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

1,3-丁二烯及相关环氧化物形成化学品的机理研究

• 批准号: 6106803
• 负责人: RONALD L MELNICK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6106803
• 关键词: carcinogen testing; chemical carcinogen; chemical carcinogenesis; chemical structure function; epoxides; mutagen testing; mutagens; pharmacokinetics

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.

工作总结：吸入致癌性 1，3-丁二烯、异戊二烯的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）， 表现出多器官致癌作用，包括几个 作为1，3-丁二烯致癌性靶点的位点。多 研究方法已经采取了理解和量化 环氧化物形成化学品的影响，有助于 这类化学物质的致癌性。基因分析 在这些诱导的肿瘤中ras原癌基因的改变 化学物质显示K-ras基因的A到T颠换占优势 密码子61。特定环氧化物反应性的速率常数 （包括丁二烯代谢的两种环氧化物中间体） 和环氧-DNA自发释放的动力学 测定了加合物。使用文献数据，三个PBPK模型 不同程度的解剖细节被构建， 用于预测从封闭室中摄取1，3-BaO 3。 只有当血液分布在动脉、静脉和组织中时 毛细管床将模型精确地再现数据， 这表明，通常的假设流量有限的交付， 组织可能不适合这种化合物。生理 建立了吸入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 大鼠中异戊二烯的剂量反应数据。