Dorman David C, Struve Melanie F, Wong Brian A, Gross Elizabeth A, Parkinson Carl, Willson Gabrielle A, Tan Yu-Mei, Campbell Jerry L, Teeguarden Justin G, Clewell Harvey J, Andersen Melvin E
CIIT at The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA. david
Inhal Toxicol. 2008 Feb;20(3):245-56. doi: 10.1080/08958370701864250.
Acetaldehyde inhalation induces neoplastic and nonneoplastic responses in the rodent nasal cavity. This experiment further characterizes the dose-response relationship for nasal pathology, nasal epithelial cell proliferation, and DNA-protein cross-link formation in F-344 rats exposed subchronically to acetaldehyde. Animals underwent whole-body exposure to 0, 50, 150, 500, or 1500 ppm acetaldehyde for 6 h/day, 5 days/wk for up to 65 exposure days. Respiratory tract histopathology was evaluated after 4, 9, 14, 30, and 65 exposure days. Acetaldehyde exposure was not associated with reduced body weight gain or other evidence of systemic toxicity. Histologic evaluation of the nasal cavity showed an increased incidence of olfactory neuronal loss (ONL) following acute to subchronic exposure to > or = 150 ppm acetaldehyde and increased olfactory epithelial cell proliferation following exposure to 1500 ppm acetaldehyde. The severity of the ONL demonstrated dose- and temporal-dependent behaviors, with minimal effects noted at 150-500 ppm acetaldehyde and moderately severe lesions seen in the highest exposure group, with increased lesion severity and extent as the exposure duration increased. Acetaldehyde exposure was also associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. These responses were seen in animals exposed to > or = 500 ppm acetaldehyde. Acetaldehyde exposure was not associated with increased DNA-protein cross-link formation in the respiratory or olfactory epithelium. A model of acetaldehyde pharmacokinetics in the nose was used to derive an inhalation reference concentration (RfC) of 0.4 ppm, based on the no-observed-adverse-effect level (NOAEL) of 50 ppm for the nasal pathology seen in this study.
吸入乙醛可诱导啮齿动物鼻腔出现肿瘤性和非肿瘤性反应。本实验进一步阐述了F-344大鼠亚慢性暴露于乙醛后，鼻腔病理学、鼻上皮细胞增殖及DNA-蛋白质交联形成的剂量-反应关系。动物每天6小时、每周5天全身暴露于0、50、150、500或1500 ppm乙醛中，暴露天数最多可达65天。在暴露4、9、14、30和65天后评估呼吸道组织病理学。乙醛暴露与体重增加减少或其他全身毒性证据无关。鼻腔组织学评估显示，急性至亚慢性暴露于≥150 ppm乙醛后，嗅觉神经元丧失（ONL）发生率增加；暴露于1500 ppm乙醛后，嗅觉上皮细胞增殖增加。ONL的严重程度呈现剂量和时间依赖性，在150 - 500 ppm乙醛时影响最小，在最高暴露组中可见中度严重病变，且随着暴露持续时间增加，病变严重程度和范围也增加。乙醛暴露还与呼吸道上皮的炎症、增生和鳞状化生有关。在暴露于≥500 ppm乙醛的动物中可见这些反应。乙醛暴露与呼吸道或嗅觉上皮中DNA-蛋白质交联形成增加无关。基于本研究中观察到的鼻腔病理学无可见不良反应水平（NOAEL）为50 ppm，使用鼻腔乙醛药代动力学模型得出吸入参考浓度（RfC）为0.4 ppm。
