Department of Innovative Testing Strategies, Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
Department of Food Safety, Center for Food, Prevention and Care, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
Food Chem Toxicol. 2020 Jun;140:111284. doi: 10.1016/j.fct.2020.111284. Epub 2020 Mar 20.
The embryonic stem cell test (EST) was applied to evaluate dose addition in combined exposures of teratogenic compounds in the EFSA-defined cumulative assessment group "craniofacial malformations", which was one of the selected cases in the EU-H2020 project "EuroMix". Test compounds were selected through reported effects in rodents, and represented a wide variety of chemical families and modes of action (MOA), including triazoles to inhibit CYP26; (synthetic) retinoids, to activate RAR/RXR; valproic acid, to inhibit histone deacetylase; dithiocarbamates, to disrupt extracellular matrix formation; dioxin (-like) compounds, to activate the aryl hydrocarbon receptor; 17alpha-ethynylestradiol, to activate the estrogen receptor; 5-fluorouracil, to disrupt DNA-synthesis; MEHP and PFOS, to activate peroxisome proliferation activated receptors; and methyl mercury, to induce oxidative stress and inhibit protein function. The EST appeared particularly useful to evaluate differentiation-inhibiting effects of compounds targeting early processes in craniofacial development, possibly related to the early fate of neural crest cells. Mixtures, designed as equipotent concentrations of two compounds with similar or dissimilar MOA, and single compounds showed overlapping dose-responses. This observation is consistent with dose addition in the EST in all studied binary mixtures, irrespective of MOA, and thereby supports the application of dose-addition as a default in cumulative risk assessment.
胚胎干细胞测试（EST）被应用于评估致畸化合物联合暴露在 EFSA 定义的“颅面畸形”累积评估组中的加性效应，这是欧盟 H2020 项目“EuroMix”中选定的案例之一。受试化合物是通过在啮齿动物中报告的效应选择的，代表了广泛的化学家族和作用模式（MOA），包括三唑类化合物抑制 CYP26；（合成）视黄醇类，激活 RAR/RXR；丙戊酸，抑制组蛋白去乙酰化酶；二硫代氨基甲酸盐，破坏细胞外基质形成；二噁英（类）化合物，激活芳香烃受体；17α-乙炔雌二醇，激活雌激素受体；5-氟尿嘧啶，破坏 DNA 合成；MEHP 和 PFOS，激活过氧化物酶体增殖物激活受体；以及甲基汞，诱导氧化应激和抑制蛋白质功能。EST 似乎特别有助于评估针对颅面发育早期过程的化合物的分化抑制作用，这些化合物可能与神经嵴细胞的早期命运有关。设计为两种具有相似或不同 MOA 的化合物等效浓度的混合物和单一化合物显示出重叠的剂量反应。这一观察结果与 EST 中所有研究的二元混合物中的剂量相加一致，无论 MOA 如何，从而支持将剂量相加作为累积风险评估的默认方法。
