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

Abstract:

: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.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Staal YCM,Meijer J,van der Kris RJC,de Bruijn AC,Boersma AY,Gremmer ER,Zwart EP,Beekhof PK,Slob W,van der Ven LTM

doi

10.1007/s00204-018-2320-y

subject

Has Abstract

pub_date

2018-12-01 00:00:00

pages

3549-3564

issue

12

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-018-2320-y

journal_volume

92

pub_type

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