Toxicity profiles and solvent-toxicant interference in the planarian Schmidtea mediterranea after dimethylsulfoxide (DMSO) exposure.

PubMed

Stevens, An-Sofie; Pirotte, Nicky; Plusquin, Michelle; Willems, Maxime; Neyens, Thomas; Artois, Tom; Smeets, Karen

2015-03-01

To investigate hydrophobic test compounds in toxicological studies, solvents like dimethylsulfoxide (DMSO) are inevitable. However, using these solvents, the interpretation of test compound-induced responses can be biased. DMSO concentration guidelines are available, but are mostly based on acute exposures involving one specific toxicity endpoint. Hence, to avoid solvent-toxicant interference, we use multiple chronic test endpoints for additional interpretation of DMSO concentrations and propose a statistical model to assess possible synergistic, antagonistic or additive effects of test compounds and their solvents. In this study, the effects of both short- (1 day) and long-term (2 weeks) exposures to low DMSO concentrations (up to 1000 µl l(-1) ) were studied in the planarian Schmidtea mediterranea. We measured different biological levels in both fully developed and developing animals. In a long-term exposure set-up, a concentration of 500 µl l(-1) DMSO interfered with processes on different biological levels, e.g. behaviour, stem cell proliferation and gene expression profiles. After short exposure times, 500 µl l(-1) DMSO only affected motility, whereas the most significant changes on different parameters were observed at a concentration of 1000 µl l(-1) DMSO. As small sensitivity differences exist between biological levels and developmental stages, we advise the use of this solvent in concentrations below 500 µl l(-1) in this organism. In the second part of our study, we propose a statistical approach to account for solvent-toxicant interactions and discuss full-scale solvent toxicity studies. In conclusion, we reassessed DMSO concentration limits for different experimental endpoints in the planarian S. mediterranea. Copyright © 2014 John Wiley & Sons, Ltd.

Comparison of the toxicities, activities and chemical profiles of raw and processed Xanthii Fructus.

PubMed

Su, Tao; Cheng, Brian Chi-Yan; Fu, Xiu-Qiong; Li, Ting; Guo, Hui; Cao, Hui-Hui; Kwan, Hiu-Yee; Tse, Anfernee Kai-Wing; Yu, Hua; Cao, Hui; Yu, Zhi-Ling

2016-01-22

Although toxic, the Chinese medicinal herb Xanthii Fructus (XF) is commonly used to treat traditional Chinese medicine (TCM) symptoms that resemble cold, sinusitis and arthritis. According to TCM theory, stir-baking (a processing method) can reduce the toxicity and enhance the efficacy of XF. Cytotoxicities of raw XF and processed XF (stir-baked XF, SBXF) were determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay in normal liver derived MIHA cells. Nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) mRNA expression were measured by the Griess reagent and quantitative real-time PCR, respectively. The chemical profiles of XF and SBXF were compared using an established ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) method. SBXF was less toxic than XF in MIHA cells. Both XF and SBXF had anti-inflammatory effects as demonstrated by their abilities to reduce nitric oxide production as well as inducible nitric oxide synthase mRNA expression in lipopolysaccharide-stimulated RAW 264.7 macrophages. Interestingly, the anti-inflammatory effects of SBXF were more potent than that of XF. By comparing the chemical profiles, we found that seven peaks were lower, while nine other peaks were higher in SBXF than in XF. Eleven compounds including carboxyatractyloside, atractyloside and chlorogenic acid corresponding to eleven individual changed peaks were tentatively identified by matching with empirical molecular formulae and mass fragments, as well as literature data. Our study showed that stir-baking significantly reduced the cytotoxicity and enhanced the anti-inflammatory effects of XF; moreover, with a developed ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry method we differentiated XF and SBXF by their chemical profiles. Further studies are warranted to establish the relationship between the alteration of chemical profiles and the

Sensory profile and acceptability for pitanga (Eugenia uniflora L.) nectar with different sweeteners.

PubMed

Freitas, Mírian Luisa Faria; Dutra, Mariana Borges de Lima; Bolini, Helena Maria André

2016-12-01

The objective of this study was to evaluate the sensory properties and acceptability of pitanga nectar samples prepared with sucrose and different sweeteners (sucralose, aspartame, stevia with 40% rebaudioside A, stevia with 95% rebaudioside A, neotame, and a 2:1 cyclamate/saccharin blend). A total of 13 assessors participated in a quantitative descriptive analysis and evaluated the samples in relation to the descriptor terms. The acceptability test was carried out by 120 fruit juice consumers. The results of the quantitative descriptive analysis of pitanga nectar showed that samples prepared with sucralose, aspartame, and the 2:1 cyclamate/saccharin blend had sensory profiles similar to that of the sample prepared with sucrose. Consumers' most accepted samples were prepared with sucrose, sucralose, aspartame, and neotame. The sweeteners that have the greatest potential to replace sucrose in pitanga nectar are sucralose and aspartame. © The Author(s) 2016.

KSC 50-MHz Doppler Radar Wind Profiler (DRWP) Operational Acceptance Test (OAT) Report

NASA Technical Reports Server (NTRS)

Barbre, Robert E.

2015-01-01

This report documents analysis results of the Kennedy Space Center updated 50-MHz Doppler Radar Wind Profiler (DRWP) Operational Acceptance Test (OAT). This test was designed to demonstrate that the new DRWP operates in a similar manner to the previous DRWP for use as a situational awareness asset for mission operations at the Eastern Range to identify rapid changes in the wind environment that weather balloons cannot depict. Data examination and two analyses showed that the updated DRWP meets the specifications in the OAT test plan and performs at least as well as the previous DRWP. Data examination verified that the DRWP provides complete profiles every five minutes from 1.8-19.5 km in vertical increments of 150 m. Analysis of 5,426 wind component reports from 49 concurrent DRWP and balloon profiles presented root mean square (RMS) wind component differences around 2.0 m/s. The DRWP's effective vertical resolution (EVR) was found to be 300 m for both the westerly and southerly wind component, which the best EVR possible given the DRWP's vertical sampling interval. A third analysis quantified the sensitivity to rejecting data that do not have adequate signal by assessing the number of first-guess propagations at each altitude. This report documents the data, quality control procedures, methodology, and results of each analysis. It also shows that analysis of the updated DRWP produced results that were at least as good as the previous DRWP with proper rationale. The report recommends acceptance of the updated DRWP for situational awareness usage as per the OAT's intent.

¹H NMR-based metabolic profiling of naproxen-induced toxicity in rats.

PubMed

Jung, Jeeyoun; Park, Minhwa; Park, Hye Jin; Shim, Sun Bo; Cho, Yang Ha; Kim, Jinho; Lee, Ho-Sub; Ryu, Do Hyun; Choi, Donwoong; Hwang, Geum-Sook

2011-01-15

The dose-dependent perturbations in urinary metabolite concentrations caused by naproxen toxicity were investigated using ¹H NMR spectroscopy coupled with multivariate statistical analysis. Histopathologic evaluation of naproxen-induced acute gastrointestinal damage in rats demonstrated a significant dose-dependent effect. Furthermore, principal component analysis (PCA) of ¹H NMR from rat urine revealed a dose-dependent metabolic shift between the vehicle-treated control rats and rats treated with low-dose (10 mg/kg body weight), moderate-dose (50 mg/kg), and high-dose (100 mg/kg) naproxen, coinciding with their gastric damage scores after naproxen administration. The resultant metabolic profiles demonstrate that the naproxen-induced gastric damage exhibited energy metabolism perturbations that elevated their urinary levels of citrate, cis-aconitate, creatine, and creatine phosphate. In addition, naproxen administration decreased choline level and increased betaine level, indicating that it depleted the main protective constituent of the gastric mucosa. Moreover, naproxen stimulated the decomposition of tryptophan into kynurenate, which inhibits fibroblast growth factor-1 and delays ulcer healing. These findings demonstrate that ¹H NMR-based urinary metabolic profiling can facilitate noninvasive and rapid diagnosis of drug side effects and is suitable for elucidating possible biological pathways perturbed by drug toxicity. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Dose-finding designs using a novel quasi-continuous endpoint for multiple toxicities

PubMed Central

Ezzalfani, Monia; Zohar, Sarah; Qin, Rui; Mandrekar, Sumithra J; Deley, Marie-Cécile Le

2013-01-01

The aim of a phase I oncology trial is to identify a dose with an acceptable safety profile. Most phase I designs use the dose-limiting toxicity, a binary endpoint, to assess the unacceptable level of toxicity. The dose-limiting toxicity might be incomplete for investigating molecularly targeted therapies as much useful toxicity information is discarded. In this work, we propose a quasi-continuous toxicity score, the total toxicity profile (TTP), to measure quantitatively and comprehensively the overall severity of multiple toxicities. We define the TTP as the Euclidean norm of the weights of toxicities experienced by a patient, where the weights reflect the relative clinical importance of each grade and toxicity type. We propose a dose-finding design, the quasi-likelihood continual reassessment method (CRM), incorporating the TTP score into the CRM, with a logistic model for the dose–toxicity relationship in a frequentist framework. Using simulations, we compared our design with three existing designs for quasi-continuous toxicity score (the Bayesian quasi-CRM with an empiric model and two nonparametric designs), all using the TTP score, under eight different scenarios. All designs using the TTP score to identify the recommended dose had good performance characteristics for most scenarios, with good overdosing control. For a sample size of 36, the percentage of correct selection for the quasi-likelihood CRM ranged from 80% to 90%, with similar results for the quasi-CRM design. These designs with TTP score present an appealing alternative to the conventional dose-finding designs, especially in the context of molecularly targeted agents. PMID:23335156

Plasma metabolic profiling analysis of toxicity induced by brodifacoum using metabonomics coupled with multivariate data analysis.

PubMed

Yan, Hui; Qiao, Zheng; Shen, Baohua; Xiang, Ping; Shen, Min

2016-10-01

Brodifacoum is one of the most widely used rodenticides for rodent control and eradication; however, human and animal poisoning due to primary and secondary exposure has been reported since its development. Although numerous studies have described brodifacoum induced toxicity, the precise mechanism still needs to be explored. Gas chromatography mass spectrometry (GC-MS) coupled with an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was applied to characterize the metabolic profile of brodifacoum induced toxicity and discover potential biomarkers in rat plasma. The toxicity of brodifacoum was dose-dependent, and the high-dose group obviously manifested toxicity with subcutaneous hemorrhage. The blood brodifacoum concentration showed a positive relation to the ingestion dose in toxicological analysis. Significant changes of twenty-four metabolites were identified and considered as potential toxicity biomarkers, primarily involving glucose metabolism, lipid metabolism and amino acid metabolism associated with anticoagulant activity, nephrotoxicity and hepatic damage. MS-based metabonomics analysis in plasma samples is helpful to search for potential poisoning biomarkers and to understand the underlying mechanisms of brodifacoum induced toxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Honeybee (Apis cerana) foraging responses to the toxic honey of Tripterygium hypoglaucum (Celastraceae): changing threshold of nectar acceptability.

PubMed

Tan, K; Guo, Y H; Nicolson, S W; Radloff, S E; Song, Q S; Hepburn, H R

2007-12-01

To investigate honeybee foraging responses to toxic nectar, honey was collected from Apis cerana colonies in the Yaoan county of Yunnan Province, China, during June, when flowers of Tripterygium hypoglaucum were the main nectar source available. Pollen analysis confirmed the origin of the honey, and high-performance liquid chromatography showed the prominent component triptolide to be present at a concentration of 0.61 mug/g +/- 0.11 SD. In cage tests that used young adult worker bees, significantly more of those provided with a diet of T. hypoglaucum honey mixed with sugar powder (1:1) died within 6 d (68.3%) compared to control groups provided with normal honey mixed with sugar powder (15.8%). Honeybees were trained to visit feeders that contained honey of T. hypoglaucum (toxic honey) as the test group and honey of Vicia sativa or Elsholtzia ciliata as control groups (all honeys diluted 1:3 with water). Bees preferred the feeders with normal honey to those with toxic honey, as shown by significantly higher visiting frequencies and longer imbibition times. However, when the feeder of normal honey was removed, leaving only honey of T. hypoglaucum, the foraging bees returned to the toxic honey after a few seconds of hesitation, and both visiting frequency and imbibition time increased to values previously recorded for normal honey. Toxic honey thus became acceptable to the bees in the absence of other nectar sources.

Mechanisms of crystalline silica-induced pulmonary toxicity revealed by global gene expression profiling

PubMed Central

Sellamuthu, Rajendran; Umbright, Christina; Li, Shengqiao; Kashon, Michael; Joseph, Pius

2015-01-01

A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatics analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top ranking biological functions perturbed by silica exposure in A549 cells and rat lungs. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study may result in better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure. PMID:22087542

Toxicity Profile of a Nutraceutical Formulation Derived from Green Mussel Perna viridis

PubMed Central

Joseph, Deepu; Chakkalakal, Selsa J.

2014-01-01

The short-term (acute) and long-term (subchronic) toxicity profile, mean lethal dose 50 (LD50), and no-observed-adverse-effect level (NOAEL) of a nutraceutical formulation developed from green mussel Perna viridis, which showed in vitro and in vivo anti-inflammatory properties, were evaluated in the present study. The formulation was administered to the male and female Wistar rats at graded doses (0.5, 1.0, and 2.5 g/kg body weight) for two weeks of acute toxicity study and 0.5, 1.0, and 2.0 g/kg body weight for 90 days in subchronic toxicity study. The LD50, variations in clinical signs, changes in body weight, body weight, food/water consumption, organ weight (liver, kidney, spleen, and brain), hematology, serum chemistry, and histopathological changes were evaluated. The LD50 of the formulation was 5,000 mg/kg BW. No test article related mortalities as well as change in body weight, and food and water consumption were observed. No toxicity related significant changes were noted in renal/hepatic function, hematological indices, and serum biochemical parameters between the control and treated groups. Histopathological alterations were not observed in the vital organs of rats. The subchronic NOAEL for the formulation in rats is greater than 2000 mg/kg. This study demonstrated that the green mussel formulation is safe to consume without any adverse effects in the body. PMID:24995298

The affective profiles, psychological well-being, and harmony: environmental mastery and self-acceptance predict the sense of a harmonious life

PubMed Central

Al Nima, Ali; Kjell, Oscar N.E.

2014-01-01

Background. An important outcome from the debate on whether wellness equals happiness, is the need of research focusing on how psychological well-being might influence humans’ ability to adapt to the changing environment and live in harmony. To get a detailed picture of the influence of positive and negative affect, the current study employed the affective profiles model in which individuals are categorised into groups based on either high positive and low negative affect (self-fulfilling); high positive and high negative affect (high affective); low positive and low negative affect (low affective); and high negative and low positive affect (self-destructive). The aims were to (1) investigate differences between affective profiles in psychological well-being and harmony and (2) how psychological well-being and its dimensions relate to harmony within the four affective profiles. Method. 500 participants (mean age = 34.14 years, SD. = ±12.75 years; 187 males and 313 females) were recruited online and required to answer three self-report measures: The Positive Affect and Negative Affect Schedule; The Scales of Psychological Well-Being (short version) and The Harmony in Life Scale. We conducted a Multivariate Analysis of Variance where the affective profiles and gender were the independent factors and psychological well-being composite score, its six dimensions as well as the harmony in life score were the dependent factors. In addition, we conducted four multi-group (i.e., the four affective profiles) moderation analyses with the psychological well-being dimensions as predictors and harmony in life as the dependent variables. Results. Individuals categorised as self-fulfilling, as compared to the other profiles, tended to score higher on the psychological well-being dimensions: positive relations, environmental mastery, self-acceptance, autonomy, personal growth, and purpose in life. In addition, 47% to 66% of the variance of the harmony in life was explained by

Sensory profiling and consumer acceptability of new dark cocoa bars containing Tuscan autochthonous food products.

PubMed

Cantini, Claudio; Salusti, Patrizia; Romi, Marco; Francini, Alessandra; Sebastiani, Luca

2018-03-01

A new set of cocoa bars named Toscolata ® were developed containing top-quality extra virgin olive oil, dried apples cultivars, and chestnut flour. The present work has been conducted to define the sensory profile of these products through tasting by trained experts and consumers to study the acceptability, preference, and quality perception. The four sensorial profiles of the bars differed in the level of persistence, bitterness, aromaticity, acidity, astringency, and tastiness. In particular, the sour attribute could be traced to the presence of dried apple. Bars containing apple and chestnut flour obtained higher acceptance ratings, compared to those with extra virgin olive oil. The bar with chestnut flour was preferred by consumers who considered it to be sweeter due to the presence of natural sugars, which lowered the bitter sensation of cocoa. These results showed that the selection of the preferred bar by consumers was mainly based on the level of bitterness and, in particular, elderly consumers expressed a strong preference for the sweetest product. As far as we know, this is the first study comparing the results of a panel of expert tasters with that of consumers in the tasting of dark chocolate.

Sensory Profile and Consumer Acceptability of Prebiotic White Chocolate with Sucrose Substitutes and the Addition of Goji Berry (Lycium barbarum).

PubMed

Morais Ferreira, Janaína Madruga; Azevedo, Bruna Marcacini; Luccas, Valdecir; Bolini, Helena Maria André

2017-03-01

Functional food is a product containing nutrients that provide health benefits beyond basic nutrition. The objective of the present study was to evaluate the descriptive sensory profile and consumers' acceptance of functional (prebiotic) white chocolates with and without the addition of an antioxidant source (goji berry [GB]) and sucrose replacement. The descriptive sensory profile was determined by quantitative descriptive analysis (QDA) with trained assessors (n = 12), and the acceptance test was performed with 120 consumers. The correlation of descriptive and hedonic data was determined by partial least squares (PLS). The results of QDA indicated that GB reduces the perception of most aroma and flavor attributes, and enhances the bitter taste, bitter aftertaste, astringency, and most of the texture attributes. The consumers' acceptance of the chocolates was positive for all sensory characteristics, with acceptance scores above 6 on a 9-point scale. According to the PLS regression analysis, the descriptors cream color and cocoa butter flavor contributed positively to the acceptance of functional white chocolates. Therefore, prebiotic white chocolate with or without the addition of GB is innovative and can attract consumers, due to its functional properties, being a promising alternative for the food industry. © 2017 Institute of Food Technologists®.

Profile of vemurafenib-induced severe skin toxicities.

PubMed

Peuvrel, L; Quéreux, G; Saint-Jean, M; Brocard, A; Nguyen, J M; Khammari, A; Knol, A C; Varey, E; Dréno, B

2016-02-01

Vemurafenib, a BRAF inhibitor, is commonly associated with skin toxicity. The impact of severe forms is unknown. To determine the rate of permanent vemurafenib discontinuation due to grade 3-4 skin toxicity, features of these toxicities, their recurrence rate after a switch to dabrafenib and their impact on overall survival. Retrospective cohort study of 131 patients treated with vemurafenib for melanoma between November 2010 and December 2014. Data on skin toxicities, the need for vemurafenib adjustment and the impact of switching to dabrafenib were collected. Regarding survival analysis, a conditional landmark analysis was performed to correct lead-time bias. Among the 131 vemurafenib-treated patients, 26% developed grade 3-4 skin toxicity. Forty-four percent of them permanently discontinued their treatment, mainly due to rash and classic skin adverse reactions (Steven-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms). Conversely, photosensitivity and carcinomas rarely required treatment adjustment. Grade 3-4 rashes were associated with clinical or biological abnormalities in 94% of patients. Among the 10 patients who subsequently switched to dabrafenib, skin toxicity recurred only in one patient. Overall survival was significantly prolonged in case of severe skin toxicity emerging within the first 4 (P = 0.014) and 8 weeks (P = 0.038) on vemurafenib, with only a trend at 12 weeks (P = 0.052). Median overall survival was also prolonged in case of severe rash. In this study, vemurafenib was continued in 56% of patients with grade 3-4 skin toxicity, which was associated with prolonged overall survival when emerging within the first 4 and 8 weeks of treatment. While developing severe skin adverse reactions permanently contraindicates vemurafenib use, other rashes should lead to retreatment attempts with dose reduction. In case of recurrence, dabrafenib seems to be an interesting option. For other skin toxicities, including photosensitivity and

In Vitro and In Vivo Toxicity Profiling of Ammonium-Based Deep Eutectic Solvents

PubMed Central

Hayyan, Maan; Looi, Chung Yeng; Hayyan, Adeeb; Wong, Won Fen; Hashim, Mohd Ali

2015-01-01

The cytotoxic potential of ammonium-based deep eutectic solvents (DESs) with four hydrogen bond donors, namely glycerine (Gl), ethylene glycol (EG), triethylene glycol (TEG) and urea (U) were investigated. The toxicity of DESs was examined using In Vitro cell lines and In Vivo animal model. IC50 and selectivity index were determined for the DESs, their individual components and their combinations as aqueous solutions for comparison purposes. The cytotoxicity effect of DESs varied depending on cell lines. The IC50 for the GlDES, EGDES, UDES and TEGDES followed the sequence of TEGDES< GlDES< EGDES< UDES for OKF6, MCF-7, A375, HT29 and H413, respectively. GlDES was selective against MCF-7 and A375, EGDES was selective against MCF-7, PC3, HepG2 and HT29, UDES was selective against MCF-7, PC3, HepG2 and HT29, and TEGDES was selective against MCF-7 and A375. However, acute toxicity studies using ICR mice showed that these DESs were relatively toxic in comparison to their individual components. DES did not cause DNA damage, but it could enhance ROS production and induce apoptosis in treated cancer cells as evidenced by marked LDH release. Furthermore, the examined DESs showed less cytotoxicity compared with ionic liquids. To the best of our knowledge, this is the first time that combined In Vitro and In Vivo toxicity profiles of DESs were being demonstrated, raising the toxicity issue of these neoteric mixtures and their potential applicability to be used for therapeutic purposes. PMID:25679975

Toxic substances handbook

NASA Technical Reports Server (NTRS)

Junod, T. L.

1979-01-01

Handbook, published in conjunction with Toxic Substances Alert Program at NASA Lewis Research Center, profiles 187 toxic chemicals in their relatively pure states and include 27 known or suspected carcinogens.

Metabolic Profiling in Association with Vascular Endothelial Cell Dysfunction Following Non-Toxic Cadmium Exposure

PubMed Central

Li, Xiaofei; Nong, Qingjiao; Mao, Baoyu; Pan, Xue

2017-01-01

This study aimed to determine the metabolic profile of non-toxic cadmium (Cd)-induced dysfunctional endothelial cells using human umbilical vein endothelial cells (HUVECs). HUVECs (n = 6 per group) were treated with 0, 1, 5, or 10 μM cadmium chloride (CdCl2) for 48 h. Cell phenotypes, including nitric oxide (NO) production, the inflammatory response, and oxidative stress, were evaluated in Cd-exposed and control HUVECs. Cd-exposed and control HUVECs were analysed using gas chromatography time-of-flight/mass spectrometry. Compared to control HUVECs, Cd-exposed HUVECs were dysfunctional, exhibiting decreased NO production, a proinflammatory state, and non-significant oxidative stress. Further metabolic profiling revealed 24 significantly-altered metabolites in the dysfunctional endothelial cells. The significantly-altered metabolites were involved in the impaired tricarboxylic acid (TCA) cycle, activated pyruvate metabolism, up-regulated glucogenic amino acid metabolism, and increased pyrimidine metabolism. The current metabolic findings further suggest that the metabolic changes linked to TCA cycle dysfunction, glycosylation of the hexosamine biosynthesis pathway (HBP), and compensatory responses to genomic instability and energy deficiency may be generally associated with dysfunctional phenotypes, characterized by decreased NO production, a proinflammatory state, and non-significant oxidative stress, in endothelial cells following non-toxic Cd exposure. PMID:28872622

Classification and prediction of toxicity of chemicals using an automated phenotypic profiling of Caenorhabditis elegans.

PubMed

Gao, Shan; Chen, Weiyang; Zeng, Yingxin; Jing, Haiming; Zhang, Nan; Flavel, Matthew; Jois, Markandeya; Han, Jing-Dong J; Xian, Bo; Li, Guojun

2018-04-18

Traditional toxicological studies have relied heavily on various animal models to understand the effect of various compounds in a biological context. Considering the great cost, complexity and time involved in experiments using higher order organisms. Researchers have been exploring alternative models that avoid these disadvantages. One example of such a model is the nematode Caenorhabditis elegans. There are some advantages of C. elegans, such as small size, short life cycle, well defined genome, ease of maintenance and efficient reproduction. As these benefits allow large scale studies to be initiated with relative ease, the problem of how to efficiently capture, organize and analyze the resulting large volumes of data must be addressed. We have developed a new method for quantitative screening of chemicals using C. elegans. 33 features were identified for each chemical treatment. The compounds with different toxicities were shown to alter the phenotypes of C. elegans in distinct and detectable patterns. We found that phenotypic profiling revealed conserved functions to classify and predict the toxicity of different chemicals. Our results demonstrate the power of phenotypic profiling in C. elegans under different chemical environments.

Mechanistic-based non-animal assessment of eye toxicity: Inflammatory profile of human keratinocytes cells after exposure to eye damage/irritant agents.

PubMed

da Silva, Artur Christian Garcia; Chialchia, Adrienny Rodrigues; de Ávila, Renato Ivan; Valadares, Marize Campos

2018-06-25

Eye toxicity is a mandatory parameter in human risk and safety evaluation for products including chemicals, pesticides, medicines and cosmetics. Historically, this endpoint has been evaluated using the Draize rabbit eye test, an in vivo model that was never formally validated. Due to advances in scientific knowledge, economic and ethical issues, non-animal methods based on mechanisms of toxicity are being developed and validated for increasing the capability of these models to predict eye toxicity. In this study, the Cytometric Bead Array (CBA) and ELISA assays were used to evaluate the inflammatory cytokine profile produced by HaCaT human keratinocytes after exposure to chemicals with different UN GHS eye toxicity classifications, aiming to stablish a correlation between inflammatory endpoints and eye toxicity (damage/irritation) potential. As a first step, cytotoxic profile of the chemicals, including 3 non-irritants and 10 eye toxicants (GHS Category 1, 2A and 2B), was evaluated after 24 h exposure using MTT assay and Inhibitory Concentration of 20% of cell viability (IC 20 ) was calculated for each chemical. Then, the cells were exposed to these chemicals at IC 20 for 24 h and supernatants and cell lysates were analyzed by CBA assay for quantification of the following cytokines: IL-6, IL-8, IL-10, IL-1β, TNF and IL-12p70. Regarding cytotoxicity evaluation, chemicals showed different cytotoxicity profiles and data demonstrated no correlation with their UN GHS classification. Among the cytokines evaluated, IL-1β production has changed after exposure and such alterations were confirmed by quantification employing ELISA method. The higher intracellular levels of IL-1β were found in GHS Category 1 chemicals, followed by Category 2A and 2B, while non irritants did not induce such increase. Thus, these findings show that IL-1β measurement, using HaCaT model, can be a considerable biomarker to identify chemicals according to their potential in promote eye

GENE EXPRESSION PROFILING OF ACCESSIBLE SURROGATE TISSUES TO MONITOR MOLECULAR CHANGES IN INACCESSIBLE TARGET TISSUES FOLLOWING TOXICANT EXPOSURE

EPA Science Inventory

Gene Expression Profiling Of Accessible Surrogate Tissues To Monitor Molecular Changes In Inaccessible Target Tissues Following Toxicant Exposure
John C. Rockett, Chad R. Blystone, Amber K. Goetz, Rachel N. Murrell, Judith E. Schmid and David J. Dix
Reproductive Toxicology ...

A Prospective Comparative Study of the Toxicity Profile of 5-Flurouracil, Adriamycin, Cyclophosphamide Regime VS Adriamycin, Paclitaxel Regime in Patients with Locally Advanced Breast Carcinoma

PubMed Central

Pillai, Pradeep Sadasivan; Jayakumar, Krishnan Nair Lalithamma

2015-01-01

Introduction A 5-flurouracil, Adriamycin, Cyclophosphamide (FAC) and Adriamycin, Paclitaxel (AT) are two popular chemotherapeutic regimens for treatment of breast carcinoma. The most time tested and popular regimen is FAC. It is extensively studied for efficacy and toxicity. But data regarding toxicity profile and efficacy of AT regimen is sparse. Aim To study the toxicity profile, severity of toxicities and clinical response rate of FAC and AT regimens in patients with locally advanced breast carcinoma. Materials and Methods A prospective observational study with 50 patients in each treatment arm. Study duration was 12 months from November 2012 to October 2013. Consecutive patients with locally advanced breast carcinoma receiving treatment with either FAC or AT regimen, satisfying inclusion criteria were enrolled into the study after getting informed written consent. Prior to initiation of treatment detailed medical history was taken from all patients. General clinical examination, examination of organ systems and local examination of breast lump were done. After each cycle of chemotherapy and after completion of treatment patients were interviewed and examined for clinical response and toxicities. Toxicities were graded with WHO toxicity grading criteria. All data were entered in a structured proforma. At least 50% reduction in tumour size was taken as adequate clinical response. Statistical Analysis Data was analysed using Chi-square test with help of Excel 2007 and SPSS-16 statistical software. Results Different pattern of toxicities were seen with FAC and AT regimens. Anaemia, thrombocytopenia, stomatitis, hyperpigmentation, photosensitivity and diarrhoea were more common with patients receiving FAC regimen. Leucopenia, peripheral neuropathy, myalgia, arthralgia, vomiting and injection site reactions were more common in AT regimen. Both FAC and AT regimens gave 100% clinical response. Conclusion FAC and AT regimens are equally efficacious but have different

Toxicity Ranking and Toxic Mode of Action Evaluation of Commonly Used Agricultural Adjuvants on the Basis of Bacterial Gene Expression Profiles

PubMed Central

Nobels, Ingrid; Spanoghe, Pieter; Haesaert, Geert; Robbens, Johan; Blust, Ronny

2011-01-01

The omnipresent group of pesticide adjuvants are often referred to as “inert” ingredients, a rather misleading term since consumers associate this term with “safe”. The upcoming new EU regulation concerning the introduction of plant protection products on the market (EC1107/2009) includes for the first time the demand for information on the possible negative effects of not only the active ingredients but also the used adjuvants. This new regulation requires basic toxicological information that allows decisions on the use/ban or preference of use of available adjuvants. In this study we obtained toxicological relevant information through a multiple endpoint reporter assay for a broad selection of commonly used adjuvants including several solvents (e.g. isophorone) and non-ionic surfactants (e.g. ethoxylated alcohols). The used assay allows the toxicity screening in a mechanistic way, with direct measurement of specific toxicological responses (e.g. oxidative stress, DNA damage, membrane damage and general cell lesions). The results show that the selected solvents are less toxic than the surfactants, suggesting that solvents may have a preference of use, but further research on more compounds is needed to confirm this observation. The gene expression profiles of the selected surfactants reveal that a phenol (ethoxylated tristyrylphenol) and an organosilicone surfactant (ethoxylated trisiloxane) show little or no inductions at EC20 concentrations, making them preferred surfactants for use in different applications. The organosilicone surfactant shows little or no toxicity and good adjuvant properties. However, this study also illustrates possible genotoxicity (induction of the bacterial SOS response) for several surfactants (POEA, AE, tri-EO, EO FA and EO NP) and one solvent (gamma-butyrolactone). Although the number of compounds that were evaluated is rather limited (13), the results show that the used reporter assay is a promising tool to rank commonly used

Understanding Genetic Toxicity Through Data Mining: The ...

