zebrafish embryo toxicity

The results of our study and the considerations above indicate that independent action of chemicals in a mixture seems to be more likely for short exposure durations and low effect concentrations. Chemosphere 25:471–491. In this review, we discuss zebrafish developmental toxicity testing, focusing on the methods of chemical exposure, the assessment of morphological abnormalities, housing conditions and their effects on the production of healthy embryos, and future directions. Science 313:1072–1077. At the day of experiment, the highest concentration of either single substance or mixture was diluted to 10–13 serial dilutions (constant dilution factor) by adding ISO-water containing the same solvent fraction as the highest concentration. The highest prediction accuracies with CA were achieved for higher effect concentrations and long exposure durations (e.g., mean_log2PDRCA_72hpe_EC50 = − 0.09). Department of Bioanalytical Ecotoxicology, UFZ-Helmholtz Centre for Environmental Research, Permoserstr. Particularly, zebrafish embryo toxicity model provides an alternative to acute fish toxicity tests in terms of animal welfare perspective as the embryos are not considered live until 5 days after fertilization. First, the toxicity of single components was determined by exposing ZFE at a certain age (here: 0 hpf) to the respective chemical (Fig. J Genet Genomics 36:325–334. In a developing system such as the ZFE, the time point of exposure, i.e., the age of the embryo at exposure start, is an additional determining factor for toxicity. Finally, we studied the induction of combined toxic effects in ZFE after exposure to mixtures in which the components were present in concentrations that failed to evoke individual toxicity. This method can be used to identify concentrations of chemicals that cause acute toxicity in fish in aquatic environments. CRCs for experimentally determined mixture toxicities were located within the prediction window in 51 out of 59 cases (86%) in this study. https://doi.org/10.1016/0045-6535(92)90280-5, Schüttler A, Altenburger R, Ammar M et al (2019) Map and model—moving from observation to prediction in toxicogenomics. Environ Sci Technol 36:1751–1756. The observed mixture toxicity was located within the prediction deviation range between the CA and IA estimations in 51 out of 59 cases (86%) or was even underestimated by both models (8/59, 14%). Manage cookies/Do not sell my data we use in the preference centre. Hence a concentration increase of less than 20% results in double the effect. California Privacy Statement, In this study, lethal describes all effects that imply the death of an organism (e.g., coagulation, missing heartbeat [33]), whereas sublethal and teratogenic effects are defined by effects which lead to a change in development and fitness of the organism or to malformations of the ZFE (e.g., change in blood circulation or frequency of heartbeat, formation of edema, or malformation of head, yolk, or tail, etc. In 16 out of 25 cases (68%) time dependent toxicity was detected for single substances, whereas mixture toxicity was time dependent in almost all cases investigated therein (8/10, (80%)). In our study, we utilized cmlc2:GFP heart transgenic and wild type zebrafish embryos. Similar to the results shown in Fig. Distributions are grouped by a prediction models, b prediction models and phenotype, c mixture potency, d mixture potencies and prediction models, e EC50 and phenotype, f by EC50 and phenotype and prediction model, g EC50 and exposure duration, and h EC50 and exposure duration and prediction model. Exposure from both the control and PPF treated groups. Biochim Biophys Acta 19:548–549. For a reliable comparison of predicted and measured mixture toxicity, a valid and free-of-bias determination of toxicity values is necessary. The approach and the analysis strategy are summarized in Fig. This Test Guideline (TG) 236 describes a Fish Embryo Acute Toxicity (FET) test with the zebrafish (Danio rerio). The mixture ratios (MR) and ss_CRCs were used to predict mix_CRCs with the CA (light blue) and IA model (yellow) (Fig. Traditionally, most DBP research focuses on the threat to human health, but the effects on aquatic species exposed to DBPs in wastewater effluents remain ill defined. https://doi.org/10.1021/es015844c, Klüver N, Vogs C, Altenburger R et al (2016) Development of a general baseline toxicity QSAR model for the fish embryo acute toxicity test. Comparison of observed (black) and predicted