The morphologic changes induced in the lungs of rats and guinea pigs exposed to high concentrations of MIC vapor (100, 600, and 1000 ppm in the rat and 25, 125, 225, and 675 ppm in the guinea pig) for a short time (15 min) in a static exposure chamber were evaluated at varying postexposure periods (0, 1, 2, 4, and 16 hr). The 675 ppm-exposed guinea pigs were evaluated only immediately following removal from the chamber. Attention was primarily focused on the intrapulmonary conducting airways and the parenchyma (gas exchange region) of the lungs. The severity of morphologic changes observed by light microscopy was directly correlated with exposure concentration and time postexposure in both species. Specifically, degenerative changes were observed in the bronchial, bronchiolar, and alveolar epithelium in both species. Quantitative differences were observed; 100 ppm of MIC in the rat resulted in much less damage than did 125 ppm of MIC in the guinea pig. Morphologic evidence of sloughing of large sheets of conducting airway epithelium with fibrin buildup and increased mucus production resulted in plugging of major airways and atelectasis. These observations support the hypothesis that tissue hypoxia was a major contributing factor resulting in death.

Investigation of an outbreak of prolonged febrile illness in medical center personnel at the University of Rochester School of Medicine and Dentistry revealed lymphocytic choriomeningitis (LCM) virus to be the causative agent. Syrian or golden hamsters (Mesocricetus auratus) were found to be the only animals involved in maintaining the virus and were the source of human infections. Isolations of LCM virus were made from autopsy specimens of 13 of 46 (28%) golden hamsters. Virus isolations were made from 22 of 28 (79%) frozen specimens of 11 tumor lines transplanted repeatedly in golden hamster cheek pouches. No virus isolations were made from 86 autopsied laboratory mice, laboratory rats, Chinese hamsters (Cricetulus griseus), or laboratory rabbits or from 10 tumor cell lines transplanted in laboratory mice. Complement-fixation testing of 301 animal sera from the vivarium also revealed involvement primarily of golden hamsters. The probable source of virus introduction into the Rochester facilities was found to be two LCM-contaminated tumor lines sent from a biological supplier to Rochester in 1969.

The influence of methyl isocyanate (MIC) inhalation on the gas exchange function of the lungs in guinea pigs was studied by measuring arterial blood gases, pH, and tracheal pressure during constant-volume, artificial ventilation with air or lOO1 02 at 40 and 120 min after exposure. A 15 min exposure to MIC at concentrations of 240 to 628 ppm caused a marked reduction in Pao2 and PHa and an elevated tracheal pressure during artificial ventilation. The low Pao2 was only slightly elevated when the animals were ventilated with 100% 02. Although the dry-wet lung weight ratio was reduced at the highest exposure concentration, the effect was not severe and no significant increase in lung water was found at the lower concentrations. MIC inhalation caused severe pulmonary blood shunting and ventilation/perfusion imbalance. This, in turn, led to hypoxemia, metabolic acidosis, and tissue hypoxia, which could produce death. The pulmonary gas exchange deficit likely resulted from bronchial and bronchiolar obstruction caused by sloughed epithelium and other debris from intra-and extrapulmonary airways.

Human, rat, and guinea pig packed erythrocytes exposed to 100, 500, or 1000 ppm of methyl isocyanate (MIC) vapor in vitro showed a concentration-related inhibition of cholinesterase (ChE) activity. Rat and guinea pig packed erythrocytes showed an almost complete inhibition of ChE activity at 2000 ppm. In vitro exposures of human and guinea pig blood to 1000 or 2000 ppm of MIC vapor resulted in qualitative alterations in the electrophoretic mobility of hemoglobin (Hb) as measured by citrated agar electrophoresis. In rats and guinea pigs, neither IV injection of liquid MIC nor in vivo exposure to 1000 ppm of MIC by inhalation resulted in any inhibition of erythrocyte ChE activity or alteration in Hb electrophoretic mobility. As a result of these observations, it was concluded that neither ChE inhibition nor structural alteration of Hb were major contributing factors to death resulting from MIC exposure. Rats and guinea pigs receiving IV injections of liquid MIC showed an increase in creatine kinase (CK) levels. This increase could not be attributed to a specific isoenzyme of CK by ion exchange chromatography. Rats exposed to 100, 600, or 1000 ppm of MIC and guinea pigs exposed to 25, 125, or 225 ppm of MIC and bled immediately following a 15-min exposure or at 1, 2, 4, or 16 hr postexposure had the following alterations in blood parameters: a) an increase in CK, b) increases in hemoglobin concentration and hematocrit, c) reticulocytosis (rats only), d) neutrophilia, e) a decrease in blood pH and Po2, and f) an increase in blood Pco2. These findings indicate the occurrence of generalized hypoxic injury with concomitant pathophysiologic alterations, e.g., increases in hemoglobin and hematocrit concentrations.

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