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Concept: Toxicity

142

Concentration addition (CA) was proposed as a reasonable default approach for the ecological risk assessment of chemical mixtures. However, CA cannot predict the toxicity of mixture at some effect zones if not all components have definite effective concentrations at the given effect, such as some compounds induce hormesis. In this paper, we developed a new method for the toxicity prediction of various types of binary mixtures, an interpolation method based on the Delaunay triangulation (DT) and Voronoi tessellation (VT) as well as the training set of direct equipartition ray design (EquRay) mixtures, simply IDVequ. At first, the EquRay was employed to design the basic concentration compositions of five binary mixture rays. The toxic effects of single components and mixture rays at different times and various concentrations were determined by the time-dependent microplate toxicity analysis. Secondly, the concentration-toxicity data of the pure components and various mixture rays were acted as a training set. The DT triangles and VT polygons were constructed by various vertices of concentrations in the training set. The toxicities of unknown mixtures were predicted by the linear interpolation and natural neighbor interpolation of vertices. The IDVequ successfully predicted the toxicities of various types of binary mixtures.

Concepts: CGAL, Chemical substance, Computational geometry, Voronoi diagram, Mixture, Toxicity, Chemical compound, Delaunay triangulation

138

Chlorhexidine gluconate (CHX) and benzalkonium chloride (BZK) formulations are frequently used as antiseptics in healthcare and consumer products. Burkholderia cepacia complex (BCC) contamination of pharmaceutical products could be due to the use of contaminated water in the manufacturing process, over-diluted antiseptic solutions in the product, and the use of outdated products, which in turn, reduces the antimicrobial activity of CHX and BZK. To establish a “safe use” period following opening containers of CHX and BZK, we measured the antimicrobial effects of CHX (2 ~ 10 µg/ml) and BZK (10 ~ 50 µg/ml) at sub-lethal concentrations on six strains of Burkholderia cenocepacia using chemical and microbiological assays. CHX (2, 4 and 10 µg/ml) and BZK (10, 20 and 50 µg/ml) stored for 42 days at 23°C showed almost the same concentration and toxicity compared to freshly prepared CHX and BZK on B. cenocepacia strains. When 5 µg/ml CHX and 20 µg/ml BZK were spiked with six B. cenocepacia strains with different inoculum sizes (10⁰ ~ 10⁵CFU/mL), their toxic effects were not changed for 28 days. B. cenocepacia strains in diluted CHX and BZK were detectable at concentration up to 10² CFU/mL after incubation for 28 days at 23°C. Although abiotic and biotic changes in the toxicity of both antiseptics were not observed, our results indicate that B. cenocepacia strains could remain viable in CHX and BZK for 28 days, which in turn, indicates the importance of control measures to monitor BCC contamination in pharmaceutical products.

Concepts: Disinfectant, Toxicity, Burkholderiales, Mouthwash, Burkholderia, Antiseptics, Antiseptic, Microbiology

128

Timolol (generic name) is a frequently used medication for the control of glaucoma. Benzalkonium chloride (BAK) is a commonly used preservative in ophthalmic solutions with a broad range of antimicrobial activity; however, this nonspecificity can result in toxicity. Adverse effects attributed to BAK, including conjunctival inflammation and fibrosis, tear film instability, corneal cytotoxicity, anterior chamber inflammation, trabecular meshwork cell apoptosis, cataract development, macular edema, and even systemic effects, have been well documented. These effects can lead to ocular discomfort, poor intraocular pressure control, glaucoma surgery failure, and decreased patient compliance. BAK use in topical medications has decreased recently as newer and less toxic preservatives have become available. Yet these preservatives still exert some toxic effects, especially in patients with chronic eye disease who use multiple drops over extended periods of time. Thus, attempts to reduce overall preservative loads for patients are important, whether it be decreasing the amount of preservative, decreasing the total number of drops patients use, or eliminating preservatives entirely. A preservative-free formulation of timolol, TIMOPTIC® in OCUDOSE®, is available in unit-dose vials. Preservative-free unit-dose vials minimize toxic adverse effects and are a good option for patients with ocular surface disease, on long-term multidrop therapy, or who simply do not tolerate the effects of preservatives due to discomfort.