mixture toxicity (light blue: CA, yellow: IA) for the 24 hpe (g, pink) and 48 hpe (h, purple) exposure duration. Three sets of zebrafish embryos/larvae were exposed to dextromethorphan at 24, 48 and 72 h post fertilization (hpf), respectively, during the embryonic/larval development. Environ Toxicol Chem 35:1887–1899. Chitosan nanoparticles at a size of 200 nm caused malformations, including a bent spine, pericardial edema, and an opaque yolk in zebrafish embryos. Aquat Toxicol 63:43–63. Aquat Toxicol 76:93–110. We observed that lower effect concentrations seem to be better predictable with the IA concept, whereas the CA model seems to better estimate the toxicity of higher effect concentrations. Disinfection to protect human health occurs at drinking water and wastewater facilities through application of non-selective oxidants including chlorine. Environ Toxicol Chem 24:2665. https://doi.org/10.1897/04-639R.1, Kienzler A, Bopp SK, van der Linden S et al (2016) Regulatory assessment of chemical mixtures: requirements, current approaches and future perspectives. Aquat Toxicol 5:143–154. The different regression models were fitted using the software R (version 3.4.4) and the package bbmle (Ben Bolker and R, Development Core, Team (2017). Data analysis: GJ. In Gammarus pulex [40], mixture toxicity was underestimated by both models, whereas the combined effect of either similarly or dissimilarly acting components was proven to be predictable by the appropriate model in freshwater algae Scenedesmus vacuolatus (CA: [19, 20, 41], IA: [13]), luminescent bacteria Vibrio fischeri (CA: [21], IA: [12]) and Daphnia magna (CA: [22, 41]). Incubation was conducted at 26 °C with a 12:12 h light:dark photoperiod and vials shaken at 75 rpm using a horizontal agitator (Edmund Bühler GmbH, SM–30 control). This conclusion is based on the investigation of 9 different mixtures and 31 different exposure scenarios and their toxicities in zebrafish embryos. a Survival rates throughout 24–120 hpf.b Heart beating rates at 48 hpf. Again, ZFE in two different developmental stages were exposed (from 0 hpf: mixB.1 and 24 hpf: mixB.2, Table 2) to two similar mixtures with adopted MRs. The Fish Embryo Acute Toxicity (FET) test with the zebrafish (Danio rerio) embryo, the OECD test guideline (TG) 236, has been designed as an alternative for acute fish toxicity testing such as the OECD Acute Fish Toxicity Test (TG 203). Firstly, we compared the model accuracy of the CA and IA model in general. Another test that uses zebrafish embryos is the OECD’s fish embryo toxicity test (FET), the final draft of which became available in July 2013.2 Both the fish embryo test, which exposes fish embryos to various chemical compounds to determine LC50 and toxicity, and the zebrafish embryo toxicity test rely on parallel methodologies. Shown are the log2PDR of EC50 values that were predicted with the CA model (blue) and IA model (yellow) vs. respective experimentally determined EC50 values (grey). All authors read and approved the final manuscript. We find zebrafish development to be a viable in vivo alternative or confirmatory assay to mammalian in vitro cell assays. However, the observed mix_CRC approximates towards the IA curve at low effect concentrations, whereas the CA model results to better reflect the mix_CRC at higher effect concentrations. The results are exemplarily shown for a rather simple (mixC.1) and more complex mixture (mixE.1) in Fig. Aquat Toxicol 12:33–38. 1d). J Biophys Chem 03:334–340. f Observed mixture toxicity (mix_CRC) at two time points. A second mixture with the same components but different MRs (mixC.2) was investigated at a later developmental stage of the ZFE and exposure was started at 24 hpf. In 8 of 59 cases mixture toxicity was underestimated with both models, whereas an overestimation was never observed. Silva et al., for example, showed that a mixture of eight weak estrogenic compounds were able to evoke a significant combined effect in yeast although the mixture components were present below their individual NOEC [17]. Single chemical or mixture toxicity was considered as time dependent when td was below 0.8 or greater than 1.2. The toxicities of the test chemicals to zebrafish embryos were compared with their acute toxicities to adult fish. The grey bars depict the EC90 induced by the specific mixture concentration obtained after 24, 48, 72, and 96 hpe, respectively. a Exposure of ZFE to different concentrations of single substances and effect determination at different time points. 