CHRONIC INHALATION TOXICITY AND CARCINOGENICITY STUDY OF RESPIRABLE POLYMERIC METHYLENE DIPHENYL DIISOCYANATE (POLYMERIC MDI) AEROSOL IN RATS

Four groups of 60 Wistar rats of each sex were exposed by inhalation t o 0, 0.2, 1.0, or 6.0 mg/m(3) respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol (93.5% < 4.2 mu m) for 6 hr a day , 5 days a week for up to 24 months. In addition, satellite groups of 10 rats/sex/group received the same treatment for 12 months. There was no adverse effect on general health, survival, body weight, or hemato logical or clinical chemistry parameters. Lung weights were increased in both males and females exposed to 6.0 mg polymeric MDI/ m(3) for 12 or 24 months. Gross examination at autopsy of males exposed to 6.0 mg polymeric MDI/m(3) for 24 months revealed an increased incidence of s potted and discolored lungs. Increased incidences of degeneration and basal cell hyperplasia of the nasal olfactory epithelium, often accomp anied by hyperplasia of Bowman's glands, were found in the 1.0 and 6.0 mg/m(3) groups. Light and electron microscopic studies of the lungs r evealed accumulations of alveolar macrophages containing polymeric MDI -associated refractile yellowish material at the level of the alveolar duct in all exposed groups. Alveolar duct epithelialization as well a s fibrosis of tissues surrounding the macrophage accumulations occurre d at the 1.0 and 6.0 mg/m(3) exposure levels. In addition, increased i ncidences of calcareous deposits and localized alveolar bronchiolizati on were seen in the 6.0 mg/m(3) group. Moreover, eight pulmonary adeno mas (six in males and two in females) and one pulmonary adenocarcinoma (in a male) were observed in the 6.0 mg/m(3) exposure group. The time sequence of the spectrum of pulmonary changes indicates that recurren t alveolar wall damage by polymeric MDI and/or polymeric MDI-containin g alveolar macrophages leads to alveolar bronchiolization and ultimate ly to bronchioloalveolar tumors. No lung tumors were found in the lowe r concentration groups and in the control group. The incidence and dis tribution of other types of tumors were not influenced by polymeric MD I. It was concluded that in the present study, the ''no-observed-adver se-effect level'' of polymeric MDI was 0.2 mg/m(3), and that chronic e xposure to polymeric MDI at a level of 6.0 mg/m(3) was related to the occurrence of pulmonary tumors. It was also concluded that exposure to polymeric MDI at concentrations not leading to recurrent lung tissue damage will not produce pulmonary tumors. (C) 1991 Society of Toxicolo gy.