Sorsa M, Peltonen K, Anderson D, Demopoulos N A, Neumann H G, Osterman-Golkar S
Finnish Institute of Occupational Health, Helsinki, Finland.
Mutagenesis. 1996 Jan;11(1):9-17. doi: 10.1093/mutage/11.1.9.
1,3-Butadiene (BD) is an important industrial chemical and environmental contaminant, e.g. in urban air, traffic exhausts and tobacco smoke. It has been shown to be genotoxic in vitro and in vivo and carcinogenic in rodents, mice being more sensitive than rats. The present study confirmed this species difference. Using micronuclei in erythrocytes or bone marrow as a marker, mice responded at an effective level of 50 p.p.m., while the highest ineffective level in rats was 500 p.p.m. (inhalation of BD for 5 days). A dose-dependent increase in N-terminal valine haemoglobin adducts was seen in both rats and mice, but the adduct levels in the latter species were on average five times higher. For the first time, specific N6-alkyldeoxyadenosine adducts were identified in lung and liver DNA of rats exposed to BD by inhalation. No significant difference in DNA adduct level was seen in lung tissue of rats and mice at similar exposure levels. Occupational exposure levels to BD in the European Process industry are variable, but generally < 1 p.p.m. Haemoglobin adduct levels were seen to be increased among the worker groups with higher potential exposure to BD (process work, bomb voiding and repair duties) as compared with adduct levels in less exposed workers in maintenance and the laboratory or control personnel. However, the N-terminal valine haemoglobin adducts measured in the workers were one to two orders of magnitude lower than extrapolated for the same exposure dose in mice. In the same workers no exposure-related effects were seen in the cytogenetic parametres studied, i.e. chromosomal aberrations, sister chromatid exchanges or micronuclei in peripheral blood lymphocytes, or in the Ras oncoprotein levels of plasma samples. The studies so far conducted suggest that human exposure at the levels seen in the present day process industry can be documented at the biological dose level using haemoglobin adduct measurement, but not at the biological effect level using cytogenetic biomarkers. In order to quantitate the human genotoxic risk of BD exposure more work needs to be done on the role of other active BD metabolites than 1,2-epoxy-3-butene and on the genetic polymorphisms controlling the variability of individual responses.
1,3 - 丁二烯（BD）是一种重要的工业化学品和环境污染物，例如存在于城市空气、交通尾气和烟草烟雾中。已证明其在体外和体内具有遗传毒性，在啮齿动物中具有致癌性，小鼠比大鼠更敏感。本研究证实了这种物种差异。以红细胞或骨髓中的微核为标志物，小鼠在50 ppm的有效水平下有反应，而大鼠的最高无效水平为500 ppm（吸入BD 5天）。在大鼠和小鼠中均观察到N - 末端缬氨酸血红蛋白加合物呈剂量依赖性增加，但后者的加合物水平平均高出五倍。首次在吸入BD的大鼠的肺和肝DNA中鉴定出特定的N6 - 烷基脱氧腺苷加合物。在相似暴露水平下，大鼠和小鼠肺组织中的DNA加合物水平未见显著差异。欧洲加工行业中BD的职业暴露水平各不相同，但一般<1 ppm。与维护部门、实验室或对照组中暴露较少的工人相比，在具有较高BD潜在暴露风险的工人组（工艺工作、炸弹排空和维修任务）中，血红蛋白加合物水平有所升高。然而，工人中测得的N - 末端缬氨酸血红蛋白加合物比在相同暴露剂量下小鼠的外推值低一到两个数量级。在同一批工人中，在所研究的细胞遗传学参数方面未见与暴露相关的影响，即外周血淋巴细胞中的染色体畸变、姐妹染色单体交换或微核，以及血浆样本中的Ras癌蛋白水平。迄今为止的研究表明，利用血红蛋白加合物测量可以在生物剂量水平记录当今加工行业中人类的暴露情况，但利用细胞遗传学生物标志物则无法在生物效应水平进行记录。为了更准确地量化BD暴露对人类的遗传毒性风险，需要进一步研究1,2 - 环氧 - 3 - 丁烯以外的其他活性BD代谢物的作用以及控制个体反应变异性的基因多态性。
