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

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    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
    Type
    Article
    Language
    en
    
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    Title
    Head skeleton malformations in zebrafish (Danio rerio) to assess adverse effects of mixtures of compounds.
    Published in
    Arch Toxicol 2018; advance online publication (ahead of print)
    Publiekssamenvatting
    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.
    DOI
    10.1007/s00204-018-2320-y
    PMID
    30288550
    URI
    http://hdl.handle.net/10029/622260
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00204-018-2320-y
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