Comparative assessment of early acute lung injury in mice and rats exposed to 1,6-hexamethylene diisocyanate-polyisocyanate aerosols.
The aliphatic diisocyanate monomer 1,6-hexamethylene diisocyanate (HDI) is used as a building block for non-volatile polycondensation products, such as HDI-isocyanurate (HDI-IC) and HDI-biuret (HDI-BT). This paper describes the results from acute inhalation studies with these types of polyisocyanate aerosols in OF1 and C57BL/6J mice and in Wistar rats. The modifying role of different concentrations of residual HDI in HDI-BT on pulmonary irritation was also addressed. These data close data gaps for acute mouse inhalation studies in direct comparison with rats. The sensory irritant potency was examined in OF1 mice during a 3h nose-only exposure to the polyisocyanate aerosols. Concurrent with exposure, breathing patterns suitable to distinguish upper/lower respiratory tract irritation where examined. Functional measurements in barometric plethysmographs (Penh) addressed changes in respiratory function in C57BL/6J mice exposed for 6h up to 16h postexposure. These measurements revealed that these polyisocyanates elicit changes slow in onset suggestive of pulmonary irritation rather than upper airway irritation. This conclusion was supported by similarly exposed OF1 mice exposed to non-irritant, surface active respirable particles of amorphous silica. In C57BL/6J mice and Wistar rats, nose-only exposed for 6h to 10mg/m(3) of aerosolized HDI-BT HDI (0.1% or 2% residual HDI), the pulmonary irritation potency was comparatively assessed by bronchoalveolar lavage (BAL) on postexposure day 1. Similarly air-exposed animals served as concurrent controls. Most changes in BAL suggestive of acute pulmonary irritation were more pronounced in Wistar rats than in C57BL/6J mice. A conclusive dependence of BAL endpoints on the residual content of residual HDI monomer in the polyisocyanate was not found. The results of this study show that mice may be particularly suitable to functionally analyze at which location of the respiratory tract predominant irritation may occur. However, with regard to analysis of lower respiratory tract irritation, rats were demonstrated to be more susceptible than mice. In summary, this study supports the conclusion that data from rat inhalation studies with these types of isocyanates appear to be more conservative and less variable than the respective data from mice.
Pauluhn
Jürgen
J
Institute of Toxicology, Bayer Healthcare AG, Bayer Schering Pharmaceuticals, 42096 Wuppertal, Germany. juergen.pauluhn@bayerhealthcare.com
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001737:Biuret / Q000737:chemistry / Q000633:toxicity*; D018893:Bronchoalveolar Lavage; D003485:Cyanates / Q000737:chemistry / Q000633:toxicity*; D004350:Drug Residues / Q000737:chemistry / Q000633:toxicity; D019570:Inhalation Exposure; D007509:Irritants / Q000737:chemistry / Q000633:toxicity*; D017953:Isocyanates; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010991:Plethysmography; D011140:Polyurethanes / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000139:chemically induced*; D013045:Species Specificity; D013997:Time Factors; D023382:Toxicity Tests, Acute
D000336:Aerosols; D003485:Cyanates; D007509:Irritants; D017953:Isocyanates; D011140:Polyurethanes; C015262:1,6-hexamethylene diisocyanate; D001737:Biuret