Cruzan George, Carlson Gary P, Johnson Keith A, Andrews Larry S, Banton Marcy I, Bevan Christopher, Cushman Janette R
ToxWorks, Bridgeton, New Jersey 08302-6640, USA.
Regul Toxicol Pharmacol. 2002 Jun;35(3):308-19. doi: 10.1006/rtph.2002.1545.
Mice are particularly sensitive to respiratory tract toxicity following styrene exposure. Inhalation of styrene by mice results in cytotoxicity in terminal bronchioles, followed by increased incidence of bronchioloalveolar tumors, as well as degeneration and atrophy of nasal olfactory epithelium. In rats, no effects on terminal bronchioles are seen, but effects in the nasal olfactory epithelium do occur, although to a lesser degree and from higher exposure concentrations. In addition, cytotoxicity and tumor formation are not related to blood levels of styrene or styrene oxide (SO) as measured in chronic studies. Whole-body metabolism studies have indicated major differences in styrene metabolism between rats and mice. The major differences are 4- to 10-fold more ring-oxidation and phenylacetaldehyde pathways in mice compared to rats. The data indicate that local metabolism of styrene is responsible for cytotoxicity in the respiratory tract. Cytotoxicity is seen in tissues that are high in CYP2F P450 isoforms. These tissues have been demonstrated to produce a high ratio of R-SO compared to S-SO (at least 2.4 : 1). In other rat tissues the ratio is less than 1, while in mouse liver the ratio is about 1.1. Inhibition of CYP2F with 5-phenyl-1-pentyne prevents the styrene-induced cytotoxicity in mouse terminal bronchioles and nasal olfactory epithelium. R-SO has been shown to be more toxic to mouse terminal bronchioles than S-SO. In addition, 4-vinylphenol (ring oxidation of styrene) has been shown to be highly toxic to mouse terminal bronchioles and is also metabolized by CYP2F. In human nasal and lung tissues, styrene metabolism to SO is below the limit of detection in nearly all samples, and the most active sample of lung was approximately 100-fold less active than mouse lung tissue. We conclude that styrene respiratory tract toxicity in mice and rats, including mouse lung tumors, are mediated by CYP2F-generated metabolites. The PBPK model predicts that humans do not generate sufficient levels of these metabolites in the terminal bronchioles to reach a toxic level. Therefore, the postulated mode of action for these effects indicates that respiratory tract effects in rodents are not relevant for human risk assessment.
小鼠对苯乙烯暴露后的呼吸道毒性特别敏感。小鼠吸入苯乙烯会导致终末细支气管出现细胞毒性，随后细支气管肺泡瘤的发病率增加，同时鼻嗅上皮会发生变性和萎缩。在大鼠中，未观察到对终末细支气管的影响，但鼻嗅上皮确实会出现影响，不过程度较轻且暴露浓度较高。此外，在慢性研究中，细胞毒性和肿瘤形成与血液中的苯乙烯或环氧苯乙烯（SO）水平无关。全身代谢研究表明，大鼠和小鼠在苯乙烯代谢方面存在重大差异。主要差异在于，与大鼠相比，小鼠的环氧化和苯乙醛途径多4至10倍。数据表明，苯乙烯的局部代谢是呼吸道细胞毒性的原因。在富含CYP2F P450同工型的组织中可见细胞毒性。这些组织已被证明产生的R - SO与S - SO的比例很高（至少2.4 : 1）。在大鼠的其他组织中，该比例小于1，而在小鼠肝脏中该比例约为1.1。用5 - 苯基 - 1 - 戊炔抑制CYP2F可防止苯乙烯诱导的小鼠终末细支气管和鼻嗅上皮细胞毒性。已证明R - SO对小鼠终末细支气管的毒性比S - SO更大。此外，4 - 乙烯基苯酚（苯乙烯的环氧化产物）已被证明对小鼠终末细支气管具有高毒性，并且也由CYP2F代谢。在人类鼻和肺组织中，几乎所有样本中苯乙烯代谢为SO的水平都低于检测限，肺组织中活性最高的样本比小鼠肺组织的活性低约100倍。我们得出结论，小鼠和大鼠中苯乙烯的呼吸道毒性，包括小鼠肺部肿瘤，是由CYP2F产生的代谢产物介导的。PBPK模型预测，人类在终末细支气管中不会产生足够水平的这些代谢产物以达到中毒水平。因此，这些效应的假定作用模式表明，啮齿动物的呼吸道效应与人类风险评估无关。