Concepts: Toxicology, Immune system, Intraocular pressure, Glaucoma, Eye, Toxicity, Trabecular meshwork, Ophthalmology

88

The major pesticides of the world are glyphosate-based herbicides (GBH), and their toxicity is highly debated. To understand their mode of action, the comparative herbicidal and toxicological effects of glyphosate (G) alone and 14 of its formulations were studied in this work, as a model for pesticides. GBH are mixtures of water, with commonly 36-48% G claimed as the active principle. As with other pesticides, 10-20% of GBH consist of chemical formulants. We previously identified these by mass spectrometry and found them to be mainly families of petroleum-based oxidized molecules, such as POEA, and other contaminants. We exposed plants and human cells to the components of formulations, both mixed and separately, and measured toxicity and human cellular endocrine disruption below the direct toxicity experimentally measured threshold. G was only slightly toxic on plants at the recommended dilutions in agriculture, in contrast with the general belief. In the short term, the strong herbicidal and toxic properties of its formulations were exerted by the POEA formulant family alone. The toxic effects and endocrine disrupting properties of the formulations were mostly due to the formulants and not to G. In this work, we also identified by mass spectrometry the heavy metals arsenic, chromium, cobalt, lead and nickel, which are known to be toxic and endocrine disruptors, as contaminants in 22 pesticides, including 11 G-based ones. This could also explain some of the adverse effects of the pesticides. In in vivo chronic regulatory experiments that are used to establish the acceptable daily intakes of pesticides, G or other declared active ingredients in pesticides are assessed alone, without the formulants. Considering these new data, this assessment method appears insufficient to ensure safety. These results, taken together, shed a new light on the toxicity of these major herbicides and of pesticides in general.

Concepts: Pharmacology, Heavy metal music, Chemistry, Toxicity, Poison, Endocrine disruptor, Biological activity, Toxicology

69

Background Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. Methods In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. Results The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. Conclusions Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Concepts: Normal distribution, Disease, Vascular endothelial growth factor, Toxicity, Chemotherapy, Cancer, Clinical trial, Renal cell carcinoma

54

The quality of diets in rodent feeding trials is crucial. We describe the contamination with environmental pollutants of 13 laboratory rodent diets from 5 continents. Measurements were performed using accredited methodologies. All diets were contaminated with pesticides (1-6 out of 262 measured), heavy metals (2-3 out of 4, mostly lead and cadmium), PCDD/Fs (1-13 out of 17) and PCBs (5-15 out of 18). Out of 22 GMOs tested for, Roundup-tolerant GMOs were the most frequently detected, constituting up to 48% of the diet. The main pesticide detected was Roundup, with residues of glyphosate and AMPA in 9 of the 13 diets, up to 370 ppb. The levels correlated with the amount of Roundup-tolerant GMOs. Toxic effects of these pollutants on liver, neurodevelopment, and reproduction are documented. The sum of the hazard quotients of the pollutants in the diets (an estimator of risk with a threshold of 1) varied from 15.8 to 40.5. Thus the chronic consumption of these diets can be considered at risk. Efforts toward safer diets will improve the reliability of toxicity tests in biomedical research and regulatory toxicology.

Concepts: Neurotoxicity, Environment, Heavy metal music, Pollution, Toxicity, Poison, Soil contamination, Toxicology

46

Amyloid β1-42 (Aβ1-42) plays a central role in Alzheimer’s disease. The link between structure, assembly and neuronal toxicity of this peptide is of major current interest but still poorly defined. Here, we explored this relationship by rationally designing a variant form of Aβ1-42 (vAβ1-42) differing in only two amino acids. Unlike Aβ1-42, we found that the variant does not self-assemble, nor is it toxic to neuronal cells. Moreover, while Aβ1-42 oligomers impact on synaptic function, vAβ1-42 does not. In a living animal model system we demonstrate that only Aβ1-42 leads to memory deficits. Our findings underline a key role for peptide sequence in the ability to assemble and form toxic structures. Furthermore, our non-toxic variant satisfies an unmet demand for a closely related control peptide for Aβ1-42 cellular studies of disease pathology, offering a new opportunity to decipher the mechanisms that accompany Aβ1-42-induced toxicity leading to neurodegeneration.

