Immunologic tolerance in rats during 13 weeks of inhalation exposure to trimellitic anhydride

Trimellitic anhydride (TMA) causes several immunologically based pulmonary syndromes in humans. We developed a rat model representative of some of those syndromes whereby rats exposed for 2 weeks to TMA by inhalation developed hemorrhagic lung foci and pneumonitis accompanied by the appearance of TMA-specific serum antibody. The purpose of the study reported here was to examine the long-term, low-dose effects of TMA inhalation. Rats were exposed to target concentrations of 0, 2, 15, or 50 micrograms/m3 TMA 6 hr/day, 5 days/week for 13 weeks. The study included an interim 6.5-week termination and two recovery periods of 3 and 38 weeks, each with and without a final TMA inhalation challenge. Additional rats were bled regularly throughout the study and monitored for the appearance of TMA-specific antibody; other rats were terminated periodically during the 13-week exposure and examined for lung lesions. These serially terminated rats showed that TMA-induced lung lesions reached a maximum after approximately 2 weeks of exposure, but began to diminish thereafter. Rats bled regularly showed increasing TMA-specific antibody titers through the first 6 weeks of exposure, after which antibody titers diminished. Serum antibody levels rose sharply after the 13-week exposure ended and tapered off throughout the recovery period. Rats terminated after 6.5 weeks of exposure showed a dose-dependent increase in lung lesions and serum antibody. However, rats exposed to TMA for 13 weeks showed greatly reduced lung lesions and antibody titers. Rats exposed for 13 weeks and allowed to recover for 3 weeks showed increased antibody titers but few lesions, even after a TMA challenge. Rats exposed for 13 weeks and allowed to recover 38 weeks had reduced but still significant antibody titers; however, no lung lesions were noted even after a TMA inhalation challenge prior to termination. These results indicated that rats became tolerant to TMA and that 13 weeks of exposure to TMA did not produce lesions of any type, even after 38 weeks of recovery.