title: Chronic inhalation toxicity and carcinogenicity study of respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol in rats.
abstract: Four groups of 60 Wistar rats of each sex were exposed by inhalation to 0, 0.2, 1.0, or 6.0 mg/m3 respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol (93.5% < 4.2 microns) 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 hematological or clinical chemistry parameters. Lung weights were increased in both males and females exposed to 6.0 mg polymeric MDI/m3 for 12 or 24 months. Gross examination at autopsy of males exposed to 6.0 mg polymeric MDI/m3 for 24 months revealed an increased incidence of spotted and discolored lungs. Increased incidences of degeneration and basal cell hyperplasia of the nasal olfactory epithelium, often accompanied by hyperplasia of Bowman's glands, were found in the 1.0 and 6.0 mg/m3 groups. Light and electron microscopic studies of the lungs revealed 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 as fibrosis of tissues surrounding the macrophage accumulations occurred at the 1.0 and 6.0 mg/m3 exposure levels. In addition, increased incidences of calcareous deposits and localized alveolar bronchiolization were seen in the 6.0 mg/m3 group. Moreover, eight pulmonary adenomas (six in males and two in females) and one pulmonary adenocarcinoma (in a male) were observed in the 6.0 mg/m3 exposure group. The time sequence of the spectrum of pulmonary changes indicates that recurrent alveolar wall damage by polymeric MDI and/or polymeric MDI-containing alveolar macrophages leads to alveolar bronchiolization and ultimately to bronchioloalveolar tumors. No lung tumors were found in the lower concentration groups and in the control group. The incidence and distribution of other types of tumors were not influenced by polymeric MDI. It was concluded that in the present study, the "no-observed-adverse-effect level" of polymeric MDI was 0.2 mg/m3, and that chronic exposure to polymeric MDI at a level of 6.0 mg/m3 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.
authors.affiliation: TNO Toxicology and Nutrition Institute, Zeist, The Netherlands.
authors.forename: P G
authors.initials: PG
authors.lastname: Reuzel
authors.forename: J H
authors.initials: JH
authors.lastname: Arts
authors.forename: L G
authors.initials: LG
authors.lastname: Lomax
authors.forename: M H
authors.initials: MH
authors.lastname: Kuijpers
authors.forename: C F
authors.initials: CF
authors.lastname: Kuper
authors.forename: C
authors.initials: C
authors.lastname: Gembardt
authors.forename: V J
authors.initials: VJ
authors.lastname: Feron
authors.forename: E
authors.initials: E
authors.lastname: Löser
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000473:pathology; D000336:Aerosols; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D017953:Isocyanates / Q000633:toxicity*; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D009296:Nasal Cavity / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011140:Polyurethanes / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000336:Aerosols; D002273:Carcinogens; D017953:Isocyanates; D011140:Polyurethanes; C087867:polymeric 4,4'-diphenylmethane diisocyanate