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.

scholarly journals New Insight Regarding the Relationship Between Enantioselective Toxicity Difference and Enantiomeric Toxicity Interaction from Chiral Ionic Liquids

2019 ◽  
Vol 20 (24) ◽  
pp. 6163 ◽  
Author(s):  
Huilin Ge ◽  
Min Zhou ◽  
Daizhu Lv ◽  
Mingyue Wang ◽  
Cunzhu Dong ◽  
...  
Keyword(s):  
Ionic Liquids ◽  
Environmental Science ◽  
Practical Significance ◽  
Concentration Addition ◽  
Chiral Molecules ◽  
Equimolar Ratio ◽  
Chiral Ionic Liquids ◽  
Molar Ratios ◽  
Additive Action ◽  
Toxicity Analysis

Chirality is an important property of molecules. The study of biological activity and toxicity of chiral molecules has important theoretical and practical significance for toxicology, pharmacology, and environmental science. The toxicological significance of chiral ionic liquids (ILs) has not been well revealed. In the present study, the enantiomeric joint toxicities of four pairs of chiral ILs 1-alkyl-3-methylimidazolium lactate to Allivibrio fischeri were systematically investigated by using a comprehensive approach including the co-toxicity coefficient (CTC) integrated with confidence interval (CI) method (CTCICI), concentration-response curve (CRC), and isobole analysis. The direct equipartition ray (EquRay) design was used to design five binary mixtures of enantiomers according to molar ratios of 1:5, 2:4, 3:3, 4:2, and 5:1. The toxicities of chiral ILs and their mixtures were determined using the microplate toxicity analysis (MTA) method. Concentration addition (CA) and independent action (IA) were used as the additive reference models to construct the predicted CRC and isobole of mixtures. On the whole, there was an enantioselective toxicity difference between [BMIM]D-Lac and [BMIM]L-Lac, and [HMIM]D-Lac and [HMIM]L-Lac, while no enantioselective toxicity difference was observed for [EMIM]D-Lac and [EMIM]L-Lac, and [OMIM]D-Lac and [OMIM]L-Lac. Thereinto, the enantiomer mixtures of [BMIM]D-Lac and [BMIM]L-Lac, and [HMIM]D-Lac and [HMIM]L-Lac presented antagonistic action, and the enantiomer mixtures of [EMIM]D-Lac and [EMIM]L-Lac, and [OMIM]D-Lac and [OMIM]L-Lac overall presented additive action. Moreover, the greatest antagonistic toxicity interaction occurred at the equimolar ratio of enantiomers. Based on these results, we proposed two hypotheses, (1) chiral molecules with enantioselective toxicity difference tended to produce toxicity interactions, (2) the highest or lowest toxicity was usually at the equimolar ratio and its adjacent ratio for the enantiomer mixture. These hypotheses will need to be further validated by other enantiomer mixtures.

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.

Analysis of efficiency of application of media with hyaluronic acid in cryoprotocols

GYNECOLOGY ◽  
2020 ◽  
Vol 22 (2) ◽  
pp. 26-29
Author(s):  
Natalia V. Protopopova ◽  
Elena B. Druzhinina ◽  
Kseniia V. Krylova ◽  
Iuliia V. Mylnikova ◽  
Jan A. Dvoryanov ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Pregnancy Rate ◽  
Embryo Transfer ◽  
Culture Medium ◽  
Genetic Diagnosis ◽  
World Health ◽  
Practical Significance ◽  
Pelvic Surgery ◽  
High Concentration ◽  
Tubal Infertility