EPA Pesticide Factsheets

This paper demonstrates the usefulness of representing a chemical by its structural features and the use of these features to profile a battery of tests rather than relying on a single toxicity test of a given chemical. This paper presents data mining/profiling methods applied in a weight-of-evidence approach to assess potential for genetic toxicity, and to guide the development of intelligent testing strategies. This paper demonstrates the usefulness of representing a chemical by its structural features and the use of these features to profile a battery of tests rather than relying on a single toxicity test of a given chemical. This paper presents data mining/profiling methods applied in a weight-of-evidence approach to assess potential for genetic toxicity, and to guide the development of intelligent testing strategies.

Toxic effects of arsenic on semen and hormonal profile and their amelioration with vitamin E in Teddy goat bucks.

PubMed

Zubair, M; Ahmad, M; Jamil, H; Deeba, F

2016-12-01

The present environmental study has been planned to investigate the toxic effects of arsenic on reproductive functions of Teddy bucks as well as to examine whether these toxic effects are ameliorated by vitamin E. Sixteen adult Teddy bucks were divided randomly into four equal groups A, B, C and D with following treatment: A (control), B (sodium arsenite 5 mg kg -1 BW day -1 ), C (vit E 200 mg kg -1 BW day -1  + Arsenic 5 mg kg -1 BW day -1 ) and D (vit E 200 mg kg -1 BW day -1 ). This treatment was continued for 84 days. Semen quality parameters were evaluated weekly. Male testosterone, luteinising hormone (LH), follicle-stimulating hormone (FSH) and cortisol levels were measured through enzyme-linked immunosorbent assay (ELISA) after every 2 weeks. The data were subjected to two-way analysis of variance followed by Duncan test for multiple comparisons. Semen evaluation parameters were reduced significantly (P < 0.05) in arsenic-treated animals. The serum hormonal profile of testosterone, LH and FSH was reduced significantly (P < 0.05) in arsenic group, while the serum level of cortisol was increased. Vitamin E alleviated the toxic effects of arsenic on semen and hormonal parameters. It may be concluded from this study that sodium arsenite causes major toxicity changes in semen and hormonal profile in Teddy goat bucks and vitamin E has ameliorative effects on these toxic changes. © 2016 Blackwell Verlag GmbH.

Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer.

PubMed

Costa, Rubens Barros; Costa, Ricardo L B; Talamantes, Sarah M; Kaplan, Jason B; Bhave, Manali A; Rademaker, Alfred; Miller, Corinne; Carneiro, Benedito A; Mahalingam, Devalingam; Chae, Young Kwang

2018-04-24

Anaplastic lymphoma kinase ( ALK ) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update. A systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included. Data were analyzed using random effects meta-analysis for absolute risks (AR), study heterogeneity, publication bias and differences among treatments. Fifteen trials with a total of 2,005 patients with evaluable toxicity data were included in this report. There was significant heterogeneity amongst different studies. The pooled AR of death and severe adverse events were 0.5% and 34.5%, respectively. Grade 3/4 nausea, vomiting, diarrhea, and constipation were uncommon: 2.6%, 2.5%, 2.7%, 1.2%, respectively. ALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Important differences in toxicity profile were detected amongst the different drugs.

Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer

PubMed Central

Costa, Rubens Barros; Costa, Ricardo L.B.; Talamantes, Sarah M.; Kaplan, Jason B.; Bhave, Manali A.; Rademaker, Alfred; Miller, Corinne; Carneiro, Benedito A.; Mahalingam, Devalingam; Chae, Young Kwang

2018-01-01

Introduction Anaplastic lymphoma kinase (ALK) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update. Materials and Methods A systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included. Data were analyzed using random effects meta-analysis for absolute risks (AR), study heterogeneity, publication bias and differences among treatments. Results Fifteen trials with a total of 2,005 patients with evaluable toxicity data were included in this report. There was significant heterogeneity amongst different studies. The pooled AR of death and severe adverse events were 0.5% and 34.5%, respectively. Grade 3/4 nausea, vomiting, diarrhea, and constipation were uncommon: 2.6%, 2.5%, 2.7%, 1.2%, respectively. Conclusions ALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Important differences in toxicity profile were detected amongst the different drugs. PMID:29774128

Toxicity and biocompatibility profile of 3D bone scaffold developed by Universitas Indonesia: A preliminary study

NASA Astrophysics Data System (ADS)

Rahyussalim A., J.; Kurniawati, T.; Aprilya, D.; Anggraini, R.; Ramahdita, Ghiska; Whulanza, Yudan

2017-02-01

Scaffold as a biomaterial must fulfill some requirements to be safely implanted to the human body. Toxicity and biocompatibility test are needed to evaluate scaffold material in mediating cell proliferation and differentiation, secreting extracelullar matrix and carrying biomolecular signals for cell communication. An in vitro study with mesenchymal stem cells consisted of direct contact test and indirect contact test using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay was conducted on 4 scaffolds made of poly-L-lactic acid (PLA), polyvinyl alcohol (PVA), and hydroxyapatite-poly (vinyl alcohol) composite. There were cells-substrate adhesion impairment, morphological changes, cell death and reduction in cell proliferation seen at 2nd and 6th day in most tested scaffold. Cell count result at day-6 showed proliferation inhibition of more than 50% cell death (inhibition value >50) in all tested scaffold. In MTT assay, two scaffolds were proven non-toxic. In conclusion, various scaffold materials showed different toxicity effect. The toxicity and biocompatibility profile in this study is a preliminary data for further research aiming to use those local-made scaffolds to fill human bone defect in various needs.

GENE EXPRESSION PROFILING IN TESTIS AND LIVER OF MICE TO IDENTIFY MODES OF ACTION OF CONAZOLE TOXICITIES

EPA Science Inventory

Gene Expression Profiling in Testis and Liver of Mice to Identify MODES OF ACTION OF Conazole TOXICITies

Amber K. Goetz1, Wenjun Bao2, Judith E. Schmid2, Carmen Wood2, Hongzu Ren2, Deborah S. Best2, Rachel N. Murrell1, John C. Rockett2, Michael G. Narotsky2, Douglas C. Wol...

Protein profiling as early detection biomarkers for TiO2 nanoparticle toxicity in Daphnia magna.

PubMed

Sá-Pereira, Paula; Diniz, Mário S; Moita, Liliana; Pinheiro, Teresa; Mendonça, Elsa; Paixão, Susana M; Picado, Ana

2018-05-01

The mode of action for nanoparticle (NP) toxicity in aquatic organisms is not yet fully understood. In this work, a strategy other than toxicity testing was applied to Daphnia magna exposed to TiO 2 -NPs: the use of nuclear microscopy and the assessment of protein profile. D. magna is a keystone species broadly used as a model system in ecotoxicology. Titanium (Ti) was found in the D. magna digestive tract, mainly in the gut. The penetration of Ti into the epithelial region was greater at higher exposure levels and also observed in eggs in the brood pouch. The protein profile of individuals exposed to different concentrations showed that 2.8 and 5.6 mg/L TiO 2 -NP concentrations induced an over-expression of the majority of proteins, in particular proteins with molecular weight of ∼120, 85 and 15 kDa, while 11.2 mg/L TiO 2 -NP had an inhibitory effect on protein expression. The Matrix-assisted laser desorption ionization with tandem time of flight mass spectrometry (MALDI-TOF/TOF MS) analysis of these proteins consistently identified them as vitellogenin (Vtg)-like proteins, associated with enzymes involved in redox balance. These results indicate that Vtg-like proteins are up-regulated in D. magna exposed to TiO 2 -NPs. Vitellogenesis is associated with the reproduction system, suggesting that TiO 2 -NP exposure can impair reproduction by affecting this process. The precise mode of action of TiO 2 -NPs is still unclear and the results from this study are a first attempt to identify specific proteins as potential markers of TiO 2 -NP toxicity in D. magna, providing useful information for future research.

Profiling the reproductive toxicity of chemicals from multigeneration studies in the toxicity reference database

EPA Science Inventory

Multigeneration reproduction studies are used to characterize parental and offspring systemic toxicity, as well as reproductive toxicity of pesticides, industrial chemicals and pharmaceuticals. Results from 329 multigeneration studies on 316 chemicals have been digitized into sta...

Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline*

PubMed Central

Ranninger, Christina; Rurik, Marc; Limonciel, Alice; Ruzek, Silke; Reischl, Roland; Wilmes, Anja; Jennings, Paul; Hewitt, Philip; Dekant, Wolfgang; Kohlbacher, Oliver; Huber, Christian G.

2015-01-01

Untargeted metabolomics has the potential to improve the predictivity of in vitro toxicity models and therefore may aid the replacement of expensive and laborious animal models. Here we describe a long term repeat dose nephrotoxicity study conducted on the human renal proximal tubular epithelial cell line, RPTEC/TERT1, treated with 10 and 35 μmol·liter−1 of chloroacetaldehyde, a metabolite of the anti-cancer drug ifosfamide. Our study outlines the establishment of an automated and easy to use untargeted metabolomics workflow for HPLC-high resolution mass spectrometry data. Automated data analysis workflows based on open source software (OpenMS, KNIME) enabled a comprehensive and reproducible analysis of the complex and voluminous metabolomics data produced by the profiling approach. Time- and concentration-dependent responses were clearly evident in the metabolomic profiles. To obtain a more comprehensive picture of the mode of action, transcriptomics and proteomics data were also integrated. For toxicity profiling of chloroacetaldehyde, 428 and 317 metabolite features were detectable in positive and negative modes, respectively, after stringent removal of chemical noise and unstable signals. Changes upon treatment were explored using principal component analysis, and statistically significant differences were identified using linear models for microarray assays. The analysis revealed toxic effects only for the treatment with 35 μmol·liter−1 for 3 and 14 days. The most regulated metabolites were glutathione and metabolites related to the oxidative stress response of the cells. These findings are corroborated by proteomics and transcriptomics data, which show, among other things, an activation of the Nrf2 and ATF4 pathways. PMID:26055719

ACCEPT 2: A public library of cluster properties

NASA Astrophysics Data System (ADS)

Donahue, Megan

2012-09-01

The current public ACCEPT database of cluster properties includes radial profiles of Tx, n_elec, entropy, and cooling time. We propose to more than double the current number of clusters in ACCEPT and to expand the current suite of properties to include uniformly measured profiles of gas mass and hydrostatic equilibrium mass along with signatures of dynamical relaxation (centroid shift, power ratios, surface brightness concentration, temperature ratios) and global quantities such as core-excised Tx, Lx, and metallicities. We will explore the relationship between cool cores and dynamical relaxation, the reliability of hydrostatic mass profiles, and the dependence of the gas mass fraction on halo mass, redshift, and the degree of relaxation. ACCEPT2 will enable further community science.

Schiff Bases of Benzothiazol-2-ylamine and Thiazolo[5,4-b] pyridin-2-ylamine as Anticonvulsants: Synthesis, Characterization and Toxicity Profiling.

PubMed

Shukla, Rashmi; Singh, Ajeet P; Sonar, Pankaj K; Mishra, Mudita; Saraf, Shailendra K

2016-01-01

Schiff bases have a broad spectrum of biological activities like antiinflammatory, analgesic, antimicrobial, anticonvulsant, antitubercular, anticancer, antioxidant, anthelmintic and so forth. Thus, after a thorough perusal of literature, it was decided to conjugate benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine with aromatic and heteroaromatic aldehydes to get a series of Schiff bases. Synthesis, characterization, in-silico toxicity profiling and anticonvulsant activity of the Schiff bases of Benzothiazol-2-ylamine and Thiazolo [5, 4-b] pyridin-2-ylamine. Aniline/4-aminopyridine was converted to the corresponding thiourea derivatives, which were cyclized to obtain benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine. Finally, these were condensed with various aromatic and heteroaromatic aldehydes to obtain Schiff bases of benzothiazol-2-ylamine and thiazolo [5, 4-b] pyridin-2-ylamine. The synthesized compounds were characterized and screened for their anticonvulsant activity using maximal electroshock (MES) test and isoniazid (INH) induced convulsions test. In-silico toxicity profiling of all the synthesized compounds was done through "Lazar" and "Osiris" properties explorer. Majority of the compounds were more potent against MES induced convulsions than INH induced convulsions. Schiff bases of benzothiazol-2-ylamine were more effective than thiazolo [5, 4-b] pyridin-2-ylamine against MES induced convulsions. The compound benzothiazol-2-yl-(1H-indol-2-ylmethylene)-amine (VI) was the most potent member of the series against both types of convulsions. Compound VI exhibited the most significant activity profile in both the models. The compounds did not exhibit any carcinogenicity or acute toxicity in the in-silico studies. Thus, it may be concluded that the Schiff bases of benzothiazol-2-ylamine exhibit the potential to be promising and non-toxic anticonvulsant agents.

Results of the Updated NASA Kennedy Space Center 50-MHz Doppler Radar Wind Profiler Operational Acceptance Test

NASA Technical Reports Server (NTRS)

Barbre', Robert E., Jr.; Deker, Ryan K.; Leahy, Frank B.; Huddleston, Lisa

2016-01-01

We present here the methodology and results of the Operational Acceptance Test (OAT) performed on the new Kennedy Space Center (KSC) 50-MHz Doppler Radar Wind Profiler (DRWP). On day-of-launch (DOL), space launch vehicle operators have used data from the DRWP to invalidate winds in prelaunch loads and trajectory assessments due to the DRWP's capability to quickly identify changes in the wind profile within a rapidly-changing wind environment. The previous DRWP has been replaced with a completely new system, which needs to undergo certification testing before being accepted for use in range operations. The new DRWP replaces the previous three-beam system made of coaxial cables and a copper wire ground plane with a four-beam system that uses Yagi antennae with enhanced beam steering capability. In addition, the new system contains updated user interface software while maintaining the same general capability as the previous system. The new DRWP continues to use the Median Filter First Guess (MFFG) algorithm to generate a wind profile from Doppler spectra at each range gate. DeTect (2015) contains further details on the upgrade. The OAT is a short-term test designed so that end users can utilize the new DRWP in a similar manner to the previous DRWP during mission operations at the Eastern Range in the midst of a long-term certification process. This paper describes the Marshall Space Flight Center Natural Environments Branch's (MSFC NE's) analyses to verify the quality and accuracy of the DRWP's meteorological data output as compared to the previous DRWP. Ultimately, each launch vehicle program has the responsibility to certify the system for their own use.

Phenolic profile and antioxidant activity from non-toxic Mexican Jatropha curcas L. shell methanolic extracts.

PubMed

Perea-Domínguez, Xiomara Patricia; Espinosa-Alonso, Laura Gabriela; Hosseinian, Farah; HadiNezhad, Mehri; Valdez-Morales, Maribel; Medina-Godoy, Sergio

2017-03-01

Jatropha curcas seed shells are the by-product obtained during oil extraction process. Recently, its chemical composition has gained attention since its potential applications. The aim of this study was to identify phenolic compounds profile from a non-toxic J. curcas shell from Mexico, besides, evaluate J. curcas shell methanolic extract (JcSME) antioxidant activity. Free, conjugate and bound phenolics were fractionated and quantified (606.7, 193.32 and 909.59 μg/g shell, respectively) and 13 individual phenolic compounds were detected by HPLC. The radical-scavenging activity of JcSME was similar to Trolox and ascorbic acid by DPPH assay while by ABTS assay it was similar to BHT. Effective antioxidant capacity by ORAC was found (426.44 ± 53.39 μmol Trolox equivalents/g shell). The Mexican non-toxic J. curcas shell is rich in phenolic compounds with high antioxidant activity; hence, it could be considerate as a good source of natural antioxidants.

Toxic substances alert program

NASA Technical Reports Server (NTRS)

Junod, T. L.

1978-01-01

A toxicity profile is provided, of 187 toxic substances procured by NASA Lewis Research Center during a 3 1/2 year period, including 27 known or suspected carcinogens. The goal of the program is to assure that the center's health and safety personnel are aware of the procurement and use of toxic substances and to alert and inform the users of these materials as to the toxic characteristics and the control measures needed to ensure their safe use. The program also provides a continuing record of the toxic substances procured, who procured them, what other toxic substances the user has obtained in the past, and where similar materials have been used elsewhere at the center.

Gene expression profiling to characterize sediment toxicity – a pilot study using Caenorhabditis elegans whole genome microarrays

PubMed Central

Menzel, Ralph; Swain, Suresh C; Hoess, Sebastian; Claus, Evelyn; Menzel, Stefanie; Steinberg, Christian EW; Reifferscheid, Georg; Stürzenbaum, Stephen R

2009-01-01

Background Traditionally, toxicity of river sediments is assessed using whole sediment tests with benthic organisms. The challenge, however, is the differentiation between multiple effects caused by complex contaminant mixtures and the unspecific toxicity endpoints such as survival, growth or reproduction. The use of gene expression profiling facilitates the identification of transcriptional changes at the molecular level that are specific to the bio-available fraction of pollutants. Results In this pilot study, we exposed the nematode Caenorhabditis elegans to three sediments of German rivers with varying (low, medium and high) levels of heavy metal and organic contamination. Beside chemical analysis, three standard bioassays were performed: reproduction of C. elegans, genotoxicity (Comet assay) and endocrine disruption (YES test). Gene expression was profiled using a whole genome DNA-microarray approach to identify overrepresented functional gene categories and derived cellular processes. Disaccharide and glycogen metabolism were found to be affected, whereas further functional pathways, such as oxidative phosphorylation, ribosome biogenesis, metabolism of xenobiotics, aging and several developmental processes were found to be differentially regulated only in response to the most contaminated sediment. Conclusion This study demonstrates how ecotoxicogenomics can identify transcriptional responses in complex mixture scenarios to distinguish different samples of river sediments. PMID:19366437

Investigating the chemical profile of regenerated scorpion (Parabuthus transvaalicus) venom in relation to metabolic cost and toxicity.

PubMed

Nisani, Zia; Boskovic, Danilo S; Dunbar, Stephen G; Kelln, Wayne; Hayes, William K

2012-09-01

We investigated the biochemical profile of regenerated venom of the scorpion Parabuthus transvaalicus in relation to its metabolic cost and toxicity. Using a closed-system respirometer, we compared oxygen consumption between milked and unmilked scorpions to determine the metabolic costs associated with the first 192 h of subsequent venom synthesis. Milked scorpions had a substantially (21%) higher mean metabolic rate than unmilked scorpions, with the largest increases in oxygen consumption occurring at approximately 120 h, 162 h, and 186 h post-milking. Lethality tests in crickets indicated that toxicity of the regenerated venom returned to normal levels within 4 d after milking. However, the chemical profile of the regenerated venom, as evaluated by FPLC and MALDI-TOF mass spectrometry, suggested that regeneration of different venom components was asynchronous. Some peptides regenerated quickly, particularly those associated with the scorpion's "prevenom," whereas others required much or all of this time period for regeneration. This asynchrony could explain the different spikes detected in oxygen consumption of milked scorpions as various peptides and other venom components were resynthesized. These observations confirm the relatively high metabolic cost of venom regeneration and suggest that greater venom complexity can be associated with higher costs of venom production. Copyright © 2012 Elsevier Ltd. All rights reserved.

Treosulfan induces distinctive gonadal toxicity compared with busulfan

PubMed Central

Levi, Mattan; Stemmer, Salomon M.; Stein, Jerry; Shalgi, Ruth; Ben-Aharon, Irit

2018-01-01

Treosulfan (L-treitol-1,4-bis-methanesulfonate) has been increasingly incorporated as a main conditioning protocol for hematopoietic stem cell transplantation in pediatric malignant and non-malignant diseases. Treosulfan presents lower toxicity profile than other conventional alkylating agents containing myeloablative and immunosuppressive traits such as busulfan. Yet, whereas busulfan is considered highly gonadotoxic, the gonadal toxicity profile of treosulfan remains to be elucidated. To study the gonadotoxicity of treosulfan, pubertal and prepubertal male and female mice were injected with treosulfan or busulfan and sacrificed one week, one month or six months later. Testicular function was assessed by measurements of sperm properties, testes and epididymides weights as well as markers for testicular reserve, proliferation and apoptosis. Ovarian function was assessed by measurements of ovary weight and markers for ovarian reserve, proliferation and apoptosis. Treosulfan testicular toxicity was milder than that of busulfan toxicity; possibly by sparing the stem spermatogonia in the testicular sanctuary. By contrast, ovarian toxicity of both treosulfan and busulfan was severe and permanent and displayed irreversible reduction of reserve primordial follicles in the ovaries. Our data indicate that treosulfan exerts a different gonadal toxicity profile from busulfan, manifested by mild testicular toxicity and severe ovarian toxicity. PMID:29721205

Major Pesticides Are More Toxic to Human Cells Than Their Declared Active Principles

PubMed Central

Spiroux de Vendômois, Joël; Séralini, Gilles-Eric

2014-01-01

Pesticides are used throughout the world as mixtures called formulations. They contain adjuvants, which are often kept confidential and are called inerts by the manufacturing companies, plus a declared active principle, which is usually tested alone. We tested the toxicity of 9 pesticides, comparing active principles and their formulations, on three human cell lines (HepG2, HEK293, and JEG3). Glyphosate, isoproturon, fluroxypyr, pirimicarb, imidacloprid, acetamiprid, tebuconazole, epoxiconazole, and prochloraz constitute, respectively, the active principles of 3 major herbicides, 3 insecticides, and 3 fungicides. We measured mitochondrial activities, membrane degradations, and caspases 3/7 activities. Fungicides were the most toxic from concentrations 300–600 times lower than agricultural dilutions, followed by herbicides and then insecticides, with very similar profiles in all cell types. Despite its relatively benign reputation, Roundup was among the most toxic herbicides and insecticides tested. Most importantly, 8 formulations out of 9 were up to one thousand times more toxic than their active principles. Our results challenge the relevance of the acceptable daily intake for pesticides because this norm is calculated from the toxicity of the active principle alone. Chronic tests on pesticides may not reflect relevant environmental exposures if only one ingredient of these mixtures is tested alone. PMID:24719846

Sensory Profile, Drivers of Liking, and Influence of Information on the Acceptance of Low-Calorie Synbiotic and Probiotic Chocolate Ice Cream.

PubMed

Peres, Juliana; Esmerino, Erick; da Silva, Alessandra Lins; Racowski, Ilana; Bolini, Helena

2018-05-01

The objective of this study was to evaluate the sensory profile and the influence of the information on the acceptance of the symbiotic chocolate ice cream made with sucrose and different sweeteners (aspartame, sucralose, neotame, Stevia with 60%, 85%, 95%, and 97% of rebaudioside A) through analysis of variance (ANOVA), Tukey's test, and partial least of square (PLS) regression. Quantitative descriptive analysis (QDA) was carried out by 18 assessors, who evaluated the samples in relation to the raised descriptors. Additionally, two acceptance tests (blind/informed) were performed with 120 consumers. The samples sweetened with sucralose and rebaudioside 97% presented similar profile to the control sample, thus having a better potential to replace sucrose in chocolate ice cream. The acceptance test carried out with information had higher scores for the attributes appearance, aroma, flavor, texture, and overall impression. The correlation between data from the acceptance tests and QDA showed that the descriptors "low-energy" and "natural sweetener" claims interfered negatively in the drivers of liking of chocolate ice cream. Therefore, we can conclude that some characteristics unnoticed by consumers were highlighted after providing the information about the product's characteristics. This research is important and contributes to the manufacture and development of low-calorie chocolate ice cream with functional properties, guiding, through suitable sensory and statistical tools, the application of stevia and other artificial sweeteners in products with reduction or total absence of sucrose and highlighting the impact of the labeling of these products on consumer perception. © 2018 Institute of Food Technologists®.

Organic and conventional nonflavored yogurts from the Italian market: study on sensory profiles and consumer acceptability.

PubMed

Toschi, Tullia Gallina; Bendini, Alessandra; Barbieri, Sara; Valli, Enrico; Cezanne, Marie Louise; Buchecker, Kirsten; Canavari, Maurizio

2012-11-01

The sensory properties of food products are an important success factor, especially in the organic market, where many producers and distributors of organic food claim superior taste for their products compared to the conventional alternative. For this reason consumer expectations and preferences, as well as the sensory properties of conventional and organic yogurt, have to be investigated in depth. In this work, the sensory profiling and consumer data of six nonflavored organic and conventional Italian yogurts were elaborated. Some results on the data segmentation (heavy and light users of organic food) and on the effect of information on liking (blind and labeled test) were obtained. Multivariate analysis was carried out to study how the sensory characteristics of 'natural yogurts' drive consumer liking. Consumers' preferences were oriented towards a creamy mouthfeel and smooth visual appearance and for a less acid and fresh taste. In particular, a conventional yogurt was the least accepted, because it was not creamy enough. This paper shows there is room to improve unflavored yogurt to better meet consumer expectations. Sensory profiling did not allow a distinction in odor/taste/texture between organic and conventional samples. However, three of four organic samples were in the region of highest consumer acceptability, fitting well consumers' preference. There was no clear tendency that heavy or light users scored differently in the blind and labeled tests regarding overall liking but, for all, the most liked conventional yogurt scored higher when labeled as organic. Copyright © 2012 Society of Chemical Industry.

Assessing mechanisms of toxicant response in the amphipod Melita plumulosa through transcriptomic profiling.

PubMed

Hook, Sharon E; Osborn, Hannah L; Spadaro, David A; Simpson, Stuart L

2014-01-01

This study describes the function of transcripts with altered abundance in the epibenthic amphipod, Melita plumulosa, following whole-sediment exposure to a series of common environmental contaminants. M. plumulosa were exposed for 48 h to sediments spiked and equilibrated with the following contaminants at concentrations predicted to cause sublethal effects to reproduction: porewater ammonia 30 mg L(-1); bifenthrin at 100 μg kg(-1); fipronil at 50 μg kg(-1); 0.6% diesel; 0.3% crude oil; 250 mg Cu kg(-1); 400 mg Ni kg(-1); and 400 mg Zn kg(-1). RNA was extracted and hybridized against a custom Agilent microarray developed for this species. Although the microarray represented a partial transcriptome and not all features on the array could be annotated, unique transcriptomic profiles were generated for each of the contaminant exposures. Hierarchical clustering grouped the expression profiles together by contaminant class, with copper and zinc, the petroleum products and nickel, and the pesticides each forming a distinct cluster. Many of the transcriptional changes observed were consistent with patterns previously described in other crustaceans. The changes in the transcriptome demonstrated that contaminant exposure caused changes in digestive function, growth and moulting, and the cytoskeleton following metal exposure, whereas exposure to petroleum products caused changes in carbohydrate metabolism, xenobiotic metabolism and hormone cycling. Functional analysis of these gene expression profiles can provide a better understanding of modes of toxic action and permits the prediction of mixture effects within contaminated ecosystems. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Social Acceptance of Wind: A Brief Overview (Presentation)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lantz, E.

This presentation discusses concepts and trends in social acceptance of wind energy, profiles recent research findings, and discussions mitigation strategies intended to resolve wind power social acceptance challenges as informed by published research and the experiences of individuals participating in the International Energy Agencies Working Group on Social Acceptance of Wind Energy

SEDIMENT TOXICITY ASSESSMENT: COMPARISON OF STANDARD AND NEW TESTING DESIGNS

EPA Science Inventory

Standard methods of sediment toxicity testing are fairly well accepted; however, as with all else, evolution of these methods is inevitable. We compared a standard ASTM 10-day amphipod toxicity testing method with smaller, 48- and 96-h test methods using very toxic and reference ...

Toxicity profile of choline chloride-based deep eutectic solvents for fungi and Cyprinus carpio fish.

PubMed

Juneidi, Ibrahim; Hayyan, Maan; Mohd Ali, Ozair

2016-04-01

An investigation on the toxicological assessment of 10 choline chloride (ChCl)-based deep eutectic solvents (DESs) towards four fungi strains and Cyprinus carpio fish was conducted. ChCl was combined with materials from different chemical groups such as alcohols, sugars, acids and others to form DESs. The study was carried out on the individual DES components, their aqueous mixture before DES formation and their formed DESs. The agar disc diffusion method was followed to investigate their toxicity on four fungi strains selected as a model of eukaryotic microorganisms (Phanerochaete chrysosporium, Aspergillus niger, Lentinus tigrinus and Candida cylindracea). Among these DESs, ChCl:ZnCl2 exhibited the highest inhibition zone diameter towards the tested fungi growth in vitro, followed by the acidic group (malonic acid and p-toluenesulfonic acid). Another study was conducted to test the acute toxicity and determine the lethal concentration at 50 % (LC50) of the same DESs on C. carpio fish. The inhibition range and LC50 of DESs were found to be different from their individual components. DESs were found to be less toxic than their mixture or individual components. The LC50 of ChCl:MADES is much higher than that of ChCl:MAMix. Moreover, the DESs acidic group showed a lower inhibition zone on fungi growth. Thus, DESs should be considered as new components with different physicochemical properties and toxicological profiles, and not merely compositions of compounds.

Screening of toxic potential of graphene family nanomaterials using in vitro and alternative in vivo toxicity testing systems.

PubMed

Chatterjee, Nivedita; Yang, Ji Su; Park, Kwangsik; Oh, Seung Min; Park, Jeonggue; Choi, Jinhee

2015-01-01

The widely promising applications of graphene nanomaterials raise considerable concerns regarding their environmental and human health risk assessment. The aim of the current study was to evaluate the toxicity profiling of graphene family nananomaterials (GFNs) in alternative in vitro and in vivo toxicity testing models. The GFNs used in this study are graphene nanoplatelets ([GNPs]-pristine, carboxylate [COOH] and amide [NH2]) and graphene oxides (single layer [SLGO] and few layers [FLGO]). The human bronchial epithelial cells (Beas2B cells) as in vitro system and the nematode Caenorhabditis elegans as in vivo system were used to profile the toxicity response of GFNs. Cytotoxicity assays, colony formation assay for cellular toxicity and reproduction potentiality in C. elegans were used as end points to evaluate the GFNs' toxicity. In general, GNPs exhibited higher toxicity than GOs in Beas2B cells, and among the GNPs the order of toxicity was pristine>NH2>COOH. Although the order of toxicity of the GNPs was maintained in C. elegans reproductive toxicity, but GOs were found to be more toxic in the worms than GNPs. In both systems, SLGO exhibited profoundly greater dose dependency than FLGO. The possible reason of their differential toxicity lay in their distinctive physicochemical characteristics and agglomeration behavior in the exposure media. The present study revealed that the toxicity of GFNs is dependent on the graphene nanomaterial's physical forms, surface functionalizations, number of layers, dose, time of exposure and obviously, on the alternative model systems used for toxicity assessment.

Results of the NASA Kennedy Space Center 50-MHz Doppler Radar Wind Profiler Operational Acceptance Test

NASA Technical Reports Server (NTRS)

Barbre', Robert E., Jr.; Decker, Ryan K.; Leahy, Frank B.; Huddleston, Lisa

2016-01-01

This paper presents results of the new Kennedy Space Center (KSC) 50-MHz Doppler Radar Wind Profiler (DRWP) Operational Acceptance Test (OAT). The goal of the OAT was to verify the data quality of the new DRWP against the performance of the previous DRWP in order to use wind data derived by the new DRWP for space launch vehicle operations support at the Eastern Range. The previous DRWP was used as a situational awareness asset for mission operations to identify rapid changes in the wind environment that weather balloons cannot depict. The Marshall Space Flight Center's Natural Environments Branch assessed data from the new DRWP collected during Jan-Feb 2015 against a specified set of test criteria. Data examination verified that the DRWP provides complete profiles every five minutes from 1.8-19.5 km in vertical increments of 150 m. Analysis of 49 concurrent DRWP and balloon profiles presented root mean square wind component differences around 2.0 m/s. Evaluation of the DRWP's coherence between five-minute wind pairs found the effective vertical resolution to be Nyquist-limited at 300 m for both wind components. In addition, the sensitivity to rejecting data that do not have adequate signal was quantified. This paper documents the data, quality control procedures, methodology, and results of each analysis.

