MIC were released from a chemical plant in Bhopal, India, resulting in one of the worst industrial accidents in history (Karlsson et al. 1985).

Signs of severe irritation to the respiratory tract were reported for victims of the Bhopal disaster, and autopsies revealed the cause of death to be acute pulmonary edema (Weill 1988). Long-term pulmonary and ocular sequelae have been documented in survivors. The spontaneous abortion rate (Arbuckle and Sever 1998) and the infant death rate (Varma 1987) among women who were pregnant at the time of the release were significantly increased in the months following the disaster. Numerous animal studies corroborate the epidemiological findings in humans. A compilation of case reports in industrial workers consistently noted skin and respiratory irritation in MIC-exposed workers but no definitive case of sensitization (Ketcham 1973). The mechanism of action for the pulmonary, skin, and ocular toxicity is irritation, but the mechanism of action for the systemic effects is unknown.

AEGL-1 values were not derived. Although human and animal data were available for irritation levels, the irritation threshold for MIC may be above the level of concern for systemic effects. Experimental studies in humans indicate that both duration of exposure and concentration of MIC contribute to the severity of irritation. However, extrapolation from the short experimental durations to the longer AEGL time points may not be predictive of adverse health effects. It is not known at what concentration the risk for systemic effects, other than pulmonary edema, becomes a concern. The concentrations causing irritation in humans after several minutes (1–4 parts per million [ppm]) are similar to, or higher than, the concentrations resulting in embryo and fetal lethality in well conducted animal studies. Therefore, the results of controlled human exposures were not used in derivation of AEGL-1. However, it should be noted that exposures to MIC at concentrations below those used to calculate AEGL-1 might be associated with systemic toxicity.

Systemic toxicity data from rats and mice were used for derivation of AEGL-2. An increase in cardiac arrhythmias occurred in rats 4 months (mo) after a 2-hour (h) exposure to 3 ppm (Tepper et al. 1987). Pregnant Swiss-Webster mice were exposed to analytically monitored concentrations of MIC at 0, 2, 6, 9, and 15 ppm for 3 h on gestation day 8 (Varma 1987). Placental weights and fetal body weights were significantly reduced at all concentrations. Exposures to concentrations at 9 ppm and 15 ppm resulted in deaths of two dams in each group, a significant increase in complete litter resorption among surviving dams, and fetuses with significant reduc-



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