Morgan M S, Dills R L, Kalman D A
Department of Environmental Health, University of Washington, Seattle 98195.
Int Arch Occup Environ Health. 1993;65(1 Suppl):S139-42. doi: 10.1007/BF00381326.
The relationship between biomarkers of exposure (such as concentrations of toxicants in blood or breath, or metabolites in urine) and toxicant dose for individuals is influenced by many person- and episode-specific factors which contribute to overall variability in biomarker level for a given dose. This variability results in imprecise biological marker-based estimates of dose for individuals. We hypothesize that pharmacokinetic data from stable-isotope (deuterated) analogs can be used with a pharmacokinetic model to account for individual-related sources of variation, leading to more precise methods of dose estimation for individuals. To establish the degree of similarity in the pharmacokinetics of unlabeled (d0-) and fully deuterated (D8-) toluene, 21 men (ages 20-45) inhaled an equal molar mixture for 2h. Washout kinetics for both compounds were followed for 4 d in alveolar air and blood. Both compounds exhibited three-phase elimination kinetics in both fluids. The third phase was not always definable for d0-toluene because of concurrent uncontrolled environmental exposures. Considering data from only the first two phases, concentrations of d0- and d8-toluene in alveolar air and blood were well correlated for all subjects, even though pharmacokinetic parameters varied among individuals by 5-9 folds. Further experiments are needed to discern whether correlations between d0- and d8-toluene for the third phase are influenced by an isotope effect; present data support use of d8-toluene as a suitable probe for d0-kinetics.
接触生物标志物（如血液或呼吸中有毒物质的浓度，或尿液中的代谢物）与个体接触毒物剂量之间的关系受到许多个体和特定暴露事件因素的影响，这些因素导致了给定剂量下生物标志物水平的总体变异性。这种变异性导致基于生物标志物的个体剂量估计不准确。我们假设，来自稳定同位素（氘代）类似物的药代动力学数据可与药代动力学模型一起使用，以解释个体相关的变异来源，从而产生更精确的个体剂量估计方法。为了确定未标记（d0-）和全氘代（D8-）甲苯药代动力学的相似程度，21名年龄在20至45岁之间的男性吸入等摩尔混合物2小时。在肺泡气和血液中对两种化合物的清除动力学进行了4天的跟踪。两种化合物在两种液体中均表现出三相消除动力学。由于同时存在未控制的环境暴露，d0-甲苯的第三相并不总是能够明确界定。仅考虑前两个阶段的数据，尽管个体的药代动力学参数相差5至9倍，但所有受试者肺泡气和血液中d0-和d8-甲苯的浓度相关性良好。需要进一步的实验来确定第三阶段d0-和d8-甲苯之间的相关性是否受同位素效应的影响；目前的数据支持将d8-甲苯用作d0-动力学的合适探针。
