Short-term inhalation toxicity of polyisocyanate aerosols in rats: comparative assessment of irritant-threshold concentrations by bronchoalveolar lavage.
The object of this study was to compare the relative potency of respirable aerosols of the aliphatic hexamethylene 1,6-diisocyanate homopolymer of the isocyanurate type (HDI-IC) and the aromatic polymeric methylenediphenyl-4,4'-diisocyanate (pMDI) to elicit early changes in bronchoalveolar lavage fluid (BALF). The validity of the concentration x time (C x t) concept was addressed in rats exposed to concentrations from 3.4 to 58.1 mg pMDI/m3 and exposure durations of 6 h to 23 min, respectively (C x t approximately 1200 mg/m3-min). One additional group of rats was exposed to 2.7 mg MDA/m3 for 1 x 6 h, a putative product of hydrolysis of pMDI. In rats repeatedly exposed to 12.9 mg pMDI/m3 (6 h/day, 5 days/wk for 14 days), cumulative exposure-related changes were examined. Results show that total protein and angiotensin-converting enzyme (ACE) in BALF were among the most sensitive endpoints to probe early effects caused by exposure to irritant polyisocyanate aerosols. In the repeated-exposure study, BALF protein was maximal after the first exposure day. Based on these most sensitive endpoints in BALF, a benchmark no-effect threshold concentration of 0.5 and 3 mg/m3 was estimated for the pMDI and HDI-IC aerosol, respectively. The slope of the concentration-effect curve was steeper following exposure to HDI-IC than to pMDI. These estimated acute no-observed-effect levels (NOELs) were almost identical to those observed in longer term inhalation studies using conventional endpoints. It is concluded that pulmonary irritation caused by polyisocyanate aerosols can readily be quantified in an acute rat bioassay by the analysis of total protein in BALF.
Pauluhn
Jürgen
J
Institute of Toxicology, Bayer AG, Wuppertal, Germany. juergen.pauluhn.jp@bayer-ag.de
D000336:Aerosols; D000818:Animals; D001681:Biological Assay / Q000379:methods; D015415:Biomarkers / Q000032:analysis*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005260:Female; D019570:Inhalation Exposure; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D011140:Polyurethanes / Q000008:administration & dosage / Q000633:toxicity*; D011506:Proteins / Q000032:analysis*; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity
D000336:Aerosols; D015415:Biomarkers; D011140:Polyurethanes; D011506:Proteins