title: Inhalation toxicity of soman vapor in non-anesthetized rats: a preliminary assessment of inhaled bronchodilator or steroid therapy.
abstract: 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.
authors.affiliation: Analytical Toxicology Division, Medical Toxicology Branch, United States Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010, United States.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Perkins
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wong
authors.forename: Ashley
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Devorak
authors.forename: Derron A
authors.initials: DA
authors.lastname: Alves
authors.forename: Gleeson
authors.initials: G
authors.lastname: Murphy
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Sciuto
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D055371:Acute Lung Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000420:Albuterol / Q000008:administration & dosage; D000068600:Albuterol, Ipratropium Drug Combination; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D019819:Budesonide / Q000008:administration & dosage; D000069502:Budesonide, Formoterol Fumarate Drug Combination; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage; D019570:Inhalation Exposure; D009241:Ipratropium / Q000008:administration & dosage; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012999:Soman / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000305:Adrenal Cortex Hormones; D000068600:Albuterol, Ipratropium Drug Combination; D001993:Bronchodilator Agents; D000069502:Budesonide, Formoterol Fumarate Drug Combination; D002619:Chemical Warfare Agents; D004338:Drug Combinations; D004983:Ethanolamines; D019819:Budesonide; D012999:Soman; D000110:Acetylcholinesterase; D009241:Ipratropium; D000420:Albuterol
keywords: 2-PAM; 2-pralidoxime; 4,4′-dithidiopyridine; AChE; ATC; ATCH; BAL; BALC; BALF; Bronchodilators; CWNA; Chemical warfare nerve agents; Cholinesterases; DFP; DTP; GD; Inhalation exposure; LCt(50); MDI; MV; PBS; PFH; Respiratory toxicity; SLPM; Soman; acetylcholinesterase; acetylthiocholine iodide; bronchoalveolar lavage; bronchoalveolar lavage cells; bronchoalveolar lavage fluid; chemical warfare nerve agent; diisopropyl fluorophosphate; i.m.; i.p.; intramuscular; intraperitoneal; lethal concentration measured in mg×min/m(3) of a vapor exposure to cause death in 50% of the exposed population multiplied by the time the individual is exposed; metered dose inhaler; minute volume; perfluorohexane; phosphate buffered saline; s.c.; soman; standard liters per minute; subcutaneous