Welsch Frank
Orbitox, International Toxicology Consultants, 1 Caliente Place, Santa Fe, NM 87508, USA.
Toxicol Lett. 2005 Mar 28;156(1):13-28. doi: 10.1016/j.toxlet.2003.08.010.
Numerous experimental studies have established that only a few among the large family of ethylene glycol ethers (EGEs) elicit toxicity on reproduction in either gender. Notable are the monomethyl (EGME) and monoethyl (EGEE) ethers and their respective acetate esters whose production volumes have dramatically declined. Oxidation to the respective monoalkoxy acids is a prerequisite for toxicity. The most potent EGE reproductive toxicant is EGME (via 2-methoxyacetic acid; MAA), which elicits developmental phase-specific insults on either conceptus or on testes. Toxicity at either target site is markedly attenuated by simple physiological compounds such as acetate, formate, glycine, D-glucose and serine. Lack of solid EGME occupational exposure data and the need to improve the scientific foundations for animal data extrapolations, prompted the development of physiologically based pharmacokinetic (PBPK) models for pregnancy application. Interspecies (mouse-rat) and different exposure routes (including inhalation) were experimentally validated. Such PBPK models were then extrapolated to potential occupational exposures, using rather limited human MAA pharmacokinetic data. PBPK model predictions of human blood levels upon simulated inhalation exposure to the 5 ppm threshold limit value (TLV) for 8 h were approximately 60 microM were well below those causing adverse effects in pregnant mice or rats. This conclusion concurs with the lack of objective analytical chemistry data for EGME/MAA in occupational settings, regardless of the potential route of exposure. There are no exposure data that can be linked in a cause-and-effect association to adverse human reproductive outcomes.
众多实验研究表明，在庞大的乙二醇醚（EGEs）家族中，只有少数几种会对两性生殖产生毒性。值得注意的是单甲醚（EGME）和单乙醚（EGEE）及其各自的醋酸酯，它们的产量已大幅下降。氧化成相应的单烷氧基酸是产生毒性的前提条件。最具毒性的EGE生殖毒物是EGME（通过2-甲氧基乙酸；MAA），它会对胚胎或睾丸造成发育阶段特异性损伤。简单的生理化合物如醋酸盐、甲酸盐、甘氨酸、D-葡萄糖和丝氨酸可显著减轻任一靶部位的毒性。由于缺乏可靠的EGME职业暴露数据，且需要改进动物数据外推的科学基础，促使人们开发用于孕期的基于生理的药代动力学（PBPK）模型。种间（小鼠-大鼠）和不同暴露途径（包括吸入）均通过实验得到验证。然后，利用相当有限的人类MAA药代动力学数据，将此类PBPK模型外推至潜在的职业暴露情况。对于模拟吸入8小时5 ppm阈限值（TLV）的情况，PBPK模型预测的人体血液水平约为60微摩尔，远低于对怀孕小鼠或大鼠产生不良影响的水平。这一结论与职业环境中缺乏EGME/MAA的客观分析化学数据一致，无论潜在的暴露途径如何。没有可与不良人类生殖结果建立因果关联的暴露数据。
