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

描述：个体暴露于代谢活化的 和/或解毒剂的剂量由暴露强度和 持续时间与控制代谢酶活性的遗传因素有关。第一 该项目的第一阶段测量了丁二烯的吸收和氧化代谢 (BD)在一组140名受试者中（男女平等;四个种族组）。 总代谢范围从12%到74%的BD进入井 灌注组织，并根据性别和年龄显着变化，并显示 种族的暗示性差异。有明显的肝外 在大约15%的受试者中，更新项目 建议改进方法，并通过 新示踪法具体目标：（1）优化曝光系统， 示踪剂方法;（2）收集实时测量的呼吸 肺泡浓度（~ 700 obs.）并优化一个基于生理学的 药代动力学（PBPK）模型估计代谢率;（3）测量 选择200名受试者，测定BD-BDO的群体代谢分布 按性别、种族和年龄进行横断面调查;（5）选择40名高摄取和 200名快速代谢者暴露于C14标记的BD，以进行质量分析 环氧化物及其 呼吸血液和尿液中的代谢物方法：PBPK参数将 通过蒙特-卡罗马尔可夫链（MCMC）模拟分析拟合， 体内环氧化物形成和清除率以及随人群的变化。一 实时质谱（MS）呼吸监测系统将用于测量 暴露期间和暴露后的呼吸肺泡浓度。这些数据 最初将用于优化测试方案，随后用于研究模型 结构约200名成年受试者将通过现有的 社区外展计划。志愿者在知情同意后， 完成一份问卷，包括饮食和酒精使用，并提供血液 sample.将其暴露于2.0 ppm BD 20 min，然后暴露40 min 冲洗期使用我们的计算机控制曝光系统。基因型将 测定CYP 2A 6、EH、GST θ和GST mu。一组40人高摄取， 将要求快速代谢者进行第二次暴露于C14标记的BD（非常 低活性，0.82 microCi/L）;个体剂量范围 6-55 microCi，平均24 microCi。一种极其敏感的…加速器 质谱仪（AMS）将用于确定C14与 散装样品和代谢产物馏分中的C12。约2 x 10-18摩尔 可以在1分钟内测量C14的含量，统计精度为10 百分之，而检测放射性将需要80多年。数据 分析：MCMCMC-PBPK建模将用于拟合PBPK模型参数， 探索模型结构。广义似然比检验将用于 检测丁二烯的单个氧化速率是否存在任何显著差异 与人群特征相关，如基因型、年龄、种族或 性别，同时控制饮食和生活方式因素。类似地 将测试形成和解毒率的差异， 与受试者特征的关联，如基因型和饮食 抗氧化剂这些发现对美国的风险评估很重要。

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.