Clewell H J, Efremenko A, Campbell J L, Dodd D E, Thomas R S
The Hamner Institutes for Health Sciences, Research Triangle Park, NC.
The Hamner Institutes for Health Sciences, Research Triangle Park, NC.
Toxicol Appl Pharmacol. 2014 Oct 1;280(1):78-85. doi: 10.1016/j.taap.2014.06.015. Epub 2014 Jun 27.
Male and female Fischer 344 rats were exposed to naphthalene vapors at 0 (controls), 0.1, 1, 10, and 30ppm for 6h/d, 5 d/wk, over a 90-day period. Following exposure, the respiratory epithelium and olfactory epithelium from the nasal cavity were dissected separately, RNA was isolated, and gene expression microarray analysis was conducted. Only a few significant gene expression changes were observed in the olfactory or respiratory epithelium of either gender at the lowest concentration (0.1ppm). At the 1.0ppm concentration there was limited evidence of an oxidative stress response in the respiratory epithelium, but not in the olfactory epithelium. In contrast, a large number of significantly enriched cellular pathway responses were observed in both tissues at the two highest concentrations (10 and 30ppm, which correspond to tumorigenic concentrations in the NTP bioassay). The nature of these responses supports a mode of action involving oxidative stress, inflammation and proliferation. These results are consistent with a dose-dependent transition in the mode of action for naphthalene toxicity/carcinogenicity between 1.0 and 10ppm in the rat. In the female olfactory epithelium (the gender/site with the highest incidences of neuroblastomas in the NTP bioassay), the lowest concentration at which any signaling pathway was significantly affected, as characterized by the median pathway benchmark dose (BMD) or its 95% lower bound (BMDL) was 6.0 or 3.7ppm, respectively, while the lowest female olfactory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 16.1, 11.1, and 8.4ppm, respectively. In the male respiratory epithelium (the gender/site with the highest incidences of adenomas in the NTP bioassay), the lowest pathway BMD and BMDL were 0.4 and 0.3ppm, respectively, and the lowest male respiratory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 0.5, 0.7, and 0.9ppm, respectively. Using a published physiologically based pharmacokinetic (PBPK) model to estimate target tissue dose relevant to the proposed mode of action (total naphthalene metabolism per gram nasal tissue), the lowest transcriptional BMDLs from this analysis equate to human continuous naphthalene exposure at approximately 0.3ppm. It is unlikely that significant effects of naphthalene or its metabolites will occur at exposures below this concentration.
将雄性和雌性Fischer 344大鼠暴露于浓度分别为0（对照组）、0.1、1、10和30ppm的萘蒸气中，每天暴露6小时，每周暴露5天，持续90天。暴露后，分别解剖鼻腔的呼吸上皮和嗅觉上皮，分离RNA，并进行基因表达微阵列分析。在最低浓度（0.1ppm）下，无论是雄性还是雌性的嗅觉上皮或呼吸上皮中，仅观察到少数显著的基因表达变化。在1.0ppm浓度下，呼吸上皮中有有限的氧化应激反应证据，但嗅觉上皮中没有。相比之下，在两个最高浓度（10和30ppm，这与NTP生物测定中的致癌浓度相对应）下，在两种组织中均观察到大量显著富集的细胞途径反应。这些反应的性质支持一种涉及氧化应激、炎症和增殖的作用模式。这些结果与大鼠中萘毒性/致癌性作用模式在1.0至10ppm之间的剂量依赖性转变一致。在雌性嗅觉上皮（在NTP生物测定中神经母细胞瘤发病率最高的性别/部位）中，任何信号通路受到显著影响的最低浓度，以中位通路基准剂量（BMD）或其95%下限（BMDL）表示时，分别为6.0或3.7ppm，而与谷胱甘肽稳态、炎症和增殖相关通路的最低雌性嗅觉BMD值分别为16.1、11.1和8.4ppm。在雄性呼吸上皮（在NTP生物测定中腺瘤发病率最高的性别/部位）中，最低通路BMD和BMDL分别为0.4和0.3ppm，与谷胱甘肽稳态、炎症和增殖相关通路的最低雄性呼吸BMD值分别为0.5、0.7和0.9ppm。使用已发表的基于生理学的药代动力学（PBPK）模型来估计与所提出的作用模式相关的靶组织剂量（每克鼻组织中萘的总代谢量），该分析中最低的转录BMDL相当于人类持续接触萘的浓度约为0.3ppm。在低于该浓度的暴露下，萘或其代谢产物不太可能产生显著影响。
