scholarly journals Mixture toxicity analysis in zebrafish embryo: a time and concentration resolved study on mixture effect predictivity

2020 ◽  
Vol 32 (1) ◽  
Author(s):  
Gianina Jakobs ◽  
Janet Krüger ◽  
Andreas Schüttler ◽  
Rolf Altenburger ◽  
Wibke Busch
Keyword(s):  
Exposure Duration ◽  
Prediction Accuracy ◽  
Mixture Toxicity ◽  
Concentration Addition ◽  
Short Term ◽  
Response Curves ◽  
Low Concentrations ◽  
Short Term Exposure ◽  
Deviation Factor ◽  
Ca Model

Abstract Background Humans and wildlife are continuously exposed to chemical mixtures. These mixtures vary in composition but typically contain hundreds of micropollutants at low concentrations. As it is not feasible to measure the toxicity of all possibly occurring mixtures, there is a need to predict mixture toxicity. Two models, Concentration Addition (CA) and Independent Action (IA), have been applied to estimate mixture toxicity. Here, we compared measured with predicted toxicity of nine mixtures designed from 15 environmentally relevant substances in zebrafish embryos to investigate the usability of these models for predicting phenotypic effects in a whole organism short term acute assay. Results In total, we compared 177 toxicity values derived from 31 exposure scenarios with their predicted counterparts. Our results show that mixture toxicity was either correctly estimated (86%) by the prediction window, the concentration-effect space that is spanned between both models, or was underestimated with both models (14%). The CA model correctly predicted the measured mixture toxicity in 100% of cases when a prediction deviation factor of 2.5 was allowed. However, prediction accuracy of mixture toxicity prediction was dependent on exposure duration and mixture potency. The CA model showed highest prediction quality for long-term exposure with highly potent mixtures, respectively, whereas IA proved to be more accurate for short-term exposure with less potent mixtures. Obtained mixture concentration–response curves were steep and indicated the occurrence of remarkable combined effects as mixture constituents were applied at concentrations below their respective individual effect threshold in 90% of all investigated cases. Conclusions Experimental factors, such as exposure duration or mixture potency, influence the prediction accuracy of both inspected models. The CA model showed highest prediction accuracy even for a set of diverse mixtures and various exposure conditions. However, the prediction window served as the most robust predicator to estimate mixture toxicity. Overall, our results demonstrate the importance of considering mixture toxicity in risk assessment schemes and give guidance for future experiment design regarding mixture toxicity investigations.

scholarly journals Novel Segmented Concentration Addition Method to Predict Mixture Hormesis of Chlortetracycline Hydrochloride and Oxytetracycline Hydrochloride to Aliivibrio fischeri

2020 ◽  
Vol 21 (2) ◽  
pp. 481 ◽  
Author(s):  
Huilin Ge ◽  
Min Zhou ◽  
Daizhu Lv ◽  
Mingyue Wang ◽  
Defang Xie ◽  
...  
Keyword(s):  
Mixture Toxicity ◽  
Practical Significance ◽  
Concentration Addition ◽  
High Concentration ◽  
Cross Point ◽  
Antagonistic Action ◽  
Interval Method ◽  
Molar Ratios ◽  
Ca Model ◽  
Aliivibrio Fischeri

Hormesis is a concentration-response phenomenon characterized by low-concentration stimulation and high-concentration inhibition, which typically has a nonmonotonic J-shaped concentration-response curve (J-CRC). The concentration addition (CA) model is the gold standard for studying mixture toxicity. However, the CA model had the predictive blind zone (PBZ) for mixture J-CRC. To solve the PBZ problem, we proposed a segmented concentration addition (SCA) method to predict mixture J-CRC, which was achieved through fitting the left and right segments of component J-CRC and performing CA prediction subsequently. We selected two model compounds including chlortetracycline hydrochloride (CTCC) and oxytetracycline hydrochloride (OTCC), both of which presented J-CRC to Aliivibrio fischeri (AVF). The seven binary mixtures (M1–M7) of CTCC and OTCC were designed according to their molar ratios of 12:1, 10:3, 8:5, 1:1, 5:8, 3:10, and 1:12 referring to the direct equipartition ray design. These seven mixtures all presented J-CRC to AVF. Based on the SCA method, we obtained mixture maximum stimulatory effect concentration (ECm) and maximum stimulatory effect (Em) predicted by SCA, both of which were not available for the CA model. The toxicity interactions of these mixtures were systematically evaluated by using a comprehensive approach, including the co-toxicity coefficient integrated with confidence interval method (CTCICI), CRC, and isobole analysis. The results showed that the interaction types were additive and antagonistic action, without synergistic action. In addition, we proposed the cross point (CP) hypothesis for toxic interactive mixtures presenting J-CRC, that there was generally a CP between mixture observed J-CRC and CA predicted J-CRC; the relative positions of observed and predicted CRCs on either side of the CP would exchange, but the toxic interaction type of mixtures remained unchanged. The CP hypothesis needs to be verified by more mixtures, especially those with synergism. In conclusion, the SCA method is expected to have important theoretical and practical significance for mixture hormesis.

scholarly journals Mixture toxicity of six pharmaceuticals towards Aliivibrio fischeri, Daphnia magna, and Lemna minor

2021 ◽  
Author(s):  
Anna Białk-Bielińska ◽  
Łukasz Grabarczyk ◽  
Ewa Mulkiewicz ◽  
Alan Puckowski ◽  
Stefan Stolte ◽  
...  
Keyword(s):  
Daphnia Magna ◽  
Lemna Minor ◽  
Opioid Analgesic ◽  
Mixture Toxicity ◽  
Concentration Addition ◽  
Case Scenario ◽  
Worst Case ◽  
Ca Model ◽  
Inflammatory Drugs ◽  
Aliivibrio Fischeri