Haematolohical profile of subacute oral toxicity of molybdenum and ameliorative efficacy of copper salt in goats.

PubMed

Kusum; Raina, R; Verma, P K; Pankaj, N K; Kant, V; Kumar, J; Srivastava, A K

2010-07-01

Molybdenum toxicity produces a state of secondary hypocuprosis, resulting into alterations in normal hematological profile. In the present study, ammonium molybdate alone and with copper sulfate (II) pentahydrate (ameliorative agent) was administered orally for 30 consecutive days in healthy goats of group 1 and 2, respectively, to access the effect on the hematological profile on different predetermined days of dosing. Administration of ammonium molybdate alone produced significant decline in the mean values of hemoglobin (Hb), packed cell volume (PCV), total leukocyte count (TLC), total erythrocyte count (TEC), and mean corpuscular hemoglobin concentration (MCHC), with a significant increase in neutrophil level and mean corpuscular volume (MCV). However, values of erythrocyte sedimentation rate, mean corpuscular hemoglobin, and differential leukocyte count were not significantly altered. On comparing observations of ameliorative group with the group 1 goats, it is concluded that the ameliorative copper salt has beneficial effects in alleviating the alterations in the values of Hb, PCV, TLC, TEC, MCV, MCHC, and neutrophils.

Haematolohical Profile of Subacute Oral Toxicity of Molybdenum and Ameliorative Efficacy of Copper Salt in Goats

PubMed Central

Kusum; Raina, R.; Verma, P. K.; Pankaj, N. K.; Kant, V.; Kumar, J.; Srivastava, A. K.

2010-01-01

Molybdenum toxicity produces a state of secondary hypocuprosis, resulting into alterations in normal hematological profile. In the present study, ammonium molybdate alone and with copper sulfate (II) pentahydrate (ameliorative agent) was administered orally for 30 consecutive days in healthy goats of group 1 and 2, respectively, to access the effect on the hematological profile on different predetermined days of dosing. Administration of ammonium molybdate alone produced significant decline in the mean values of hemoglobin (Hb), packed cell volume (PCV), total leukocyte count (TLC), total erythrocyte count (TEC), and mean corpuscular hemoglobin concentration (MCHC), with a significant increase in neutrophil level and mean corpuscular volume (MCV). However, values of erythrocyte sedimentation rate, mean corpuscular hemoglobin, and differential leukocyte count were not significantly altered. On comparing observations of ameliorative group with the group 1 goats, it is concluded that the ameliorative copper salt has beneficial effects in alleviating the alterations in the values of Hb, PCV, TLC, TEC, MCV, MCHC, and neutrophils. PMID:21170251

Profiling Developmental Toxicity of 387 Environmental Chemicals using EPA’s Toxicity Reference Database (ToxRefDB)

EPA Science Inventory

EPA's Toxicity Reference Databases (ToxRefDB) was developed by the National Center for Computational Toxicology in partnership with EPA's Office of Pesticide Programs, to store data derived from in vivo animal toxicity studies [www.epa.gov/ncct/toxrefdb/]. The initial build of To...

Acylcarnitine Profiles in Acetaminophen Toxicity in the Mouse: Comparison to Toxicity, Metabolism and Hepatocyte Regeneration

PubMed Central

Bhattacharyya, Sudeepa; Pence, Lisa; Beger, Richard; Chaudhuri, Shubhra; McCullough, Sandra; Yan, Ke; Simpson, Pippa; Hennings, Leah; Hinson, Jack; James, Laura

2013-01-01

High doses of acetaminophen (APAP) result in hepatotoxicity that involves metabolic activation of the parent compound, covalent binding of the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI) to liver proteins, and depletion of hepatic glutathione. Impaired fatty acid β-oxidation has been implicated in previous studies of APAP-induced hepatotoxicity. To better understand relationships between toxicity and fatty acid β-oxidation in the liver in APAP toxicity, metabolomic assays for long chain acylcarnitines were examined in relationship to established markers of liver toxicity, oxidative metabolism, and liver regeneration in a time course study in mice. Male B6C3F1 mice were treated with APAP (200 mg/kg IP) or saline and sacrificed at 1, 2, 4, 8, 24 or 48 h after APAP. At 1 h, hepatic glutathione was depleted and APAP protein adducts were markedly increased. Alanine aminotransferase (ALT) levels were elevated at 4 and 8 h, while proliferating cell nuclear antigen (PCNA) expression, indicative of hepatocyte regeneration, was apparent at 24 h and 48 h. Elevations of palmitoyl, oleoyl and myristoyl carnitine were apparent by 2–4 h, concurrent with the onset of Oil Red O staining in liver sections. By 8 h, acylcarnitine levels were below baseline levels and remained low at 24 and 48 h. A partial least squares (PLS) model suggested a direct association of acylcarnitine accumulation in serum to APAP protein adduct and hepatic glutathione levels in mice. Overall, the kinetics of serum acylcarnitines in APAP toxicity in mice followed a biphasic pattern involving early elevation after the metabolism phases of toxicity and later depletion of acylcarnitines. PMID:24958141

Examining the antimicrobial activity and toxicity to animal cells of different types of CO-releasing molecules.

PubMed

Nobre, Lígia S; Jeremias, Hélia; Romão, Carlos C; Saraiva, Lígia M

2016-01-28

can show opposite toxicity profiles towards bacteria and eukaryotic cells; (ii) their activity can be modulated through manipulation of the ancillary ligands, as shown with the three {Ru(CO)3}(2+) and two zerovalent Mo based CORMs; and (iii) their toxicity to eukaryotic cells can be made acceptably low. With this new approach, this work contributes to the understanding of the roots of the bactericidal action of CORMs and helps in establishing strategies for their development into a new class of antibiotics.

Longitudinal Stability of Social Competence Indicators in a Portuguese Sample: Q-Sort Profiles of Social Competence, Measures of Social Engagement, and Peer Sociometric Acceptance

ERIC Educational Resources Information Center

Santos, António J.; Vaughn, Brian E.; Peceguina, Inês; Daniel, João R.

2014-01-01

This study examines the temporal stability (over 3 years) of individual differences in 3 domains relevant to preschool children's social competence: social engagement/motivation, profiles of behavior and personality attributes characteristic of socially competent young children, and peer acceptance. Each domain was measured with multiple…

Informing the Selection of Screening Hit Series with in Silico Absorption, Distribution, Metabolism, Excretion, and Toxicity Profiles.

PubMed

Sanders, John M; Beshore, Douglas C; Culberson, J Christopher; Fells, James I; Imbriglio, Jason E; Gunaydin, Hakan; Haidle, Andrew M; Labroli, Marc; Mattioni, Brian E; Sciammetta, Nunzio; Shipe, William D; Sheridan, Robert P; Suen, Linda M; Verras, Andreas; Walji, Abbas; Joshi, Elizabeth M; Bueters, Tjerk

2017-08-24

High-throughput screening (HTS) has enabled millions of compounds to be assessed for biological activity, but challenges remain in the prioritization of hit series. While biological, absorption, distribution, metabolism, excretion, and toxicity (ADMET), purity, and structural data are routinely used to select chemical matter for further follow-up, the scarcity of historical ADMET data for screening hits limits our understanding of early hit compounds. Herein, we describe a process that utilizes a battery of in-house quantitative structure-activity relationship (QSAR) models to generate in silico ADMET profiles for hit series to enable more complete characterizations of HTS chemical matter. These profiles allow teams to quickly assess hit series for desirable ADMET properties or suspected liabilities that may require significant optimization. Accordingly, these in silico data can direct ADMET experimentation and profoundly impact the progression of hit series. Several prospective examples are presented to substantiate the value of this approach.

Occurrence, profiles, and toxic equivalents of chlorinated and brominated polycyclic aromatic hydrocarbons in E-waste open burning soils.

PubMed

Nishimura, Chiya; Horii, Yuichi; Tanaka, Shuhei; Asante, Kwadwo Ansong; Ballesteros, Florencio; Viet, Pham Hung; Itai, Takaaki; Takigami, Hidetaka; Tanabe, Shinsuke; Fujimori, Takashi

2017-06-01

We conducted this study to assess the occurrence, profiles, and toxicity of chlorinated polycyclic aromatic hydrocarbons (Cl-PAHs) and brominated polycyclic aromatic hydrocarbons (Br-PAHs) in e-waste open burning soils (EOBS). In this study, concentrations of 15 PAHs, 26 Cl-PAHs and 14 Br-PAHs were analyzed in EOBS samples. We found that e-waste open burning is an important emission source of Cl-PAHs and Br-PAHs as well as PAHs. Concentrations of total Cl-PAHs and Br-PAHs in e-waste open burning soil samples ranged from 21 to 2800 ng/g and from 5.8 to 520 ng/g, respectively. Compared with previous studies, the mean of total Cl-PAH concentrations of the EOBS samples in this study was higher than that of electronic shredder waste, that of bottom ash, and comparable to fly ash from waste incinerators in Korea and Japan. The mean of total Br-PAH concentrations of the EOBS samples was generally three to four orders of magnitude higher than those in incinerator bottom ash and comparable to incinerator fly ash, although the number of Br-PAH congeners measured differed among studies. We also found that the Cl-PAH and Br-PAH profiles were similar among all e-waste open burning soil samples but differed from those in waste incinerator fly ash. The profiles and principal component analysis results suggested a unique mechanism of Cl-PAH and Br-PAH formation in EOBS. In addition, the Cl-PAHs and Br-PAHs showed high toxicities equivalent to PCDD/Fs measured in same EOBS samples when calculated based on their relative potencies to benzo[a]pyrene. Along with chlorinated and brominated dioxins and PAHs, Cl-PAHs and Br-PAHs are important environmental pollutants to investigate in EOBS. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Simplest Flowchart Stating the Mechanisms for Organic Xenobiotics-induced Toxicity: Can it Possibly be Accepted as a "Central Dogma" for Toxic Mechanisms?

PubMed

Park, Yeong-Chul; Lee, Sundong; Cho, Myung-Haing

2014-09-01

Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems.

Prevalidation of an Acute Inhalation Toxicity Test Using the EpiAirway In Vitro Human Airway Model.

PubMed

Jackson, George R; Maione, Anna G; Klausner, Mitchell; Hayden, Patrick J

2018-06-01

Introduction: Knowledge of acute inhalation toxicity potential is important for establishing safe use of chemicals and consumer products. Inhalation toxicity testing and classification procedures currently accepted within worldwide government regulatory systems rely primarily on tests conducted in animals. The goal of the current work was to develop and prevalidate a nonanimal ( in vitro ) test for determining acute inhalation toxicity using the EpiAirway™ in vitro human airway model as a potential alternative for currently accepted animal tests. Materials and Methods: The in vitro test method exposes EpiAirway tissues to test chemicals for 3 hours, followed by measurement of tissue viability as the test endpoint. Fifty-nine chemicals covering a broad range of toxicity classes, chemical structures, and physical properties were evaluated. The in vitro toxicity data were utilized to establish a prediction model to classify the chemicals into categories corresponding to the currently accepted Globally Harmonized System (GHS) and the Environmental Protection Agency (EPA) system. Results: The EpiAirway prediction model identified in vivo rat-based GHS Acute Inhalation Toxicity Category 1-2 and EPA Acute Inhalation Toxicity Category I-II chemicals with 100% sensitivity and specificity of 43.1% and 50.0%, for GHS and EPA acute inhalation toxicity systems, respectively. The sensitivity and specificity of the EpiAirway prediction model for identifying GHS specific target organ toxicity-single exposure (STOT-SE) Category 1 human toxicants were 75.0% and 56.5%, respectively. Corrosivity and electrophilic and oxidative reactivity appear to be the predominant mechanisms of toxicity for the most highly toxic chemicals. Conclusions: These results indicate that the EpiAirway test is a promising alternative to the currently accepted animal tests for acute inhalation toxicity.

Deriving allowable daily intakes for systemic toxicants lacking chronic toxicity data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Layton, D.W.; Mallon, B.J.; Rosenblatt, D.H.

1987-03-01

The lack of human toxicological data for most chemical compounds makes it difficult to quickly assess health risks associated with exposure to contaminants at hazardous waste sites. It would therefore be advantageous to have a technique for estimating acceptable daily intakes (ADIs) of potentially toxic substances based on more widely available animal toxicity data. This article focuses on the use of LD50 data to derive provisional ADIs, and it suggests multiplying oral LD50 values (expressed in mg/kg of body wt) by a factor in the range of 5 X 10(-6) to 1 X 10(-5) day-1 to convert them to suchmore » ADIs. It is emphasized that these interim ADI values are no substitute for toxicity testing, but that such testing would most likely result in higher ADI estimates.« less

Understanding Genetic Toxicity Through Data Mining: The Process of Building Knowledge by Integrating Multiple Genetic Toxicity Databases

EPA Science Inventory

This paper demonstrates the usefulness of representing a chemical by its structural features and the use of these features to profile a battery of tests rather than relying on a single toxicity test of a given chemical. This paper presents data mining/profiling methods applied in...

PROFILING GENE EXPRESSION IN HUMAN H295R ADRENOCORTICAL CARCINOMA CELLS AND RAT TESTES TO IDENTIFY PATHWAYS OF TOXICITY FOR CONAZOLE FUNGICIDES

EPA Science Inventory

Profiling Gene Expression in Human H295R Adrenocortical Carcinoma Cells and Rat Testes to Identify Pathways of Toxicity for Conazole Fungicides
Ren1, H., Schmid1, J., Retief2, J., Turpaz2, Y.,Zhang3, X.,Jones3, P., Newsted3, J.,Giesy3, J., Wolf1, D.,Wood1, C., Bao1, W., Dix1, ...

Prevalidation of an Acute Inhalation Toxicity Test Using the EpiAirway In Vitro Human Airway Model

PubMed Central

Jackson, George R.; Maione, Anna G.; Klausner, Mitchell

2018-01-01

Abstract Introduction: Knowledge of acute inhalation toxicity potential is important for establishing safe use of chemicals and consumer products. Inhalation toxicity testing and classification procedures currently accepted within worldwide government regulatory systems rely primarily on tests conducted in animals. The goal of the current work was to develop and prevalidate a nonanimal (in vitro) test for determining acute inhalation toxicity using the EpiAirway™ in vitro human airway model as a potential alternative for currently accepted animal tests. Materials and Methods: The in vitro test method exposes EpiAirway tissues to test chemicals for 3 hours, followed by measurement of tissue viability as the test endpoint. Fifty-nine chemicals covering a broad range of toxicity classes, chemical structures, and physical properties were evaluated. The in vitro toxicity data were utilized to establish a prediction model to classify the chemicals into categories corresponding to the currently accepted Globally Harmonized System (GHS) and the Environmental Protection Agency (EPA) system. Results: The EpiAirway prediction model identified in vivo rat-based GHS Acute Inhalation Toxicity Category 1–2 and EPA Acute Inhalation Toxicity Category I–II chemicals with 100% sensitivity and specificity of 43.1% and 50.0%, for GHS and EPA acute inhalation toxicity systems, respectively. The sensitivity and specificity of the EpiAirway prediction model for identifying GHS specific target organ toxicity-single exposure (STOT-SE) Category 1 human toxicants were 75.0% and 56.5%, respectively. Corrosivity and electrophilic and oxidative reactivity appear to be the predominant mechanisms of toxicity for the most highly toxic chemicals. Conclusions: These results indicate that the EpiAirway test is a promising alternative to the currently accepted animal tests for acute inhalation toxicity. PMID:29904643

"Would you accept having your DNA profile inserted in the National Forensic DNA database? Why?" Results of a questionnaire applied in Portugal.

PubMed

Machado, Helena; Silva, Susana

2014-01-01

The creation and expansion of forensic DNA databases might involve potential threats to the protection of a range of human rights. At the same time, such databases have social benefits. Based on data collected through an online questionnaire applied to 628 individuals in Portugal, this paper aims to analyze the citizens' willingness to donate voluntarily a sample for profiling and inclusion in the National Forensic DNA Database and the views underpinning such a decision. Nearly one-quarter of the respondents would indicate 'no', and this negative response increased significantly with age and education. The overriding willingness to accept the inclusion of the individual genetic profile indicates an acknowledgement of the investigative potential of forensic DNA technologies and a relegation of civil liberties and human rights to the background, owing to the perceived benefits of protecting both society and the individual from crime. This rationale is mostly expressed by the idea that all citizens should contribute to the expansion of the National Forensic DNA Database for reasons that range from the more abstract assumption that donating a sample for profiling would be helpful in fighting crime to the more concrete suggestion that everyone (criminals and non-criminals) should be in the database. The concerns with the risks of accepting the donation of a sample for genetic profiling and inclusion in the National Forensic DNA Database are mostly related to lack of control and insufficient or unclear regulations concerning safeguarding individuals' data and supervising the access and uses of genetic data. By providing an empirically-grounded understanding of the attitudes regarding willingness to donate voluntary a sample for profiling and inclusion in a National Forensic DNA Database, this study also considers the citizens' perceived benefits and risks of operating forensic DNA databases. These collective views might be useful for the formation of international common

The Simplest Flowchart Stating the Mechanisms for Organic Xenobiotics-induced Toxicity: Can it Possibly be Accepted as a “Central Dogma” for Toxic Mechanisms?

PubMed Central

Lee, Sundong; Cho, Myung-Haing

2014-01-01

Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems. PMID:25343011

[Acceptance and rejection of vasectomy in rural males].

PubMed

García Moreno, Juan; Solano Sainos, Luis Miguel

2005-01-01

One problem in rural population is the gap between coverage of contraception and scant masculine participation, which could be due to lack of information of to other sociocultural factors. We investigated, in two stages, the characteristics or the profile of the sexual and reproductive behavior of males in an exploratory study by means of focus groups to determine their relevant motivations and characteristics and subsequently, a structured questionnaire to ascertain the magnitude of the factors explored. The population corresponded to zones of rural hospital medical services zones of medical services in seven ethnic groups of the Mexican Republic and included men who accepted and who rejected vasectomy. The profile of males who accepted vasectomy allowed to determine that there exist a unsatisfied demand for contraceptive protection and the desire of not having additional children; in addition, we found that the decision to accept vasectomy is determined to a greater extent for reasons different from that of information on the contraceptive method. The important proportion of males who were non-users of contraceptive methods who accepted vasectomy supposed information on contraception to be the most consistent reason; nonetheless, this information was not considered sufficient and timely; thus, adverse economic situation, a certain condition related with the couple such as health or love for the female partner are the more weighty reasons for deciding to accept vasectomy, while the fear of poor sexual performance is the most powerful factor for rejection of vasectomy. Masculine participation in family planning is a factor that conditions contraceptive coverage and its respective benefits. The profile of the male who accepts vasectomy aids in identifying candidates forthe procedure and in reducing unsatisfied demand. Greater diffusion of information of the contraceptive method of vasectomy, greater links between male needs and vasectomy, and maintaining or

Environmental Pollution, Toxicity Profile and Treatment Approaches for Tannery Wastewater and Its Chemical Pollutants.

PubMed

Saxena, Gaurav; Chandra, Ram; Bharagava, Ram Naresh

Leather industries are key contributors in the economy of many developing countries, but unfortunately they are facing serious challenges from the public and governments due to the associated environmental pollution. There is a public outcry against the industry due to the discharge of potentially toxic wastewater having alkaline pH, dark brown colour, unpleasant odour, high biological and chemical oxygen demand, total dissolved solids and a mixture of organic and inorganic pollutants. Various environment protection agencies have prioritized several chemicals as hazardous and restricted their use in leather processing however; many of these chemicals are used and discharged in wastewater. Therefore, it is imperative to adequately treat/detoxify the tannery wastewater for environmental safety. This paper provides a detail review on the environmental pollution and toxicity profile of tannery wastewater and chemicals. Furthermore, the status and advances in the existing treatment approaches used for the treatment and/or detoxification of tannery wastewater at both laboratory and pilot/industrial scale have been reviewed. In addition, the emerging treatment approaches alone or in combination with biological treatment approaches have also been considered. Moreover, the limitations of existing and emerging treatment approaches have been summarized and potential areas for further investigations have been discussed. In addition, the clean technologies for waste minimization, control and management are also discussed. Finally, the international legislation scenario on discharge limits for tannery wastewater and chemicals has also been discussed country wise with discharge standards for pollution prevention due to tannery wastewater.

Gene expression profiling in liver and testis of rats to characterize the toxicity of triazole fungicides.

PubMed

Tully, Douglas B; Bao, Wenjun; Goetz, Amber K; Blystone, Chad R; Ren, Hongzu; Schmid, Judith E; Strader, Lillian F; Wood, Carmen R; Best, Deborah S; Narotsky, Michael G; Wolf, Douglas C; Rockett, John C; Dix, David J

2006-09-15

Four triazole fungicides were studied using toxicogenomic techniques to identify potential mechanisms of action. Adult male Sprague-Dawley rats were dosed for 14 days by gavage with fluconazole, myclobutanil, propiconazole, or triadimefon. Following exposure, serum was collected for hormone measurements, and liver and testes were collected for histology, enzyme biochemistry, or gene expression profiling. Body and testis weights were unaffected, but liver weights were significantly increased by all four triazoles, and hepatocytes exhibited centrilobular hypertrophy. Myclobutanil exposure increased serum testosterone and decreased sperm motility, but no treatment-related testis histopathology was observed. We hypothesized that gene expression profiles would identify potential mechanisms of toxicity and used DNA microarrays and quantitative real-time PCR (qPCR) to generate profiles. Triazole fungicides are designed to inhibit fungal cytochrome P450 (CYP) 51 enzyme but can also modulate the expression and function of mammalian CYP genes and enzymes. Triazoles affected the expression of numerous CYP genes in rat liver and testis, including multiple Cyp2c and Cyp3a isoforms as well as other xenobiotic metabolizing enzyme (XME) and transporter genes. For some genes, such as Ces2 and Udpgtr2, all four triazoles had similar effects on expression, suggesting possible common mechanisms of action. Many of these CYP, XME and transporter genes are regulated by xeno-sensing nuclear receptors, and hierarchical clustering of CAR/PXR-regulated genes demonstrated the similarities of toxicogenomic responses in liver between all four triazoles and in testis between myclobutanil and triadimefon. Triazoles also affected expression of multiple genes involved in steroid hormone metabolism in the two tissues. Thus, gene expression profiles helped identify possible toxicological mechanisms of the triazole fungicides.

Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review.

PubMed

Mushtaq, Adeela; Kapoor, Vikas; Latif, Azka; Iftikhar, Ahmad; Zahid, Umar; McBride, Ali; Abraham, Ivo; Riaz, Irbaz Bin; Anwer, Faiz

2018-05-01

Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70 mg/m2 dose of CFZ vs standard 20-27 mg/m2 dose in NDMM and RRMM. Copyright © 2018 Elsevier B.V. All rights reserved.

Ocular toxicity of fludarabine

PubMed Central

Ding, Xiaoyan; Herzlich, Alexandra A; Bishop, Rachel; Tuo, Jingsheng; Chan, Chi-Chao

2008-01-01

The purine analogs, fludarabine and cladribine represent an important class of chemotherapy agents used to treat a broad spectrum of lymphoid malignancies. Their toxicity profiles include dose-limiting myelosuppression, immunosuppression, opportunistic infection and severe neurotoxicity. This review summarizes the neurotoxicity of high- and standard-dose fludarabine, focusing on the clinical and pathological manifestations in the eye. The mechanisms of ocular toxicity are probably multifactorial. With increasing clinical use, an awareness of the neurological and ocular vulnerability, particularly to fludarabine, is important owing to the potential for life- and sight-threatening consequences. PMID:18461151

Management of pegylated interferon alpha toxicity in adjuvant therapy of melanoma.

PubMed

Daud, Adil; Soon, Christopher; Dummer, Reinhard; Eggermont, Alexander M M; Hwu, Wen-Jen; Grob, Jean Jacques; Garbe, Claus; Hauschild, Axel

2012-08-01

Both native IFNα2b and pegylated IFNα2b (PegIFNα2b) are approved for the adjuvant treatment of high-risk melanoma. This review compares the toxicity profiles of high-dose IFNα2b (HDI) and PegIFNα2b, and provides recommendations on the management of common PegIFNα2b-related toxicities, based on available clinical data and published literature. The toxicity profile of PegIFNα2b at the approved dose (6 μg/kg/week for 8 weeks then 3 μg/kg/week for up to 5 years) is qualitatively similar to HDI in melanoma. The most common adverse events (AEs) are fatigue, anorexia, hepatotoxicity, flu-like symptoms, injection site reactions and depression. However, fatigue and flu-like symptoms appear less severe with PegIFNα2b, and toxicity seems to occur earlier, whereas with HDI toxicity may increase with time. Most AEs can be managed effectively by dose modification and aggressive symptom control. Dosing to tolerance using a three-step dose reduction schedule to maintain an ECOG performance status of 0 - 1 may enable patients experiencing toxicity to remain on treatment; this can be applied readily in clinical practice. PegIFNα2b is therefore a valuable alternative option for adjuvant treatment in melanoma, with a toxicity profile similar to that of HDI overall but a more convenient administration schedule.

Fluorinated analogs of malachite green: synthesis and toxicity.

PubMed

Kraus, George A; Jeon, Insik; Nilsen-Hamilton, Marit; Awad, Ahmed M; Banerjee, Jayeeta; Parvin, Bahram

2008-04-27

A series of fluorinated analogs of malachite green (MG) have been synthesized and their toxicity to Saccharomyces cerevisiae and a human ovarian epithelial cell line examined. The toxicity profiles were found to be different for these two species. Two analogs, one with 2,4-difluoro substitution and the other with 2-fluoro substitution seem to be the most promising analogs because they showed the lowest toxicity to the human cells.

Use of Zebrafish Larvae as a Multi-Endpoint Platform to Characterize the Toxicity Profile of Silica Nanoparticles.

PubMed

Pham, Duc-Hung; De Roo, Bert; Nguyen, Xuan-Bac; Vervaele, Mattias; Kecskés, Angela; Ny, Annelii; Copmans, Daniëlle; Vriens, Hanne; Locquet, Jean-Pierre; Hoet, Peter; de Witte, Peter A M

2016-11-22

Nanomaterials are being extensively produced and applied in society. Human and environmental exposures are, therefore, inevitable and so increased attention is being given to nanotoxicity. While silica nanoparticles (NP) are one of the top five nanomaterials found in consumer and biomedical products, their toxicity profile is poorly characterized. In this study, we investigated the toxicity of silica nanoparticles with diameters 20, 50 and 80 nm using an in vivo zebrafish platform that analyzes multiple endpoints related to developmental, cardio-, hepato-, and neurotoxicity. Results show that except for an acceleration in hatching time and alterations in the behavior of zebrafish embryos/larvae, silica NPs did not elicit any developmental defects, nor any cardio- and hepatotoxicity. The behavioral alterations were consistent for both embryonic photomotor and larval locomotor response and were dependent on the concentration and the size of silica NPs. As embryos and larvae exhibited a normal touch response and early hatching did not affect larval locomotor response, the behavior changes observed are most likely the consequence of modified neuroactivity. Overall, our results suggest that silica NPs do not cause any developmental, cardio- or hepatotoxicity, but they pose a potential risk for the neurobehavioral system.

Acute and sub-chronic toxicity of Cajanus cajan leaf extracts.

PubMed

Tang, Rong; Tian, Ru-Hua; Cai, Jia-Zhong; Wu, Jun-Hui; Shen, Xiao-Ling; Hu, Ying-Jie

2017-12-01

The leaves of Cajanus cajan (L.) Millsp. (Fabaceae) have diverse bioactivities, but little safety data are reported. This study examines the toxicological profiles of C. cajan leaf extracts. The leaves were extracted by water or 90% ethanol to obtain water or ethanol extract (WEC or EEC). EEC was suspended in water and successively fractionated into dichloroform and n-butanol extracts (DEC and BEC). Marker compounds of the extracts were monitored by high-performance liquid chromatography (HPLC). Kunming mice were administered with a single maximum acceptable oral dose (15.0 g/kg for WEC, EEC and BEC and 11.3 g/kg for DEC) to determine death rate or maximal tolerated doses (MTDs). In sub-chronic toxicity investigation, Sprague-Dawley rats were orally given WEC or EEC at 1.5, 3.0 or 6.0 g/kg doses for four weeks and observed for two weeks after dosing to determine toxicological symptoms, histopathology, biochemistry and haematology. Flavonoids and stilbenes in the extracts were assayed. In acute toxicity test, no mortality and noted alterations in weight and behavioural abnormality were observed, and the maximum oral doses were estimated as MTDs. In sub-chronic toxicity study, no mortality and significant variances in haematological and biochemical parameters or organ histopathology were observed, but increased kidney weight in 3.0 g/kg WEC- or 3.0 and 6.0 g/kg EEC-treated female rats, and reduced testes and epididymis weight in EEC-treated male rats were recorded. These changes returned to the level of control after recovery period. Acute and sub-chronic toxicity of Cajanus cajan leaf extracts was not observed.

Bully/Victim Profiles’ Differential Risk for Worsening Peer Acceptance: The Role of Friendship

PubMed Central

Kochel, Karen P.; Ladd, Gary W.; Bagwell, Catherine L.; Yabko, Brandon A.

2015-01-01

Study aims were to: (1) evaluate the association between bully/victim profiles, derived via latent profile analysis (LPA), and changes in peer acceptance from the fall to spring of 7th grade, and (2) investigate the likelihood of friendlessness, and the protective function of mutual friendship, among identified profiles. Participants were 2,587 7th graders; peer nomination and rating-scale data were collected in the fall and spring. Four profiles, including bullies, victims, bully-victims, and uninvolved adolescents, were identified at each time point. Findings showed that for victims, more so than for bullies and uninvolved profiles, acceptance scores worsened over time. Results further revealed that bully-victim and victim profiles included a greater proportion of friendless youth relative to the bully profile, which, in turn, contained a greater proportion of friendless adolescents than the uninvolved profile. Findings also provided evidence for the buffering role of friendship among all bully/victim profiles and among bully-victims especially. PMID:26309346

Transcriptome assembly and expression profiling of molecular responses to cadmium toxicity in hepatopancreas of the freshwater crab Sinopotamon henanense

NASA Astrophysics Data System (ADS)

Sun, Min; Ting Li, Yi; Liu, Yang; Chin Lee, Shao; Wang, Lan

2016-01-01

Cadmium (Cd) pollution is a serious global problem, which causes irreversible toxic effects on animals. Freshwater crab, Sinopotamon henanense, is a useful environmental indicator since it is widely distributed in benthic habitats whereby it tends to accumulate Cd and other toxicants. However, its molecular responses to Cd toxicity remain unclear. In this study, we performed transcriptome sequencing and gene expression analyses of its hepatopancreas with and without Cd treatments. A total of 7.78 G clean reads were obtained from the pooled samples, and 68,648 unigenes with an average size of 622 bp were assembled, in which 5,436 were metabolism-associated and 2,728 were stimulus response-associated that include 380 immunity-related unigenes. Expression profile analysis demonstrated that most genes involved in macromolecular metabolism, oxidative phosphorylation, detoxification and anti-oxidant defense were up-regulated by Cd exposure, whereas immunity-related genes were down-regulated, except the genes involved in phagocytosis were up-regulated. The current data indicate that Cd exposure alters gene expressions in a concentration-dependent manner. Therefore, our results provide the first comprehensive S.henanense transcriptome dataset, which is useful for biological and ecotoxicological studies on this crab and its related species at molecular level, and some key Cd-responsive genes may provide candidate biomarkers for monitoring aquatic pollution by heavy metals.

Literature-based compound profiling: application to toxicogenomics.

