Immunologic Tolerance in Rats during 13 Weeks of Inhalation Exposure to Trimellitic Anhydride

Immunologic Tolerance in Rats during 13 Weeks of InhalationExposure to Trimellitic Anhydride. LEACH, C. L., HATOUM, N.S., ZEISS, C. R., AND GARVIN, P. J. (1989). Fundam. Appl. Toxicol.12, 519–529. Trimellitic anhydride (TMA) causes severalimmunologically based pulmonary syndromes in humans. We developeda rat model representative of some of those syndromes wherebyrats exposed for 2 weeks to TMA by inhalation developed hemorrhagiclung foci and pneumonitis accompanied by the appearance of TMA-specificserum antibody. The purpose of the study reported here was toexamine the long-term, low-dose effects of TMA inhalation. Ratswere exposed to target concentrations of 0, 2, 15, or 50 µg/m³TMA 6 hr/day, 5 days/week for 13 weeks. The study included aninterim 6.5-week termination and two recovery periods of 3 and38 weeks, each with and without a final TMA inhalation challenge.Adrlitional rats were bled regularly throughout the study andmonitored for the appearance ofTMA-specific antibody; otherrats were terminated periodically during the 13-week exposureand examined for lung lesions. These serially terminated ratsshowed that TMA-induced lung lesions reached a maximum afterapproximately 2 weeks of exposure, but began to diminish thereafter.Rats bled regularly showed increasing TMA-specific antibodytiters through the first 6 weeks of exposure, after which antibodytiters diminished. Serum antibody levels rose sharply afterthe 13-week exposure ended and tapered off throughout the recoveryperiod. Rats terminated after 6.5 weeks of exposure showed adose-dependent increase in lung lesions and serum antibody.However, rats exposed to TMA for 13 weeks showed greatly reducedlung lesions and antibody titers. Rats exposed for 13 weeksand allowed to recover for 3 weeks showed increased antibodytiters but few lesions, even after a TMA challenge. Rats exposedfor 13 weeks and allowed to recover 38 weeks had reduced butstill significant antibody titers; however, no lung lesionswere noted even after a TMA inhalation challenge prior to termination.These results indicated that rats became tolerant to TMA andthat 13 weeks of exposure to TMA did not produce lesions ofany type, even after 38 weeks of recovery.