI), including the ventilator-induced lung injury (VILI) and the more severe acute respiratory distress syndrome (ARDS), are common and complex inflammatory lung diseases potentially affected by various genetic and nongenetic factors. Using the candidate gene approach, genetic variants associated with immune response and inflammatory pathways have been identified and implicated in ALI. Because gene expression is an intermediate phenotype that resides between the DNA sequence variation and the higher level cellular or whole-body phenotypes, the illustration of gene expression regulatory networks potentially could enhance understanding of disease susceptibility and the development of inflammatory lung syndromes. MicroRNAs (miRNAs) have emerged as a novel class of gene regulators that play critical roles in complex diseases including ALI. Comparisons of global miRNA profiles in animal models of ALI and VILI identified several miRNAs (eg, miR-146a and miR-155) previously implicated in immune response and inflammatory pathways. Therefore, via regulation of target genes in these biological processes and pathways, miRNAs potentially contribute to the development of ALI. Although this line of inquiry exists at a nascent stage, miRNAs have the potential to be critical components of a comprehensive model for inflammatory lung disease built by a systems biology approach that integrates genetic, genomic, proteomic, epigenetic as well as environmental stimuli information. Given their particularly recognized role in regulation of immune and inflammatory responses, miRNAs also serve as novel therapeutic targets and biomarkers for ALI/ARDS or VILI, thus facilitating the realization of personalized medicine for individuals with acute inflammatory lung disease. Copyright © 2011 Mosby, Inc. All rights reserved.

The Role of Alveolar Macrophage Beta-2 Adrenergic Receptors in Acute Lung Injury

DTIC Science & Technology

2017-10-01

macrophages contributes to Acute Respiratory Distress Syndrome , which is a significant contributor to morbidity and mortality in military and civilian settings...carbonic anhydrase (Ca2). 15. SUBJECT TERMS Acute lung injury, Acute Respiratory Distress Syndrome , ARDS, pulmonary edema, influenza, viral pneumonia...to understand how β2AR signaling in macrophages contributes to Acute Respiratory Distress Syndrome (ARDS). ARDS is a significant contributor to

Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection.

PubMed

Gregson, Aric L; Hoji, Aki; Injean, Patil; Poynter, Steven T; Briones, Claudia; Palchevskiy, Vyacheslav; Weigt, S Sam; Shino, Michael Y; Derhovanessian, Ariss; Sayah, David; Saggar, Rajan; Ross, David; Ardehali, Abbas; Lynch, Joseph P; Belperio, John A

2015-12-15

The mechanism by which acute allograft rejection leads to chronic rejection remains poorly understood despite its common occurrence. Exosomes, membrane vesicles released from cells within the lung allograft, contain a diverse array of biomolecules that closely reflect the biologic state of the cell and tissue from which they are released. Exosome transcriptomes may provide a better understanding of the rejection process. Furthermore, biomarkers originating from this transcriptome could provide timely and sensitive detection of acute cellular rejection (AR), reducing the incidence of severe AR and chronic lung allograft dysfunction and improving outcomes. To provide an in-depth analysis of the bronchoalveolar lavage fluid exosomal shuttle RNA population after lung transplantation and evaluate for differential expression between acute AR and quiescence. Serial bronchoalveolar lavage specimens were ultracentrifuged to obtain the exosomal pellet for RNA extraction, on which RNA-Seq was performed. AR demonstrates an intense inflammatory environment, skewed toward both innate and adaptive immune responses. Novel, potential upstream regulators identified offer potential therapeutic targets. Our findings validate bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation.

Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection

PubMed Central

Hoji, Aki; Injean, Patil; Poynter, Steven T.; Briones, Claudia; Palchevskiy, Vyacheslav; Sam Weigt, S.; Shino, Michael Y.; Derhovanessian, Ariss; Saggar, Rajan; Ross, David; Ardehali, Abbas; Lynch, Joseph P.; Belperio, John A.

2015-01-01

Rationale: The mechanism by which acute allograft rejection leads to chronic rejection remains poorly understood despite its common occurrence. Exosomes, membrane vesicles released from cells within the lung allograft, contain a diverse array of biomolecules that closely reflect the biologic state of the cell and tissue from which they are released. Exosome transcriptomes may provide a better understanding of the rejection process. Furthermore, biomarkers originating from this transcriptome could provide timely and sensitive detection of acute cellular rejection (AR), reducing the incidence of severe AR and chronic lung allograft dysfunction and improving outcomes. Objectives: To provide an in-depth analysis of the bronchoalveolar lavage fluid exosomal shuttle RNA population after lung transplantation and evaluate for differential expression between acute AR and quiescence. Methods: Serial bronchoalveolar lavage specimens were ultracentrifuged to obtain the exosomal pellet for RNA extraction, on which RNA-Seq was performed. Measurements and Main Results: AR demonstrates an intense inflammatory environment, skewed toward both innate and adaptive immune responses. Novel, potential upstream regulators identified offer potential therapeutic targets. Conclusions: Our findings validate bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation. PMID:26308930

Metachronous and Synchronous Presentation of Acute Myeloid Leukemia and Lung Cancer

PubMed Central

Varadarajan, Ramya; Ford, LaurieAnn; Sait, Sheila NJ; Block, AnneMarie W.; Barcos, Maurice; Wallace, Paul K.; Ramnath, Nithya; Wang, Eunice S.; Wetzler, Meir

2009-01-01

Smoking is associated with both acute myeloid leukemia (AML) and lung cancer. We therefore searched our database for concomitant presentation of AML and lung cancer. Among 775 AML cases and 5225 lung cancer cases presenting to Roswell Park Cancer Institute between the years January 1992 and May 2008 we found 12 (1.5% of AML cases; 0.23% of lung cancer cases) cases (seven metachronous and five synchronous) with AML and lung cancer. All but one patient were smokers. There were no unique characteristic of either AML or lung cancer in these patients. Nine patients succumbed to AML, one died from an unrelated cause while undergoing treatment for AML, one died of lung cancer and one patient is alive after allogeneic transplantation for AML. In summary, this study supports the need for effective smoking cessation programs. PMID:19181380

Chemical warfare agent and biological toxin-induced pulmonary toxicity: could stem cells provide potential therapies?

PubMed

Angelini, Daniel J; Dorsey, Russell M; Willis, Kristen L; Hong, Charles; Moyer, Robert A; Oyler, Jonathan; Jensen, Neil S; Salem, Harry

2013-01-01

Chemical warfare agents (CWAs) as well as biological toxins present a significant inhalation injury risk to both deployed warfighters and civilian targets of terrorist attacks. Inhalation of many CWAs and biological toxins can induce severe pulmonary toxicity leading to the development of acute lung injury (ALI) as well as acute respiratory distress syndrome (ARDS). The therapeutic options currently used to treat these conditions are very limited and mortality rates remain high. Recent evidence suggests that human stem cells may provide significant therapeutic options for ALI and ARDS in the near future. The threat posed by CWAs and biological toxins for both civilian populations and military personnel is growing, thus understanding the mechanisms of toxicity and potential therapies is critical. This review will outline the pulmonary toxic effects of some of the most common CWAs and biological toxins as well as the potential role of stem cells in treating these types of toxic lung injuries.

[Protective effect of curcumin on oleic-induced acute lung injury in rats].

PubMed

Zhu, Rui-fang; Zhou, Min; He, Jian-lin; Ding, Fu-yun; Yu, Shu-qin; Xu, Guang-lin

2008-09-01

To investigate the effect of curcumine on acute lung injury induced by oleic acid in rat and the possible mechanism of action. The rats were divided into 6 groups randomly: normal group, control group, curcumine groups (5, 10, 20 mg x kg(-1)) and dexamethasone group (1 mg x kg(-1)). During the experiment, acute lung injury was induced by oleic acid in rat. The changes of dynamic lung compliance were recorded by anrise 2005 pulmonary function test apparatus, light microscope was used to examine histological changes and lung index as well as wet to dry weight ratio was calculated by weighting method. Lung vascular permeability and protein level in BALF were detected by ultraviolet spectrophotometry, and the concentrations of TNF-alpha, IL-6 and IL-10 in BALF were measured by enzyme linked immunosorbent assay (ELISA). The result showed that the changes of pulmonary compliance were inhibited and pulmonary function was improved by curcumine. The OA-induced elevation of lung index was restrained, as well as wet to dry weight ratio, lung vascular permeability, protein level, TNF-alpha (250.4 +/- 21.6 vs. 172.53 +/- 14.88, 122.2 +/- 10.98, 108.69 +/- 3.39) ng x L(-1), IL-6 (763.6 +/- 88.33 vs. 207.41 +/- 15.55, 172.13 +/- 21.91, 142.92 +/- 4.32) ng x L(-1) in BALF in curcumine groups, IL-10 (98.90 +/- 2.99 vs. 208.44 +/- 16.30, 218.43 +/- 6.23, 252.70 +/- 20.58) ng x L(-1) in BALF was increased, respectively significantly. Light microscope findings shown that the impairment in curcumine groups was far less severe than that in model groups. Pretreatment of curcumine showed beneficial effect on acute lung injury induced by oleic acid in rats. The mediation of both proinflammatory factor and anti-inflammatory factor by curcumine may be involved in mechanism of action of curcumine effects.

Mechanical Ventilation–associated Lung Fibrosis in Acute Respiratory Distress Syndrome A Significant Contributor to Poor Outcome

PubMed Central

Cabrera-Benitez, Nuria E.; Laffey, John G.; Parotto, Matteo; Spieth, Peter M.; Villar, Jesús; Zhang, Haibo; Slutsky, Arthur S.

2016-01-01

One of the most challenging problems in critical care medicine is the management of patients with the acute respiratory distress syndrome. Increasing evidence from experimental and clinical studies suggests that mechanical ventilation, which is necessary for life support in patients with acute respiratory distress syndrome, can cause lung fibrosis, which may significantly contribute to morbidity and mortality. The role of mechanical stress as an inciting factor for lung fibrosis versus its role in lung homeostasis and the restoration of normal pulmonary parenchymal architecture is poorly understood. In this review, the authors explore recent advances in the field of pulmonary fibrosis in the context of acute respiratory distress syndrome, concentrating on its relevance to the practice of mechanical ventilation, as commonly applied by anesthetists and intensivists. The authors focus the discussion on the thesis that mechanical ventilation—or more specifically, that ventilator-induced lung injury—may be a major contributor to lung fibrosis. The authors critically appraise possible mechanisms underlying the mechanical stress–induced lung fibrosis and highlight potential therapeutic strategies to mitigate this fibrosis. PMID:24732023

Mechanical ventilation-associated lung fibrosis in acute respiratory distress syndrome: a significant contributor to poor outcome.

PubMed

Cabrera-Benitez, Nuria E; Laffey, John G; Parotto, Matteo; Spieth, Peter M; Villar, Jesús; Zhang, Haibo; Slutsky, Arthur S

2014-07-01

One of the most challenging problems in critical care medicine is the management of patients with the acute respiratory distress syndrome. Increasing evidence from experimental and clinical studies suggests that mechanical ventilation, which is necessary for life support in patients with acute respiratory distress syndrome, can cause lung fibrosis, which may significantly contribute to morbidity and mortality. The role of mechanical stress as an inciting factor for lung fibrosis versus its role in lung homeostasis and the restoration of normal pulmonary parenchymal architecture is poorly understood. In this review, the authors explore recent advances in the field of pulmonary fibrosis in the context of acute respiratory distress syndrome, concentrating on its relevance to the practice of mechanical ventilation, as commonly applied by anesthetists and intensivists. The authors focus the discussion on the thesis that mechanical ventilation-or more specifically, that ventilator-induced lung injury-may be a major contributor to lung fibrosis. The authors critically appraise possible mechanisms underlying the mechanical stress-induced lung fibrosis and highlight potential therapeutic strategies to mitigate this fibrosis.

Technetium-99m diethylenetriaminepentaacetic acid radioaerosol scintigraphy in organophosphate induced pulmonary toxicity: experimental study.

PubMed

Yavuz, Yucel; Kaya, Eser; Yurumez, Yusuf; Sahin, Onder; Bas, Orhan; Fidan, Huseyin; Sezer, Murat

2008-09-01

The aim of this experimental study was to investigate pathological signs of lung damages caused by acute organophosphate (OP) poisoning by using Tc-99m DTPA radioaerosol scintigraphy and histopathological investigation. Fourteen rabbits were divided into two equal groups (n = 7). Group 1 (control group) received normal saline (same volume of fenthion, 2 ml/kg) via orogastric tube. Group 2 (OP toxicity group) received 150 mg/kg of fenthion (diluted fenthion, 2 ml/kg) via orogastric tube. Six hours later, Tc-99m-DTPA aerosol inhalation lung scintigraphy was performed in both groups. Then all rabbits were anesthetized with ketamine hydrochloride (35 mg/kg, i.p.) and xysilazine (5 mg/kg, i.p.), and sacrificed by intracardiac blood discharge. The lungs were then removed. There was a significant difference in T1/2 values of Tc-99m DTPA clearance between control group and OP toxicity group (p = 0.04). Intraparenchymal vascular congestion and thrombosis, intraparenchymal hemorrhage, respiratory epithelial proliferation, number of macrophages in the alveolar, and bronchial lumen, alveolar destruction, emphysematous changes, and bronchoalveolar hemorrhage scores were significantly higher in the rabbits exposed to OP compared with the control group (p < 0.05). This study showed that OP toxicity caused a decrease in the alveolar clearance. Tc-99m DTPA radioaerosol inhalation lung scintigraphy was found to be a sensitive determination of acute lung damage in OP poisoning.

Thalidomide alleviates acute pancreatitis-associated lung injury via down-regulation of NFκB induced TNF-α.

PubMed

Lv, Peng; Li, Hong-Yun; Ji, Shu-Sheng; Li, Wen; Fan, Li-Juan

2014-09-01

We studied the effect of thalidomide on NFκB-induced TNF-α in acute pancreatitis-associated lung injury in the rat. Rats were intragastrically administered thalidomide (100mg/kg) daily for 8 days and then acute pancreatitis was induced by retrograde infusion of 5% sodium taurocholate into the rat biliopancreatic duct. Serum amylase (AMY), blood oxygen partial pressure (PaO2), ratios of lung wet/dry weight, and cytoplasmic IκBα and TNF-α protein and nuclear NFκBp65 protein were measured. Also, lung NFκBp65 and TNF-α mRNA were measured. Compared with the model group, the pathological score of the pancreas and lung, serum AMY, ratios of lung wet/dry weight, and lung NFκBp65 and TNF-α mRNA and protein of rats given thalidomide were decreased significantly (P<0.01), but PaO2 and IκBα protein was elevated significantly (P<0.01). Thalidomide may inhibit TNF-α expression via down-regulation of the NFκB signaling pathway to alleviate acute pancreatitis-associated lung injury in rats. Copyright © 2014 Elsevier GmbH. All rights reserved.

Mutagenicity and Acute Oral Toxicity Test for Herbal Poultry Feed Supplements.

PubMed

Srinivasa Rao, Boddapati; Chandrasekaran, C V; Srikanth, H S; Sasikumar, Murugan; Edwin Jothie, R; Haseena, Begum; Bharathi, Bethapudi; Selvam, Ramasamy; Prashanth, D'Souza

2018-01-01

Herbal products are being used and trusted globally for thousands of years for their health benefits and limited side effects. Globally, a general belief amongst the consumers is that herbal supplements are always safe because they are "natural." But later, research reveals that they may not be safe. This raises concern on their safety and implications for their use as feed supplement or medicine. Toxicity testing can reveal some of the risks that may be associated with use of herbs, therefore avoiding potential harmful effects. The present study was designed to investigate five poultry feed supplements (PFS), EGMAX® (to revitalize ovarian activity), FEED-X ™ (feed efficiency enhancer), KOLIN PLUS ™ (natural replacer of synthetic choline chloride), PHYTOCEE® (natural defence enhancer), and STODI® (to prevent and control loose droppings), for their possible mutagenicity and toxicity. Bacterial reverse mutation (BRMT) and acute oral toxicity tests were employed to assess the PFS for their possible mutagenicity and toxicity. Results indicated that the PFS were devoid of mutagenic effects in BRMT and showed higher safety profile in rodent acute oral toxicity test.

Hyperactive immune cells (T cells) may be responsible for acute lung injury in influenza virus infections: a need for early immune-modulators for severe cases.

PubMed

Lee, Kyung-Yil; Rhim, Jung-Woo; Kang, Jin-Han

2011-01-01

It has been believed that acute lung injury in influenza virus infections is caused by a virus-induced cytopathy; viruses that have multiplied in the upper respiratory tract spread to lung tissues along the lower respiratory tract. However, some experimental and clinical studies have suggested that the pathogenesis of acute lung injury in influenza virus infections is associated with excessive host response including a cell-mediated immune reaction. During the pandemic H1N1 2009 influenza A virus infections in Korea, we experienced a dramatic effect of immune-modulators (corticosteroids) on the patients with severe pneumonia who had significant respiratory distress at presentation and those who showed rapidly progressive pneumonia during oseltamivir treatment. We also found that the pneumonia patients treated with corticosteroids showed the lowest lymphocyte differential and that the severity of pneumonia was associated with the lymphocyte count at presentation. From our findings and previous experimental and clinical studies, we postulated that hyperactive immune cells (T cells) may be involved in the acute lung injury of influenza virus infections, using a hypothesis of 'protein homeostasis system'; the inducers of the cell-mediated immune response are initially produced at the primary immune sites by the innate immune system. These substances reach the lung cells, the main target organ, via the systemic circulation, and possibly the cells of other organs, including myocytes or central nerve system cells, leading to extrapulmonary symptoms (e.g., myalgia and rhabdomyolysis, and encephalopathy). To control these substances that may be possibly toxic to host cells, the adaptive immune reaction may be operated by immune cells, mainly lymphocytes. Hyperimmune reaction of immune cells produces higher levels of cytokines which may be associated with acute lung injury, and may be controlled by early use of immune-modulators. Early initiation and proper dosage of immune

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement

PubMed Central

Ali, Rashid; Ali, Raisuddin; Jaimini, Abhinav; Nishad, Dhruv Kumar; Mittal, Gaurav; Chaurasia, Om Prakash; Kumar, Raj; Bhatnagar, Aseem; Singh, Shashi Bala

2012-01-01

Objectives: Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). Materials and Methods: In vivo toxicity studies were performed in male balb ‘C’ mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. Results: No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. Conclusion: The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement. PMID:23087514

Acute toxicity and its dosimetric correlates for high-risk prostate cancer treated with moderately hypofractionated radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arunsingh, Moses; Mallick, Indranil, E-mail: imallick@gmail.com; Prasath, Sriram

Aims: To report the acute toxicity and the dosimetric correlates after moderately hypofractionated radiotherapy for localized prostate cancer. Methods: A total of 101 patients with localized prostate cancer were treated with image-guided intensity-modulated radiation therapy. Patients were treated to 65 Gy/25 Fr/5 weeks (n = 18), or 60 Gy/20 Fr/4 weeks (n = 83). Most (82.2%) had high-risk or pelvic node-positive disease. Acute toxicity was assessed using Radiation Therapy Oncology Group (RTOG) acute morbidity scoring criteria. Dose thresholds for acute rectal and bladder toxicity were identified. Results: The incidence of acute grade 2 GI toxicity was 20.8%, and grade 2more » genitourinary (GU) toxicity was 6.9%. No Grade 3 to 4 toxicity occurred. Small bowel toxicity was uncommon (Gr 2 = 4%). The 2 Gy equivalent doses (EQD2) to the rectum and bladder (α/β = 3) calculated showed that the absolute doses were more consistent predictors of acute toxicities than the relative volumes. Those with grade 2 or more GI symptoms had significantly higher V{sub EQD2-60} {sub Gy} (13.2 vs 9.9 cc, p = 0.007) and V{sub EQD2-50} {sub Gy} (20.6 vs 15.4 cc, p = 0.005). Those with grade 2 or more GU symptoms had significantly higher V{sub EQD2-70} {sub Gy} (30.4 vs 18.4 cc, p = 0.001) and V{sub EQD2-65} {sub Gy} (44.0 vs 28.8 cc, p = 0.001). The optimal cutoff value for predicting grade 2 acute proctitis, for V{sub EQD2-60} {sub Gy} was 9.7 cc and for V{sub EQD2-50} {sub Gy} was 15.9 cc. For grade 2 GU symptoms, the threshold values were 23.6 cc for V{sub EQD2-70} {sub Gy} and 38.1 cc for V{sub EQD2-65} {sub Gy}. Conclusions: Hypofractionated radiotherapy for prostate cancer is well tolerated and associated with manageable acute side effects. The absolute dose-volume parameters of rectum and bladder predict for acute toxicities.« less

Acute lethal toxicity of environmental pollutants to aquatic organisms.

PubMed

Yen, Jui-Hung; Lin, Kuo-Hsiung; Wang, Yei-Shung

2002-06-01

The acute lethal toxicity of environment pollutants including chlorophenol, haloalkane, quinone, and substituted nitrobenzene (i.e., nitrophenol, nitrobenzene, nitrotoluene, and aniline) compounds to aquatic organisms was determined. Determination of toxicity of chemicals was performed with chlorella, daphnia, carp, and tilapia. The toxicity of chlorophenols had no relation to the number of chlorine atoms on the benzene ring, but monochlorophenol had lower activity than more chlorine-substituted compounds. The tolerance levels of daphnia and carp to haloalkanes was found to be higher than that of chlorella; toxicity to chlorella was several hundred times higher than to daphnia. The toxicity of naphthoquinone compounds to chlorella and carp was higher than that of anthraquinone. A compound with a monochloride substitution on anthraquinone ring was less toxic to carp than those substituted with amine, hydroxyl, and dichlorine groups. Nitrobenzene compounds with an additional substitution group on the p position were extremely toxic to daphnia and carp. (c) 2002 Elsevier Science (USA).

Clinical review: Lung imaging in acute respiratory distress syndrome patients - an update

PubMed Central

2013-01-01

Over the past 30 years lung imaging has greatly contributed to the current understanding of the pathophysiology and the management of acute respiratory distress syndrome (ARDS). In the past few years, in addition to chest X-ray and lung computed tomography, newer functional lung imaging techniques, such as lung ultrasound, positron emission tomography, electrical impedance tomography and magnetic resonance, have been gaining a role as diagnostic tools to optimize lung assessment and ventilator management in ARDS patients. Here we provide an updated clinical review of lung imaging in ARDS over the past few years to offer an overview of the literature on the available imaging techniques from a clinical perspective. PMID:24238477

INTER-SPECIES MODELS FOR ACUTE AQUATIC TOXICITY BASED ON MECHANISM OF ACTION

EPA Science Inventory

This presentation will provide interspecies QSARs for acute toxicity to 17 aquatic species, such as fish, snail, tadpole, hydrozoan, crustacean, insect larvae, and bacteria developed using 5,000 toxic effect results for approximately 2400 chemicals.

Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice

PubMed Central

Pope-Varsalona, Hannah; Concel, Vincent J.; Liu, Pengyuan; Bein, Kiflai; Berndt, Annerose; Martin, Timothy M.; Ganguly, Koustav; Jang, An Soo; Brant, Kelly A.; Dopico, Richard A.; Upadhyay, Swapna; Di, Y. P. Peter; Hu, Zhen; Vuga, Louis J.; Medvedovic, Mario; Kaminski, Naftali; You, Ming; Alexander, Danny C.; McDunn, Jonathan E.; Prows, Daniel R.; Knoell, Daren L.

2012-01-01

The genetic basis for the underlying individual susceptibility to chlorine-induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling. Using ≥ 10% allelic frequency and ≥ 10% phenotype explained as threshold criteria, promoter SNPs that could eliminate putative transcriptional factor recognition sites in candidate genes were assessed by determining transcript levels through microarray and reverse real-time PCR during chlorine exposure. The mean survival time varied by approximately 5-fold among strains, and SNP associations were identified for 13 candidate genes on chromosomes 1, 4, 5, 9, and 15. Microarrays revealed several differentially enriched pathways, including protein transport (decreased more in the sensitive C57BLKS/J lung) and protein catabolic process (increased more in the resistant C57BL/10J lung). Lung metabolomic profiling revealed 95 of the 280 metabolites measured were altered by chlorine exposure, and included alanine, which decreased more in the C57BLKS/J than in the C57BL/10J strain, and glutamine, which increased more in the C57BL/10J than in the C57BLKS/J strain. Genetic associations from haplotype mapping were strengthened by an integrated assessment using transcriptomic and metabolomic profiling. The leading candidate genes associated with increased susceptibility to acute lung injury in mice included Klf4, Sema7a, Tns1, Aacs, and a gene that encodes an amino acid carrier, Slc38a4. PMID:22447970

Feasibility and Acute Toxicity of Hypofractionated Radiation in Large-breasted Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dorn, Paige L., E-mail: pdorn@radonc.uchicago.edu; Corbin, Kimberly S.; Al-Hallaq, Hania

Purpose: To determine the feasibility of and acute toxicity associated with hypofractionated whole breast radiation (HypoRT) after breast-conserving surgery in patients excluded from or underrepresented in randomized trials comparing HypoRT with conventional fractionation schedules. Methods and Materials: A review was conducted of all patients consecutively treated with HypoRT at University of Chicago. All patients were treated to 42.56 Gy in 2.66 Gy daily fractions in either the prone or supine position. Planning was performed in most cases using wedges and large segments or a 'field-in-field' technique. Breast volume was estimated using volumetric measurements of the planning target volume (PTV). Dosimetricmore » parameters of heterogeneity (V105, V107, V110, and maximum dose) were recorded for each treatment plan. Acute toxicity was scored for each treated breast. Results: Between 2006 and 2010, 78 patients were treated to 80 breasts using HypoRT. Most women were overweight or obese (78.7%), with a median body mass index of 29.2 kg/m{sup 2}. Median breast volume was 1,351 mL. Of the 80 treated breasts, the maximum acute skin toxicity was mild erythema or hyperpigmentation in 70.0% (56/80), dry desquamation in 21.25% (17/80), and focal moist desquamation in 8.75% (7/80). Maximum acute toxicity occurred after the completion of radiation in 31.9% of patients. Separation >25 cm was not associated with increased toxicity. Breast volume was the only patient factor significantly associated with moist desquamation on multivariable analysis (p = 0.01). Patients with breast volume >2,500 mL experienced focal moist desquamation in 27.2% of cases compared with 6.34% in patients with breast volume <2,500 mL (p = 0.03). Conclusions: HypoRT is feasible and safe in patients with separation >25 cm and in patients with large breast volume when employing modern planning and positioning techniques. We recommend counseling regarding expected increases in skin toxicity in women

Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice.

