Assessment of inhaled acute ammonia-induced lung injury in rats.

This study examined acute toxicity and lung injury following inhalation exposure to ammonia. Male Sprague-Dawley rats (300-350 g) were exposed to 9000, 20,000, 23,000, 26,000, 30,000 or 35,000 ppm of ammonia for 20 min in a custom head-out exposure system. The exposure atmosphere, which attained steady state within 3 min for all ammonia concentrations, was monitored and verified using a Fourier transform infrared spectroscopy (FTIR) gas analyzer. Animals exposed to ammonia resulted in dose-dependent increases in observed signs of intoxication, including increased chewing and licking, ocular irritation, salivation, lacrimation, oronasal secretion and labored breathing. The LCt50 of ammonia within this head-out inhalation exposure model was determined by probit analysis to be 23,672 ppm (16,489 mg/m(3)) for the 20 min exposure in male rats. Exposure to 20,000 or 23,000 ppm of ammonia resulted in significant body weight loss 24-h post-exposure. Lung edema increased in all ammonia-exposed animal groups and was significant following exposure to 9000 ppm. Bronchoalveolar fluid (BALF) protein concentrations significantly increased following exposure to 20,000 or 23,000 ppm of ammonia in comparison to controls. BAL cell (BALC) death and total cell counts increased in animals exposed to 20,000 or 23,000 ppm of ammonia in comparison to controls. Differential cell counts of white blood cells, neutrophils and platelets from blood and BALF were significantly increased following exposure to 23,000 ppm of ammonia. The following studies describe the validation of a head-out inhalation exposure model for the determination of acute ammonia-induced toxicity; this model will be used for the development and evaluation of potential therapies that provide protection against respiratory and systemic toxicological effects.

Vapor inhalation exposure to soman in conscious untreated rats: preliminary assessment of neurotoxicity.

Neurological toxicity and brain injury following vapor inhalation exposure to the chemical warfare nerve agent (CWNA) soman (GD) were examined in untreated non-anesthetized rats. In this study, male Sprague-Dawley rats (300-350 g) were exposed to 600 mg × min/m(3) of soman or vehicle in a customized head-out inhalation system for 7 min. Convulsant animals were observed for clinical signs and various regions of the brain (dorsolateral thalamus, basolateral amygdala, piriform cortex, and lateral cortex) were collected for pathological observations 24 h post-exposure. Signs of CWNA-induced cholinergic crises including salivation, lacrimation, increased urination and defecation, and tremors were observed in all soman-exposed animals. Soman-exposed animals at 24 h post-exposure lost 11% of their body weight in comparison to 2% in vehicle-exposed animals. Whole blood acetylcholinesterase (AChE) activity was significantly inhibited in all soman-exposed groups in comparison to controls. Brain injury was confirmed by the neurological assessment of hematoxylin-eosin (H&E) staining and microscopy in the piriform cortex, dorsolateral thalamus, basolateral amygdala, and lateral cortex. Severe damage including prominent lesions, edematous, congested, and/or hemorrhagic tissues was observed in the piriform cortex, dorsolateral thalamus, and lateral cortex in soman-exposed animals 24 h post-exposure, while only minimal damage was observed in the basolateral amygdala. These results indicate that inhalation exposure to soman vapor causes neurological toxicity and brain injury in untreated unanesthetized rats. This study demonstrates the ability of the described soman vapor inhalation exposure model to cause neurological damage 24 h post-exposure in rats.

Inhalation toxicity of soman vapor in non-anesthetized rats: a preliminary assessment of inhaled bronchodilator or steroid therapy.

Respiratory toxicity, injury and treatment following vapor inhalational exposure to the chemical warfare nerve agent (CWNA) soman (GD) were examined in non-anesthetized rats. This study exposed male Sprague-Dawley rats (250-300g) to 520, 560, 600, 825 or 1410mg×min/m(3) of soman in a customized head-out inhalation system. Signs of CWNA-induced cholinergic crises were observed in all soman-exposed animals. The LCt50 of vaporized soman as determined by probit analysis was 593.1mg×min/m(3). All animals exposed to 825 and 1410mg×min/m(3) developed severe convulsions and died within 4-8min post-exposure. Edema measured by wet/dry weight ratio of the left lung lobe increased in a dose-dependent manner in all soman-exposed animals. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase (AChE) activities were inhibited dose-dependently in soman-exposed groups at 24h. A significant increase in total BAL protein was observed in soman-exposed animals at all doses. AChE activity was inhibited in lung and whole brain tissues in all soman-exposed animals. Histopathological analysis of the lungs of animals exposed to 600mg×min/m(3) of soman revealed prominent morphological changes including alveolar histiocytosis, hemorrhage and inflammation consisting of neutrophilic exudate. Exposure of animals to 600mg×min/m(3) of soman followed by treatment with two actuations for 10s of Combivent (21µg of ipratropium bromide and 120µg of albuterol sulfate) and Symbicort (80µg budesonide and 4.5µg formoterol) by inhalation into a modified metered dose inhaler (MDI) 10min post-exposure resulted in increased minute volume, but did not decrease mortality. These results indicate that inhalation exposure to soman vapor causes acute respiratory toxicity and injury in untreated, un-anesthetized rats and that inhalation treatment with Combivent or Symbicort did improve the respiratory outcomes, but did not influence lethality.