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.

Effect of organic compounds on nanoparticle formation in diluted diesel exhaust

“…Inhalation of acid aerosols in laboratory animal studies causes genotoxic damage in cells (Soskolne et al, 1984;Swenberg and Beauchamp, 1997). Kilgour et al (2002) showed cell proliferation of the respiratory tract in rats due to exposure to sulfuric acid.…”

4,4′‐Methylene diphenyl diisocyanate (MDI) [101‐68‐8] and “polymeric” MDI (PMDI) [9016‐87‐9] [MAK Value Documentation, 2008]

“…Complexes made up of completely reacted MDI and precipitated surfactant are phagocytized by alveolar macrophages or eliminated via mucociliary clearance from the site of deposition (Pauluhn 2000. The initial event is accompanied by alveolar protein exudation; increased concentrations of total protein serve as a measurement of acute alveolar irritation (Kilgour et al 2002;Pauluhn 2000;. The available findings thus support the hypothesis that lung tumours are caused by chronic regenerative cell proliferation and not by genotoxic initiation and promotion.…”

“…Cell proliferation data and changes in the BAL seem to correspond (Kilgour et al 2002;. In the case of PMDI, a significant increase in proteins in the BAL of rats was observed immediately after exposure even after single 6-hour exposures to the lowest concentration used of 0.7 mg/m 3 .…”

“…At this concentration an increase in GSH in the BAL, a typical effect of irritating substances, an increase in cell count and γ-GT, a marker enzyme for damage or increased activity of Clara cells or type II pneumocytes (Pauluhn 2000) and effects on functional respiratory parameters (Pauluhn 2004 b) were observed. At 10 mg/ m 3 , the incorporation of BrdU in terminal bronchioles, an indication of cell proliferation, was increased (Kilgour et al 2002). Concentrations of 20 mg/m 3 produced laboured breathing, nasal discharge, incrustations around the nostrils, transient body weight loss and increased lung weights (Pauluhn 2000.…”

“…On the basis of all available data, a mechanism via the local irritating effects of MDI in the lungs is considered relevant (AGS 2000;EU 2005;Gledhill et al 2005;Kilgour et al 2002; b; see also Figure 2):…”