PubMed

Bhargava, Rhea; Janssen, William; Altmann, Christopher; Andrés-Hernando, Ana; Okamura, Kayo; Vandivier, R William; Ahuja, Nilesh; Faubel, Sarah

2013-01-01

Serum and bronchoalveolar fluid IL-6 are increased in patients with acute respiratory distress syndrome (ARDS) and predict prolonged mechanical ventilation and poor outcomes, although the role of intra-alveolar IL-6 in indirect lung injury is unknown. We investigated the role of endogenous and exogenous intra-alveolar IL-6 in AKI-mediated lung injury (indirect lung injury), intraperitoneal (IP) endotoxin administration (indirect lung injury) and, for comparison, intratracheal (IT) endotoxin administration (direct lung injury) with the hypothesis that IL-6 would exert a pro-inflammatory effect in these causes of acute lung inflammation. Bronchoalveolar cytokines (IL-6, CXCL1, TNF-α, IL-1β, and IL-10), BAL fluid neutrophils, lung inflammation (lung cytokines, MPO activity [a biochemical marker of neutrophil infiltration]), and serum cytokines were determined in adult male C57Bl/6 mice with no intervention or 4 hours after ischemic AKI (22 minutes of renal pedicle clamping), IP endotoxin (10 µg), or IT endotoxin (80 µg) with and without intratracheal (IT) IL-6 (25 ng or 200 ng) treatment. Lung inflammation was similar after AKI, IP endotoxin, and IT endotoxin. BAL fluid IL-6 was markedly increased after IT endotoxin, and not increased after AKI or IP endotoxin. Unexpectedly, IT IL-6 exerted an anti-inflammatory effect in healthy mice characterized by reduced BAL fluid cytokines. IT IL-6 also exerted an anti-inflammatory effect in IT endotoxin characterized by reduced BAL fluid cytokines and lung inflammation; IT IL-6 had no effect on lung inflammation in AKI or IP endotoxin. IL-6 exerts an anti-inflammatory effect in direct lung injury from IT endotoxin, yet has no role in the pathogenesis or treatment of indirect lung injury from AKI or IP endotoxin. Since intra-alveolar inflammation is important in the pathogenesis of direct, but not indirect, causes of lung inflammation, IT anti-inflammatory treatments may have a role in direct, but not indirect, causes of ARDS.

In silico assessment of the acute toxicity of chemicals: recent advances and new model for multitasking prediction of toxic effect.

PubMed

Kleandrova, Valeria V; Luan, Feng; Speck-Planche, Alejandro; Cordeiro, M Natália D S

2015-01-01

The assessment of acute toxicity is one of the most important stages to ensure the safety of chemicals with potential applications in pharmaceutical sciences, biomedical research, or any other industrial branch. A huge and indiscriminate number of toxicity assays have been carried out on laboratory animals. In this sense, computational approaches involving models based on quantitative-structure activity/toxicity relationships (QSAR/QSTR) can help to rationalize time and financial costs. Here, we discuss the most significant advances in the last 6 years focused on the use of QSAR/QSTR models to predict acute toxicity of drugs/chemicals in laboratory animals, employing large and heterogeneous datasets. The advantages and drawbacks of the different QSAR/QSTR models are analyzed. As a contribution to the field, we introduce the first multitasking (mtk) QSTR model for simultaneous prediction of acute toxicity of compounds by considering different routes of administration, diverse breeds of laboratory animals, and the reliability of the experimental conditions. The mtk-QSTR model was based on artificial neural networks (ANN), allowing the classification of compounds as toxic or non-toxic. This model correctly classified more than 94% of the 1646 cases present in the whole dataset, and its applicability was demonstrated by performing predictions of different chemicals such as drugs, dietary supplements, and molecules which could serve as nanocarriers for drug delivery. The predictions given by the mtk-QSTR model are in very good agreement with the experimental results.

A combined evaluation of the characteristics and acute toxicity of antibiotic wastewater.

PubMed

Yu, Xin; Zuo, Jiane; Li, Ruixia; Gan, Lili; Li, Zaixing; Zhang, Fei

2014-08-01

The conventional parameters and acute toxicities of antibiotic wastewater collected from each treatment unit of an antibiotic wastewater treatment plant have been investigated. The investigation of the conventional parameters indicated that the antibiotic wastewater treatment plant performed well under the significant fluctuation in influent water quality. The results of acute toxicity indicated that the toxicity of antibiotic wastewater could be reduced by 94.3 percent on average after treatment. However, treated antibiotic effluents were still toxic to Vibrio fischeri. The toxicity of antibiotic production wastewater could be attributed to the joint effects of toxic compound mixtures in wastewater. Moreover, aerobic biological treatment processes, including sequencing batch reactor (SBR) and aerobic biofilm reactor, played the most important role in reducing toxicity by 92.4 percent. Pearson׳s correlation coefficients revealed that toxicity had a strong and positive linear correlation with organic substances, nitrogenous compounds, S(2-), volatile phenol, cyanide, As, Zn, Cd, Ni and Fe. Ammonia nitrogen (NH4(+)) was the greatest contributor to toxicity according to the stepwise regression method. The multiple regression model was a good fit for [TU50-15 min] as a function of [NH₄(+)] with the determination coefficient of 0.981. Copyright © 2014 Elsevier Inc. All rights reserved.

Acute oral toxicity of Pereskia bleo and Pereskia grandifolia in mice

PubMed Central

Sim, K. S.; Sri Nurestri, A. M.; Sinniah, S. K.; Kim, K. H.; Norhanom, A. W.

2010-01-01

Pereskia bleo and Pereskia grandifolia, belonging to the botanical family Cactaceae, have been traditionally used by the locals in Malaysia for treatment of various ailments. The current study reports the outcome of acute oral toxicity investigation of Pereskia bleo and Pereskia grandifolia, on ICR mice. No mortalities or evidence of adverse effects have been observed in ICR mice following acute oral administration at the highest dose of 2500 mg/ kg crude extracts of Pereskia bleo and Pereskia grandifolia. This is the first report on the acute oral toxicity of Pereskia bleo and Pereskia grandifolia and the findings of this study are in agreement with those of in vitro experiments and thus provide scientific validation on the use of the leaves of Pereskia bleo and Pereskia grandifolia. PMID:20548939

Acute radiotherapy toxicity in 57 dogs with gross and microscopic mast cell tumours.

PubMed

Blackwood, L; Tanis, J B; Harper, A; Amores-Fuster, I; Killick, D R; Finotello, R

2018-05-15

Mast cell tumours (MCTs) are commonly treated with radiation therapy, most often in a microscopic disease setting. Poorer outcomes are expected in patients with gross disease, and irradiation of gross disease may be associated with greater toxicity. The aim of this study was to compare acute radiation adverse events (AE) in dogs with gross and microscopic MCTs receiving radiotherapy. Fifty-seven dogs were included, 28 with gross disease and 29 with microscopic. In order to assess mucosal and skin toxicity, patients were assigned to 2 groups: head (29 patients, 14 patients with gross and 15 microscopic) and other sites (28 patients, 14 each). All were treated with external beam radiotherapy, and toxicity assessed at the end of treatment and 10 to 14 days later (first recheck). All patients developed some acute radiation toxicity by the end of the course. However, there was no difference in the severity of toxicity between gross and microscopic disease in either site group at either time point. The only variable associated with an increased frequency of grade 2 or 3 toxicity at the first recheck was the use of prednisolone prior to radiotherapy (P = .05). No other factors were identified which were associated with increased toxicity. For the head group, the site of highest grade toxicity was mucosa or, if included in the field, nasal planum, which was often more severely affected than the mucosa. No significant late toxicity was identified. Two dogs developed acute haematemesis during the radiotherapy course, but both completed the course without further events. © 2018 John Wiley & Sons Ltd.

Acute toxicity of chlorantraniliprole to non-target crayfish (Procambarus clarkii) associated with rice-crayfish cropping systems.

PubMed

Barbee, Gary C; McClain, W Ray; Lanka, Srinivas K; Stout, Michael J

2010-09-01

Chlorantraniliprole, a novel anthranilic diamide insecticide, was recently introduced into the United States where rice-crayfish crop rotations are practiced to control rice water weevil (Lissorhoptrus oryzophilus Kuschel) infestations. Chlorantraniliprole has high margins of mammalian safety and excellent insecticidal efficacy, but its toxicity to non-target crayfish is uncertain. In this study, the acute toxicity of chlorantraniliprole to the red swamp crayfish Procambarus clarkii Girard was determined using aquatic and feeding assays. The aquatic 96 h median lethal toxicity (LC(50)) data indicate that technical-grade chlorantraniliprole is highly toxic (US EPA category) to crayfish with an LC(50) of 951 microg L(-1) (95% CL = 741-1118 microg L(-1)). A no observed effect concentration (NOEC) of 480 microg L(-1) was recorded. Neither the 36 day chronic feeding study, where crayfish fed on chlorantraniliprole-treated rice seed in aquaria, nor the 144 h acute feeding test, where crayfish fed on rice seeds treated with chlorantraniliprole, produced mortality or abnormal behavior. Chlorantraniliprole is three orders of magnitude less acutely toxic to P. clarkii than lambda-cyhalothrin and etofenprox, two pyrethroid insecticides also used in rice, and is less likely to cause acute crayfish toxicity in rice pond ecosystems. Based on acute toxicity data, the use of chlorantraniliprole should be more compatible with rice-crayfish crop rotations than pyrethroids. (c) 2010 Society of Chemical Industry.

Acute oral and percutaneous toxicity of pesticides to mallards: Correlations with mammalian toxicity data

USGS Publications Warehouse

Hudson, R.H.; Haegele, M.A.; Tucker, R.K.

1979-01-01

Acute oral (po) and 24-hr percutaneous (perc) LD50 values for 21 common pesticides (19 anticholinesterases, of which 18 were organophosphates, and one was a carbamate; one was an organochlorine central nervous system stimulant; and one was an organonitrogen pneumotoxicant) were determined in mallards (Anas platyrhynchos). Three of the pesticides tested were more toxic percutaneously than orally. An index to the percutaneous hazard of a pesticide, the dermal toxicity index (DTI = po LD50/perc LD50 ? 100), was also calculated for each pesticide. These toxicity values in mallards were compared with toxicity data for rats from the literature. Significant positive correlations were found between log po and log percutaneous LD50 values in mallards (r = 0.65, p 0.10). Variations in percutaneous methodologies are discussed with reference to interspecies variation in toxicity values. It is recommended that a mammalian DTI value approaching 30 be used as a guideline for the initiation of percutaneous toxicity studies in birds, when the po LD50 and/or projected percutaneous LD50 are less than expected field exposure levels.

Systemic Lupus Erythematosus, Radiotherapy, and the Risk of Acute and Chronic Toxicity: The Mayo Clinic Experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pinn, Melva E.; Gold, Douglas G. M.; Petersen, Ivy A.

2008-06-01

Purpose: To determine the acute and chronic toxic effects of radiotherapy in patients with systemic lupus erythematosus (SLE). Methods and Materials: Medical records of 21 consecutive patients with SLE, who had received 34 courses of external beam radiotherapy and one low-dose-rate prostate implant, were retrospectively reviewed. Patients with discoid lupus erythematosus were excluded. Results: Median survival was 2.3 years and median follow-up 5.6 years. Eight (42%) of 19 patients evaluable for acute toxicity during radiotherapy experienced acute toxicity of Grade 1 or greater, and 4 (21%) had acute toxicity of Grade 3 or greater. The 5- and 10-year incidence ofmore » chronic toxicity of Grade 1 or greater was 45% (95% confidence interval [CI], 22-72%) and 56% (95% CI, 28-81%), respectively. The 5- and 10-year incidence of chronic toxicity of Grade 3 or greater was 28% (95% CI, 18-60%) and 40% (95% CI, 16-72%), respectively. Univariate analysis showed that chronic toxicity of Grade 1 or greater correlated with SLE renal involvement (p < 0.006) and possibly with the presence of five or more American Rheumatism Association criteria (p < 0.053). Chronic toxicity of Grade 3 or greater correlated with an absence of photosensitivity (p < 0.02), absence of arthritis (p < 0.03), and presence of a malar rash (p < 0.04). Conclusions: The risk of acute and chronic toxicity in patients with SLE who received radiotherapy was moderate but was not prohibitive of the use of radiotherapy. Patients with more advanced SLE may be at increased risk for chronic toxicity.« less

Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

PubMed Central

2012-01-01

Objective Sulfur mustard (SM) is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980–1988). It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries. Method This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment. Results Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. Conclusion Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments. PMID:23351279

Why is particulate matter produced by wildfires toxic to lung macrophages?

PubMed

Franzi, Lisa M; Bratt, Jennifer M; Williams, Keisha M; Last, Jerold A

2011-12-01

The mechanistic basis of the high toxicity to lung macrophages of coarse PM from the California wildfires of 2008 was examined in cell culture experiments with mouse macrophages. Wildfire PM directly killed macrophages very rapidly in cell culture at relatively low doses. The wildfire coarse PM is about four times more toxic to macrophages on an equal weight basis than the same sized PM collected from normal ambient air (no wildfires) from the same region and season. There was a good correlation between the extent of cytotoxicity and the amount of oxidative stress observed at a given dose of wildfire PM in vitro. Our data implicate NF-κB signaling in the response of macrophages to wildfire PM, and suggest that most, if not all, of the cytotoxicity of wildfire PM to lung macrophages is the result of oxidative stress. The relative ratio of toxicity and of expression of biomarkers of oxidant stress between wildfire PM and "normal" PM collected from ambient air is consistent with our previous results in mice in vivo, also suggesting that most, if not all, of the cytotoxicity of wildfire PM to lung macrophages is the result of oxidative stress. Our findings from this and earlier studies suggest that the active components of coarse PM from the wildfire are heat-labile organic compounds. While we cannot rule out a minor role for endotoxin in coarse PM preparations from the collected wildfire PM in our observed results both in vitro and in vivo, based on experiments using the inhibitor Polymyxin B most of the oxidant stress and pro-inflammatory activity observed was not due to endotoxin. Copyright © 2011 Elsevier Inc. All rights reserved.

Why is Particulate Matter Produced by Wildfires Toxic To Lung Macrophages?

PubMed Central

Franzi, Lisa M.; Bratt, Jennifer M.; Williams, Keisha M.; Last, Jerold A.

2011-01-01

The mechanistic basis of the high toxicity to lung macrophages of coarse PM from the California wildfires of 2008 was examined in cell culture experiments with mouse macrophages. Wildfire PM directly killed macrophages very rapidly in cell culture at relatively low doses. The wildfire coarse PM are about four times more toxic to macrophages on an equal weight basis than the same sized PM collected from normal ambient air (no wildfires) from the same region and season. There was a good correlation between the extent of cytotoxicity and the amount of oxidative stress observed at a given dose of wildfire PM in vitro. Our data implicate NF-kB signaling in the response of macrophages to wildfire PM, and suggest that most, if not all, of the cytotoxicity of wildfire PM to lung macrophages is the result of oxidative stress. The relative ratio of toxicity and of expression of biomarkers of oxidant stress between wildfire PM and “normal” PM collected from ambient air is consistent with our previous results in mice in vivo, also suggesting that most, if not all, of the cytotoxicity of wildfire PM to lung macrophages is the result of oxidative stress. Our findings from this and earlier studies suggest that the active components of coarse PM from the wildfire are heat-labile organic compounds. While we can not rule out a minor role for endotoxin in coarse PM preparations from the collected wildfire PM in our observed results both in vitro and in vivo, based on experiments using the inhibitor Polymyxin B most of the oxidant stress and pro-inflammatory activity observed was not due to endotoxin. PMID:21945489

A unified approach for EIT imaging of regional overdistension and atelectasis in acute lung injury.

PubMed

Gómez-Laberge, Camille; Arnold, John H; Wolf, Gerhard K

2012-03-01

Patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS) are vulnerable to ventilator-induced lung injury. Although this syndrome affects the lung heterogeneously, mechanical ventilation is not guided by regional indicators of potential lung injury. We used electrical impedance tomography (EIT) to estimate the extent of regional lung overdistension and atelectasis during mechanical ventilation. Techniques for tidal breath detection, lung identification, and regional compliance estimation were combined with the Graz consensus on EIT lung imaging (GREIT) algorithm. Nine ALI/ARDS patients were monitored during stepwise increases and decreases in airway pressure. Our method detected individual breaths with 96.0% sensitivity and 97.6% specificity. The duration and volume of tidal breaths erred on average by 0.2 s and 5%, respectively. Respiratory system compliance from EIT and ventilator measurements had a correlation coefficient of 0.80. Stepwise increases in pressure could reverse atelectasis in 17% of the lung. At the highest pressures, 73% of the lung became overdistended. During stepwise decreases in pressure, previously-atelectatic regions remained open at sub-baseline pressures. We recommend that the proposed approach be used in collaborative research of EIT-guided ventilation strategies for ALI/ARDS.

Intensity-modulated radiotherapy as primary treatment for prostate cancer: acute toxicity in 114 patients.

PubMed

De Meerleer, Gert; Vakaet, Luc; Meersschout, Sabine; Villeirs, Geert; Verbaeys, Antony; Oosterlinck, Wim; De Neve, Wilfried

2004-11-01

Dose escalation improves local control in prostate cancer. At Ghent University Hospital, intensity-modulated radiotherapy (IMRT) is used to increase the dose to the prostate and/or seminal vesicles. We report on acute toxicity in 114 patients who received IMRT for prostate cancer. Intensity-modulated radiotherapy was initiated after approval of our ethics committee. A class solution was used to plan all cases. Three beams (gantry 0 degrees , 116 degrees , and 244 degrees ) and anatomy-based segmentation were used to create an intensity-modulated dose distribution. Maximal rectal dose was set at 2 Gy per fraction. Detailed dose-volume histograms for all relevant structures were present. For all patients, we determined the pretreatment morbidity by a detailed preradiotherapy, in-house developed symptom scale. All patients were treated with 18 MV photons of an Elekta linear accelerator. Patients were seen on a weekly basis during treatment, and 1 month (M1) and 3 months (M3) thereafter. The registration of acute toxicity was standardized by a fixed questionnaire. The Radiation Therapy Oncology Group (RTOG) toxicity scale served as a basis, but additional symptoms, such as rectal blood loss, urgency, and incontinence, were scored as well. All 114 IMRT plans were delivered successfully without any interruption or technical problem. Daily treatment time was always less than 8 min and less than 6 min in 90% of the cases. Grade 1 and Grade 2 gastrointestinal (GI) toxicities were observed in 44% and 29% of the patients, respectively, during the whole period. If only the RTOG scale was used, Grade 1 and Grade 2 GI toxicities were noted in 39% and 27% of the patients, respectively, leaving 34% free of acute RTOG-scaled toxicity. Grade 3 genitourinary (GU) toxicity was seen in 8 patients (7%), all but 1 during treatment. Grade 2 and Grade 1 GU toxicities were seen in 36% and 47% of the patients, respectively, leaving only 10% free of acute GU toxicity. Anatomy-based IMRT to

Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis

PubMed Central

Mittal, Anubhav; Hickey, Anthony JR; Chai, Chau C; Loveday, Benjamin PT; Thompson, Nichola; Dare, Anna; Delahunt, Brett; Cooper, Garth JS; Windsor, John A; Phillips, Anthony RJ

2011-01-01

Introduction Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis. Methods Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n = 8), saline control; Group 2 (n = 6), caerulein-induced mild acute pancreatitis; Group 3 (n = 7) sham surgical controls; and Group 4 (n = 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry. Results Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected. Conclusions The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis. PMID:21492333

Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein.

PubMed

Conklin, Daniel J; Haberzettl, Petra; Jagatheesan, Ganapathy; Kong, Maiying; Hoyle, Gary W

2017-06-01

Acrolein is a highly toxic, volatile, unsaturated aldehyde generated during incomplete combustion as in tobacco smoke and indoor fires. Because the transient receptor potential ankyrin 1 (TRPA1) channel mediates tobacco smoke-induced lung injury, we assessed its role in high-level acrolein-induced toxicity in mice. Acrolein (100-275ppm, 10-30min) caused upper airway epithelial sloughing, bradypnea and oral gasping, hypothermia, cardiac depression and mortality. Male wild-type mice (WT, C57BL/6; 5-52weeks) were significantly more sensitive to high-level acrolein than age-matched, female WT mice. Both male and female TRPA1-null mice were more sensitive to acrolein-induced mortality than age- and sex-matched WT mice. Acrolein exposure increased lung weight:body weight ratios and lung albumin and decreased plasma albumin to a greater extent in TRPA1-null than in WT mice. Lung and plasma protein-acrolein adducts were not increased in acrolein-exposed TRPA1-null mice compared with WT mice. To assess TRPA1-dependent protective mechanisms, respiratory parameters were monitored by telemetry. TRPA1-null mice had a slower onset of breathing rate suppression ('respiratory braking') than WT mice suggesting TRPA1 mediates this protective response. Surprisingly, WT male mice treated either with a TRPA1 antagonist (HC030031; 200mg/kg) alone or with combined TRPA1 (100mg/kg) and TRPV1 (capsazepine, 10mg/kg) antagonists at 30min post-acrolein exposure (i.e., "real world" delay in treatment) were significantly protected from acrolein-induced mortality. These data show TRPA1 protects against high-level acrolein-induced toxicity in a sex-dependent manner. Post-exposure TRPA1 antagonism also protected against acrolein-induced mortality attesting to a complex role of TRPA1 in cardiopulmonary injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Use of fish embryo toxicity tests for the prediction of acute fish toxicity to chemicals.

PubMed

Belanger, Scott E; Rawlings, Jane M; Carr, Gregory J

2013-08-01

The fish embryo test (FET) is a potential animal alternative for the acute fish toxicity (AFT) test. A comprehensive validation program assessed 20 different chemicals to understand intra- and interlaboratory variability for the FET. The FET had sufficient reproducibility across a range of potencies and modes of action. In the present study, the suitability of the FET as an alternative model is reviewed by relating FET and AFT. In total, 985 FET studies and 1531 AFT studies were summarized. The authors performed FET-AFT regressions to understand potential relationships based on physical-chemical properties, species choices, duration of exposure, chemical classes, chemical functional uses, and modes of action. The FET-AFT relationships are very robust (slopes near 1.0, intercepts near 0) across 9 orders of magnitude in potency. A recommendation for the predictive regression relationship is based on 96-h FET and AFT data: log FET median lethal concentration (LC50) = (0.989 × log fish LC50) - 0.195; n = 72 chemicals, r = 0.95, p < 0.001, LC50 in mg/L. A similar, not statistically different regression was developed for the entire data set (n = 144 chemicals, unreliable studies deleted). The FET-AFT regressions were robust for major chemical classes with suitably large data sets. Furthermore, regressions were similar to those for large groups of functional chemical categories such as pesticides, surfactants, and industrial organics. Pharmaceutical regressions (n = 8 studies only) were directionally correct. The FET-AFT relationships were not quantitatively different from acute fish-acute fish toxicity relationships with the following species: fathead minnow, rainbow trout, bluegill sunfish, Japanese medaka, and zebrafish. The FET is scientifically supportable as a rational animal alternative model for ecotoxicological testing of acute toxicity of chemicals to fish. Copyright © 2013 SETAC.

Nitrite therapy prevents chlorine gas toxicity in rabbits.

PubMed

Honavar, Jaideep; Doran, Stephen; Ricart, Karina; Matalon, Sadis; Patel, Rakesh P

2017-04-05

Chlorine (Cl 2 ) gas exposure and toxicity remains a concern in military and industrial sectors. While post-Cl 2 exposure damage to the lungs and other tissues has been documented and major underlying mechanisms elucidated, no targeted therapeutics that are effective when administered post-exposure, and which are amenable to mass-casualty scenarios have been developed. Our recent studies show nitrite administered by intramuscular (IM) injection post-Cl 2 exposure is effective in preventing acute lung injury and improving survival in rodent models. Our goal in this study was to develop a rabbit model of Cl 2 toxicity and test whether nitrite affords protection in a non-rodent model. Exposure of New Zealand White rabbits to Cl 2 gas (600ppm, 45min) caused significant increases in protein and neutrophil accumulation in the airways and ∼35% mortality over 18h. Nitrite administered 30min post Cl 2 exposure by a single IM injection, at 1mg/kg or 10mg/kg, prevented indices of acute lung injury at 6h by up to 50%. Moreover, all rabbits that received nitrite survived over the study period. These data provide further rationale for developing nitrite as post-exposure therapeutic to mitigate against Cl 2 gas exposure injury. Copyright © 2017 Elsevier B.V. All rights reserved.

Nitrite therapy prevents chlorine gas toxicity in rabbits

PubMed Central

Honavar, Jaideep; Doran, Stephen; Ricart, Karina; Matalon, Sadis; Patel, Rakesh P.

2017-01-01

Chlorine (Cl2) gas exposure and toxicity remains a concern in military and industrial sectors. While post-Cl2 exposure damage to the lungs and other tissues has been documented and major underlying mechanisms elucidated, no targeted therapeutics that are effective when administered post-exposure, and which are amenable to mass-casualty scenarios have been developed. Our recent studies show nitrite administered by intramuscular (IM) injection post-Cl2 exposure is effective in preventing acute lung injury and improving survival in rodent models. Our goal in this study was to develop a rabbit model of Cl2 toxicity and test whether nitrite affords protection in a non-rodent model. Exposure of New Zealand White rabbits to Cl2 gas (600ppm, 45min) caused significant increases in protein and neutrophil accumulation in the airways and ~35% mortality over 18h. Nitrite administered 30min post Cl2 exposure by a single IM injection, at 1mg/Kg or 10mg/Kg, prevented indices of acute lung injury at 6h by up to 50%. Moreover, all rabbits that received nitrite survived over the study period. These data provide further rationale for developing nitrite as post-exposure therapeutic to mitigate against Cl2 gas exposure injury. PMID:28237808

Acute toxicity and genotoxicity of fermented traditional medicine oyaksungi-san.

PubMed

Park, Hwayong; Hwang, Youn-Hwan; Ma, Jin Yeul

2017-06-01

The traditional medicine oyaksungi-san (OY) has been prescribed in East Asia for hundreds of years for the treatment of stroke, paralysis, and ataxia. OY also has therapeutic effects on arthralgia, myalgia, and rheumatoid arthritis, and recent studies have shown its protective effects against apoptosis of hippocampal cells and its anti-inflammatory effects on the peripheral blood cells of patient with cerebral infarction. Many studies have explored the use of traditional medicine and herb materials in the development of safe, novel, and effective pharmaceuticals with fewer side effects. These efforts commonly adopt a bioconversion tool for fermentation with beneficial microbes. However, only pharmaceuticals with high levels of safety and low levels of toxicity can be used in healthcare system. OY water extract was fermented with Lactobacillus and assayed for acute toxicity and genotoxicity. Single dose acute toxicity, bacterial reverse mutation, chromosome aberrations, and micronucleus were observed and assayed in rats, histidine/tryptophan auxotrophic bacteria, Chinese hamster ovary fibroblast cells, and mice bone marrow cells, respectively. All the experimental animals showed no abnormal behavior, clinical signs, body weight increases, or mortality. In the bacterial cultures, no revertant colonies were observed. Morphological and numerical chromosomal aberrations were not found in all metaphases examined. Frequency of induced micronuclei was not significantly increased in all doses applied. As a whole, no acute toxicity or genotoxicity were observed in all the assays examined. Therefore, fermented OY is considered to be a safe material that can be used for development of complementary and alternative medicine using bioconversion.

Evaluation of pulmonary and systemic toxicity following lung exposure to graphite nanoplates: a member of the graphene-based nanomaterial family.

