Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674, USA.
Toxicol Sci. 2011 Jan;119(1):178-88. doi: 10.1093/toxsci/kfq310. Epub 2010 Oct 15.
High-dose bolus exposure of rats to ethylene glycol (EG) causes developmental toxicity mediated by a metabolite, glycolic acid (GA), whose levels increase disproportionately when its metabolism is saturated. However, low-level exposures that do not saturate GA metabolism have a low potential for developmental effects. Toward the goal of developing EG risk assessments based on internal dose metrics, this study examined the differences between fast (bolus) and slow (continuous infusion) dose-rate exposures to EG on developmental outcome and pharmacokinetics. Time-mated female CD rats received sc bolus injections of 0, 1000, or 2000 mg/kg/day of EG on gestation day (GD) 6-15 once daily, whereas three corresponding groups were given the same daily doses as an infusion administered continuously from GD 6-15 via an sc implantable pump. In the sc bolus groups, increases in 11 fetal malformations (major defects) and 12 variations (minor alterations) were seen at the 2000 mg/kg/day dose level, whereas increases in 2 malformations and 2 variations occurred at 1000 mg/kg/day. In contrast, equivalent daily doses of EG given slowly via infusion did not cause any developmental effects. A pharmacokinetics time course was then conducted to compare GD 11-12 kinetics from oral bolus (gavage) exposure versus sc infusion of EG. Although dose rate had a modest impact (8- to 11-fold difference) on peak EG levels, peak levels of GA in maternal blood, kidney, embryo, and exocoelomic fluid were 59, 100, 49, and 56 times higher, respectively, following gavage versus the same dose given by infusion. These data illustrate how high-dose bolus exposure to EG causes a dramatic shift to nonlinear GA kinetics, an event which is highly unlikely to occur following exposures to humans associated with consumer and worker uses.
大剂量乙二醇（EG）经静脉推注暴露于大鼠可引起发育毒性，其代谢产物甘醇酸（GA）介导这种毒性，当 GA 代谢饱和时，GA 水平会不成比例地增加。然而，不会使 GA 代谢饱和的低水平暴露对发育影响的可能性较低。为了基于内剂量指标制定 EG 风险评估，本研究探讨了 EG 快速（推注）和缓慢（连续输注）剂量率暴露对发育结果和药代动力学的差异。时间匹配的雌性 CD 大鼠在妊娠第 6-15 天（GD）每天经皮注射 0、1000 或 2000mg/kg 的 EG 作为推注，而三个相应的组则通过皮下植入式泵从 GD 6-15 连续输注相同的日剂量。在静脉推注组中，在 2000mg/kg/天剂量水平下，11 个胎儿畸形（主要缺陷）和 12 个变异（轻微改变）增加，而在 1000mg/kg/天剂量水平下，2 个畸形和 2 个变异增加。相比之下，通过缓慢输注给予相同的 EG 日剂量不会引起任何发育影响。然后进行了药代动力学时间过程研究，以比较口服推注（灌胃）暴露与 EG 皮下输注的 GD 11-12 药代动力学。尽管剂量率对 EG 峰值水平有适度影响（8-11 倍差异），但经灌胃给予相同剂量后，母体血液、肾脏、胚胎和腔液中 GA 的峰值水平分别高 59、100、49 和 56 倍。这些数据说明了 EG 大剂量静脉推注暴露如何导致 GA 药代动力学从线性向非线性剧烈转变，而这种情况在与人类接触相关的消费和工人用途暴露中极不可能发生。
