Janer G, Verhoef A, Gilsing H D, Piersma A H
National Institute of Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands.
Toxicol In Vitro. 2008 Oct;22(7):1797-805. doi: 10.1016/j.tiv.2008.07.007. Epub 2008 Jul 15.
The implementation of in vitro alternatives in the safety evaluation of chemicals in the animal intensive area of reproductive toxicity testing is highly desirable, but has been limited by issues around predictivity and applicability domains. The validation of alternatives may gain from a category approach, in which, rather than validating a test for the universe of chemicals, its predictive value is assessed for each class of chemicals for which the test represents relevant end point(s). We studied the embryotoxicity in rodent postimplantation whole embryo culture (WEC) of a series of phthalates and their metabolites. Phthalate diesters are widely applied industrial chemicals, their monoester derivatives being considered as their embryotoxic metabolites. The relative in vitro potency of three out of four monophthalates was found to mimick that of corresponding diphthalates tested in vivo. The phthalate that deviated from this ranking, monoethylhexylphthalate (MEHP), showed a relatively high in vitro toxicity as compared to in vivo data. This deviation could be explained through kinetic differences among phthalates, as shown between MEHP and monobutylphthalate. In addition, in vitro testing of specific secondary MEHP metabolites showed that they were all less potent than MEHP. This finding confirmed that MEHP in vitro embryotoxicity is most likely the best correlate to DEHP in vivo embryotoxicity. This study shows that a category approach in the assessment of the validation of in vitro alternatives is feasible, and can be improved when kinetic considerations are taken into account.
在生殖毒性测试的动物密集区域，将体外替代方法应用于化学品安全评估是非常可取的，但一直受到预测性和适用范围等问题的限制。替代方法的验证可采用分类法，即不是针对所有化学品验证一种测试，而是针对该测试代表相关终点的每类化学品评估其预测价值。我们研究了一系列邻苯二甲酸盐及其代谢物在啮齿动物植入后全胚胎培养（WEC）中的胚胎毒性。邻苯二甲酸二酯是广泛应用的工业化学品，其单酯衍生物被认为是其胚胎毒性代谢物。发现四种单邻苯二甲酸盐中的三种的相对体外效力与体内测试的相应双邻苯二甲酸盐的效力相似。偏离此排名的邻苯二甲酸盐单乙基己基邻苯二甲酸酯（MEHP）与体内数据相比显示出相对较高的体外毒性。这种偏差可以通过邻苯二甲酸盐之间的动力学差异来解释，如MEHP和单丁基邻苯二甲酸酯之间所示。此外，对特定的二级MEHP代谢物的体外测试表明，它们的效力都低于MEHP。这一发现证实，MEHP的体外胚胎毒性最有可能与DEHP的体内胚胎毒性具有最佳相关性。这项研究表明，在评估体外替代方法的验证时采用分类法是可行的，并且在考虑动力学因素时可以得到改进。
