Chronic Pneumonitis Caused by Phosgene

Gross, Paul; Rinehart, William E.; Hatch, Theodore F.

doi:10.1080/00039896.1965.10664088

Cited by 47 publications

(17 citation statements)

References 4 publications

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“…After high-level acute exposure of experimental animals, the histopathological lesions were characterized by acute changes consisting of alveolar and interstitial edema, fibrin, and hemorrhage, followed by significant alveolar and interstitial flooding with inflammatory cell infiltrates and scattered bronchiolar and terminal airway degeneration and necrosis. Partial resolution of edema and degenerative changes was followed by epithelial and fibroblastic regeneration (Gross et al, 1965;Duniho et al, 2001;Hatch et al, 2001). There are a plethora of data from wholebody mode acute inhalation studies in a variety of experimental species.…”

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confidence: 96%

Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC₅₀s, Nonlethal-Threshold Concentrations, and Analysis of Breathing Patterns

Pauluhn

2006

Inhalation Toxicology

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Groups of young adult Wistar rats were acutely exposed to phosgene gas using a directed-flow nose-only mode of exposure. The exposure durations used were 10, 30, 60, and 240 min and the corresponding C x t products bracketed a range from 1538 to 2854 mg/m3 x min. The postexposure period was 2 wk. Subgroups of rats were subjected to respiratory function measurements. With few exceptions, mortality occurred within 24 h after exposure. The median lethal concentration (LC50) and the estimated nonlethal threshold concentrations (LC01) for 10, 30, 60, and 240 min were 253.3 (105.3), 54.5 (29.2), 31.3 (21.1), and 8.6 (5.3) mg/m3, respectively. With regard to the fixed outcome Cn x t product, the exponent n was found to be approximately 0.9 for both the LC50 and the LC01. Due to an apparent rodent-specific transient depression in ventilation, results from 10-min exposures were excluded for the calculation of average C x t products. The average LCt50 (and confidence interval 95%) and LCt01 were 1741 (1547-1929) mg/m3 x min and 1075 mg/m3 x min, respectively, with a LCt50/LCt01 ratio of 1.6. Respiratory function measurements revealed an increased apnea time (AT), which is typical for lower respiratory tract irritants. This response was associated with transiently decreased respiratory minute volumes. Borderline, although distinct, changes in AT occurred at 1.2 x 30 mg/m3 x min and above, which did not show evidence of recovery during a 30-min postexposure period at 47.6 x 30 mg/m3 x min and above. In an ancillary study, one group of rats was exposed to 1008 mg/m3 x min (at 4.2 mg/m3 for 240 min; postexposure period 4 wk). Emphasis was on the time course of nonlethal endpoints (bronchoalveolar lavage, BAL) and histopathology of the lungs of rats sacrificed at the end of the 4-wk postexposure period. The climax of BAL protein was on the first postexposure day and exceeded approximately 70 times the control without causing mortality. The changes in BAL protein resolved within 2 wk. Histopathology did not show evidence of lung remodeling or progressive, potentially irreversible changes 4 wk postexposure. In summary, the analysis of the C x t dependent mortality revealed a steep C x t mortality relationship. The C x t product in the range of the nonlethal threshold concentration (1008 mg/m3 x min) caused pulmonary injury as indicated by markedly increased protein in BAL. Changes resolved almost entirely within the 4-wk postexposure period.

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confidence: 96%

Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC₅₀s, Nonlethal-Threshold Concentrations, and Analysis of Breathing Patterns

Pauluhn

2006

Inhalation Toxicology

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“…Impaired alveolar macrophage function and clearance of microorganisms from the lung as a result of subchronic phosgene exposure have also been reported (Selgrade et al, 1995). At lower concentrations, phosgene appears to preferentially deposit in and affect terminal bronchioles, whereas at higher concentrations phosgene damage clearly extends to include alveolar epithelial cells (Gross et al, 1965;Pawlowski and Frosolono, 1977). It has been suggested that the mechanism of action of phosgene is similar to that of ozone and other oxidants (Kennedy et al, 1989;Ghio et al, 1991).…”