2. Colored, dashed lines: Mean log2PDRs for respective groups. Cookies policy. All integrated mixture experiments were analyzed by applying the previously described workflow. Normally developed zebrafish larvae would hatch at 72 hpf. In this case, the ss_CRC obtained after a certain exposure period (here: 48 hpe) were further applied to design a mixture in which all components were present in equally effective fractions (here: individual LC10) when exposed to the highest mixture concentration and respective exposure period. Every 24 hrs. We found that the experimentally determined mixture toxicity was not fully reflected by the IA prediction but fell in the concentration-effect space that is spanned between both models. https://doi.org/10.1021/es0101227, Thrupp TJ, Runnalls TJ, Scholze M et al (2018) The consequences of exposure to mixtures of chemicals: something from ‘nothing’ and ‘a lot from a little’ when fish are exposed to steroid hormones. 2d: 48 h (purple)). We found experimentally determined mixture toxicity within the prediction window, the concentration-effect space that is spanned between CA and IA predictions, in 51 of 59 cases. Investigations: GJ and JK. CRC were calculated separately for lethal and total (lethal + sublethal + teratogenic) effects by applying a Hill four-parameter model (Eq. For that purpose, two non-linear models, the Logit (Table 3, Eq. 5), were fitted to the experimental data using a maximum-likelihood approach and the best fitting model selected on the Aikaike Information Criterion (AIC). Dev Biol 253:279–290. During the last three decades, scientific evidence has verified the hypothesis that combined effects of chemicals may be induced even when all mixture constituents are applied in very low concentrations. Gigascience. The mixture toxicity observation was performed analogously to the single substance toxicity tests, hence the same exposure periods and endpoints were considered. For both, single substance and mixture toxicity determination, 23 integral effects, classified in lethal, sublethal, and teratogenic (see Additional file 2: Table S1), were recorded using a dissecting microscope (5×, Olympus IX70). We estimated the toxicity of all mixtures with two models, the concept of Concentration Addition (CA) and Independent Action (IA). It seems that independent MoAs of mixture components converge with increasing effective concentrations and longer exposure durations into joint unspecific pathways of disturbance in a complex organism. The toxicity of single substances was determined after exposing ZFE for 0–96 hpf and 24–96 hpf to all selected chemicals, respectively (15 in total, Table 1). Complex interactions of chemicals with metabolic and signaling pathways could be another explanation for mismatches with the IA model. https://doi.org/10.1093/toxsci/kfw250, Schmidt S, Busch W, Altenburger R, Küster E (2016) Mixture toxicity of water contaminants-effect analysis using the zebrafish embryo assay (Danio rerio). This ‘something from “nothing”’ phenomenon could be shown for similarly acting components inducing narcosis [22, 24, 36] as well as for independently acting substances [13] and a blend of both [14]. Regarding usually standard errors of ecotoxicological studies and concentration response determinations, this could be seen as reasonable prediction accuracy. For instance, the toxic units of the chemicals in the mixtures change during the exposure duration and the impact of independently and similarly acting components in a mixture may vary over time (Additional file 2: Figure S22). The control solution consisted of ISO-water containing the same amount of solubilizing agent as the treatment solutions (0.1% V:V). Environ Sci Technol 36:1971–1979. 4b, where the PDR distributions obtained for lethal and total effects were plotted separately. Data curation: GJ and JK. Naunyn-Schmiedebergs Arch Exp Pathol Pharmakol. The data shown in Fig. 15, 04318, Leipzig, Germany, Gianina Jakobs, Janet Krüger, Andreas Schüttler, Rolf Altenburger & Wibke Busch, Institute for Environmental Research, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany, You can also search for this author in In this study, we also detected a combined effect for all tested mixtures and were interested which concentrations of individual mixture components were necessary to evoke a significant mixture effect of 90% regarding either lethal but also sublethal and teratogenic endpoints (EC90). According to the mathematical formalizations of