Fisher J W, Mahle D, Abbas R
Armstrong Laboratory, Toxicology Division, Wright-Patterson AFB, Ohio, USA.
Toxicol Appl Pharmacol. 1998 Oct;152(2):339-59. doi: 10.1006/taap.1998.8486.
Nine male and eight female healthy volunteers were exposed to 50 or 100 ppm trichloroethylene vapors for 4 h. Blood, urine, and exhaled breath samples were collected for development of a physiologically based pharmacokinetic (PBPK) model for trichloroethylene and its two major P450-mediated metabolites, trichloroacetic acid and free trichloroethanol. Blood and urine were analyzed for trichloroethylene, chloral hydrate, free trichloroethanol and trichloroethanol glucuronide, and trichloroacetic acid. Plasma was analyzed for dichloroacetic acid. Trichloroethylene was also measured in exhaled breath samples. Trichloroethylene, free trichloroethanol, and trichloroacetic acid were found in blood samples of all volunteers and only trace amounts of dichloroacetic acid (4-12 ppb) were found in plasma samples from a few volunteers. Trichloroethanol glucuronide and trichloroacetic acid were found in urine of all volunteers. No chloral hydrate was detected in the volunteers. Gender-specific PBPK models were developed with fitted urinary rate constant values for each individual trichloroethylene exposure to describe urinary excretion of trichloroethanol glucuronide and trichloroacetic acid. Individual urinary excretion rate constants were necessary to account for the variability in the measured cumulative amount of metabolites excreted in the urine. However, the average amount of trichloroacetic acid and trichloroethanol glucuronide excreted in urine for each gender was predicted using mean urinary excretion rate constant values for each sex. A four-compartment physiological flow model was used for the metabolites (lung, liver, kidney, and body) and a six-compartment physiological flow model was used for trichloroethylene (lung, liver, kidney, fat, and slowly and rapidly perfused tissues). Metabolic capacity (Vmaxc) for oxidation of trichloroethylene was estimated to be 4 mg/kg/h in males and 5 mg/kg/h in females. Metabolized trichloroethylene was assumed to be converted to either free trichloroethanol (90%) or trichloroacetic acid (10%). Free trichloroethanol was glucuronidated forming trichloroethanol glucuronide or converted to trichloroacetic acid via back conversion of trichloroethanol to chloral (trichloroacetaldehyde). Trichloroethanol glucuronide and trichloroacetic acid were then excreted in urine. Gender-related pharmacokinetic differences in the uptake and metabolism of trichloroethylene were minor, but apparent. In general, the PBPK models for the male and female volunteers provided adequate predictions of the uptake of trichloroethylene and distribution of trichloroethylene and its metabolites, trichloroacetic acid and free trichloroethanol. The PBPK models for males and females consistently overpredicted exhaled breath concentrations of trichloroethylene immediately following the TCE exposure for a 2- to 4-h period. Further research is needed to better understand the biological determinants responsible for the observed variability in urinary excretion of trichloroethanol glucuronide and trichloroacetic acid and the metabolic pathway resulting in formation of dichloroacetic acid.
9名男性和8名女性健康志愿者暴露于50或100 ppm的三氯乙烯蒸气中4小时。采集血液、尿液和呼出气体样本，用于建立三氯乙烯及其两种主要的细胞色素P450介导的代谢产物——三氯乙酸和游离三氯乙醇的基于生理的药代动力学（PBPK）模型。分析血液和尿液中的三氯乙烯、水合氯醛、游离三氯乙醇和三氯乙醇葡糖醛酸以及三氯乙酸。分析血浆中的二氯乙酸。还测量呼出气体样本中的三氯乙烯。在所有志愿者的血液样本中均发现了三氯乙烯、游离三氯乙醇和三氯乙酸，并且在少数志愿者的血浆样本中仅发现痕量的二氯乙酸（4 - 12 ppb）。在所有志愿者的尿液中均发现了三氯乙醇葡糖醛酸和三氯乙酸。在志愿者中未检测到水合氯醛。针对每种三氯乙烯暴露情况，通过拟合个体的尿排泄速率常数，建立了性别特异性的PBPK模型，以描述三氯乙醇葡糖醛酸和三氯乙酸的尿排泄情况。个体尿排泄速率常数对于解释尿液中排泄的代谢产物累积量的变异性是必要的。然而，使用每种性别的平均尿排泄速率常数来预测每种性别尿液中排泄的三氯乙酸和三氯乙醇葡糖醛酸的平均量。代谢产物（肺、肝、肾和身体）采用四室生理流动模型，三氯乙烯（肺、肝、肾、脂肪以及缓慢和快速灌注组织）采用六室生理流动模型。男性三氯乙烯氧化的代谢能力（Vmaxc）估计为4 mg/kg/h，女性为5 mg/kg/h。假定代谢的三氯乙烯转化为游离三氯乙醇（90%）或三氯乙酸（10%）。游离三氯乙醇经葡糖醛酸化形成三氯乙醇葡糖醛酸，或通过三氯乙醇逆向转化为氯醛（三氯乙醛）转化为三氯乙酸。然后三氯乙醇葡糖醛酸和三氯乙酸经尿液排泄。三氯乙烯摄取和代谢方面与性别相关的药代动力学差异较小，但很明显。总体而言，男性和女性志愿者的PBPK模型对三氯乙烯的摄取以及三氯乙烯及其代谢产物三氯乙酸和游离三氯乙醇的分布提供了充分的预测。男性和女性的PBPK模型在三氯乙烯暴露后2至4小时内持续高估了呼出气体中三氯乙烯的浓度。需要进一步研究以更好地理解导致观察到的三氯乙醇葡糖醛酸和三氯乙酸尿排泄变异性的生物学决定因素以及导致二氯乙酸形成的代谢途径。
