Nikula K J, Sun J D, Barr E B, Bechtold W E, Haley P J, Benson J M, Eidson A F, Burt D G, Dahl A R, Henderson R F
Inhalation Toxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico 87185.
Fundam Appl Toxicol. 1993 Aug;21(2):127-39. doi: 10.1006/faat.1993.1082.
Ferrocene (dicyclopentadienyl iron; CAS No. 102-54-5) is a relatively volatile compound used as a chemical intermediate, a catalyst, and an antiknock additive in gasoline. This organometallic chemical is of particular interest because of its structural similarities to other metallocenes, some of which are carcinogenic. F344/N rats and B6C3F1 mice were exposed to 0, 3.0, 10, and 30 mg ferrocene vapor/m3, 6 hr/day, 5 days/week, for 13 weeks. During these exposures, no rats or mice died, nor were any clinical signs of ferrocene-related toxicity observed. At the end of the exposures, male rats exposed to the lowest and highest level of ferrocene had decreased body weight gains compared to filtered-air-exposed control male rats, while body weight gains for all groups of both ferrocene- and filtered-air-exposed female rats were similar. Male mice exposed to ferrocene had no differences in body weight gains, compared to controls, but female mice had decreases in body weight gains at the 10 and 30 mg/m3 exposure levels. There were exposure concentration- and exposure-time-related increases in lung burdens of iron. The mean iron lung burden in rats exposed to 30 mg ferrocene vapor/m3 for 90 days was four times greater than the burden in control rats. No exposure-related changes in respiratory function, lung biochemistry, bronchoalveolar lavage cytology, total lung collagen, clinical chemistry, and hematology parameters were observed. This suggests that the accumulations of iron in lung did not cause an inflammatory response nor any functional impairment of the lung. There were no indications of developing pulmonary fibrosis nor of any hematologic toxicity. No exposure-related gross lesions were seen in any of the rats or mice at necropsy. Exposure-related histopathologic alterations, primarily pigment accumulations, were observed in the nose, larynx, trachea, lung, and liver of both species, and in the kidneys of mice. Lesions were most severe in the nasal olfactory epithelium where pigment accumulation, necrotizing inflammation, metaplasia, and epithelial regeneration occurred. Nasal lesions were observed in all ferrocene-exposed animals and differed only in severity, which was dependent on the exposure concentration. Histochemical stains of these target tissues showed the presence of iron ions. The results suggest that the mechanism of ferrocene toxicity may be the intracellular release of ferrous ion through ferrocene metabolism, followed by either iron-catalyzed lipid peroxidation of cellular membranes or the iron-catalyzed Fenton reaction to form hydroxyl radicals that directly react with other key cellular components, such as protein or DNA.
二茂铁（二环戊二烯基铁；化学物质登记号：102-54-5）是一种相对易挥发的化合物，用作化学中间体、催化剂以及汽油中的抗爆添加剂。这种有机金属化合物因其与其他金属茂结构相似而备受关注，其中一些金属茂具有致癌性。将F344/N大鼠和B6C3F1小鼠暴露于浓度为0、3.0、10和30毫克二茂铁蒸气/立方米的环境中，每天暴露6小时，每周暴露5天，持续13周。在这些暴露期间，没有大鼠或小鼠死亡，也未观察到与二茂铁相关的毒性临床症状。暴露结束时，与暴露于过滤空气的对照雄性大鼠相比，暴露于最低和最高二茂铁水平的雄性大鼠体重增加减少，而暴露于二茂铁和过滤空气的所有雌性大鼠组的体重增加相似。与对照组相比，暴露于二茂铁的雄性小鼠体重增加没有差异，但在10和30毫克/立方米暴露水平下，雌性小鼠体重增加减少。铁在肺部的负荷呈现出与暴露浓度和暴露时间相关的增加。暴露于30毫克二茂铁蒸气/立方米90天的大鼠肺部铁的平均负荷是对照大鼠的四倍。未观察到与暴露相关的呼吸功能、肺生化、支气管肺泡灌洗细胞学、肺总胶原蛋白、临床化学和血液学参数的变化。这表明肺中铁的蓄积并未引发炎症反应或对肺造成任何功能损害。没有迹象表明会发展为肺纤维化或出现任何血液学毒性。在尸检时，未在任何大鼠或小鼠中观察到与暴露相关的大体病变。在两种动物的鼻、喉、气管、肺和肝脏以及小鼠的肾脏中均观察到与暴露相关的组织病理学改变，主要是色素蓄积。病变在鼻嗅觉上皮最为严重，出现色素蓄积、坏死性炎症、化生和上皮再生。在所有暴露于二茂铁的动物中均观察到鼻病变，仅严重程度不同，这取决于暴露浓度。这些靶组织的组织化学染色显示存在铁离子。结果表明，二茂铁毒性的机制可能是通过二茂铁代谢使亚铁离子在细胞内释放，随后亚铁离子催化细胞膜的脂质过氧化反应，或通过亚铁离子催化的芬顿反应形成羟基自由基，这些羟基自由基直接与其他关键细胞成分如蛋白质或DNA发生反应。