PubMed

Roberts, Jenny R; Mercer, Robert R; Stefaniak, Aleksandr B; Seehra, Mohindar S; Geddam, Usha K; Chaudhuri, Ishrat S; Kyrlidis, Angelos; Kodali, Vamsi K; Sager, Tina; Kenyon, Allison; Bilgesu, Suzan A; Eye, Tracy; Scabilloni, James F; Leonard, Stephen S; Fix, Natalie R; Schwegler-Berry, Diane; Farris, Breanne Y; Wolfarth, Michael G; Porter, Dale W; Castranova, Vincent; Erdely, Aaron

2016-06-21

Graphene, a monolayer of carbon, is an engineered nanomaterial (ENM) with physical and chemical properties that may offer application advantages over other carbonaceous ENMs, such as carbon nanotubes (CNT). The goal of this study was to comparatively assess pulmonary and systemic toxicity of graphite nanoplates, a member of the graphene-based nanomaterial family, with respect to nanoplate size. Three sizes of graphite nanoplates [20 μm lateral (Gr20), 5 μm lateral (Gr5), and <2 μm lateral (Gr1)] ranging from 8-25 nm in thickness were characterized for difference in surface area, structure,, zeta potential, and agglomeration in dispersion medium, the vehicle for in vivo studies. Mice were exposed by pharyngeal aspiration to these 3 sizes of graphite nanoplates at doses of 4 or 40 μg/mouse, or to carbon black (CB) as a carbonaceous control material. At 4 h, 1 day, 7 days, 1 month, and 2 months post-exposure, bronchoalveolar lavage was performed to collect fluid and cells for analysis of lung injury and inflammation. Particle clearance, histopathology and gene expression in lung tissue were evaluated. In addition, protein levels and gene expression were measured in blood, heart, aorta and liver to assess systemic responses. All Gr samples were found to be similarly composed of two graphite structures and agglomerated to varying degrees in DM in proportion to the lateral dimension. Surface area for Gr1 was approximately 7-fold greater than Gr5 and Gr20, but was less reactive reactive per m(2). At the low dose, none of the Gr materials induced toxicity. At the high dose, Gr20 and Gr5 exposure increased indices of lung inflammation and injury in lavage fluid and tissue gene expression to a greater degree and duration than Gr1 and CB. Gr5 and Gr20 showed no or minimal lung epithelial hypertrophy and hyperplasia, and no development of fibrosis by 2 months post-exposure. In addition, the aorta and liver inflammatory and acute phase genes were transiently

Experimental study on acute toxicity of Qingnao tablet to mice

NASA Astrophysics Data System (ADS)

Xie, Guoqi; Wang, Huamin; Ma, Zhenzhen; Hao, Shaojun; Li, Jun; Wang, Hongyu; Wen, Zhonghua; Zhang, Zhengchen

2018-04-01

To investigate the effect of Qingnao tablets on acute toxicity in mice. Forty mice, half male and half female, were randomly divided into normal saline group and Qingnao tablet group. After fasting for 12 hours, the mice were given 0. 4 ml / 10 g in maximum volume. In 1st, the rats were perfused 3 times (every 8 hours). The rats in the saline group were perfused with the same volume of saline in the same way. The mice were observed continuously within 3 hours and then every hour. The mice were given a normal diet for 14 consecutive days, and the changes of autonomous activity, reaction, diet, stool, secretion, eye and nose were observed daily. The mice fasted on the 13th day and weighed on the 14th day. And then put the mice to death, The changes of the liver, heart, spleen, lung, kidney, stomach, intestines, and brain were observed by the naked eye. There was no obvious abnormality in normal saline group. The autonomous activity of mice in the administration group decreased after initial administration, and gradually returned to normal after 2 hours of administration. On the day of administration, the stool of the mice became dark brown, and the feces returned to normal after 1.1 days of normal urination. No other mice had abnormal secretion, reaction, eye nose, diet, etc. On the 14th day, there were no visible heart, liver, spleen, lung, kidney, gastrointestinal tract in normal saline group and Qingnao tablet group. Abnormal changes in brain and other organs (edema, color, etc.). In the normal saline group and Qingnao tablet group, the initial weight of the mice was: 21.70 ± 0.97N 21.71 ± 1.13, and the weight of the mice on the 7th day was 29.70 ± 2.4c28.65 ± 3.11. On the 14th day, the body weight was 32.38 ± 3.40, 33.77 ± 3.82. Qingnao tablet has no obvious toxicity to the main organs of mice, so it can be considered safe in clinical use.

Acute methaemoglobinaemia initially treated as organophosphate poisoning leading to atropine toxicity.

PubMed

Kakhandki, Srinivas; Yahya, Mohammed; Praveen, Mudalgi

2012-07-01

A case of unknown compound poisoning is presented. It was initially treated as organophosphate poisoning with lack of response. A timely diagnosis of acute methaemoglobinaemia and iatrogenic atropine toxicity was made based on clinical evaluation. Treatment of methaemoglobinaemia using oral methylene blue and of atropine toxicity with supportive measures could save the patient.

Evaluation of acute and sub-acute toxicity of Pinus eldarica bark extract in Wistar rats

PubMed Central

Ghadirkhomi, Akram; Safaeian, Leila; Zolfaghari, Behzad; Agha Ghazvini, Mohammad Reza; Rezaei, Parisa

2016-01-01

Objective: Pinus eldarica (P. eldarica) is one of the most common pines in Iran which has various bioactive constituents and different uses in traditional medicine. Since there is no documented evidence for P. eldarica safety, the acute and sub-acute oral toxicities of hydroalcoholic extract of P. eldarica bark were investigated in male and female Wistar rats in this study. Materials and Methods: In the acute study, a single dose of extract (2000 mg/kg) was orally administered and animals were monitored for 7 days. In the sub-acute study, repeated doses (125, 250 and 500 mg/kg/day) of the extract were administered for 28 days and biochemical, hematological and histopathological parameters were evaluated. Results: Our results showed no sign of toxicity and no mortality after single or repeated administration of P. eldarica. The median lethal dose (LD50) of P. eldarica was determined to be higher than 2000 mg/kg. The mean body weight and most of the biochemical and hematological parameters showed normal levels. There were only significant decreases in serum triglyceride levels at the doses of 250 and 500 mg/kg of the extract in male rats (p<0.05 and p<0.01, respectively) and in monocyte counts at the highest dose of the extract in both male and female rats (p<0.05). Mild inflammation was also found in histological examination of kidney and liver tissues at the highest dose of extract. Conclusion: Oral administration of the hydroalcoholic extract of P. eldarica bark may be considered as relatively non-toxic particularly at the doses of 125 and 250 mg/kg. PMID:27761426

Status of acute systemic toxicity testing requirements and data uses by U.S. regulatory agencies.

PubMed

Strickland, Judy; Clippinger, Amy J; Brown, Jeffrey; Allen, David; Jacobs, Abigail; Matheson, Joanna; Lowit, Anna; Reinke, Emily N; Johnson, Mark S; Quinn, Michael J; Mattie, David; Fitzpatrick, Suzanne C; Ahir, Surender; Kleinstreuer, Nicole; Casey, Warren

2018-04-01

Acute systemic toxicity data are used by a number of U.S. federal agencies, most commonly for hazard classification and labeling and/or risk assessment for acute chemical exposures. To identify opportunities for the implementation of non-animal approaches to produce these data, the regulatory needs and uses for acute systemic toxicity information must first be clarified. Thus, we reviewed acute systemic toxicity testing requirements for six U.S. agencies (Consumer Product Safety Commission, Department of Defense, Department of Transportation, Environmental Protection Agency, Food and Drug Administration, Occupational Safety and Health Administration) and noted whether there is flexibility in satisfying data needs with methods that replace or reduce animal use. Understanding the current regulatory use and acceptance of non-animal data is a necessary starting point for future method development, optimization, and validation efforts. The current review will inform the development of a national strategy and roadmap for implementing non-animal approaches to assess potential hazards associated with acute exposures to industrial chemicals and medical products. The Acute Toxicity Workgroup of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), U.S. agencies, non-governmental organizations, and other stakeholders will work to execute this strategy. Copyright © 2018 Elsevier Inc. All rights reserved.

Geographic boundaries in breast, lung and colorectal cancers in relation to exposure to air toxics in Long Island, New York

PubMed Central

Jacquez, Geoffrey M; Greiling, Dunrie A

2003-01-01

Background This two-part study employs several statistical techniques to evaluate the geographic distribution of breast cancer in females and colorectal and lung cancers in males and females in Nassau, Queens, and Suffolk counties, New York, USA. In this second paper, we compare patterns in standardized morbidity ratios (SMR values), calculated from New York State Department of Health (NYSDOH) data, to geographic patterns in overall predicted risk (OPR) from air toxics using exposures estimated in the USEPA National Air Toxics Assessment database. Results We identified significant geographic boundaries in SMR and OPR. We found little or no association between the SMR of colorectal and breast cancers and the OPR for each cancer from exposure to the air toxics. We did find boundaries in male and female lung cancer SMR and boundaries in lung cancer OPR to be closer to one another than expected. Conclusion While consistent with a causal relationship between air toxics and lung cancer incidence, the boundary analysis does not demonstrate the existence of a causal relationship. However, now that the areas of overlap between boundaries in lung cancer incidence and potential airborne exposures have been identified, we can begin to evaluate local- as well as large-scale determinants of lung cancer. PMID:12633502

Timed Get Up and Go Test and Geriatric 8 Scores and the Association With (Chemo-)Radiation Therapy Noncompliance and Acute Toxicity in Elderly Cancer Patients.

PubMed

Middelburg, Judith G; Mast, Mirjam E; de Kroon, Maaike; Jobsen, Jan J; Rozema, Tom; Maas, Huub; Baartman, Elizabet A; Geijsen, Debby; van der Leest, Annija H; van den Bongard, Desirée J; van Loon, Judith; Budiharto, Tom; Coebergh, Jan Willem; Aarts, Mieke J; Struikmans, Henk

2017-07-15

To investigate whether the Geriatric 8 (G8) and the Timed Get Up and Go Test (TGUGT) and clinical and demographic patient characteristics were associated with acute toxicity of radiation therapy and noncompliance in elderly cancer patients being irradiated with curative intent. Patients were eligible if aged ≥65 years and diagnosed with breast, non-small cell lung, prostate, head and neck, rectal, or esophageal cancer, and were referred for curative radiation therapy. We recorded acute toxicity and noncompliance and identified potential predictors, including the G8 and TGUGT. We investigated 402 patients with a median age of 72 years (range, 65-96 years). According to the G8, 44.4% of the patients were frail. Toxicity grade ≥3 was observed in 22% of patients who were frail according to the G8 and 9.1% of patients who were not frail. The difference was 13% (confidence interval 5.2%-20%; P=.0006). According to the TGUGT 18.8% of the patients were frail; 21% of the frail according to the TGUGT developed toxicity grade ≥3, compared with 13% who were not frail. The difference was 7.3% (confidence interval -2.7% to 17%; P=.11). Overall compliance was 95%. Toxicity was most strongly associated with type of primary tumor, chemotherapy, age, and World Health Organization performance status. Compliance was associated with type of primary tumor and age. The usefulness of the TGUGT and G8 score in daily practice seems to be limited. Type of primary tumor, chemoradiotherapy, age, and World Health Organization performance status were more strongly associated with acute toxicity. Only chemoradiotherapy and age were associated with noncompliance. Overall the compliance was very high. To allow better-informed treatment decisions, a more accurate prediction of toxicity is desirable. Copyright © 2017. Published by Elsevier Inc.

The acute toxicity of major ion salts to Ceriodaphnia dubia: I. ...

EPA Pesticide Factsheets

The ions Na+, K+, Ca2+, Mg2+, Cl-, SO42-, and HCO3-/CO32- (referred to as “major ions”) are present in all fresh waters and are physiologically required by aquatic organisms, but can be increased to harmful levels by a variety of anthropogenic activities that speed geochemical weathering or otherwise introduce or concentrate ions. While toxicity of these ions to aquatic organisms has been previously shown, it is also known that their toxicity can vary depending on the concentrations of other co-occurring anions, and understanding these relationships is key to predicting toxicity and establishing appropriate environmental limits. In this paper we conduct a series of experiments with Ceriodaphnia dubia to evaluate the acute toxicity of all twelve major ionsalts (pairing one of the cations with one of the anions) and to determine how toxicity of these salts varies as a function of background water chemistry. All salts except CaSO4 and CaCO3 were acutely toxic to C. dubia below saturation, with the lowest LC50s found for K salts. Of the remaining salts, all but CaCl2 showed some degree of decreased toxicity as the ionic content of the background water increased. Experiments that independently varied Ca:Mg ratio, Na:K ratio, Cl:SO4 ratio, and alkalinity/pH were used to show that Ca concentration was the primary factor influencing the toxicities of Na and Mg salts. In contrast, the toxicities of K salts were primarily influenced by the concentration of Na. Th

Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-γ.

PubMed

Shen, Yongbin; Sun, Zhanfeng; Guo, Xiaotong

2015-01-15

Citral, a component of lemongrass oil, has been reported to have many pharmacological activities such as anti-bacterial and anti-inflammatory effects. However, the effects of citral on acute lung injury (ALI) and the molecular mechanisms have not been reported. The aim of this study was to detect the effects of citral on lipopolysaccharide (LPS)-induced acute lung injury and investigate the molecular mechanisms. LPS-induced acute lung injury model was used to detect the anti-inflammatory effect of citral in vivo. The alveolar macrophages were used to investigate the molecular mechanism of citral in vitro. The results showed that pretreatment with citral remarkably attenuated pulmonary edema, histological severities, TNF-α, IL-6 and IL-1β production in LPS-induced ALI in vivo. In vitro, citral inhibited LPS-induced TNF-α, IL-6 and IL-1β production in alveolar macrophages. LPS-induced NF-κB activation was also inhibited by citral. Furthermore, we found that citral activated PPAR-γ and the anti-inflammatory effects of citral can be reversed by PPAR-γ antagonist GW9662. In conclusion, this is the first to demonstrate that citral protects LPS-induced ALI in mice. The anti-inflammatory mechanism of citral is associated with activating PPAR-γ, thereby inhibiting LPS-induced inflammatory response. Copyright © 2014 Elsevier B.V. All rights reserved.

Acute Toxicity and Environmental Risks of Five Veterinary Pharmaceuticals for Aquatic Macroinvertebrates.

PubMed

Bundschuh, Mirco; Hahn, Torsten; Ehrlich, Bert; Höltge, Sibylla; Kreuzig, Robert; Schulz, Ralf

2016-02-01

Due to the high use of antibiotics and antiparasitics for the treatment of livestock, there is concern about the potential impacts of the release of these compounds into freshwater ecosystems. In this context, the present study quantified the acute toxicity of two antibiotics (sulfadiazine and sulfadimidine), and three antiparasitic agents (flubendazole, fenbendazole, ivermectin) for nine freshwater invertebrate species. These experiments revealed a low degree of toxicity for the sulfonamide antibiotics, with limited implications in the survival of all test species at the highest test concentrations (50 and 100 mg/L). In contrast, all three antiparasitic agents indicated on the basis of their acute toxicity risks for the aquatic environment. Moreover, chronic toxicity data from the literature for antiparasitics, including effects on reproduction in daphnids, support the concern about the integrity of aquatic ecosystems posed by releases of these compounds. Thus, these pharmaceuticals warrant further careful consideration by environmental risk managers.

Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction.

PubMed

Lu, Qing; Mundy, Miles; Chambers, Eboni; Lange, Thilo; Newton, Julie; Borgas, Diana; Yao, Hongwei; Choudhary, Gaurav; Basak, Rajshekhar; Oldham, Mahogany; Rounds, Sharon

2017-12-01

Inhalation of acrolein, a highly reactive aldehyde, causes lung edema. The underlying mechanism is poorly understood and there is no effective treatment. In this study, we demonstrated that acrolein not only dose-dependently induced lung edema but also promoted LPS-induced acute lung injury. Importantly, acrolein-induced lung injury was prevented and rescued by Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2. Acrolein also dose-dependently increased monolayer permeability, disrupted adherens junctions and focal adhesion complexes, and caused intercellular gap formation in primary cultured lung microvascular endothelial cells (LMVECs). These effects were attenuated by Alda-1 and the antioxidant N-acetylcysteine, but not by the NADPH inhibitor apocynin. Furthermore, acrolein inhibited AMP-activated protein kinase (AMPK) and increased mitochondrial reactive oxygen species levels in LMVECs-effects that were associated with impaired mitochondrial respiration. AMPK total protein levels were also reduced in lung tissue of mice and LMVECs exposed to acrolein. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside blunted an acrolein-induced increase in endothelial monolayer permeability, but not mitochondrial oxidative stress or inhibition of mitochondrial respiration. Our results suggest that acrolein-induced mitochondrial dysfunction may not contribute to endothelial barrier dysfunction. We speculate that detoxification of acrolein by Alda-1 and activation of AMPK may be novel approaches to prevent and treat acrolein-associated acute lung injury, which may occur after smoke inhalation.

Prostate Hypofractionated Radiation Therapy With Injection of Hyaluronic Acid: Acute Toxicities in a Phase 2 Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chapet, Olivier, E-mail: olivier.chapet@chu-lyon.fr; EMR3738, Université Lyon 1, Lyon; Decullier, Evelyne

Purpose: Hypofractionated radiation therapy (RT) in prostate cancer can be developed only if the risk of rectal toxicity is controlled. In a multicenter phase 2 trial, hypofractionated irradiation was combined with an injection of hyaluronic acid (HA) to preserve the rectal wall. Tolerance of the injection and acute toxicity rates are reported. Methods and Materials: The study was designed to assess late grade 2 toxicity rates. The results described here correspond to the secondary objectives. Acute toxicity was defined as occurring during RT or within 3 months after RT and graded according to the Common Terminology Criteria for Adverse Eventsmore » version 4.0. HA tolerance was evaluated with a visual analog scale during the injection and 30 minutes after injection and then by use of the Common Terminology Criteria at each visit. Results: From 2010 to 2012, 36 patients with low-risk to intermediate-risk prostate cancer were included. The HA injection induced a mean pain score of 4.6/10 ± 2.3. Thirty minutes after the injection, 2 patients still reported pain (2/10 and 3/10), which persisted after the intervention. Thirty-three patients experienced at least 1 acute genitourinary toxicity and 20 patients at least 1 acute gastrointestinal toxicity. Grade 2 toxicities were reported for 19 patients with urinary obstruction, frequency, or both and for 1 patient with proctitis. No grade 3 or 4 toxicities were reported. At the 3-month visit, 4 patients described grade 2 obstruction or frequency, and no patients had any grade 2 gastrointestinal toxicities. Conclusions: The injection of HA makes it possible to deliver hypofractionated irradiation over 4 weeks with a dose per fraction of > 3 Gy, with limited acute rectal toxicity.« less

Variability of LD50 Values from Rat Oral Acute Toxicity Studies: Implications for Alternative Model Development

EPA Science Inventory

Alternative models developed for estimating acute systemic toxicity are generally evaluated using in vivo LD50 values. However, in vivo acute systemic toxicity studies can produce variable results, even when conducted according to accepted test guidelines. This variability can ma...

Radiation-induced heart disease in lung cancer radiotherapy

PubMed Central

Ming, Xin; Feng, Yuanming; Yang, Chengwen; Wang, Wei; Wang, Ping; Deng, Jun

2016-01-01

Abstract Background: Radiation-induced heart disease (RIHD), which affects the patients’ prognosis with both acute and late side effects, has been published extensively in the radiotherapy of breast cancer, lymphoma and other benign diseases. Studies on RIHD in lung cancer radiotherapy, however, are less extensive and clear even though the patients with lung cancer are delivered with higher doses to the heart during radiation treatment. Methods: In this article, after extensive literature search and analysis, we reviewed the current evidence on RIHD in lung cancer patients after their radiation treatments and investigated the potential risk factors for RIHD as compared to other types of cancers. Result: Cardiac toxicity has been found highly relevant in lung cancer radiotherapy. So far, the crude incidence of cardiac complications in the lung cancer patients after radiotherapy has been up to 33%. Conclusion: The dose to the heart, the lobar location of tumor, the treatment modality, the history of heart and pulmonary disease and smoking were considered as potential risk factors for RIHD in lung cancer radiotherapy. As treatment techniques improve over the time with better prognosis for lung cancer survivors, an improved prediction model can be established to further reduce the cardiac toxicity in lung cancer radiotherapy. PMID:27741117

Evaluation of the toxic effect of endocrine disruptor Bisphenol A (BPA) in the acute and chronic toxicity tests with Pomacea lineata gastropod.

PubMed

de Andrade, André Lucas Correa; Soares, Priscila Rafaela Leão; da Silva, Stephannie Caroline Barros Lucas; da Silva, Marília Cordeiro Galvão; Santos, Thamiris Pinheiro; Cadena, Marilia Ribeiro Sales; Soares, Pierre Castro; Cadena, Pabyton Gonçalves

2017-07-01

Bisphenol A (BPA) is a plasticizer and a risk when it interacts with organisms, and can cause changes in the development and reproduction of them. This study aimed to evaluate the effects of BPA, by acute and chronic toxicity tests with neonates and adults of Pomacea lineata. Adults and neonates were divided into groups exposed to BPA (1-20mg/L), or 17β-estradiol (1mg/L) and control in the acute and chronic toxicity tests. Behavior, heart rate, reproduction and hemolymph biochemical analysis were measured. In the acute toxicity test, the 96-h LC 50 with adults was 11.09 and with neonates was 3.14mg/L. In this test, it was observed lethargic behavior and an increase of 77.6% of aspartate aminotransferase in the adults' hemolymph (p<0.05); and neonates' heart rate decreased 72.7% (p<0.05). In the chronic toxicity test, it was observed behaviors associated with reproduction, as Copulate, in the groups exposed to BPA. The results that were found in this study proved that BPA is a potentially toxic agent to Pomacea lineata according to biological parameters evaluated. These data contribute to the understanding of BPA toxic effects' in the aquatic invertebrates. Copyright © 2017 Elsevier Inc. All rights reserved.

[The use of Timalin in the treatment of the acute lung abscess].

PubMed

Tsybikov, M N; Likhanov, I D; Borshchevskiĭ, V S; Kuznik, B I; Tsepelev, V L; Maslo, E Iu; Tsybikov, N N

2012-01-01

The study was aimed to research levels of main acute inflammation phase peptides, coagulative and fibrinolitic plasma activity on the background of traditional treatment and with addition of Timalin in patients with acute lung abscess. The study demonstrated that induction of bioregulative therapy leads to faster normalization of main indicators of SIRS and plasma fibrinolitic activity and eliminates hypercoagulation.

Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Conklin, Daniel J., E-mail: dj.conklin@louisville.

Acrolein is a highly toxic, volatile, unsaturated aldehyde generated during incomplete combustion as in tobacco smoke and indoor fires. Because the transient receptor potential ankyrin 1 (TRPA1) channel mediates tobacco smoke-induced lung injury, we assessed its role in high-level acrolein-induced toxicity in mice. Acrolein (100–275 ppm, 10–30 min) caused upper airway epithelial sloughing, bradypnea and oral gasping, hypothermia, cardiac depression and mortality. Male wild-type mice (WT, C57BL/6; 5–52 weeks) were significantly more sensitive to high-level acrolein than age-matched, female WT mice. Both male and female TRPA1-null mice were more sensitive to acrolein-induced mortality than age- and sex-matched WT mice. Acroleinmore » exposure increased lung weight:body weight ratios and lung albumin and decreased plasma albumin to a greater extent in TRPA1-null than in WT mice. Lung and plasma protein-acrolein adducts were not increased in acrolein-exposed TRPA1-null mice compared with WT mice. To assess TRPA1-dependent protective mechanisms, respiratory parameters were monitored by telemetry. TRPA1-null mice had a slower onset of breathing rate suppression (‘respiratory braking’) than WT mice suggesting TRPA1 mediates this protective response. Surprisingly, WT male mice treated either with a TRPA1 antagonist (HC030031; 200 mg/kg) alone or with combined TRPA1 (100 mg/kg) and TRPV1 (capsazepine, 10 mg/kg) antagonists at 30 min post-acrolein exposure (i.e., “real world” delay in treatment) were significantly protected from acrolein-induced mortality. These data show TRPA1 protects against high-level acrolein-induced toxicity in a sex-dependent manner. Post-exposure TRPA1 antagonism also protected against acrolein-induced mortality attesting to a complex role of TRPA1 in cardiopulmonary injury. - Highlights: • TRPA1 protects mice against toxicity and mortality of inhaled high-level acrolein. • TRPA1 protection against inhaled high-level acrolein is

Association of prehospitalization aspirin therapy and acute lung injury: results of a multicenter international observational study of at-risk patients.

PubMed

Kor, Daryl J; Erlich, Jason; Gong, Michelle N; Malinchoc, Michael; Carter, Rickey E; Gajic, Ognjen; Talmor, Daniel S

2011-11-01

To evaluate the association between prehospitalization aspirin therapy and incident acute lung injury in a heterogeneous cohort of at-risk medical patients. This is a secondary analysis of a prospective multicenter international cohort investigation. Multicenter observational study including 20 US hospitals and two hospitals in Turkey. Consecutive, adult, nonsurgical patients admitted to the hospital with at least one major risk factor for acute lung injury. None. Baseline characteristics and acute lung injury risk factors/modifiers were identified. The presence of aspirin therapy and the propensity to receive this therapy were determined. The primary outcome was acute lung injury during hospitalization. Secondary outcomes included intensive care unit and hospital mortality and intensive care unit and hospital length of stay. Twenty-two hospitals enrolled 3855 at-risk patients over a 6-month period. Nine hundred seventy-six (25.3%) were receiving aspirin at the time of hospitalization. Two hundred forty (6.2%) patients developed acute lung injury. Univariate analysis noted a reduced incidence of acute lung injury in those receiving aspirin therapy (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.46-0.90; p = .010). This association was attenuated in a stratified analysis based on deciles of aspirin propensity scores (Cochran-Mantel-Haenszel pooled OR, 0.70; 95% CI, 0.48-1.03; p = .072). After adjusting for the propensity to receive aspirin therapy, no statistically significant associations between prehospitalization aspirin therapy and acute lung injury were identified; however, a prospective clinical trial to further evaluate this association appears warranted.

A preclinical rodent model of acute radiation-induced lung injury after ablative focal irradiation reflecting clinical stereotactic body radiotherapy.

PubMed

Hong, Zhen-Yu; Lee, Hae-June; Choi, Won Hoon; Lee, Yoon-Jin; Eun, Sung Ho; Lee, Jung Il; Park, Kwangwoo; Lee, Ji Min; Cho, Jaeho

2014-07-01

In a previous study, we established an image-guided small-animal micro-irradiation system mimicking clinical stereotactic body radiotherapy (SBRT). The goal of this study was to develop a rodent model of acute phase lung injury after ablative irradiation. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice using a small animal stereotactic irradiator. At days 1, 3, 5, 7, 9, 11 and 14 after irradiation, the lungs were perfused with formalin for fixation and paraffin sections were stained with hematoxylin and eosin (H&E) and Masson's trichrome. At days 7 and 14 after irradiation, micro-computed tomography (CT) images of the lung were taken and lung functional measurements were performed with a flexiVent™ system. Gross morphological injury was evident 9 days after irradiation of normal lung tissues and dynamic sequential events occurring during the acute phase were validated by histopathological analysis. CT images of the mouse lungs indicated partial obstruction located in the peripheral area of the left lung. Significant alteration in inspiratory capacity and tissue damping were detected on day 14 after irradiation. An animal model of radiation-induced lung injury (RILI) in the acute phase reflecting clinical stereotactic body radiotherapy was established and validated with histopathological and functional analysis. This model enhances our understanding of the dynamic sequential events occurring in the acute phase of radiation-induced lung injury induced by ablative dose focal volume irradiation.

Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans.

PubMed

Parrella, Alfredo; Lavorgna, Margherita; Criscuolo, Emma; Russo, Chiara; Fiumano, Vittorio; Isidori, Marina

2014-11-01

The growing use of cytostatic drugs is gaining relevance as an environmental concern. Environmental and distribution studies are increasing due to the development of accurate analytical methods, whereas ecotoxicological studies are still lacking. The aim of the present study was to investigate the acute and chronic toxicity of six cytostatics (5-fluorouracil, capecitabine, cisplatin, doxorubicin, etoposide, and imatinib) belonging to five classes of Anatomical Therapeutic Classification (ATC) on primary consumers of the aquatic chain (Daphnia magna, Ceriodaphnia dubia, Brachionus calyciflorus, and Thamnocephalus platyurus). Acute ecotoxicological effects occurred at concentrations in the order of mgL(-)(1), higher than those predicted in the environment, and the most acutely toxic drugs among those tested were cisplatin and doxorubicin for most aquatic organisms. For chronic toxicity, cisplatin and 5-fluorouracil showed the highest toxic potential in all test organisms, inducing 50% reproduction inhibition in crustaceans at concentrations on the order of μgL(-)(1). Rotifers were less susceptible to these pharmaceuticals. On the basis of chronic results, the low effective concentrations suggest a potential environmental risk of cytostatics. Thus, this study could be an important starting point for establishing the real environmental impact of these substances. Copyright © 2014 Elsevier Ltd. All rights reserved.

