Modeling Human Exposure-Dose Relationships:1,3-Butadiene

描述：一个人因接触代谢激活的 和/或解毒剂由暴露强度和 持续时间与控制代谢酶活性的遗传因素有关。第一 本项目阶段测量了丁二烯的吸收和氧化代谢 (Bd)一组140名受试者(男女平等；四个种族组)。 进入油井的总代谢率从12%到74%不等 灌流组织，性别和年龄差异显著，并显示 因种族而产生的差异。有明显的证据表明肝外 大约15%的受试者的新陈代谢。重建项目 建议改进方法，并观察环氧化物的形成和清除 新的示踪方法。具体目标：(1)优化曝光系统和 示踪方法；(2)收集逐一呼吸的实时测量 肺泡浓度(-700ob.)并优化基于生理的 估计代谢率的药物动力学(PBPK)模型；(3)测量 200名受试者BD-BDO人群代谢分布 作为按性别、种族和年龄划分的横截面；以及(5)选择40个高摄取率和 来自200的快速代谢物用于暴露于C14标记的BD以执行质量 环氧化物及其化合物的平衡研究和时间历程测定 呼吸、血液和尿液中的代谢物。方法：PBPK参数将为 用蒙特卡洛马尔可夫链(MCMC)模拟分析拟合估计 活体环氧化物的形成和清除速率及其随种群的变化。一个 将使用实时质谱仪(MS)呼气监测系统来测量 暴露期间和暴露后的每一次呼吸的肺泡浓度。那些数据 最初将用于优化测试协议，稍后将用于研究模型 结构。大约200名成年受试者将通过现有的 社区外展计划。在给予知情同意后，志愿者将 填写一份调查问卷，包括饮食和饮酒情况，并提供血液 样本。他们将暴露在20分钟至2.0ppm的BD，然后是40分钟 使用我们的计算机控制曝光系统进行冲洗。基因分型将 被确定为CYP2A6、EH、GSTtheta和GSTmu.一组40人的高摄取率， 快速代谢剂将被要求进行第二次接触标记为BD的C14(非常 低活度，0.82microCi/L)；个人剂量范围 6~55microCi，平均24microCi。一种极其灵敏的加速器 将使用质谱仪(AMS)来确定C14到 大量样品和代谢物组分中的C12。大约2 x 10-18摩尔 可在不到1分钟的时间内测量C14，统计精度为10 而检测放射性则需要80多年的时间。数据 分析：将使用MCMC-PBPK建模来拟合PBPK模型参数和 探索模型结构。广义似然比检验将用于 检测丁二烯的单独氧化速率是否有显著差异 与群体特征相关的，如基因、年龄、种族或 性，同时控制饮食和生活方式因素。类似 将测试形成率和解毒率的差异 与受试者特征的关系，如基因类型和饮食 抗氧化剂。调查结果将对美国的风险评估具有重要意义。

DESCRIPTION: 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. The first phase of this project measured the uptake and oxidative metabolism of butadiene (BD) in a set of 140 subjects (equal males and females; four racial groups). Total metabolism ranged from 12 percent to 74 percent of BD entering the well perfused tissues, and varied significantly by sex and age, and showed suggestive differences by race. There was clear evidence of extrahepatic metabolism in approximately 15 percent of the subjects. The renewal project proposes to improve methods, and observe epoxide formation and removal via a new tracer method. Specific Aims: (1) To optimize the exposure system and tracer methods; (2) To collect real-time measurements of breath-by-breath alveolar concentrations (-700 obs.) and optimize a physiologically-based pharmacokinetic (PBPK) model for estimating of metabolism rates; (3) To measure the distribution of population metabolism of BD-BDO for 200 subjects selected as a cross-section by sex, race, and age; and (5) To select 40 high uptake and fast metabolizers from the 200 for exposure to C14 labeled BD to perform mass balance studies and time course determinations for epoxides and their metabolites in breath, blood, and urine. Methods: PBPK parameters will be fitted by Monte-Carlo Markov chain (MCMC) simulation analyses to estimate in vivo epoxide formation and removal rates and variation with the population. A real-time mass spectroscopic (MS) breath monitoring system will used to measure breath-by-breath alveolar concentrations during and after exposure. Those data will be used initially to optimize testing protocols and later to study model structure. About 200 adult subjects will be recruited through existing community outreach programs. After giving informed consent, volunteers will complete a questionnaire including diet and alcohol use, and provide a blood sample. They will be exposed for 20 min to 2.0 ppm BD followed by a 40 min wash-out period using our computer controlled exposure system. Genotypes will be determined for CYP2A6, EH, GSTtheta and GSTmu. A group of 40 high uptake, fast metabolizers will be asked to do a second exposure to C14 labeled BD (very low activity, 0.82 microCi/L) in our hospital lab; individual doses will range 6- 55 microCi with a mean of 24 microCi. An extremely sensitive, accelerator mass spectrometer (AMS) will be used to determine relative amounts of C14 to C12 in bulk samples and the metabolite fractions. Approximately 2 x 10-18 mole of C14 can be measured in under 1 minute with a statistical accuracy of 10 percent, whereas detection radioactivity would take over 80 years. Data Analysis: MCMC-PBPK modeling will be used to fit the PBPK model parameters and explore model structure. Generalized likelihood ratio testing will be used to detect any significant differences in individual oxidation rates for butadiene associated with population characteristics, such as genotype, age, race, or sex, while controlling for dietary and life style factors. Similarly differences in the formation and detoxification rates will be tested for associations with subject characteristics, such as genotypes and dietary antioxidants. Findings will be important for US risk assessments.