title: Pulmonary irritant potency of polyisocyanate aerosols in rats: comparative assessment of irritant threshold concentrations by bronchoalveolar lavage.
abstract: The object of this study was to compare the relative acute pulmonary irritant potency of respirable aerosols of a variety of non-volatile polyisocyanates. The types of polyisocyanates examined included aliphatic homopolymers and mixed aliphatic-aromatic polyisocyanates consisting of the following monomers: HDI (hexamethylene 1,6-diisocyanate), IPDI (isophorone diisocyanate), MDI (methylene-diphenyl-4,4'-diisocyanate) and TDI (toluene diisocyanate). For reference purposes, the pulmonary irritant polyisocyanate aerosols were compared with monomeric IPDI, a semi-volatile respiratory tract (airway) irritant. In the substances tested, the concentration of free isocyanate moieties ranged from 11% to 38%. The relative potency to elicit pulmonary irritation was assessed by measurements of lung weights and total protein and lactate dehydrogenase (LDH) in the bronchoalveolar lavage fluid (BALF) following a single 6-h exposure of male rats. The time course of changes was analysed 3 h and 1, 3 and 7 days after exposure. When exposed to irritant concentrations of aerosol, BALF protein was maximal on post-exposure day 1 and returned to the level of the controls on post-exposure day 7. In contrast, rats exposed to sub-lethal concentrations of monomeric IPDI experienced a time-related increase in BALF protein. Based on this most sensitive endpoint, extrapolated no-observed-effect concentrations (NOECs) were in the range of 2-3 mg m(-3) for most polyisocyanates examined. The NOECs from all the substances investigated were in the range 1-50 mg m(-3). Thus, this methodology is adequate to rank the pulmonary irritant potency of polyisocyanate aerosols and to differentiate pulmonary from airway irritants. For pulmonary irritants the estimated acute NOECs were essentially similar to the no-observed-adverse effect concentrations (NOAECs) from long-term, repeated-exposure inhalation studies available for some of the polyisocyanates. A clear dependence of the NOAECs on the content of free isocyanate moieties was not observed. In summary, it is concluded that pulmonary irritation caused by polyisocyanate aerosols can be quantified readily in an acute rat bioassay by analysis of total protein in BALF. Moreover, this experimental evidence suggests that the NOECs of pulmonary irritants based on this endpoint are predictive of the NOAECs observed after subacute/subchronic inhalation exposure, suggesting that acute pulmonary irritation governs the outcome of repeated inhalation studies with such aerosols. However, for isocyanates where airway irritation predominates the pulmonary irritation, long(er)-term inhalation studies appear to be indispensable. The content of free NCO per se appears to be a poor predictor of the pulmonary irritant potency of polyisocyanate aerosols.
authors.affiliation: Institute of Toxicology, BAYER HealthCare AG, 42096 Wuppertal, Germany. juergen.pauluhn@bayerhealthcare.com
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D018893:Bronchoalveolar Lavage; D007770:L-Lactate Dehydrogenase / Q000302:isolation & purification; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D011140:Polyurethanes / Q000008:administration & dosage / Q000633:toxicity*; D011506:Proteins / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000336:Aerosols; D011140:Polyurethanes; D011506:Proteins; D007770:L-Lactate Dehydrogenase