PubMed

Frijters, Raoul; Verhoeven, Stefan; Alkema, Wynand; van Schaik, René; Polman, Jan

2007-11-01

To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects

Classification of Chemicals Based On Structured Toxicity ...

EPA Pesticide Factsheets

Thirty years and millions of dollars worth of pesticide registration toxicity studies, historically stored as hardcopy and scanned documents, have been digitized into highly standardized and structured toxicity data within the Toxicity Reference Database (ToxRefDB). Toxicity-based classifications of chemicals were performed as a model application of ToxRefDB. These endpoints will ultimately provide the anchoring toxicity information for the development of predictive models and biological signatures utilizing in vitro assay data. Utilizing query and structured data mining approaches, toxicity profiles were uniformly generated for greater than 300 chemicals. Based on observation rate, species concordance and regulatory relevance, individual and aggregated effects have been selected to classify the chemicals providing a set of predictable endpoints. ToxRefDB exhibits the utility of transforming unstructured toxicity data into structured data and, furthermore, into computable outputs, and serves as a model for applying such data to address modern toxicological problems.

Steam pressure treatment of defective Coffea canephora beans improves the volatile profile and sensory acceptance of roasted coffee blends.

PubMed

Kalschne, Daneysa Lahis; Viegas, Marcelo Caldeira; De Conti, Antonio José; Corso, Marinês Paula; Benassi, Marta de Toledo

2018-03-01

Between 15 and 20% of Brazilian coffee production corresponds to defective beans (PVA), which decreases the quality of the coffee brew. Steam treatment has been reported as an alternative to improve the volatile profile and cup quality of coffee. The aim of this study was to propose a steam treatment of defective Coffea canephora beans to improve the volatile profile of the roasted coffee. The sensory impacts of adding steamed coffee (SC) in Coffea arabica blends were evaluated. The steam treatments studied modified the volatile profile of roasted SCs, increasing the contents of acetoin, benzyl alcohol, maltol, 2,6-dimethylpyrazine, 2-furfurylthiol, and 5-methylfurfural and decreasing the contents of 4-ethylguaiacol, isovaleric acid, methional, 2,3-diethyl-5-methylpyrazine, and 3-methoxy-3-methylpyrazine. Among the evaluated parameters, the best condition to maximized the content of the volatiles with a potential positive impact and minimize those with a potential negative impact was 5bar/16min (SC 5). The thresholds of consumer rejection and of detection indicate that up to 30% SC 5 can be added to a high cup quality Coffea arabica coffee without perception or rejection of the coffee brew. A blend of 30% of SC 5 and 70% of Coffea arabica was well accepted. Copyright © 2017 Elsevier Ltd. All rights reserved.

Substituent Effects on Desferrithiocin and Desferrithiocin Analogue Iron Clearing and Toxicity Profiles

PubMed Central

Bergeron, Raymond J.; Wiegand, Jan; Bharti, Neelam; McManis, James S.

2012-01-01

Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure-activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto the aromatic ring resulted in orally active iron chelators that were much less toxic than 1. The purpose of the current study was to determine if a comparable reduction in renal toxicity could be achieved by performing the same structural manipulations on 1 itself. Accordingly, three DFT analogues were synthesized. Iron clearing efficiency and ferrokinetics were evaluated in rats and primates; toxicity assessments were carried out in rodents. The resulting DFT ligands demonstrated a reduction in toxicity that was equivalent to that of the DADFT analogues and presented with excellent iron clearing properties. PMID:22889170

Effect of flax addition on the flavor profile and acceptability of bagels.

PubMed

Aliani, Michel; Ryland, Donna; Pierce, Grant N

2012-01-01

Bakery products containing flaxseed, a rich source of alpha linolenic acid (ALA), may provide health benefits. However, the effect of adding flaxseed, especially in the high amounts required for use as the food supplement in clinical trials (23% by weight of the raw ingredients), may affect the flavor characteristics and consumer acceptability. Sensory attributes of bagels containing 30 g of milled flaxseed were evaluated by a 9 member trained panel using a descriptive test and by 89 participants using a consumer test. Grain/flax aroma and flavor were significantly higher for the flax bagels compared to the nonflax bagels. The cinnamon raisin bagel had significantly lower grain/flax aroma and flavor and significantly higher sweet aroma and taste compared to the plain and sunflower sesame types. Older consumers rated the appearance, color, and flavor of the bagels significantly higher than the younger consumers possibly leading to higher compliance in clinical studies for this age group. Bagels with flax showed a significantly lower mean value for flavor acceptability, overall acceptability, and frequency of eating compared to bagels without flax. Appearance, color, and texture acceptability showed no significant differences. The cinnamon raisin bagel had significantly higher flavor acceptance compared to sunflower sesame and plain bagels. In conclusion, for bagels containing 6 g ALA in the form of milled flaxseed, cinnamon raisin appears to be a promising flavoring alternative for ALA fortification for use in clinical trials or as part of the daily diet. Consumers are seeking functional foods that contain omega-3 fatty acids. Bagels made with 23% milled flaxseed (approximately 2 times the amount in regular flax baked products) provided 6 g ALA, an amount high enough to test the efficacy of ALA in human subjects without causing gastrointestinal distress. This study showed that flaxseed aroma and flavor were detected in fortified compared to nonfortified bagels but

In Silico Prediction of Organ Level Toxicity: Linking Chemistry to Adverse Effects.

PubMed

Cronin, Mark T D; Enoch, Steven J; Mellor, Claire L; Przybylak, Katarzyna R; Richarz, Andrea-Nicole; Madden, Judith C

2017-07-01

In silico methods to predict toxicity include the use of (Quantitative) Structure-Activity Relationships ((Q)SARs) as well as grouping (category formation) allowing for read-across. A challenging area for in silico modelling is the prediction of chronic toxicity and the No Observed (Adverse) Effect Level (NO(A)EL) in particular. A proposed solution to the prediction of chronic toxicity is to consider organ level effects, as opposed to modelling the NO(A)EL itself. This review has focussed on the use of structural alerts to identify potential liver toxicants. In silico profilers, or groups of structural alerts, have been developed based on mechanisms of action and informed by current knowledge of Adverse Outcome Pathways. These profilers are robust and can be coded computationally to allow for prediction. However, they do not cover all mechanisms or modes of liver toxicity and recommendations for the improvement of these approaches are given.

Effects of High Toxic Boron Concentration on Protein Profiles in Roots of Two Citrus Species Differing in Boron-Tolerance Revealed by a 2-DE Based MS Approach

PubMed Central

Sang, Wen; Huang, Zeng-Rong; Yang, Lin-Tong; Guo, Peng; Ye, Xin; Chen, Li-Song

2017-01-01

Citrus are sensitive to boron (B)-toxicity. In China, B-toxicity occurs in some citrus orchards. So far, limited data are available on B-toxicity-responsive proteins in higher plants. Thirteen-week-old seedlings of “Sour pummelo” (Citrus grandis) and “Xuegan” (Citrus sinensis) was fertilized every other day until dripping with nutrient solution containing 10 μM (control) or 400 μM (B-toxicity) H3BO3 for 15 weeks. The typical B-toxic symptom only occurred in 400 μM B-treated C. grandis leaves, and that B-toxicity decreased root dry weight more in C. grandis seedlings than in C. sinensis ones, demonstrating that C. sinensis was more tolerant to B-toxicity than C. grandis. Using a 2-dimensional electrophoresis (2-DE) based MS approach, we identified 27 up- and four down-accumulated, and 28 up- and 13 down-accumulated proteins in B-toxic C. sinensis and C. grandis roots, respectively. Most of these proteins were isolated only from B-toxic C. sinensis or C. grandis roots, only nine B-toxicity-responsive proteins were shared by the two citrus species. Great differences existed in B-toxicity-induced alterations of protein profiles between C. sinensis and C. grandis roots. More proteins related to detoxification were up-accumulated in B-toxic C. grandis roots than in B-toxic C. sinensis roots to meet the increased requirement for the detoxification of the more reactive oxygen species and other toxic compounds such as aldehydes in the former. For the first time, we demonstrated that the active methyl cycle was induced and repressed in B-toxic C. sinensis and C. grandis roots, respectively, and that C. sinensis roots had a better capacity to keep cell wall and cytoskeleton integrity than C. grandis roots in response to B-toxicity, which might be responsible for the higher B-tolerance of C. sinensis. In addition, proteins involved in nucleic acid metabolism, biological regulation and signal transduction might play a role in the higher B-tolerance of C. sinensis

Factors influencing alert acceptance: a novel approach for predicting the success of clinical decision support

PubMed Central

Seidling, Hanna M; Phansalkar, Shobha; Seger, Diane L; Paterno, Marilyn D; Shaykevich, Shimon; Haefeli, Walter E

2011-01-01

Background Clinical decision support systems can prevent knowledge-based prescription errors and improve patient outcomes. The clinical effectiveness of these systems, however, is substantially limited by poor user acceptance of presented warnings. To enhance alert acceptance it may be useful to quantify the impact of potential modulators of acceptance. Methods We built a logistic regression model to predict alert acceptance of drug–drug interaction (DDI) alerts in three different settings. Ten variables from the clinical and human factors literature were evaluated as potential modulators of provider alert acceptance. ORs were calculated for the impact of knowledge quality, alert display, textual information, prioritization, setting, patient age, dose-dependent toxicity, alert frequency, alert level, and required acknowledgment on acceptance of the DDI alert. Results 50 788 DDI alerts were analyzed. Providers accepted only 1.4% of non-interruptive alerts. For interruptive alerts, user acceptance positively correlated with frequency of the alert (OR 1.30, 95% CI 1.23 to 1.38), quality of display (4.75, 3.87 to 5.84), and alert level (1.74, 1.63 to 1.86). Alert acceptance was higher in inpatients (2.63, 2.32 to 2.97) and for drugs with dose-dependent toxicity (1.13, 1.07 to 1.21). The textual information influenced the mode of reaction and providers were more likely to modify the prescription if the message contained detailed advice on how to manage the DDI. Conclusion We evaluated potential modulators of alert acceptance by assessing content and human factors issues, and quantified the impact of a number of specific factors which influence alert acceptance. This information may help improve clinical decision support systems design. PMID:21571746

In Silico Prediction of Organ Level Toxicity: Linking Chemistry to Adverse Effects

PubMed Central

Cronin, Mark T.D.; Enoch, Steven J.; Mellor, Claire L.; Przybylak, Katarzyna R.; Richarz, Andrea-Nicole; Madden, Judith C.

2017-01-01

In silico methods to predict toxicity include the use of (Quantitative) Structure-Activity Relationships ((Q)SARs) as well as grouping (category formation) allowing for read-across. A challenging area for in silico modelling is the prediction of chronic toxicity and the No Observed (Adverse) Effect Level (NO(A)EL) in particular. A proposed solution to the prediction of chronic toxicity is to consider organ level effects, as opposed to modelling the NO(A)EL itself. This review has focussed on the use of structural alerts to identify potential liver toxicants. In silico profilers, or groups of structural alerts, have been developed based on mechanisms of action and informed by current knowledge of Adverse Outcome Pathways. These profilers are robust and can be coded computationally to allow for prediction. However, they do not cover all mechanisms or modes of liver toxicity and recommendations for the improvement of these approaches are given. PMID:28744348

An evaluation of the seven-day toxicity test with Americamysis bahia (formerly Mysidopsis bahia)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lussier, S.M.; Kuhn, A.; Comeleo, R.

The 7-d test measuring survival, growth, and fecundity of Americamysis bahia (formerly Mysidopsis bahia) was developed for estimating the chronic toxicity of effluents and associated receiving waters for National Pollutant Discharge Elimination System permits. Currently, this test and its derivatives are also used in toxicity identification evaluation (TIE), risk assessment, and other applications. To evaluate the relative sensitivity of three measurement endpoints (survival, growth, and fecundity), the authors analyzed results from 115 tests with effluents, organic or inorganic chemicals, and receiving waters suspected of being toxic. Controls for 78 of these achieved acceptable survival and growth. Fifty of these 78more » tests also achieved acceptable control fecundity. In the 47 tests with significant effects, survival was the most sensitive response in 57%, fecundity in 30%, and growth in 30%. There was little duplication in responses. Improving pretest holding conditions by decreasing the maximum density from {approximately}20 to 10 animals/L and increasing the temperature from {approximately}26 C to a range of 26 to 27 C improved the growth and fecundity in controls. Although the percentage of tests achieving acceptable control survival and growth decreased from 93 to 86%, the percentage achieving acceptable fecundity in controls increased from 60 to 97%. Seasonal differences in fecundity were detected among control groups. Although variable, fecundity is often the most sensitive measure of response. The 7-d mysid test estimates the chronic toxicity of effluents most effectively when all three endpoints are used.« less

VIRTUAL EMBRYO: SYSTEMS MODELING IN DEVELOPMENTAL TOXICITY - Symposium: SOT 2012

EPA Science Inventory

High-throughput screening (HTS) studies are providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential toxicity. Chemical profiling in ToxCast covered 965 drugs-chemicals in over 500 diverse assays testing...

Decision support tools for proton therapy ePR: intelligent treatment planning navigator and radiation toxicity tool for evaluating of prostate cancer treatment

NASA Astrophysics Data System (ADS)

Le, Anh H.; Deshpande, Ruchi; Liu, Brent J.

2010-03-01

The electronic patient record (ePR) has been developed for prostate cancer patients treated with proton therapy. The ePR has functionality to accept digital input from patient data, perform outcome analysis and patient and physician profiling, provide clinical decision support and suggest courses of treatment, and distribute information across different platforms and health information systems. In previous years, we have presented the infrastructure of a medical imaging informatics based ePR for PT with functionality to accept digital patient information and distribute this information across geographical location using Internet protocol. In this paper, we present the ePR decision support tools which utilize the imaging processing tools and data collected in the ePR. The two decision support tools including the treatment plan navigator and radiation toxicity tool are presented to evaluate prostate cancer treatment to improve proton therapy operation and improve treatment outcomes analysis.

ADME-Tox profiles of some food additives and pesticides

NASA Astrophysics Data System (ADS)

Craciun, Dana; Modra, Dorina; Isvoran, Adriana

2015-12-01

Within this study we compute the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) profiles of several commonly used food additives and some pesticides. As expected, all the food additives considered in this study provided to be safe, their ADME-Tox profiles indicating that they have a good oral bioavailability and they do not produce phosphoslipidosis. The ADME-Tox profiles of the pesticides indicate that, with a few exceptions, they are highly toxic (some of them being not approved in the EU, but still used in other countries) and may cause many diseases. Our results are in good agreement with published data concerning the considered food additives and pesticides revealing that the ADME-Tox profiling method may be successfully used to test other chemicals than drug candidates.

Acceptability of hypothetical dengue vaccines among travelers.

PubMed

Benoit, Christine M; MacLeod, William B; Hamer, Davidson H; Sanchez-Vegas, Carolina; Chen, Lin H; Wilson, Mary E; Karchmer, Adolf W; Yanni, Emad; Hochberg, Natasha S; Ooi, Winnie W; Kogelman, Laura; Barnett, Elizabeth D

2013-01-01

Dengue viruses have spread widely in recent decades and cause tens of millions of infections mostly in tropical and subtropical areas. Vaccine candidates are being studied aggressively and may be ready for licensure soon. We surveyed patients with past or upcoming travel to dengue-endemic countries to assess rates and determinants of acceptance for four hypothetical dengue vaccines with variable efficacy and adverse event (AE) profiles. Acceptance ratios were calculated for vaccines with varied efficacy and AE risk. Acceptance of the four hypothetical vaccines ranged from 54% for the vaccine with lower efficacy and serious AE risk to 95% for the vaccine with higher efficacy and minor AE risk. Given equal efficacy, vaccines with lower AE risk were better accepted than those with higher AE risk; given equivalent AE risk, vaccines with higher efficacy were better accepted than those with lower efficacy. History of Japanese encephalitis vaccination was associated with lower vaccine acceptance for one of the hypothetical vaccines. US-born travelers were more likely than non-US born travelers to accept a vaccine with 75% efficacy and a risk of minor AEs (p = 0.003). Compared with North American-born travelers, Asian- and African-born travelers were less likely to accept both vaccines with 75% efficacy. Most travelers would accept a safe and efficacious dengue vaccine if one were available. Travelers valued fewer potential AEs over increased vaccine efficacy. © 2013 International Society of Travel Medicine.

CHEMICAL STRUCTURE INDEXING OF TOXICITY DATA ON ...

EPA Pesticide Factsheets

Standardized chemical structure annotation of public toxicity databases and information resources is playing an increasingly important role in the 'flattening' and integration of diverse sets of biological activity data on the Internet. This review discusses public initiatives that are accelerating the pace of this transformation, with particular reference to toxicology-related chemical information. Chemical content annotators, structure locator services, large structure/data aggregator web sites, structure browsers, International Union of Pure and Applied Chemistry (IUPAC) International Chemical Identifier (InChI) codes, toxicity data models and public chemical/biological activity profiling initiatives are all playing a role in overcoming barriers to the integration of toxicity data, and are bringing researchers closer to the reality of a mineable chemical Semantic Web. An example of this integration of data is provided by the collaboration among researchers involved with the Distributed Structure-Searchable Toxicity (DSSTox) project, the Carcinogenic Potency Project, projects at the National Cancer Institute and the PubChem database. Standardizing chemical structure annotation of public toxicity databases

Elucidation of Adverse Bioactivity Profiles as Predictors of Toxicity Potential

EPA Science Inventory

Toxicity testing in vitro remains a formidable challenge due to lack of understanding of key molecular targets and pathways underlying many pathological events. The combination of genome sequencing and widespread application of high-throughput screening tools have provided the me...

Distribution, diffusive fluxes, and toxicity of heavy metals and PAHs in pore water profiles from the northern bays of Taihu Lake.

PubMed

Lei, Pei; Zhang, Hong; Shan, Baoqing; Zhang, Bozheng

2016-11-01

Pore water plays a more significant role than do sediments in pollutant cycling dynamics. Also, concentrations of pollutants in pore water provide important information about their bioavailability or eco-toxicity; however, very few studies have focused on this topic. In this study, four duplicate sediment cores from three typical northern bays as well as the central part of Taihu Lake were collected to investigate the distribution, diffusive fluxes, and toxicity of heavy metals and polycyclic aromatic hydrocarbons (PAHs) in pore water profiles, which will be good in understanding the mobility and toxicity of these toxic pollutants and achieving better environmental management. The diffusive fluxes of heavy metals across the sediment-water interface was estimated through Fick's First Law, and the toxicity of heavy metals and PAHs in pore water was assessed by applying a water quality index (interstitial water toxicity criteria unit, IWCTU) and a hazard index (HI), respectively. The average concentrations of Cr, Cu, Ni, Pb, and Zn in surface pore water were 18.8, 23.4, 12.0, 13.5, and 42.5 μg L -1 , respectively. Also, concentrations of the selected heavy metals in both overlying water and pore water from Taihu Lake were all lower than the standard values of the environmental quality standards for surface water. The concentrations as the pore water depth increased, and the highest detected concentrations of heavy metals were recorded between 3 and 5 cm below the sediment surface. The average diffusive fluxes of these metals were 27.3, 24.8, 7.03, 7.81, and -3.32 μg (m 2 day) -1 , respectively, indicating export from sediment into overlying water, with the exception of Zn. There was a potential risk of toxicity, mainly from Pb and Cu, indicating that heavy metals in pore water had slight to moderate impact on sediment-dwelling organisms by values of the IWCTU and the Nemeraw index. The total PAH concentrations in pore water were higher than those in overlying

Variability of LD50 Values from Rat Oral Acute Toxicity Studies: Implications for Alternative Model Development

EPA Science Inventory

Alternative models developed for estimating acute systemic toxicity are generally evaluated using in vivo LD50 values. However, in vivo acute systemic toxicity studies can produce variable results, even when conducted according to accepted test guidelines. This variability can ma...

Albendazole Induced Recurrent Acute Toxic Hepatitis: A Case Report.

PubMed

Bilgic, Yilmaz; Yilmaz, Cengiz; Cagin, Yasir Furkan; Atayan, Yahya; Karadag, Nese; Harputluoglu, Murat Muhsin Muhip

2017-01-01

Drug induced acute toxic hepatitis can be idiosyncratic. Albendazole, a widely used broad spectrum antiparasitic drug is generally accepted as a safe drug. It may cause asymptomatic transient liver enzyme abnormalities but acute toxic hepatitis is very rare. Case Report : Herein, we present the case of 47 year old woman with recurrent acute toxic hepatitis after a single intake of albendazole in 2010 and 2014. The patient was presented with symptoms and findings of anorexia, vomiting and jaundice. For diagnosis, other acute hepatitis etiologies were excluded. Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated and found to be 10, which meant highly probable drug hepatotoxicity. Within 2 months, all pathological findings came to normal. There are a few reported cases of albendazole induced toxic hepatitis, but at adults, there is no known recurrent acute toxic hepatitis due to albendazole at this certainty according to RUCAM score. Physicians should be aware of this rare and potentially fatal adverse effect of albendazole. © Acta Gastro-Enterologica Belgica.

Free radicals quenching potential, protective properties against oxidative mediated ion toxicity and HPLC phenolic profile of a Cameroonian spice: Piper guineensis.

PubMed

Moukette Moukette, Bruno; Constant Anatole, Pieme; Nya Biapa, Cabral Prosper; Njimou, Jacques Romain; Ngogang, Jeanne Yonkeu

2015-01-01

Considerations on antioxidants derived from plants have continuously increased during this decade because of their beneficial effects on human health. In the present study we investigated the free radical scavenging properties of extracts from Piper guineense ( P. guineense ) and their inhibitory potentials against oxidative mediated ion toxicity. The free radical quenching properties of the extracts against [1,1-diphenyl-2-picrylhydrazyl (DPPH•), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS•), hydroxyl radical (HO•), nitric oxide (NO•)] radical and their antioxidant potentials by FRAP and phosphomolybdenum were determined as well as their protective properties on liver enzymes. The phenolic profile was also investigated by HPLC. The results obtained, revealed that the extracts significantly inhibited the DPPH, NO, HO and ABTS radicals in a concentration depending manner. They also showed a significant ferrous ion chelating ability through FRAP and phosphomolybdenum antioxidant potential. Their polyphenol contents varied depending on the type of extracts and the solvent used. The hydroethanolic extracts (FFH) and the ethanolic extracts (FFE) of P. guineense leaves showed the higher level of phenolic compounds respectively of 21.62 ± 0.06 mg caffeic acid/g dried extract (CAE/g DE) and 19.01 ± 0.03 CAE/g DE. The HPLC phenolic compounds profile revealed a higher quantity of Eugenol, quercetin, rutin and catechin in the stem than in the leaves. The presence of these molecules could be responsible of the protective potentials of P. guineense extracts against lipid peroxidation and SOD, catalase and peroxidase. In conclusion, P. guineense extracts demonstrated significant antioxidant property and may be used as a prospective protector against metal related toxicity.

Acceptance threshold hypothesis is supported by chemical similarity of cuticular hydrocarbons in a stingless bee, Melipona asilvai.

PubMed

Nascimento, D L; Nascimento, F S

2012-11-01

The ability to discriminate nestmates from non-nestmates in insect societies is essential to protect colonies from conspecific invaders. The acceptance threshold hypothesis predicts that organisms whose recognition systems classify recipients without errors should optimize the balance between acceptance and rejection. In this process, cuticular hydrocarbons play an important role as cues of recognition in social insects. The aims of this study were to determine whether guards exhibit a restrictive level of rejection towards chemically distinct individuals, becoming more permissive during the encounters with either nestmate or non-nestmate individuals bearing chemically similar profiles. The study demonstrates that Melipona asilvai (Hymenoptera: Apidae: Meliponini) guards exhibit a flexible system of nestmate recognition according to the degree of chemical similarity between the incoming forager and its own cuticular hydrocarbons profile. Guards became less restrictive in their acceptance rates when they encounter non-nestmates with highly similar chemical profiles, which they probably mistake for nestmates, hence broadening their acceptance level.

Sensory characteristics and consumer acceptability of fermented soybean paste (Doenjang).

PubMed

Kim, H G; Hong, J H; Song, C K; Shin, H W; Kim, K O

2010-09-01

This study was conducted to examine the sensory profiles of fermented soybean paste (Doenjang), to understand consumers' acceptability of different types of Doenjang samples and to identify the sensory characteristics that drive consumer acceptability of Doenjang products. Descriptive analysis and consumer acceptability test were conducted for 7 different types of Doenjang samples. The samples included 2 types of Doenjang made by either traditional or commercially modified methods. For the descriptive analysis, 8 trained panelists developed and evaluated 31 descriptors. There were significant differences in all 31 attributes among the samples. Principal component analysis was also performed to summarize the sensory characteristics of the samples. In consumer testing, 200 consumers evaluated the acceptability of Doenjang samples. Significant differences in consumer acceptability were observed among the samples. The consumers preferred the Doenjang samples manufactured using a commercially modified method. In overall point of view, most consumers liked the Doenjang samples that had strong "sweet" and "MSG (monosodium glutamate)" tastes. It appears that "sweet" and "MSG" tastes are the drivers of liking for Doenjang. "Salty" taste, "meju,"traditional Korean soy sauce," and "fermented fish" odor/flavors seem to be the drivers of disliking for Doenjang. Cluster analysis identified 3 subconsumer segments sharing a common preference pattern for the 7 samples within a cluster. The results showed that each consumer cluster preferred different Doenjang samples. External preference mapping was performed to establish the relationships between the sensory attributes and consumer acceptability in each cluster. Consumption of the fermented soybean products is gradually expanding around the world, due to their various health benefits. Therefore, understanding sensory characteristics and consumer acceptability of Doenjang are becoming increasingly important. The intense and complex

Toxicity and repellency to rats of actidione

USGS Publications Warehouse

Traub, R.; DeWitt, J.B.; Welch, J.F.; Newman, D.

1950-01-01

The antibiotic actidione was found to be highly repellent to laboratory rats and to significantly reduce gnawing attacks upon treated paperboards. Rats refused to accept food or water containing this material even under conditions of acute starvation and died of starvation and thirst,rather than accept water containing l.0 mg. of actidione per liter. The compound is highly toxic to .rats with the minimum .lethal dose by oral administration being approximately l.0 mg./Kg body weight. Paperboard treated with the compound resisted gnawing attacks by specially trained and motivated rats for periods of two hundred hours, although similar .untreated boards were pierced within thirty-to sixty minutes.

Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data

EPA Science Inventory

EPA's ToxCast™ project is profiling the in vitro bioactivity of chemicals to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesized that developmental toxicity in guideline animal studies captured in the ToxRefDB database wou...

Virtual Embryo: Systems Modeling in Developmental Toxicity

EPA Science Inventory

High-throughput and high-content screening (HTS-HCS) studies are providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential toxicity. EPA’s ToxCast™ project, and the broader Tox21 consortium, in addition t...

Protective effect of Withania somnifera roots extract on hematoserological profiles against lead nitrate-induced toxicity in mice.

PubMed

Sharma, Veena; Sharma, Sadhana; Pracheta

2012-12-01

The in vivo protective role of hydro-methanolic root extract of Withania somnifera (WS) was evaluated in alleviating lead nitrate (LN)-induced toxicity in male Swiss albino mice by measuring hematoserological profiles. The lead-treated (20 mg/kg body wt, p.o.) albino mice (25-30 g) concurrently received the root extract (200 and 500 mg/kg body wt, p.o.) once daily for the duration of six weeks. Animals exposed to LN showed significant (P < 0.001) decline in haemoglobin content, red blood cell count, white blood cell count, packed cell volume and insignificant decrease in mean corpuscular haemoglobin and mean corpuscular haemoglobin content, while mean corpuscular volume and platelet count were increased. A significant elevation (P < 0.001) in serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, acid phosphatase and total cholesterol were also observed, when compared with control mice. Thus, the study demonstrated that the concurrent daily administration of root extract of WS protected the adverse effects of LN intoxication in mice.

Lead toxicity.

PubMed

Gidlow, D A

2015-07-01

Since the last In-Depth Review of lead toxicity in 2004 there have been further developments with regard to safe exposure levels for lead workers. To advise occupational health professionals of the latest research on the multi-system toxic effects of lead and the implications of this research for setting new safe and appropriate occupational suspension limits. An extensive review of the current literature and an investigation of the database used by lead users to produce their submission under the REACH Regulations. Much of the published research on lead toxicity is on the effects of lead on the general population where blood lead levels are considerably lower than those seen in lead-exposed workers. It is always difficult to compare such studies with those undertaken on exposed workers as they may not be directly comparable and may not have taken into account all confounding variables and the well-acknowledged 'healthy worker' concept. However, it is clear that there is substantial evidence that potential health effects on lead workers may be seen at levels which were previously accepted as 'safe'. There is undoubtedly a narrow margin of safety between current occupational blood lead suspension limits and subclinical effect. As a result, the lead users have produced a voluntary Code of Practice with suspension limits significantly below those seen in some national legislation, particularly the Control of Lead at Work Act 2002. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Metabolic profiling study on potential toxicity and immunotoxicity-biomarker discovery in rats treated with cyclophosphamide using HPLC-ESI-IT-TOF-MS.

PubMed

Li, Jing; Lin, Wensi; Lin, Weiwei; Xu, Peng; Zhang, Jianmei; Yang, Haisong; Ling, Xiaomei

2015-05-01

Despite the recent advances in understanding toxicity mechanism of cyclophosphamide (CTX), the development of biomarkers is still essential. CTX-induced immunotoxicity in rats by a metabonomics approach was investigated using high-performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry (HPLC-ESI-IT-TOF-MS). The rats were orally administered CTX (30 mg/kg/day) for five consecutive days, and on the fifth day samples of urine, thymus and spleen were collected and analyzed. A significant difference in metabolic profiling was observed between the CTX-treated group and the control group by partial least squares-discriminant analysis (PLS-DA), which indicated that metabolic disturbances of immunotoxicity in CTX-treated rats had occurred. One potential biomarker in spleen, three in urine and three in thymus were identified. It is suggested that the CTX-toxicity mechanism may involve the modulation of tryptophan metabolism, phospholipid metabolism and energy metabolism. This research can help to elucidate the CTX-influenced pathways at a low dose and can further help to indicate the patients' pathological status at earlier stages of toxicological progression after drug administration. Copyright © 2014 John Wiley & Sons, Ltd.

[Toxicity and toxin profiles of xanthid crabs collected around Nakanoshima in the Tokara Islands, Japan].

PubMed

Sagara, Takefumi; Taniyama, Shigeto; Takatani, Tomohiro; Nishibori, Naoyoshi; Nishio, Sachio; Noguchi, Tamao; Arakawa, Osamu

2009-10-01

A total of 36 specimens of 5 xanthid crab species, Zosimus aeneus (n=16), Xanthias lividus (n=4), Leptodius sanguineus (n=3), Daira perlata (n=10) and Eriphia sebana (n=3), were collected around Nakanoshima Island, which is located at the northeastern part of the Tokara Islands, Kagoshima Prefecture, Japan in May and July 2000, and their toxicity was determined by mouse bioassay. Nine of 16 Z. aeneus specimens and all of 4 X. lividus specimens showed lethal potency to mice (2.1-11 MU/g, 2.8-8.6 MU/g, respectively), whereas all the other species were non-toxic (less than 2.0 MU/g). LC/MS analyses indicated that the toxin of the Z. aeneus specimens was mainly composed of tetrodotoxin (41% of total toxicity), and 11-oxotetrodotoxin contributed to the remaining toxicity. The toxin of the X. lividus specimens, however, was apparently not tetrodotoxin. In HPLC-FLD analyses, no paralytic shellfish poison component was detected in either of the two toxic species.

