Adler I D, Cochrane J, Osterman-Golkar S, Skopek T R, Sorsa M, Vogel E
GSF-Institut für Säugetiergenetik, Oberschleissheim, Germany.
Mutat Res. 1995 Aug;330(1-2):101-14. doi: 10.1016/0027-5107(95)00038-k.
During the Workshop in North Carolina, the in vivo metabolism, adduct formation and genotoxicity data available from rodent and human exposure to 1,3-butadiente (BD) were reviewed and they are summarized in the present report. BD is metabolized by cytochrome P-450-dependent monoxygenases to the primary metabolite 1,2-epoxybutene-3 (epoxybutene, EB). EB is subjected to further metabolism: oxidation to 1,2:3,4-diepoxybutane (DEB), hydrolysis to 3-butene-1,2-diol and conjugation to glutathione. The first pathway seems to prevail in mice while the latter is characteristic for rats and possibly for humans. Species differences exist in adduct formation of the monoepoxide to hemoglobin, for which the following pattern has been found: mice > rats > humans. Genotoxity of BD was found in mice with all applied tests; however, negative results were obtained in rats. In exposed humans, the cytogenetic studies in peripheral blood lymphocytes did not show genotoxic effects, although one report described elevated hprt variant levels in peripheral blood lymphocytes of exposed workers. It was concluded that the presently available data are insufficient for the application of the parallelogram model to estimate genetic risk for humans. As an alternative approach, a tentative estimate of the doubling dose for induction of hprt mutations in somatic cells of mice and men was performed and the calculated values were surprisingly similar, i.e. 9000 ppmh. However, this estimate is burdened with a number of caveats which were discussed in detail. The working group identified a series of urgent research needs to provide the appropriate data for the application of the parallelogram model, such as identification of metabolic pathways in different rodent species and humans, metabolic studies in mice, rats and humans considering metabolic polymorphisms, studies of adducts to DNA and hemoglobin especially of DEB and other butadiene metabolites in rodents and humans, studies of mutational spectra (mutational fingerprinting) in somatic and germinal cells, confirmation of the human hprt mutation data, conformation of the rodent malformation data, dose-response studies in rodent germ cell tests and studies on repair kinetics of mono-adducts induced by EB as opposed to repair of cross-links produced by DEB. Finally, it was suggested that the original parallelogram consisting of data from somatic cell studies in rodents and humans plus studies of heritable effects in rodents to extrapolate to germ cell risk for humans should be supplemented with studies in sperm of experimental animals and exposed men.
在北卡罗来纳州举办的研讨会上，对啮齿动物和人类接触1,3 - 丁二烯（BD）后可获得的体内代谢、加合物形成及遗传毒性数据进行了回顾，并在本报告中进行了总结。BD通过细胞色素P - 450依赖性单加氧酶代谢为主要代谢产物1,2 - 环氧丁烯 - 3（环氧丁烯，EB）。EB会进一步代谢：氧化为1,2:3,4 - 二环氧丁烷（DEB），水解为3 - 丁烯 - 1,2 - 二醇并与谷胱甘肽结合。第一条途径似乎在小鼠中占主导，而后者是大鼠以及可能人类的特征。单环氧化物与血红蛋白形成加合物存在物种差异，已发现以下模式：小鼠>大鼠>人类。在所有应用的试验中，BD在小鼠中具有遗传毒性；然而，在大鼠中得到的是阴性结果。在接触BD的人类中，外周血淋巴细胞的细胞遗传学研究未显示遗传毒性效应，尽管有一份报告描述了接触BD的工人外周血淋巴细胞中次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶（hprt）变异水平升高。得出的结论是，目前可获得的数据不足以应用平行四边形模型来估计人类的遗传风险。作为一种替代方法，对小鼠和人类体细胞中诱导hprt突变的加倍剂量进行了初步估计，计算值惊人地相似，即9000 ppmh。然而，这一估计存在许多需要详细讨论的注意事项。工作组确定了一系列迫切的研究需求，以提供应用平行四边形模型所需的适当数据，例如确定不同啮齿动物物种和人类中的代谢途径，考虑代谢多态性的小鼠、大鼠和人类的代谢研究，啮齿动物和人类中DNA和血红蛋白加合物尤其是DEB和其他丁二烯代谢产物加合物的研究，体细胞和生殖细胞中突变谱（突变指纹）的研究，人类hprt突变数据的确认，啮齿动物畸形数据的确认，啮齿动物生殖细胞试验中的剂量反应研究，以及与DEB产生的交联修复相反的EB诱导的单加合物修复动力学研究。最后，有人建议，由啮齿动物和人类体细胞研究数据以及啮齿动物遗传效应研究组成的原始平行四边形，用于推断人类生殖细胞风险，应补充实验动物和接触BD男性精子的研究。
