Pauluhn Jürgen
Institute of Toxicology, BAYER HealthCare AG, 42096 Wuppertal, Germany.
J Appl Toxicol. 2004 May-Jun;24(3):231-47. doi: 10.1002/jat.977.
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.
本研究的目的是比较多种非挥发性多异氰酸酯的可吸入气雾剂的相对急性肺刺激效能。所检测的多异氰酸酯类型包括脂肪族均聚物以及由以下单体组成的脂肪族 - 芳香族混合多异氰酸酯：HDI（六亚甲基1,6 - 二异氰酸酯）、IPDI（异佛尔酮二异氰酸酯）、MDI（亚甲基 - 二苯基 - 4,4'-二异氰酸酯）和TDI（甲苯二异氰酸酯）。作为参考，将肺刺激性多异氰酸酯气雾剂与单体IPDI（一种半挥发性呼吸道刺激物）进行比较。在所测试的物质中，游离异氰酸酯基团的浓度范围为11%至38%。通过在雄性大鼠单次暴露6小时后测量肺重量以及支气管肺泡灌洗液（BALF）中的总蛋白和乳酸脱氢酶（LDH），评估引发肺刺激的相对效能。在暴露后3小时以及1、3和7天分析变化的时间进程。当暴露于刺激性气雾剂浓度时，BALF蛋白在暴露后第1天达到最大值，并在暴露后第7天恢复到对照水平。相比之下，暴露于亚致死浓度单体IPDI的大鼠BALF蛋白出现与时间相关的增加。基于这个最敏感的终点，对于所检测的大多数多异氰酸酯，外推的未观察到效应浓度（NOECs）在2 - 3 mg m(-3)范围内。所有研究物质的NOECs在1 - 50 mg m(-3)范围内。因此，该方法足以对多异氰酸酯气雾剂的肺刺激效能进行排名，并区分肺刺激物和气道刺激物。对于肺刺激物，估计的急性NOECs与一些多异氰酸酯长期重复暴露吸入研究中的未观察到不良效应浓度（NOAECs）基本相似。未观察到NOAECs对游离异氰酸酯基团含量有明显依赖性。总之，得出的结论是，通过分析BALF中的总蛋白，可在急性大鼠生物测定中轻松量化多异氰酸酯气雾剂引起的肺刺激。此外，该实验证据表明，基于此终点的肺刺激物的NOECs可预测亚急性/亚慢性吸入暴露后观察到的NOAECs，这表明急性肺刺激决定了此类气雾剂重复吸入研究的结果。然而，对于气道刺激占主导地位的异氰酸酯，长期吸入研究似乎是必不可少的。游离NCO本身似乎不能很好地预测多异氰酸酯气雾剂的肺刺激效能。