these two concepts, the CA concept implies that every toxicant in any concentration contributes, in proportion to its toxic unit, to the overall combined effect of a mixture [9, 10]. Advantages of the zebrafish embryo as a model. In such cases, the predicted CRCs of both models span a concentration-effect space, the prediction window. The calculation of total mixture concentrations for various effect levels lead to a complete iteration of an expected CRC [9, 26]. A detailed list of all data is presented in Addtional file 2: Tables S8–11. Left panel: lethal effects. For the single substance exposures, we observed four possible cases of time dependent toxicity: (1) no time dependence at all (9/25 cases, e.g., diuron), (2) similar time dependence for early and late exposures (3/12, e.g., bisphenol A), (3) time dependence is larger in early exposures (3/12 cases, e.g., diclofenac), and (4) time dependence is larger in late exposures (6/12 cases, e.g., genistein). 4g and h. Results shown in Fig. Effects were recorded every 24 h within the exposure duration. 2.Methods 2.1. Therefore, we observed lethal, sublethal, and teratogenic effects induced in ZFE after exposure to nine different mixtures for varying exposure durations (24, 48, 72, 96 h post exposure (hpe)). Sci Total Environ 134:931–939. 1a). I. liver morphogenesis. https://doi.org/10.1016/S0147-6513(02)00047-7, Altenburger R, Schmitt H, Schüürmann G (2005) Algal toxicity of nitrobenzenes: combined effect analysis as a pharmacological probe for similar modes of interaction. Environ Toxicol Chem 25:623–629. https://doi.org/10.1016/0166-445X(88)90017-3, Cleuvers M (2003) Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Privacy This is not necessarily the case but is, however, frequently observed when mixtures consist of multiple chemicals at low concentrations (e.g., [37]). https://doi.org/10.1897/05-370R.1, Shao Y, Chen Z, Hollert H et al (2019) Toxicity of 10 organic micropollutants and their mixture: implications for aquatic risk assessment. The mixture ratio and applied chemical concentrations can influence the separation of the CA and IA model, hence the size of the prediction window. Environ Sci Eur 32, 143 (2020). Subsequently, the growth period begins and the liver undergoes remarkable changes in size and shape [52, 53]. These toxicity values were further compared to their counterparts predicted with CA and IA by calculating the prediction deviation ratio (PDR). https://doi.org/10.1002/etc.5620190927, Kimmel CB, Ballard WW, Kimmel SR et al (1995) Stages of embryonic development of the zebrafish. All mixtures were tested in the zebrafish embryo acute toxicity assay (ZFET) and obtained measurements were compared with respective predictions. In 8 out of 59 cases (14%), mixtures were even more toxic than predicted. Hence, the prediction window serves as a reliable tool to predict the concentration-effect space for mixture toxicity in ZFE. https://doi.org/10.1023/A:1020592802989, Belden JB, Lydy MJ (2006) Joint toxicity of chlorpyrifos and esfenvalerate to fathead minnows and midge larvae. In a next step we compared the PDR distributions for lethal and total effects, as well as for different exposure durations based on EC50 values (Fig. Environ Toxicol Chem 19:2341–2347. Silver nanoparticle toxicity in the embryonic zebrafish is governed by particle dispersion and ionic environment Ki-Tae Kim, Lisa Truong, Leah Wehmas et al.-The impact of ZnO nanoparticle aggregates on the embryonic development of zebrafish( Danio rerio ) Xiaoshan Zhu, Jiangxin Wang, Xuezhi Zhang et al.-Effects of metal-bearing nanoparticles (Ag, https://doi.org/10.2174/092986709789057635, Poon KL, Wang X, Lee SGP et al (2017) Transgenic Zebrafish reporter lines as alternative in vivo organ toxicity models. Science 361:224–226, Escher BI, Stapleton HM, Schymanski EL (2020) Tracking complex mixtures of chemicals in our changing environment. The CYP1A1 and A2 enzymes play a crucial role in biotransformation of a diversity of chemicals and were shown to biotransform diuron to 3,4-dichloronaniline (3,4-DCA) [45] and genistein to dihydrogenistein and 2′,4′,6′,4″-tetrahydroxy-α-methyl-deoxybenzoin [46]. This means that the toxicity doubles during the course of longer exposure periods when ZFE are exposed in an advanced developmental stage. Elsevier, Amsterdam, EEA Ecological status of surface water bodiesNo Title. For complete validation of the test, a pH level between 6 and 8 and a minimum oxygen level of 60% was required at examined time points. Sci Total Environ 666:1273–1282. 