Significant Pulmonary Response to a Brief High-Level, Nose-Only Nitrogen Dioxide Exposure: An Interspecies Dosimetry Perspective

Abstract

Brief, high-level nitrogen dioxide (NO 2) exposures are major hazards during fires and heat-generating explosions. To characterize the lung response to a brief high-level NO 2 exposure, we exposed two groups ( n = 5) of 325–375 g, male, Sprague–Dawley rats to either 200 ± 5 ppm (376 ± 9 mg/m 3) NO 2 or room air for 15 min. The rats were nose-only exposed in a multiport exposure chamber fitted with pressure transducers to monitor their respiration during exposure. One hour after exposure, we euthanized the rats, collected blood samples, lavaged the lungs with warm saline, and then excised them. One lung lobe was cooled to −196°C and used for low-temperature electron paramagentic resonance (EPR) analysis. The remainder was homogenized and used for biochemical analyses. Inspired minute ventilation ( V i) during exposure decreased 59% ( p < 0.05). Calculated total inspired dose was 0.880 mg NO 2. In lung lavage, both total and alveolar macrophage cell counts declined (∼75%, p < 0.05), but epithelial cell count increased 8.5-fold. Lung weight increased 40% ( p < 0.05) after exposure. In the blood, potassium and methemoglobin increased 45 and 18% ( p < 0.05), respectively; glucose, lactate, and total hemoglobin were not altered significantly. EPR analysis of lung tissue revealed hemoglobin oxidation and carbon-centered radical formation. Vitamins E and C and uric acid were depleted, and lipid peroxidation measured by three different methods (TBARS, conjugated dienes, and fluorescent peroxidation end products) was elevated, but total protein, DNA, and lipid contents were unchanged. These observations combined demonstrate that a brief (15 min) high-level (200 ppm) NO 2 exposure of rats was sufficient to cause significant damage. However, comparison of the exposure dose normalized to rat body weight with previously reported sheep and estimated human values revealed significant differences. This raises a question about interspecies dosimetry and species-specific responses when animal data are extrapolated to humans and used for safety standard setting, particularly with high-level brief exposures.