According to the World Health Organization, about 2 million new couples experience infertility annually, and their number is growing. An effective way to overcome infertility is assisted reproductive technology (ART). Cryopreservation will rationally solve the issue of preservation and further use of embryos: to delay pregnancy for some time considering womans desire and to prevent ovarian hyperstimulation syndrome. Embryo freezing allows to reduce the rate of repeated ovarian stimulation and perform preimplantation genetic diagnosis. Over the past decades, various cryotransfer options have been proposed to increase ART treatment efficacy, including the use of a culture medium with a high concentration of hyaluronic acid, but there are conflicting data on the use of such a medium in ART programs. Aim. Evaluation of thawed embryo transfers efficacy using the hyaluronic acid-containing culture medium. To achieve the goal, the following tasks were set: to evaluate clinical and medical history data of patients with tubal infertility in cryoprotocols, to analyze the previous cycle of in vitro fertilization and embryological stage, to evaluate the effectiveness of the culture medium with a high content of hyaluronic acid. Materials and methods. A detailed description of the patient sample, inclusion and exclusion criteria, embryological stage, embryo grading, devitrified embryo transfer technique. The article includes 3 tables which present the groups general clinical characteristics, the embryological stage, the rate of pregnancy, depending on the cultivation day. Results. The authors established that in patients with a history of pelvic surgery and sexually transmitted infections, it is advisable to use the culture medium with a high content of hyaluronic acid to transfer the thawed embryo. It was shown that pregnancy rate is 1.5 times higher when transferring devitrified embryos on the 5th day of development with the use of hyaluronic acid-containing culture medium. The conclusion about the pregnancy rate in obese patients is not indisputable, which requires further study. The authors also provide practical recommendations on the use of the culture medium with hyaluronic acid in cryoprotocols. Conclusion. The study allows to optimize the devitrified embryo transfer in patients with tubal infertility using a culture medium with a high content of hyaluronan. This work has undoubted scientific and practical significance.

Mixture Effects of 3 Mechanistically Different Steroidogenic Disruptors (Prochloraz, Genistein, and Ketoconazole) in the H295R Cell Assay

2015 ◽  
Vol 34 (6) ◽  
pp. 534-542 ◽  
Author(s):  
Frederik Knud Nielsen ◽  
Cecilie Hurup Hansen ◽  
Jennifer Anna Fey ◽  
Martin Hansen ◽  
Bent Halling-Sørensen ◽  
...  
Keyword(s):  
Cell Line ◽  
Endocrine Disruptors ◽  
Mixture Toxicity ◽  
Concentration Addition ◽  
Mixture Effects ◽  
Modes Of Action ◽  
Cell Assay ◽  
17Β Estradiol ◽  
H295r Cells ◽  
The Individual

Mixture effects of 3 model endocrine disruptors, prochloraz, ketoconazole, and genistein, on steroidogenesis were tested in the adrenocortical H295R cell line. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone, and 17β-estradiol) were analyzed using gas chromatography and tandem mass spectrometry (GC-MS/MS) to investigate the effects throughout the steroidogenic pathway. Current modeling approaches often rely on models assuming compounds acting independently and that the individual effects in some way can be summarized to predict a mixture effect. In H295R cells with an intact steroidogenic pathway, such assumptions may not be feasible. The purpose of this study was therefore to evaluate whether effects of a mixture with differing modes of action followed or deviated from additivity (concentration addition) and whether the H295R cell line was suitable for evaluating mixture toxicity of endocrine disruptors with different modes of action. The compounds were chosen because they interfere with steroidogenesis in different ways. They all individually decrease the concentrations of the main sex steroids downstream but exert different effects upstream in the steroidogenic pathway. Throughout the study, we observed lowest observed effect concentrations of mixtures at levels 2 to 10 times higher than the predicted EC50, strongly indicating antagonistic effects. The results demonstrate that chemical analysis combined with the H295R cell assay is a useful tool also for studying how mixtures of endocrine disruptors with differing modes of action interfere with the steroidogenic pathway and that existing models like concentration addition are insufficient in such cases. Furthermore, for end points where compounds exert opposite effects, no relevant models are available.

The Optimum Arrangement of Working Face Ventilation System for Coal Mine

2012 ◽  
Vol 482-484 ◽  
pp. 1691-1694
Author(s):  
Ning He ◽  
Qiu Ju Ma ◽  
Yu Zhu Shi
Keyword(s):  
Coal Mine ◽  
Ventilation System ◽  
Dynamics Simulation ◽  
Practical Significance ◽  
Gas Migration ◽  
Optimal Layout ◽  
High Concentration ◽  
Working Surface ◽  
Working Face ◽  
Optimum Arrangement

It was most effective and practical that using computational fluid dynamics simulation to analyze the distribution of flow field in gob for studying optimal layout scheme of the working face ventilation system. In this paper, numerical simulation was applied for studying the migration laws and high concentration of gas gathering area of N1201 working face in Tunliu Coal Mine; the gob of robbing working surface gas migration laws and high concentration of gas gathering area was obtained; the optimum arrangement of ventilation system for the working face was given. The conclusions had a certain theoretical value and practical significance for controlling the working face gas.

