title: Attempts to counteract phosgene-induced acute lung injury by instant high-dose aerosol exposure to hexamethylenetetramine, cysteine or glutathione.
abstract: Phosgene is an important high-production-volume intermediate with widespread industrial use. Consistent with other lung irritants causing ALI (acute lung injury), mode-of-action-based countermeasures remain rudimentary. This study was conducted to analyze whether extremely short high-level exposure to phosgene gas could be mitigated using three different inhaled nucleophiles administered by inhalation instantly after exposure to phosgene. Groups of young adult male Wistar rats were acutely exposed to carbonyl chloride (phosgene) using a directed-flow nose-only mode of exposure of 600 mg/m³ for 1.5 min (225 ppm × min). Immediately after exposure to phosgene gas the rats were similarly exposed to three strong nucleophiles with and without antioxidant properties for 5 or 15 min. The following nucleophiles were used: hexamethylenetetramine (HMT), l-cysteine (Cys), and l-glutathione (GSH). The concentration of the aerosol (mass median aerodynamic diameter 1.7-2 µm) was targeted to be in the range of 1 mg/L. Cys and GSH have antioxidant properties in addition. The calculated alveolar molar dosage of phosgene was 9 µmol/kg. At 15-min exposure duration, the respective inhaled dose of HMT, Csy, and GSH were 111, 103, and 46 µmol/kg, respectively. The alveolar dose of drugs was ~10-times lower. The efficacy of treatment was judged by protein concentrations in bronchoalveolar lavage fluid (BALF) collected 1 day post-exposure. In spite of using optimized aerosolization techniques, none of the nucleophiles chosen had any mitigating effect on BALF-protein extravasation. This finding appear to suggest that inhaled phosgene gas acylates instantly nucleophilic moieties at the site of initial deposition and that the resultant reaction products can not be reactivated even following instant inhalation treatment with competing nucleophilic agents. In spite of using maximal technically attainable concentrations, it appears to be experimentally challenging to deliver such nucleophiles to the lower respiratory tract at high dosages.
authors.affiliation: Institute of Toxicology, Bayer HealthCare AG, 42096 Wuppertal, Germany. juergen.pauluhn@bayer.com
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
authors.forename: Chun Xue
authors.initials: CX
authors.lastname: Hai
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000517:prevention & control; D000280:Administration, Inhalation; D000336:Aerosols / Q000494:pharmacology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D003545:Cysteine / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology*; D019570:Inhalation Exposure; D008297:Male; D008709:Methenamine / Q000494:pharmacology*; D010705:Phosgene / Q000633:toxicity*; D011506:Proteins / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000336:Aerosols; D011506:Proteins; D010705:Phosgene; D005978:Glutathione; D008709:Methenamine; D003545:Cysteine