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DOI | 10.1289/EHP9888 |
Dose Addition in the Induction of Craniofacial Malformations in Zebrafish Embryos Exposed to a Complex Mixture of Food-Relevant Chemicals with Dissimilar Modes of Action | |
Leo T.M. Van Der Ven; Paul Van Ommeren; Edwin P. Zwart; Eric R. Gremmer; Hennie M. Hodemaekers; Harm J. Heusinkveld; Jacob D. van Klaveren; Emiel Rorije | |
2022-04-08 | |
发表期刊 | Environmental Health Perspectives
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出版年 | 2022 |
英文摘要 | AbstractBackground:Humans are exposed to combinations of chemicals. In cumulative risk assessment (CRA), regulatory bodies such as the European Food Safety Authority consider dose addition as a default and sufficiently conservative approach. The principle of dose addition was confirmed previously for inducing craniofacial malformations in zebrafish embryos in binary mixtures of chemicals with either similar or dissimilar modes of action (MOAs). Objectives:In this study, we explored a workflow to select and experimentally test multiple compounds as a complex mixture with each of the compounds at or below its no observed adverse effect level (NOAEL), in the same zebrafish embryo model. Methods:Selection of candidate compounds that potentially induce craniofacial malformations was done using in silico methods—structural similarity, molecular docking, and quantitative structure–activity relationships—applied to a database of chemicals relevant for oral exposure in humans via food (EuroMix inventory, ). A final subselection was made manually to represent different regulatory fields (e.g., food additives, industrial chemicals, plant protection products), different chemical families, and different MOAs. Results:A final selection of eight compounds was examined in the zebrafish embryo model, and craniofacial malformations were observed in embryos exposed to each of the compounds, thus confirming the developmental toxicity as predicted by the in silico methods. When exposed to a mixture of the eight compounds, each at its NOAEL, substantial craniofacial malformations were observed; according to a dose–response analysis, even embryos exposed to a 7-fold dilution of this mixture still exhibited a slight abnormal phenotype. The cumulative effect of the compounds in the mixture was in accordance with dose addition (added doses of the individual compounds after adjustment for relative potencies), despite different MOAs of the compounds involved. Discussion:This case study of a complex mixture inducing craniofacial malformations in zebrafish embryos shows that dose addition can adequately predicted the cumulative effect of a mixture of multiple substances at low doses, irrespective of the (expected) MOA. The applied workflow may be useful as an approach for CRA in general. https://doi.org/10.1289/EHP9888 |
领域 | 资源环境 |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/347886 |
专题 | 资源环境科学 |
推荐引用方式 GB/T 7714 | Leo T.M. Van Der Ven,Paul Van Ommeren,Edwin P. Zwart,et al. Dose Addition in the Induction of Craniofacial Malformations in Zebrafish Embryos Exposed to a Complex Mixture of Food-Relevant Chemicals with Dissimilar Modes of Action[J]. Environmental Health Perspectives,2022. |
APA | Leo T.M. Van Der Ven.,Paul Van Ommeren.,Edwin P. Zwart.,Eric R. Gremmer.,Hennie M. Hodemaekers.,...&Emiel Rorije.(2022).Dose Addition in the Induction of Craniofacial Malformations in Zebrafish Embryos Exposed to a Complex Mixture of Food-Relevant Chemicals with Dissimilar Modes of Action.Environmental Health Perspectives. |
MLA | Leo T.M. Van Der Ven,et al."Dose Addition in the Induction of Craniofacial Malformations in Zebrafish Embryos Exposed to a Complex Mixture of Food-Relevant Chemicals with Dissimilar Modes of Action".Environmental Health Perspectives (2022). |
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