scholarly journals Acidosis antagonizes intracellular calcium response to κ-opioid receptor stimulation in the rat heart

1999 ◽  
Vol 277 (3) ◽  
pp. C492-C500 ◽  
Author(s):  
Jian-Ming Pei ◽  
Xiao-Chun Yu ◽  
Jin-Song Bian ◽  
Tak-Ming Wong
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Ventricular Myocytes ◽  
High Concentration ◽  
Receptor Stimulation ◽  
Antagonistic Action ◽  
Extracellular Acidosis ◽  
Opioid Receptor Agonist ◽  
Intracellular Ca ◽  
First Time

To study the effects of κ-opioid receptor stimulation on intracellular Ca2+ concentration ([Ca2+]i) homeostasis during extracellular acidosis, we determined the effects of κ-opioid receptor stimulation on [Ca2+]iresponses during extracellular acidosis in isolated single rat ventricular myocytes, by a spectrofluorometric method. U-50488H (10–30 μM), a selective κ-opioid receptor agonist, dose dependently decreased the electrically induced [Ca2+]itransient, which results from the influx of Ca2+ and the subsequent mobilization of Ca2+ from the sarcoplasmic reticulum (SR). U-50488H (30 μM) also increased the resting [Ca2+]iand inhibited the [Ca2+]itransient induced by caffeine, which mobilizes Ca2+ from the SR, indicating that the effects of the κ-opioid receptor agonist involved mobilization of Ca2+ from its intracellular pool into the cytoplasm. The Ca2+responses to 30 μM U-50488H were abolished by 5 μM nor-binaltorphimine, a selective κ-opioid receptor antagonist, indicating that the event was mediated by the κ-opioid receptor. The effects of the agonist on [Ca2+]iand the electrically induced [Ca2+]itransient were significantly attenuated when the extracellular pH (pHe) was lowered to 6.8, which itself reduced intracellular pH (pHi) and increased [Ca2+]i. The inhibitory effects of U-50488H were restored during extracellular acidosis in the presence of 10 μM ethylisopropyl amiloride, a potent Na+/H+exchange blocker, or 0.2 mM Ni2+, a putative Na+/Ca2+exchange blocker. The observations indicate that acidosis may antagonize the effects of κ-opioid receptor stimulation via Na+/H+and Na+/Ca2+exchanges. When glucose at 50 mM, known to activate the Na+/H+exchange, was added, both the resting [Ca2+]iand pHi increased. Interestingly, the effects of U-50488H on [Ca2+]iand the electrically induced [Ca2+]itransient during superfusion with glucose were significantly attenuated; this mimicked the responses during extracellular acidosis. When a high-Ca2+ (3 mM) solution was superfused, the resting [Ca2+]iincreased; the increase was abolished by 0.2 mM Ni2+, but the pHi remained unchanged. Like the responses to superfusion with high-concentration glucose and extracellular acidosis, the responses of the [Ca2+]iand electrically induced [Ca2+]itransients to 30 μM U-50488H were also significantly attenuated. Results from the present study demonstrated for the first time that extracellular acidosis antagonizes the effects of κ-opioid receptor stimulation on the mobilization of Ca2+ from SR. Activation of both Na+/H+and Na+/Ca2+exchanges, leading to an elevation of [Ca2+]i, may be responsible for the antagonistic action of extracellular acidosis against κ-opioid receptor stimulation.

scholarly journals Combined Toxicity of TiO2 Nanospherical Particles and TiO2 Nanotubes to Two Microalgae with Different Morphology

Nanomaterials ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2559
Author(s):  
Zhuang Wang ◽  
Shiguang Jin ◽  
Fan Zhang ◽  
Degao Wang
Keyword(s):  
Binary Mixtures ◽  
Tio2 Nanotubes ◽  
Binary Systems ◽  
Scenedesmus Obliquus ◽  
Mixture Toxicity ◽  
Dispersion Stability ◽  
Concentration Addition ◽  
Combined Toxicity ◽  
Tio2 Nps ◽  
Different Dimensions

