Smith T J, Lin Y S, Mezzetti M, Bois F Y, Kelsey K, Ibrahim J
Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
Chem Biol Interact. 2001 Jun 1;135-136:407-28. doi: 10.1016/s0009-2797(01)00180-6.
The objective of this project was to determine the factors associated with differences in butadiene (BD) inhalation uptake and the rate of metabolism for BD to epoxy butene by monitoring exhaled breath during and after a brief exposure to BD in human volunteers. A total of 133 subjects (equal males and females; four racial groups) provided final data. Volunteers gave informed consent and completed a questionnaire including diet and alcohol use. A venous blood sample was collected for genotyping CYP2E1. Subjects received a 20 min exposure to 2.0 ppm of BD, followed by a 40 min washout period. The total administered dose was 0.6 ppm*h, which is in the range of everyday exposures. Ten, 1 or 2 min exhaled breath samples (five during and five after exposure) were collected using an optimized strategy. BD was determined by GC-FID analysis. Breathing activity (minute ventilation, breath frequency and tidal volume) was measured to estimate alveolar ventilation. After the washout period, 250 mg of chlorzoxazone were administered and urine samples collected for 6 h to measure 2E1 phenotype. The total BD uptake during exposure (inhaled BD minus exhaled) was estimated. A three-compartment PBPK model was fitted to each subject's breath measurements to estimate personal and population model parameters, including in-vivo BD metabolic rate. A hierarchical Bayesian PBPK model was fit by Monte Carlo simulations to estimate model parameters. Regression and ANOVA analyses were performed. Earlier data analysis showed wide ranges for both total uptake BD and metabolic rate. Both varied significantly by sex and age, and showed suggestive differences by race, with Asians having the highest rates. The analyses reported here found no correlation between total BD uptake and metabolic rate. No significant differences were found for oxidation rates by 2E1 genotype or phenotype, but the rates showed trends consistent with reported differences by genotype and phenotype for chlorzoxazone metabolism. No effects on metabolic rate were observed for long-term alcohol consumption, or consumption in the past 24 h. Overall, neither dietary factors nor genetic differences explained much of the wide variability in metabolic rates. Population characteristics, age, sex, and race, were the most important explanatory variables, but a large fraction of the total variability in metabolism remains to be explained.
本项目的目的是通过监测人类志愿者在短时间接触丁二烯（BD）期间及之后的呼出气体，来确定与BD吸入摄取差异以及BD代谢为环氧丁烯的代谢速率相关的因素。共有133名受试者（男女各半；四个种族群体）提供了最终数据。志愿者签署了知情同意书并完成了一份包括饮食和饮酒情况的问卷。采集静脉血样本进行CYP2E1基因分型。受试者接受2.0 ppm BD的20分钟暴露，随后是40分钟的清除期。总给药剂量为0.6 ppm*h，处于日常暴露范围内。采用优化策略采集10、1或2分钟的呼出气体样本（暴露期间5个，暴露后5个）。通过气相色谱 - 火焰离子化检测（GC - FID）分析测定BD。测量呼吸活动（分钟通气量、呼吸频率和潮气量）以估计肺泡通气量。清除期后，给予250 mg氯唑沙宗，并收集6小时的尿液样本以测量2E1表型。估计暴露期间的总BD摄取量（吸入的BD减去呼出的BD）。将三室生理药代动力学（PBPK）模型拟合到每个受试者的呼吸测量数据，以估计个体和群体模型参数，包括体内BD代谢率。通过蒙特卡罗模拟拟合分层贝叶斯PBPK模型以估计模型参数。进行回归分析和方差分析。早期数据分析表明总摄取BD和代谢率的范围都很广。两者在性别和年龄上有显著差异，并且在种族上显示出提示性差异，亚洲人的速率最高。此处报告的分析发现总BD摄取量与代谢率之间没有相关性。在2E1基因型或表型的氧化速率方面未发现显著差异，但这些速率显示出与氯唑沙宗代谢的基因型和表型差异一致的趋势。对于长期饮酒或过去24小时内的饮酒情况，未观察到对代谢率的影响。总体而言，饮食因素和基因差异都不能很好地解释代谢率的广泛变异性。人群特征、年龄、性别和种族是最重要的解释变量，但代谢中总变异性的很大一部分仍有待解释。