Protective effects of erythropoietin against acute lung injury in a rat model of acute necrotizing pancreatitis

PubMed Central

Tascilar, Oge; Cakmak, Güldeniz Karadeniz; Tekin, Ishak Ozel; Emre, Ali Ugur; Ucan, Bulent Hamdi; Bahadir, Burak; Acikgoz, Serefden; Irkorucu, Oktay; Karakaya, Kemal; Balbaloglu, Hakan; Kertis, Gürkan; Ankarali, Handan; Comert, Mustafa

2007-01-01

AIM: To investigate the effect of exogenous erythro-poietin (EPO) administration on acute lung injury (ALI) in an experimental model of sodium taurodeoxycholate-induced acute necrotizing pancreatitis (ANP). METHODS: Forty-seven male Wistar albino rats were randomly divided into 7 groups: sham group (n = 5), 3 ANP groups (n = 7 each) and 3 EPO groups (n = 7 each). ANP was induced by retrograde infusion of 5% sodium taurodeoxycholate into the common bile duct. Rats in EPO groups received 1000 U/kg intramuscular EPO immediately after induction of ANP. Rats in ANP groups were given 1 mL normal saline instead. All animals were sacrificed at postoperative 24 h, 48 h and 72 h. Serum amilase, IL-2, IL-6 and lung tissue malondialdehyde (MDA) were measured. Pleural effusion volume and lung/body weight (LW/BW) ratios were calculated. Tissue levels of TNF-α, IL-2 and IL-6 were screened immunohistochemically. Additionally, ox-LDL accumulation was assessed with immune-fluorescent staining. Histopathological alterations in the lungs were also scored. RESULTS: The mean pleural effusion volume, calculated LW/BW ratio, serum IL-6 and lung tissue MDA levels were significantly lower in EPO groups than in ANP groups. No statistically significant difference was observed in either serum or tissue values of IL-2 among the groups. The level of tumor necrosis factor-α (TNF-α) and IL-6 and accumulation of ox-LDL were evident in the lung tissues of ANP groups when compared to EPO groups, particularly at 72 h. Histopathological evaluation confirmed the improvement in lung injury parameters after exogenous EPO administration, particularly at 48 h and 72 h. CONCLUSION: EPO administration leads to a significant decrease in ALI parameters by inhibiting polymorphonuclear leukocyte (PMNL) accumulation, decreasing the levels of proinflammatory cytokines in circulation, preserving microvascular endothelial cell integrity and reducing oxidative stress-associated lipid peroxidation and therefore, can

Dredged Material Analysis Tools; Performance of Acute and Chronic Sediment Toxicity Methods

DTIC Science & Technology

2008-04-01

Chronic Sediment Toxicity Methods Jeffery Steevens, Alan Kennedy, Daniel Farrar, Cory McNemar, Mark R. Reiss, Roy K. Kropp, Jon Doi, and Todd Bridges...Research Program ERDC/EL TR-08-16 April 2008 Dredged Material Analysis Tools Performance of Acute and Chronic Sediment Toxicity Methods Jeffery...potential advan- tages and disadvantages of using chronic sediment toxicity tests with relevant benthic macroinvertebrates as part of dredged material

Dredged Material Analysis Tools; Performance of Acute and Chronic Sediment Toxicity Methods

DTIC Science & Technology

2008-07-01

Chronic Sediment Toxicity Methods Jeffery Steevens, Alan Kennedy, Daniel Farrar, Cory McNemar, Mark R. Reiss, Roy K. Kropp, Jon Doi, and Todd Bridges...Environmental Research Program ERDC/EL TR-08-16 July 2008 Revised Dredged Material Analysis Tools Performance of Acute and Chronic Sediment Toxicity ...insight into the potential advan- tages and disadvantages of using chronic sediment toxicity tests with relevant benthic macroinvertebrates as part of

Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoo, Seong Ho, E-mail: yoosh@snu.ac.kr; Abdelmegeed, Mohamed A.; Song, Byoung-Joon, E-mail: bj.song@nih.gov

Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigatedmore » in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI.« less

40 CFR 797.1400 - Fish acute toxicity test.

Code of Federal Regulations, 2010 CFR

2010-07-01

... prescribes tests to be used to develop data on the acute toxicity of chemicals to fish. The United States...) Death means the lack of opercular movement by a test fish. (6) Flow-through means a continuous or an... dilution water. If a flow-through test is performed, the flow of dilution water through each chamber is...

Hydrogen alleviates hyperoxic acute lung injury related endoplasmic reticulum stress in rats through upregulation of SIRT1.

PubMed

Sun, Qiang; Han, Wenjie; Hu, Huijun; Fan, Danfeng; Li, Yanbo; Zhang, Yu; Lv, Yan; Li, Mingxin; Pan, Shuyi

2017-06-01

Hyperoxic acute lung injury (HALI) is a major clinical problem for patients undergoing supplemental oxygen therapy. Currently in clinical settings there exist no effective means of prevention or treatment methods. Our previous study found that: hydrogen could reduce HALI, as well as oxidative stress. This research will further explore the mechanism underlying the protective effect of hydrogen on oxygen toxicity. Rats were randomly assigned into three experimental groups and were exposed in a oxygen chamber for 60 continuous hours: 100% balanced air (control); 100% oxygen (HALI); 100% oxygen with hydrogen treatment (HALI + HRS). We examined lung function by wet to dry ratio of lung, lung pleural effusion and cell apoptosis. We also detected endoplasmic reticulum stress (ERS) by examining the expression of CHOP, GRP78 and XBP1. We further investigated the role of Sirtuin 1 (SIRT1) in HALI, which contributes to cellular regulation including ERS, by examining its expression after hydrogen treatment with SIRT1 inhibitor. Hydrogen could significantly reduce HALI by reducing lung edema and apoptosis, inhibiting the elevating of ERS and increased SIRT1 expression. By inhibition of SIRT1 expression, the effect of hydrogen on prevention of HALI is significantly weakened, the inhibition of the ERS was also reversed. Our findings indicate that hydrogen could reduce HALI related ERS and the mechanism of hydrogen may be associated with upregulation of SIRT1, this study reveals the molecular mechanisms underlying the protective effect of hydrogen, which provides a new theoretical basis for clinical application of hydrogen.

Sub-Acute Toxicity Study of Graphene Oxide in the Sprague-Dawley Rat.

PubMed

Li, Yingbo; Wang, Yan; Tu, Liu; Chen, Di; Luo, Zhi; Liu, Dengyuan; Miao, Zhuang; Feng, Gang; Qing, Li; Wang, Shali

2016-11-17

Graphene oxide (GO) is an oxidized derivative of graphene used in biotechnology and medicine. The safety of GO is uncertain, so we evaluated its toxicity in male rats. Rat tail veins were injected with 2.5, 5, or 10 mg/kg GO for seven days and behavioral patterns, pathology, and tissue morphology were assessed. Data show that behaviors were not altered according to an open field test and a functional observational battery test, but histopathological analysis indicated that GO caused inflammation of the lung, liver, and spleen. GO also reduced cholesterol, high density lipoprotein (HDL), and low density lipoprotein (LDL). No other organs were modified. Thus, high concentrations of GO are toxic for the lung, liver, and spleen, but the mechanism by which this occurs requires more study.

Sirc-cvs cytotoxicity test: an alternative for predicting rodent acute systemic toxicity.

PubMed

Kitagaki, Masato; Wakuri, Shinobu; Hirota, Morihiko; Tanaka, Noriho; Itagaki, Hiroshi

2006-10-01

An in vitro crystal violet staining method using the rabbit cornea-derived cell line (SIRC-CVS) has been developed as an alternative to predict acute systemic toxicity in rodents. Seventy-nine chemicals, the in vitro cytotoxicity of which was already reported by the Multicenter Evaluation of In vitro Toxicity (MEIC) and ICCVAM/ECVAM, were selected as test compounds. The cells were incubated with the chemicals for 72 hrs and the IC(50) and IC(35) values (microg/mL) were obtained. The results were compared to the in vivo (rat or mouse) "most toxic" oral, intraperitoneal, subcutaneous and intravenous LD(50) values (mg/kg) taken from the RTECS database for each of the chemicals by using Pearson's correlation statistics. The following parameters were calculated: accuracy, sensitivity, specificity, prevalence, positive predictability, and negative predictability. Good linear correlations (Pearson's coefficient; r>0.6) were observed between either the IC(50) or the IC(35) values and all the LD(50) values. Among them, a statistically significant high correlation (r=0.8102, p<0.001) required for acute systemic toxicity prediction was obtained between the IC(50) values and the oral LD(50) values. By using the cut-off concentrations of 2,000 mg/kg (LD(50)) and 4,225 microg/mL (IC(50)), no false negatives were observed, and the accuracy was 84.8%. From this, it is concluded that this method could be used to predict the acute systemic toxicity potential of chemicals in rodents.

Acute toxicity and genotoxicity study of fermented traditional herb formula Guibi-tang.

PubMed

Park, Hwayong; Hwang, Youn-Hwan; Yang, Hye Jin; Kim, Hyun-Kyu; Song, Kyung Seuk; Ma, Jin Yeul

2014-10-28

Guibi-tang (Guipi-tang in Chinese and Kihi-to in Japanese) is a multi-herb traditional medicine commonly prescribed to treat psychoneurosis in East Asia. Although this medicine has been widely used, there is little available information on the safety and toxicity of Guibi-tang, especially on the fermented one. Guibi-tang, composed of 12 herbs, was fermented with bacteria and lyophilized. Single dose acute toxicity in rats was observed for 14 days after administration. Genetic toxicity of fermented Guibi-tang was evaluated on bacterial reverse mutation in Salmonella and Escherichia spp., chromosome aberrations in Chinese hamster ovary cells, and micronucleus formation in mice. Ingredients in FGBT were identified and quantified by high performance liquid chromatography-mass spectrometry. In acute oral toxicity study, behavior, clinical signs and body weight changes were normal observing in all experimental animals. No revertant colonies were found in any bacterial cultures examined. Morphological or numerical anomalies and significant increased number of aberrant metaphases were not observed. Micronucleus assay showed no significant increases in the frequency of inducing micronuclei in any dose examined. Decursinol, decursin, glycyrrhizin, and 6-gingerol in fermented Guibi-tang were identified and quantitated. As a whole, no acute and genotoxic effects were found in all the assays and parameters analyzed. Fermented Guibi-tang was recognized as safe and non-toxic, and therefore can be used for applications of traditional medicine in modern complementary and alternative therapeutics and health care. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Small cell lung cancer with metastasis to the thyroid in a patient with toxic multinodular goiter.

PubMed

Ozgu, Eylem Sercan; Gen, Ramazan; Ilvan, Ahmet; Ozge, Cengiz; Polat, Ayşe; Vayisoglu, Yusuf

2012-11-01

Thyroid metastasis of lung cancer is rarely observed in clinical practice. The primary cancers which metastasize to the thyroid gland are mostly renal cell carcinoma, lung cancer, and breast cancer. Transient destructive thyrotoxicosis is caused by massive metastasis of extrathyroid tumors. We herein present a case report of a patient with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. A 66-year-old man complained of swelling around the right side of the neck, dyspnea, progressive weight loss, and palpitation starting since 3 months before his admission. The patient was diagnosed with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. The case report presented here illustrates the challenge of making a definitive and adequate diagnosis, particularly if the patient presents with 2 potential causes of thyrotoxicosis. Thyroid scintigraphy is an important tool for differential diagnosis of thyrotoxicosis.

Protective effect of U74500A on phorbol myristate acetate-induced acute lung injury.

PubMed

Chu, Shi-Jye; Chang, Deh-Ming; Wang, David; Lin, Hen-I; Lin, Shih-Hua; Hsu, Kang

2004-08-01

1. The present study was designed to determine whether U74500A could ameliorate acute lung injury (ALI) induced by phorbol myristate acetate (PMA) in our rat isolated lung model compared with any amelioration induced by dimethylthiourea (DMTU), superoxide dismutase (SOD) and catalase. 2. Acute lung injury was induced successfully by PMA during 60 min of observation. At 2 microg/kg, PMA elicited a significant increase in microvascular permeability (measured using the capillary filtration coefficient Kfc), lung weight gain, the lung weight/bodyweight ratio, pulmonary arterial pressure and protein concentration of the bronchoalveolar lavage fluid. 3. Pretreatment with 1.5 mg/kg U74500A significantly attenuated ALI; there was no significant increase in any parameters measured, except for pulmonary arterial pressure. The protective effect of U74500A was approximately the same as that of 600 mg/kg DMTU. However, 6000 U/kg SOD, 50,000 U/kg catalase and 6000 U/kg SOD + 50,000 U/kg catalase had no protective effect. 4. These experimental data suggest that U74500A significantly ameliorates ALI induced by PMA in rats.

Propagation prevention: a complementary mechanism for "lung protective" ventilation in acute respiratory distress syndrome.

PubMed

Marini, John J; Gattinoni, Luciano

2008-12-01

To describe the clinical implications of an often neglected mechanism through which localized acute lung injury may be propagated and intensified. Experimental and clinical evidence from the medical literature relevant to the airway propagation hypothesis and its consequences. The diffuse injury that characterizes acute respiratory distress syndrome is often considered a process that begins synchronously throughout the lung, mediated by inhaled or blood-borne noxious agents. Relatively little attention has been paid to possibility that inflammatory lung injury may also begin focally and propagate sequentially via the airway network, proceeding mouth-ward from distal to proximal. Were this true, modifications of ventilatory pattern and position aimed at geographic containment of the injury process could help prevent its generalization and limit disease severity. The purposes of this communication are to call attention to this seldom considered mechanism for extending lung injury that might further justify implementation of low tidal volume/high positive end-expiratory pressure ventilatory strategies for lung protection and to suggest additional therapeutic measures implied by this broadened conceptual paradigm.

Acute oral toxicities of wildland fire control chemicals to birds

USGS Publications Warehouse

Vyas, N.B.; Spann, J.W.; Hill, E.F.

2009-01-01

Wildland fire control chemicals are released into the environment by aerial and ground applications to manage rangeland, grassland, and forest fires. Acute oral 24 h median lethal dosages (LD50) for three fire retardants (Fire-Trol GTS-R?, Phos-Chek D-75F?, and Fire-Trol LCG-R?) and two Class A fire suppressant foams (Silv-Ex? and Phos-Chek WD881?) were estimated for northern bobwhites, Colinus virginianus, American kestrels, Falco sparverius, and red-winged blackbirds, Agelaius phoeniceus. The LD50s of all chemicals for the bobwhites and red-winged blackbirds and for kestrels dosed with Phos-Chek WD881? and Silv-Ex? were above the predetermined 2000 mg chemical/kg body mass regulatory limit criteria for acute oral toxicity. The LD50s were not quantifiable for kestrels dosed with Fire-Trol GTS-R?, Phos-Chek D-75F?, and Fire-Trol LCG-R? because of the number of birds which regurgitated the dosage. These chemicals appear to be of comparatively low order of acute oral toxicity to the avian species tested.

Acute toxicity, twenty-eight days repeated dose toxicity and genotoxicity of vanadyl trehalose in kunming mice.

PubMed

Jiang, Pingzhe; Ni, Zaizhong; Wang, Bin; Ma, Baicheng; Duan, Huikun; Li, Xiaodan; Ma, Xiaofeng; Wei, Qian; Ji, Xiangzhen; Liu, Qiqi; Xing, Shuguang; Li, Minggang

2017-04-01

A new trend has been developed using vanadium and organic ligands to form novel compounds in order to improve the beneficial actions and reduce the toxicity of vanadium compounds. In present study, vanadyl trehalose was explored the oral acute toxicity, 28 days repeated dose toxicity and genotoxicity in Kunming mice. The Median Lethal Dose (LD 50 ) of vanadyl trehalose was revealed to be 1000 mg/kg body weight in fasted Kunming mice. Stomach and intestine were demonstrated to be the main target organs of vanadyl trehalose through 28 days repeated dose toxicity study. And vanadyl trehalose also showed particular genotoxicity through mouse bone marrow micronucleus and mouse sperm malformation assay. In brief, vanadyl trehalose presented certain, but finite toxicity, which may provide experimental basis for the clinical application. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of tidal volume on work of breathing during lung-protective ventilation in patients with acute lung injury and acute respiratory distress syndrome.

PubMed

Kallet, Richard H; Campbell, Andre R; Dicker, Rochelle A; Katz, Jeffrey A; Mackersie, Robert C

2006-01-01

To assess the effects of step-changes in tidal volume on work of breathing during lung-protective ventilation in patients with acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS). Prospective, nonconsecutive patients with ALI/ARDS. Adult surgical, trauma, and medical intensive care units at a major inner-city, university-affiliated hospital. Ten patients with ALI/ARDS managed clinically with lung-protective ventilation. Five patients were ventilated at a progressively smaller tidal volume in 1 mL/kg steps between 8 and 5 mL/kg; five other patients were ventilated at a progressively larger tidal volume from 5 to 8 mL/kg. The volume mode was used with a flow rate of 75 L/min. Minute ventilation was maintained constant at each tidal volume setting. Afterward, patients were placed on continuous positive airway pressure for 1-2 mins to measure their spontaneous tidal volume. Work of breathing and other variables were measured with a pulmonary mechanics monitor (Bicore CP-100). Work of breathing progressively increased (0.86 +/- 0.32, 1.05 +/- 0.40, 1.22 +/- 0.36, and 1.57 +/- 0.43 J/L) at a tidal volume of 8, 7, 6, and 5 mL/kg, respectively. In nine of ten patients there was a strong negative correlation between work of breathing and the ventilator-to-patient tidal volume difference (R = -.75 to -.998). : The ventilator-delivered tidal volume exerts an independent influence on work of breathing during lung-protective ventilation in patients with ALI/ARDS. Patient work of breathing is inversely related to the difference between the ventilator-delivered tidal volume and patient-generated tidal volume during a brief trial of unassisted breathing.

Acute Oral Toxicity of Trimethylolethane Trinitrate (TMETN) in Sprague- Dawley Rats

DTIC Science & Technology

1989-07-01

classification scheme of Hodge and Steiner, these results indicate that TMETN is a slightly toxic compound.1 20. ON-RIBUTION /AVAILABILITY OF ABSTRACT 21. ABSTRACT...the classification scheme of Hodge and Sterner, these results indcate that TMETN is a slightly toxic compound. KEY WORDS: Acute Oral Toxicit-y...Dawley rats and 1027.4 63.7 mg/kg in female Sprague-Dawley rats. These MLD values place TMETN in the "slightly toxic" range by the system of Hodge and

Baclofen Toxicity Causing Acute, Reversible Dyskinesia.

PubMed

Niehaus, Matthew T; Elliott, Nicole C; Katz, Kenneth D

2016-12-01

The following unique case demonstrates an episode of acute dyskinesia secondary to oral baclofen toxicity. We discuss an 80-year-old man with a history of Stage III chronic kidney disease, coronary artery disease, diabetes and stroke who presented to the Emergency Department with new onset of behavioral changes and irregular jerking movements. The patient had been recently prescribed baclofen 10mg twice daily for a back strain he suffered; he subsequently was admitted to the hospital, and his symptoms resolved within 48 hours of admission and discontinuance of baclofen.

Hydrogen Gas Inhalation Attenuates Seawater Instillation-Induced Acute Lung Injury via the Nrf2 Pathway in Rabbits.

PubMed

Diao, Mengyuan; Zhang, Sheng; Wu, Lifeng; Huan, Le; Huang, Fenglou; Cui, Yunliang; Lin, Zhaofen

2016-12-01

Seawater instillation-induced acute lung injury involves oxidative stress and apoptosis. Although hydrogen gas inhalation is reportedly protective in multiple types of lung injury, the effect of hydrogen gas inhalation on seawater instillation-induced acute lung injury remains unknown. This study investigated the effect of hydrogen gas on seawater instillation-induced acute lung injury and explored the mechanisms involved. Rabbits were randomly assigned to control, hydrogen (2 % hydrogen gas inhalation), seawater (3 mL/kg seawater instillation), and seawater + hydrogen (3 mL/kg seawater instillation + 2 % hydrogen gas inhalation) groups. Arterial partial oxygen pressure and lung wet/dry weight ratio were detected. Protein content in bronchoalveolar lavage fluid (BALF) and serum as well as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels were determined. Hematoxylin-eosin staining was used to monitor changes in lung specimens, and malondialdehyde (MDA) content and myeloperoxidase (MPO) activity were assayed. In addition, NF-E2-related factor (Nrf) 2 and heme oxygenase (HO)-1 mRNA and protein expression were measured, and apoptosis was assessed by measuring caspase-3 expression and using terminal deoxy-nucleotidyl transferase dUTP nick end-labeling (TUNEL) staining. Hydrogen gas inhalation markedly improved lung endothelial permeability and decreased both MDA content and MPO activity in lung tissue; these changes were associated with decreases in TNF-α, IL-1β, and IL-6 in BALF. Hydrogen gas also alleviated histopathological changes and cell apoptosis. Moreover, Nrf2 and HO-1 expressions were significantly activated and caspase-3 expression was inhibited. These results demonstrate that hydrogen gas inhalation attenuates seawater instillation-induced acute lung injury in rabbits and that the protective effects observed may be related to the activation of the Nrf2 pathway.

QSAR Modeling of Rat Acute Toxicity by Oral Exposure

PubMed Central

Zhu, Hao; Martin, Todd M.; Ye, Lin; Sedykh, Alexander; Young, Douglas M.; Tropsha, Alexander

2009-01-01

Few Quantitative Structure-Activity Relationship (QSAR) studies have successfully modeled large, diverse rodent toxicity endpoints. In this study, a comprehensive dataset of 7,385 compounds with their most conservative lethal dose (LD50) values has been compiled. A combinatorial QSAR approach has been employed to develop robust and predictive models of acute toxicity in rats caused by oral exposure to chemicals. To enable fair comparison between the predictive power of models generated in this study versus a commercial toxicity predictor, TOPKAT (Toxicity Prediction by Komputer Assisted Technology), a modeling subset of the entire dataset was selected that included all 3,472 compounds used in the TOPKAT’s training set. The remaining 3,913 compounds, which were not present in the TOPKAT training set, were used as the external validation set. QSAR models of five different types were developed for the modeling set. The prediction accuracy for the external validation set was estimated by determination coefficient R2 of linear regression between actual and predicted LD50 values. The use of the applicability domain threshold implemented in most models generally improved the external prediction accuracy but expectedly led to the decrease in chemical space coverage; depending on the applicability domain threshold, R2 ranged from 0.24 to 0.70. Ultimately, several consensus models were developed by averaging the predicted LD50 for every compound using all 5 models. The consensus models afforded higher prediction accuracy for the external validation dataset with the higher coverage as compared to individual constituent models. The validated consensus LD50 models developed in this study can be used as reliable computational predictors of in vivo acute toxicity. PMID:19845371

Investigation of acute toxicity of fenitrothion on peppered corydoras (Corydoras paleatus) (Jenyns, 1842).

PubMed

Sarikaya, Rabia; Selvi, Mahmut; Erkoç, Figen

2004-08-01

Fenitrothion, as an organophosphothionate insecticide, is a contact insecticide and selective acaricide, also used as a vector control agent for malaria in public health programs. A 96 h LC50 value of fenitrothion, a potential toxic pollutant contaminating aquatic ecosystems, was determined on the adult peppered corydoras (Corydoras paleatus). The experiments were repeated three times. The static test method of acute toxicity test was used. Water temperature was regulated at 23 +/- 1 degrees C. In addition, behavioral changes at each fenitrothion concentration were observed for the individual fish. Data obtained from acute toxicity tests were evaluated using the Probit Analysis Statistical Method. The 96 h LC50 value for peppered corydoras was estimated as 3.51 mg/l.

Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice

PubMed Central

Soeiro-Pereira, Paulo V.; Gomes, Eliane; Neto, Antonio Condino; D' Império Lima, Maria R.; Alvarez, José M.; Portugal, Silvia; Epiphanio, Sabrina

2016-01-01

Malaria remains one of the greatest burdens to global health, causing nearly 500,000 deaths in 2014. When manifesting in the lungs, severe malaria causes acute lung injury/acute respiratory distress syndrome (ALI/ARDS). We have previously shown that a proportion of DBA/2 mice infected with Plasmodium berghei ANKA (PbA) develop ALI/ARDS and that these mice recapitulate various aspects of the human syndrome, such as pulmonary edema, hemorrhaging, pleural effusion and hypoxemia. Herein, we investigated the role of neutrophils in the pathogenesis of malaria-associated ALI/ARDS. Mice developing ALI/ARDS showed greater neutrophil accumulation in the lungs compared with mice that did not develop pulmonary complications. In addition, mice with ALI/ARDS produced more neutrophil-attracting chemokines, myeloperoxidase and reactive oxygen species. We also observed that the parasites Plasmodium falciparum and PbA induced the formation of neutrophil extracellular traps (NETs) ex vivo, which were associated with inflammation and tissue injury. The depletion of neutrophils, treatment with AMD3100 (a CXCR4 antagonist), Pulmozyme (human recombinant DNase) or Sivelestat (inhibitor of neutrophil elastase) decreased the development of malaria-associated ALI/ARDS and significantly increased mouse survival. This study implicates neutrophils and NETs in the genesis of experimentally induced malaria-associated ALI/ARDS and proposes a new therapeutic approach to improve the prognosis of severe malaria. PMID:27926944

Dosimetric rationale and early experience at UFPTI of thoracic proton therapy and chemotherapy in limited-stage small cell lung cancer.

PubMed

Colaco, Rovel J; Huh, Soon; Nichols, Romaine C; Morris, Christopher G; D'Agostino, Harry; Flampouri, Stella; Li, Zuofeng; Pham, Dat C; Bajwa, Abubakr A; Hoppe, Bradford S

2013-04-01

Concurrent chemoradiotherapy (CRT) is the standard of care in patients with limited-stage small cell lung cancer (SCLC). Treatment with conventional x-ray therapy (XRT) is associated with high toxicity rates, particularly acute grade 3+ esophagitis and pneumonitis. We present outcomes for the first known series of limited-stage SCLC patients treated with proton therapy and a dosimetric comparison of lung and esophageal doses with intensity-modulated radiation therapy (IMRT). Six patients were treated: five concurrently and one sequentially. Five patients received 60-66 CGE in 30-34 fractions once daily and one patient received 45 CGE in 30 fractions twice daily. All six patients received prophylactic cranial irradiation. Common Terminology Criteria for Adverse Events, v3.0, was used to grade toxicity. IMRT plans were also generated and compared with proton plans. The median follow-up was 12.0 months. The one-year overall and progression-free survival rates were 83% and 66%, respectively. There were no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis, and no other acute grade 3+ non-hematological toxicities were seen. One patient with a history of pulmonary fibrosis and atrial fibrillation developed worsening symptoms four months after treatment requiring oxygen. Three patients died: two of progressive disease and one after a fall; the latter patient was disease-free at 36 months after treatment. Another patient recurred and is alive, while two patients remain disease-free at 12 months of follow-up. Proton therapy proved superior to IMRT across all esophageal and lung dose volume points. In this small series of SCLC patients treated with proton therapy with radical intent, treatment was well tolerated with no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis. Dosimetric comparison showed better sparing of lung and esophagus with proton therapy. Proton therapy merits further investigation as a method of reducing the toxicity of CRT.

