Two-hour methyl isocyanate inhalation exposure and 91-day recovery: a preliminary description of pathologic changes in F344 rats.

Abstract

The accidental release of methyl isocyanate (MIC) in Bhopal, India, was reportedly responsible for the deaths of more than 2,000 people. To study the pathology of acute inhalation exposure to MIC, the tissues of male and female Fischer 344 rats were evaluated immediately after a single 2-hr exposure to 0, 3, 10, or 30 ppm MIC, and through day 91. Early gross pathologic changes in the 30 ppm-exposed rats included a reddish white encrustation around the mouth and nose, a small thymus, and distension of the gastrointestinal tract with gas. Lungs (middle and median lobes) showed consolidation and hemorrhage and failed to deflate when the chest cavity was opened. Microscopic changes in the upper respiratory tract 3 hr after exposure included marked erosion and separation of olfactory and respiratory epithelia from the basement membrane with accumulation of serofibrinous fluid. On day 1, acute inflammation and fibrinopurulent exudate partially blocked the nasal passages. Epithelial cells had sloughed from the nasopharynx, trachea, bronchi, and major bronchioles, leaving the basement membrane covered with fibrin and exudate. Granulomatous inflammation and intraluminal fibrosis of the airways were observed by day 3, with increased intraluminal fibrosis by day 7. Lower airways became blocked by exfoliated cells, mucous plugs, and/or intraluminal fibrosis. Damage to the lung parenchyma, even at lethal concentrations, was limited to moderate inflammation. Intraluminal fibrosis, mild bronchitis and bronchiolitis, and mucous plugs persisted throughout the 91-day study. These changes could account for evidence of obstructive lung disease detected in pulmonary function studies in companion studies. Evidence of direct injury to nonrespiratory tissues was not found; pulmonary injury and associated respiratory obstruction appeared sufficient to cause both early and delayed deaths.

The toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. II. Repeated exposure and recovery studies.

“…This exposure pattern was chosen to mimic in duration and result the December 3, 1984, release of methyl isocyanate from a storage tank at an agricultural chemical plant in Bhopal, India. The results of this study (1)(2)(3) demonstrated that the lung and upper respiratory tract were the primary targets of methyl isocyanate injury and suggested that damage to the respiratory tract was severe enough to account for the observed mortality. Results of the previous study also demonstrated a very steep dose response for lethality of inhaled methyl isocyanate, with concentrations of 10 ppm causing few or no deaths in rats or mice, but concentrations of 20 to 30 ppm being lethal to 60 to 80% of exposed animals.…”

Toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. I. Acute exposure and recovery studies.

“…Changes in absolute organ weights and in organ- to-body weight ratios for brain, liver, kidney, spleen, and testis (not shown) were statistically significant at certain time points in certain experimental groups, but the differences were not consistent between groups, and did not suggest a selective toxicity to any of these organs. With the exception of mild cytoplasmic vacuolization of the liver in mice, significant pathologic changes were not found in these organs (6,7). However, changes in lung-and thymus-to-body weight ratios were consistent and were dose-related in mice and rats.…”

“…Within 3 hr following the exposures (day 0), and again on days 1, 3, 7, 14, 49 and 91 after exposure, five predesignated animals per group were killed by pentobarbital overdose and given a complete gross necropsy. The lungs, brain, liver, kidney, thymus, testis, and spleen were weighed prior to fixation for histopathologic analysis [see accompanying papers (6,7)]. The right apical lobe of the lung was removed from male rats killed on days 0, 1, 3 and 7, weighed, and allowed to dry to constant weight for determination of wet-to-dry weight ratio.…”

Effect of Methyl Isocyanate (MIC) Gas on the Eyes of Fischer 344 Rats

“…Exposure to these concentrations resulted in a severe necrotizing effect on the olfactory and respiratory epithelium lining the respiratory tract; no effect was observed in those areas of the nose lined with stratified squamous epithelium (9). Stratified squamous epithelium also covers the anterior portion of the cornea, and the apparent lower sensitivity of this cell type to MIC-induced damage may account at least in part for our negative findings.…”