Changes in lung ATP concentration in the rat after low‐level phosgene exposure

Currie, William D.; Hatch, Gary E.; Frosolono, M.F.

doi:10.1002/jbt.2570020204

Cited by 30 publications

(12 citation statements)

References 20 publications

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“…-, Data from 10-min exposures were excluded in the concentration-time-response analysis used in the "toxic load model." synthesis of glutathione and redox regulation, arachidonic acid metabolism, the release of proinflammatory cytokines, and cytoskeletal effects (F-actin organization) Franch & Hatch, 1986;Currie et al, 1985Currie et al, , 1987aCurrie et al, , 1987bGhio et al, 2005;Sciuto et al, 2002;Sciuto et al, 2003aSciuto et al, , 2003bSciuto et al, , 2003cSciuto et al, 2005;Duniho et al, 2002;Deshpande et al, 1996;Madden et al, 1991;Werrlein et al, 1994). Phosgeneinduced apoptotic changes in pneumocytes and inflammatory cells were described (Li et al, 2006).…”

Section: Inhalation Toxicity Of Phosgene In Experimental Modelsmentioning

confidence: 95%

Workshop Summary: Phosgene-Induced Pulmonary Toxicity Revisited: Appraisal of Early and Late Markers of Pulmonary Injury From Animal Models With Emphasis on Human Significance

Pauluhn

Carson

Costa

et al. 2007

Inhalation Toxicology

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A workshop was held February 14, 2007, in Arlington, VA, under the auspices of the Phosgene Panel of the American Chemistry Council. The objective of this workshop was to convene inhalation toxicologists and medical experts from academia, industry and regulatory authorities to critically discuss past and recent inhalation studies of phosgene in controlled animal models. This included presentations addressing the benefits and limitations of rodent (mice, rats) and nonrodent (dogs) species to study concentration x time (C x t) relationships of acute and chronic types of pulmonary changes. Toxicological endpoints focused on the primary pulmonary effects associated with the acute inhalation exposure to phosgene gas and responses secondary to injury. A consensus was reached that the phosgene-induced increased pulmonary extravasation of fluid and protein can suitably be probed by bronchoalveolar lavage (BAL) techniques. BAL fluid analyses rank among the most sensitive methods to detect phosgene-induced noncardiogenic, pulmonary high-permeability edema following acute inhalation exposure. Maximum protein concentrations in BAL fluid occurred within 1 day after exposure, typically followed by a latency period up to about 15 h, which is reciprocal to the C x t exposure relationship. The C x t relationship was constant over a wide range of concentrations and single exposure durations. Following intermittent, repeated exposures of fixed duration, increased tolerance to recurrent exposures occurred. For such exposure regimens, chronic effects appear to be clearly dependent on the concentration rather than the cumulative concentration x time relationship. The threshold C x t product based on an increased BAL fluid protein following single exposure was essentially identical to the respective C x t product following subchronic exposure of rats based on increased pulmonary collagen and influx of inflammatory cells. Thus, the chronic outcome appears to be contingent upon the acute pulmonary threshold dose. Exposure concentrations high enough to elicit an increased acute extravasation of plasma constituents into the alveolus may also be associated with surfactant dysfunction, intra-alveolar accumulation of fibrin and collagen, and increased recruitment and activation of inflammatory cells. Although the exact mechanisms of toxicity have not yet been completely elucidated, consensus was reached that the acute pulmonary toxicity of phosgene gas is consistent with a simple, irritant mode of action at the site of its initial deposition/retention. The acute concentration x time mortality relationship of phosgene gas in rats is extremely steep, which is typical for a local, directly acting pulmonary irritant gas. Due to the high lipophilicity of phosgene gas, it efficiently penetrates the lower respiratory tract. Indeed, more recent published evidence from animals or humans has not revealed appreciable irritant responses in central and upper airways, unless exposure was to almost lethal concentrations. The comparison of acute inhalation s...

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Section: Inhalation Toxicity Of Phosgene In Experimental Modelsmentioning

confidence: 95%

Workshop Summary: Phosgene-Induced Pulmonary Toxicity Revisited: Appraisal of Early and Late Markers of Pulmonary Injury From Animal Models With Emphasis on Human Significance

Pauluhn

Carson

Costa

et al. 2007

Inhalation Toxicology

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“…In laboratory animals, exposure to phosgene throughout a range of concentrations causes severe pathophysiologica l changes speci cally in the bronchoalveolar region (19,23). Exposure also produces changes in energy metabolism (3), disruption of the GSH redox cycle (22), and release of reactive arachidonic acid metabolites (9,12,21). Phosgene poisoning in man is associated with the development of latent noncardiogenic pulmonary edema, which can occur within 24 hours after exposure (5,24).…”

Section: Introductionmentioning

confidence: 99%

Acute Changes in Lung Histopathology and Bronchoalveolar Lavage Parameters in Mice Exposed to the Choking Agent Gas Phosgene

