Thier R, Bolt H M
Institut für Arbeitsphysiologie an der Universität Dortmund, Germany.
Crit Rev Toxicol. 2000 Sep;30(5):595-608. doi: 10.1080/10408440008951121.
Long-term inhalation studies in rodents have presented unequivocal evidence of experimental carcinogenicity of ethylene oxide, based on the formation of malignant tumors at multiple sites. However, despite a considerable body of epidemiological data only limited evidence has been obtained of its carcinogenicity in humans. Ethylene oxide is not only an important exogenous toxicant, but it is also formed from ethylene as a biological precursor. Ethylene is a normal body constituent; its endogenous formation is evidenced by exhalation in rats and in humans. Consequently, ethylene oxide must also be regarded as a physiological compound. The most abundant DNA adduct of ethylene oxide is 7-(2-hydroxyethyl)guanine (HOEtG). Open questions are the nature and role of tissue-specific factors in ethylene oxide carcinogenesis and the physiological and quantitative role of DNA repair mechanisms. The detection of remarkable individual differences in the susceptibility of humans has promoted research into genetic factors that influence the metabolism of ethylene oxide. With this background it appears that current PBPK models for trans-species extrapolation of ethylene oxide toxicity need to be refined further. For a cancer risk assessment at low levels of DNA damage, exposure-related adducts must be discussed in relation to background DNA damage as well as to inter- and intraindividual variability. In rats, subacute ethylene oxide exposures on the order of 1 ppm (1.83 mg/m3) cause DNA adduct levels (HOEtG) of the same magnitude as produced by endogenous ethylene oxide. Based on very recent studies the endogenous background levels of HOEtG in DNA of humans are comparable to those that are produced in rodents by repetitive exogenous ethylene oxide exposures of about 10 ppm (18.3 mg/m3). Experimentally, ethylene oxide has revealed only weak mutagenic effects in vivo, which are confined to higher doses. It has been concluded that long-term human occupational exposure to low airborne concentrations to ethylene oxide, at or below current occupational exposure limits of 1 ppm (1.83 mg/m3), would not produce unacceptable increased genotoxic risks. However, critical questions remain that need further discussions relating to the coherence of animal and human data of experimental data in vitro vs. in vivo and to species-specific dynamics of DNA lesions.
对啮齿动物的长期吸入研究已提供了明确证据，证明环氧乙烷具有实验致癌性，这基于多个部位出现恶性肿瘤。然而，尽管有大量流行病学数据，但关于其对人类致癌性的证据仍然有限。环氧乙烷不仅是一种重要的外源性毒物，而且它还作为生物前体由乙烯形成。乙烯是人体的正常组成成分；大鼠和人类呼出乙烯证明了其内源形成。因此，环氧乙烷也必须被视为一种生理化合物。环氧乙烷最丰富的DNA加合物是7-(2-羟乙基)鸟嘌呤(HOEtG)。尚未解决的问题是组织特异性因素在环氧乙烷致癌过程中的性质和作用以及DNA修复机制的生理和定量作用。对人类易感性存在显著个体差异的检测促进了对影响环氧乙烷代谢的遗传因素的研究。在此背景下，目前用于跨物种推断环氧乙烷毒性的PBPK模型似乎需要进一步完善。对于低水平DNA损伤的癌症风险评估，必须结合背景DNA损伤以及个体间和个体内的变异性来讨论与暴露相关的加合物。在大鼠中，约1 ppm(1.83 mg/m3)的亚急性环氧乙烷暴露导致的DNA加合物水平(HOEtG)与内源性环氧乙烷产生的水平相当。基于最近的研究，人类DNA中HOEtG的内源性背景水平与啮齿动物通过约10 ppm(18.3 mg/m3)的重复外源性环氧乙烷暴露所产生的水平相当。在实验中，环氧乙烷在体内仅显示出微弱的诱变作用，且仅限于较高剂量。得出的结论是，长期职业性接触空气中低浓度的环氧乙烷，即处于或低于当前职业接触限值1 ppm(1.83 mg/m3)，不会产生不可接受的遗传毒性风险增加。然而，仍然存在关键问题，需要进一步讨论动物和人类数据的一致性、体外与体内实验数据以及DNA损伤的物种特异性动态。
