TOXICOKINETICS OF ETHYL TERTIARY-BUTYL ETHER

描述：(改编自《调查者摘要》) 这项研究的目标是开发定量的预测模型， 考虑到影响ETBE毒代动力学的特定人的因素， 从而更好地评估人类暴露后的生物水平。 职业和环境暴露于含氧燃料添加剂是一种 由于这些物质的使用日益广泛而引起的重要关切 以及相关毒性的多样性。人与人之间的关系 暴露，体内组织中毒物或代谢物的随时间变化的水平 或体液，以及短期或长期的生物反应 受特定于暴露于此的人甚至是 实际曝光事件。对这些问题进行调查的重要工具 申请者和他的同事之间发展起来的复杂关系 先前的研究包括：受控暴露于稳定的同位素标记 和未标记的化合物；准确测量这些化合物和 血液、呼吸和尿液中的代谢物；以及实施 基于生理的模型。 一种基于人体特定生理的毒物动力学(PBTK)模型 以前开发的方法对苯乙烯使用稳定的同位素示踪剂， 甲苯和二甲苯暴露，通过 吸气。个人特定参数的作用，包括体重， 脂肪组织百分比、肺通气率、心输出量和 血液/空气分配系数是为每个受试者确定的，而其他 个人参数(肝外代谢率和脂肪灌注量)为 通过对实验数据进行拟合得到。特定于个人的输入参数 用于容纳33次受控暴露于50ppm的2H8-甲苯，解释了915% (平均75%-96%)的数据可变性；输入参数的平均值 同一受试者给出的模型拟合率为81.9%(范围50-94%) 可变性，文献值的使用仅允许53.36%(范围 1.3-94%)的变异性待解释。这项建议有明确的目的 将这项技术推广到评估男女ETBE动力学 受试者，以验证跨性别的建模框架， 检验性别差异在以下项目的PBTK参数中的作用 并为评估针对性别的应对措施提供依据。 ETBE暴露

DESCRIPTION: (Adapted from the Investigator's Abstract) The overall objective of this study is to develop quantitative, predictive models that account for person-specific factors that influence ETBE toxicokinetics, leading to better assessment of biological levels following human exposures. Occupational and environmental exposure to oxygenated fuel additives is an important concern due to the increasingly widespread use of these substances and the diversity of associated toxicities. The relationships among human exposures, time-varying levels of toxicants or metabolites in body tissues or fluids, and short or long-term biological responses are greatly influenced by factors that are specific to the person exposed or even to the actual exposure event. Important tools for the investigation of these intricate relationships that the applicant and his associates have developed in prior studies include: controlled exposures to stable isotope-labeled and unlabeled compounds; accurate measurements of these compounds and metabolites in blood, breath, and urine; and implementation of physiologically based models. A person-specific physiologically-based toxicokinetic (PBTK) modeling approach developed previously uses stable isotope tracers for styrene, toluene and xylene exposures, administered to male volunteers via inhalation. The role of person-specific parameters including body weight, per cent adipose tissue, pulmonary ventilation rate, cardiac output, and blood/air partition coefficient are determined for each subject, while other personal parameters (extra-hepatic metabolic rate and adipose perfusion) are obtained by fitting to experimental data. Person-specific input parameters used to fit 33 controlled exposures to 50 ppm 2H8-toluene explained 91 5% (mean 75-96%) of data variability; averaged values of input parameters from the same subjects gave model fits accounting for 81 9% (range 50-94%) of variability, and use of literature values permitted only 53 36% (range 1.3-94%) of variability to be explained. This proposal has the specific aim of extending this technique to evaluate ETBE kinetics in men and women subjects in order to validate the modeling framework across gender, to examine the role of gender-specific differences in PBTK parameters for women, and to provide a basis for assessing gender-specific responses to ETBE exposures