Toxic interaction between atorvastatin and clarithromycin causing myositis and rhabdomyolysis.

A novel method for predicting the emergence of toxicity interaction in ternary mixtures

The history, theory, statistics, and development of mathematical models that assess biological responses to combinations of chemicals are well represented in the literature. A relative paucity of literature focuses on the actual application of methods and experimental guidelines for assessing toxic interactions. The wide variety of methods in use—some complicated, many nonideal—confounds the comparison of results from different laboratories. This communication is not a comprehensive exposition of the methods appropriate for the study of toxic or pharmacologic interactions of combinations of chemical agents. The modular approach presented here is intended to offer a unifying framework for such studies and to provide a simple yet versatile procedure for new investigators in this area. This approach is modular in that the components, such as experimental designs and mathematical models, can be (re)selected to suit specific research questions and to test the generality of conclusions without altering the overall structure of the approach. A brief background is given with references to some of the most rigorous and recent theoretical developments and reviews of this topic. The strategy and steps of the modular approach are outlined, followed by a more detailed description of these steps, general considerations, and suggested guidelines. Each step (such as experimental design, data analysis) is illustrated by an example. Advantages and disadvantages as well as assumptions and limitations of selected methods are discussed. Also addressed are aspects of in vitro systems that make them particularly conducive to investigations of toxic interactions.

Quantitative characterization of toxicity interaction within antibiotic-heavy metal mixtures on Chlorella pyrenoidosa by a novel area-concentration ratio method

In order to investigate the combined toxicity of compound contaminated azole fungicides on alage. Systematic investigation of Difenoconazole, Penconazole, Metconazole, Tetraconazole, Flutriafol, Fuberidazole, Triflumizole, Terrazole, HyMexazol, 9 azole fungicides as the components of the mixture. Thirty-five binary mixture systems with 173 mixture rays were designed by direct equipartition ray method. The growth inhibition toxicity of binary mixtures to Raphidocelis subcapitata was determined by 96-well microplates. Toxic interactions were qualitatively analyzed by Concentration addition (CA) and Independent Action (IA) models. Model Deviation Ratio (MDR) was used to quantitatively evaluate the toxic interaction of binary mixtures of azole fungicides, as well as the equivalent graph method, Toxic Unit (TU) method, additivity Index method (AI), Toxicity Index (MTI) and Combination Index (CI) methods were used to analyze the combined toxicity and toxic interaction of the mixture. The results showed that the frequency of synergistic effect was higher when mixed with Difenoconazole, Penconazole and Triflumizole, and the binary mixing with Flutriafol, Fuberidazole and Metconazole could reduce the toxicity of the mixture, showing additive and antagonistic effects. The toxicity of the mixture ranged from 3.053 to 6.415. In addition, at ambient concentrations, the mixture interaction is dominated by addition.

No toxic effects or interactions between aflatoxin B1 and zearalenone in broiler chickens fed diets at China's regulatory limits.

Chemical characterization of organic contaminants of coal conversion processes such as gasification or liquefaction has revealed them to be a potential source of environmental hazards. The majority of these compounds may be divided into four major classes: (1) phenols, (2) aromatic hydrocarbons, (3) aromatic amines, and (4) sulfur-containing compounds. Little is known about nitrogen-substituted aromatics. The data available, however, suggest that they are toxic and, even more importantly, are resistant to structural degradation. Examination of their water solubility reveals that although they are not as soluble as low-molecular-weight phenols, arylamines are more soluble than their nonsubstituted or sulfur-containing analogs. Thus, with existing technologies there is a real possibility that nitrogen-containing aromatic compounds may be discharged from coal conversion facilities as aqueous effluent in large enough concentration to have a pemicious effect on aquatic biota. Acute toxicity thresholds of several nitrogen-containing aromatic compounds have been tabulated for aquatic organisms, but potential toxic interactions between these compounds have not been investigated.

