Melnick R L, Huff J
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Rev Environ Contam Toxicol. 1992;124:111-44. doi: 10.1007/978-1-4612-2864-6_5.
1,3-Butadiene is a high production volume chemical used largely in the manufacture of synthetic rubber. The production and use of 1,3-butadiene increased dramatically during World War II with the development of the synthetic rubber industry. Before the 1980s, 1,3-butadiene was not considered to be particularly hazardous to human health; therefore, OSHA established a permissible limit of 1,000 ppm for occupational exposure to this chemical. Results of recent inhalation carcinogenicity studies have demonstrated clearly that 1,3-butadiene is a multiple-organ carcinogen in Sprague-Dawley rats and in B6C3F1 mice. Particularly noteworthy in mice were the early occurrences and extensive development of lymphomas, the induction of uncommon hemangiosarcomas of the heart, and the development of malignant lung tumors at exposure concentrations as low as 6.25 ppm. Because 6.25 ppm was the lowest concentration ever used in a long-term carcinogenicity of this gas, it is likely that lower exposure levels would also cause cancers in laboratory animals. In addition, multiple organ site neoplasia was induced in mice after only 13 weeks of exposure. Two reactive epoxides, 1,2-epoxy-3-butene and diepoxybutane, have been identified as intermediates in the biotransformation of 1,3-butadiene in rats and mice. Metabolism is probably an important factor in the carcinogenicity of 1,3-butadiene, because in vitro mutagenicity of 1,3-butadiene requires metabolic activation, whereas these epoxide intermediates are direct acting mutagens in bacteria and are carcinogens in rats and mice. The metabolism of 1,3-butadiene in rats and mice is linear up to concentrations of at least 1000 ppm. Pharmacokinetic studies on 1,3-butadiene and on 1,2-epoxy-3-butene have revealed certain quantitative differences in metabolic rates between Sprague-Dawley rats and B6C3F1 mice; however, these differences were not of sufficient magnitude to account for the reported different target site carcinogenic responses in these two strains of animals. Thus, additional factors must be involved in distinguishing site specificity in the carcinogenicity of 1,3-butadiene between species. In addition to its carcinogenic effects, 1,3-butadiene is a potent in vivo genotoxic agent to mouse bone marrow cells. Hematologic changes indicative of a partially regenerative anemia were induced in mice at 62.5 and higher concentrations. 1,3-Butadiene is also a reproductive and developmental toxicant. Epidemiology studies of workers employed in the production of 1,3-butadiene or of styrene-butadiene rubber have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers.(ABSTRACT TRUNCATED AT 400 WORDS)
1,3 - 丁二烯是一种大量生产的化学品，主要用于合成橡胶的制造。随着合成橡胶工业的发展，二战期间1,3 - 丁二烯的生产和使用急剧增加。在20世纪80年代之前，1,3 - 丁二烯被认为对人类健康没有特别危害；因此，美国职业安全与健康管理局（OSHA）规定该化学品职业接触的允许限值为1000 ppm。近期吸入致癌性研究结果清楚地表明，1,3 - 丁二烯在斯普拉格 - 道利大鼠和B6C3F1小鼠中是一种多器官致癌物。在小鼠中特别值得注意的是淋巴瘤的早期发生和广泛发展、心脏罕见的血管肉瘤的诱导以及在低至6.25 ppm的暴露浓度下恶性肺肿瘤的发展。由于6.25 ppm是该气体长期致癌性研究中使用过的最低浓度，较低的暴露水平很可能也会在实验动物中引发癌症。此外，仅暴露13周后小鼠就出现了多器官部位肿瘤形成。两种活性环氧化物，1,2 - 环氧 - 3 - 丁烯和1,2 - 二环氧丁烷，已被确定为大鼠和小鼠体内1,3 - 丁二烯生物转化的中间体。代谢可能是1,3 - 丁二烯致癌性的一个重要因素，因为1,3 - 丁二烯的体外诱变性需要代谢激活，而这些环氧化物中间体在细菌中是直接作用的诱变剂，在大鼠和小鼠中是致癌物。大鼠和小鼠体内1,3 - 丁二烯的代谢在浓度至少达到1000 ppm时呈线性。对1,3 - 丁二烯和1,2 - 环氧 - 3 - 丁烯的药代动力学研究揭示了斯普拉格 - 道利大鼠和B6C3F1小鼠之间代谢率的某些定量差异；然而，这些差异的幅度不足以解释这两种动物品系中报道的不同靶位点致癌反应。因此，在区分1,3 - 丁二烯在不同物种间致癌性的位点特异性方面，必定涉及其他因素。除了致癌作用外，1,3 - 丁二烯对小鼠骨髓细胞是一种强大的体内遗传毒性剂。在62.5 ppm及更高浓度下，小鼠出现了指示部分再生性贫血的血液学变化。1,3 - 丁二烯也是一种生殖和发育毒物。对从事1,3 - 丁二烯或丁苯橡胶生产的工人的流行病学研究一直表明，职业性接触1,3 - 丁二烯与淋巴和造血系统癌症导致的超额死亡率之间存在关联。（摘要截短于400字）