Strategies for integrating transcriptional profiling into high throughput toxicity testing (SOT Symposium Workshop presentation)

EPA Science Inventory

Presentation Description: The release of the National Research Council’s Report “Toxicity Testing in the 21st Century: A Vision and a Strategy” in 2007 initiated a broad-based movement in the toxicology community to re-think how toxicity testing and risk assessment are performed....

Vertical profile, source apportionment, and toxicity of PAHs in sediment cores of a wharf near the coal-based steel refining industrial zone in Kaohsiung, Taiwan.

PubMed

Chen, Chih-Feng; Chen, Chiu-Wen; Ju, Yun-Ru; Dong, Cheng-Di

2016-03-01

Three sediment cores were collected from a wharf near a coal-based steel refining industrial zone in Kaohsiung, Taiwan. Analyses for 16 polycyclic aromatic hydrocarbons (PAHs) of the US Environmental Protection Agency priority list in the core sediment samples were conducted using gas chromatography-mass spectrometry. The vertical profiles of PAHs in the core sediments were assessed, possible sources and apportionment were identified, and the toxicity risk of the core sediments was determined. The results from the sediment analyses showed that total concentrations of the 16 PAHs varied from 11774 ± 4244 to 16755 ± 4593 ng/g dry weight (dw). Generally, the vertical profiles of the PAHs in the sediment cores exhibited a decreasing trend from the top to the lower levels of the S1 core and an increasing trend of PAHs from the top to the lower levels of the S2 and S3 cores. Among the core sediment samples, the five- and six-ring PAHs were predominantly in the S1 core, ranging from 42 to 54 %, whereas the composition of the PAHs in the S2 and S3 cores were distributed equally across three groups: two- and three-ring, four-ring, and five- and six-ring PAHs. The results indicated that PAH contamination at the site of the S1 core had a different source. The molecular indices and principal component analyses with multivariate linear regression were used to determine the source contributions, with the results showing that the contributions of coal, oil-related, and vehicle sources were 38.6, 35.9, and 25.5 %, respectively. A PAH toxicity assessment using the mean effect range-median quotient (m-ERM-q, 0.59-0.79), benzo[a]pyrene toxicity equivalent (TEQ(carc), 1466-1954 ng TEQ/g dw), and dioxin toxicity equivalent (TEQ(fish), 3036-4174 pg TEQ/g dw) identified the wharf as the most affected area. The results can be used for regular monitoring, and future pollution prevention and management should target the coal-based industries in this region for pollution reduction.

Health-related behavior, profile of health locus of control and acceptance of illness in patients suffering from chronic somatic diseases.

PubMed

Janowski, Konrad; Kurpas, Donata; Kusz, Joanna; Mroczek, Bozena; Jedynak, Tomasz

2013-01-01

The purpose of the study was to determine health-related behaviors, profile of health locus of control (HLC), and to assess the relationships between these constructs among patients suffering from chronic somatic diseases. Three-hundred adult patients suffering from various chronic diseases participated in the study. The patients' mean age was 54.6 years (SD = 17.57). No statistically significant differences were found between the different clinical groups in health-related behavior, acceptance of illness, internal HLC or chance HLC. Patients with neurologic conditions showed slightly lower powerful others HLC than did some other clinical groups. Health-related behavior was significantly positively related to all three categories of HLC, with most prominent associations observed with powerful others HLC. Only one type of health-related behavior--preventive behavior--correlated significantly and negatively with acceptance of illness. Differences in the frequency of health-related behavior were also found due to gender (women showing more healthy nutritional habits than men), age (older subjects showing more frequent health-promoting behavior), education (higher education was associated with less frequent health-promoting behavior) and marital status (widowed subjects reporting more frequent health-promoting behavior). Health-related behavior in patients with chronic diseases seems to be unrelated to a specific diagnosis; however it shows associations with both internal and external HLC. Sociodemographic factors are also crucial factors determining frequency of health-related behavior in such patients.

20180311 - Variability of LD50 Values from Rat Oral Acute Toxicity Studies: Implications for Alternative Model Development (SOT)

EPA Science Inventory

Alternative models developed for estimating acute systemic toxicity are generally evaluated using in vivo LD50 values. However, in vivo acute systemic toxicity studies can produce variable results, even when conducted according to accepted test guidelines. This variability can ma...

Insecticide treated curtains and residual insecticide treatment to control Aedes aegypti: An acceptability study in Santiago de Cuba

PubMed Central

Van der Stuyft, Patrick; Toledo, María Eugenia; Ceballos, Enrique; Fabré, Francisco; Lefèvre, Pierre

2018-01-01

Background Within the context of a field trial conducted by the Cuban vector control program (AaCP), we assessed acceptability of insecticide-treated curtains (ITCs) and residual insecticide treatment (RIT) with deltamethrin by the community. We also assessed the potential influence of interviewees’ risk perceptions for getting dengue and disease severity. Methodology/principal findings We embedded a qualitative study using in-depth interviews in a cluster randomized trial (CRT) testing the effectiveness of ITCs and RIT in Santiago de Cuba. In-depth interviews (N = 38) were conducted four and twelve months after deployment of the tools with people who accepted the tools, who stopped using them and who did not accept the tools. Data analysis was deductive. Main reasons for accepting ITCs at the start of the trial were perceived efficacy and not being harmful to health. Constraints linked to manufacturer instructions were the main reason for not using ITCs. People stopped using the ITCs due to perceived allergy, toxicity and low efficacy. Few heads of households refused RIT despite the noting reasons for rejection, such as allergy, health hazard and toxicity. Positive opinions of the vector control program influenced acceptability of both tools. However, frequent insecticide fogging as part of routine AaCP vector control actions diminished perceived efficacy of both tools and, therefore, acceptability. Fifty percent of interviewees did feel at risk for getting dengue and considered dengue a severe disease. However, this did not appear to influence acceptability of ITCs or RIT. Conclusion/significance Acceptability of ITCs and RIT was linked to acceptability of AaCP routine vector control activities. However, uptake and use were not always an indication of acceptability. Factors leading to acceptability may be best identified using qualitative methods, but more research is needed on the concept of acceptability and its measurement. PMID:29293501

Insecticide treated curtains and residual insecticide treatment to control Aedes aegypti: An acceptability study in Santiago de Cuba.

PubMed

Pérez, Dennis; Van der Stuyft, Patrick; Toledo, María Eugenia; Ceballos, Enrique; Fabré, Francisco; Lefèvre, Pierre

2018-01-01

Within the context of a field trial conducted by the Cuban vector control program (AaCP), we assessed acceptability of insecticide-treated curtains (ITCs) and residual insecticide treatment (RIT) with deltamethrin by the community. We also assessed the potential influence of interviewees' risk perceptions for getting dengue and disease severity. We embedded a qualitative study using in-depth interviews in a cluster randomized trial (CRT) testing the effectiveness of ITCs and RIT in Santiago de Cuba. In-depth interviews (N = 38) were conducted four and twelve months after deployment of the tools with people who accepted the tools, who stopped using them and who did not accept the tools. Data analysis was deductive. Main reasons for accepting ITCs at the start of the trial were perceived efficacy and not being harmful to health. Constraints linked to manufacturer instructions were the main reason for not using ITCs. People stopped using the ITCs due to perceived allergy, toxicity and low efficacy. Few heads of households refused RIT despite the noting reasons for rejection, such as allergy, health hazard and toxicity. Positive opinions of the vector control program influenced acceptability of both tools. However, frequent insecticide fogging as part of routine AaCP vector control actions diminished perceived efficacy of both tools and, therefore, acceptability. Fifty percent of interviewees did feel at risk for getting dengue and considered dengue a severe disease. However, this did not appear to influence acceptability of ITCs or RIT. Acceptability of ITCs and RIT was linked to acceptability of AaCP routine vector control activities. However, uptake and use were not always an indication of acceptability. Factors leading to acceptability may be best identified using qualitative methods, but more research is needed on the concept of acceptability and its measurement.

Real-time cell toxicity profiling of Tox21 10K compounds reveals cytotoxicity dependent toxicity pathway linkage

PubMed Central

Huang, Ruili; Lin, Ja-An; Sedykh, Alexander; Zhao, Jinghua; Tice, Raymond R.; Paules, Richard S.; Xia, Menghang; Auerbach, Scott S.

2017-01-01

Cytotoxicity is a commonly used in vitro endpoint for evaluating chemical toxicity. In support of the U.S. Tox21 screening program, the cytotoxicity of ~10K chemicals was interrogated at 0, 8, 16, 24, 32, & 40 hours of exposure in a concentration dependent fashion in two cell lines (HEK293, HepG2) using two multiplexed, real-time assay technologies. One technology measures the metabolic activity of cells (i.e., cell viability, glo) while the other evaluates cell membrane integrity (i.e., cell death, flor). Using glo technology, more actives and greater temporal variations were seen in HEK293 cells, while results for the flor technology were more similar across the two cell types. Chemicals were grouped into classes based on their cytotoxicity kinetics profiles and these classes were evaluated for their associations with activity in the Tox21 nuclear receptor and stress response pathway assays. Some pathways, such as the activation of H2AX, were associated with the fast-responding cytotoxicity classes, while others, such as activation of TP53, were associated with the slow-responding cytotoxicity classes. By clustering pathways based on their degree of association to the different cytotoxicity kinetics labels, we identified clusters of pathways where active chemicals presented similar kinetics of cytotoxicity. Such linkages could be due to shared underlying biological processes between pathways, for example, activation of H2AX and heat shock factor. Others involving nuclear receptor activity are likely due to shared chemical structures rather than pathway level interactions. Based on the linkage between androgen receptor antagonism and Nrf2 activity, we surmise that a subclass of androgen receptor antagonists cause cytotoxicity via oxidative stress that is associated with Nrf2 activation. In summary, the real-time cytotoxicity screen provides informative chemical cytotoxicity kinetics data related to their cytotoxicity mechanisms, and with our analysis, it is

Acute Toxicity Profile and Compliance to Accelerated Radiotherapy Plus Carbogen and Nicotinamide for Clinical Stage T2-4 Laryngeal Cancer: Results of a Phase III Randomized Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janssens, Geert O., E-mail: g.janssens@rther.umcn.nl; Terhaard, Chris H.; Doornaert, Patricia A.

2012-02-01

Purpose: To report the acute toxicity profile and compliance from a randomized Phase III trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen and nicotinamide (ARCON) in laryngeal cancer. Methods and Materials: From April 2001 to February 2008, 345 patients with cT2-4 squamous cell laryngeal cancer were randomized to AR (n = 174) and ARCON (n = 171). Acute toxicity was scored weekly until Week 8 and every 2-4 weeks thereafter. Compliance to carbogen and nicotinamide was reported. Results: Between both treatment arms (AR vs. ARCON) no statistically significant difference was observed for incidence of acute skin reactions (moistmore » desquamation: 56% vs. 58%, p = 0.80), acute mucosal reactions (confluent mucositis: 79% vs. 85%, p = 0.14), and symptoms related to acute mucositis (severe pain on swallowing: 53% vs. 58%, p = 0.37; nasogastric tube feeding: 28% vs. 28%, p = 0.98; narcotic medicines required: 58% vs. 58%, p = 0.97). There was a statistically significant difference in median duration of confluent mucositis in favor of AR (2.0 vs 3.0 weeks, p = 0.01). There was full compliance with carbogen breathing and nicotinamide in 86% and 80% of the patients, with discontinuation in 6% and 12%, respectively. Adjustment of antiemesis prophylaxis was needed in 42% of patients. Conclusion: With the exception of a slight increase in median duration of acute confluent mucositis, the present data reveal a similar acute toxicity profile between both regimens and a good compliance with ARCON for clinical stage T2-4 laryngeal cancers. Treatment outcome and late morbidity will determine the real therapeutic benefit.« less

Species-Specific Predictive Signatures of Developmental Toxicity Using the ToxCast Chemical Library

EPA Science Inventory

EPA’s ToxCastTM project is profiling the in vitro bioactivity of chemicals to generate predictive signatures that correlate with observed in vivo toxicity. In vitro profiling methods from ToxCast data consist of over 600 high-throughput screening (HTS) and high-content screening ...

The Role of Biomarkers in Detection of Cardio-toxicity.

PubMed

Shah, Kevin S; Yang, Eric H; Maisel, Alan S; Fonarow, Gregg C

2017-06-01

The goal of this paper is to review the current literature on the role of biomarkers in the detection and management of patients with cardio-oncologic disease. The role of biomarker surveillance in patients with known cardiac disease, as a result of chemotherapy or with the potential to develop cardio-toxicity, will be discussed. In addition, the studies surrounding sub-clinical cardiac toxicity monitoring during therapy, identification of high-risk patients prior to therapy, and tailoring oncologic therapies to potential biomarker risk profiles are reviewed. Based on evidence, to date, troponin and natriuretic peptides have the greatest potential to detect sub-clinical cardiac dysfunction and even tailor therapy to prevent progression based on biomarker profiles. Finally, future directions for potential utilization of novel biomarkers for the improvement of care of patients in the field of cardio-oncology are discussed.

Biomolecular Profiling of Jet Fuel Toxicity Using Proteomics

DTIC Science & Technology

2006-02-28

pulmonary alveolar type II cells and macrophages, and human epidermal keratinocytes in various exposure models. Results strongly suggest an injurious effect ...of exposure on all cells studied. In both pulmonary and skin cells, the protein profiles of JP-8 effect corroborates previous histological findings...potential intervention by Substance P (SP) in the pulmonary effects of JP-8 exposure , studies incorporating SP treatment along with JP-8 exposure

78 FR 4147 - Notice of Development of Set 26 Toxicological Profiles

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-18

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [ATSDR-277] Notice of Development of Set 26 Toxicological Profiles AGENCY: Agency for Toxic Substances and Disease Registry (ATSDR), Department of Health and Human Services (HHS). ACTION: Notice. SUMMARY: This...

77 FR 6800 - Notice of Development of Set 25 Toxicological Profiles

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [ATSDR-273] Notice of Development of Set 25 Toxicological Profiles AGENCY: Agency for Toxic Substances and Disease Registry (ATSDR), Department of Health and Human Services (DHHS). ACTION: Notice. SUMMARY: This...

Species-specific predictive models of developmental toxicity using the ToxCast chemical library

EPA Science Inventory

EPA’s ToxCastTM project is profiling the in vitro bioactivity of chemicals to generate predictive models that correlate with observed in vivo toxicity. In vitro profiling methods are based on ToxCast data, consisting of over 600 high-throughput screening (HTS) and high-content sc...

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion.

PubMed

Pěnčíková, Kateřina; Svržková, Lucie; Strapáčová, Simona; Neča, Jiří; Bartoňková, Iveta; Dvořák, Zdeněk; Hýžďalová, Martina; Pivnička, Jakub; Pálková, Lenka; Lehmler, Hans-Joachim; Li, Xueshu; Vondráček, Jan; Machala, Miroslav

2018-06-01

The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were

Social acceptability of phytoremediation: The role of risk and values.

PubMed

Weir, Ellen; Doty, Sharon

2016-10-02

A former gas production site that was converted to a public park was chosen as the research location for the present study. Some of the contaminants at the site have been remediated; however, much of the soil is still contaminated with polycyclic aromatic hydrocarbons (PAHs). PAHs are toxic pollutants that have been shown to have numerous negative health effects. The primary form of remediation at the site has been capping, which is usually considered a temporary remediation strategy since it does not remove contaminants from the site but simply covers them, and this requires repeated re-capping efforts. Endophyte-assisted phytoremediation using willow shrubs is an alternative remediation strategy that could improve soil quality and permanently reduce contaminant levels in the soil. The goal of the present study was to explore the social acceptability of utilizing phytoremediation strategies. Surveys were used to explore public perceptions of the park and of using phytoremediation to clean up existing contamination. Results indicated a high level of social acceptability of phytoremediation at the park. Additionally, ecocentrism was shown to be a significant predictor of phytoremediation acceptability. Risk and anthropocentrism were not significant predictors of acceptability. Results suggest that messages intended to encourage the use and acceptability of phytoremediation should focus on the environmental benefits of phytoremediation.

Toxicity profile and treatment delays in NOPHO ALL2008-comparing adults and children with Philadelphia chromosome-negative acute lymphoblastic leukemia.

PubMed

Toft, Nina; Birgens, Henrik; Abrahamsson, Jonas; Griškevičius, Laimonas; Hallböök, Helene; Heyman, Mats; Klausen, Tobias Wirenfeldt; Jónsson, Ólafur Gísli; Palk, Katrin; Pruunsild, Kaie; Quist-Paulsen, Petter; Vaitkeviciene, Goda; Vettenranta, Kim; Asberg, Ann; Helt, Louise Rold; Frandsen, Thomas; Schmiegelow, Kjeld

2016-02-01

Cure rates improve when adolescents and young adults with acute lymphoblastic leukemia (ALL) are treated according to pediatric protocols. Assumed risks of toxicities and associated delays in treatment have played a role in setting upper age limits. The aim of this study was to examine the toxicity profile and treatment delays in NOPHO ALL2008 comparing children and adults. We collected information on 19 treatment-related toxicities, systematically captured at 3-month intervals throughout therapy, and time intervals between 12 consecutive treatment phases for 1076 patients aged 1-45 yrs treated according to the Nordic/Baltic ALL2008 protocol. No adults died during induction. The duration of induction therapy and postinduction treatment phases did not differ between children and adults, except for patients 18-45 yrs being significantly delayed during two of nine high-risk blocks (median number of days for patients 1-9, 10-17, and 18-45 yrs; the glucocorticosteroid/antimetabolite-based block B1: 24, 26, and 29 d, respectively, P = 0.001, and Block 5 (in most cases also a B block): 29, 29, and 37 d, respectively, P = 0.02). A higher incidence of thrombosis with increasing age was found; highest odds ratio 5.4 (95% CI: (2.6;11.0)) for patients 15-17 yrs compared with children 1-9 yrs (P < 0.0001). Risk of avascular osteonecrosis was related to age with the highest OR for patients 10-14 yrs (OR = 10.4 (95% CI: (4.4;24.9)), P < 0.0001). Adults followed and tolerated the NOPHO ALL2008 protocol virtually as well as children, although thrombosis and avascular osteonecrosis was most common among adolescents. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Toxic epidermal necrolysis: a paradigm of critical illness

PubMed Central

Estrella-Alonso, Alfonso; Aramburu, José Antonio; González-Ruiz, Mercedes Yolanda; Cachafeiro, Lucía; Sánchez, Manuel Sánchez; Lorente, José A.

2017-01-01

Toxic epidermal necrolysis is an adverse immunological skin reaction secondary in most cases to the administration of a drug. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and multiform exudative erythema are part of the same disease spectrum. The mortality rate from toxic epidermal necrolysis is approximately 30%. The pathophysiology of toxic epidermal necrolysis is similar in many respects to that of superficial skin burns. Mucosal involvement of the ocular and genital epithelium is associated with serious sequelae if the condition is not treated early. It is generally accepted that patients with toxic epidermal necrolysis are better treated in burn units, which are experienced in the management of patients with extensive skin loss. Treatment includes support, elimination, and coverage with biosynthetic derivatives of the skin in affected areas, treatment of mucosal involvement, and specific immunosuppressive treatment. Of the treatments tested, only immunoglobulin G and cyclosporin A are currently used in most centers, even though there is no solid evidence to recommend any specific treatment. The particular aspects of the treatment of this disease include the prevention of sequelae related to the formation of synechiae, eye care to prevent serious sequelae that can lead to blindness, and specific immunosuppressive treatment. Better knowledge of the management principles of toxic epidermal necrolysis will lead to better disease management, higher survival rates, and lower prevalence of sequelae. PMID:29340540

Speciation Profiles and Toxic Emission Factors for Nonroad Engines: DRAFT REPORT

EPA Science Inventory

This document details the research and development behind how MOVES2014a estimates air toxic emissions for nonroad engines and equipment run on conventional gasoline without ethanol (E0) and gasoline blended with 10% ethanol (E10) as well as diesel fuel, compressed natural gas (C...

ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity (S)

EPA Science Inventory

ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry, bioactivity profiling and toxicogenomic data to predict potential for toxicity and prioritize limited testing resour...

Profiling Chemicals Based on Chronic Toxicity Results from the U.S. EPA ToxRef Database

EPA Science Inventory

Thirty years of pesticide registration toxicity data have been historically stored as hardcopy and scanned documents by the U.S. Environmental Protection Agency (EPA) . A significant portion of these data have now been processed into standardized and structured toxicity data with...

Validation, acceptance, and extension of a predictive model of reproductive toxicity using ToxCast data

EPA Science Inventory

The EPA ToxCast research program uses a high-throughput screening (HTS) approach for predicting the toxicity of large numbers of chemicals. Phase-I tested 309 well-characterized chemicals (mostly pesticides) in over 500 assays of different molecular targets, cellular responses an...

Surface chemistry of gold nanoparticles determines the biocorona composition impacting cellular uptake, toxicity and gene expression profiles in human endothelial cells.

PubMed

Chandran, Parwathy; Riviere, Jim E; Monteiro-Riviere, Nancy A

2017-05-01

This study investigated the role of nanoparticle size and surface chemistry on biocorona composition and its effect on uptake, toxicity and cellular responses in human umbilical vein endothelial cells (HUVEC), employing 40 and 80 nm gold nanoparticles (AuNP) with branched polyethyleneimine (BPEI), lipoic acid (LA) and polyethylene glycol (PEG) coatings. Proteomic analysis identified 59 hard corona proteins among the various AuNP, revealing largely surface chemistry-dependent signature adsorbomes exhibiting human serum albumin (HSA) abundance. Size distribution analysis revealed the relative instability and aggregation inducing potential of bare and corona-bound BPEI-AuNP, over LA- and PEG-AuNP. Circular dichroism analysis showed surface chemistry-dependent conformational changes of proteins binding to AuNP. Time-dependent uptake of bare, plasma corona (PC) and HSA corona-bound AuNP (HSA-AuNP) showed significant reduction in uptake with PC formation. Cell viability studies demonstrated dose-dependent toxicity of BPEI-AuNP. Transcriptional profiling studies revealed 126 genes, from 13 biological pathways, to be differentially regulated by 40 nm bare and PC-bound BPEI-AuNP (PC-BPEI-AuNP). Furthermore, PC formation relieved the toxicity of cationic BPEI-AuNP by modulating expression of genes involved in DNA damage and repair, heat shock response, mitochondrial energy metabolism, oxidative stress and antioxidant response, and ER stress and unfolded protein response cascades, which were aberrantly expressed in bare BPEI-AuNP-treated cells. NP surface chemistry is shown to play the dominant role over size in determining the biocorona composition, which in turn modulates cell uptake, and biological responses, consequently defining the potential safety and efficacy of nanoformulations.

Constructing, Quantifying, and Validating an Adverse Outcome Pathway for Vascular Developmental Toxicity

EPA Science Inventory

Constructing, Quantifying, and Validating an Adverse Outcome Pathway for Vascular Developmental Toxicity The adverse outcome pathway (AOP) for embryonic vascular disruption1 leading to a range of adverse prenatal outcomes was recently entered into the AOP wiki and accepted as par...

Statewide implementation of the total pavement acceptance device (TPAD) : final report.

DOT National Transportation Integrated Search

2016-07-01

Construction and development of the Total Pavement Acceptance Device (TPAD) was completed at the end of August 2012 through TxDOT Research Project 0-6005-01. The TPAD is a multi-function pavement evaluation device used to profile continuously along p...

Phytoremediation: A novel strategy for the removal of toxic metals from the environment using plants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Salt, D.E.; Blaylock, M.; Kumar, N. P.B.A.

1995-05-01

Toxic metal pollution of waters and soils is a major environmental problem, and most conventional remediation approaches do not provide acceptable solutions. The use of specially selected and engineered metal-accumulating plants for environmental clean-up is an emerging technology called phytoremediation. Three subsets of this technology are applicable to toxic metal remediation: (1) Phytoextraction: the use of metal-accumulating plants to remove toxic metals from soil; (2) Rhizofiltration: the use of plant roots to remove toxic metals from polluted waters; and (3) Phytostabilization: the use of plants to eliminate the bioavailability of toxic metals in soils. Biological mechanisms of toxic metal uptake,more » translocation and resistance as well as strategies for improving phytoremediation are also discussed. 83 refs., 4 figs., 1 tab.« less

Antidiabetic, antidyslipidemic and toxicity profile of ENV-2: A potent pyrazole derivative against diabetes and related diseases.

PubMed

Hernández-Vázquez, Eduardo; Ocampo-Montalban, Hugo; Cerón-Romero, Litzia; Cruz, Miguel; Gómez-Zamudio, Jaime; Hiriart-Valencia, Guadalupe; Villalobos-Molina, Rafael; Flores-Flores, Angelica; Estrada-Soto, Samuel

2017-05-15

Diabetes is a major health problem and a predisposition factor for further degenerative complications and, therefore, novel therapies are urgently needed. Currently, cannabinoid receptor 1 (CB 1 receptor) antagonists have been considered as promissory entities for metabolic disorders treatment. Accordingly, the purpose of this work was the evaluation of the sub-acute antidiabetic, anti-hyperglycemic, antidyslipidemic and toxicological profile of ENV-2, a potent hypoglycemic and antioxidant CB 1 receptor antagonist. In this study, ENV-2 showed a pronounced anti-hyperglycemic effect even at a dose of 5mg/kg (P<0.05) in a glucose tolerance test on normoglycemic rats. Moreover, after administration of ENV-2 (16mg/kg) to diabetic rats, a prominent antidiabetic activity was observed (P<0.05), which was higher than glibenclamide. Sub-acute treatment (10 days) of ENV-2 resulted in a significant reduction of plasma glucose (P<0.05). Also, the levels of peripheral lipids were improved; blood triacylglycerols (TG) and cholesterol (CHOL) were diminished (P<0.05). In addition, it was found that ENV-2 reduced IL-1β and IL-18 mRNA expression in adipose tissue (P<0.05). Due to the satisfactory outcomes, we were interested in evaluating the toxicity of ENV-2 in both acute and sub-chronic approaches. Regarding the acute administration, the compound resulted to be non-toxic and was grouped in category 5 according to OECD. It was also found that sub-chronic administration did not increase the size of the studied organs, while no structural damage was observed in heart, lung, liver and kidney tissues. Finally, neither AST nor ALT damage hepatic markers were augmented. Copyright © 2017 Elsevier B.V. All rights reserved.

Anti-Candida activity and brine shrimp toxicity assay of Ganoderma boninense.

PubMed

Daruliza, K M A; Fernandez, L; Jegathambigai, R; Sasidharan, S

2012-01-01

Ganoderma (G.) boninense is a white rot fungus, which can be found in the palm oil tree. Several studies have shown that G. boninense has antimicrobial and antagonistic properties. However, there is limited information reported on antifungal properties especially on Candida (C) albicans. Hence, this study was conducted to determine the anti-Candida activity of G. boninense against C albicans. Crude methanolic extracts of G. boninense was obtained by maceration method with 70% methanol. Anti-Candida test was carried out using disc diffusion assay, broth dilution method, time killing profile and brine shrimp toxicity assay. Anti-Candida activity indicated that the mean zone of inhibition was 12.5 +/- 0.6 mm. The MIC value for C. albicans found to be 3.125 mg/ml. The result from time-killing profile showed that the growth of C albicans was inhibited hence decreases its exponential phase. For brine shrimp toxicity assay, the LC50 value was 3.59 mg/ml which proved that the extract of G. boninense is not toxic.

Monitoring late-onset toxicities in phase I trials using predicted risks

PubMed Central

Bekele, B. Nebiyou; Ji, Yuan; Shen, Yu; Thall, Peter F.

2008-01-01

Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective doses for future patients is unacceptably high. If additional follow-up data reduce the predicted risk of toxicity to an acceptable level, then accrual is restarted, and this process may be repeated several times during the trial. A simulation study shows that the proposed method provides a greater degree of safety than the TITE-CRM, while still reliably choosing the preferred dose. This advantage increases with accrual rate, but the price of this additional safety is that the trial takes longer to complete on average. PMID:18084008

Automated Test Systems for Toxic Vapor Detectors

NASA Technical Reports Server (NTRS)

Mattson, C. B.; Hammond, T. A.; Schwindt, C. J.

1997-01-01

The NASA Toxic Vapor Detection Laboratory (TVDL) at the Kennedy Space Center (KSC), Florida, has been using Personal Computer based Data Acquisition and Control Systems (PCDAS) for about nine years. These systems control the generation of toxic vapors of known concentrations under controlled conditions of temperature and humidity. The PCDAS also logs the test conditions and the test article responses in data files for analysis by standard spreadsheets or custom programs. The PCDAS was originally developed to perform standardized qualification and acceptance tests in a search for a commercial off-the-shelf (COTS) toxic vapor detector to replace the hydrazine detectors for the Space Shuttle launch pad. It has since become standard test equipment for the TVDL and is indispensable in producing calibration standards for the new hydrazine monitors at the 10 part per billion (ppb) level. The standard TVDL PCDAS can control two toxic vapor generators (TVG's) with three channels each and two flow/ temperature / humidity (FTH) controllers and it can record data from up to six toxic vapor detectors (TVD's) under test and can deliver flows from 5 to 50 liters per minute (L/m) at temperatures from near zero to 50 degrees Celsius (C) using an environmental chamber to maintain the sample temperature. The concentration range for toxic vapors depends on the permeation source installed in the TVG. The PCDAS can provide closed loop control of temperature and humidity to two sample vessels, typically one for zero gas and one for the standard gas. This is required at very low toxic vapor concentrations to minimize the time required to passivate the sample delivery system. Recently, there have been several requests for information about the PCDAS by other laboratories with similar needs, both on and off KSC. The purpose of this paper is to inform the toxic vapor detection community of the current status and planned upgrades to the automated testing of toxic vapor detectors at the

Automated Test Systems for Toxic Vapor Detectors

NASA Technical Reports Server (NTRS)

Mattson, C. B.; Hammond, T. A.; Schwindt, C. J.

1997-01-01

The NASA Toxic Vapor Detection Laboratory (TVDL) at the Kennedy Space Center (KSC), Florida, has been using Personal Computer based Data Acquisition and Control Systems (PCDAS) for about nine years. These systems control the generation of toxic vapors of known concentrations under controlled conditions of temperature and humidity. The PCDAS also logs the test conditions and the test article responses in data files for analysis by standard spreadsheets or custom programs. The PCDAS was originally developed to perform standardized qualification and acceptance tests in a search for a commercial off-the-shelf (COTS) toxic vapor detector to replace the hydrazine detectors for the Space Shuttle launch pad. It has since become standard test equipment for the TVDL and is indispensable in producing calibration standards for the new hydrazine monitors at the 10 part per billion (ppb) level. The standard TVDL PCDAS can control two toxic vapor generators (TVG's) with three channels each and two flow/temperature/humidity (FIFH) controllers and it can record data from up to six toxic vapor detectors (TVD's) under test and can deliver flows from 5 to 50 liters per minute (L/m) at temperatures from near zero to 50 degrees Celsius (C) using an environmental chamber to maintain the sample temperature. The concentration range for toxic vapors depends on the permeation source installed in the TVG. The PCDAS can provide closed loop control of temperature and humidity to two sample vessels, typically one for zero gas and one for the standard gas. This is required at very low toxic vapor concentrations to minimize the time required to passivate the sample delivery system. Recently, there have been several requests for information about the PCDAS by other laboratories with similar needs, both on and off KSC. The purpose of this paper is to inform the toxic vapor detection community of the current status and planned upgrades to the automated testing of toxic vapor detectors at the Kennedy

Transcriptome assembly and expression profiling of the molecular responses to cadmium toxicity in cerebral ganglia of wolf spider Pardosa pseudoannulata (Araneae: Lycosidae).