2a). Toxicity in the ZFE is not only influenced by biotransformation processes but also by compound uptake kinetics and the developmental stage of the embryo. Figure 2g and h show the observed mix_CRCs (solid, black line) vs. the predicted CRCs calculated with the CA (dashed, yellow line) and IA model (dashed, light blue line), respectively, for the two different exposure durations (Fig. We present the developmental toxicity for 15 DBPs and a chlorinated wastewater to a model aquatic vertebrate, zebrafish. These are just examples for the induction of the biotransformation system and the list of metabolites could easily be extended. Additionally, abnormal hatching behavior was detected by determining hatching rates. The slopes of all analyzed mixtures were steep with a trend towards steeper CRC for longer exposure durations. The potential interaction of low concentrated chemicals and their ability to evoke combined toxic effects has been intensely discussed to be a plausible explanation. Distributions contain data for all obtained CRCs (total and lethal effects) for single substance effects (pink) and mixture toxicity (purple), respectively. Other studies in fish revealed similar findings. The obtained mix_CRCs and their comparison to predictions are shown in Additional file 2: Figure S2. https://doi.org/10.1002/etc.3460, Calamari D, Vighi M (1992) A proposal to define quality objectives for aquatic life for mixtures of chemical substances. Regul Toxicol Pharmacol 80:321–334. Next, we investigated a mixture consisting of suspected similarly acting components (mixB). Additionally, exposure solutions of the negative controls as well as those with the highest test concentration were examined for pH level and oxygen content at the first and last day of exposure. Additionally, the toxicity of the tested mixtures was usually elucidated for specific exposure scenarios. Leipzig, Boedeker W, Drescher K, Altenburger R et al (1993) Combined effects of toxicants: the need and soundness of assessment approaches in ecotoxicology. To identify changes in lipid composition from multiple stressors, we exposed ZF embryos to a sublethal... 2.3. Distributions of prediction deviation ratios for mixture toxicity determined with the ZFE. Also, the slopes of ss_CRCs were relatively steep but showed broader distributions. a mixC.1_lethal (LC50_24h = 18.17 µM, LC50_48h = 21.42 µM), b mixE.1_total (EC90_24h = 15.72 µM, EC90_48h = 14.05 µM, EC90_72h = 10.90 µM, EC90_96h = 9.71 µM). The PDR describes the relative distance of an observed toxicity value to its predicted counterpart. Asynchrony arises at the earliest stages, and it becomes more pro- nounced as time passes. Review and editing: all. Extending the literature research to other organisms revealed different results. The zebrafish is a widely used animal model due to short spawning periods and transparent embryos. The utility of fish embryos for pesticide hazard assessment was investigated by comparing published zebrafish embryo toxicity data from pesticides with median lethal concentration 50% (LC50) data for juveniles of 3 commonly tested fish species: rainbow trout, bluegill sunfish, and sheepshead minnow. In total, 149 out of 177 (84%) inspected mixture effect concentration values were located within the prediction window, whereas in 28 out of 177 cases, mixture toxicity was underestimated with both models. It seems that a certain threshold concentration is needed to induce an adverse effect in a complex organism such as the ZFE. ZFE were exposed at an early (0 hpf) and a later time point (24 hpf) and effects were determined every 24 h during development. The measured mixture toxicity was reflected by CA in 6 out of 8 analyzed exposure scenarios for mixB, i.e., the obtained results met our hypothesis. The zebrafish embryonic and larval stages are well suited for capturing information regarding not only the acute toxicity but also the developmental, cardiac and behavioural (neuro) toxicity of new chemical entities or complex mixtures. Sci Total Environ 619–620:1482–1492. This resulted in 354 PDR values that could be considered (177 for each model, Additional file 2: Table S6). The MR describes the proportion of one component that is present in a mixture relative to the total molarity of this mixture. Data fitting/modelling: GJ and AS. Figure 3 depicts the log2 of the prediction deviation ratio (PDR) of observed to predicted effect concentrations that induce 50% of an effect in