Concepts: Model organism, Typography, Toxicity, Neuron, Peptide, Amino acid, Alzheimer's disease, Protein

44

Ice-free cryopreservation, known as vitrification, is an appealing approach for banking of adherent cells and tissues because it prevents dissociation and morphological damage that may result from ice crystal formation. However, current vitrification methods are often limited by the cytotoxicity of the concentrated cryoprotective agent (CPA) solutions that are required to suppress ice formation. Recently, we described a mathematical strategy for identifying minimally toxic CPA equilibration procedures based on the minimization of a toxicity cost function. Here we provide direct experimental support for the feasibility of these methods when applied to adherent endothelial cells. We first developed a concentration- and temperature-dependent toxicity cost function by exposing the cells to a range of glycerol concentrations at 21°C and 37°C, and fitting the resulting viability data to a first order cell death model. This cost function was then numerically minimized in our state constrained optimization routine to determine addition and removal procedures for 17 molal (mol/kg water) glycerol solutions. Using these predicted optimal procedures, we obtained 81% recovery after exposure to vitrification solutions, as well as successful vitrification with the relatively slow cooling and warming rates of 50°C/min and 130°C/min. In comparison, conventional multistep CPA equilibration procedures resulted in much lower cell yields of about 10%. Our results demonstrate the potential for rational design of minimally toxic vitrification procedures and pave the way for extension of our optimization approach to other adherent cell types as well as more complex systems such as tissues and organs.

Concepts: Constraint satisfaction, Toxicity, Operations research, Cell, Mathematics, Cytotoxicity, Concentration, Ice

41

Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18-2000 times for co-formulants, 8-141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine-POEA and alkyl polyglucoside-APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone.

Concepts: Cytotoxicity, Poison, Glyphosate, Pharmacology, Pesticide formulation, Biological activity, Toxicity, Toxicology

40

Soluble oligomers of the amyloid-β (Aβ) peptide cause neurotoxicity, synaptic dysfunction and memory impairments which underlie Alzheimers disease (AD). The cellular prion protein (PrPC) was recently identified as a high-affinity neuronal receptor for Aβ oligomers. We report that fibrillar Aβ oligomers recognised by the OC antibody, which have been shown to correlate with the onset and severity of AD, bind preferentially to cells and neurons expressing PrPC. The binding of Aβ oligomers to cell surface PrPC, as well as their downstream activation of Fyn kinase, was dependent on the integrity of cholesterol-rich lipid rafts. In SH-SY5Y cells, fluorescence microscopy and co-localisation with sub-cellular markers revealed that the Aβ oligomers co-internalised with PrPC, accumulated in endosomes and subsequently trafficked to lysosomes. The cell surface binding, internalisation and downstream toxicity of Aβ oligomers was dependent on the transmembrane low density lipoprotein receptor-related protein-1 (LRP1). The binding of Aβ oligomers to cell surface PrPC impaired its ability to inhibit the activity of the β-secretase BACE1 which cleaves the amyloid precursor protein to produce Aβ. The green tea polyphenol (-)-epigallocatechin gallate (EGCG) and the red wine extract resveratrol both re-modelled the fibrillar conformation of Aβ oligomers. The resulting non-fibrillar oligomers displayed significantly reduced binding to PrPC-expressing cells and were no longer cytotoxic. These data indicate that soluble, fibrillar Aβ oligomers bind to PrPC in a conformation-dependent manner and require the integrity of lipid rafts and the transmembrane LRP1 for their cytotoxicity, thus revealing potential targets to alleviate the neurotoxic properties of Aβ oligomers in AD.

Concepts: Green tea, Adenosine triphosphate, Toxicity, Cytotoxicity, Alzheimer's disease, Cell, Cell membrane, Protein