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

Abstract

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.

Functional Genomic Assessment of Phosgene-Induced Acute Lung Injury in Mice

“…In previous studies (53)(54)(55)(56)(57)(58)(59)(60)(61)(62), increased bronchoalveolar lavage protein has been reported to be a sensitive endpoint in detecting early responses to phosgene. In this study, phosgene increased lavage protein at 6 hours from sensitive SM/J mice and resistant 129X1/SvJ mice (Table 1).…”

Effect of PEEP on phosgene-induced lung edema: Pilot study on dogs using protective ventilation strategies

“…The pretest dose of 1980 mg/m 3 × min (480 ppm × min) was estimated to be the transitional dose between non-lethal to lethal outcomes. In rats, the average time-adjusted median lethal and non-lethal concentrations (LCt 50 and LCt 01 ) were 1741 and 1075 mg/m 3 × min, respectively (Pauluhn, 2006a). The head-only exposure methodology used in this study, including the generation and characterization of phosgene atmospheres, have been described in detail elsewhere (Pauluhn, 2006a,b,c).…”

“…These exposure intensities were selected based on previous nose/head-only inhalation studies in rats and dogs (Pauluhn, 2002(Pauluhn, , 2005(Pauluhn, , 2006a. This exposure intensity to phosgene was high enough to produce unequivocal clinical evidence of a pulmonary edema.…”

Phosgene- and chlorine-induced acute lung injury in rats: Comparison of cardiopulmonary function and biomarkers in exhaled breath

“…Previous inhalation studies with phosgene in rats yielded a non-lethal time-adjusted threshold concentration (LCt 01 ) of 250 ppm  min. Opposite to chlorine, phosgene-induced pulmonary injury was clearly Cxt-related with minimal, if any, modifying concentration-dependent effects (apart from transient changes in ventilation; Pauluhn, 2006a). The ensuing pulmonary edema reaches its climax about 1 day post-exposure (Pauluhn, 2006a,b,b).…”