The effect of the light schedule on toxic interactions between propranolol and disopyramide were studied in chick embryos. Fertilized eggs of White Leghorns were incubated under dark conditions and investigated, on two occasions, under light conditions or under dark conditions. Propranolol, with and without disopyramide, was injected into the air sac of fertilized eggs on the 16th day of incubation. Electrocardiograms (ECGs) were recorded 0 to 60 min after the injection. After the injection of propranolol with disopyramide, the heart rate was significantly decreased compared with the injection of propranolol alone under light conditions. In addition, this toxic interaction between propranolol and disopyramide was more severe under dark conditions than under light conditions. These findings indicate that manipulation of the light schedule has a marked influence on the toxic interaction between propranolol and disopyramide in chick embryos.

Predicting the occurrence of antagonism within ternary guanidine mixture pollutants based on the concentration ratio of components

To the Editor. — Toxic interactions between disulfiram (Antabuse) and a number of drugs (including isoniazid, metronidazole, phenytoin sodium, and oral anticoagulants) have been well documented. Similarly, the adverse interaction of amitriptyline hydrochloride (Elavil) with various medications (including anticholinergic and sympathomimetic drugs, and ethchlorvynol and other CNS depressants) has been established. We describe two patients of the Alcoholism Treatment Unit (ATU) of the Philadelphia Veterans Administration Medical Center, in each of whom we observed an unusual clinical course that may have been the result of a toxic interaction between disulfiram and amitriptyline not reported previously. Report of Cases. —Case1.—A 33-yearold alcoholic man, treated with disulfiram, manifested symptoms of endogenous depression. Amitriptyline hydrochloride therapy was started, at a dosage of 25 mg at bedtime, to be increased to 100 mg during the next week. After only five days on the amitriptyline regimen, the patient reported improvement of his insomnia

Objectives:In this research, individual toxicity evaluation of heavy metals (Hg2+, Cr6+, Cd2+) was performed using a semi-continuous type bioreactor based on changes in the activity of sulfur oxidizing bacteria(SOB), and the purpose is to evaluate the toxic interaction of heavy metals through mixture toxicity evaluation and prediction modeling based on individual toxicity evaluation.Methods:SOB were separated into a reactor, and then the culture medium and heavy metal influent were automatically injected at 1-hour intervals under the optimized conditions. Heavy metal mixture influent for composite toxicity evaluation was produced and tested based on the individual EC50 value of each heavy metal based on the change in electrical conductivity(EC). Based on the results of the mixture toxicity evaluation, the CA, IA, and CI models are implemented, and after comparison with the actual experimental values, similarity with the model was verified through the MDR index. And the type of interaction (synergism, antagonism) was evaluated by CI value.Results and Discussion:In case of individual toxicity evaluation experiments, the individual EC50 of each heavy metal was derived at Hg2+ 0.71mg/L, Cr6+ 1.02 mg/L, and Cd2+ 8.82 mg/L in the order of strong toxicity. As a result of performing a combined toxicity evaluation based on individual EC50 values, it was judged that the combination of Hg2++Cd2+ showed a strong similarity with the IA model and no toxic interaction was developed, but all the remaining combinations were with the CI model. A similar relationship was shown and the existence of toxic interactions could be determined. As a result of analyzing the CI value, synergistic effects appeared in all combinations in which the interaction existed, and based on this result, it was possible to determine that Cr6+ is a factor that induces the toxic interaction. Conclusion:This study allowed a real-time toxicity monitoring system for SOB to verify sensitive toxicity detection for functional and non-essential metals. In addition, most heavy metal combinations generate synergistic effects during toxic interactions, and additional research on heavy metals and organic pollutants other than heavy metals used in this study will result in a more systematic ecotoxicity monitoring system.

Various chemicals emerge in environment and exist as mixtures with different forms and concentrations. Toxicity interaction by mixtures may pose potential hazards and risks to the environmental safety and human health. Recent data show that toxicity interaction within ionic liquid (IL) mixtures related with some certain component. However, how to determine the specific component in a mixture is not an easy work and needs more researches about it. Therefore, we investigated the toxicity of twelve groups of mixtures by using three ILs and one pesticide aldicarb as mixture components. Four binary and eight pseduo-binary mixtures were designed by equivalent effect concentration ratio ray method using EC5and EC50of individual component. The toxicities of single chemicals and these mixtures to a freshwater photobacteriumVibrio qinghaiensissp.-Q67 were determined by using the microplate toxicity analysis method. Toxicity interaction within mixtures were determined based on an additive referrence model, concentration addition (CA). The results showed that three binary IL mixture exhibited additive action and one antagonism. Interstingly, most pusedo-mixtures of aldicab and binary IL mixture exhibited cleary synergism especialy when they were mixed in the ratio of components EC5.