PubMed

Yang, Huilin; Peng, Yuande; Shi, Yixue; Tian, Jianxiang; Wang, Juan; Peng, Xianjin; Xie, Chunliang; Xu, Xiang; Song, Qisheng; Wang, Zhi; Lv, Zhiyue

2018-03-01

Cadmium (Cd) is a heavy metal that can cause irreversible toxicity to animals, and is an environmental pollutant in farmlands. Spiders are considered to be an excellent model for investigating the impacts of heavy metals on the environment. To date, the changes at the molecular level in the cerebral ganglia of spiders are poorly understood. Cd exposure leads to strong damage in the nervous system, such as apoptosis and necrosis of nerve cells, therefore we conducted a transcriptomic analysis of Pardosa pseudoannulata cerebral ganglia under Cd stress to profile differential gene expression (DGE). We obtained a total of 123,328 assembled unigenes, and 1441 Cd stress-associated DEGs between the Cd-treated and control groups. Expression profile analysis demonstrated that many genes involved in calcium signaling, cGMP-PKG signaling, tyrosine metabolism, phototransduction-fly, melanogenesis and isoquinoline alkaloid biosynthesis were up-regulated under Cd stress, whereas oxidative phosphorylation-related, nervous disease-associated, non-alcoholic fatty liver disease-associated, and ribosomal-associated genes were down-regulated. Here, we provide a comprehensive set of DEGs influenced by Cd stress, and heavy metal stress, and provide new information for elucidating the neurotoxic mechanisms of Cd stress in spiders.

Picking Cell Lines for High-Throughput Transcriptomic Toxicity Screening (SOT)

EPA Science Inventory

High throughput, whole genome transcriptomic profiling is a promising approach to comprehensively evaluate chemicals for potential biological effects. To be useful for in vitro toxicity screening, gene expression must be quantified in a set of representative cell types that captu...

76 FR 10906 - Proposed Substances To Be Evaluated for Set 25 Toxicological Profiles

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-28

...-269] Proposed Substances To Be Evaluated for Set 25 Toxicological Profiles AGENCY: Agency for Toxic... comments on the proposed substances to be evaluated for Set 25 toxicological profiles. SUMMARY: ATSDR is initiating the development of its 25th set of toxicological profiles (CERCLA Set 25). This notice announces...

The perception of children's computer-imaged facial profiles by patients, mothers and clinicians.

PubMed

Miner, Robert M; Anderson, Nina K; Evans, Carla A; Giddon, Donald B

2007-11-01

To demonstrate the usefulness of a new imaging system for comparing the morphometric bases of children's self-perception of their facial profile with the perceptions of their mothers and treating clinicians. Rather than choosing among a series of static images, a computer imaging program was developed to elicit a range of acceptable responses or tolerance for change from which a midpoint of acceptability was derived. Using the method of Giddon et al, three profile features (upper and lower lips and mandible) from standardized images of 24 patients aged 8- 15 years were distorted and presented to patients, parents, and clinicians in random order as slowly moving images (four frames per second) from retrusive and protrusive extremes. Subjects clicked the mouse when the image became acceptable and released it when it was no longer acceptable. Subjects responded similarly to a neutral facial profile. Patients and their mothers overestimated the protrusiveness of the mandible of the actual pretreatment profile. Consistent with related studies, mothers had a smaller tolerance for change in the soft tissue profile than the children or clinicians. The magnitudes of the children's self-preference and preferred change in a neutral face were also significantly correlated. Both patients and mothers preferred a more protrusive profile than that of the actual or neutral face for the patient and neutral face. Imaging software can be used with children to compare their preferences with those of parents and clinicians to facilitate treatment planning and patient satisfaction.

Cheminformatics Analysis of EPA ToxCast Chemical Libraries to Identify Domains of Applicability for Predictive Toxicity Models and Prioritize Compounds for Toxicity Testing

EPA Science Inventory

An important goal of toxicology research is the development of robust methods that use in vitro and chemical structure information to predict in vivo toxicity endpoints. The US EPA ToxCast program is addressing this goal using ~600 in vitro assays to create bioactivity profiles o...

75 FR 52535 - Availability of Draft Toxicological Profile

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-26

... toxicological profile on unregulated hazardous substances that was prepared for the Department of Defense (DOD... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [ATSDR... Registry (ATSDR), [[Page 52536

Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition.

PubMed

Sørli, Jorid B; Huang, Yishi; Da Silva, Emilie; Hansen, Jitka S; Zuo, Yi Y; Frederiksen, Marie; Nørgaard, Asger W; Ebbehøj, Niels E; Larsen, Søren T; Hougaard, Karin S

2018-01-01

Private consumers and professionals may experience acute inhalation toxicity after inhaling aerosolized impregnation products. The distinction between toxic and non-toxic products is difficult to make for producers and product users alike, as there is no clearly described relationship between the chemical composition of the products and induction of toxicity. The currently accepted method for determination of acute inhalation toxicity is based on experiments on animals; it is time-consuming, expensive and causes stress for the animals. Impregnation products are present on the market in large numbers and amounts and exhibit great variety. Therefore, an alternative method to screen for acute inhalation toxicity is needed. The aim of our study was to determine if inhibition of lung surfactant by impregnation products in vitro could accurately predict toxicity in vivo in mice. We tested 21 impregnation products using the constant flow through set-up of the constrained drop surfactometer to determine if the products inhibited surfactant function or not. The same products were tested in a mouse inhalation bioassay to determine their toxicity in vivo. The sensitivity was 100%, i.e., the in vitro method predicted all the products that were toxic for mice to inhale. The specificity of the in vitro test was 63%, i.e., the in vitro method found three false positives in the 21 tested products. Six of the products had been involved in accidental human inhalation where they caused acute inhalation toxicity. All of these six products inhibited lung surfactant function in vitro and were toxic to mice.

Gene expression patterns in rainbow trout, Oncorhynchus mykiss, exposed to a suite of model toxicants

PubMed Central

Hook, Sharon E.; Skillman, Ann D.; Small, Jack A.; Schultz, Irvin R.

2008-01-01

The increased availability and use of DNA microarrays has allowed the characterization of gene expression patterns associated with exposure to different toxicants. An important question is whether toxicant induced changes in gene expression in fish are sufficiently diverse to allow for identification of specific modes of action and/or specific contaminants. In theory, each class of toxicant may generate a gene expression profile unique to its mode of toxic action. In this study, isogenic (cloned) rainbow trout Oncorhynchus mykiss were exposed to sublethal levels of a series of model toxicants with varying modes of action, including ethynylestradiol (xeno-estrogen), 2,2,4,4′-tetrabromodiphenyl ether (BDE-47, thyroid active), diquat (oxidant stressor), chromium VI, and benzo[a]pyrene (BaP) for a period of 1–3 weeks. An additional experiment measured trenbolone (anabolic steroid; model androgen) induced gene expression changes in sexually mature female trout. Following exposure, fish were euthanized, livers removed and RNA extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon/Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNA’s. The slides were scanned to measure abundance of a given transcript in each sample relative to controls. Data were analyzed via Genespring (Silicon Genetics) to identify a list of up- and downregulated genes, as well as to determine gene clustering patterns that can be used as “expression signatures”. The results indicate each toxicant exposure caused between 64 and 222 genes to be significantly altered in expression. Most genes exhibiting altered expression responded to only one of the toxicants and relatively few were co-expressed in multiple treatments. For example, BaP and Diquat, both of which exert toxicity via oxidative stress, upregulated 28 of the same genes, of over 100 genes altered by either treatment. Other genes associated with

Gene expression patterns in rainbow trout, Oncorhynchus mykiss, exposed to a suite of model toxicants.

PubMed

Hook, Sharon E; Skillman, Ann D; Small, Jack A; Schultz, Irvin R

2006-05-25

The increased availability and use of DNA microarrays has allowed the characterization of gene expression patterns associated with exposure to different toxicants. An important question is whether toxicant induced changes in gene expression in fish are sufficiently diverse to allow for identification of specific modes of action and/or specific contaminants. In theory, each class of toxicant may generate a gene expression profile unique to its mode of toxic action. In this study, isogenic (cloned) rainbow trout Oncorhynchus mykiss were exposed to sublethal levels of a series of model toxicants with varying modes of action, including ethynylestradiol (xeno-estrogen), 2,2,4,4'-tetrabromodiphenyl ether (BDE-47, thyroid active), diquat (oxidant stressor), chromium VI, and benzo[a]pyrene (BaP) for a period of 1-3 weeks. An additional experiment measured trenbolone (anabolic steroid; model androgen) induced gene expression changes in sexually mature female trout. Following exposure, fish were euthanized, livers removed and RNA extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon/Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNA's. The slides were scanned to measure abundance of a given transcript in each sample relative to controls. Data were analyzed via Genespring (Silicon Genetics) to identify a list of up- and downregulated genes, as well as to determine gene clustering patterns that can be used as "expression signatures". The results indicate each toxicant exposure caused between 64 and 222 genes to be significantly altered in expression. Most genes exhibiting altered expression responded to only one of the toxicants and relatively few were co-expressed in multiple treatments. For example, BaP and Diquat, both of which exert toxicity via oxidative stress, upregulated 28 of the same genes, of over 100 genes altered by either treatment. Other genes associated with steroidogenesis

Validation of alternative methods for toxicity testing.

PubMed Central

Bruner, L H; Carr, G J; Curren, R D; Chamberlain, M

1998-01-01

Before nonanimal toxicity tests may be officially accepted by regulatory agencies, it is generally agreed that the validity of the new methods must be demonstrated in an independent, scientifically sound validation program. Validation has been defined as the demonstration of the reliability and relevance of a test method for a particular purpose. This paper provides a brief review of the development of the theoretical aspects of the validation process and updates current thinking about objectively testing the performance of an alternative method in a validation study. Validation of alternative methods for eye irritation testing is a specific example illustrating important concepts. Although discussion focuses on the validation of alternative methods intended to replace current in vivo toxicity tests, the procedures can be used to assess the performance of alternative methods intended for other uses. Images Figure 1 PMID:9599695

A MODE-OF-ACTION-BASED QSAR APPROACH TO IMPROVE UNDERSTANDING OF DEVELOPMENTAL TOXICITY

EPA Science Inventory

QSAR models of developmental toxicity (devtox) have met with limited regulatory acceptance due to the use of ill-defined endpoints, lack of biological interpretability, and poor model performance. More generally, the lack of biological inference of many QSAR models is often due t...

Lead Toxicity in the Pediatric Patient with Sickle Cell Disease: Unique Risks and Management.

PubMed

Jung, Josephine Misun; Peddinti, Radhika

2018-01-01

Lead toxicity is the result of lead ingestion, one of the most common ingestions in the pediatric population. Nationwide and statewide efforts to recognize and curtail this epidemic have led to declining rates of toxicity. In patients with sickle cell disease (SCD), lead toxicity can be an elusive diagnosis due to overlapping symptom profiles, and inconsistent follow-up with a primary care physician can make the diagnosis even more difficult. In this article, two illustrative cases of lead toxicity in patients with SCD are described. The discussion reviews the current risk factors, screening, and inpatient management of lead toxicity, as well as describing the unique and sometimes confounding presentations of lead toxicity versus sickle cell crisis. [Pediatr Ann. 2018;47(1):e36-e40.]. Copyright 2018, SLACK Incorporated.

A confirmed case of toxic shock syndrome associated with the use of a menstrual cup

PubMed Central

Mitchell, Michael A; Bisch, Steve; Arntfield, Shannon; Hosseini-Moghaddam, Seyed M

2015-01-01

Menstrual cups have been reported to be an acceptable substitute for tampons. These flexible cups have also been reported to provide a sustainable solution to menstrual management, with modest cost savings and no significant health risk. The present article documents the first case of toxic shock syndrome associated with the use of a menstrual cup in a woman 37 years of age, using a menstrual cup for the first time. Toxic shock syndrome and the literature on menstrual cups is reviewed and a possible mechanism for the development of toxic shock syndrome in the patient is described. PMID:26361491

A confirmed case of toxic shock syndrome associated with the use of a menstrual cup.

PubMed

Mitchell, Michael A; Bisch, Steve; Arntfield, Shannon; Hosseini-Moghaddam, Seyed M

2015-01-01

Menstrual cups have been reported to be an acceptable substitute for tampons. These flexible cups have also been reported to provide a sustainable solution to menstrual management, with modest cost savings and no significant health risk. The present article documents the first case of toxic shock syndrome associated with the use of a menstrual cup in a woman 37 years of age, using a menstrual cup for the first time. Toxic shock syndrome and the literature on menstrual cups is reviewed and a possible mechanism for the development of toxic shock syndrome in the patient is described.

Assessing Children's Perceptions of Academic Interventions: The Kids Intervention Profile

ERIC Educational Resources Information Center

Eckert, Tanya L.; Hier, Bridget O.; Hamsho, Narmene F.; Malandrino, Rigby D.

2017-01-01

The psychometric properties of the Kids Intervention Profile (KIP), a rating scale designed to measure academic intervention acceptability from the perspective of students, were examined as well as the influence of background factors on students' acceptability ratings. Data were extracted from 4 randomized controlled trials investigating the…

Is the Factor-of-2 Rule Broadly Applicable for Evaluating the Prediction Accuracy of Metal-Toxicity Models?

PubMed

Meyer, Joseph S; Traudt, Elizabeth M; Ranville, James F

2018-01-01

In aquatic toxicology, a toxicity-prediction model is generally deemed acceptable if its predicted median lethal concentrations (LC50 values) or median effect concentrations (EC50 values) are within a factor of 2 of their paired, observed LC50 or EC50 values. However, that rule of thumb is based on results from only two studies: multiple LC50 values for the fathead minnow (Pimephales promelas) exposed to Cu in one type of exposure water, and multiple EC50 values for Daphnia magna exposed to Zn in another type of exposure water. We tested whether the factor-of-2 rule of thumb also is supported in a different dataset in which D. magna were exposed separately to Cd, Cu, Ni, or Zn. Overall, the factor-of-2 rule of thumb appeared to be a good guide to evaluating the acceptability of a toxicity model's underprediction or overprediction of observed LC50 or EC50 values in these acute toxicity tests.

The physiological adaptations and toxin profiles of the toxic Alexandrium fundyense on the eastern Bering Sea and Chukchi Sea shelves.

PubMed

Natsuike, Masafumi; Oikawa, Hiroshi; Matsuno, Kohei; Yamaguchi, Atsushi; Imai, Ichiro

2017-03-01

Abundant cyst distributions of the toxic dinoflagellate Alexandrium fundyense (previous A. tamarense north American clade) were recently observed on the north Chukchi Sea shelf and on the eastern Bering Sea shelf, suggesting that A. fundyense is both highly adapted to the local environments in the high latitude areas and might cause toxin contamination of plankton feeders. However, little is known about the physiological characteristics and toxin profiles of A. fundyense in these areas, which are characterized by low water temperatures, weak sunlight, and more or less permanent ice cover during winter. To clarify the physiological characteristics of A. fundyense, the effects of water temperature and light intensity on the vegetative growth and toxin profiles of this species were examined using A. fundyense strains isolated from one sediment sample collected from each area. Using the same sediments samples, seasonal changes of the cyst germination in different water temperatures were investigated. Vegetative cells grew at temperatures as low as 5°C and survived at 1°C under relatively low light intensity. They also grew at moderate water temperatures (10-15°C). Their cysts could germinate at low temperatures (1°C) and have an endogenous dormancy period from late summer to early spring, and warmer water temperatures (5-15°C) increased germination success. These physiological characteristics suggest that A. fundyense in the Chukchi Sea and eastern Bering Sea is adapted to the environments of high latitude areas. In addition, the results suggest that in the study areas A. fundyense has the potential to germinate and grow when water temperatures increase. Cellular toxin amounts of A. fundyense strains from the eastern Bering Sea and Chukchi Sea were ranged from 7.2 to 38.2 fmol cell -1 . These toxin amounts are comparable with A. fundyense strains isolated from other areas where PSP toxin contamination of bivalves occurs. The dominant toxin of the strains isolated

Gaining Acceptance for the use of in vitro Toxicity Assays and QIVIVE in Regulatory Risk Assessment

EPA Science Inventory

Testing strategies are anticipated to increasingly rely on in vitro data as a basis to characterize early steps or key events in toxicity at relevant dose levels in human tissues. This requires quantitative in vitro to in vivo extrapolation to characterize dose-response as a bas...

Demonstration of a Non-Toxic Reaction Control Engine

NASA Technical Reports Server (NTRS)

Robinson, Philip J.; Turpin, Alicia A.; Veith, Eric M.

2007-01-01

T:hree non-toxic demonstration reaction control engines (RCE) were successfully tested at the Aerojet Sacramento facility under a technology contract sponsored by the National Aeronautics and Space Administration's (NASA) Marshall Space Flight Center (MSFC). The goals of the NASA MSFC contract (NAS8-01109) were to develop and expand the technical maturity of a non-toxic, on-orbit auxiliary propulsion system (APS) thruster under the auspices of the Exploration Systems Mission Directorate. The demonstration engine utilized Liquid Oxygen (LOX) and Ethanol as propellants to produce 870 lbf thrust. The Aerojet RCE's were successfully acceptance tested over a broad range of operating conditions. Steady state tests evaluated engine response to varying chamber pressures and mixture ratios. In addition to the steady state tests, a variety of pulsing tests were conducted over a wide range of electrical pulse widths (EPW). Each EPW condition was also tested over a range of percent duty cycles (DC), and bit impulse and pulsing specific impulse were determined for each of these conditions. Subsequent to acceptance testing at Aerojet, these three engines were delivered to the NASA White Sands Test Facility (WSTF) in April 2005 for incorporation into a cryogenic Auxiliary Propulsion System Test Bed (APSTB). The APSTB is a test article that will be utilized in an altitude test cell to simulate anticipated mission applications. The objectives of this APSTB testing included evaluation of engine performance over an extended duty cycle map of propellant pressure and temperature, as well as engine and system performance at typical mission duty cycles over extended periods of time. This paper provides acceptance test results and a status of the engine performance as part of the system level testing.

Learning Style Profile: Examiner's Manual.

ERIC Educational Resources Information Center

Keefe, James W.; Monk, John S.

This examiner's manual accompanies the Learning Style Profile (LSP), which measures cognitive skills as well as affective and environmental preferences. Charles Letteri's General Operations Model was accepted as the prototype for relating learning styles to cognitive information processing. The LSP was developed from 1983 to 1986; several versions…

40 CFR 227.8 - Limitations on the disposal rates of toxic wastes.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) OCEAN DUMPING CRITERIA FOR THE EVALUATION OF PERMIT APPLICATIONS FOR OCEAN DUMPING OF MATERIALS Environmental Impact § 227.8 Limitations on the disposal rates of toxic wastes. No wastes will be deemed acceptable for ocean dumping unless such wastes can be dumped so as not to exceed the limiting permissible...

40 CFR 227.8 - Limitations on the disposal rates of toxic wastes.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) OCEAN DUMPING CRITERIA FOR THE EVALUATION OF PERMIT APPLICATIONS FOR OCEAN DUMPING OF MATERIALS Environmental Impact § 227.8 Limitations on the disposal rates of toxic wastes. No wastes will be deemed acceptable for ocean dumping unless such wastes can be dumped so as not to exceed the limiting permissible...

40 CFR 227.8 - Limitations on the disposal rates of toxic wastes.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) OCEAN DUMPING CRITERIA FOR THE EVALUATION OF PERMIT APPLICATIONS FOR OCEAN DUMPING OF MATERIALS Environmental Impact § 227.8 Limitations on the disposal rates of toxic wastes. No wastes will be deemed acceptable for ocean dumping unless such wastes can be dumped so as not to exceed the limiting permissible...

40 CFR 227.8 - Limitations on the disposal rates of toxic wastes.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) OCEAN DUMPING CRITERIA FOR THE EVALUATION OF PERMIT APPLICATIONS FOR OCEAN DUMPING OF MATERIALS Environmental Impact § 227.8 Limitations on the disposal rates of toxic wastes. No wastes will be deemed acceptable for ocean dumping unless such wastes can be dumped so as not to exceed the limiting permissible...

40 CFR 227.8 - Limitations on the disposal rates of toxic wastes.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) OCEAN DUMPING CRITERIA FOR THE EVALUATION OF PERMIT APPLICATIONS FOR OCEAN DUMPING OF MATERIALS Environmental Impact § 227.8 Limitations on the disposal rates of toxic wastes. No wastes will be deemed acceptable for ocean dumping unless such wastes can be dumped so as not to exceed the limiting permissible...

US EPA - A*Star Partnership - Accelerating the Acceptance of ...

EPA Pesticide Factsheets

The path for incorporating new alternative methods and technologies into quantitative chemical risk assessment poses a diverse set of scientific challenges. Some of these challenges include development of relevant and predictive test systems and computational models to integrate and extrapolate experimental data, and rapid characterization and acceptance of these systems and models. The series of presentations will highlight a collaborative effort between the U.S. Environmental Protection Agency (EPA) and the Agency for Science, Technology and Research (A*STAR) that is focused on developing and applying experimental and computational models for predicting chemical-induced liver and kidney toxicity, brain angiogenesis, and blood-brain-barrier formation. In addressing some of these challenges, the U.S. EPA and A*STAR collaboration will provide a glimpse of what chemical risk assessments could look like in the 21st century. Presentation on US EPA – A*STAR Partnership at international symposium on Accelerating the acceptance of next-generation sciences and their application to regulatory risk assessment in Singapore.

Comparative Toxicity and Dosimetric Profile of Whole-Pelvis Versus Prostate Bed-Only Intensity-Modulated Radiation Therapy After Prostatectomy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deville, Curtiland, E-mail: deville@uphs.upenn.edu; Vapiwala, Neha; Hwang, Wei-Ting

2012-03-15

Purpose: To assess whether whole-pelvis (WP) intensity modulated radiation therapy (IMRT) for prostate cancer (PCa) after prostatectomy is associated with increased toxicity compared to prostate-bed only (PB) IMRT. Methods and Materials: All patients (n = 67) undergoing postprostatectomy IMRT to 70.2 Gy at our institution from January 2006 to January 2009 with minimum 12-month follow-up were divided into WP (n = 36) and PB (n = 31) comparison groups. WP patients received initial pelvic nodal IMRT to 45 Gy. Pretreatment demographics, bladder and rectal dose-volume histograms, and maximum genitourinary (GU) and gastrointestinal (GI) toxicities were compared. Logistic regression models evaluatedmore » uni- and multivariate associations between pretreatment demographics and toxicities. Results: Pretreatment demographics including age and comorbidities were similar between groups. WP patients had higher Gleason scores, T stages, and preoperative prostate-specific antigen (PSA) levels, and more WP patients underwent androgen deprivation therapy (ADT). WP minimum (Dmin) and mean bladder doses, bladder volumes receiving more than 5 Gy (V5) and V20, rectal Dmin, and PB bladder and rectal V65 were significantly increased. Maximum acute GI toxicity was Grade 2 and was increased for WP (61%) vs. PB (29%) patients (p = 0.001); there was no significant difference in acute Grade {>=}2 GU toxicity (22% WP vs. 10% PB; p = 0.193), late Grade {>=}2 GI toxicity (3% WP vs. 0% PB; p = 0.678), or late Grade {>=}2 GU toxicity (28% WP vs. 19% PB; p = 0.274) with 25-month median follow-up (range, 12-44 months). On multivariate analysis, long-term ADT use was associated with Grade {>=}2 late GU toxicity (p = 0.02). Conclusion: Despite dosimetric differences in irradiated bowel, bladder, and rectum, WP IMRT resulted only in clinically significant increased acute GI toxicity in comparison to that with PB IMRT, with no differences in GU or late GI toxicity.« less

Natural deep eutectic solvents: cytotoxic profile.

PubMed

Hayyan, Maan; Mbous, Yves Paul; Looi, Chung Yeng; Wong, Won Fen; Hayyan, Adeeb; Salleh, Zulhaziman; Mohd-Ali, Ozair

2016-01-01

The purpose of this study was to investigate the cytotoxic profiles of different ternary natural deep eutectic solvents (NADESs) containing water. For this purpose, five different NADESs were prepared using choline chloride as a salt, alongside five hydrogen bond donors (HBD) namely glucose, fructose, sucrose, glycerol, and malonic acid. Water was added as a tertiary component during the eutectics preparation, except for the malonic acid-based mixture. Coincidentally, the latter was found to be more toxic than any of the water-based NADESs. A trend was observed between the cellular requirements of cancer cells, the viscosity of the NADESs, and their cytotoxicity. This study also highlights the first time application of the conductor-like screening model for real solvent (COSMO-RS) software for the analysis of the cytotoxic mechanism of NADESs. COSMO-RS simulation of the interactions between NADESs and cellular membranes' phospholipids suggested that NADESs strongly interacted with cell surfaces and that their accumulation and aggregation possibly defined their cytotoxicity. This reinforced the idea that careful selection of NADESs components is necessary, as it becomes evident that organic acids as HBD highly contribute to the increasing toxicity of these neoteric mixtures. Nevertheless, NADESs in general seem to possess relatively less acute toxicity profiles than their DESs parents. This opens the door for future large scale utilization of these mixtures.

Pharmacology-based toxicity assessment: towards quantitative risk prediction in humans.

PubMed

Sahota, Tarjinder; Danhof, Meindert; Della Pasqua, Oscar

2016-05-01

Despite ongoing efforts to better understand the mechanisms underlying safety and toxicity, ~30% of the attrition in drug discovery and development is still due to safety concerns. Changes in current practice regarding the assessment of safety and toxicity are required to reduce late stage attrition and enable effective development of novel medicines. This review focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is needed to (i) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; (ii) facilitate the integration of historical evidence and thereby the translation of findings across species as well as between in vitro and in vivo experiments and (iii) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Based on historical examples, we highlight the challenges for the early characterisation of the safety profile of a new molecule and discuss how model-based methodologies can be applied for the design and analysis of experimental protocols. Issues relative to the scientific rationale are categorised and presented as a hierarchical tree describing the decision-making process. Focus is given to four different areas, namely, optimisation, translation, analytical construct and decision criteria. From a methodological perspective, the relevance of quantitative methods for estimation and extrapolation of risk from toxicology and safety pharmacology experimental protocols, such as points of departure and potency, is discussed in light of advancements in population and Bayesian modelling techniques (e.g. non-linear mixed effects modelling). Their use in the evaluation of pharmacokinetics (PK) and pharmacokinetic-pharmacodynamic relationships (PKPD) has enabled great insight into the dose rationale for medicines in humans, both in terms of efficacy and adverse events. Comparable benefits

Framework for a Quantitative Systemic Toxicity Model (FutureToxII)

EPA Science Inventory

EPA’s ToxCast program profiles the bioactivity of chemicals in a diverse set of ~700 high throughput screening (HTS) assays. In collaboration with L’Oreal, a quantitative model of systemic toxicity was developed using no effect levels (NEL) from ToxRefDB for 633 chemicals with HT...

Monitoring and Management of Toxicities of Novel B Cell Signaling Agents.

PubMed

Rhodes, Joanna; Mato, Anthony; Sharman, Jeff P

2018-04-11

B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management. Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications. Patients on idelalisib require close clinical and frequent laboratory monitoring, particularly of liver function tests to ensure there are no serious adverse events. Monitoring for infections is important in patients on both idelalisib and ibrutinib. Venetoclax requires close clinical and laboratory monitoring to prevent significant tumor lysis. Targeted B cell receptor therapies each have unique side effect profiles which require careful clinical monitoring. As we continue to use these therapies, optimal management strategies will continue to be elucidated.

78 FR 38982 - Availability of Draft Toxicological Profiles

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-28

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [Docket... and Disease Registry (ATSDR), Department of Health and Human Services (DHHS). ACTION: Notice of... substances during the profile development process, this Federal Register notice solicits any relevant...

Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Nanoparticle Titanium Dioxide

EPA Science Inventory

Identification of toxicity pathways linked to chemical -exposure is critical for a better understanding of biological effects of the exposure, toxic mechanisms, and for enhancement of the prediction of chemical toxicity and adverse health outcomes. To identify toxicity pathways a...

Intra- and interlaboratory variability in acute toxicity tests with glochidia and juveniles of freshwater mussels (Unionidae)

USGS Publications Warehouse

Wang, N.; Augspurger, T.; Barnhart, M.C.; Bidwell, Joseph R.; Cope, W.G.; Dwyer, F.J.; Geis, S.; Greer, I.E.; Ingersoll, C.G.; Kane, C.M.; May, T.W.; Neves, R.J.; Newton, T.J.; Roberts, A.D.; Whites, D.W.

2007-01-01

The present study evaluated the performance and variability in acute toxicity tests with glochidia and newly transformed juvenile mussels using the standard methods outlined in American Society for Testing and Materials (ASTM). Multiple 48-h toxicity tests with glochidia and 96-h tests with juvenile mussels were conducted within a single laboratory and among five laboratories. All tests met the test acceptability requirements (e.g., ???90% control survival). Intralaboratory tests were conducted over two consecutive mussel-spawning seasons with mucket (Actinonaias ligamentina) or fatmucket (Lampsilis siliquoidea) using copper, ammonia, or chlorine as a toxicant. For the glochidia of both species, the variability of intralaboratory median effective concentrations (EC50s) for the three toxicants, expressed as the coefficient of variation (CV), ranged from 14 to 27% in 24-h exposures and from 13 to 36% in 48-h exposures. The intralaboratory CV of copper EC50s for juvenile fatmucket was 24% in 48-h exposures and 13% in 96-h exposures. Interlaboratory tests were conducted with fatmucket glochidia and juveniles by five laboratories using copper as a toxicant. The interlaboratory CV of copper EC50s for glochidia was 13% in 24-h exposures and 24% in 48-h exposures, and the interlaboratory CV for juveniles was 22% in 48-h exposures and 42% in 96-h exposures. The high completion success and the overall low variability in test results indicate that the test methods have acceptable precision and can be performed routinely. ?? 2007 SETAC.

Establishment of an equivalence acceptance criterion for accelerated stability studies.

PubMed

Burdick, Richard K; Sidor, Leslie

2013-01-01

In this article, the use of statistical equivalence testing for providing evidence of process comparability in an accelerated stability study is advocated over the use of a test of differences. The objective of such a study is to demonstrate comparability by showing that the stability profiles under nonrecommended storage conditions of two processes are equivalent. Because it is difficult at accelerated conditions to find a direct link to product specifications, and hence product safety and efficacy, an equivalence acceptance criterion is proposed that is based on the statistical concept of effect size. As with all statistical tests of equivalence, it is important to collect input from appropriate subject-matter experts when defining the acceptance criterion.

76 FR 23600 - Availability of Draft Toxicological Profile

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-27

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [CDC-2011... Registry (ATSDR), Department of Health and Human Services (DHHS). ACTION: Notice of availability. SUMMARY... of uranium. Although ATSDR considered key studies for uranium during the profile development process...

Pharmacogenetic profile of xenobiotic enzyme metabolism in survivors of the Spanish toxic oil syndrome.