Developmental toxicity, acute toxicity and mutagenicity testing in freshwater snails Biomphalaria glabrata (Mollusca: Gastropoda) exposed to chromium and water samples.

PubMed

Tallarico, Lenita de Freitas; Borrely, Sueli Ivone; Hamada, Natália; Grazeffe, Vanessa Siqueira; Ohlweiler, Fernanda Pires; Okazaki, Kayo; Granatelli, Amanda Tosatte; Pereira, Ivana Wuo; Pereira, Carlos Alberto de Bragança; Nakano, Eliana

2014-12-01

A protocol combining acute toxicity, developmental toxicity and mutagenicity analysis in freshwater snail Biomphalaria glabrata for application in ecotoxicological studies is described. For acute toxicity testing, LC50 and EC50 values were determined; dominant lethal mutations induction was the endpoint for mutagenicity analysis. Reference toxicant potassium dichromate (K2Cr2O7) was used to characterize B. glabrata sensitivity for toxicity and cyclophosphamide to mutagenicity testing purposes. Compared to other relevant freshwater species, B. glabrata showed high sensitivity: the lowest EC50 value was obtained with embryos at veliger stage (5.76mg/L). To assess the model applicability for environmental studies, influent and effluent water samples from a wastewater treatment plant were evaluated. Gastropod sensitivity was assessed in comparison to the standardized bioassay with Daphnia similis exposed to the same water samples. Sampling sites identified as toxic to daphnids were also detected by snails, showing a qualitatively similar sensitivity suggesting that B. glabrata is a suitable test species for freshwater monitoring. Holding procedures and protocols implemented for toxicity and developmental bioassays showed to be in compliance with international standards for intra-laboratory precision. Thereby, we are proposing this system for application in ecotoxicological studies. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparing anti-hyperglycemic activity and acute oral toxicity of three different trivalent chromium complexes in mice.

PubMed

Li, Fang; Wu, Xiangyang; Zou, Yanmin; Zhao, Ting; Zhang, Min; Feng, Weiwei; Yang, Liuqing

2012-05-01

Three different ligands (rutin, folate and stachyose) of chromium(III) complexes were compared to examine whether they have similar effect on anti-hyperglycemic activity as well as the acute toxicity status. Anti-hyperglycemic activities of chromium rutin complex (CrRC), chromium folate complex (CrFC) and chromium stachyose complex (CrSC) were examined in alloxan-induced diabetic mice with daily oral gavage for a period of 2 weeks at the dose of 0.5-3.0 mg Cr/kg. Acute toxicities of CrRC and CrFC were tested using ICR mice at the dose of 1.0-5.0 g/kg with a single oral gavage and observed for a period of 2 weeks. Biological activities results indicated that only CrRC and CrFC could decrease blood glucose level, reduce the activities of aspartate transaminase, alanine transaminase, alkaline phosphatase, and increase liver glycogen level. In acute toxicity study, LD(50) values for both CrRC and CrFC were above 5.0 g/kg. The minimum lethal dose for CrFC was above 5.0 g/kg, while that for CrRC was 1.0 g/kg. Anti-diabetic activity of those chromium complexes was not similar and their acute toxicities were also different. CrFC represent an optimal chromium supplement among those chromium complexes with potential therapeutic value to control blood glucose in diabetes and non-toxicity in acute toxicity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veen, Sonja J. van der; Faber, Hette; Ghobadi, Ghazaleh

2016-01-01

Purpose: Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed themore » dose-limiting toxicity. Methods and Materials: A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects. Results: Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD. Conclusions: In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and

Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

PubMed

Tominaga, Masaki; Okamoto, Masaki; Kawayama, Tomotaka; Matsuoka, Masanobu; Kaieda, Shinjiro; Sakazaki, Yuki; Kinoshita, Takashi; Mori, Daisuke; Inoue, Akira; Hoshino, Tomoaki

2017-09-01

Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Acute and subacute toxicity of the Carapa guianensis Aublet (Meliaceae) seed oil.

PubMed

Costa-Silva, J H; Lima, C R; Silva, E J R; Araújo, A V; Fraga, M C C A; Ribeiro E Ribeiro, A; Arruda, A C; Lafayette, S S L; Wanderley, A G

2008-03-28

Carapa guianensis (Meliaceae), known as Andiroba in Brazil, has been used by Amazon Rainforest indigenous communities for treatment of coughs, convulsions, skin diseases, arthritis, rheumatism, ear infections, to heal wounds and bruises and as an insect repellent. Carapa guianensis seed oil (SO) was evaluated for its acute and subacute toxicity (30 days) by the oral route in Wistar rats. In the acute toxicity test, SO (0.625-5.0g/kg, n=5/sex) did not produce any hazardous symptoms or deaths. The subacute treatment with SO (0.375, 0.75 and 1.5g/kg, n=10/group) failed to change body weight gain, food and water consumption. Hematological analysis showed no significant differences in any of the parameters examined. However, in the biochemical parameters, there was an increase in the alanine aminotransferase (ALT) serum level (29%) in the group SO 1.5g/kg. In addition, absolute and relative liver weights were increased at the doses of 0.75g/kg (23.4 and 19.1%) and 1.5g/kg (18.7 and 33.1%). In conclusion, acute and subacute administration of Carapa guianensis seed oil did not produce toxic effects in male Wistar rats. However, the increase in the ALT serum level and in both absolute and relative liver weights may indicate a possible hepatic toxicity.

Attenuation of acute lung injury with propofol in endotoxemia.

PubMed

Takao, Yumiko; Mikawa, Katsuya; Nishina, Kahoru; Obara, Hidefumi

2005-03-01

Endotoxin causes acute lung injury (ALI) through many mediators of inflammatory and immune responses. Propofol is an antiinflammatory and immunosuppressive drug. We conducted this study to evaluate whether propofol attenuates ALI associated with endotoxemia. Thirty-two anesthetized rabbits were randomly divided into four groups (n = 8 each). ALI was induced by IV endotoxin 5 mg/kg over 30 min in 3 groups. In 2 of the ALI groups, IV administration of propofol (2 or 5 mg/kg as a bolus followed by continuous infusion at 4 or 15 mg x kg(-1) x h(-1)) was started 15 min before endotoxin. The other ALI group received soybean-oil emulsion. The nonlung injury control group received infusion of both vehicles. The lungs were mechanically ventilated with 40% oxygen for 6 h after endotoxin. Hemodynamics did not differ among groups. The large dose of propofol attenuated lung leukosequestration, pulmonary edema (as assessed by lung wet/dry weight ratio), and pulmonary hyperpermeability (as assessed by albumin levels in bronchoalveolar lavage fluid) and resulted in better oxygenation, lung mechanics, and histological change. The small dose of propofol failed to do so. Our findings suggest that a large dose of propofol successfully mitigates physiological, biochemical, and histological deterioration in ALI in endotoxemia.

Chemoradiation related acute morbidity in carcinoma cervix and correlation with hematologic toxicity: a South Indian prospective study.

PubMed

Kumaran, Aswathy; Guruvare, Shyamala; Sharan, Krishna; Rai, Lavanya; Hebbar, Shripad

2014-01-01

To assess chemoradiation related acute morbidity in women with carcinoma cervix and to find and correlation between hematologic toxicity and organ system specific damage. A prospective study was carried out between August 2012 and July 2013 enrolling 79 women with cancer cervix receiving chemo-radiotherapy. Weekly assessment of acute morbidity was done using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4 and the toxicities were graded. Anemia [77 (97.5%)], vomiting [75 (94.8%)] and diarrhea [72 (91.1%)], leukopenia [11 (13.9%)], cystitis [28 (35.4%], dermatitis [19 (24.1%)] and fatigue [29 (36.71%)] were the acute toxicities noted. The toxicities were most severe in 3rd and 5th week. All women could complete radiotherapy except two due to causes unrelated to radiation morbidity; seven (8.86%) had to discontinue chemotherapy due to leukopenia and intractable diarrhea. Though there was no correlation between anemia and other toxicities, it was found that all with leukopenia had diarrhea. Chemoradiation for cancer cervix is on the whole well tolerated. Leukopenia and severe diarrhea were the acute toxicities that compelled discontinuation of chemotherapy in two women. Though anemia had no correlation with gastrointestinal toxicity, all of those with leukopenia had diarrhea.

Radiation-induced heart disease in lung cancer radiotherapy: A dosimetric update.

PubMed

Ming, Xin; Feng, Yuanming; Yang, Chengwen; Wang, Wei; Wang, Ping; Deng, Jun

2016-10-01

Radiation-induced heart disease (RIHD), which affects the patients' prognosis with both acute and late side effects, has been published extensively in the radiotherapy of breast cancer, lymphoma and other benign diseases. Studies on RIHD in lung cancer radiotherapy, however, are less extensive and clear even though the patients with lung cancer are delivered with higher doses to the heart during radiation treatment. In this article, after extensive literature search and analysis, we reviewed the current evidence on RIHD in lung cancer patients after their radiation treatments and investigated the potential risk factors for RIHD as compared to other types of cancers. Cardiac toxicity has been found highly relevant in lung cancer radiotherapy. So far, the crude incidence of cardiac complications in the lung cancer patients after radiotherapy has been up to 33%. The dose to the heart, the lobar location of tumor, the treatment modality, the history of heart and pulmonary disease and smoking were considered as potential risk factors for RIHD in lung cancer radiotherapy. As treatment techniques improve over the time with better prognosis for lung cancer survivors, an improved prediction model can be established to further reduce the cardiac toxicity in lung cancer radiotherapy.

Identification of acute toxicants in New Bedford Harbor sediments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ho, K.T.; McKinney, R.A.; Kuhn, A.

1997-03-01

New Bedford Harbor (NBH) is a marine Superfund site contaminated with high concentrations of polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and metals. Experiments were conducted to determine the causal toxic agent(s) in pore waters from New Bedford Harbor sediments to amphipods and mysid shrimp. Chemical manipulations to characterize toxicity revealed that pore-water toxicity was organic in nature. Fractionation and subsequent mass spectral identification of peaks in the toxic fraction indicated that PCBs. PAHs, and unknown compounds were present. Comparisons of PAH LC50s and PAH concentrations in this fraction indicated that the toxicity was not due to PAHs because themore » PAH concentrations were much lower than the reported PAH LC50s. One unknown peak was positively identified as bis(2-ethylhexyl) phthalate, and the other tentatively identified as pyrazole. Toxicity tests and comparison of toxicity in the blank and toxic fractions eliminated the two unknowns as toxic causal agents. The authors determined the range of PCB LC50s to fall between 10 and 110 ppb for Mysidopsis bahia and Ampelisca abdita. Concentrations of PCBs for the toxic fractions ranged from 12 to 27 ppb. This range falls within the observed PCB LC50s for M. bahia and A. abdita. Based upon these PCB concentrations, they concluded that PCBs were the acute toxic agents in NBH pore waters. Other compounds in the toxic fractions, or compounds that coeluted and were undistinguished from PCBs had minor contributions to the measured toxicity.« less

Factors associated with elevated plateau pressure in patients with acute lung injury receiving lower tidal volume ventilation.

PubMed

Prescott, Hallie C; Brower, Roy G; Cooke, Colin R; Phillips, Gary; O'Brien, James M

2013-03-01

Lung-protective ventilation with lower tidal volume and lower plateau pressure improves mortality in patients with acute lung injury and acute respiratory distress syndrome. We sought to determine the incidence of elevated plateau pressure in acute lung injury /acute respiratory distress syndrome patients receiving lower tidal volume ventilation and to determine the factors that predict elevated plateau pressure in these patients. We used data from 1398 participants in Acute Respiratory Distress Syndrome Network trials, who received lower tidal volume ventilation (≤ 6.5mL/kg predicted body weight). We considered patients with a plateau pressure greater than 30cm H2O and/or a tidal volume less than 5.5mL/kg predicted body weight on study day 1 to have "elevated plateau pressure." We used logistic regression to identify baseline clinical variables associated with elevated plateau pressure and to develop a model to predict elevated plateau pressure using a subset of 1,188 patients. We validated the model in the 210 patients not used for model development. Medical centers participating in Acute Respiratory Distress Syndrome Network clinical trials. None. Of the 1,398 patients in our study, 288 (20.6%) had elevated plateau pressure on day 1. Severity of illness indices and demographic factors (younger age, greater body mass index, and non-white race) were independently associated with elevated plateau pressure. The multivariable logistic regression model for predicting elevated plateau pressure had an area under the receiving operator characteristic curve of 0.71 for both the developmental and the validation subsets. acute lung injury patients receiving lower tidal volume ventilation often have a plateau pressure that exceeds Acute Respiratory Distress Syndrome Network goals. Race, body mass index, and severity of lung injury are each independently associated with elevated plateau pressure. Selecting a smaller initial tidal volume for non-white patients and patients

Acute and subacute toxicity of 10B-paraboronophenylalanine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taniyama, K.; Fujiwara, H.; Kuno, T.

1989-07-01

The acute and subacute toxicities of 10B-paraboronophenylalanine (10B-BPA) were investigated in the rat, according to the Good Laboratory Practice Standard for safety studies on drugs in Japan. In the acute toxicity test of 10B-BPA, LD50 values of acidic 10B-BPA for intraperitoneal and subcutaneous injections were 640 mg/kg for male and 710 mg/kg for female rats, and more than 1,000 mg/kg for male and female rats, respectively. The LD50 values of neutral 10B-BPA for intraperitoneal and subcutaneous injections were more than 3,000 mg/kg for male and female rats. The difference in LD50 values between acidic and neutral 10B-BPA may be attributedmore » to the acidity of material. From the subacute toxicity test, in which the rats were injected daily subcutaneously for 28 days, the following toxic effects of 10B-BPA were observed. Increase in ketone level in the urine was induced in all rats treated with 10B-BPA. High dose of 10B-BPA (1,500 mg/kg) induced increase in spleen weight and reticulocyte count, and decrease in hemoglobin count, thereby suggesting that 10B-BPA causes hemolysis. Increases in the leukocyte count and the ratio of neutrophils and lymphocytes were also observed in rats treated with a high dose of 10B-BPA. This may be attributed to local reactions at the injection site. There were no significant differences in the findings between control rats and rats treated with a low dose of 10B-BPA (300 mg/kg). Thus, low doses of neutral 10B-BPA may be available for use as a drug.« less

Osthole protects lipopolysaccharide-induced acute lung injury in mice by preventing down-regulation of angiotensin-converting enzyme 2.

PubMed

Shi, Yun; Zhang, Bo; Chen, Xiang-Jun; Xu, Dun-Quan; Wang, Yan-Xia; Dong, Hai-Ying; Ma, Shi-Rong; Sun, Ri-He; Hui, Yan-Ping; Li, Zhi-Chao

2013-03-12

The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Angiotensin converting enzyme 2 (ACE2) plays a protective role in acute lung injury. Osthole, a natural coumarin derivative extracted from traditional Chinese medicines, is known to have anti-inflammatory effect, but the effect of osthole on the ALI is largely unknown. The aim of this study is to explore whether and by what mechanisms osthole protects lipopolysaccharide(LPS)-induced acute lung injury. Herein, we found that osthole had a beneficial effect on LPS-induced ALI in mice. As revealed by survival study, pretreatment with high doses of osthole reduced the mortality of mice from ALI. Osthole pretreatment significantly improved LPS-induced lung pathological changes, reduced lung wet/dry weight ratios and total protein in BALF. Osthole also inhibited the release of inflammatory mediators TNF-α and IL-6. Meanwhile, osthole markedly prevented the loss of ACE2 and Ang1-7 in lung tissue of ALI mice. ACE2 inhibitor blocked the protective effect of osthole in NR 8383 cell lines. Taken together, our study showed that osthole improved survival rate and attenuated LPS-induced ALI and ACE2 may play a role in it. Copyright © 2013 Elsevier B.V. All rights reserved.

40 CFR 797.1930 - Mysid shrimp acute toxicity test.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 31 2010-07-01 2010-07-01 true Mysid shrimp acute toxicity test. 797... acclimated in accordance with the test design into the test chambers. Mysids in the test chambers are... individuals are of similar age and experimental history. Mysids used for establishing laboratory cultures may...

Physical complications in acute lung injury survivors: a two-year longitudinal prospective study.

PubMed

Fan, Eddy; Dowdy, David W; Colantuoni, Elizabeth; Mendez-Tellez, Pedro A; Sevransky, Jonathan E; Shanholtz, Carl; Himmelfarb, Cheryl R Dennison; Desai, Sanjay V; Ciesla, Nancy; Herridge, Margaret S; Pronovost, Peter J; Needham, Dale M

2014-04-01

Survivors of severe critical illness frequently develop substantial and persistent physical complications, including muscle weakness, impaired physical function, and decreased health-related quality of life. Our objective was to determine the longitudinal epidemiology of muscle weakness, physical function, and health-related quality of life and their associations with critical illness and ICU exposures. A multisite prospective study with longitudinal follow-up at 3, 6, 12, and 24 months after acute lung injury. Thirteen ICUs from four academic teaching hospitals. Two hundred twenty-two survivors of acute lung injury. None. At each time point, patients underwent standardized clinical evaluations of extremity, hand grip, and respiratory muscle strength; anthropometrics (height, weight, mid-arm circumference, and triceps skin fold thickness); 6-minute walk distance, and the Medical Outcomes Short-Form 36 health-related quality of life survey. During their hospitalization, survivors also had detailed daily evaluation of critical illness and related treatment variables. Over one third of survivors had objective evidence of muscle weakness at hospital discharge, with most improving within 12 months. This weakness was associated with substantial impairments in physical function and health-related quality of life that persisted at 24 months. The duration of bed rest during critical illness was consistently associated with weakness throughout 24-month follow-up. The cumulative dose of systematic corticosteroids and use of neuromuscular blockers in the ICU were not associated with weakness. Muscle weakness is common after acute lung injury, usually recovering within 12 months. This weakness is associated with substantial impairments in physical function and health-related quality of life that continue beyond 24 months. These results provide valuable prognostic information regarding physical recovery after acute lung injury. Evidence-based methods to reduce the duration of

ASEPTIC INFLAMMATION IN THE LUNGS IN ACUTE RADIATION SICKNESS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ivanov, A.E.

1963-09-01

Inflammation in the lungs of irradiated rabbits at the site of turpentine injection has much in common with the inflammatory changes arising in other tissues and organs during local irradiation or acute radiation sickness. The fact that the inflammatory changes under different conditions of irradiation are similar in type regardless of the character of the inflammatory agent suggests that the phenomenon has a common mechanism. The absence of polymorphonuclear (eosinophtlic) leukocytes from inflammatory foci in irradiated rabbits is due not only to the developing leukopenia, but also to a disturbance of the leukocyte emigration process into the inflammatory focus. Inmore » irradiated rabbits in cortrast to the controls, the normal arrangement of the fibrous structures is preserved in the necrotic lung tissue at the site of turpentine injection. In animals with severe acute radiation sickness induced by external irradiation in sublethal doses, the ability of the organism to respond to introduction of an inflammatory agent by an increase in the number of leukocytes in the blood and by a rise of the body temperature is to some extent preserved. (auth)« less

Noninvasive ventilation for patients with acute lung injury or acute respiratory distress syndrome.

PubMed

Nava, Stefano; Schreiber, Ania; Domenighetti, Guido

2011-10-01

Few studies have been performed on noninvasive ventilation (NIV) to treat hypoxic acute respiratory failure in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The outcomes of these patients, for whom endotracheal intubation is not mandatory, depend on the degree of hypoxia, the presence of comorbidities and complications, and their illness severity. The use of NIV as an alternative to invasive ventilation in severely hypoxemic patients with ARDS (ie, P(aO(2))/F(IO(2)) < 200) is not generally advisable and should be limited to hemodynamically stable patients who can be closely monitored in an intensive care unit by highly skilled staff. Early NIV application may be extremely helpful in immunocompromised patients with pulmonary infiltrates, in whom intubation dramatically increases the risk of infection, pneumonia, and death. The use of NIV in patients with severe acute respiratory syndrome and other airborne diseases has generated debate, despite encouraging clinical results, mainly because of safety issues. Overall, the high rate of NIV failure suggests a cautious approach to NIV use in patients with ALI/ARDS, including early initiation, intensive monitoring, and prompt intubation if signs of NIV failure emerge.

Investigation of Acute and Chronic Toxicity Trends of Pesticides Using High-Throughput Bioluminescence Assay Based on the Test Organism Vibrio fischeri.

PubMed

Westlund, Paul; Nasuhoglu, Deniz; Isazadeh, Siavash; Yargeau, Viviane

2018-05-01

High-throughput acute and chronic toxicity tests using Vibrio fischeri were used to assess the toxicity of a variety of fungicides, herbicides, and neonicotinoids. The use of time points beyond the traditional 30 min of an acute test highlighted the sensitivity and applicability of the chronic toxicity test and indicated that for some compounds toxicity is underestimated using only the acute test. The comparison of EC 50 values obtained from acute and chronic tests provided insight regarding the toxicity mode of action, either being direct or indirect. Using a structure-activity relationship approach similar to the one used in hazard assessments, the relationship between toxicity and key physicochemical properties of pesticides was investigated and trends were identified. This study not only provides new information regarding acute toxicity of some pesticides but also is one of the first studies to investigate the chronic toxicity of pesticides using the test organism V. fischeri. The findings demonstrated that the initial bioluminescence has a large effect on the calculated effective concentrations for target compounds in both acute and chronic tests, providing a way to improve and standardize the test protocol. In addition, the findings emphasize the need for additional investigation regarding the relationship between a toxicant's physicochemical properties and mode of action in nontarget organisms.

Acute and subchronic oral toxicity of Coriolus versicolor standardized water extract in Sprague-Dawley rats.

PubMed

Hor, Sook Yee; Ahmad, Mariam; Farsi, Elham; Lim, Chung Pin; Asmawi, Mohd Zaini; Yam, Mun Fei

2011-10-11

Coriolus versicolor, which is known as Yun Zhi, is one of the commonly used Chinese medicinal herbs. Recent studies have demonstrated its antitumor activities on cancer cells which led to its widespread use in cancer patient. However, little toxicological information is available regarding its safety. The present study evaluated the potential toxicity of Coriolus versicolor standardized water extract after acute and subchronic administration in rats. In acute toxicity study, Coriolus versicolor water extract was administered by oral gavage to Sprague-Dawley (SD) rats (6 males, 6 females) at single doses of varying concentrations 1250, 2500 and 5000 mg/kg. In subchronic toxicity study, the extract was administered orally at doses of 1250, 2500 and 5000 mg/kg/day for 28 days to male and female SD rats respectively. General behavior, adverse effects and mortality were determined throughout the experimental period. Haematological and biochemical parameters, relative organ weights and histopathological were evaluated at the end of the experiment. There were no mortality and signs of toxicity in acute and subchronic toxicity studies. In the single dose acute toxicity and repeated dose 28-day subchronic toxicity studies, there were no significant difference in body weight, relative organ weight, haematological parameters, clinical chemistry, gross pathology and histopathology between treatment and control groups. Coriolus versicolor water extract did not cause remarkable adverse effect in SD rats. The oral lethal dose of Coriolus versicolor water extract is more than 5000 mg/kg and no-observed-adverse-effect level (NOAEL) of the extract for both male and female rats is 5000 mg/kg per day for 28 days. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

[Cigarette smoking in different manners induces acute lung injury in rats].

PubMed

Xiao, Weiqiang; Zhou, Guojun; Xu, Chengyun; Xu, Jian; Huang, Fangfang; Lu, Xinbo; Li, Xia; Wu, Ximei

2016-05-25

Objective: To investigate the effects of cigarette smoking in different manners on acute lung injury in rats. Methods: The commercially available cigarettes with tar of 1,5, 11 mg were smoked in Canada depth smoking (health canada method, HCM) manner, and those with tar of 11 mg were also smoked in international standard (ISO) smoking manner. Rats were fixed and exposed to mainstream in a manner of nose-mouth exposure. After 28 days, the bronchoalveolar lavage fluids from left lung were collected for counting and classification of inflammatory cells and determination of pro-inflammatory cytokines IL-1β and TNF-α. The right lungs were subjected to histological examination and determination of myeloperoxidase (MPO) and superoxide dismutase (SOD) activities and glutathione, reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Results: In both HCM and ISO manners, the degree of lung injury was closely related to the tar content of cigarettes, and significant decrease in the body weight of rats was observed after smoking for one week. In a HCM manner, smoking with cigarette of 11 mg tar resulted in robust infiltration of macrophages, lymphocytes and neutrophils into lungs, significant increase in IL-1β and TNF-α levels and MPO activities, and significant decrease in GSH levels and SOD activities and increase in ROS and MDA levels (all P <0.05). Smoking with cigarette of 5 mg tar led to moderate increase in IL-1β and TNF-α levels, and MPO activities (all P <0.05), and moderate decrease in GSH levels and SOD activities and increase of ROS and MDA levels (all P <0.05). However, smoking with cigarette of 1 mg tar affected neither inflammatory cell infiltration nor IL-1β and TNF-α levels. Conclusion: Cigarette smoking in nose-mouth exposure manner can induce acute lung injury in rats; and the degree of lung injury is closely related to the content of tar and other hazards in cigarettes.

Toxic alveolitis after inhalation of a water repellent.

PubMed

Epping, Guido; Van Baarlen, Joop; Van Der Valk, Paul D L P M

2011-12-01

Inhalation of fluorocarbon polymers can cause pulmonary toxicity. Although multiple cases of lung injury have been reported, cellular characterization of the associated alveolitis occurring acutely after inhalation is limited. We report the case of a previously healthy woman who presented at our Emergency Department with an acute pneumonitis following inhalation of a fluorocarbon polymer-based rain-proofing spray. Bronchoalveolar lavage (BAL) performed shortly after the presentation showed an elevated total cell count, with a high proportion of neutrophils (58%) and eosinophils (9%). In addition, a lipid stain (Oil-Red-O-stain) showed a high level of lipid laden macrophages, a marker that could reflect a direct toxic effect of the spray on alveolar cells. The patient made a full recovery after four days of in-hospital observation with supportive care.

Attenuation of acute lung inflammation induced by cigarette smoke in CXCR3 knockout mice.

PubMed

Nie, Li; Xiang, Ruolan; Zhou, Weixun; Lu, Bao; Cheng, Deyun; Gao, Jinming

2008-12-16

CD8+ T cells may participate in cigarette smoke (CS) induced-lung inflammation in mice. CXCL10/IP-10 (IFNgamma-inducible protein 10) and CXCL9/Mig (monokine induced by IFN-gamma) are up-regulated in CS-induced lung injury and may attract T-cell recruitment to the lung. These chemokines together with CXCL11/ITAC (IFN-inducible T-cell alpha chemoattractant) are ligands for the chemokine receptor CXCR3 which is preferentially expressed chiefly in activated CD8+ T cells. The purpose of this investigation was to study the contribution of CXCR3 to acute lung inflammation induced by CS using CXCR3 knockout (KO) mice. Mice (n = 8 per group) were placed in a closed plastic box connected to a smoke generator and were exposed whole body to the tobacco smoke of five cigarettes four times a day for three days. Lung pathological changes, expression of inflammatory mediators in bronchoalveolar lavage (BAL) fluid and lungs at mRNA and protein levels, and lung infiltration of CD8+ T cells were compared between CXCR3-/- mice and wild type (WT) mice. Compared with the WT littermates, CXCR3 KO mice showed less CS-induced lung inflammation as evidenced by less infiltration of inflammatory cells in airways and lung tissue, particularly fewer CD8+ T cells, lower levels of IFNgamma and CXCR3 ligands (particularly CXCL10). Our findings show that CXCR3 is important in promoting CD8+ T cell recruitment and in initiating IFNgamma and CXCL10 release following CS exposure. CXCR3 may represent a promising therapeutic target for acute lung inflammation induced by CS.

