Head skeleton malformations in zebrafish (Danio rerio) to assess adverse effects of mixtures of compounds

The EU-EuroMix project adopted the strategy of the European Food Safety Authority (EFSA) for cumulative risk assessment, which limits the number of chemicals to consider in a mixture to those that induce a specific toxicological phenotype. These so-called cumulative assessment groups (CAGs) are refi...

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Bibliographic Details
Published in:	Archives of toxicology Vol. 92; no. 12; pp. 3549 - 3564
Main Authors:	Staal, Yvonne C. M., Meijer, Jeroen, van der Kris, Remco J. C., de Bruijn, Annamaria C., Boersma, Anke Y., Gremmer, Eric R., Zwart, Edwin P., Beekhof, Piet K., Slob, Wout, van der Ven, Leo T. M.
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2018 Springer Nature B.V
Subjects:	2,4-Dinitrophenol 5-Fluorouracil Animals Biomedical and Life Sciences Biomedicine Bone Development - drug effects Boric acid Cartilage Cleft lip/palate Confidence intervals Craniofacial Abnormalities - chemically induced Danio rerio Dimethylmercury Dioxins Dose-Response Relationship, Drug Embryo, Nonmammalian - drug effects Embryonic Development - drug effects Embryos Environmental Health Ethanol Exposure Food safety Imidacloprid Insecticides Mercury (metal) Methylmercury Model testing Occupational Medicine/Industrial Medicine Organic chemistry PCB PCB compounds Pharmacology/Toxicology Phenotypes Pirimiphos-methyl Polychlorinated biphenyls Quantitative analysis Reproductive Toxicology Retinoic acid Risk assessment Risk Assessment - methods Skeleton Skull - abnormalities Skull - drug effects Skull - embryology TCDD Thiram Toxicity Tests - methods Triazoles Trinucleotide repeats Zebrafish Zebrafish embryos Craniofacial malformations Mixture toxicology Cumulative assessment groups Head skeleton
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Summary:	The EU-EuroMix project adopted the strategy of the European Food Safety Authority (EFSA) for cumulative risk assessment, which limits the number of chemicals to consider in a mixture to those that induce a specific toxicological phenotype. These so-called cumulative assessment groups (CAGs) are refined at several levels, including the target organ and specific phenotype. Here, we explore the zebrafish embryo as a test model for quantitative evaluation in one such CAG, skeletal malformations, through exposure to test compounds 0–120 hpf and alcian blue cartilage staining at 120 hpf, focusing on the head skeleton. Reference compounds cyproconazole, flusilazole, metam, and thiram induced distinctive phenotypes in the head skeleton between the triazoles and dithiocarbamates. Of many evaluated parameters, the Meckel’s–palatoquadrate (M–PQ) angle was selected for further assessment, based on the best combination of a small confidence interval, an intermediate maximal effect size and a gentle slope of the dose–response curve with cyproconazole and metam. Additional test compounds included in the CAG skeletal malformations database were tested for M–PQ effects, and this set was supplemented with compounds associated with craniofacial malformations or cleft palate to accommodate otherwise organized databases. This additional set included hexaconazole, all-trans-retinoic acid, AM580, CD3254, maneb, pyrimethanil, imidacloprid, pirimiphos-methyl, 2,4-dinitrophenol, 5-fluorouracil, 17alpha-ethynylestradiol (EE2), ethanol, 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), PCB 126, methylmercury, boric acid, and MEHP. Most of these compounds produced a dose–response for M–PQ effects. Application of the assay in mixture testing was provided by combined exposure to cyproconazole and TCDD through the isobole method, supporting that in this case the combined effect can be modeled through concentration addition.
ISSN:	0340-5761 1432-0738
DOI:	10.1007/s00204-018-2320-y