Duniho¹,

Martin²,

Forster³

et al. 2002

Toxicol Pathol

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Phosgene (CG) is a highly irritant gas widely used industrially as a chemical intermediate for the production of dyes, pesticides, and plastics, and can cause life-threatening pulmonar y edema within 24 hours of exposure. This study was designed to investigate acute changes in lung tissue histopathology and selected bronchoalveola r lavage uid (BALF) factors over time to determine early diagnostic indicators of exposure. Three groups of 40 male mice each were exposed to 32 mg/m 3 (8 ppm) CG for 20 minutes, and 3 groups of 40 control male mice were exposed to ltered room air for 20 minutes, both exposures were followed by room air washout for 5 minutes. At 1,4,8,12,24, 48, and 72 hours after exposure each group of mice was euthanized and processed for histopatholog y, bronchoalveola r lavage or gravimetric measurements , respectively. Over time, the histopathologica l lesions were characterized by acute changes consisting of alveolar and interstitial edema, brin and hemorrhage , followed by signi cant alveolar and interstitial ooding with in ammatory cell in ltrates and scattered bronchiolar and terminal airway epithelial degeneratio n and necrosis. From 48 to 72 hours, there was partial resolution of the edema and degenerative changes, followed by epithelial and broblastic regeneration centered on the terminal bronchiolar areas. Bronchoalveola r lavage was processed for cell differential counts, LDH, and protein determination. Comparative analysis revealed signi cant increases in both postexposur e lung wet/dry weight ratios, and early elevations of BALF LDH and protein, and later elevations in leukocytes. This article describes the use of histopathology to chronicle the temporal pulmonary changes subsequent to whole body exposure to phosgene , and correlate these changes with BALF ingredients and postexposur e lung wet weights in an effort to characterize toxic gas-induced acute lung injury and identify early markers of phosgene exposure.

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“…Because of its insoluble nature, phosgene causes these effects in the deeper regions of the lung where it can deplete ATP, important metabolic and antioxidant enzymes, and glutathione (Currie et al, 1987;Jaskot et al, 1991;Sciuto et al, 1995). Furthermore, phosgene has been show n to increase lipid peroxidation, cause the release of sulfidopeptide leukotrienes, alter important cell ultrastructures, and react directly with lung surfactant (Kennedy et al, 1989;Sciuto et al, 1996 a;Werrlein et al, 1994;Pawlow ski & Frosolono, 1977;Frosolono & Currie, 1985).…”

Section: Discussionmentioning

confidence: 93%

Ibuprofen Treatment Enhances the Survival of Mice Following Exposure to Phosgene

Sciuto

1997

Inhalation Toxicology

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The present study was designed to investigate the efficacy of ibuprofen ( IBU) administered after a lethal dose of phosgene. Mice were exposed to 32 mg/m 3 phosgene for 20 min and immediately injected with IBU ( 0, 3, 9, or 15 mg/mouse, ip) . Five hours later, a second IBU injection was given but at half the original doses ( 0, 1.5, 4.5, and 7.5 mg/mouse). These are referred to throughout as the 0/ 0, 3/ 1. 5, 9/ 4.5, and 15/7.5 mg IBU/ mouse groups. Survival in these groups was determined at 12 and 24 h. In mice that died within 12 h, the lungs were removed, and lung wet weights, dry weights, wet/ dry weight ratios, malondialdedyde (MDA) , and nonprotein sulfhydryls ( NPSH) were measured. Survival odds ratios were calculated for each dose at 12 and 24 h. The 12-h survival was 63% for 9/ 4.5 mg IBU and 82% for the 15/7.5 mg IBU group compared with 25% for saline-treated mice. At 24 h, survival rates were reduced to 19% , 19%, and 6% , respectively. In the 15/7.5 mg IBU group, dry weights, wet/ dry weight ratios, and wet weights were significantly lower than in saline-treated mice at 12 h. MDA was lower only for the 9/ 4.5 mg IBU dose; however, NPSHs were greater across all IBU doses. The survival odds ratio was 5 for the 9/ 4.5 IBU group at 12 h and 13 for the 15/7.5 mg IBU group compared with 3.5 for both groups at 24 h. Therefore, IBU treatment increased the survival of mice at 12 h by reducing edema formation, lipid peroxidation, and glutathione depletion.

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Changes in lung ATP concentration in the rat after low‐level phosgene exposure

Cited by 30 publications

References 20 publications

Workshop Summary: Phosgene-Induced Pulmonary Toxicity Revisited: Appraisal of Early and Late Markers of Pulmonary Injury From Animal Models With Emphasis on Human Significance

Workshop Summary: Phosgene-Induced Pulmonary Toxicity Revisited: Appraisal of Early and Late Markers of Pulmonary Injury From Animal Models With Emphasis on Human Significance

Acute Changes in Lung Histopathology and Bronchoalveolar Lavage Parameters in Mice Exposed to the Choking Agent Gas Phosgene

Ibuprofen Treatment Enhances the Survival of Mice Following Exposure to Phosgene

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