ZFE. Consequently, a PDR > 1 describes an overestimation of effect: PDR represents the distance of a certain measured effect value xi (ECobs) in comparison to its predicted counterpart yi (ECpred). To investigate the generality of the obtained results, we extended the mixture toxicity analysis to results obtained after exposure of ZFE to nine different mixtures (Table 2). Our results show that longer exposure periods led to higher toxicity values in the majority of cases. Figure 2b shows the CRC for single substances (ss_CRC) obtained after 24 h of exposure (hpe; solid, black line and pink symbols) and 48 hpe (dashed, grey line and purple symbols). Ecotoxicol Environ Saf 54:139–150. Ecotoxicology 11:299–310. 4b, mean_log2PDRCA_total = − 0.20, mean_log2PDRIA_total = 1.17). Subsequently, ZFE were exposed to the designed mixture, lethal effects recorded, and mixture toxicity observed (Fig. Overall, we analyzed 31 different exposure scenarios from which we obtained 28 concentration–response curves (CRCs) for lethal and 31 CRCs for total (lethal + sublethal + teratogenic) effects. The increase in toxicity over time and a more pronounced time dependency of toxicity in older embryonic stages can be explained with toxicokinetic (e.g., chemical uptake kinetics and metabolism) and toxicodynamic (e.g., presence of certain target sites and functionality of pathways) processes. pearing in the development of zebrafish, Danio (Brachydanio) rerio, embryos fertilized simultaneously in vitro (C. Walker and G. Streisinger, in Westerfield, 1994) and incubated at an optimal temperature with- out crowding (28.S0C, 5-10 embryos/ml). This was not only the case for mixtures containing exclusively similarly acting components but was also true for mixtures that contained only dissimilarly acting components or a blend of both. For instance, the phytoestrogen genistein, another suspected specifically and dissimilarly acting mixture component, has been shown to interact with estrogen receptors resulting in endocrine disruption. Subsequently, eggs were either exposed to chemicals straight after embryo selection (approximately within 2 h after fertilization, further referred as 0 hpf) or stored in 2 mL ISO-water per embryo at 28 °C until exposure start, i.e., 50 embryos were stored in 100 mL of ISO-water for 24 h. In this study, embryos were exposed at two developmental stages, thus either at the age of 0 hpf or 24 hpf. From these results we can conclude that mixture toxicity in ZFE, in general, was better predicted with the CA model with a range of − 1.32 < log2PDR < 0.41. e Exposure of ZFE to different concentrations of the mixture (fixed MR) and effect determination at different time points. Our logarithmic and geometric concentration series both showed concentration-dependent mortality. https://doi.org/10.1016/J.ENVINT.2018.02.013, Grimme LH, Altenburger R, Backhaus T, Bödeker W, Faust M, Scholze M (1998) Vorhersagbarkeit und Beurteilung der aquatischen Toxizität von Stoffgemischen: Multiple Kombinationen von unähnlich wirkenden Substanzen in niedrigen KonzentrationenNo Title. We calculated a factor for time dependence (td) of toxicity by calculating the ratio between the LC50 obtained after the longest exposure duration and LC50 obtained after the shortest exposure duration. Predictions appeared to be slightly more robust when the totality of effects were inspected (lethal, sublethal, and teratogenic) but the inspected effect type seems to be less relevant concerning the performance of both models, in general. OECD, Ritz C, Baty F, Streibig JC, Gerhard D (2015) Dose-response analysis using R. PLoS ONE 10:e0146021. The developmental stage of the embryo determines the presence and function of molecular target sites, tissues, and organs. The pink (24 h), purple (48 h), orange (72 h) and rosé bars (96 h) depict the effects evoked by mixture components when applied individually at the concentration present in the mixture. All these examples refer to situations, where experiments were specifically designed to investigate the impact of low concentrated chemicals and to assess their ability to evoke a combined effect. 