MECHANISTIC STUDIES ON 1,3-BUTADIENE AND RELATED EPOXIDE-FORMING CHEMICALS

工作总结：两种结构的吸入致癌性研究 1，3-丁二烯的类似物、异戊二烯（2-甲基-1，3-丁二烯）和 氯丁二烯（2-氯-1，3-丁二烯），显示多器官 致癌作用，包括几个部位， 1，3-丁二烯致癌性。 多种研究方法已经 用来理解和量化环氧化合物的影响 导致这类化学物质致癌的原因。 恶性肿瘤ras原癌基因的遗传变异分析 这些化学物质诱导的突变显示A=T颠换占优势 在K-ras密码子61处。 特定环氧化物反应性的速率常数 （包括丁二烯代谢的两个环氧化物中间体）， 研究了环氧-DNA加合物的自发释放动力学 测定使用文献数据，三个PBPK模型在其 构建了解剖细节程度，并用于预测摄取 1，3-硼氢化钠的含量只有当血液被分发时 在动脉、静脉和组织毛细血管床之间， 准确地再现数据，这表明， 向组织的限流输送可能不适合于此 化合物.

Summary of Work: Inhalation carcinogenicity studies on two structural analogues of 1,3-butadiene, isoprene (2-methyl-1,3-butadiene) and chloroprene (2-chloro-1,3-butadiene), demonstrated multiple-organ carcinogenic effects including several sites that were targets of 1,3-butadiene carcinogenicity. Multiple research approaches have been taken to understand and quantify the effects of epoxide-forming chemicals that contribute to the carcinogenicity of this family of chemicals. Analyses of genetic alterations in ras protooncogenes in neoplasms induced by these chemicals revealed a predominance of A=T transversions at K-ras codon 61. Rate constants of the reactivity of specific epoxides (including the two epoxide intermediates of butadiene metabolism) with DNA and the kinetics of spontaneous release of epoxide-DNA adducts were determined. Using literature data, three PBPK models differing in their degree of anatomical detail were constructed and used to predict uptake of 1,3-bautadiene from closed chambers. Only when blood was distributed among arteries, veins, and tissue capillary beds would the model accurately reproduce the data, suggesting that the common assumption of flow-limited delivery to tissues may not be appropriate for this compound.