PubMed Central

Ladona, M G; Izquierdo-Martinez, M; Posada de la Paz, M P; de la Torre, R; Ampurdanés, C; Segura, J; Sanz, E J

2001-01-01

In 1981, the Spanish toxic oil syndrome (TOS) affected more than 20,000 people, and over 300 deaths were registered. Assessment of genetic polymorphisms on xenobiotic metabolism would indicate the potential metabolic capacity of the victims at the time of the disaster. Thus, impaired metabolic pathways may have contributed to the clearance of the toxicant(s) leading to a low detoxification or accumulation of toxic metabolites contributing to the disease. We conducted a matched case-control study using 72 cases (54 females, 18 males) registered in the Official Census of Affected Patients maintained by the Spanish government. Controls were nonaffected siblings (n =72) living in the same household in 1981 and nonaffected nonrelatives (n = 70) living in the neighborhood at that time, with no ties to TOS. Genotype analyses were performed to assess the metabolic capacity of phase I [cytochrome P450 1A1 (CYP1A1), CYP2D6] and phase II [arylamine N-acetyltransferase-2 (NAT2), GSTM1 (glutathione S-transferase M1) and GSTT1] enzyme polymorphisms. The degree of association of the five metabolic pathways was estimated by calculating their odds ratios (ORs) using conditional logistic regression analysis. In the final model, cases compared with siblings (72 pairs) showed no differences either in CYP2D6 or CYP1A1 polymorphisms, or in conjugation enzyme polymorphisms, whereas cases compared with the unrelated controls (70 pairs) showed an increase in NAT2 defective alleles [OR = 6.96, 95% confidence interval (CI), 1.46-33.20] adjusted by age and sex. Glutathione transferase genetic polymorphisms (GSTM1, GSTT1) showed no association with cases compared with their siblings or unrelated controls. These findings suggest a possible role of impaired acetylation mediating susceptibility in TOS. PMID:11335185

A first-line nurse manager's goal-profile.

PubMed

Johansson, Gunilla; Pörn, Ingmar; Theorell, Töres; Gustafsson, Barbro

2007-01-01

The aim of this case study was to acquire understanding concerning the first-line nurse manager's goal-profile, i.e. prioritization of goals in her work as a first-line nurse manager, through use of an action-theoretic and confirmatory theory. The first-line nurse manager's pivotal role regarding quality of care and development in relation to on-going changes in the health care sector is stressed by many researchers and the transition from nurse to manager is described as a demanding challenge for the first-line nurse manager. The case study described in this paper concerns a first-line nurse manager in an actual working environment in care of older people. Data collection comprised interviews, observations, a job description and policy documents. A hermeneutic interpretation was used for data analysis. The results showed that the first-line nurse manager had three goals in her goal-profile, in the following order of priority: (i) a nurse goal that she had strongly accepted and in which she had excellent control, (ii) an administrator goal that she had accepted and in which she had control, (iii) a leadership goal that she had not accepted and in which she did not have control. Both the administrator and leadership goals were based on her job description, but the nurse goal was a personally chosen goal based on her own self-relation/goal-fulfillment. The first-line nurse manager's prioritized self-identity, based on successful realization of goals in her goal-profile, was decisive in the manifestation of her work. This study contributes to a new understanding of the first-line nurse manager's self-identity related to work in terms of goal acceptance and goal control of prioritized goals. This action-theoretic approach could be a valuable 'key' for understanding leadership (or lack of leadership) in clinical practice.

Mutagenicity and Acute Oral Toxicity Test for Herbal Poultry Feed Supplements.

PubMed

Srinivasa Rao, Boddapati; Chandrasekaran, C V; Srikanth, H S; Sasikumar, Murugan; Edwin Jothie, R; Haseena, Begum; Bharathi, Bethapudi; Selvam, Ramasamy; Prashanth, D'Souza

2018-01-01

Herbal products are being used and trusted globally for thousands of years for their health benefits and limited side effects. Globally, a general belief amongst the consumers is that herbal supplements are always safe because they are "natural." But later, research reveals that they may not be safe. This raises concern on their safety and implications for their use as feed supplement or medicine. Toxicity testing can reveal some of the risks that may be associated with use of herbs, therefore avoiding potential harmful effects. The present study was designed to investigate five poultry feed supplements (PFS), EGMAX® (to revitalize ovarian activity), FEED-X ™ (feed efficiency enhancer), KOLIN PLUS ™ (natural replacer of synthetic choline chloride), PHYTOCEE® (natural defence enhancer), and STODI® (to prevent and control loose droppings), for their possible mutagenicity and toxicity. Bacterial reverse mutation (BRMT) and acute oral toxicity tests were employed to assess the PFS for their possible mutagenicity and toxicity. Results indicated that the PFS were devoid of mutagenic effects in BRMT and showed higher safety profile in rodent acute oral toxicity test.

Demonstration of a Non-Toxic Reaction Control Engine

NASA Technical Reports Server (NTRS)

Robinson, Philip J.; Veith, Eric M.; Turpin, Alicia A.

2006-01-01

Three non-toxic demonstration reaction control engines (RCE) were successfully tested at the Aerojet Sacramento facility under a technology contract sponsored by the National Aeronautics and Space Administration s (NASA) Marshall Space Flight Center (MSFC). The goals of the NASA MSFC contract (NAS8-01109) were to develop and expand the technical maturity of a non-toxic, on-orbit auxiliary propulsion system (APS) thruster under the auspices of the Exploration Systems Mission Directorate. The demonstration engine utilized Liquid Oxygen (LOX) and Ethanol as propellants to produce 870 lbf thrust. The Aerojet RCE s were successfully acceptance tested over a broad range of operating conditions. Steady state tests evaluated engine response to varying chamber pressures and mixture ratios. In addition to the steady state tests, a variety of pulsing tests were conducted over a wide range of electrical pulse widths (EPW). Each EPW condition was also tested over a range of percent duty cycles (DC), and bit impulse and pulsing specific impulse were determined for each of these conditions. White Sands Test Facility (WSTF) in April 2005 for incorporation into a cryogenic Auxiliary Propulsion System Test Bed (APSTB). The APSTB is a test article that will be utilized in an altitude test cell to simulate anticipated mission applications. The objectives of this APSTB testing included evaluation of engine performance over an extended duty cycle map of propellant pressure and temperature, as well as engine and system performance at typical mission duty cycles over extended periods of time. This paper provides acceptance test results and a status of the engine performance as part of the system level testing. Subsequent to acceptance testing at Aerojet, these three engines were delivered to the NASA

Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data.

PubMed

Kim, Marlene Thai; Huang, Ruili; Sedykh, Alexander; Wang, Wenyi; Xia, Menghang; Zhu, Hao

2016-05-01

Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Quantitative structure-activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro-in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and big data. Environ Health Perspect 124:634-641;�

A hypothetical model for predicting the toxicity of high aspect ratio nanoparticles (HARN)

NASA Astrophysics Data System (ADS)

Tran, C. L.; Tantra, R.; Donaldson, K.; Stone, V.; Hankin, S. M.; Ross, B.; Aitken, R. J.; Jones, A. D.

2011-12-01

The ability to predict nanoparticle (dimensional structures which are less than 100 nm in size) toxicity through the use of a suitable model is an important goal if nanoparticles are to be regulated in terms of exposures and toxicological effects. Recently, a model to predict toxicity of nanoparticles with high aspect ratio has been put forward by a consortium of scientists. The High aspect ratio nanoparticles (HARN) model is a platform that relates the physical dimensions of HARN (specifically length and diameter ratio) and biopersistence to their toxicity in biological environments. Potentially, this model is of great public health and economic importance, as it can be used as a tool to not only predict toxicological activity but can be used to classify the toxicity of various fibrous nanoparticles, without the need to carry out time-consuming and expensive toxicology studies. However, this model of toxicity is currently hypothetical in nature and is based solely on drawing similarities in its dimensional geometry with that of asbestos and synthetic vitreous fibres. The aim of this review is two-fold: (a) to present findings from past literature, on the physicochemical property and pathogenicity bioassay testing of HARN (b) to identify some of the challenges and future research steps crucial before the HARN model can be accepted as a predictive model. By presenting what has been done, we are able to identify scientific challenges and research directions that are needed for the HARN model to gain public acceptance. Our recommendations for future research includes the need to: (a) accurately link physicochemical data with corresponding pathogenicity assay data, through the use of suitable reference standards and standardised protocols, (b) develop better tools/techniques for physicochemical characterisation, (c) to develop better ways of monitoring HARN in the workplace, (d) to reliably measure dose exposure levels, in order to support future epidemiological

Changes in lipid membranes may trigger amyloid toxicity in Alzheimer's disease

PubMed Central

Drolle, Elizabeth; Negoda, Alexander; Hammond, Keely; Pavlov, Evgeny

2017-01-01

Amyloid-beta peptides (Aβ), implicated in Alzheimer’s disease (AD), interact with the cellular membrane and induce amyloid toxicity. The composition of cellular membranes changes in aging and AD. We designed multi-component lipid models to mimic healthy and diseased states of the neuronal membrane. Using atomic force microscopy (AFM), Kelvin probe force microscopy (KPFM) and black lipid membrane (BLM) techniques, we demonstrated that these model membranes differ in their nanoscale structure and physical properties, and interact differently with Aβ1–42. Based on our data, we propose a new hypothesis that changes in lipid membrane due to aging and AD may trigger amyloid toxicity through electrostatic mechanisms, similar to the accepted mechanism of antimicrobial peptide action. Understanding the role of the membrane changes as a key activating amyloid toxicity may aid in the development of a new avenue for the prevention and treatment of AD. PMID:28767712

Transcriptional profile and differential fitness in a specialist milkweed insect across host plants varying in toxicity.

PubMed

Birnbaum, Stephanie S L; Rinker, David C; Gerardo, Nicole M; Abbot, Patrick

2017-12-01

Interactions between plants and herbivorous insects have been models for theories of specialization and co-evolution for over a century. Phytochemicals govern many aspects of these interactions and have fostered the evolution of adaptations by insects to tolerate or even specialize on plant defensive chemistry. While genomic approaches are providing new insights into the genes and mechanisms insect specialists employ to tolerate plant secondary metabolites, open questions remain about the evolution and conservation of insect counterdefences, how insects respond to the diversity defences mounted by their host plants, and the costs and benefits of resistance and tolerance to plant defences in natural ecological communities. Using a milkweed-specialist aphid (Aphis nerii) model, we test the effects of host plant species with increased toxicity, likely driven primarily by increased secondary metabolites, on aphid life history traits and whole-body gene expression. We show that more toxic plant species have a negative effect on aphid development and lifetime fecundity. When feeding on more toxic host plants with higher levels of secondary metabolites, aphids regulate a narrow, targeted set of genes, including those involved in canonical detoxification processes (e.g., cytochrome P450s, hydrolases, UDP-glucuronosyltransferases and ABC transporters). These results indicate that A. nerii marshal a variety of metabolic detoxification mechanisms to circumvent milkweed toxicity and facilitate host plant specialization, yet, despite these detoxification mechanisms, aphids experience reduced fitness when feeding on more toxic host plants. Disentangling how specialist insects respond to challenging host plants is a pivotal step in understanding the evolution of specialized diet breadths. © 2017 John Wiley & Sons Ltd.

The toxic chemistry of methyl bromide.

PubMed

Bulathsinghala, A T; Shaw, I C

2014-01-01

Methyl bromide (MeBr) is a chemically reactive compound that has found use as a fire retardant and fumigant used for wood, soil, fruits and grains. Its use is banned in many countries because of its ozone-depleting properties. Despite this ban, the use of MeBr persists in some parts of the world (e.g. New Zealand) due to its important role in maintaining strict biosecurity of exported and imported products. Its high chemical reactivity leads to a broad toxicological profile ranging from acute respiratory toxicity following inhalation exposure, through carcinogenicity to neurotoxicty. In this article, we discuss the chemistry of MeBr in the context of its mechanisms of toxicity. The chemical reactivity of MeBr clearly underlies its toxicity. Bromine (Br) is electronegative and a good leaving group; the δ+ carbon thus facilitates electrophilic methylation of biological molecules including glutathione (GSH) via its δ- sulphur atom, leading to downstream effects due to GSH depletion. DNA alkylation, either directly by MeBr or indirectly due to reduction in GSH-mediated detoxification of reactive alkylating chemical species, might explain the carcinogenicity of MeBr. The neurotoxicity of MeBr is much more difficult to understand, but we speculate that methyl phosphates formed in cells might contribute to its neurone-specific toxicity via cholinesterase inhibition. Finally, evidence reviewed shows that it is unlikely for Br⁻ liberated by the metabolism of MeBr to have any toxicological effect because the Br⁻ dose is very low.

Antibiotic toxicity and absorption in zebrafish using liquid chromatography-tandem mass spectrometry.

PubMed

Zhang, Fan; Qin, Wei; Zhang, Jing-Pu; Hu, Chang-Qin

2015-01-01

Evaluation of drug toxicity is necessary for drug safety, but in vivo drug absorption is varied; therefore, a rapid, sensitive and reliable method for measuring drugs is needed. Zebrafish are acceptable drug toxicity screening models; we used these animals with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in a multiple reaction monitoring mode to quantify drug uptake in zebrafish to better estimate drug toxicity. Analytes were recovered from zebrafish homogenate by collecting supernatant. Measurements were confirmed for drugs in the range of 10-1,000 ng/mL. Four antibiotics with different polarities were tested to explore any correlation of drug polarity, absorption, and toxicity. Zebrafish at 3 days post-fertilization (dpf) absorbed more drug than those at 6 h post-fertilization (hpf), and different developmental periods appeared to be differentially sensitive to the same compound. By observing abnormal embryos and LD50 values, zebrafish embryos at 6 hpf were considered to be suitable for evaluating embryotoxicity. Also, larvae at 3 dpf were adapted to measure acute drug toxicity in adult mammals. Thus, we can exploit zebrafish to study drug toxicity and can reliably quantify drug uptake with LC-MS/MS. This approach will be helpful for future studies of toxicology in zebrafish.

Comparison of effluent toxicity results using Ceriodaphnia dubia cultured on several diets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Norberg-King, T.J.; Schmidt, S.

1993-10-01

Several diets have been proposed for Ceriodaphnia dubia, but no single diet has been universally accepted as optimal for toxicity testing. Although several diets for Ceriodaphnia dubia culturing and testing are commonly used, little or no data exist on whether toxicity varies with the diet. This study evaluated several combinations of yeast-Cerophyl-trout chow (YCT), Selenastrum capricornutum, and Selenastrum capricornutum-Cerophyl foods for routine culture performance and the sensitivity of the offspring in subsequent acute toxicity tests with effluents. Variations in the diets included use of a vitamin-fortified yeast added to the YCT, algae (Selenastrum capricornutum) grown in two different algal media,more » and different feeding rates of the algae-Cerophyl diets. Eleven diets were evaluated in a multigeneration feeding study, but only seven were used in subsequent toxicity tests. The young produced from each of the seven diets were tested in 48-h acute tests with three different effluents across the generations. Toxicity tests with the effluents gave LC50s that were within a factor of two of one another, regardless of the food used for culturing. These results indicate that several diets are satisfactory for culturing Ceriodaphnia dubia and that the results of the toxicity tests are comparable.« less

Peer consultation on relationship between PAC profile and toxicity of petroleum substances.

PubMed

Patterson, Jacqueline; Maier, Andrew; Kohrman-Vincent, Melissa; Dourson, Michael L

2013-11-01

An expert peer consultation panel reviewed a report by the PAC Analysis Task Group, which hypothesized that systemic, developmental, and reproductive toxicity observed in repeated-dose dermal toxicity studies was related to polycyclic aromatic compound (PAC) content. Peer consultations seek to solicit scientific and technical input from experts on the scientific basis and merits of the subject report. This peer consultation panel included nine scientists with expertise in petroleum chemistry, biostatistics, toxicology, risk assessment, structure activity, and reproductive and developmental toxicology. The panel evaluated the technical quality of the PAC report and provided recommendations for improving the statistical and biological approaches. The PAC report authors revised their methods and documentation, which are published elsewhere in this supplement. A review of the post peer consultation manuscripts confirmed that many of the key suggestions from expert panel members were considered and incorporated. In cases where the PAC report authors did not fully incorporate panel suggestions from the peer consultation, they have provided an explanation and support for their decision. This peer consultation demonstrates the value of formal engagement of peers in development of new scientific methods and approaches. Copyright © 2012 Elsevier Inc. All rights reserved.

Probing the ToxCast Chemical Library for Predictive Signatures of Developmental Toxicity

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesize that cell signaling pathways are primary targets for diverse environmental chemicals ...

Bridging the Gap between Social Acceptance and Ethical Acceptability.

PubMed

Taebi, Behnam

2017-10-01

New technology brings great benefits, but it can also create new and significant risks. When evaluating those risks in policymaking, there is a tendency to focus on social acceptance. By solely focusing on social acceptance, we could, however, overlook important ethical aspects of technological risk, particularly when we evaluate technologies with transnational and intergenerational risks. I argue that good governance of risky technology requires analyzing both social acceptance and ethical acceptability. Conceptually, these two notions are mostly complementary. Social acceptance studies are not capable of sufficiently capturing all the morally relevant features of risky technologies; ethical analyses do not typically include stakeholders' opinions, and they therefore lack the relevant empirical input for a thorough ethical evaluation. Only when carried out in conjunction are these two types of analysis relevant to national and international governance of risky technology. I discuss the Rawlsian wide reflective equilibrium as a method for marrying social acceptance and ethical acceptability. Although the rationale of my argument is broadly applicable, I will examine the case of multinational nuclear waste repositories in particular. This example will show how ethical issues may be overlooked if we focus only on social acceptance, and will provide a test case for demonstrating how the wide reflective equilibrium can help to bridge the proverbial acceptance-acceptability gap. © 2016 The Authors Risk Analysis published by Wiley Periodicals, Inc. on behalf of Society for Risk Analysis.

Phytochemical, sub-acute toxicity, and antibacterial evaluation of Cordia sebestena leaf extracts.

PubMed

Osho, Adeleke; Otuechere, Chiagoziem A; Adeosun, Charles B; Oluwagbemi, Tolu; Atolani, Olubunmi

2016-03-01

In Nigeria, Cordia sebestena (Boraginaceae), an understudied medicinal plant, is used in traditional medicine for the treatment of gastrointestinal disorders. In this study, we investigated the chemical composition, antibacterial potential, and sub-acute toxicity of C. sebestena leaves. Ethyl acetate extracts were analyzed using thin layer chromatography (TLC) and Fourier transform infrared (FTIR) spectrophotometry. The antibacterial potential of the extracts was tested against five standard bacteria, namely Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Clinical observations and blood parameters were used to evaluate the possible toxicity of C. sebestena. The TLC profile yielded 39 fractions, which were pooled to nine combined sub-fractions (A-I). The FTIR spectrum of sub-fraction H indicated the presence of aliphatic C-H stretching vibration at 2922 and 2850 cm-1, C=O stretch at 1734 and 1708 cm-1, and C=C stretch of aromatics and aliphatics at 1464 and (shoulder) 1618 cm-1, respectively. The fractions of the C. sebestena ethyl acetate leaf extract showed antibacterial potential across board, but fraction H had the highest antibacterial activity against B. cereus and S. aureus. The study also indicated the relatively low toxicity profile of the ethyl acetate leaf extract of C. sebestena in the liver of rats. The study showed that C. sebestena leaves have strong antibacterial potential and low toxicity, thereby underlying the scientific basis for their folkloric use in the management of microbial infections and its associated complications.

Testicular distribution and toxicity of a novel LTA4H inhibitor in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ward, P.D., E-mail: pward4@its.jnj.com; La, D.

JNJ 40929837, a novel leukotriene A4 hydrolase inhibitor in drug development, was reported to induce testicular toxicity in rats. The mechanism of toxicity was considered to be rodent specific and not relevant to humans. To further investigate this finding in rats, the distribution and toxicokinetics of JNJ 40929837 and its two metabolites, M1 and M2, were investigated. A quantitative whole body autoradiography study showed preferential distribution and retention of JNJ 40929837-derived radioactivity in the testes consistent with the observed site of toxicity. Subsequent studies with unlabeled JNJ 40929837 showed different metabolite profiles between the plasma and testes. Following a singlemore » oral 50 mg/kg dose of JNJ 40929837, M2 was the primary metabolite in plasma whereas M1 was the primary metabolite in testes. The exposure of M1 was 386-fold higher in the testes compared to plasma whereas M2 had limited exposure in testes. Furthermore, the T{sub max} of M1 was 48 h in testes suggesting a large accumulation potential of this metabolite in testes compared to plasma. Following six months of repeated daily oral dosing, M1 accumulated approximately five-fold in the testes whereas the parent did not accumulate. These results indicate that the toxicokinetic profiles of JNJ 40929837 and its two metabolites in testes are markedly different compared to plasma and support the importance of understanding the toxicokinetic profiles of compounds and their metabolites in organs/tissues where toxicity is observed. - Highlights: • JNJ 40929837-derived radioactivity preferentially distributed into testes • Primary metabolite flip-flop in plasma and testes • The primary metabolite in testes accumulated 5-fold but not parent.« less

Chlorpyrifos chronic toxicity in broilers and effect of vitamin C.

PubMed

Kammon, A M; Brar, R S; Sodhi, S; Banga, H S; Singh, J; Nagra, N S

2011-01-01

An experiment was conducted to study chlorpyrifos chronic toxicity in broilers and the protective effect of vitamin C. Oral administration of 0.8 mg/kg body weight (bw) (1/50 LD50) chlorpyrifos (Radar(®)), produced mild diarrhea and gross lesions comprised of paleness, flaccid consistency and slightly enlargement of liver. Histopathologically, chlorpyrifos produced degenerative changes in various organs. Oral administration of 100 mg/kg bw vitamin C partially ameliorated the degenerative changes in kidney and heart. There was insignificant alteration in biochemical and haematological profiles. It is concluded that supplementation of vitamin C reduced the severity of lesions induced by chronic chlorpyrifos toxicity in broilers.

Facial profile esthetics in operated children with bilateral cleft lip and palate

PubMed Central

Lauris, Rita de Cássia Moura Carvalho; Capelozza, Leopoldino; Calil, Louise Resti; Lauris, José Roberto Pereira; Janson, Guilherme; Garib, Daniela Gamba

2017-01-01

ABSTRACT Objective: The aim of this study was to evaluate the facial profile esthetics of rehabilitated children with complete bilateral cleft lip and palate (BCLP), comparing the judgment of professionals related and not related to cleft rehabilitation and laypersons. Methods: Thirty children in the mixed dentition (24 male; 6 female) with a mean age of 7.8 years were evaluated using facial profile photographs by 25 examiners: 5 orthodontists and 5 plastic surgeons with experience in cleft care, 5 orthodontists and 5 plastic surgeons without experience in oral cleft rehabilitation and 5 graduated laymen. Their facial profiles were classified into esthetically unpleasant (grade 1 to 3), esthetically acceptable (grade 4 to 6), and esthetically pleasant (grade 7 to 9). Intraexaminer and interexaminer errors were evaluated using Spearman correlation coefficient and Kendall’s test, respectively. Inter-rater differences were analyzed using Friedman test and Student-Newman-Keuls test for multiple comparisons. Results: Orthodontists dealing with oral clefts rehabilitation considered the majority of the sample as esthetically pleasant. Plastic surgeons of the cleft team and laypersons classified most of the sample as esthetically acceptable. Most of the orthodontists and plastic surgeons not related to cleft care evaluated the facial profile as esthetically unpleasant. The structures associated to unpleasant profiles were the nose, the midface and the upper lip. Conclusions: The facial profile of children with BCLP was classified as esthetically acceptable by laypersons. Professionals related to cleft rehabilitation were more lenient and those not related to cleft care were stricter to facial esthetics than laypersons. PMID:28902248

Large Dataset of Acute Oral Toxicity Data Created for Testing in Silico Models (ASCCT meeting)

EPA Science Inventory

Acute toxicity data is a common requirement for substance registration in the US. Currently only data derived from animal tests are accepted by regulatory agencies, and the standard in vivo tests use lethality as the endpoint. Non-animal alternatives such as in silico models are ...

Predictive Model of Rat Reproductive Toxicity from ToxCast High Throughput Screening

EPA Science Inventory

The EPA ToxCast research program uses high throughput screening for bioactivity profiling and predicting the toxicity of large numbers of chemicals. ToxCast Phase‐I tested 309 well‐characterized chemicals in over 500 assays for a wide range of molecular targets and cellular respo...

78 FR 63981 - Availability of Interaction Profile for Chlorinated Dibenzo-p -Dioxins, Polybrominated Diphenol...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-25

... found in human blood, adipose tissue, and breast milk. The purpose of this interaction profile is to... endpoints in humans. This interaction profile has undergone external peer-review and review by ATSDR's... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [Docket...

Metabolism and toxicity of arsenicals in mammals.

PubMed

Sattar, Adeel; Xie, Shuyu; Hafeez, Mian Abdul; Wang, Xu; Hussain, Hafiz Iftikhar; Iqbal, Zahid; Pan, Yuanhu; Iqbal, Mujahid; Shabbir, Muhammad Abubakr; Yuan, Zonghui

2016-12-01

Arsenic (As) is a metalloid usually found in organic and inorganic forms with different oxidation states, while inorganic form (arsenite As-III and arsenate As-v) is considered to be more hazardous as compared to organic form (methylarsonate and dimethylarsinate), with mild or no toxicity in mammals. Due to an increasing trend to using arsenicals as growth promoters or for treatment purposes, the understanding of metabolism and toxicity of As gets vital importance. Its toxicity is mainly depends on oxi-reduction states (As-III or As-v) and the level of methylation during the metabolism process. Currently, the exact metabolic pathways of As have yet to be confirmed in humans and food producing animals. Oxidative methylation and glutathione conjugation is believed to be major pathways of As metabolism. Oxidative methylation is based on conversion of Arsenite in to mono-methylarsonic acid and di-methylarsenic acid in mammals. It has been confirmed that As is only methylated in the presence of glutathione or thiol compounds, suggesting that As is being methylated in trivalent states. Subsequently, non-conjugated trivalent arsenicals are highly reactive with thiol which converts the trivalent arsenicals in to less toxic pentavalent forms. The glutathione conjugate stability of As is the most important factor for determining the toxicity. It can lead to DNA damage by alerting enzyme profile and production of reactive oxygen and nitrogen species which causes the oxidative stress. Moreover, As causes immune-dysfunction by hindering cellular and humeral immune response. The present review discussed different metabolic pathways and toxic outcomes of arsenicals in mammals which will be helpful in health risk assessment and its impact on biological world. Copyright © 2016. Published by Elsevier B.V.

Toxicities of Immunosuppressive Treatment of Autoimmune Neurologic Diseases

PubMed Central

Lallana, Enrico C; Fadul, Camilo E

2011-01-01

In parallel to our better understanding of the role of the immune system in neurologic diseases, there has been an increased availability in therapeutic options for autoimmune neurologic diseases such as multiple sclerosis, myasthenia gravis, polyneuropathies, central nervous system vasculitides and neurosarcoidosis. In many cases, the purported benefits of this class of therapy are anecdotal and not the result of good controlled clinical trials. Nonetheless, their potential efficacy is better known than their adverse event profile. A rationale therapeutic decision by the clinician will depend on a comprehensive understanding of the ratio between efficacy and toxicity. In this review, we outline the most commonly used immune suppressive medications in neurologic disease: cytotoxic chemotherapy, nucleoside analogues, calcineurin inhibitors, monoclonal antibodies and miscellaneous immune suppressants. A discussion of their mechanisms of action and related toxicity is highlighted, with the goal that the reader will be able to recognize the most commonly associated toxicities and identify strategies to prevent and manage problems that are expected to arise with their use. PMID:22379461

Otorhinolaryngological Toxicities of New Drugs in Oncology.

PubMed

Hartl, Dana M; Morel, Daphné; Saavedra, Erika; Massard, Christophe; Rinaldo, Alessandra; Saba, Nabil F; Ferlito, Alfio; Soria, Jean-Charles

2017-04-01

Many new or relatively new cancer drugs-personalized anticancer agents-have been approved for use in various clinical settings in oncology or are still under evaluation in clinical trials. Targeted therapies as well as new immune checkpoint blockers have toxicity profiles that differ from conventional cytotoxic chemotherapy, and many can cause adverse effects that affect the mouth and pharynx, the nasal cavities, and the larynx. This review aims to provide an overview of current knowledge concerning these side effects and contemporary management. Adverse effects of the mouth/pharynx, nasal cavities, larynx, and cochlear-vestibular system are generally low grade (according to the Common Terminology Criteria for Adverse Events) and generally present non-life-threatening symptoms. However, the impact on patients' quality of life could be important. The incidence and severity vary according to the drug, its target(s), and dose, but there are currently no known predictive factors, and each patient has an individual toxicity profile. Management guidelines are based on expert opinion. These ear, nose, and throat adverse effects are not frequently mentioned in the literature because of the often non-specific nature of the symptoms and their mildness, but also the absence of specific treatment. These symptoms can contribute to decreased quality of life and lead to drug compliance issues if not diagnosed and managed appropriately.

Proteome Profiling of BEAS-2B Cells Treated with Titanium Dioxide Reveals Potential Toxicity of and Detoxification Pathways for Nanomaterial

EPA Science Inventory

Oxidative stress is known to play important roles in nanomaterial-induced toxicities. However, the proteins and signaling pathways associated with nanomaterial-mediated oxidative stress and toxicity are largely unknown. To identify oxidative stress-responding toxicity pathways an...

Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Titanium Dioxide Nanoparticles

EPA Science Inventory

Oxidative stress is known to play important roles in engineered nanomaterial induced cellular toxicity. However, the proteins and signaling pathways associated with the engineered nanomaterial mediated oxidative stress and toxicity are largely unknown. To identify these toxicity ...

The regulatory acceptance of alternatives in the European Union.

PubMed

Warbrick, E Vicky; Evans, Peter F

2004-06-01

Recently, progress has been made toward the regulatory acceptance of replacements in the European Union (EU), particularly with the introduction of in vitro methods for the prediction of skin corrosivity, dermal penetration, phototoxicity and embryotoxicity. In vitro genotoxicity tests are well established, and testing for this endpoint can be completed without animals, provided that clear negative outcomes are obtained. Tiered approaches including in vitro tests can also be used to address skin and eye irritation endpoints. Reductions and/or refinements in animal use are being achieved following the replacement of the oral LD50 test with alternative methods and the adoption of reduced test packages for materials, such as closed-system intermediates and certain polymers. Furthermore, the use of a "read-across" approach has reduced animal testing. Substantial gains in refinement will also be made with the recent acceptance of the local lymph node assay for skin sensitisation and the development of an acute inhalation toxicity method that avoids lethality as the endpoint. For the future, under the proposed EU Registration, Evaluation and Authorisation of Chemicals (REACH) scheme, it is envisaged that, where suitable in vitro methods exist, these should be used to support registration of substances produced at up to ten tonnes per annum. This proposal can only accelerate the further development, validation and regulatory acceptance of such alternative methods.

High Throughput Prioritization for Integrated Toxicity Testing Based on ToxCast Chemical Profiling

EPA Science Inventory

The rational prioritization of chemicals for integrated toxicity testing is a central goal of the U.S. EPA’s ToxCast™ program (http://epa.gov/ncct/toxcast/). ToxCast includes a wide-ranging battery of over 500 in vitro high-throughput screening assays which in Phase I was used to...

Comparison of the toxicity of fluoridation compounds in the nematode Caenorhabditis elegans.

PubMed

Rice, Julie R; Boyd, Windy A; Chandra, Dave; Smith, Marjolein V; Den Besten, Pamela K; Freedman, Jonathan H

2014-01-01

Fluorides are commonly added to drinking water in the United States to decrease the incidence of dental caries. Silicofluorides, such as sodium hexafluorosilicate (Na2 SiF6 ) and fluorosilicic acid (H2 SiF6 ), are mainly used for fluoridation, although fluoride salts such as sodium fluoride (NaF) are also used. Interestingly, only the toxicity of NaF has been examined and not that of the more often used silicofluorides. In the present study, the toxicities of NaF, Na2 SiF6 , and H2 SiF6 were compared. The toxicity of these fluorides on the growth, feeding, and reproduction in the alternative toxicological testing organism Caenorhabditis elegans was examined. Exposure to these compounds produced classic concentration-response toxicity profiles. Although the effects of the fluoride compounds varied among the 3 biological endpoints, no differences were found between the 3 compounds, relative to the fluoride ion concentration, in any of the assays. This suggests that silicofluorides have similar toxicity to NaF. © 2013 SETAC.

