MODELING HUMAN EXPOSURE DOSE RELATIONSHIPS--1,3-BUTADIEN

描述：(改编自《调查员摘要》)个人 接触代谢活性和/或解毒剂的风险是 由暴露强度和持续时间与基因的交互作用定义 控制代谢酶活性的因素。因此，那些拥有 持续高暴露于1，3-丁二烯(BD)，两者均有高度氧化 戒毒率和戒毒率慢最有可能有很高的风险 不良影响。然而，关于人体内BD代谢的数据并不是 可用。需要实验室暴露来填补这一关键缺口。 具体目标：(1)招募潜在受试者人数：每人400人 来自高加索人、非裔美国人和西班牙裔群体，160人来自 华裔美国人；(2)对所有潜在对象进行预筛选，以确定他们的 EH和GST-theta基因分型。选择一组60个测试对象(等于 来自每个种族亚组的男性和女性的数量)，他们与人类 受试者标准，并在EH等位基因变异的受试者中过度表达 (水解酶活性降低)和GST-theta零基因。(3)揭露 选定的受试者在实验室中进行低水平的BD，并定时收集 暴露前、暴露期间和暴露后的血液、呼吸和尿液样本。 氯沙宗氧化活性的表型研究对象。 分析血液和呼吸样本中的BD和尿样中的代谢物。 (4)利用实验室数据，利用SimuSolv软件对个人PBPK模型的参数进行拟合 程序。(5)按基因、性别、 种族亚群、饮食和生活方式因素。方法：志愿者将 知情同意，填写一份调查问卷，包括饮食和酒精 使用并将与医生会面，以进行面谈和收集 用于筛查的血液样本。样本将进行基因分型以确定 EH和GST-theta的多态类型。被选中进行测试的对象将 在他们收到简报之前被要求戒酒7天， 低水平接触BD(总剂量0.5ppm/小时)；暴露在 日常暴露于香烟烟雾和城市空气污染的范围。 Johanson和Filser(1993)开发的11个隔室的PBPK模型将是 适合BD在呼吸、血液和尿液中的定时测量 用于推算体内表观代谢率的代谢物数据 常量。20次呼气测量和5次静脉血 测量时间为15-60分钟。曝光时间和80分钟。曝光后。引航员 研究和初步的计算机模拟表明，合理的 精度(系数瓦尔10%-20%)可以实现特定于主题的BD 氧化速率。尿液样本将在12小时前和12小时后采集 曝光。来自快速氧化剂的尿液(约占人口的三分之一) 将由工研院贝克泰德分析EH特有的硫代尿酸 和GST途径。数据分析：最大似然技术将是 用来拟合丁二烯氧化速率的PBPK拟合项为 与群体特征相关联，如2E1的表型、种族、 或性，同时控制饮食因素。同样，两国之间的差异 总的排毒率和尿代谢物的组成 将测试快速氧化剂与人口之间的联系 特征，如EH或GST的基因、种族和性别，而 控制饮食和生活方式因素。观测到的氧化速率 尿代谢物随基因和2E1表型的变化 用于为美国主要细分群体制定个性化的PBPK模型 人口。这些模型将适用于美国人口风险 评估。

DESCRIPTION: (Adapted from the Investigator's Abstract) An individual's risk from exposure to a metabolically activated and/or detoxified agent is defined by the interaction of exposure intensity and duration with genetic factors that control metabolic enzyme activity. Thus individuals who have sustained high exposure to 1,3-butadiene (BD), and have both high oxidation rates and slow detoxification rates are most likely to have high risk of adverse effects. However, in vivo data on human metabolism of BD are not available. Laboratory exposures are needed to fill this critical gap. Specific Aims: (1) Recruit populations of potential subjects: 400 each from Caucasian, African-American, and Hispanic groups, and 160 from Chinese-Americans; (2) Prescreen all potential subjects to determine their genotypes for EH and GST-theta. Select a set of 60 test subjects (equal numbers of males and females) from each racial subgroup, who meet human subject criteria and are over-represented in subjects with variant EH allele (reduced hydrolase activity) and GST-theta null genotypes. (3) Expose the selected subjects to low levels of BD in the laboratory, and collect timed blood, breath and urine samples before, during and after the exposure. Phenotype subjects for oxidative activity of CYP2E1 with chlorooxazone. Analyze blood and breath samples for BD and urine samples for metabolites. (4) Use lab data to fit parameters of personal PBPK model using SimuSolv program. (5) Characterize variation in BD metabolism by genotype, sex, racial subgroups, diet, and lifestyle factors. Methods: Volunteers will give informed consent, complete a questionnaire including diet and alcohol use and will meet with a physician for an interview and collection of a blood sample for screening. Samples will be genotyped to determine polymorphic types for EH and GST-theta. Subjects selected for testing will be asked to abstain from alcohol for 7 days before they receive a brief, low-level exposure to BD (total dose 0.5 ppm/hr); the exposures are in the range of everyday exposures from cigarette smoke and urban air pollution. An 11-compartment PBPK model developed by Johanson and Filser (1993) will be fitted to the timed measurements of BD in breath and blood, and urinary metabolite data to derive estimates of apparent in vivo metabolic rate constants. Twenty exhaled breath measurements and 5 venous blood measurements during 15-60 min. exposures and 80 min. post exposure. Pilot studies and preliminary computer simulations indicate that reasonable precision (coeff. var. 10-20%) can be achieved for subject-specific BD oxidation rates. Urine samples will be collected before and for 12-hr post exposure. Urine from fast oxidizers (about one-third of the population) will be analyzed by Bechtold, ITRI, for mercapturic acids specific for EH and GST pathways. Data Analysis: A maximum likelihood technique will be used to fit the oxidation rates for butadiene from PBPK fitting are associated with population characteristics such as phenotype for 2E1, race, or sex, while controlling for dietary factors. Similarly, differences in the overall detoxification rates and composition of urinary metabolites for fast oxidizers will be tested for associations with population characteristics, such as genotype for EH or GST, race, and sex, while controlling for dietary and lifestyle factors. The observed oxidation rates and variations in urinary metabolites with genotypes and 2E1 phenotype will be used to formulate personalized PBPK models for major subgroups of the US population. These models will be suitable for US population risk assessment.