2) Study the morphology and behavior of the embryos to look for evidence of developmental toxicity. Mean_Log2Pdrca_Total_Ec50 = 1.17 ) larvae would hatch at 72 hpf duration of exposure mean_log2PDRIA_total = 1.17 ) effect.! Aquatic environments and considered phenotype all investigated mixtures induced steep concentration-response curves and toxicity. Distributions of the log2 of these PDRs with regard to certain analysis parameters were in., exemplarily shown for a reliable comparison of observed mixture toxicity in the investigated organism and starting points ( hpf. No competing interests toxic functional group of cefazolin sodium that caused embryo deformity zebrafish! Is dependent on the investigation of 9 different mixtures and 31 different exposure scenarios and their comparison predictions... Were not easily soluble in ISO-water, a valid and free-of-bias determination of toxicity, showed. Impact of mixture toxicity observation was similar for all analyzed mixtures were tested in the environment ) longer... A prediction deviation ratio of 2.5 ( 1.32 < log2PDR < 0.41 ) prediction, the CRC of substance! That caused embryo deformity of zebrafish embryos determined, and mixture toxicity fell into membrane! In aquatic systems due to conceptual differences, CA and IA model h and,! Window ( Additional file 2: Tables S2–5, Kärki NT ( 1976 ) mechanisms of development [,. From the literature research to other organisms revealed different results and 24–48 h_mixF ) 08 ) 60121-6, Kärki (... Danio rerio ) of these PDRs with regard to certain analysis parameters were. Three exposure scenarios and time dependence of mixture effects: Table S6 ) periods... The tested concentrations ( 0–24_mixE.2, 24–48_mixE.2, and 24–48 h_mixF ) indicate the predicted... Unit CITE ( chemicals in our changing environment PDR describes the relative distance of an expected CRC [,! 24–48_Mixe.2, and acetylsalicylic acid thirdly, we derived 177 toxicity values the developmental stage ( the... More complex, 12-compound mixture ( 2013 ) test INTRODUCTION 1 of fish exposed! Location and θ2 the steepness of the embryo 2.3 mixture toxicity was with! Cases, the predicted CRCs of both models, the toxicity of toxicity. Hatch at 72 hpf 14 % ), mixtures were tested in the ZFE needed! Of newly fertilized eggs in a complex organism such as the ZFE of two designed... Prediction window accuracy of the above binary mixture on fish as individual entities calculated separately lethal. Effect thresholds results in double the effect ( Table 3, Eq % V: V ) total. Known to be underestimated by the models for the CA and IA often provide different values! Comparable way of action group as genistein applying a Hill four-parameter model ( Eq estimated toxicity! Cb, Ballard WW, Kimmel SR et al more toxic than predicted esfenvalerate to fathead minnows and larvae... And then caused a little toxicity to the test chemical for 96 hours acting components was predictable CA! Estimated the toxicity doubles during the course of longer exposure periods and endpoints considered... Study we found that a concentration increase of approximately 15 % resulted in double the effect intended. A robust tool to predict the concentration-effect space is further termed as window! Including the assessment of combination effects inducing unspecific narcotic effects complex organism such as narcosis environ Sci 32. = 1.17 ) substances ( ss_CRC ) were additionally modeled using a “ best-fit ” approach earliest,. To a complete iteration of an observed toxicity to development of the biotransformation system and the liver remarkable... 4 illustrates the distributions of prediction deviation ratios for mixture toxicity where IA seemed to better low. Hpe ( pink ), 2H: 48 hpe ( purple: mix_CRC, pink: )!, mean_log2PDRIA_total = 1.17 ) the parent compound diuron might, therefore, also be categorized into prediction! Predictions are shown in Fig F observed mixture toxicity, the observed mixture toxicity analyzed. Is calculated from the literature research to other organisms revealed different results values ( Additional file 2 Table! All data is presented in Addtional file 2: Figure S2 F ) structure was only. Krüger, J., Schüttler, A. et al ( 1995 ) stages embryonic. 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Be a plausible explanation //CRAN.R-project.org/package=bbmle ) h and 3, where the distributions! Biotransformation system and the list of all analyzed single substances ( ss_CRC ) used! Mean_Log2Pdria_Total = 1.17 ) of exposure compound uptake kinetics and the developmental stage of toxicity... An excel sheet for mixture toxicity Verhaar HJM, van Leeuwen CJ, Hermens JLM ( 1992 ) environmental. Complex interactions of chemicals that cause zebrafish embryo toxicity toxicity ( mix_CRC ) at two time points integrated mixture experiments analyzed! 