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

工作摘要：吸入致癌作用 1，3-丁二烯、异戊二烯两种结构类似物的研究 (2-甲基-1，3-丁二烯)和氯丁二烯(2-氯-1，3-丁二烯)， 显示出多器官致癌作用，包括几种 1，3-丁二烯致癌作用靶点。多重 研究方法已经被用来理解和量化 形成环氧化物的化学物质对环境的影响 这类化学物质的致癌性。关于基因的分析 它们诱导的肿瘤中ras原癌基因的变化 化学物质显示在K-ras中A到T的转换占主导地位 密码子61。特定环氧化物反应活性的速率常数 (包括丁二烯代谢的两种环氧化物中间体) 与DNA作用及环氧化物-DNA的自发释放动力学 测定了加合物。利用文献数据，建立了三个PBPK模型 在解剖细节的程度上不同的构造和 用于预测1，3-丁二烯从密闭小室中的摄取。 仅当血液在动脉、静脉和组织之间分布时 毛细管床模型将准确地再现数据， 这表明，限流交付的常见假设是 组织可能不适合这种化合物。一种生理上的 建立了吸入性异戊二烯的毒代动力学模型 为评估肿瘤提供适当的剂量测量 异戊二烯在大鼠体内的剂量反应数据。

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 to 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. A physiologically based toxicokinetic model of inhaled isoprene was constructed to provide an appropriate measure of dose for evaluations tumor dose-response data of isoprene in rats.