Sweeney L M, Tyler T R, Kirman C R, Corley R A, Reitz R H, Paustenbach D J, Holson J F, Whorton M D, Thompson K M, Gargas M L
The Sapphire Group, Inc., 2928 Idaho Falls Drive, Suite 100, Beavercreek, Ohio 45431, USA.
Toxicol Sci. 2001 Jul;62(1):124-39. doi: 10.1093/toxsci/62.1.124.
Methoxyethanol (ethylene glycol monomethyl ether, EGME), ethoxyethanol (ethylene glycol monoethyl ether, EGEE), and ethoxyethyl acetate (ethylene glycol monoethyl ether acetate, EGEEA) are all developmental toxicants in laboratory animals. Due to the imprecise nature of the exposure data in epidemiology studies of these chemicals, we relied on human and animal pharmacokinetic data, as well as animal toxicity data, to derive 3 occupational exposure limits (OELs). Physiologically based pharmacokinetic (PBPK) models for EGME, EGEE, and EGEEA in pregnant rats and humans have been developed (M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 53-62; M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 63-73). These models were used to calculate estimated human-equivalent no adverse effect levels (NAELs), based upon internal concentrations in rats exposed to no observed effect levels (NOELs) for developmental toxicity. Estimated NAEL values of 25 ppm for EGEEA and EGEE and 12 ppm for EGME were derived using average values for physiological, thermodynamic, and metabolic parameters in the PBPK model. The uncertainties in the point estimates for the NOELs and NAELs were estimated from the distribution of internal dose estimates obtained by varying key parameter values over expected ranges and probability distributions. Key parameters were identified through sensitivity analysis. Distributions of the values of these parameters were sampled using Monte Carlo techniques and appropriate dose metrics calculated for 1600 parameter sets. The 95th percentile values were used to calculate interindividual pharmacokinetic uncertainty factors (UFs) to account for variability among humans (UF(h,pk)). These values of 1.8 for EGEEA/EGEE and 1.7 for EGME are less than the default value of 3 for this area of uncertainty. The estimated human equivalent NAELs were divided by UF(h,pk) and the default UFs for pharmacodynamic variability among animals and among humans to calculate the proposed OELs. This methodology indicates that OELs (8-h time-weighted average) that should protect workers from the most sensitive adverse effects of these chemicals are 2 ppm EGEEA and EGEE (11 mg/m(3) EGEEA, 7 mg/m(3) EGEE) and 0.9 ppm (3 mg/m(3)) EGME. These recommendations assume that dermal exposure will be minimal or nonexistent.
甲氧基乙醇（乙二醇单甲醚，EGME）、乙氧基乙醇（乙二醇单乙醚，EGEE）和乙氧基乙酸乙酯（乙二醇单乙醚乙酸酯，EGEEA）在实验动物中均为发育毒性物质。由于这些化学物质的流行病学研究中暴露数据的不精确性，我们依靠人类和动物的药代动力学数据以及动物毒性数据来推导3个职业接触限值（OELs）。已建立了怀孕大鼠和人类中EGME、EGEE和EGEEA的基于生理的药代动力学（PBPK）模型（M. L. Gargas等人，2000年，《毒理学与应用药理学》165卷，53 - 62页；M. L. Gargas等人，2000年，《毒理学与应用药理学》165卷，63 - 73页）。这些模型用于根据发育毒性未观察到效应水平（NOELs）下大鼠的体内浓度计算估计的人类等效无不良反应水平（NAELs）。使用PBPK模型中生理、热力学和代谢参数的平均值，得出EGEEA和EGEE的估计NAEL值为25 ppm，EGME为12 ppm。通过在预期范围和概率分布内改变关键参数值获得的体内剂量估计值的分布，估计了NOELs和NAELs点估计值的不确定性。通过敏感性分析确定关键参数。使用蒙特卡罗技术对这些参数值的分布进行采样，并为1600个参数集计算适当的剂量指标。第95百分位数用于计算个体间药代动力学不确定性因子（UFs），以考虑人类之间的变异性（UF(h,pk)）。EGEEA/EGEE的这些值为1.8，EGME为1.7，低于该不确定性领域的默认值3。将估计的人类等效NAELs除以UF(h,pk)以及动物和人类之间药效学变异性的默认UFs，以计算建议的OELs。该方法表明，应能保护工人免受这些化学物质最敏感不良反应影响的OELs（8小时时间加权平均值）为EGEEA和EGEE为2 ppm（EGEEA为11 mg/m³，EGEE为7 mg/m³），EGME为0.9 ppm（3 mg/m³）。这些建议假设皮肤接触将最小或不存在。