AbstractAs the knowledge on the joint effects of pharmaceuticals towards different non-target organisms is still limited, the aim of our study was to evaluate the toxicity of mixtures of pharmaceuticals, as well as their baseline toxicity towards three selected organisms, namely the bioluminescent bacteria Aliivibrio fischeri, the crustacean Daphnia magna, and the duckweed Lemna minor. Different mixtures composed of three up to five pharmaceuticals having the same or different mechanisms of action in terms of their therapeutic activity (non-steroidal anti-inflammatory drugs, opioid analgesic, antibacterial and anti-epileptic drugs) were investigated. The observed EC50s were compared with those predicted using the concentration addition (CA) and independent action (IA) models. In general, the EC50 values for mixtures predicted with the CA model were lower than those obtained with the IA model, although, in some cases, test predictions of these two models were almost identical. Most of the experimentally determined EC50 values for the specific mixtures were slightly higher than those predicted with the CA model; hence, a less than additive effect was noted. Based on the obtained results, it might be concluded that the CA model assumes the worst-case scenario and gives overall closer predictions; therefore, it should be recommended also for modeling the mixture toxicity of pharmaceuticals with different modes of action.

Short-term exposure to low concentrations of copper oxide nanoparticles can negatively impact the ecological performance of a cosmopolitan freshwater fungus

2019 ◽  
Vol 21 (12) ◽  
pp. 2001-2007 ◽  
Author(s):  
Sahadevan Seena ◽  
Santosh Kumar
Keyword(s):  
Copper Oxide ◽  
Copper Oxide Nanoparticles ◽  
Oxide Nanoparticles ◽  
Short Term ◽  
Ecological Processes ◽  
Cuo Nps ◽  
Ecological Performance ◽  
Low Concentrations ◽  
Short Term Exposure ◽  
Freshwater Fungus

Short term exposure to very low concentrations of CuO NPs can have an impact on freshwater ecological processes.

Short-term exposure to low concentrations of the synthetic androgen methyltestosterone affects vitellogenin and steroid levels in adult male zebrafish (Danio rerio)

2006 ◽  
Vol 76 (3-4) ◽  
pp. 343-352 ◽  
Author(s):  
Lene Andersen ◽  
Rie Goto-Kazeto ◽  
John M. Trant ◽  
Jon P. Nash ◽  
Bodil Korsgaard ◽  
...  
Keyword(s):  
Adult Male ◽  
Danio Rerio ◽  
Short Term ◽  
Low Concentrations ◽  
Short Term Exposure

scholarly journals Restoration of endothelin-1-induced impairment in endothelium-dependent relaxation by interleukin-10 in murine aortic ringsThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.

2008 ◽  
Vol 86 (8) ◽  
pp. 557-565 ◽  
Author(s):  
Saiprasad M. Zemse ◽  
Rob H.P. Hilgers ◽  
G. Bryan Simkins ◽  
R. Daniel Rudic ◽  
R. Clinton Webb
Keyword(s):  
Endothelial Dysfunction ◽  
Immunohistochemical Analysis ◽  
Interleukin 10 ◽  
Enos Expression ◽  
Short Term ◽  
Response Curves ◽  
Endothelin 1 ◽  
Short Term Exposure ◽  
Endothelium Dependent Relaxation ◽  
Antiinflammatory Cytokine

Endothelin-1 (ET-1) is implicated in the development of endothelial dysfunction through the generation of reactive oxygen species by NADPH oxidase activation. Interleukin-10 (IL-10) is an antiinflammatory cytokine that stimulates nitric oxide production, decreases superoxide production, and restores endothelial integrity after vascular injury. In this study, we tested whether IL-10 attenuates ET-1-induced endothelial dysfunction by improving acetylcholine (ACh)-induced relaxation of cultured murine aortic rings. Aortic rings (2 mm long) of C57BL/6 mice were incubated in 2 mL DMEM containing 120 U/mL penicillin and 120 μg/mL streptomycin in the presence of one of 4 treatments: vehicle (deionized water), ET-1 (100 nmol/L), recombinant mouse IL-10 (300 ng/mL), or a combination of both ET-1 and IL-10. After incubation at 37 °C for either 1 or 6 h (short-term exposure) or 22 h (overnight exposure), rings were mounted in a wire myograph and stretched to a passive force of 5 mN. Endothelium-dependent vasorelaxation was assessed by constructing cumulative concentration–response curves to ACh (0.001–10 μmol/L) during 10 μmol/L phenylephrine (PE)-induced contraction. Short-term exposure of ET-1 did not result in an impairment of ACh-induced relaxation. Overnight exposure of aortic rings to ET-1 resulted in a statistically significant endothelial dysfunction characterized by a reduced maximal relaxation response to ACh compared with that of untreated rings (Emax 57% ± 3% versus 82% ± 4%). IL-10 treatment restored ACh-induced relaxation (Emax 77% ± 3%). Western blotting showed decreased eNOS expression in response to ET-1, whereas vessels treated with a combination of ET-1 and IL-10 showed increased expression of eNOS. Immunohistochemical analysis showed decreased eNOS expression in ET-1-treated vessels compared with those treated with both ET-1 and IL-10. We conclude that, in murine aorta, the antiinflammatory cytokine IL-10 prevents impairment in endothelium-dependent relaxation induced in response to long-term incubation with ET-1 via normalization of eNOS expression.

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