HEMOGLOBIN ADDUCTS AND URINE METABOLITES OF 4,4'-METHYLENEDIANILINE AFTER 4,4'-METHYLENEDIPHENYL DIISOCYANATE EXPOSURE OF RATS

4,4'-Methylenediphenyl diisocyanate (MDI) is a very important componen t in the production of polyurethane. In a long-term experiment, design ed to determine the carcinogenic and toxic effects of MDI, rats were e xposed chronically for 3 and 12 months, to 0.0 (control), 0.26, 0.70 a nd 2.06 mg MDI/m(3) as aerosols. Hemoglobin adducts and urine metaboli tes of MDI were determined at the different doses in order to develop methods to biomonitor workers exposed to MDI and to assess a risk resu lting from such exposure. Hemoglobin adducts and urine metabolites of 4,4'-methylenedianiline (MDA) were found in all rats, including contro ls. MDA and N-acetyl-MDA (AcMDA) Were quantified by GC-MS after deriva tization with heptafluorobutyric anhydride. The dose-response relation ships for hemoglobin adducts and urine metabolites were non-linear ove r this dose range. In urine, free AcMDA and MDA were found after base extraction. The amount of MDA present in urine and to a lesser extent the AcMDA found in urine correlate well with the corresponding amount determined as hemoglobin adducts for all dose groups. In order to rele ase MDA from possible conjugates of MDA and AcMDA, urine was treated u nder strong acidic conditions. Following this procedure higher MDA lev els were found than the sum of MDA and AcMDA from mild base hydrolysis , Similar results were obtained with the rats exposed for 3 and 12 mon ths, indicating that a steady state had been reached by 3 months. In o rder to perform further investigations of the bronchoalveolar lavage f luid one group of animals was given a 1 week recovery period before sa crifice, Hemoglobin adducts from these animals showed a decrease of ap proximately 40% for all dose groups. According to the lifetime of rat erythrocytes the levels of hemoglobin adducts should have decreased by only 22%. This suggests that the erythrocytes with modified hemoglobi n have a shorter lifespan. In order to exclude the possibility that he moglobin adducts may have resulted from ingestion of hydrolyzed MDI vi a licking of the fur, a single dose experiment with rats exposed throu gh the nose only or with the whole body was carried out. The only diff erence observed between these two exposure regimes was that the hemogl obin adduct levels of AcMDA after nose only exposure were significantl y higher than after total body exposure. The presence of AcMDA in urin e and as a hemoglobin adduct indicates that MDA was bioavailable after MDI exposure. The presence of MDA may contribute significantly to the carcinogenic potential of MDI, since MDA has been shown to be carcino genic in animals.