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confidence: 96%

Pulmonary Structural and Extracellular Matrix Alterations in Fischer 344 Rats Following Subchronic Phosgene Exposure

Kodavanti¹,

Costa²,

Giri

et al. 1997

Toxicol Sci

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Phosgene, an acylating agent, is a very potent inducer of pulmonary edema. Subchronic effects of phosgene in laboratory animals are not well characterized. The purpose of the study was to elucidate potential long-term effects on collagen and elastin metabolism during pulmonary injury/recovery and obtain information about the concentration X time (C X T) behavior of low levels of phosgene. Male Fischer 344 rats (60 days old) were exposed either to clean air or phosgene, 6 hr/day: 0.1 ppm (5 days/week), 0.2 ppm (5 days/week), 0.5 ppm (2 days/week), and 1.0 ppm (1 day/week), for 4 or 12 weeks. A group of rats was allowed clean air recovery for 4 weeks after 12 weeks of phosgene exposure. This exposure scenario was designed to provide equal C x T product for all concentrations at one particular time point except for 0.1 ppm (50% C X T). Phosgene exposure for 4 or 12 weeks increased lung to body weight ratio and lung displacement volume in a concentration-dependent manner. The increase in lung displacement volume was significant even at 0.1 ppm phosgene at 4 weeks. Light microscopic level histopathology examination of lung was conducted at 0.0, 0.1, 0.2, and 1.0 ppm phosgene following 4 and 12 and 16 weeks (recovery). Small but clearly apparent terminal bronchiolar thickening and inflammation were evident with 0.1 ppm phosgene at both 4 and 12 weeks. At 0.2 ppm phosgene, terminal bronchiolar thickening and inflammation appeared to be more prominent when compared to the 0.1 ppm group and changes in alveolar parenchyma were minimal. At 1.0 ppm, extensive inflammation and thickening of terminal bronchioles as well as alveolar walls were evident. Concentration rather than C X T seems to drive pathology response. Trichrome staining for collagen at the terminal bronchiolar sites indicated a slight increase at 4 weeks and marked increase at 12 weeks in both 0.2 and 1.0 ppm groups (0.5 ppm was not examined), 1.0 ppm being more intense. Wholelung prolyl hydroxylase activity and hydroxyproline, taken as an index of collagen synthesis, were increased following 1.0 ppm phosgene exposure at 4 as well as 12 weeks, respectively. Desmosine levels, taken as an index of changes in elastin, were increased in the lung after 4 or 12 weeks in the 1.0 ppm phosgene group. Following 4 weeks of air recovery, lung hydroxyproline was further increased in 0.5 and 1.0 ppm phosgene groups. Lung weight also remained significantly higher than the controls; however, desmosine and lung displacement volume in phosgene-exposed animals were similar to controls. In summary, terminal bronchiolar and lung volume displacement changes occurred at very low phosgene concentrations (0.1 ppm). Phosgene concentration, rather than C X T product appeared to drive toxic responses. The changes induced by phosgene (except of collagen) following 4 weeks were not further amplified at 12 weeks despite continued exposure. Phosgene-induced alterations of matrix were only partially reversible after 4 weeks of clean air exposure, c 1997 sod«y or To

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“…Nevertheless, the time to death and the type and severity of the lung histopathology recorded in this study were similar to those found in other species such as the sheep 12 and the dog. 13 Data from animal studies 14 and cases of accidental human exposure 15 have confirmed that following phosgene exposure there is a latent period during which few adverse effects could be detected. This is followed by gradual development of a pulmonary oedema that leads to significant pulmonary insufficiency.…”

Section: Discussionmentioning

confidence: 57%

“…Reduced lung compliance has been associated with an increase in fluid accumulation within the interstitial regions. 23 Further evidence of lung injury was shown by the increase in shunt fraction over the experimental period. The changes in arterial pH reflect systemic changes resulting from reduced oxygen delivery with a reliance on anaerobic respiration at the cellular level.…”

