Pauluhn Jürgen
Bayer Pharma AG, Experimental Toxicology , Wuppertal , Germany (retired) and.
Inhal Toxicol. 2015 Mar;27(4):191-206. doi: 10.3109/08958378.2015.1026619. Epub 2015 Apr 29.
This paper summarizes a range of experimental data central for developing a science-based approach for hazard identification of monomeric and polymeric aliphatic 1,6-hexamethylene diisocyanate (HDI). The dose-response curve of HDI-induced pulmonary responses in naïve or dermally sensitized rats after one or several inhalation priming exposures was examined in the Brown Norway (BN) rat asthma model. Emphasis was directed to demonstrate the need and the difficulty in selecting an appropriate pulmonary dose when much of the inhaled chemically reactive vapor may concentration dependently be retained in the upper airways of obligate nose-breathing rats. The course taken acknowledges the experimental challenges in identifying an elicitation threshold for HDI-monomer near or above the saturated vapor concentration or in the presence of a HDI-polymer aerosol. The inhalation threshold dose on elicitation was determined based on a fixed concentration (C) × variable exposure duration (t) protocol for improving inhalation dosimetry of the lower airways. Neutrophilic granulocytes (PMN) in bronchoalveolar lavage (BAL) fluid in equally inhalation primed naïve and dermally sensitized rats were used to define the inhalation elicitation threshold C × t. Sensitized rats elaborated markedly increased PMN challenged sensitized rats relative to equally challenged naïve rats at 5625 mg HDI/m(3) × min (75 mg/m(3) for 75 min). PMN were essentially indistinguishable at 900 mg HDI/m(3) × min. By applying adjustment factors accounting for both inter-species differences in inhalation dosimetry and intra-species susceptibility, the workplace human-equivalent threshold C × t was estimated to be in the range of the current ACGIH TLV® of HDI. Thus, this rat "asthma" model was suitable to demonstrate elicitation thresholds for HDI-vapor after one or several inhalation priming exposures and seems to be suitable to derive occupational exposure values (OELs) for diisocyanates in general.
本文总结了一系列实验数据，这些数据对于开发一种基于科学的方法来识别单体和聚合脂肪族1,6 - 六亚甲基二异氰酸酯（HDI）的危害至关重要。在棕色挪威（BN）大鼠哮喘模型中，研究了初次或经皮肤致敏的大鼠在一次或多次吸入预激发暴露后，HDI诱导的肺部反应的剂量 - 反应曲线。重点在于证明，当大部分吸入的化学反应性蒸气可能会根据浓度依赖性地滞留在专性鼻呼吸大鼠的上呼吸道时，选择合适的肺部剂量存在必要性和困难。所采用的方法认识到，在确定接近或高于饱和蒸气浓度的HDI单体激发阈值或存在HDI聚合物气雾剂的情况下，识别激发阈值存在实验挑战。基于固定浓度（C）×可变暴露持续时间（t）方案确定激发的吸入阈值剂量，以改善下呼吸道的吸入剂量测定。在同样经吸入预激发的初次致敏和经皮肤致敏的大鼠的支气管肺泡灌洗（BAL）液中的中性粒细胞（PMN）被用于定义吸入激发阈值C×t。在5625 mg HDI/m³×min（75 mg/m³，持续75分钟）时，致敏大鼠相对于同样受到挑战的初次致敏大鼠，支气管肺泡灌洗液中的中性粒细胞显著增加。在900 mg HDI/m³×min时，中性粒细胞基本无差异。通过应用考虑吸入剂量测定中的种间差异和种内易感性的调整因子，估计工作场所的人体等效阈值C×t在当前HDI的美国政府工业卫生学家会议阈限值（ACGIH TLV®）范围内。因此，这种大鼠“哮喘”模型适用于证明一次或多次吸入预激发暴露后HDI蒸气的激发阈值，并且总体上似乎适用于推导二异氰酸酯的职业接触限值（OELs）。