The effect of the hypothyroidism induced by thiamazole on toxic interactions between propranolol and disopyramide were studied in chick embryos. Fertilized eggs of White Leghorns were incubated and investigated. 1.2 mg/0.2 ml/egg of thiamazole was injected into the albumen of fertilized eggs on the 9th day of incubation. The control group was given 0.2 ml/egg of physiological saline in the same manner. Propranolol at 0.1 mg/egg and disopyramide at 0.3 mg/egg were injected into the air sac of fertilized eggs on the 16th day of incubation. Electrocardiograms were recorded 0 to 60 min after the injection. After the injection of propranolol and disopyramide into the thiamazole treated eggs, the heart rate was significantly decreased compared with the thiamazole untreated eggs. These findings indicate that hypothyroidism induced by thiamazole has a marked influence on the toxic interaction between propranolol and disopyramide in chick embryos.

Pollutants always co-exist in the environment. Determining and characterizing the interaction among chemicals is an important issue. Experimental designs (ED) play an important role in evaluating the interactions. The main aim of our study is to provide the test and analysis of the toxicity interaction with a novel ED method. A novel direct equipartition ray design (EquRay) procedure was proposed to effectively and systematically determine the toxicities of binary mixtures on Vibrio qinghaiensis sp.-Q67. Here, one component is ionic liquid, 1-butyl-2,3-dimethylimidazolium chloride (IL1), 1-butylpyridinium bromide (IL2) or N-hexylpyridinium bis(trifluoromethylsulfonyl)imide (IL3), and another is dichlorvos (DIC). The toxicity interaction was evaluated by comparing experiment and additive model together with three-dimension deviation response surface (DRS) analysis. Selecting CA as a reference model, the binary mixtures exerted less than additive (antagonism). Most of the deviations occurred in the centre portion of the DRS where the dCA (deviation from CA) values are between -15% and -26% for IL1-DIC and IL2-DIC mixtures and -10% and -15% for IL3 and DIC. Selecting IA as a additive model, IL1-DIC and IL2-DIC mixtures exhibited less than additive (antagonism) while IL3-DIC displayed an addition action and the absolute values of dIAs (deviation from IA) were less than 10%. A novel EquRay procedure was developed in this study and the EquRay can provide us with the information about the toxicity interaction between binary mixture components (such as DIC and IL) in different concentration regions across different mixture ratios.

Chronicle of mixture effects: Sensitivity differences in multiple toxicity endpoints of transgenic C. elegans and assessment of combined toxicity interactions.

To explore the correlation between financial toxicity, social support, and social functioning in post-chemotherapy breast cancer patients, as well as any possible interaction of financial toxicity and social support on social functioning. Post-chemotherapy breast cancer patients admitted to the thyroid and breast surgery departments of three first-class general hospitals in East China from December 2020 to January 2022 were recruited by convenience sampling for a cross-sectional survey. The survey instruments included the general information form, the comprehensive scores for financial toxicity based on the patient-reported outcome measures (COST-PROM), the social roles and activity participation subscale from the patient-reported outcomes measurement system-breast-chemotherapy (PROMS-B-C) (score range: 8-40), and the social support subscale from PROMS-B-C (score range: 16-80). The results showed that low social functioning (low score) in post-chemotherapy breast cancer patients was positively correlated with high financial toxicity (low score) as well as poor economic resources (low score) and poor psychosocial responses (low score) (P<0.01) and negatively correlated with low economic expenditures (low score) (P<0.01); high social functioning (high score) was positively correlated with high social support (high score) (P<0.01). The interaction analysis results showed an additive interaction between financial toxicity and social support in social functioning. There was an additive interaction of financial toxicity and social support in the social functioning of post-chemotherapy breast cancer patients. Those patients with high financial toxicity and low social support are the most likely to benefit from relevant intervention measures compared to other breast cancer populations.