Section: Discussionmentioning

confidence: 98%

Pathophysiological responses following phosgene exposure in the anaesthetized pig

Brown

Jugg

Harban

et al. 2002

J of Applied Toxicology

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This study aimed to develop a reproducible model of phosgene-induced lung injury in the pig to facilitate the future development of therapeutic strategies. Ten female young adult large white pigs were used. Following induction of anaesthesia using a halothane/oxygen/nitrous oxide mixture, arterial and venous catheters were inserted together with a pulmonary artery thermodilution catheter, and a suprapubic urinary catheter by laparotomy. Anaesthesia was maintained throughout the experiment by intravenous infusion of ketamine, midazolam and alfentanil. On completion of surgery the animals were allowed to equilibrate for 1 h and then were divided into two groups. Group 1 (n = 5) was exposed to phosgene for 10 min (mean Ct = 2443 +/- 35 mg min m(-3)) while spontaneously breathing, whereas control animals (Group 2 n = 5) were exposed to air. At 30 min post-exposure, anaesthesia was deepened in order to allow the initiation of intermittent positive pressure ventilation and the animals were monitored for up to 24 h. Cardiovascular and respiratory parameters were monitored every 30 min and blood samples were taken for arterial and mixed venous blood gas analysis and clinical chemistry. A detailed post-mortem and histopathology was carried out on all animals following death or euthanasia at the end of the 24-h monitoring period. Control animals (Group 2) all survived until the end of the 24-h monitoring period with normal pathophysiological parameters. Histopathology showed only minimal passive congestion of the lung. Following exposure to phosgene (Group 1) there was one survivor to 24 h, with the remainder dying between 16.5 and 23 h (mean = 20 h). Histopathology from these animals showed areas of widespread pulmonary oedema, petechial haemorrhage and bronchial epithelial necrosis. There was also a significant increase in lung wet weight/body weight ratio (P < 0.001). During and immediately following exposure, a transient decrease in oxygen saturation and stroke volume index was observed. From 6 h there were significant decreases in arterial pH (P < 0.01), P(a)O(2) (P < 0.01) and lung compliance (P < 0.01), whereas oxygen delivery and consumption was reduced from 15 h onwards in phosgene-exposed animals. Mean pulmonary artery pressure of phosgene-exposed animals was increased from 15 h post-exposure, with periods of increased pulmonary vascular resistance index being recorded from 9 h onwards. We have developed a reproducible model of phosgene-induced lung injury in the anaesthetized pig. We have followed changes in cardiovascular and pulmonary dynamics for up to 24 h after exposure in order to demonstrate evidence of primary acute lung injury from 16 h post-exposure. Histopathology showed evidence of widespread damage to the lung and there was also a significant increase in lung wet weight/body weight ratio (P < 0.001).

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Chronic Pneumonitis Caused by Phosgene

Cited by 47 publications

References 4 publications

Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC₅₀s, Nonlethal-Threshold Concentrations, and Analysis of Breathing Patterns

Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC₅₀s, Nonlethal-Threshold Concentrations, and Analysis of Breathing Patterns

Pulmonary Structural and Extracellular Matrix Alterations in Fischer 344 Rats Following Subchronic Phosgene Exposure

Pathophysiological responses following phosgene exposure in the anaesthetized pig

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Chronic Pneumonitis Caused by Phosgene

Cited by 47 publications

References 4 publications

Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC50s, Nonlethal-Threshold Concentrations, and Analysis of Breathing Patterns

Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC50s, Nonlethal-Threshold Concentrations, and Analysis of Breathing Patterns

Pulmonary Structural and Extracellular Matrix Alterations in Fischer 344 Rats Following Subchronic Phosgene Exposure

Pathophysiological responses following phosgene exposure in the anaesthetized pig

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Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC₅₀s, Nonlethal-Threshold Concentrations, and Analysis of Breathing Patterns

Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC₅₀s, Nonlethal-Threshold Concentrations, and Analysis of Breathing Patterns