title: Pulmonary responses and recovery following single and repeated inhalation exposure of rats to polymeric methylene diphenyl diisocyanate aerosols.
abstract: Acute and repeated inhalation exposures (for 28 days) to polymeric methylene diphenyl diisocyanate (PMDI) were performed in rats. Investigations were made at the end of exposures and after 3, 10 and 30 days of recovery following single acute exposures and after 30 days of recovery following 28 days of exposure. Acute exposures to 10, 30 or 100 mg m(-3) PMDI produced clinical signs in all animals that were consistent with exposure to irritant aerosols. An exposure concentration-related body weight loss and increase in lung weight were seen post-exposure, with complete recovery by day 8. The time course of changes in the lung over the initial days following exposure consisted of a pattern of initial toxicity, rapid and heavy influx of inflammatory cells and soluble markers of inflammation and cell damage, increased lung surfactant, a subsequent recovery and epithelial proliferative phase and, finally, a return to the normal status quo of the lung. During these stages there was evidence for perturbation of lung surfactant homeostasis, demonstrated by increased amounts of crystalline surfactant and increased number and size of lamellar bodies within type II alveolar cells. Repeated exposure over 28 days to the less toxic concentrations of 1, 4 or 10 mg m(-3) PMDI produced no clinical signs or body weight changes, but an increase in lung weight was seen in animals exposed to 10 mg m(-3), which resolved following the 30-day recovery period. Other effects seen were again consistent with exposure to irritant aerosols, but were less severe than those seen in the acute study. Analysis of bronchoalveolar lavage fluid revealed similar changes to those seen in the acute study. At both 10 and 4 mg m(-3) PMDI increased numbers of 'foamy' macrophages in lung lavage cell pellet correlated with the increased phospholipid content of the pellet. Changes in lung lavage parameters and electron microscopic evidence again suggested perturbations in surfactant homeostasis. Histologically, bronchiolitis and thickening of the central acinar regions was seen at 10 and 4 mg m(-3), reflecting changes in cell proliferation in the terminal bronchioles and centro-acinar regions. Almost all effects seen had recovered by day 30 post-exposure. Both acute and subacute studies demonstrate rapid recovery of effects in the lung following exposure to PMDI, with no progression of these effects even at concentrations higher than those shown to produce tumours in a chronic study. These findings add weight to the hypothesis that pulmonary tumours seen following chronic exposure to PMDI are most likely due to a combination of the chronic irritant effects of repeated exposure, coupled with the presence of insoluble polyureas formed by polymerization of PMDI (found in studies reported here and previous chronic studies), and therefore acute or short-term exposures to PMDI are likely to be of little concern for long-term pulmonary health.
authors.affiliation: Syngenta CTL, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK. Joanne.Kilgour@syngenta.com
authors.forename: Joanne D
authors.initials: JD
authors.lastname: Kilgour
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rattray
authors.forename: John
authors.initials: J
authors.lastname: Foster
authors.forename: Anthony
authors.initials: A
authors.lastname: Soames
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hext
mesh_terms: D000336:Aerosols; D000818:Animals; D001988:Bronchiolitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D019570:Inhalation Exposure; D017953:Isocyanates / Q000008:administration & dosage / Q000633:toxicity*; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008854:Microscopy, Electron; D009929:Organ Size / Q000187:drug effects; D011140:Polyurethanes / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000336:Aerosols; D017953:Isocyanates; D011140:Polyurethanes; C087867:polymeric 4,4'-diphenylmethane diisocyanate