Attenuation of acute lung inflammation induced by cigarette smoke in CXCR3 knockout mice

PubMed Central

Nie, Li; Xiang, Ruolan; Zhou, Weixun; Lu, Bao; Cheng, Deyun; Gao, Jinming

2008-01-01

Background CD8+ T cells may participate in cigarette smoke (CS) induced-lung inflammation in mice. CXCL10/IP-10 (IFNγ-inducible protein 10) and CXCL9/Mig (monokine induced by IFN-γ) are up-regulated in CS-induced lung injury and may attract T-cell recruitment to the lung. These chemokines together with CXCL11/ITAC (IFN-inducible T-cell alpha chemoattractant) are ligands for the chemokine receptor CXCR3 which is preferentially expressed chiefly in activated CD8+ T cells. The purpose of this investigation was to study the contribution of CXCR3 to acute lung inflammation induced by CS using CXCR3 knockout (KO) mice. Methods Mice (n = 8 per group) were placed in a closed plastic box connected to a smoke generator and were exposed whole body to the tobacco smoke of five cigarettes four times a day for three days. Lung pathological changes, expression of inflammatory mediators in bronchoalveolar lavage (BAL) fluid and lungs at mRNA and protein levels, and lung infiltration of CD8+ T cells were compared between CXCR3-/- mice and wild type (WT) mice. Results Compared with the WT littermates, CXCR3 KO mice showed less CS-induced lung inflammation as evidenced by less infiltration of inflammatory cells in airways and lung tissue, particularly fewer CD8+ T cells, lower levels of IFNγ and CXCR3 ligands (particularly CXCL10). Conclusion Our findings show that CXCR3 is important in promoting CD8+ T cell recruitment and in initiating IFNγ and CXCL10 release following CS exposure. CXCR3 may represent a promising therapeutic target for acute lung inflammation induced by CS. PMID:19087279

Corticosteroid treatment inhibits airway hyperresponsiveness and lung injury in a murine model of chemical-induced airway inflammation.

PubMed

Wigenstam, Elisabeth; Jonasson, Sofia; Koch, Bo; Bucht, Anders

2012-11-15

Exposure to toxic alkylating mustard agents causes both acute and long-term effects to the lungs as indicated by increased number of inflammatory cells in airways, lung edema and lung tissue fibrosis. We have previously demonstrated that treatment with the corticosteroid dexamethasone 1 h after lung exposure to the nitrogen mustard analog melphalan protects mice from acute and sub-acute inflammatory responses, as well as from lung tissue fibrosis. In order to address the importance of early anti-inflammatory treatment, we investigated the therapeutic effect of dexamethasone administered 1, 2 or 6 h following exposure to melphalan. C57BL/6 mice were exposed to melphalan and treated with dexamethasone 1, 2 or 6 h after exposure. Twenty hours or 14 days post exposure mice were subjected to analysis of respiratory mechanics where the effects of incremental doses of methacholine on central and peripheral lung components were measured. We also determined the amount of inflammatory cells in the bronchoalveolar lavage fluid and measured the amount of collagen content in the lungs. Melphalan exposure increased airway hyperresponsiveness in both central and peripheral airways and induced an airway inflammation dominated by infiltration of macrophages and neutrophils. Dexamethasone given 1 h after exposure to melphalan provided better protection against airway inflammation than administration 2 or 6 h after exposure. Collagen deposition 14 days after exposure was decreased due to dexamethasone treatment. Early treatment with dexamethasone is important in order to reduce the airway hyperresponsiveness and inflammation caused by toxic alkylating mustards such as melphalan. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Safety evaluation of tangeretin and the effect of using emulsion-based delivery system: Oral acute and 28-day sub-acute toxicity study using mice.

PubMed

Ting, Yuwen; Chiou, Yi-Shiou; Jiang, Yike; Pan, Min-Hsiung; Lin, Zhengyu; Huang, Qingrong

2015-08-01

Polymethoxyflavones, found widely in the peel of citrus fruits, is an emerging group of bioactive compounds with wide arrays of disease prevention functionalities. To understand the potential oral toxicity, tangeretin, being one of the most abundant polymethoxyflavones from natural sources, was used as model compound for the safety evaluation. Acute oral toxicity study was conducted using both male and female mice giving 1000, 2000, or 3000mg/kgbody weight (bw) of tangeretin in oil suspension from single gavage administration. No evidence of death was observed during 14-day post-administration period. Alterations of the hepatic cell and clinical chemistry profile increased dose dependently and exhibited distinct injury recovery pattern among different sexes. To determine the potential safety concern related to emulsification, the sub-acute toxicity of tangeretin in emulsion was evaluated and compared with un-processed oil suspension when conducting the sub-acute toxicity study over 28days. In the sub-acute study, emulsion system did not induce a significant increase of toxicity response. However, the daily low-dose application of tangeretin showed U-shaped dose-response pattern in regard to hepatic alteration. The result from this study can serve as a good safety reference for future application of polymethoxyflavone as a functional ingredient in food. Copyright © 2015 Elsevier Ltd. All rights reserved.

Transfusion-related acute lung injury (TRALI) in graft by blood donor antibodies against host leukocytes.

PubMed

Goodwin, Jodi; Tinckam, Kathryn; denHollander, Neal; Haroon, Ayesha; Keshavjee, Shaf; Cserti-Gazdewich, Christine M

2010-09-01

It is unknown the extent to which transfusion-related acute lung injury (TRALI) contributes to primary graft dysfunction (PGD), the leading cause of death after lung transplantation. In this case of suspected transfusion-associated acute bilateral graft injury in a 61-year-old idiopathic pulmonary fibrosis patient, recipient sera from before and after transplantation/transfusion, as well as the sera of 22 of the 24 implicated blood donors, were individually screened by Luminex bead assay for the presence of human leukocyte antigen (HLA) antibodies, with recipient and lung donor HLA typing to explore for cognate relationships. A red-cell-unit donor-source anti-Cw6 antibody, cognate with the HLA type of the recipient, was identified. This is the second reported case of TRALI in the setting of lung transplantation, and the first to show an associated interaction between donor antibodies (in a low-plasma volume product) with recipient leukocytes (rather than graft antigens); therefore, it should be considered in the differential diagnosis of PGD. Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

A re-evaluation of PETROTOX for predicting acute and chronic toxicity of petroleum substances.

PubMed

Redman, Aaron D; Parkerton, Thomas F; Leon Paumen, Miriam; Butler, Josh D; Letinski, Daniel J; den Haan, Klass

2017-08-01

The PETROTOX model was developed to perform aquatic hazard assessment of petroleum substances based on substance composition. The model relies on the hydrocarbon block method, which is widely used for conducting petroleum substance risk assessments providing further justification for evaluating model performance. Previous work described this model and provided a preliminary calibration and validation using acute toxicity data for limited petroleum substance. The objective of the present study was to re-evaluate PETROTOX using expanded data covering both acute and chronic toxicity endpoints on invertebrates, algae, and fish for a wider range of petroleum substances. The results indicated that recalibration of 2 model parameters was required, namely, the algal critical target lipid body burden and the log octanol-water partition coefficient (K OW ) limit, used to account for reduced bioavailability of hydrophobic constituents. Acute predictions from the updated model were compared with observed toxicity data and found to generally be within a factor of 3 for algae and invertebrates but overestimated fish toxicity. Chronic predictions were generally within a factor of 5 of empirical data. Furthermore, PETROTOX predicted acute and chronic hazard classifications that were consistent or conservative in 93 and 84% of comparisons, respectively. The PETROTOX model is considered suitable for the purpose of characterizing petroleum substance hazard in substance classification and risk assessments. Environ Toxicol Chem 2017;36:2245-2252. © 2017 SETAC. © 2017 SETAC.

Acute high-level exposure to WTC particles alters expression of genes associated with oxidative stress and immune function in the lung

PubMed Central

Cohen, Mitchell D.; Vaughan, Joshua M.; Garrett, Brittany; Prophete, Colette; Horton, Lori; Sisco, Maureen; Kodavanti, Urmila P.; Ward, William O.; Peltier, Richard E.; Zelikoff, Judith; Chen, Lung-chi

2015-01-01

First responders (FR) present at Ground Zero in the first 72 h after the World Trade Center (WTC) collapsed have progressively exhibited significant respiratory injuries. The few toxicology studies performed to date evaluated effects from just fine (<2.5 µm) WTC dusts; none examined health effects/toxicities from atmospheres bearing larger particle sizes, despite the fact the majority (496%) of dusts were >10µm and most FR likely entrained dusts by mouth breathing. Using a system that generated/delivered supercoarse (10–53 µm) WTC dusts to F344 rats (in a manner that mimicked FR exposures), this study sought to examine potential toxicities in the lungs. In this exploratory study, rats were exposed for 2 h to 100 mg WTC dust/m3 (while under isoflurane [ISO] anesthesia) or an air/ISO mixture; this dose conservatively modeled likely exposures by mouth-breathing FR facing ≈750–1000 mg WTC dust/m3. Lungs were harvested 2 h post-exposure and total RNA extracted for subsequent global gene expression analysis. Among the > 1000 genes affected by WTC dust (under ISO) or ISO alone, 166 were unique to the dust exposure. In many instances, genes maximally-induced by the WTC dust exposure (relative to in naïve rats) were unchanged/inhibited by ISO only; similarly, several genes maximally inhibited in WTC dust rats were largely induced/unchanged in rats that received ISO only. These outcomes reflect likely contrasting effects of ISO and the WTC dust on lung gene expression. Overall, the data show that lungs of rats exposed to WTC dust (under ISO) – after accounting for any impact from ISO alone – displayed increased expression of genes related to lung inflammation, oxidative stress, and cell cycle control, while several involved in anti-oxidant function were inhibited. These changes suggested acute inflammogenic effects and oxidative stress in the lungs of WTC dust-exposed rats. This study, thus, concludes that a single very high exposure to WTC dusts could

Acute high-level exposure to WTC particles alters expression of genes associated with oxidative stress and immune function in the lung.

PubMed

Cohen, Mitchell D; Vaughan, Joshua M; Garrett, Brittany; Prophete, Colette; Horton, Lori; Sisco, Maureen; Kodavanti, Urmila P; Ward, William O; Peltier, Richard E; Zelikoff, Judith; Chen, Lung-chi

2015-01-01

First responders (FR) present at Ground Zero in the first 72 h after the World Trade Center (WTC) collapsed have progressively exhibited significant respiratory injuries. The few toxicology studies performed to date evaluated effects from just fine (< 2.5 µm) WTC dusts; none examined health effects/toxicities from atmospheres bearing larger particle sizes, despite the fact the majority (> 96%) of dusts were > 10 µm and most FR likely entrained dusts by mouth breathing. Using a system that generated/delivered supercoarse (10-53 µm) WTC dusts to F344 rats (in a manner that mimicked FR exposures), this study sought to examine potential toxicities in the lungs. In this exploratory study, rats were exposed for 2 h to 100 mg WTC dust/m(3) (while under isoflurane [ISO] anesthesia) or an air/ISO mixture; this dose conservatively modeled likely exposures by mouth-breathing FR facing ≈750-1000 mg WTC dust/m(3). Lungs were harvested 2 h post-exposure and total RNA extracted for subsequent global gene expression analysis. Among the >  1000 genes affected by WTC dust (under ISO) or ISO alone, 166 were unique to the dust exposure. In many instances, genes maximally-induced by the WTC dust exposure (relative to in naïve rats) were unchanged/inhibited by ISO only; similarly, several genes maximally inhibited in WTC dust rats were largely induced/unchanged in rats that received ISO only. These outcomes reflect likely contrasting effects of ISO and the WTC dust on lung gene expression. Overall, the data show that lungs of rats exposed to WTC dust (under ISO) - after accounting for any impact from ISO alone - displayed increased expression of genes related to lung inflammation, oxidative stress, and cell cycle control, while several involved in anti-oxidant function were inhibited. These changes suggested acute inflammogenic effects and oxidative stress in the lungs of WTC dust-exposed rats. This study, thus, concludes that a single very high exposure

Intranasal Chromium Induces Acute Brain and Lung Injuries in Rats: Assessment of Different Potential Hazardous Effects of Environmental and Occupational Exposure to Chromium and Introduction of a Novel Pharmacological and Toxicological Animal Model.

PubMed

Salama, Abeer; Hegazy, Rehab; Hassan, Azza

2016-01-01

Chromium (Cr) is used in many industries and it is widely distributed in the environment. Exposure to Cr dust has been reported among workers at these industries. Beside its hazardous effects on the lungs, brain injury could be induced, as the absorption of substances through the nasal membrane has been found to provide them a direct delivery to the brain. We investigated the distribution and the effects of Cr in both brain and lung following the intranasal instillation of potassium dichromate (inPDC) in rats. Simultaneously, we used the common intraperitoneal (ipPDC) rat model of acute Cr-toxicity for comparison. Thirty male Wistar rats were randomly allocated into five groups (n = 6); each received a single dose of saline, ipPDC (15 mg/kg), or inPDC in three dose levels: 0.5, 1, or 2 mg/kg. Locomotor activity was assessed before and 24 h after PDC administration, then, the lungs and brain were collected for biochemical, histopathological, and immunohistochemical investigations. Treatment of rats with ipPDC resulted in a recognition of 36% and 31% of the injected dose of Cr in the brain and lung tissues, respectively. In inPDC-treated rats, targeting the brain by Cr was increased in a dose-dependent manner to reach 46% of the instilled dose in the group treated with the highest dose. Moreover, only this high dose of inPDC resulted in a delivery of a significant concentration of Cr, which represented 42% of the instilled dose, to the lungs. The uppermost alteration in the rats locomotor activity as well as in the brain and lung histopathological features and contents of oxidative stress biomarkers, interleukin-1β (IL-1β), phosphorylated protein kinase B (PKB), and cyclooxygenase 2 (COX-2) were observed in the rats treated with inPDC (2 mg/kg). The findings revealed that these toxic manifestations were directly proportional to the delivered concentration of Cr to the tissue. In conclusion, the study showed that a comparably higher concentrations of Cr and more

Intranasal Chromium Induces Acute Brain and Lung Injuries in Rats: Assessment of Different Potential Hazardous Effects of Environmental and Occupational Exposure to Chromium and Introduction of a Novel Pharmacological and Toxicological Animal Model

PubMed Central

Salama, Abeer; Hassan, Azza

2016-01-01

Chromium (Cr) is used in many industries and it is widely distributed in the environment. Exposure to Cr dust has been reported among workers at these industries. Beside its hazardous effects on the lungs, brain injury could be induced, as the absorption of substances through the nasal membrane has been found to provide them a direct delivery to the brain. We investigated the distribution and the effects of Cr in both brain and lung following the intranasal instillation of potassium dichromate (inPDC) in rats. Simultaneously, we used the common intraperitoneal (ipPDC) rat model of acute Cr-toxicity for comparison. Thirty male Wistar rats were randomly allocated into five groups (n = 6); each received a single dose of saline, ipPDC (15 mg/kg), or inPDC in three dose levels: 0.5, 1, or 2 mg/kg. Locomotor activity was assessed before and 24 h after PDC administration, then, the lungs and brain were collected for biochemical, histopathological, and immunohistochemical investigations. Treatment of rats with ipPDC resulted in a recognition of 36% and 31% of the injected dose of Cr in the brain and lung tissues, respectively. In inPDC-treated rats, targeting the brain by Cr was increased in a dose-dependent manner to reach 46% of the instilled dose in the group treated with the highest dose. Moreover, only this high dose of inPDC resulted in a delivery of a significant concentration of Cr, which represented 42% of the instilled dose, to the lungs. The uppermost alteration in the rats locomotor activity as well as in the brain and lung histopathological features and contents of oxidative stress biomarkers, interleukin-1β (IL-1β), phosphorylated protein kinase B (PKB), and cyclooxygenase 2 (COX-2) were observed in the rats treated with inPDC (2 mg/kg). The findings revealed that these toxic manifestations were directly proportional to the delivered concentration of Cr to the tissue. In conclusion, the study showed that a comparably higher concentrations of Cr and more

Acute toxicity of leachates of tire wear material to Daphnia magna--variability and toxic components.

PubMed

Wik, Anna; Dave, Göran

2006-09-01

Large amounts of tire rubber are deposited along the roads due to tread wear. Several compounds may leach from the rubber and cause toxicity to aquatic organisms. To investigate the toxic effects of tire wear material from different tires, rubber was abraded from the treads of twenty-five tires. Leachates were prepared by allowing the rubber to equilibrate with dilution water at 44 degrees C for 72 h. Then the rubber was filtered from the leachates, and test organisms (Daphnia magna) were added. Forty-eight hour EC50s ranged from 0.5 to >10.0 g l(-1). The toxicity identification evaluation (TIE) indicated that non-polar organic compounds caused most of the toxicity. UV exposure of the filtered tire leachates caused no significant increase in toxicity. However, when tested as unfiltered leachates (the rubber was not filtered from the leachates before addition of D. magna) photo-enhanced toxicity was considerable for some tires, which means that test procedures are important when testing tire leachates for aquatic (photo) toxicity. The acute toxicity of tire wear for Daphnia magna was found to be <40 times a predicted environmental concentration based on reports on the concentration of a tire component found in environmental samples, which emphasizes the need for a more extensive risk assessment of tire wear for the environment.

Low power infrared laser modifies the morphology of lung affected with acute injury induced by sepsis

NASA Astrophysics Data System (ADS)

Sergio, L. P. S.; Trajano, L. A. S. N.; Thomé, A. M. C.; Mencalha, A. L.; Paoli, F.; Fonseca, A. S.

2018-06-01

Acute lung injury (ALI) is a potentially fatal disease characterized by uncontrolled hyperinflammatory responses in the lungs as a consequence of sepsis. ALI is divided into two sequential and time-dependent phases, exudative and fibroproliferative phases, with increased permeability of the alveolar barrier, causing edema and inflammation. However, there are no specific treatments for ALI. Low-power lasers have been successfully used in the resolution of acute inflammatory processes. The aim of this study was to evaluate the effects of low-power infrared laser exposure on alveolus and interalveolar septa of Wistar rats affected by ALI-induced by sepsis. Laser fluences, power, and the emission mode were those used in clinical protocols for the treatment of acute inflammation. Adult male Wistar rats were randomized into six groups: control, 10 J cm‑2, 20 J cm‑2, ALI, ALI  +  10 J cm‑2, and ALI  +  20 J cm‑2. ALI was induced by intraperitoneal Escherichia coli lipopolysaccharide (LPS). Lungs were removed and processed for hematoxylin–eosin staining. Morphological alterations induced by LPS in lung tissue were quantified by morphometry with a 32-point cyclic arcs test system in Stepanizer. Data showed that exposure to low-power infrared laser in both fluences reduced the thickening of interalveolar septa in lungs affected by ALI, increasing the alveolar space; however, inflammatory infiltrate was still observed. Our research showed that exposure to low-power infrared laser improves the lung parenchyma in Wistar rats affected by ALI, which could be an alternative approach for treatment of inflammatory lung injuries.

Identifying and designing chemicals with minimal acute aquatic toxicity

PubMed Central

Kostal, Jakub; Voutchkova-Kostal, Adelina; Anastas, Paul T.; Zimmerman, Julie Beth

2015-01-01

Industrial ecology has revolutionized our understanding of material stocks and flows in our economy and society. For this important discipline to have even deeper impact, we must understand the inherent nature of these materials in terms of human health and the environment. This paper focuses on methods to design synthetic chemicals to reduce their intrinsic ability to cause adverse consequence to the biosphere. Advances in the fields of computational chemistry and molecular toxicology in recent decades allow the development of predictive models that inform the design of molecules with reduced potential to be toxic to humans or the environment. The approach presented herein builds on the important work in quantitative structure–activity relationships by linking toxicological and chemical mechanistic insights to the identification of critical physical–chemical properties needed to be modified. This in silico approach yields design guidelines using boundary values for physiochemical properties. Acute aquatic toxicity serves as a model endpoint in this study. Defining value ranges for properties related to bioavailability and reactivity eliminates 99% of the chemicals in the highest concern for acute aquatic toxicity category. This approach and its future implementations are expected to yield very powerful tools for life cycle assessment practitioners and molecular designers that allow rapid assessment of multiple environmental and human health endpoints and inform modifications to minimize hazard. PMID:24639521

Identifying and designing chemicals with minimal acute aquatic toxicity.

PubMed

Kostal, Jakub; Voutchkova-Kostal, Adelina; Anastas, Paul T; Zimmerman, Julie Beth

2015-05-19

Industrial ecology has revolutionized our understanding of material stocks and flows in our economy and society. For this important discipline to have even deeper impact, we must understand the inherent nature of these materials in terms of human health and the environment. This paper focuses on methods to design synthetic chemicals to reduce their intrinsic ability to cause adverse consequence to the biosphere. Advances in the fields of computational chemistry and molecular toxicology in recent decades allow the development of predictive models that inform the design of molecules with reduced potential to be toxic to humans or the environment. The approach presented herein builds on the important work in quantitative structure-activity relationships by linking toxicological and chemical mechanistic insights to the identification of critical physical-chemical properties needed to be modified. This in silico approach yields design guidelines using boundary values for physiochemical properties. Acute aquatic toxicity serves as a model endpoint in this study. Defining value ranges for properties related to bioavailability and reactivity eliminates 99% of the chemicals in the highest concern for acute aquatic toxicity category. This approach and its future implementations are expected to yield very powerful tools for life cycle assessment practitioners and molecular designers that allow rapid assessment of multiple environmental and human health endpoints and inform modifications to minimize hazard.

Psychosis associated with acute recreational drug toxicity: a European case series.

PubMed

Vallersnes, Odd Martin; Dines, Alison M; Wood, David M; Yates, Christopher; Heyerdahl, Fridtjof; Hovda, Knut Erik; Giraudon, Isabelle; Dargan, Paul I

2016-08-18

Psychosis can be associated with acute recreational drug and novel psychoactive substance (NPS) toxicity. However, there is limited data available on how common this is and which drugs are most frequently implicated. We describe a European case series of psychosis associated with acute recreational drug toxicity, and estimate the frequency of psychosis for different recreational drugs. The European Drug Emergencies Network (Euro-DEN) collects data on presentations to Emergency Departments (EDs) with acute recreational drug and NPS toxicity at 16 centres in ten countries. Euro-DEN data from October 2013 through September 2014 was retrospectively searched, and cases with psychosis were included. The proportion of cases with psychosis per drug was calculated in the searched Euro-DEN dataset. Psychosis was present in 348 (6.3 %) of 5529 cases. The median (interquartile range) age was 29 (24-38) years, 276 (79.3 %) were male and 114 (32.8 %) were admitted to psychiatric ward. The drugs most commonly reported were cannabis in 90 (25.9 %) cases, amphetamine in 87 (25.0 %) and cocaine in 56 (16.1 %). More than one drug was taken in 189 (54.3 %) cases. Psychosis was frequent in those ED presentations involving tryptamines (4/7; 57.1 %), methylenedioxypyrovalerone (MDPV) (6/22; 27.3 %), methylphenidate (6/26; 23.1 %), lysergic acid diethylamide (LSD) (18/86; 20.9 %), psilocybe mushrooms (3/16; 18.8 %), synthetic cannabinoid receptor agonists (4/26; 15.4 %) and amphetamine (87/593; 14.7 %), but less common in those involving mephedrone (14/245; 5.7 %), methylenedioxymethamphetamine (MDMA) (20/461; 4.3 %) and methedrone (3/92; 3.3 %). Amphetamine was the most frequent drug associated with psychosis when only one agent was reported, with psychosis occurring in 32.4 % of these presentations. The frequency of psychosis in acute recreational drug toxicity varies considerably between drugs, but is a major problem in amphetamine poisoning. In rapidly changing drug markets and

Why is particulate matter produced by wildfires toxic to lung macrophages?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Franzi, Lisa M.; Bratt, Jennifer M.; Williams, Keisha M.

The mechanistic basis of the high toxicity to lung macrophages of coarse PM from the California wildfires of 2008 was examined in cell culture experiments with mouse macrophages. Wildfire PM directly killed macrophages very rapidly in cell culture at relatively low doses. The wildfire coarse PM is about four times more toxic to macrophages on an equal weight basis than the same sized PM collected from normal ambient air (no wildfires) from the same region and season. There was a good correlation between the extent of cytotoxicity and the amount of oxidative stress observed at a given dose of wildfiremore » PM in vitro. Our data implicate NF-{kappa}B signaling in the response of macrophages to wildfire PM, and suggest that most, if not all, of the cytotoxicity of wildfire PM to lung macrophages is the result of oxidative stress. The relative ratio of toxicity and of expression of biomarkers of oxidant stress between wildfire PM and 'normal' PM collected from ambient air is consistent with our previous results in mice in vivo, also suggesting that most, if not all, of the cytotoxicity of wildfire PM to lung macrophages is the result of oxidative stress. Our findings from this and earlier studies suggest that the active components of coarse PM from the wildfire are heat-labile organic compounds. While we cannot rule out a minor role for endotoxin in coarse PM preparations from the collected wildfire PM in our observed results both in vitro and in vivo, based on experiments using the inhibitor Polymyxin B most of the oxidant stress and pro-inflammatory activity observed was not due to endotoxin. -- Highlights: Black-Right-Pointing-Pointer Wildfire coarse PM kills macrophages at lower doses than coarse. Black-Right-Pointing-Pointer Wildfire coarse PM activates the NF-kB pathway at lower doses than ambient. Black-Right-Pointing-Pointer Wildfire coarse PM in vitro and in vivo kill macrophages by oxidative stress.« less

Chronomodulation of topotecan or X-radiation treatment increases treatment efficacy without enhancing acute toxicity.

PubMed

Mullins, Dana; Proulx, Denise; Saoudi, A; Ng, Cheng E

2005-05-01

Topotecan (TPT), a camptothecin analog, is currently used to treat human ovarian and small-cell lung cancer and is in clinical trials for other tumor sites. However, it is unknown whether chronomodulation of TPT treatment is beneficial. We examined the effects of administering TPT or X-radiation (XR) alone at different times of the day or night. We treated mice bearing human colorectal tumor xenografts at four different times representing the early rest period (9 am or 3 HALO [hours after light onset]), late rest period (3 pm or 9 HALO), early active period (9 pm or 15 HALO), and late active period (3 am or 21 HALO) of the mice. We gave either TPT (12 mg/kg, injected i.p.) or XR (4 Gy, directed to the tumor) twice weekly on Days 0, 4, 7, 10 within 2 weeks. Treatment with either TPT or XR at 3 am demonstrated the greatest efficacy (measured by a tumor regrowth assay) without significantly increasing acute toxicity (assessed by a decrease in leukocyte counts or body weight). Conversely, treatment at 3 pm, in particular, showed increased toxicity without any enhanced efficacy. Our study provided the first evidence that chronomodulation of TPT treatments, consistent with the findings of other camptothecin analogs, is potentially clinically beneficial. Additionally, our findings suggest that chronomodulation of fractionated XR treatments is also potentially clinically beneficial.

Acute toxicity of peracetic acid (PAA) formulations to Ichthyophthirius multifiliis theronts.

