Schroeter Jeffry D, Kimbell Julia S, Gross Elizabeth A, Willson Gabrielle A, Dorman David C, Tan Yu-Mei, Clewell Harvey J
The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709-2137, USA.
Inhal Toxicol. 2008 Feb;20(3):227-43. doi: 10.1080/08958370701864235.
Acrolein is a highly soluble and reactive aldehyde and is a potent upper-respiratory-tract irritant. Acrolein-induced nasal lesions in rodents include olfactory epithelial atrophy and inflammation, epithelial hyperplasia, and squamous metaplasia of the respiratory epithelium. Nasal uptake of inhaled acrolein in rats is moderate to high, and depends on inspiratory flow rate, exposure duration, and concentration. In this study, anatomically accurate three-dimensional computational fluid dynamics (CFD) models were used to simulate steady-state inspiratory airflow and to quantitatively predict acrolein tissue dose in rat and human nasal passages. A multilayered epithelial structure was included in the CFD models to incorporate clearance of inhaled acrolein by diffusion, blood flow, and first-order and saturable metabolic pathways. Kinetic parameters for these pathways were initially estimated by fitting a pharmacokinetic model with a similar epithelial structure to time-averaged acrolein nasal extraction data and were then further adjusted using the CFD model. Predicted air:tissue flux from the rat nasal CFD model compared well with the distribution of acrolein-induced nasal lesions from a subchronic acrolein inhalation study. These correlations were used to estimate a tissue dose-based no-observed-adverse-effect level (NOAEL) for inhaled acrolein. A human nasal CFD model was used to extrapolate effects in laboratory animals to human exposure conditions on the basis of localized tissue dose and tissue responses. Assuming that equivalent tissue dose will induce similar effects across species, a NOAEL human equivalent concentration for inhaled acrolein was estimated to be 8 ppb.
丙烯醛是一种高度可溶且具有反应性的醛类，是一种强效的上呼吸道刺激物。丙烯醛在啮齿动物中诱发的鼻部病变包括嗅觉上皮萎缩与炎症、上皮增生以及呼吸道上皮的鳞状化生。大鼠对吸入丙烯醛的鼻腔摄取量为中等至高，且取决于吸气流量、暴露持续时间和浓度。在本研究中，使用解剖学精确的三维计算流体动力学（CFD）模型来模拟稳态吸气气流，并定量预测大鼠和人类鼻腔通道中丙烯醛的组织剂量。CFD模型中纳入了多层上皮结构，以体现通过扩散、血流以及一级和可饱和代谢途径对吸入丙烯醛的清除。这些途径的动力学参数最初是通过将具有类似上皮结构的药代动力学模型与时间平均的丙烯醛鼻腔提取数据进行拟合来估计的，然后使用CFD模型进一步调整。大鼠鼻腔CFD模型预测的气 - 组织通量与亚慢性丙烯醛吸入研究中丙烯醛诱发的鼻部病变分布情况良好吻合。这些相关性被用于估计吸入丙烯醛基于组织剂量的未观察到不良反应水平（NOAEL）。基于局部组织剂量和组织反应，使用人类鼻腔CFD模型将实验动物中的效应外推至人类暴露情况。假设等效组织剂量会在不同物种间诱发相似效应，吸入丙烯醛的NOAEL人类等效浓度估计为8 ppb。
