Corley R A, Bartels M J, Carney E W, Weitz K K, Soelberg J J, Gies R A, Thrall K D
Battelle Pacific Northwest Division, Richland, Washington 99352, USA.
Toxicol Sci. 2005 May;85(1):476-90. doi: 10.1093/toxsci/kfi119. Epub 2005 Feb 16.
An extensive database on the toxicity and modes of action of ethylene glycol (EG) has been developed over the past several decades. Although renal toxicity has long been recognized as a potential outcome, in recent years developmental toxicity, an effect observed only in rats and mice, has become the subject of extensive research and regulatory reviews to establish guidelines for human exposures. The developmental toxicity of EG has been attributed to the intermediate metabolite, glycolic acid (GA), which can become a major metabolite when EG is administered to rats and mice at high doses and dose rates. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to integrate the extensive mode of action and pharmacokinetic data on EG and GA for use in developmental risk assessments. The resulting PBPK model includes inhalation, oral, dermal, intravenous, and subcutaneous routes of administration. Metabolism of EG and GA were described in the liver with elimination via the kidneys. Metabolic rate constants and partition coefficients for EG and GA were estimated from in vitro studies. Other biochemical constants were optimized from appropriate in vivo pharmacokinetic studies. Several controlled rat and human metabolism studies were used to validate the resulting PBPK model. When internal dose surrogates were compared in rats and humans over a broad range of exposures, it was concluded that humans are unlikely to achieve blood levels of GA that have been associated with developmental toxicity in rats following occupational or environmental exposures.
在过去几十年里，已经建立了一个关于乙二醇（EG）毒性和作用模式的广泛数据库。尽管长期以来人们都认识到肾脏毒性是一种潜在后果，但近年来，发育毒性（一种仅在大鼠和小鼠中观察到的效应）已成为广泛研究和监管审查的主题，以制定人类接触的指导方针。乙二醇的发育毒性归因于中间代谢产物乙醇酸（GA），当以高剂量和高剂量率给大鼠和小鼠施用乙二醇时，乙醇酸会成为主要代谢产物。因此，开发了一种基于生理的药代动力学（PBPK）模型，以整合关于乙二醇和乙醇酸的广泛作用模式和药代动力学数据，用于发育风险评估。所得的PBPK模型包括吸入、口服、皮肤、静脉内和皮下给药途径。乙二醇和乙醇酸的代谢在肝脏中进行描述，并通过肾脏消除。乙二醇和乙醇酸的代谢速率常数和分配系数是根据体外研究估计的。其他生化常数是从适当的体内药代动力学研究中优化得到的。使用了几项对照大鼠和人类代谢研究来验证所得的PBPK模型。当在广泛的暴露范围内比较大鼠和人类的内剂量替代指标时，得出的结论是，在职业或环境暴露后，人类不太可能达到与大鼠发育毒性相关的乙醇酸血药浓度。