The joint activity of multiple engineered nanoparticles (ENPs) has attracted much attention in recent years. Many previous studies have focused on the combined toxicity of different ENPs with nanostructures of the same dimension. However, the mixture toxicity of multiple ENPs with different dimensions is much less understood. Herein, we investigated the toxicity of the binary mixture of TiO2 nanospherical particles (NPs) and TiO2 nanotubes (NTs) to two freshwater algae with different morphology, namely, Scenedesmus obliquus and Chlorella pyrenoidosa. The physicochemical properties, dispersion stability, and the generation of reactive oxygen species (ROS) were determined in the single and binary systems. Classical approaches to assessing mixture toxicity were applied to evaluate and predict the toxicity of the binary mixtures. The results show that the combined toxicity of TiO2 NPs and NTs to S. obliquus was between the single toxicity of TiO2 NTs and NPs, while the combined toxicity to C. pyrenoidosa was higher than their single toxicity. Moreover, the toxicity of the binary mixtures to C. pyrenoidosa was higher than that to S. obliquus. A toxic unit assessment showed that the effects of TiO2 NPs and NTs were additive to the algae. The combined toxicity to S. obliquus and C. pyrenoidosa can be effectively predicted by the concentration addition model and the independent action model, respectively. The mechanism of the toxicity caused by the binary mixtures of TiO2 NPs and NTs may be associated with the dispersion stability of the nanoparticles in aquatic media and the ROS-induced oxidative stress effects. Our results may offer a new insight into evaluating and predicting the combined toxicological effects of ENPs with different dimensions and of probing the mechanisms involved in their joint toxicity.

Zinc and nickel binary mixtures act additively on the tropical mysid Mysidopsis juniae

2016 ◽  
Vol 67 (3) ◽  
pp. 301 ◽  
Author(s):  
Lívia Pitombeira de Figuerêdo ◽  
Jeamylle Nilin ◽  
Allyson Queiroz da Silva ◽  
Évila Pinheiro Damasceno ◽  
Susana Loureiro ◽  
...  
Keyword(s):  
Binary Mixtures ◽  
Conceptual Models ◽  
Anthropogenic Activities ◽  
Mixture Toxicity ◽  
Marine Species ◽  
Toxicity Assessment ◽  
Concentration Addition ◽  
Mortality Data ◽  
Chemical Toxicity ◽  
Single Chemical

Heavy metals may appear in the environment as a result of different anthropogenic activities, such as agriculture practices, industry and mining. They can reach aquatic environments as complex mixtures, and single chemical toxicity as a baseline for risk assessment can underestimate the impairment of ecosystems. The aim of the present study was to evaluate combined toxicity of binary mixtures of zinc and nickel to the tropical mysid Mysidopsis juniae. Acute toxicity was assessed and mixture toxicity was modelled using the conceptual models for concentration addition and independent action to predict whether both metals act additively or whether they interact with each other inside the organism. For that, the observed mortality data were compared with the modelled data. For the single toxicity assessment, results showed that nickel induced higher toxicity than did zinc, with lethal concentrations to 50% of the organisms of 180±30μgL–1 and 260±40μg zinc L–1 respectively. In binary mixtures, both metals acted additively and no interactions were predicted by using the conceptual models. The present study has highlighted the need to fill the gaps in toxicity studies using marine species and approaches that can help improve the assessment of accurate risk in the environment.

Assessment and Prediction of Joint Toxicity of Aniline Derivatives

2013 ◽  
Vol 448-453 ◽  
pp. 217-220
Author(s):  
Hui Lin Ge ◽  
Shu Shen Liu ◽  
Hong Qiu Yuan ◽  
Gui Hao Yin ◽  
Yi Xie ◽  
...  
Keyword(s):  
Mixture Toxicity ◽  
Joint Effect ◽  
Concentration Addition ◽  
Joint Toxicity ◽  
Independent Action ◽  
Similarity Parameter ◽  
Toxicity Index ◽  
Aniline Derivatives ◽  
Toxic Units

The joint toxicity of aniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, 2-nitroaniline, 3-nitroaniline, 4-nitroaniline, 2-chloroaniline, 3-chloroaniline, and 4-chloroaniline on photobacterium were predicted and evaluated by using concentration addition (CA) and independent action (IA) models, and joint effect indices including toxic units, additive index, mixture toxicity index, and similarity parameter. The tested mixture presented synergism.

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