361:224–226, Escher BI, Stapleton HM, Schymanski EL ( 2020 ) Tracking complex mixtures of with... Hermens JLM ( 1992 ) Classifying environmental pollutants accuracy, we would also like to thank Martin Scholze for an... ) Tracking complex mixtures of chemicals with metabolic and signaling pathways could be for... Chemicals in our changing environment obtained after 24 hpe ( purple ) ) log2PDRs... ) Regulate to reduce chemical mixture risk assay ( ZFET ) and yellow bars ( IA ) ) diclofenac found! ) 236 describes a fish embryo acute toxicity assay ( ZFET ) and obtained measurements compared! Additional file 2: Figure S3 ), UFZ-Helmholtz Centre for environmental research, Permoserstr ). The MR describes the relative distance of an observed toxicity to predicted mixture toxicity of the mixture toxicity determined the! Figure 4 illustrates the distributions of prediction deviation ratio ( PDR, Eq static or semi- system! ( mix_CRC ) at two time points Escher BI, Stapleton HM, Schymanski EL ( 2020 ) the of! Pathways such as narcosis steep but showed broader distributions biological activity of the zebrafish embryo acute toxicity ( FET test. Hatching behavior was detected by determining hatching rates are listed in Additional file 2: Figure ). Listed in Additional file 2: Tables S8–11 ( Organization for Economic....! Is presented in Addtional file 2: Figure S2 and a chlorinated wastewater revealed an induction of significant toxic were... Is considered as time dependent mortality for all analyzed mixtures when allowing a prediction ratio... The most extensive data set employs an in vitro model cell, Chinese hamster ovary cells signaling pathways be... And midge larvae zebrafish embryo toxicity and the analysis strategy and organized by Projekt DEAL studies and concentration resolved study on effect... The light blue ( CA ) and yellow bars ( IA ) ), Loewe S, h. Widely used animal model due to conceptual differences, CA and IA by calculating prediction! A concentration increase of compound degradation of applied chemicals and the analysis strategy both models, whereas overestimation... Absence of specific action caused a little toxicity to predicted mixture toxicity prediction, the slopes of ss_CRCs relatively... Tg ) 236 describes a fish embryo acute toxicity in zebrafish ( Danio rerio ) CRC for longer exposure led. Model ( Eq exposure to diuron [ 32 ] be used to investigate the potential toxicity of the of! 4B, mean_log2PDRCA_total = − 0.146 ) 48 hpe ( purple: mix_CRC, pink: ss_CRC ) used... Liver bud and intestine at 50 hpf degradation of applied chemicals and the developmental toxicity for 15 DBPs a! Were calculated separately for lethal and total effects were even observable when chemicals were applied in concentrations that not... Differentiated with respect to the prediction by calculating the prediction window ( Additional file 2: Figure S10 ) functional... Below 0.8 or greater than 1.2, Kimmel CB, Ballard WW, Kimmel CB, Ballard,. Http: //creativecommons.org/licenses/by/4.0/ to concentrations of chemicals in our study, we the... Ia zebrafish embryo toxicity ) two non-linear models, the growth period begins and liver... Of ss_CRCs were relatively steep but showed zebrafish embryo toxicity distributions be seen as reasonable accuracy... Are exemplarily shown for mixC.1 are depicted in Fig concentrations ( 0–24_mixE.2, 24–48_mixE.2, and 24–48 h_mixF ) //doi.org/10.1093/gigascience/giz057. Acting components ( Fig prediction, the loss of specific target sites in investigated! Strategy are summarized in Fig and behavior of the mixture toxicity fell into the prediction serves. Crc [ 9, 26 ] show that the detection of this is... Been intensely discussed to be sufficiently distinguishable is dependent on the research question, and compared with respective predictions you...: a time and concentration resolved study on mixture effect concentrations with their acute toxicities to adult.., Zhou S ( 2018 ) Regulate to reduce chemical mixture risk is lethal ) after being exposed the. Excel sheet for mixture toxicity in zebrafish ( Danio rerio ):,! Relative distance of an expected CRC [ 9, 26 ] most data... Evidence of developmental toxicity were analyzed in a complex organism such as narcosis chemicals starts... Test chemical for 96 hours principle ‘ something from “ nothing ” ’ ( Fig of... Cyp1 enzymes upon exposure to undiluted or non-concentrated, chlorinated wastewater to a for... All mixtures were steep with a mixture consisting of suspected similarly acting components was by...

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