Dose addition in chemical mixtures inducing craniofacial malformations in zebrafish (Danio rerio) embryos. (March 2020)

• Record Type: Journal Article
• Authors: Zoupa, Maria; Zwart, Edwin P.; Gremmer, Eric R.; Nugraha, Ananditya; Compeer, Sharon; Slob, Wout; van der Ven, Leo T.M.
• Is Part Of: Food and chemical toxicology. Volume 137(2020)
• Publication Date: 2020-03
• Subjects: Dose addition -- Zebrafish model -- Craniofacial malformations -- Mixture toxicity; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2020.111117
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: A challenge in cumulative risk assessment is to model hazard of mixtures. EFSA proposed to only combine chemicals linked to a defined endpoint, in so-called cumulative assessment groups, and use the dose-addition model as a default to predict combined effects. We investigated the effect of binary mixtures of compounds known to cause craniofacial malformations, by assessing the effect in the head skeleton (M-PQ angle) in 120hpf zebrafish embryos. We combined chemicals with similar mode of action (MOA), i.e. the triazoles cyproconazole, triadimefon and flusilazole; next, reference compounds cyproconazole or triadimefon were combined with dissimilar acting compounds, TCDD, thiram, VPA, prochloraz, fenpropimorph, PFOS, or endosulfan. These mixtures were designed as (near) equipotent combinations of the contributing compounds, in a range of cumulative concentrations. Dose-addition was assessed by evaluation of the overlap of responses of each of the 14 tested binary mixtures with those of the single compounds. All 10 test compounds induced an increase of the M-PQ angle, with varying potency and specificity. Mixture responses as predicted by dose-addition did not deviate from the observed responses, supporting dose-addition as a valid assumption for mixture risk assessment. Importantly, dose-addition was found irrespective of MOA of contributing chemicals.