MODULATION OF BENZENE METABOLISM BY EXPOSURE TO ENVIRONM

描述 环境暴露是以混合物的形式发生的，而大多数毒物和 已经对单一化合物进行了药代动力学研究。苯是一种 广泛存在的污染物，作为环境混合物的一部分。它 有大量的基于单一化合物暴露或 剂量。申请人建议使用活体和在体内研究混合物中的苯 在体外实验中。要检验的假设是：1)相同 当环羟化和开环时，苯的一部分被消除 在环境水平上单独或部分吸入人体的代谢物 甲基叔丁基醚(MTBE)的混合物或可以 产生活性氧物种(ROS)，如铁；2)毒性 环境污染物混合物，如苯和MTBE、铁或 铬在一定程度上是由于 混合物各组分的活性中间体。这个 检验这些假说的具体目的和目标是：1)让人类接触到 从苯和MTBE或苯和铁的二元混合物 无抗氧化剂摄入；2)将体外培养的HL-60细胞暴露于 苯代谢物邻苯二醛和对苯二酚，有毒的MTBE 代谢物甲醛和铬(VI)或铁(II)单独或组合；以及 3)说明在受控暴露中观察到的药效学效应 在体内研究中观察到的影响在体外实验 学习。体内研究将在受控环境中进行 设施在与环境相关的浓度和持续时间内使用 同位素标记的苯。这项研究的目标包括：比较 人体以环羟化形式排出的总吸入苯所占比例 代谢物对苯二酚和苯酚开环代谢物，反式，反式 受试者暴露后的麦康酸和未代谢的苯 单用苯以及苯和MTBE的二元混合物或铁和 没有抗氧化剂摄取；测定米氏常数 苯的消除和苯代谢物的生成率； I-IL-60细胞，检测苯代谢物紫草醛的影响 和对苯二酚，MTBE的代谢物甲醛，铁(作为Fe(II))和 铬(As(Cr(Vl)在AP-I和NF-kB DNA上的单独和组合 结合活性、细胞周期分析、细胞凋亡和DNA链断裂； 为每个毒理学终点制定响应面；以及 比较两种药物在药效学方面的显著差异 体内和体外研究。

DESCRIPTION Environmental exposures occur as mixtures, while most toxicologic and pharmacokinetic studies have been done on single compounds. Benzene is a widespread contaminant that occurs as part of environmental mixtures. It has an extensive data base on toxicity based on single compound exposure or dose. The applicants propose to study benzene in mixtures using in vivo and in vitro experiments. The hypotheses to be tested are: 1) the same fraction of benzene is eliminated as the ring hydroxylated and ring opened metabolites by humans when inhaled at environmental levels alone or as part of a mixture of methyl tertiary-butyl ether (MTBE) or metals that can generate reactive oxygen species (ROS), such as iron, and 2) the toxicity of environmental pollutant mixtures, such as benzene and MTBE, iron or chromium, is due, in part, to interactive cellular effects induced by the reactive intermediates of the individual components of the mixture. The specific aims and goals to test these hypotheses are: 1) expose humans in vivo to binary mixtures of benzene and MTBE or benzene and iron with and without antioxidant ingestion; 2) expose HL-60 cells in vitro to the toxic benzene metabolites muconaldehyde and hydroquinone, the toxic MTBE metabolite formaldehyde, and Cr(VI) or Fe(II) singly and in combination; and 3) relate the pharmacodynamic effects observed in the controlled exposures in the in-vivo studies to the effects observed in the in-vitro experimental studies. The in vivo studies will be done in a Controlled Environmental Facility at environmentally relevant concentrations and durations using isotopically labeled benzene. The goals of the study include: compare the fraction of total inhaled benzene by humans excreted as ring hydroxylated metabolites, hydroquinone, and phenol, ring opened metabolite, trans, trans muconic acid, and unmetabolized benzene by human subjects following exposure to benzene alone and as binary mixtures of benzene and MTBE or iron with and without antioxidant ingestion; determine the Michaelis-Menten constants for the elimination of benzene and the formation rate of benzene metabolites; in I-IL-60 cells, examine the effects of the benzene metabolites muconaldehyde and hydroquinone, the MTBE metabolite formaldehyde, iron (as Fe(II)) and chromium (as (Cr(Vl)) singly and in combination on AP-I and NF-kB DNA binding activity, cell cycle analysis, apoptosis, and DNA strand breaks; develop response surfaces for each of the toxicological endpoints; and compare significant differences in pharmacodynamic effects between the in vivo and in vitro studies.