PubMed

Straus, David L; Meinelt, Thomas

2009-04-01

Peracetic acid (PAA) is an antimicrobial disinfectant used in agriculture, food processing, and medical facilities. It has recently been suggested as a means to control infestations of Ichthyophthirius multifiliis. The purpose of this study was to determine the acute toxicity of two products containing 4.5% and 40% PAA to I. multifiliis theronts from two geographically separate isolates. Theronts were exposed to concentrations of PAA in 96-well plates containing groundwater at 23 degrees C. Acute toxicity was observed over a 4-h period. No significant difference in the median lethal concentration (LC(50)) estimates was evident between the two isolates at 4 h with the 4.5% PAA product (0.146 versus 0.108 mg/l PAA), while there was a statistical difference between the 4 h LC(50) with the 40% PAA product (0.274 versus 0.158 mg/l PAA). These results suggest that PAA is toxic to I. multifiliis theronts at low concentrations and that one of the isolates was more resistant to this compound.

Predictors of Severe Acute and Late Toxicities in Patients With Localized Head-and-Neck Cancer Treated With Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meyer, Francois, E-mail: francois.meyer@chuq.qc.ca; Fortin, Andre; Wang, Chang Shu

2012-03-15

Purpose: Radiation therapy (RT) causes acute and late toxicities that affect various organs and functions. In a large cohort of patients treated with RT for localized head and neck cancer (HNC), we prospectively assessed the occurrence of RT-induced acute and late toxicities and identified characteristics that predicted these toxicities. Methods and Materials: We conducted a randomized trial among 540 patients treated with RT for localized HNC to assess whether vitamin E supplementation could improve disease outcomes. Adverse effects of RT were assessed using the Radiation Therapy Oncology Group Acute Radiation Morbidity Criteria during RT and one month after RT, andmore » the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme at six and 12 months after RT. The most severe adverse effect among the organs/tissues was selected as an overall measure of either acute or late toxicity. Grade 3 and 4 toxicities were considered as severe. Stepwise multivariate logistic regression models were used to identify all independent predictors (p < 0.05) of acute or late toxicity and to estimate odds ratios (OR) for severe toxicity with their 95% confidence intervals (CI). Results: Grade 3 or 4 toxicity was observed in 23% and 4% of patients, respectively, for acute and late toxicity. Four independent predictors of severe acute toxicity were identified: sex (female vs. male: OR = 1.72, 95% confidence interval [CI]: 1.06-2.80), Karnofsky Performance Status (OR = 0.67 for a 10-point increment, 95% CI: 0.52-0.88), body mass index (above 25 vs. below: OR = 1.88, 95% CI: 1.22-2.90), TNM stage (Stage II vs. I: OR = 1.91, 95% CI: 1.25-2.92). Two independent predictors were found for severe late toxicity: female sex (OR = 3.96, 95% CI: 1.41-11.08) and weight loss during RT (OR = 1.26 for a 1 kg increment, 95% CI: 1.12-1.41). Conclusions: Knowledge of these predictors easily collected in a clinical setting

Acute and Subchronic Toxic Effects of the Fruits of Physalis peruviana L.

PubMed

Perk, Basak Ozlem; Ilgin, Sinem; Atli, Ozlem; Duymus, Hale Gamze; Sirmagul, Basar

2013-01-01

The fruit of Physalis peruviana L. (PPL) has been traditionally used as antispasmodic, diuretic, antiseptic, sedative, and analgesic all over the world. We aimed to perform qualitative content analysis of the fruits of PPL and to clarify the in vitro genotoxicity and in vivo acute and subchronic toxicity of the fruit. Lyophilized fruit juice does not induce genetic damage. In the acute toxicity studies, LD50 value of the fruit was found to be more than 5000 mg kg(-1) for both sexes. According to the subchronic toxicity studies, hepatic, renal, and hematological toxic effects were not induced in both sexes. Plasma troponin I (only in the group treated with 5000 mg kg(-1) of lyophilized fruit juice) and troponin T levels were significantly increased in male groups treated with lyophilized fruit juice compared to the control group. Furthermore, potassium level was significantly increased in the male group treated with 5000 mg kg(-1) of lyophilized fruit juice. These findings were considered to indicate the myocardial damage particularly in the male group treated with 5000 mg kg(-1) of lyophilized fruit juice. In conclusion, lyophilized fruit juice of PPL is shown to induce cardiac toxicity only at high doses and in male gender.

Acute and Subchronic Toxic Effects of the Fruits of Physalis peruviana L.

PubMed Central

Perk, Basak Ozlem; Ilgin, Sinem; Atli, Ozlem; Duymus, Hale Gamze; Sirmagul, Basar

2013-01-01

The fruit of Physalis peruviana L. (PPL) has been traditionally used as antispasmodic, diuretic, antiseptic, sedative, and analgesic all over the world. We aimed to perform qualitative content analysis of the fruits of PPL and to clarify the in vitro genotoxicity and in vivo acute and subchronic toxicity of the fruit. Lyophilized fruit juice does not induce genetic damage. In the acute toxicity studies, LD50 value of the fruit was found to be more than 5000 mg kg−1 for both sexes. According to the subchronic toxicity studies, hepatic, renal, and hematological toxic effects were not induced in both sexes. Plasma troponin I (only in the group treated with 5000 mg kg−1 of lyophilized fruit juice) and troponin T levels were significantly increased in male groups treated with lyophilized fruit juice compared to the control group. Furthermore, potassium level was significantly increased in the male group treated with 5000 mg kg−1 of lyophilized fruit juice. These findings were considered to indicate the myocardial damage particularly in the male group treated with 5000 mg kg−1 of lyophilized fruit juice. In conclusion, lyophilized fruit juice of PPL is shown to induce cardiac toxicity only at high doses and in male gender. PMID:24369482

In vitro toxic effects of reduced graphene oxide nanosheets on lung cancer cells

NASA Astrophysics Data System (ADS)

Tabish, Tanveer A.; Pranjol, Md Zahidul I.; Hayat, Hasan; Rahat, Alma A. M.; Abdullah, Trefa M.; Whatmore, Jacqueline L.; Zhang, Shaowei

2017-12-01

The intriguing properties of reduced graphene oxide (rGO) have paved the way for a number of potential biomedical applications such as drug delivery, tissue engineering, gene delivery and bio-sensing. Over the last decade, there have been escalating concerns regarding the possible toxic effects, behaviour and fate of rGO in living systems and environments. This paper reports on integrative chemical-biological interactions of rGO with lung cancer cells, i.e. A549 and SKMES-1, to determine its potential toxicological impacts on them, as a function of its concentration. Cell viability, early and late apoptosis and necrosis were measured to determine oxidative stress potential, and induction of apoptosis for the first time by comparing two lung cancer cells. We also showed the general trend between cell death rates and concentrations for different cell types using a Gaussian process regression model. At low concentrations, rGO was shown to significantly produce late apoptosis and necrosis rather than early apoptotic events, suggesting that it was able to disintegrate the cellular membranes in a dose dependent manner. For the toxicity exposures undertaken, late apoptosis and necrosis occurred, which was most likely resultant from limited bioavailability of unmodified rGO in lung cancer cells.

Development of an acceptable factor to estimate chronic end points from acute toxicity data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Venman, B.C.; Flaga, C.

1985-12-01

Acceptable daily intake (ADI) values are routinely developed for threshold toxicants from NOAELs determined from human or animal chronic or subchronic data. These NOAELs are then divided by appropriate uncertainty factors ranging from 10 to 1000 depending on the quality of the data. However, for the vast majority of chemicals used industrially, adequate toxicity data needed to use this process are not available. Thus, a procedure to estimate a chronic toxicity endpoint from acute toxicity data, such as an oral rat LD50, becomes necessary. An acute-to-chronic application factor of 0.0001 was developed, which when multiplied by an oral LD50 formore » an individual chemical, yields a surrogate chronic NOAEL. This figure can then be used to estimate an acceptable daily exposure for humans. The process used to estimate this application factor is detailed.« less

Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs

PubMed Central

2012-01-01

Background Phorbol myristate acetate (PMA) is a strong neutrophil activator and has been used to induce acute lung injury (ALI). Niacinamide (NAC) is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC) on the PMA-induced ALI and associated changes. Methods The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g), PMA 4 μg/g (lung weight), cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight). There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc) were determined in isolated lungs. ATP (adenotriphosphate) and PARP [poly(adenosine diphophate-ribose) polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS). The neutrophil-derived mediators in lung perfusate were determined. Results PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Conclusions Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental role in the PMA

Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs.

PubMed

Lin, Chia-Chih; Hsieh, Nan-Kuang; Liou, Huey Ling; Chen, Hsing I

2012-03-01

Phorbol myristate acetate (PMA) is a strong neutrophil activator and has been used to induce acute lung injury (ALI). Niacinamide (NAC) is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC) on the PMA-induced ALI and associated changes. The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g), PMA 4 μg/g (lung weight), cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight). There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc) were determined in isolated lungs. ATP (adenotriphosphate) and PARP [poly(adenosine diphophate-ribose) polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS). The neutrophil-derived mediators in lung perfusate were determined. PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental role in the PMA-induced lung injury. ATP is beneficial

The Nitrated Fatty Acid 10-Nitro-oleate Diminishes Severity of LPS-Induced Acute Lung Injury in Mice

PubMed Central

Reddy, Aravind T.; Lakshmi, Sowmya P.; Reddy, Raju C.

2012-01-01

Acute lung injury (ALI) is an inflammatory condition culminating in respiratory failure. There is currently no effective pharmacological treatment. Nitrated fatty acids (NFAs) have been shown to exert anti-inflammatory effects. We therefore hypothesized that delivery of NFAs directly to the site of inflammation would reduce the severity of ALI. Pulmonary delivery of 10-nitro-oleate following endotoxin-induced ALI in mice reduced markers of lung inflammation and injury, including capillary leakage, lung edema, infiltration of neutrophils into the lung, and oxidant stress, as well as plasma levels of proinflammatory cytokines. Nitro-oleate delivery likewise downregulated expression of proinflammatory genes by alveolar macrophages, key cells in regulation of lung inflammation. These effects may be accounted for by the observed increases in the activity of PPAR-γ and the PPAR-γ-induced antioxidant transcription factor Nrf2, together with the decreased activity of NF-κB. Our results demonstrate that pulmonary delivery of NFAs reduces severity of acute lung injury and suggest potential utility of these molecules in other inflammatory lung diseases. PMID:22919366

Development of a general baseline toxicity QSAR model for the fish embryo acute toxicity test.

PubMed

Klüver, Nils; Vogs, Carolina; Altenburger, Rolf; Escher, Beate I; Scholz, Stefan

2016-12-01

Fish embryos have become a popular model in ecotoxicology and toxicology. The fish embryo acute toxicity test (FET) with the zebrafish embryo was recently adopted by the OECD as technical guideline TG 236 and a large database of concentrations causing 50% lethality (LC 50 ) is available in the literature. Quantitative Structure-Activity Relationships (QSARs) of baseline toxicity (also called narcosis) are helpful to estimate the minimum toxicity of chemicals to be tested and to identify excess toxicity in existing data sets. Here, we analyzed an existing fish embryo toxicity database and established a QSAR for fish embryo LC 50 using chemicals that were independently classified to act according to the non-specific mode of action of baseline toxicity. The octanol-water partition coefficient K ow is commonly applied to discriminate between non-polar and polar narcotics. Replacing the K ow by the liposome-water partition coefficient K lipw yielded a common QSAR for polar and non-polar baseline toxicants. This developed baseline toxicity QSAR was applied to compare the final mode of action (MOA) assignment of 132 chemicals. Further, we included the analysis of internal lethal concentration (ILC 50 ) and chemical activity (La 50 ) as complementary approaches to evaluate the robustness of the FET baseline toxicity. The analysis of the FET dataset revealed that specifically acting and reactive chemicals converged towards the baseline toxicity QSAR with increasing hydrophobicity. The developed FET baseline toxicity QSAR can be used to identify specifically acting or reactive compounds by determination of the toxic ratio and in combination with appropriate endpoints to infer the MOA for chemicals. Copyright © 2016 Elsevier Ltd. All rights reserved.

20180311 - Variability of LD50 Values from Rat Oral Acute Toxicity Studies: Implications for Alternative Model Development (SOT)

EPA Science Inventory

Alternative models developed for estimating acute systemic toxicity are generally evaluated using in vivo LD50 values. However, in vivo acute systemic toxicity studies can produce variable results, even when conducted according to accepted test guidelines. This variability can ma...

NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction.

PubMed

Wennberg, Berit M; Baumann, Pia; Gagliardi, Giovanna; Nyman, Jan; Drugge, Ninni; Hoyer, Morten; Traberg, Anders; Nilsson, Kristina; Morhed, Elisabeth; Ekberg, Lars; Wittgren, Lena; Lund, Jo-Åsmund; Levin, Nina; Sederholm, Christer; Lewensohn, Rolf; Lax, Ingmar

2011-05-01

In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman- Kutcher-Burman (LKB) model. In the LQ-correction α/β = 3 Gy was used and the USC parameters used were: α/β = 3 Gy, D(0) = 1.0 Gy, [Formula: see text] = 10, α = 0.206 Gy(-1) and d(T) = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether "high doses to small volumes" or "low doses to large volumes" are most important for lung toxicity. NTCP analysis with the LKB-model using parameters m = 0.4, D(50) = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D(50) = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ,USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.

Multivariable normal-tissue complication modeling of acute esophageal toxicity in advanced stage non-small cell lung cancer patients treated with intensity-modulated (chemo-)radiotherapy.

PubMed

Wijsman, Robin; Dankers, Frank; Troost, Esther G C; Hoffmann, Aswin L; van der Heijden, Erik H F M; de Geus-Oei, Lioe-Fee; Bussink, Johan

2015-10-01

The majority of normal-tissue complication probability (NTCP) models for acute esophageal toxicity (AET) in advanced stage non-small cell lung cancer (AS-NSCLC) patients treated with (chemo-)radiotherapy are based on three-dimensional conformal radiotherapy (3D-CRT). Due to distinct dosimetric characteristics of intensity-modulated radiation therapy (IMRT), 3D-CRT based models need revision. We established a multivariable NTCP model for AET in 149 AS-NSCLC patients undergoing IMRT. An established model selection procedure was used to develop an NTCP model for Grade ⩾2 AET (53 patients) including clinical and esophageal dose-volume histogram parameters. The NTCP model predicted an increased risk of Grade ⩾2 AET in case of: concurrent chemoradiotherapy (CCR) [adjusted odds ratio (OR) 14.08, 95% confidence interval (CI) 4.70-42.19; p<0.001], increasing mean esophageal dose [Dmean; OR 1.12 per Gy increase, 95% CI 1.06-1.19; p<0.001], female patients (OR 3.33, 95% CI 1.36-8.17; p=0.008), and ⩾cT3 (OR 2.7, 95% CI 1.12-6.50; p=0.026). The AUC was 0.82 and the model showed good calibration. A multivariable NTCP model including CCR, Dmean, clinical tumor stage and gender predicts Grade ⩾2 AET after IMRT for AS-NSCLC. Prior to clinical introduction, the model needs validation in an independent patient cohort. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Significance of Intratracheal Instillation Tests for the Screening of Pulmonary Toxicity of Nanomaterials.

PubMed

Morimoto, Yasuo; Izumi, Hiroto; Yoshiura, Yukiko; Fujisawa, Yuri; Fujita, Katsuhide

Inhalation tests are the gold standard test for the estimation of the pulmonary toxicity of respirable materials. Intratracheal instillation tests have been used widely, but they yield limited evidence of the harmful effects of respirable materials. We reviewed the effectiveness of intratracheal instillation tests for estimating the hazards of nanomaterials, mainly using research papers featuring intratracheal instillation and inhalation tests centered on a Japanese national project. Compared to inhalation tests, intratracheal instillation tests induced more acute inflammatory responses in the animal lung due to a bolus effect regardless of the toxicity of the nanomaterials. However, nanomaterials with high toxicity induced persistent inflammation in the chronic phase, and nanomaterials with low toxicity induced only transient inflammation. Therefore, in order to estimate the harmful effects of a nanomaterial, an observation period of 3 months or 6 months following intratracheal instillation is necessary. Among the endpoints of pulmonary toxicity, cell count and percentage of neutrophil, chemokines for neutrophils and macrophages, and oxidative stress markers are considered most important. These markers show persistent and transient responses in the lung from nanomaterials with high and low toxicity, respectively. If the evaluation of the pulmonary toxicity of nanomaterials is performed in not only the acute but also the chronic phase in order to avoid the bolus effect of intratracheal instillation and inflammatory-related factors that are used as endpoints of pulmonary toxicity, we speculate that intratracheal instillation tests can be useful for screening for the identification of the hazard of nanomaterials through pulmonary inflammation.

Acute oral toxicity: variability, reliability, relevance and interspecies comparison of rodent LD50 data from literature surveyed for the ACuteTox project.

PubMed

Hoffmann, Sebastian; Kinsner-Ovaskainen, Agnieszka; Prieto, Pilar; Mangelsdorf, Inge; Bieler, Christian; Cole, Thomas

2010-12-01

The ACuteTox project has aimed to optimise and prevalidate an in vitro testing strategy for predicting human acute toxicity. Ninety-seven reference substances were selected and an in vivo acute toxicity database was compiled. Comprehensive statistical analyses of the in vivo LD50 data to evaluate variability and reliability, interspecies correlation, predictive capacities with regard to EU and GHS toxicity categories, and deduction of performance criteria for in vitro methods is presented. For the majority of substances variability among rodent data followed a log normal distribution where good reproducibility was found. Rat and mouse interspecies comparison of LD50 studies by ordinary regression showed high correlation, with coefficients of determination, ranging between 0.8 and 0.9. Substance specific differences were only significant for warfarin and cycloheximide. No correlation of compound LD50 range with presumed study quality rank (by assigning Klimisch reliability scores) was found. Modelling based on LD50 variability showed that with at least 90% probability ∼54% of the substances would fall into only one GHS category and ∼44% would fall within two adjacent categories. These results could form the basis for deriving a predictive capacity that should be expected from alternative approaches to the conventional in vivo acute oral toxicity test. Copyright © 2010 Elsevier Inc. All rights reserved.

Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity.

PubMed

Botelho, Danielle J; Leo, Bey Fen; Massa, Christopher B; Sarkar, Srijata; Tetley, Terry D; Chung, Kian Fan; Chen, Shu; Ryan, Mary P; Porter, Alexandra E; Zhang, Junfeng; Schwander, Stephan K; Gow, Andrew J

2016-01-01

Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 μg/g body weight) 20 and 110 nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110 nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.

Protective effect of magnolol-loaded polyketal microparticles on lipopolysaccharide-induced acute lung injury in rats.

PubMed

Tsai, Tsuimin; Kao, Chen-Yu; Chou, Chun-Liang; Liu, Lu-Chun; Chou, Tz-Chong

2016-08-01

Magnolol has shown inhibitory effects on NO production and TNF-alpha production in lipopolysaccharide (LPS)-activated macrophages and LPS-induced acute lung injury; however, the poor solubility of magnolol has hindered its clinical success. In this study, magnolol-loaded microparticles were prepared via single emulsion method from a polyketal polymer, termed PK3. The particle sizes of magnolol-loaded PK3 microparticle is 3.73 ± 0.41 μm, and was suitable for phagocytosis by macrophages and pulmonary drug delivery. PK3 microparticles exhibited excellent biocompatibility both in vitro and in vivo. More importantly, intratracheal delivery of these magnolol-loaded microparticles significantly reduced the lung inflammatory responses at low dosage of magnolol (0.5 mg/kg), and have great clinical potential in treating acute lung injury.

Soil ingestion: a concern for acute toxicity in children.

PubMed Central

Calabrese, E J; Stanek, E J; James, R C; Roberts, S M

1997-01-01

Several soil ingestion studies have indicated that some children ingest substantial amounts of soil on given days. Although the EPA has assumed that 95% of children ingest 200 mg soil/day or less for exposure assessment purposes, some children have been observed to ingest up to 25-60 g soil during a single day. In light of the potential for children to ingest such large amounts of soil, an assessment was made of the possibility for soil pica episodes to result in acute intoxication from contaminant concentrations the EPA regards as representing conservative screening values (i.e., EPA soil screening levels and EPA Region III risk-based concentrations for residential soils). For a set of 13 chemicals included in the analysis, contaminant doses resulting from a one-time soil pica episode (5-50 g of soil ingested) were compared with acute dosages shown to produce toxicity in humans in clinical studies or case reports. For four of these chemicals, a soil pica episode was found to result in a contaminant dose approximating or exceeding the acute human lethal dose. For five of the remaining chemicals, the contaminant dose from a soil pica episode was well within the reported dose range in humans for toxicity other than lethality. Because both the exposure episodes and the toxicological response information are derived from observations in humans, these findings are regarded as particularly relevant for human health risk assessment. They suggest that, for some chemicals, ostensibly conservative soil criteria based on chronic exposure using current EPA methodology may not be protective of children during acute soil pica episodes. PMID:9405323

A NOVEL WEARABLE PUMP-LUNG DEVICE: IN-VITRO AND ACUTE IN-VIVO STUDY

PubMed Central

Zhang, Tao; Wei, Xufeng; Bianchi, Giacomo; Wong, Philip M.; Biancucci, Brian; Griffith, Bartley P.; Wu, Zhongjun J.

2011-01-01

Background To provide long-term ambulatory cardiopulmonary and respiratory support for adult patients, a novel wearable artificial pump-lung device has been developed. The design features, in-vitro and acute in-vivo performance of this device are reported in this paper. Methods This device features a uniquely designed hollow fiber membrane bundle integrated with a magnetically levitated impeller together to form one ultra-compact pump-lung device, which can be placed like current paracorporeal ventricular assist devices to allow ambulatory support. The device is 117 mm in length and 89 mm in diameter and has a priming volume of 115 ml. In-vitro hydrodynamic, gas transfer and biocompatibility experiments were carried out in mock flow loops using ovine blood. Acute in-vivo characterization was conducted in ovine by surgically implanting the device between right atrium and pulmonary artery. Results The in-vitro results showed that the device with a membrane surface area of 0.8 m2 was capable of pumping blood from 1 to 4 L/min against a wide range of pressures and transferring oxygen at a rate of up to 180 ml/min at a blood flow of 3.5 L/min. Standard hemolysis tests demonstrated low hemolysis at the targeted operating condition. The acute in-vivo results also confirmed that the device can provide sufficient oxygen transfer with excellent biocompatibility. Conclusions Base on the in-vitro and acute in-vivo study, this highly integrated wearable pump-lung device can provide efficient respiratory support with good biocompatibility and it is ready for long-term evaluation. PMID:22014451

Utilizing lung sounds analysis for the evaluation of acute asthma in small children.

PubMed

Tinkelman, D G; Lutz, C; Conner, B

1991-09-01

One of the most difficult aspects of management of acute asthma in the small child is the clinician's inability to quantitate the response or lack of response to bronchodilator agents because of the inability of a child this age to perform objective lung measurements in the acute state. The present study was designed to evaluate bronchodilator responsiveness in children between 2 and 6 years of age with wheezing by means of a computerized lung sound analysis, computer digitized airway phonopneumonography. Children between ages 2 and 6 who were experiencing acute exacerbations of asthma were included in this study population. The 43 children were evaluated by physical examination, pulmonary function testing, if possible, by use of (spirometry or peak flow meter) and transmission of lung sounds to a computer using an electronic stethoscope to obtain a phonopneumograph with sound intensity level determinations during tidal breathing. A control group of 20 known asthmatic patients between the ages of 8 and 52 years who also presented to the office with acute asthma were evaluated similarly. In each of these individuals, a physical examination was followed by complete spirometry as well as computer digitized airway phonopneumonography recordings. Following initial measurements, all patients were treated with nebulized albuterol (0.25 mL in 2 mL of saline). Five minutes after completion of the nebulization all patients were reexamined and repeat pulmonary function tests were performed followed by CDAP recordings. In the study group of children, the mean pretreatment sound intensity level was 1,694 (range 557 to 4,950 SD +/- 745).(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolomics and Its Application to Acute Lung Diseases

PubMed Central

Stringer, Kathleen A.; McKay, Ryan T.; Karnovsky, Alla; Quémerais, Bernadette; Lacy, Paige

2016-01-01

Metabolomics is a rapidly expanding field of systems biology that is gaining significant attention in many areas of biomedical research. Also known as metabonomics, it comprises the analysis of all small molecules or metabolites that are present within an organism or a specific compartment of the body. Metabolite detection and quantification provide a valuable addition to genomics and proteomics and give unique insights into metabolic changes that occur in tangent to alterations in gene and protein activity that are associated with disease. As a novel approach to understanding disease, metabolomics provides a “snapshot” in time of all metabolites present in a biological sample such as whole blood, plasma, serum, urine, and many other specimens that may be obtained from either patients or experimental models. In this article, we review the burgeoning field of metabolomics in its application to acute lung diseases, specifically pneumonia and acute respiratory disease syndrome (ARDS). We also discuss the potential applications of metabolomics for monitoring exposure to aerosolized environmental toxins. Recent reports have suggested that metabolomics analysis using nuclear magnetic resonance (NMR) and mass spectrometry (MS) approaches may provide clinicians with the opportunity to identify new biomarkers that may predict progression to more severe disease, such as sepsis, which kills many patients each year. In addition, metabolomics may provide more detailed phenotyping of patient heterogeneity, which is needed to achieve the goal of precision medicine. However, although several experimental and clinical metabolomics studies have been conducted assessing the application of the science to acute lung diseases, only incremental progress has been made. Specifically, little is known about the metabolic phenotypes of these illnesses. These data are needed to substantiate metabolomics biomarker credentials so that clinicians can employ them for clinical decision

From neurogenic pulmonary edema to fat embolism syndrome: a brief review of experimental and clinical investigations of acute lung injury and acute respiratory distress syndrome.

PubMed

Chen, Hsing I

2009-11-30

Acute respiratory distress syndrome (ARDS) is the most devastating form of acute lung injury (ALI) or pulmonary edema (PE). We presented the experimental studies and clinical investigations of two serious forms of ALI. Drastic and severe PE could be induced by intracranial hypertension or cerebral compression (CC). The CC-induced PE was attributed to overactivation of the medullary sympathetic mechanism. Sympathetic vasoconstriction of the systemic and pulmonary resistance and capacitance vessels caused shift of blood volume from the splanchnic vascular beds to the lung. The hemodynamic changes led to systemic and pulmonary hypertension. Consequently, left ventricular failure as evidenced by dramatic decline in aortic flow with a slow decrease in pulmonary flow resulted in pressure and volume loading in the pulmonary circulation. These changes finally produced severe alveolar flooding and sudden death. Vasodilators such as sodium nitroprusside or nitroglycerin were capable of reducing the CC-induced pulmonary pathology and hemodynamic alterations. Fat embolism syndrome (FES) is a serious clinical problem in patients suffering from long bone fractures. ARDS may develop and cause mortality. Our laboratory reported a total of 14 subjects associated with FES and died of ARDS. We also developed a simple technique to produce FES. Corn oil was mixed with distilled water to form fatty micelles. Intravenous administration of or introduction of fatty micelles in anesthetized rats or isolated perfused lungs caused severe alveolar damage. Our clinical observation and animal experimentation revealed that infusion of fatty acids caused physical phase, resulting in microvascular obstruction accompanied by pulmonary hypertension and increased capillary permeability. Thereafter, the lipases in the lung hydrolyzed the neutral fat and released free fatty acids and biochemical mediators which were toxic to the lung. Our data have suggested that nitric oxide (NO), inducible NO synthase

Acute toxicity, histopathology, and coagulopathy in American kestrels (Falco sparverius) following administration of the rodenticie diphacinone

USGS Publications Warehouse

Rattner, Barnett A.; Horak, Katherine E.; Warner, Sarah E.; Day, Daniel D.; Meteyer, Carol U.; Voler, Steven F.; Eisemann, John D.; Johnston, John J.

2011-01-01

The acute oral toxicity of the anticoagulant rodenticide diphacinone was found to be over 20 times greater in American kestrels (Falco sparverius; median lethal dose 96.8 mg/kg body weight) compared with Northern bobwhite (Colinus virginianus) and mallards (Anas platyrhynchos). Modest evidence of internal bleeding was observed at necropsy, although histological examination of heart, liver, kidney, lung, intestine, and skeletal muscle revealed hemorrhage over a wide range of doses (35.1-675 mg/kg). Residue analysis suggests that the half-life of diphacinone in the liver of kestrels that survived was relatively short, with the majority of the dose cleared within 7 d of exposure. Several precise and sensitive clotting assays (prothrombin time, Russell's viper venom time, thrombin clotting time) were adapted for use in this species, and oral administration of diphacinone at 50 mg/kg increased prothrombin time and Russell?s viper venom time at 48 and 96 h postdose compared with controls. Prolongation of in vitro clotting time reflects impaired coagulation complex activity, and generally corresponded with the onset of overt signs of toxicity and lethality. In view of the toxicity and risk evaluation data derived from American kestrels, the involvement of diphacinone in some raptor mortality events, and the paucity of threshold effects data following short-term dietary exposure for birds of prey, additional feeding trials with captive raptors are warranted to characterize more fully the risk of secondary poisoning.

Acute pulmonary toxicity and inflammation induced by combined exposure to didecyldimethylammonium chloride and ethylene glycol in rats.

PubMed

Kwon, Do Young; Kim, Hyun-Mi; Kim, Eunji; Lim, Yeon-Mi; Kim, Pilje; Choi, Kyunghee; Kwon, Jung-Taek

2016-02-01

Didecyldimethylammonium chloride (DDAC), an antimicrobial agent, has been reported to induce pulmonary toxicity in animal studies. DDAC is frequently used in spray-form household products in combination with ethylene glycol (EG). The purpose of this study was to evaluate the toxic interaction between DDAC and EG in the lung. DDAC at a sub-toxic dose (100 μg/kg body weight) was mixed with a non-toxic dose of EG (100 or 200 μg/kg body weight), and was administrated to rats via intratracheal instillation. Lactate dehydrogenase activity and total protein content in the bronchoalveolar lavage fluid (BALF) were not changed by singly treated DDAC or EG, but significantly enhanced at 1 d after treatment with the mixture, with the effect dependent on the dose of EG. Total cell count in BALF was largely increased and polymorphonuclear leukocytes were predominantly recruited to the lung in rats administrated with the mixture. Inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6 also appeared to be increased by the mixture of DDAC and EG (200 μg/kg body weight) at 1 d post-exposure, which might be associated with the increase in inflammatory cells in lung. BALF protein content and inflammatory cell recruitment in the lung still remained elevated at 7 d after the administration of DDAC with the higher dose of EG. These results suggest that the combination of DDAC and EG can synergistically induce pulmonary cytotoxicity and inflammation, and EG appears to amplify the harmful effects of DDAC on the lung. Therefore pulmonary exposure to these two chemicals commonly found in commercial products can be a potential hazard to human health.

Acute and chronic toxicity of sodium sulfate to four freshwater organisms in water-only exposures

USGS Publications Warehouse

Wang, Ning; Consbrock, Rebecca A.; Ingersoll, Christopher G.; Hardesty, Douglas K.; Brumbaugh, William G.; Hammer, Edward J.; Bauer, Candice R.; Mount, David R.

2016-01-01

The acute and chronic toxicity of sulfate (tested as sodium sulfate) was determined in diluted well water (hardness of 100 mg/L and pH 8.2) with a cladoceran (Ceriodaphnia dubia; 2-d and 7-d exposures), a midge (Chironomus dilutus; 4-d and 41-d exposures), a unionid mussel (pink mucket, Lampsilis abrupta; 4-d and 28-d exposures), and a fish (fathead minnow, Pimephales promelas; 4-d and 34-d exposures). Among the 4 species, the cladoceran and mussel were acutely more sensitive to sulfate than the midge and fathead minnow, whereas the fathead minnow was chronically more sensitive than the other 3 species. Acute-to-chronic ratios ranged from 2.34 to 5.68 for the 3 invertebrates but were as high as 12.69 for the fish. The fathead minnow was highly sensitive to sulfate during the transitional period from embryo development to hatching in the diluted well water, and thus, additional short-term (7- to 14-d) sulfate toxicity tests were conducted starting with embryonic fathead minnow in test waters with different ionic compositions at a water hardness of 100 mg/L. Increasing chloride in test water from 10 mg Cl/L to 25 mg Cl/L did not influence sulfate toxicity to the fish, whereas increasing potassium in test water from 1mg K/L to 3mg K/L substantially reduced the toxicity of sulfate. The results indicate that both acute and chronic sulfate toxicity data, and the influence of potassium on sulfate toxicity to fish embryos, need to be considered when environmental guidance values for sulfate are developed or refined.

The Superiority of IFN-λ as a Therapeutic Candidate to Control Acute Influenza Viral Lung Infection.

PubMed

Kim, Sujin; Kim, Min-Ji; Kim, Chang-Hoon; Kang, Ju Wan; Shin, Ha Kyung; Kim, Dong-Young; Won, Tae-Bin; Han, Doo Hee; Rhee, Chae Seo; Yoon, Joo-Heon; Kim, Hyun Jik

2017-02-01

Here, we studied the IFN-regulated innate immune response against influenza A virus (IAV) infection in the mouse lung and the therapeutic effect of IFN-λ2/3 in acute IAV lung infection. For viral infections, IAV (WS/33, H1N1, PR8 H1N1, H5N1) were inoculated into wild-type mice by intranasal delivery, and IAV mRNA level and viral titer were measured. To compare the antiviral effect of IFNs in vivo in the lung, neutralizing antibodies and recombinant IFNs were used. After intranasal inoculation of IAV into mice, viral infection peaked at 7 days postinfection, and the IAV titer also reached its peak at this time. We found that IFN-β and IFN-λ2/3 were preferentially induced after IAV infection and the IFN-λ2/3-mediated innate immune response was specifically required for the induction of IFN-stimulated genes (ISGs) transcription in the mouse respiratory tract. Neutralization of secreted IFN-λ2/3 aggravated acute IAV lung infection in mice with intact IFN-β induction; consistent with this finding, the transcription of ISGs was significantly reduced. Intranasal administration of IFN-λ2/3 significantly suppressed various strains of IAV infection, including WS/33 (H1N1), PR (H1N1), and H5N1 in the mouse lung, and was accompanied by greater up-regulation of ISGs. Taken together, our data indicate that the IFN-λ2/3-mediated innate immune response is necessary to protect the lungs from IAV infection, and intranasally delivered IFN-λ2/3 has the potential to be a useful therapeutic strategy for treating acute IAV lung infection.

Acute and Cumulative Effects of Unmodified 50-nm Nano-ZnO on Mice.

PubMed

Kong, Tao; Zhang, Shu-Hui; Zhang, Ji-Liang; Hao, Xue-Qin; Yang, Fan; Zhang, Cai; Yang, Zi-Jun; Zhang, Meng-Yu; Wang, Jie

2018-01-02

Nanometer zinc oxide (nano-ZnO) is widely used in diverse industrial and agricultural fields. Due to the extensive contact humans have with these particles, it is crucial to understand the potential effects that nano-ZnO have on human health. Currently, information related to the toxicity and mechanisms of nano-ZnO is limited. The aim of the present study was to investigate acute and cumulative toxic effects of 50-nm unmodified ZnO in mice. This investigation will seek to establish median lethal dose (LD50), a cumulative coefficient, and target organs. The acute and cumulative toxicity was investigated by Karber's method and via a dose-increasing method, respectively. During the experiment, clinical signs, mortality, body weights, hematology, serum biochemistry, gross pathology, organ weight, and histopathology were examined. The LD50 was 5177-mg/kg·bw; the 95% confidence limits for the LD50 were 5116-5238-mg/kg·bw. It could be concluded that the liver, kidney, lung, and gastrointestinal tract were target organs for the 50-nm nano-ZnO acute oral treatment. The cumulative coefficient (K) was 1.9 which indicated that the cumulative toxicity was apparent. The results also indicated that the liver, kidney, lung, and pancrea were target organs for 50-nm nano-ZnO cumulative oral exposure and might be target organs for subchronic and chronic toxicity of oral administered 50-nm ZnO.

Chemopreventive and Anti-cancer Efficacy of Silibinin against Growth and Progression of Lung Cancer

PubMed Central

Mateen, Samiha; Raina, Komal; Agarwal, Rajesh

2014-01-01

The use of systemic chemotherapeutic drugs and molecular-targeted therapies in the treatment of patients with locally advanced or metastatic lung cancer has its limitations due to the associated acute and cumulative dose limiting toxicities and acquisition of drug resistance. Prevention and therapeutic intervention by dietary agents including nutraceuticals which are non-toxic, cost-effective, and physiologically bioavailable, are emerging approaches in lung cancer management. In this regard, silibinin, a natural flavonolignan, has been rigorously evaluated for the prevention and growth control of lung cancer through extensive in vitro and in vivo studies. Successful studies conducted so far, have established that silibinin is effective both alone and in combination with other agents (e.g. chemotherapeutic and epigenetic agents) in significantly inhibiting the growth of lung cancer cells. In vivo, its effects have been shown to be mediated through inhibition of proliferation, angiogenesis and epigenetic-related events. Therefore, the present review focuses on encompassing the efficacy and mechanisms of silibinin against lung cancer. PMID:23682778

Acute Toxic Neuropathy Mimicking Guillain Barre Syndrome

PubMed Central

Jalal, Muhammed Jasim Abdul; Fernandez, Shirley Joan; Menon, Murali Krishna

2015-01-01

Case: A 30 year old male presented with numbness of palms and soles followed by weakness of upper limbs and lower limbs of 5 days duration, which was ascending and progressive. Three months back he was treated for oral and genital ulcers with oral steroids. His ulcers improved and shifted to indigenous medication. His clinical examination showed polyneuropathy. CSF study did not show albuminocytological dissociation. Nerve conduction study showed demyelinating polyneuropathy. His blood samples and the ayurvedic drug samples were sent for toxicological analysis. Inference: Acute toxic neuropathy - Arsenic PMID:25811007

Clinical and neuropathological findings of acute carbon monoxide toxicity in chihuahuas following smoke inhalation.

PubMed

Kent, Marc; Creevy, Kate E; Delahunta, Alexander

2010-01-01

Three adult Chihuahuas were presented for evaluation after smoke inhalation during a house fire. All three dogs received supportive care and supplemental oxygen. After initial improvement, the dogs developed seizures. Despite anticonvulsant therapy and supportive care, the dogs died. The brains of two dogs were examined. Lesions were identified that were compatible with acute carbon monoxide (CO) toxicity. Lesions were confined to the caudate nucleus, the globus pallidus, and the substantia nigra bilaterally, as well as the cerebellum, cerebral cortex, and dorsal thalamus. This case report describes the clinicopathological sequelae in acute CO toxicity.

Acute photo-induced toxicity and toxicokinetics of single compounds and mixtures of polycyclic aromatic hydrocarbons in zebrafish.

PubMed

Willis, Alison M; Oris, James T

2014-09-01

The present study examined photo-induced toxicity and toxicokinetics for acute exposure to selected polycyclic aromatic hydrocarbons (PAHs) in zebrafish. Photo-enhanced toxicity from co-exposure to ultraviolet (UV) radiation and PAHs enhanced the toxicity and exhibited toxic effects at PAH concentrations orders of magnitude below effects observed in the absence of UV. Because environmental exposure to PAHs is usually in the form of complex mixtures, the present study examined the photo-induced toxicity of both single compounds and mixtures of PAHs. In a sensitive larval life stage of zebrafish, acute photo-induced median lethal concentrations (LC50s) were derived for 4 PAHs (anthracene, pyrene, carbazole, and phenanthrene) to examine the hypothesis that phototoxic (anthracene and pyrene) and nonphototoxic (carbazole and phenanthrene) pathways of mixtures could be predicted from single exposures. Anthracene and pyrene were phototoxic as predicted; however, carbazole exhibited moderate photo-induced toxicity and phenanthrene exhibited weak photo-induced toxicity. The toxicity of each chemical alone was used to compare the toxicity of mixtures in binary, tertiary, and quaternary combinations of these PAHs, and a predictive model for environmental mixtures was generated. The results indicated that the acute toxicity of PAH mixtures was additive in phototoxic scenarios, regardless of the magnitude of photo-enhancement. Based on PAH concentrations found in water and circumstances of high UV dose to aquatic systems, there exists potential risk of photo-induced toxicity to aquatic organisms. © 2014 SETAC.

Amyloid associated with elastin-staining laminar aggregates in the lungs of patients diagnosed with acute respiratory distress syndrome

PubMed Central

Fan, Kang; Nagle, William A

2002-01-01

Background The heterogeneity of conditions underlying respiratory distress, whether classified clinically as acute lung injury (ALI) or the more severe acute respiratory distress syndrome (ARDS), has hampered efforts to identify and more successfully treat these patients. Examination of postmortem lungs among cases clinically diagnosed as ARDS identified a cohort that showed a consistent morphology at the light and electron microscope levels, and featured pathognomonic structures which we termed elastin-staining laminar structures (ELS). Methods Postmortem tissues were stained using the Verhoeff-Van Gieson procedure for elastic fibers, and with Congo red for examination under a polarizing microscope. Similar samples were examined by transmission EM. Results The pathognomonic ELS presented as ordered molecular aggregates when stained using the Verhoeff-van Gieson technique for elastic fibers. In several postmortem lungs, the ELS also displayed apple-green birefringence after staining with Congo red, suggesting the presence of amyloid. Remarkably, most of the postmortem lungs with ELS exhibited no significant acute inflammatory cellular response such as neutrophilic reaction, and little evidence of widespread edema except for focal intra-alveolar hemorrhage. Conclusions Postmortem lungs that exhibit the ELS constitute a morphologically-identifiable subgroup of ARDS cases. The ordered nature of the ELS, as indicated by both elastin and amyloid stains, together with little morphological evidence of inflammation or edema, suggests that this cohort of ARDS may represent another form of conformational disease. If this hypothesis is confirmed, it will require a new approach in the diagnosis and treatment of patients who exhibit this form of acute lung injury. PMID:12377106

Acute toxicity of 6 neonicotinoid insecticides to freshwater invertebrates.

PubMed

Raby, Melanie; Nowierski, Monica; Perlov, Dmitri; Zhao, Xiaoming; Hao, Chunyan; Poirier, David G; Sibley, Paul K

2018-05-01

Neonicotinoids are a group of insecticides commonly used in agriculture. Due to their high water solubility, neonicotinoids can be transported to surface waters and have the potential to be toxic to aquatic life. The present study assessed and compared the acute (48- or 96-h) toxicity of 6 neonicotinoids (acetamiprid, clothianidin, dinotefuran, imidacloprid, thiacloprid, and thiamethoxam) to 21 laboratory-cultured and field-collected aquatic invertebrates spanning 10 aquatic arthropod orders. Test conditions mimicked species' habitat, with lentic taxa exposed under static conditions, and lotic taxa exposed under recirculating systems. Median lethal concentrations (LC50s) and median effect concentrations (EC50s; immobility) were calculated and used to construct separate lethal- and immobilization-derived species sensitivity distributions for each neonicotinoid, from which 5th percentile hazard concentrations (HC5s) were calculated. The results showed that the most sensitive invertebrates were insects from the orders Ephemeroptera (Neocloeon triangulifer) and Diptera (Chironomus dilutus), whereas cladocerans (Daphnia magna, Ceriodaphnia dubia) were the least sensitive. The HC5s were compared with neonicotinoid environmental concentrations from Ontario (Canada) monitoring studies. For all neonicotinoids except imidacloprid, the resulting hazard quotients indicated little to no hazard in terms of acute toxicity to aquatic communities in Ontario freshwater streams. For the neonicotinoid imidacloprid, a moderate hazard was found when only invertebrate immobilization, and not lethality, data were considered. Environ Toxicol Chem 2018;37:1430-1445. © 2018 SETAC. © 2018 SETAC.

Quantification of Dynamic [18F]FDG Pet Studies in Acute Lung Injury.

PubMed

Grecchi, Elisabetta; Veronese, Mattia; Moresco, Rosa Maria; Bellani, Giacomo; Pesenti, Antonio; Messa, Cristina; Bertoldo, Alessandra

2016-02-01

This work aims to investigate lung glucose metabolism using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomography (PET) imaging in acute lung injury (ALI) patients. Eleven ALI patients and five healthy controls underwent a dynamic [(18)F]FDG PET/X-ray computed tomography (CT) scan. The standardized uptake values (SUV) and three different methods for the quantification of glucose metabolism (i.e., ratio, Patlak, and spectral analysis iterative filter, SAIF) were applied both at the region and the voxel levels. SUV reported a lower correlation than the ratio with the net tracer uptake. Patlak and SAIF analyses did not show any significant spatial or quantitative (R(2) > 0.80) difference. The additional information provided by SAIF showed that in lung inflammation, elevated tracer uptake is coupled with abnormal tracer exchanges within and between lung tissue compartments. Full kinetic modeling provides a multi-parametric description of glucose metabolism in the lungs. This allows characterizing the spatial distribution of lung inflammation as well as returning the functional state of the tissues.

Use of butterflies as nontarget insect test species and the acute toxicity and hazard of mosquito control insecticides.

PubMed

Hoang, Tham C; Pryor, Rachel L; Rand, Gary M; Frakes, Robert A

2011-04-01

Honeybees are the standard insect test species used for toxicity testing of pesticides on nontarget insects for the U.S. Environmental Protection Agency (U.S. EPA) under the Federal Insecticide Fungicide and Rodenticide Act (FIFRA). Butterflies are another important insect order and a valued ecological resource in pollination. The current study conducted acute toxicity tests with naled, permethrin, and dichlorvos on fifth larval instar (caterpillars) and adults of different native Florida, USA, butterfly species to determine median lethal doses (24-h LD50), because limited acute toxicity data are available with this major insect group. Thorax- and wing-only applications of each insecticide were conducted. Based on LD50s, thorax and wing application exposures were acutely toxic to both caterpillars and adults. Permethrin was the most acutely toxic insecticide after thorax exposure to fifth instars and adult butterflies. However, no generalization on acute toxicity (sensitivity) of the insecticides could be concluded based on exposures to fifth instars versus adult butterflies or on thorax versus wing exposures of adult butterflies. A comparison of LD50s of the butterflies from this study (caterpillars and adults) with honeybee LD50s for the adult mosquito insecticides on a µg/organism or µg/g basis indicates that several butterfly species are more sensitive to these insecticides than are honeybees. A comparison of species sensitivity distributions for all three insecticides shows that permethrin had the lowest 10th percentile. Using a hazard quotient approach indicates that both permethrin and naled applications in the field may present potential acute hazards to butterflies, whereas no acute hazard of dichlorvos is apparent in butterflies. Butterflies should be considered as potential test organisms when nontarget insect testing of pesticides is suggested under FIFRA. Copyright © 2011 SETAC.

Acute toxicity of selected herbicides and surfactants to larvae of the midge Chironomus riparius

USGS Publications Warehouse

Buhl, Kevin J.; Faerber, Neil L.

1989-01-01

The acute toxicities of eight commercial herbicides and two surfactants to early fourth instar larvae of the midgeChironomus riparius were determined under static conditions. The formulated herbicides tested were Eradicane® (EPTC), Fargo® (triallate), Lasso® (alachlor), ME4 Brominal® (bromoxynil), Ramrod® (propachlor), Rodeo® (glyphosate), Sencor®(metribuzin), and Sutan (+)® (butylate); the two surfactants were Activator N.F.® and Ortho X-77®. In addition, technical grade alachlor, metribuzin, propachlor, and triallate were tested for comparison with the formulated herbicides. The relative toxicity of the commercial formulations, based on percent active ingredient, varied considerably. The EC50 values ranged from 1.23 mg/L for Fargo® to 5,600 mg/L for Rodeo®. Fargo®, ME4 Brominal®, and Ramrod®were moderately toxic to midge larvae; Lasso®, Sutan (+)®, and Eradicane® were slightly toxic; and Sencor® and Rodeo® were practically non-toxic. The 48-hr EC50 values of the two surfactants were nearly identical and were considered moderately toxic to midges. For two of the herbicides in which the technical grade material was tested, the inert ingredients in the formulations had a significant effect on the toxicity of the active ingredients. Fargo® was twice as toxic as technical grade triallate, whereas Sencor® was considerably less toxic than technical grade metribuzin. A comparison of the slope function values indicated that the toxic action of all the compounds occurred within a relatively narrow range. Published acute toxicity data on these compounds for other freshwater biota were tabulated and compared with our results. In general, the relative order of toxicity toC. riparius was similar to those for other freshwater invertebrates and fish. Maximum concentrations of each herbicide in bulk runoff during a projected “critical” runoff event were calculated as a percentage of the application rate lost in a given volume of runoff. A comparison

Matrix Metalloproteinase-8 Inactivates Macrophage Inflammatory Protein-1α to Reduce Acute Lung Inflammation and Injury in Mice

PubMed Central

Quintero, Pablo A.; Knolle, Martin D.; Cala, Luisa F.; Zhuang, Yuehong; Owen, Caroline A.

2010-01-01

To determine the role of matrix metalloproteinase-8 (MMP-8) in acute lung injury (ALI), we delivered LPS or bleomycin by the intratracheal route to MMP-8−/− mice versus WT mice or subjected the mice to hyperoxia (95% O2) and measured lung inflammation and injury at intervals. MMP-8−/− mice with ALI had greater increases in lung PMN and macrophage counts, measures of alveolar capillary barrier injury, lung elastance, and mortality than WT mice with ALI. Bronchoalveolar lavage fluid (BALF) from LPS-treated MMP-8−/− mice had more macrophage inflammatory protein-1α (MIP-1α) than BALF from LPS-treated WT mice, but similar levels of other pro- and anti-inflammatory mediators. MIP-1α−/− mice with ALI had less acute lung inflammation and injury than WT mice with ALI, confirming that MIP-1α promotes acute lung inflammation and injury in mice. Genetically deleting MIP-1α in MMP-8−/− mice abrogated the increased lung inflammation and injury and mortality in MMP-8−/− mice with ALI. Soluble MMP-8 cleaved and inactivated MIP-1α in vitro, but membrane-bound MMP-8 on activated PMNs had greater MIP-1α-degrading activity than soluble MMP-8. High levels of membrane-bound MMP-8 were detected on lung PMNs from LPS-treated WT mice, but soluble, active MMP-8 was not detected in BALF samples. Thus, MMP-8 has novel roles in restraining lung inflammation and in limiting alveolar capillary barrier injury during ALI in mice by inactivating MIP-1α. In addition, membrane-bound MMP-8 on activated lung PMNs is likely to be the key bioactive form of the enzyme that limits lung inflammation and alveolar capillary barrier injury during ALI. PMID:20042585

Anti-inflammatory and Anti-oxidative Effects of Dexpanthenol on Lipopolysaccharide Induced Acute Lung Injury in Mice.

PubMed

Li-Mei, Wan; Jie, Tan; Shan-He, Wan; Dong-Mei, Meng; Peng-Jiu, Yu

2016-10-01

The aim of this study is to investigate the effects of dexpanthenol in a model of acute lung injury (ALI) induced by lipopolysaccharides (LPS). Lung injury was induced by exposure to atomized LPS. Mice were randomly divided into four groups: control group; Dxp (500 mg/kg) group; LPS group; LPS + Dxp (500 mg/kg) group. The effects of dexpanthenol on LPS-induced neutrophil recruitment, cytokine levels, total protein concentration, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) contents were examined. Additionally, lung tissue was examined by histology to investigate the changes in pathology in the presence and absence of dexpanthenol. In LPS-challenged mice, dexpanthenol significantly improved lung edema. Dexpanthenol also markedly inhibited the LPS-induced neutrophiles influx, protein leakage, and release of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Furthermore, dexpanthenol attenuated MPO activity and MDA contents and increased SOD and GSH activity in the LPS-challenged lung tissue. These data suggest that dexpanthenol protects mice from LPS-induced acute lung injury by its anti-inflammatory and anti-oxidative activities.

Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury*

PubMed Central

Enkhbaatar, Perenlei; Connelly, Rhykka; Wang, Jianpu; Nakano, Yoshimitsu; Lange, Matthias; Hamahata, Atsumori; Horvath, Eszter; Szabo, Csaba; Jaroch, Stefan; Hölscher, Peter; Hillmann, Margrit; Traber, Lillian D.; Schmalstieg, Frank C.; Herndon, David N.; Traber, Daniel L.

2013-01-01

Objective Acute respiratory distress syndrome/acute lung injury is a serious complication of burn patients with concomitant smoke inhalation injury. Nitric oxide has been shown to play a major role in pulmonary dysfunction from thermal damage. In this study, we have tested the hypothesis that inhibition of neuronal nitric oxide synthase could ameliorate the severity of acute lung injury using our well-established ovine model of cutaneous burn and smoke inhalation. Design Prospective, randomized, controlled, experimental animals study. Setting Investigational intensive care unit at university hospital. Subjects Adult female sheep Interventions Female sheep (n = 16) were surgically prepared for the study. Seven days after surgery, all sheep were randomly allocated into three study groups: sham (noninjured, nontreated, n = 6); control (injured, treated with saline, n = 6); and neuronal nitric oxide synthase (injured, treated with specific neuronal nitric oxide synthase inhibitor, ZK 234238 (n = 4). Control and neuronal nitric oxide synthase groups were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40°C) under halothane anesthesia. Animals in sham group received fake injury also under halothane anesthesia. After injury or fake injury procedure, all sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Neuronal nitric oxide synthase group was administered with continuous infusion of ZK 234238 started 1 hr postinjury with a dose of 100 μg/kg/hr. Sham and control groups received same amount of saline. Measurements and Main Results Cardiopulmonary hemodynamics monitored during the 24-hr experimental time period was stable in the sham group. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and inflammatory indices, such as interleukin-8. Treatment of

Acute toxicity assessment of explosive-contaminated soil extracting solution by luminescent bacteria assays.

PubMed

Xu, Wenjie; Jiang, Zhenming; Zhao, Quanlin; Zhang, Zhenzhong; Su, Hongping; Gao, Xuewen; Ye, Zhengfang

2016-11-01

Explosive-contaminated soil is harmful to people's health and the local ecosystem. The acute toxicity of its extracting solution was tested by bacterial luminescence assay using three kinds of luminescent bacteria to characterize the toxicity of the soil. An orthogonal test L 16 (4 5 ) was designed to optimize the soil extracting conditions. The optimum extracting conditions were obtained when the ultrasonic extraction time, ultrasonic extraction temperature, and the extraction repeat times were 6 h, 40 °C, and three, respectively. Fourier transform infrared spectroscopy (FTIR) results showed that the main components of the contaminated soil's extracting solution were 2,4-dinitrotoluene-3-sulfonate (2,4-DNT-3-SO 3 - ); 2,4-dinitrotoluene-5-sulfonate (2,4-DNT-5-SO 3 - ); and 2,6-dinitrotoluene (2,6-DNT). Compared with Photobacterium phosphoreum and Vibrio fischeri, Vibrio qinghaiensis sp. Nov. is more suitable for assessing the soil extracting solution's acute toxicity. Soil washing can remove most of the contaminants toxic to luminescent bacterium Vibrio qinghaiensis sp. Nov., suggesting that it may be a potential effective remediation method for explosive-contaminated soil.

High-Grade Acute Organ Toxicity as a Positive Prognostic Factor in Primary Radiochemotherapy for Anal Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolff, Hendrik Andreas; Raus, Ismene; Jung, Klaus