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule-Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non-Small-Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yuhchyau; Pandya, Kishan J.; Feins, Richard

Purpose: We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a Phase I study for inoperable non-small-cell lung cancer. Methods and Materials: Paclitaxel at escalating doses of 15 mg/m{sup 2}, 20 mg/m{sup 2}, and 25 mg/m{sup 2} were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by high-performance liquid chromatography. Results: Dose-limiting toxicities included 3 of 18 patients with Grade 3more » pneumonitis and 3 of 18 patients with Grade 3 esophagitis. There was no Grade 4 or 5 pneumonitis or esophagitis. There was also no Grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For Dose Levels I (15 mg/m{sup 2}), II (20 mg/m{sup 2}), and III (25 mg/m{sup 2}), the mean peak plasma level was 0.23 {+-} 0.06 {mu}mol/l, 0.32 {+-} 0.05 {mu}mol/l, and 0.52 {+-} 0.14 {mu}mol/l, respectively; AUC was 0.44 {+-} 0.09 {mu}mol/l, 0.61 {+-} 0.1 {mu}mol/l, and 0.96 {+-} 0.23 {mu}mol/l, respectively; and duration of drug concentration >0.05 {mu}mol/l (t > 0.05 {mu}mol/l) was 1.6 {+-} 0.3 h, 1.9 {+-} 0.2 h, and 3.0 {+-} 0.9 h, respectively. Conclusion: Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration >0.05 {mu}mol/l for a minimum of 1.6 h was sufficient for effective radiosensitization.« less

Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits.

PubMed

Liang, H; Brignole-Baudouin, F; Rabinovich-Guilatt, L; Mao, Z; Riancho, L; Faure, M O; Warnet, J M; Lambert, G; Baudouin, C

2008-01-31

To evaluate and compare the toxicological profiles of two quaternary ammonium compounds (QAC), benzalkonium chloride (BAK), and cetalkonium chloride (CKC), in standard solution or cationic emulsion formulations in rabbit eyes using newly developed in vivo and ex vivo experimental approaches. Seventy eyes of 35 adult male New Zealand albino rabbits were used in this study. They were randomly divided into five groups: 50 microl of phosphate-buffered saline (PBS), PBS containing 0.02% BAK or 0.002% CKC (BAK Sol and CKC Sol, respectively), and emulsion containing 0.02% BAK or 0.002% CKC (BAK Em and CKC Em, respectively) were applied to rabbit eyes 15 times at 5-min intervals. The ocular surface changes induced by these eye drops were investigated using slit-lamp examination, flow cytometry (FCM), impression cytology (IC) on conjunctiva, and corneal in vivo confocal microscopy (IVCM). Standard immunohistology in cryosections was also examined for cluster of differentiation (CD) 45+ infiltrating and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL)+ apoptotic cells. Clinical observations and IVCM showed that the highest toxicity was induced by BAK Sol, characterized by damaged corneal epithelium and a high level of inflammatory infiltration. BAK Em and CKC Sol presented moderate effects, and CKC Em showed the lowest toxicity with results similar to those of PBS. Conjunctival imprints analyzed by FCM showed a higher expression of RLA-DR and TNFR1 markers in BAK Sol-instilled eyes than in all other groups, especially at 4 h. Immunohistology was correlated with in vivo and ex vivo findings and confirmed this toxicity profile. A high level of infiltration of CD45+ inflammatory cells and TUNEL+ apoptotic cells was observed in limbus and conjunctiva, especially in QAC solution-receiving eyes compared to QAC emulsion-instilled eyes. The acute administration of 15 instillations at 5 min intervals was a rapid and efficient model to assess quaternary

[Dose-intensive chemotherapy with continuous infusion 5-fluorouracil].

PubMed

Tichler, T; Ghodsizade, E; Katz, A; Rath, P; Berger, R; Brenner, H

1999-11-01

54 patients with advanced malignancy refractory to chemotherapy were studied to evaluate efficacy and toxicity of continuous infusion of 5-fluorouracil (5FU) given for 3 weeks. We report results of the first 156 courses given in combination with other drugs. 19 (37%) of the 54 responded, including 3 (6%) with complete response. Toxicity was acceptable, with mucositis in 13 (26%) and 3 (6%) with grade II-III toxicity. Results and toxicity profile were compatible with further disease-oriented studies using this dose-intensive program.

Building predictive models of developmental toxicity from ToxRefDB and ToxCast

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that are highly correlated with observed in vivo toxicity. We hypothesize that cell signaling pathways underlying development are primary targets f...

Connection Map for Compounds (CMC): A Server for Combinatorial Drug Toxicity and Efficacy Analysis.

PubMed

Liu, Lei; Tsompana, Maria; Wang, Yong; Wu, Dingfeng; Zhu, Lixin; Zhu, Ruixin

2016-09-26

Drug discovery and development is a costly and time-consuming process with a high risk for failure resulting primarily from a drug's associated clinical safety and efficacy potential. Identifying and eliminating inapt candidate drugs as early as possible is an effective way for reducing unnecessary costs, but limited analytical tools are currently available for this purpose. Recent growth in the area of toxicogenomics and pharmacogenomics has provided with a vast amount of drug expression microarray data. Web servers such as CMap and LTMap have used this information to evaluate drug toxicity and mechanisms of action independently; however, their wider applicability has been limited by the lack of a combinatorial drug-safety type of analysis. Using available genome-wide drug transcriptional expression profiles, we developed the first web server for combinatorial evaluation of toxicity and efficacy of candidate drugs named "Connection Map for Compounds" (CMC). Using CMC, researchers can initially compare their query drug gene signatures with prebuilt gene profiles generated from two large-scale toxicogenomics databases, and subsequently perform a drug efficacy analysis for identification of known mechanisms of drug action or generation of new predictions. CMC provides a novel approach for drug repositioning and early evaluation in drug discovery with its unique combination of toxicity and efficacy analyses, expansibility of data and algorithms, and customization of reference gene profiles. CMC can be freely accessed at http://cadd.tongji.edu.cn/webserver/CMCbp.jsp .

Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use.

PubMed

Samkoe, Kimberley S; Gunn, Jason R; Marra, Kayla; Hull, Sally M; Moodie, Karen L; Feldwisch, Joachim; Strong, Theresa V; Draney, Daniel R; Hoopes, P Jack; Roberts, David W; Paulsen, Keith; Pogue, Brian W

2017-08-01

ABY-029, a synthetic Affibody peptide, Z03115-Cys, labeled with a near-infrared fluorophore, IRDye® 800CW, targeting epidermal growth factor receptor (EGFR) has been produced under good manufacturing practices for a US Food and Drug Administration-approved first-in-use human study during surgical resection of glioma, as well as other tumors. Here, the pharmacology, phototoxicity, receptor activity, and biodistribution studies of ABY-029 were completed in rats, prior to the intended human use. Male and female Sprague Dawley rats were administered a single intravenous dose of varying concentrations (0, 245, 2449, and 24,490 μg/kg corresponding to 10×, 100×, and 1000× an equivalent human microdose level) of ABY-029 and observed for up to 14 days. Histopathological assessment of organs and tissues, clinical chemistry, and hematology were performed. In addition, pharmacokinetic clearance and biodistribution of ABY-029 were studied in subgroups of the animals. Phototoxicity and ABY-029 binding to human and rat EGFR were assessed in cell culture and on immobilized receptors, respectively. Histopathological assessment and hematological and clinical chemistry analysis demonstrated that single-dose ABY-029 produced no pathological evidence of toxicity at any dose level. No phototoxicity was observed in EGFR-positive and EGFR-negative glioma cell lines. Binding strength and pharmacokinetics of the anti-EGFR Affibody molecules were retained after labeling with the dye. Based on the successful safety profile of ABY-029, the 1000× human microdose 24.5 mg/kg was identified as the no observed adverse effect level following intravenous administration. Conserved binding strength and no observed light toxicity also demonstrated ABY-029 safety for human use.

Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data

PubMed Central

Kim, Marlene Thai; Huang, Ruili; Sedykh, Alexander; Wang, Wenyi; Xia, Menghang; Zhu, Hao

2015-01-01

Background: Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. Objective: The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Methods: Quantitative structure–activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro–in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. Results: The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Conclusion: Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Citation: Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and

Organic Matter Application Can Reduce Copper Toxicity in Tomato Plants

ERIC Educational Resources Information Center

Campbell, Brian

2010-01-01

Copper fungicides and bactericides are often used in tomato cultivation and can cause toxic Cu levels in soils. In order to combat this, organic matter can be applied to induce chelation reactions and form a soluble complex by which much of the Cu can leach out of the soil profile or be taken up safely by plants. Organic acids such as citric,…

Comparative toxicities of 3 platinum-containing chemotherapy regimens in relapsed/refractory lymphoma patients.

PubMed

Tixier, F; Ranchon, F; Iltis, A; Vantard, N; Schwiertz, V; Bachy, E; Bouafia-Sauvy, F; Sarkozy, C; Tournamille, J F; Gyan, E; Salles, G; Rioufol, C

2017-12-01

Optimal salvage chemotherapy regimen for patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma remains unclear but often based on platinum regimens. This retrospective study assesses in real life the toxicities profiles of patients with relapsed or refractory lymphoma treated with DHA (dexamethasone, high dose aracytine cytarabine) plus platinum salt (dexamethasone-High dose aracytine (cis)platin (DHAP), dexamethasone-High dose aracytine carboplatin (DHAC), or dexamethasone-High dose aracytine Oxaliplatin (DHAOX)), from February 2007 to May 2013 in 2 French hospitals. Toxicities were recorded from medical files and assessed according to the National Cancer Institute Common Toxicity Criteria version 3.0. Potential risk factors of renal insufficiency were tested by univariate analyses. A total of 276 patients were treated: 168 with DHAP (60.9%), 79 with DHAOX (28.6%), and 29 with DHAC (10.5%). Rituximab was associated in 80.1% of patients (n = 221). Renal failure was reported in 97 patients, mainly with cisplatin regimen (86.6%) leading to 8.9% grade III to IV renal failure (P = .001). Renal insufficiency was reversible in most patients but remained persistent in 24, with all of them being treated with DHAP except 1. Cisplatin-based regimen (50.0% versus 12.0%, P < .05) and female (44.6% versus 29.7%, P < .05) appeared to be at higher risks of renal failure. Platinum cumulative dose is a significant risk factor of nephrotoxicity. Hematologic toxicity was more frequent with carboplatin and cisplatin with at least 1 event (all toxicity grade) respectively in 79.3% and 71.4% of patients treated (P < .005). Auditory toxicity was mainly reported with cisplatin (n = 19; 4 grade I-II and 15 grade III-IV). Oxaliplatin was implicated in 77.6% of neurotoxicity (n = 59), mainly moderate (grade I-II). In conclusion, DHAOX and DHAC regimens have more favorable toxicity profile than DHAP regimen. Their lack of renal toxicity makes them attractive

PARTICLE SPECIATION AND EMISSION PROFILES OF SMALL 2-STROKE ENGINES

EPA Science Inventory

The Human Exposure and Atmospheric Sciences Division (HEASD) conducts studies designed to acquire information from emission sources for use in source apportionment studies. The objective of this work is to characterize a complete, speciated emission profile (PM and air toxics) ...

Using in vitro Dose-Response Profiles to Enhance QSAR Modeling of in vivo Toxicity

EPA Science Inventory

To develop effective means for rapid toxicity evaluation of environmental chemicals, the Tox21 partnership among the National Toxicology Program (NTP), NIH Chemical Genomics Center, and National Center for Computational Toxicology (NCCT) at the US EPA are conducting a number of ...

The current status of biomarkers for predicting toxicity

PubMed Central

Campion, Sarah; Aubrecht, Jiri; Boekelheide, Kim; Brewster, David W; Vaidya, Vishal S; Anderson, Linnea; Burt, Deborah; Dere, Edward; Hwang, Kathleen; Pacheco, Sara; Saikumar, Janani; Schomaker, Shelli; Sigman, Mark; Goodsaid, Federico

2013-01-01

Introduction There are significant rates of attrition in drug development. A number of compounds fail to progress past preclinical development due to limited tools that accurately monitor toxicity in preclinical studies and in the clinic. Research has focused on improving tools for the detection of organ-specific toxicity through the identification and characterization of biomarkers of toxicity. Areas covered This article reviews what we know about emerging biomarkers in toxicology, with a focus on the 2012 Northeast Society of Toxicology meeting titled ‘Translational Biomarkers in Toxicology.’ The areas covered in this meeting are summarized and include biomarkers of testicular injury and dysfunction, emerging biomarkers of kidney injury and translation of emerging biomarkers from preclinical species to human populations. The authors also provide a discussion about the biomarker qualification process and possible improvements to this process. Expert opinion There is currently a gap between the scientific work in the development and qualification of novel biomarkers for nonclinical drug safety assessment and how these biomarkers are actually used in drug safety assessment. A clear and efficient path to regulatory acceptance is needed so that breakthroughs in the biomarker toolkit for nonclinical drug safety assessment can be utilized to aid in the drug development process. PMID:23961847

Metabonomics study of the effects of pretreatment with glycyrrhetinic acid on mesaconitine-induced toxicity in rats.

PubMed

Sun, Bo; Zhang, Ming; Zhang, Qi; Ma, Kunpeng; Li, Haijing; Li, Famei; Dong, Fangting; Yan, Xianzhong

2014-07-03

Aconitum carmichaelii Debx. (Fuzi), a commonly use traditional Chinese medicine (TCM), has often been used in combination with Rhizoma Glycyrrhizae (Gancao) to reduce its toxicity due to diester diterpenoid alkaloids aconitine, mesaconitine, and hypaconitine. However, the mechanism of detoxication is still unclear. Glycyrrhetinic acid (GA) is the metabolite of glycyrrhizinic acid (GL), the major component of Gancao. In present study, the effect of GA on the changes of metabolic profiles induced by mesaconitine was investigated using NMR-based metabolomic approaches. Fifteen male Wistar rats were divided into a control group, a group administered mesaconitine alone, and a group administered mesaconitine with one pretreatment with GA. Their urine samples were used for NMR spectroscopic metabolic profiling. Statistical analyses such as orthogonal projections to latent structures-discriminant analysis (OPLS-DA), t-test, hierarchical cluster, and pathway analysis were used to detect the effects of pretreatment with GA on mesaconitine-induced toxicity. The OPLS-DA score plots showed the metabolic profiles of GA-pretreated rats apparently approach to those of normal rats compared to mesaconitine-induced rats. From the t-test and boxplot results, the concentrations of leucine/isoleucine, lactate, acetate, succinate, trimethylamine (TMA), dimethylglycine (DMG), 2-oxo-glutarate, creatinine/creatine, glycine, hippurate, tyrosine and benzoate were significantly changed in metabolic profiles of mesaconitine-induced rats. The disturbed metabolic pathways include amino acid biosynthesis and metabolism. GA-pretreatment can mitigate the metabolic changes caused by mesaconitine-treatment on rats, indicating that prophylaxis with GA could reduce the toxicity of mesaconitine at the metabolic level. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Predictive Signatures of Developmental Toxicity Modeled with HTS Data from ToxCast™ Bioactivity Profiles

EPA Science Inventory

The EPA ToxCast™ research program uses a high-throughput screening (HTS) approach for predicting the toxicity of large numbers of chemicals. Phase-I contains 309 well-characterized chemicals which are mostly pesticides tested in over 600 assays of different molecular targets, cel...

Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae) in Swiss Mice

PubMed Central

Freire Rocha Caldas, Germana; Araújo, Alice Valença; Albuquerque, Giwellington Silva; Silva-Neto, Jacinto da Costa; Costa-Silva, João Henrique; de Menezes, Irwin Rose Alencar; Leite, Ana Cristina Lima; da Costa, José Galberto Martins; Wanderley, Almir Gonçalves

2013-01-01

Hyptis martiusii Benth. (Lamiaceae) is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM). Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg) for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated-doses with the essential oil of Hyptis martiusii showed low toxicity in mice. PMID:24151521

LC-MS based metabolomics and chemometrics study of the toxic effects of copper on Saccharomyces cerevisiae.

PubMed

Farrés, Mireia; Piña, Benjamí; Tauler, Romà

2016-08-01

Copper containing fungicides are used to protect vineyards from fungal infections. Higher residues of copper in grapes at toxic concentrations are potentially toxic and affect the microorganisms living in vineyards, such as Saccharomyces cerevisiae. In this study, the response of the metabolic profiles of S. cerevisiae at different concentrations of copper sulphate (control, 1 mM, 3 mM and 6 mM) was analysed by liquid chromatography coupled to mass spectrometry (LC-MS) and multivariate curve resolution-alternating least squares (MCR-ALS) using an untargeted metabolomics approach. Peak areas of the MCR-ALS resolved elution profiles in control and in Cu(ii)-treated samples were compared using partial least squares regression (PLSR) and PLS-discriminant analysis (PLS-DA), and the intracellular metabolites best contributing to sample discrimination were selected and identified. Fourteen metabolites showed significant concentration changes upon Cu(ii) exposure, following a dose-response effect. The observed changes were consistent with the expected effects of Cu(ii) toxicity, including oxidative stress and DNA damage. This research confirmed that LC-MS based metabolomics coupled to chemometric methods are a powerful approach for discerning metabolomics changes in S. cerevisiae and for elucidating modes of toxicity of environmental stressors, including heavy metals like Cu(ii).

Environmental health risks of toxic waste site exposures--an epidemiological perspective.

PubMed

von Schirnding, Y E; Ehrlich, R I

1992-06-06

A general account is given of the problems of assessing the impact of human exposure to toxic waste sites, including the identification of truly exposed populations and of exposure pathways. Epidemiological studies of populations at risk are briefly reviewed and methodological problems summarised. These include the use of relatively weak study designs, inadequate exposure assessment and recall biases associated with symptom reporting among anxious residents living in the vicinity of waste sites. In South Africa, health risks associated with exposure to toxic waste sites need to be viewed in the context of current community health concerns, competing causes of disease and ill-health, and the relative lack of knowledge about environmental contamination and associated health effects. A nonspecific deterioration of health and well-being is more likely to result from waste site exposures than is overt clinical disease. Socially acceptable policies and controls may have to be based on criteria other than demonstrable ill-health. Detailed inventories and registries of the nature of disposed materials need to be maintained, sites of poorly controlled disposal in the past identified and selective environmental monitoring conducted. Epidemiological studies may be justified in situations where exposures well in excess of acceptable norms are demonstrated. An integrated national waste management policy for the country is urgently needed.

Effects of calcium, magnesium, and sodium on alleviating cadmium toxicity to Hyalella azteca

USGS Publications Warehouse

Jackson, B.P.; Lasier, P.J.; Miller, W.P.; Winger, P.V.

2000-01-01

Toxicity of trace metal ions to aquatic organisms, arising through either anthropogenic inputs or acidification of surface waters, continues to be both a regulatory and environmental problem. It is generally accepted that the free metal ion is the major toxic species (Florence et a1.,1992) and that inorganic or organic complexation renders the metal ion non-bioavailable (Meador, 1991, Galvez and Wood, 1997). However, water chemistry parameters such as alkalinity, hardness, dissolved organic carbon and pH influence metal ion toxicity either directly by lowering free metal ion concentration or indirectly through synergistic or antagonistic effects. Alkalinity and salinity can affect the speciation of metal ions by increasing ion-pair formation, thus decreasing free metal ion concentration. For example, Cu was found to be less toxic to rainbow trout in waters of high alkalinity (Miller and Mackay, 1980), due to formation of CuCO3 ion pair, and corresponding reduction in free Cu2+ concentration. The influence of salinity on the toxicity of cadmium to various organisms has been demonstrated in a number of studies (Bervoets et al., 1995, Hall et al., 1995, Lin and Dunson, 1993, Blust et al., 1992). In all these studies the apparent toxicity of cadmium was lowered as salinity was increased due to increased formation of CdC1+ and CDCl2 aqueous complexes that are non-toxic or of much lower toxicity than the free Cd2+ ion. Changes in pH exert both a biological and chemical effect on metal ion toxicity (Campbell and Stokes, 1985). Low pH favors greater metal ion solubility, and, in the absence of complexing ions, reduced speciation of the metal ion, which tends to increase toxicity compared to higher pH. However, Iow pH also enhances competition between H+ and metal ion for cell surface binding sites, which tends to decrease metal ion toxicity.

A simple control for sediment-toxicity exposures using the amphipod, Hyalella azteca

USGS Publications Warehouse

Lasier, Peter J.; Urich, Matthew L.

2014-01-01

Sediment-toxicity exposures comparing survival and growth of the freshwater amphipod, Hyalella azteca, are often components of aquatic-habitat assessments. Standardized exposure methods have been established and require evaluations for quality assurance. Test acceptability using performance-based criteria can be determined from exposures to control sediments, which are collected from the environment or formulated from commercially available components. Amending sand with leached alfalfa solids provided a simple formulated sediment that elicited consistently acceptable survival and growth in 28-day exposures with and without a daily feeding regime. A procedure is described for preparing the sediment along with results from comparisons among sand, amended sand, and field-collected sediments that incorporated three feeding regimes.

Applications of high throughput screening to identify profiles of biological activity

EPA Science Inventory

ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry and bioactivity profiling to predict potential for toxicity and prioritize limited testing resources (www.epa.gov/toc...

Gene expression profiling to identify the toxicities and potentially relevant human disease outcomes associated with environmental heavy metal exposure.

PubMed

Korashy, Hesham M; Attafi, Ibraheem M; Famulski, Konrad S; Bakheet, Saleh A; Hafez, Mohammed M; Alsaad, Abdulaziz M S; Al-Ghadeer, Abdul Rahman M

2017-02-01

Heavy metals are the most commonly encountered toxic substances that increase susceptibility to various diseases after prolonged exposure. We have previously shown that healthy volunteers living near a mining area had significant contamination with heavy metals associated with significant changes in the expression of some detoxifying genes, xenobiotic metabolizing enzymes, and DNA repair genes. However, alterations of most of the molecular target genes associated with diseases are still unknown. Thus, the aims of this study were to (a) evaluate the gene expression profile and (b) identify the toxicities and potentially relevant human disease outcomes associated with long-term human exposure to environmental heavy metals in mining area using microarray analysis. For this purpose, 40 healthy male volunteers who were residents of a heavy metal-polluted area (Mahd Al-Dhahab city, Saudi Arabia) and 20 healthy male volunteers who were residents of a non-heavy metal-polluted area were included in the study. Total RNA was isolated from whole blood using PAXgene Blood RNA tubes and then reversed transcribed and hybridized to the gene array using the Affymetrix U219 GeneChip. Microarray analysis showed about 2129 genes were identified and differentially altered, among which a shared set of 425 genes was differentially expressed in the heavy metal-exposed groups. Ingenuity pathway analysis revealed that the most altered gene-regulated diseases in heavy metal-exposed groups included hematological and developmental disorders and mostly renal and urological diseases. Quantitative real-time polymerase chain reaction closely matched the microarray data for some genes tested. Importantly, changes in gene-related diseases were attributed to alterations in the genes encoded for protein synthesis. Renal and urological diseases were the diseases that were most frequently associated with the heavy metal-exposed group. Therefore, there is a need for further studies to validate these

Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer.

PubMed

Lousberg, Laurence; Jerusalem, Guy

2016-01-01

Everolimus combined with exemestane is an important treatment option for patients suffering from estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (ABC) who have been previously treated with a nonsteroidal aromatase inhibitor (NSAI). After presentation of phase III registration trial BOLERO-2, several phase IIIb trials have been started to evaluate this regimen in a more real-world setting. Here, we review the efficacy and safety data published or presented at selected international meetings. These studies confirmed the outcome observed in the BOLERO-2 trial. Patient acceptance rate is also discussed by focusing on the permanent everolimus discontinuation rate in these trials. Factors influencing the safety profile are also reported, including the impact of age. The optimal sequence of combined therapy approaches associating targeted and endocrine therapy (ET) has yet to be determined as new treatment options such as cyclin-dependent kinase inhibitors become available. However, everolimus-exemestane remains an important treatment option with a major impact on progression-free survival (PFS) and an acceptable safety profile.

Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer

PubMed Central

Lousberg, Laurence; Jerusalem, Guy

2016-01-01

Everolimus combined with exemestane is an important treatment option for patients suffering from estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (ABC) who have been previously treated with a nonsteroidal aromatase inhibitor (NSAI). After presentation of phase III registration trial BOLERO-2, several phase IIIb trials have been started to evaluate this regimen in a more real-world setting. Here, we review the efficacy and safety data published or presented at selected international meetings. These studies confirmed the outcome observed in the BOLERO-2 trial. Patient acceptance rate is also discussed by focusing on the permanent everolimus discontinuation rate in these trials. Factors influencing the safety profile are also reported, including the impact of age. The optimal sequence of combined therapy approaches associating targeted and endocrine therapy (ET) has yet to be determined as new treatment options such as cyclin-dependent kinase inhibitors become available. However, everolimus–exemestane remains an important treatment option with a major impact on progression-free survival (PFS) and an acceptable safety profile. PMID:28096680

Toxicity of two imidazolium ionic liquids, [bmim][BF4] and [omim][BF4], to standard aquatic test organisms: Role of acetone in the induced toxicity.

PubMed

Tsarpali, Vasiliki; Dailianis, Stefanos

2015-07-01

The main goal of this study was to investigate the toxicity of the imidazolium-based ionic liquids (ILs), [bmim][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) and [omim][BF4] (1-octyl-3-methylimidazolium tetrafluoroborate), in battery of standard aquatic toxicity test organisms. Specifically, exposure of the algae Scenedesmus rubescens, crustaceans Thamnocephalus platyurus and Artemia franciscana, rotifers Brachionus calyciflorus and Brachionus plicatilis and bivalve Mytilus galloprovincialis to different concentrations of [bmim][BF4], [omim][BF4] and/or a binary mixture of [bmim][BF4]-[omim][BF4] (1:1) with or without acetone (carrier solvent), revealed that solvent can differentially mediate ILs' toxic profile. Acetone's ability to differentially affect ILs' cation's alkyl chain length, as well as the hydrolysis of [BF4(-)] anions was evident. Given that the toxic potency of the tested ILs seemed to be equal or even higher (in some cases) than those of conventional organic solvents, the present study revealed that the characterization of imidazolium-based ILs as "green solvents" should not be generalized, at least in case of their natural occurrence in mixtures with organic solvents, such as acetone. Copyright © 2015 Elsevier Inc. All rights reserved.

Endothelial effects of emission source particles: acute toxic response gene expression profiles.

PubMed

Nadadur, Srikanth S; Haykal-Coates, Najwa; Mudipalli, Anuradha; Costa, Daniel L

2009-02-01

Air pollution epidemiology has established a strong association between exposure to ambient particulate matter (PM) and cardiovascular outcomes. Experimental studies in both humans and laboratory animals support varied biological mechanisms including endothelial dysfunction as potentially a central step to the elicitation of cardiovascular events. We therefore hypothesized that relevant early molecular alterations on endothelial cells should be assessable in vitro upon acute exposure to PM components previously shown to be involved in health outcomes. Using a model emission PM, residual oil fly ash and one of its predominant constituents (vanadium-V), we focused on the development of gene expression profiles to fingerprint that particle and its constituents to explore potential biomarkers for PM-induced endothelial dysfunction. Here we present differential gene expression and transcription factor activation profiles in human vascular endothelial cells exposed to a non-cytotoxic dose of fly ash or V following semi-global gene expression profiling of approximately 8000 genes. Both fly ash and it's prime constituent, V, induced alterations in genes involved in passive and active transport of solutes across the membrane; voltage-dependent ion pumps; induction of extracellular matrix proteins and adhesion molecules; and activation of numerous kinases involved in signal transduction pathways. These preliminary data suggest that cardiovascular effects associated with exposure to PM may be mediated by perturbations in endothelial cell permeability, membrane integrity; and ultimately endothelial dysfunction.

Assessing children's perceptions of academic interventions: The Kids Intervention Profile.

PubMed

Eckert, Tanya L; Hier, Bridget O; Hamsho, Narmene F; Malandrino, Rigby D

2017-06-01

The psychometric properties of the Kids Intervention Profile (KIP), a rating scale designed to measure academic intervention acceptability from the perspective of students, were examined as well as the influence of background factors on students' acceptability ratings. Data were extracted from 4 randomized controlled trials investigating the effects of a performance feedback intervention on third-grade students' writing fluency (n = 228). Results indicated that the KIP contains 2 factors (General Intervention Acceptability, Skill Improvement) and has adequate internal consistency and stability across a 3-week period. There were gender differences in students' acceptability ratings, with female students rating the intervention as significantly more acceptable than males. In addition, results suggested a modest, positive relationship between students' intervention acceptability ratings and their intervention outcomes. Considerations regarding the use of the KIP, as well as limitations of the study, are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Potential toxicity of improperly discarded exhausted photovoltaic cells.

PubMed

Motta, C M; Cerciello, R; De Bonis, S; Mazzella, V; Cirino, P; Panzuto, R; Ciaravolo, M; Simoniello, P; Toscanesi, M; Trifuoggi, M; Avallone, B

2016-09-01

Low tech photovoltaic panels (PVPs) installed in the early '80s are now coming to the end of their life cycle and this raises the problem of their proper disposal. As panels contain potentially toxic elements, unconventional, complex and costly procedures are required to avoid environmental health risks and in countries where environmental awareness and economic resources are limited this may be especially problematic. This work was designed to investigate potential risks from improper disposal of these panels. To accomplish this aim an exhausted panel was broken into pieces and these were placed in water for 30 days. The resulting leached solution was analyzed to determine chemical release or used in toto, to determine its potential toxicity in established tests. The end points were seed germination (on Cucumis sativus and Lens culinaris) and effects on early development in three larval models: two crustaceans, Daphnia magna and Artemia salina, and the sea urchin Paracentrotus lividus. Our results show that the panels release small amounts of electrolytes (Na, Ca and Mg) into solution, along with antimony and manganese, with a concentration under the accepted maximum contaminant level, and nickel at a potentially toxic concentration. Developmental defects are seen in the plant and animal test organisms after experimental exposure to the whole solution leached from the broken panel. The toxic effects revealed in in vitro tests are sufficient to attract attention considering that they are exerted on both plants and aquatic animals and that the number of old PVPs in disposal sites will be very high. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fish embryo toxicity test, threshold approach, and moribund as approaches to implement 3R principles to the acute fish toxicity test.

PubMed

Dang, ZhiChao; van der Ven, Leo T M; Kienhuis, Anne S

2017-11-01

The acute fish toxicity test (AFT) is requested by EU legal frameworks for hazard classification and risk assessment. AFT is one of the few regulatory required tests using death as an endpoint. This paper reviews efforts made to reduce, refine and replace (3Rs) AFT. We make an inventory of information requirements for AFT, summarize studies on 3Rs of AFT and give recommendations. The fish embryo toxicity test (FET) is proposed as a replacement of AFT and analyses have focused on two aspects: assessing the capacity of FET in predicting AFT and defining the applicability domain of FET. Six comparison studies have consistently shown a strong correlation of FET and AFT. In contrast, the applicability domain of FET has not yet been fully defined. FET has not yet been accepted as a replacement of AFT by any EU legal frameworks to fulfill information requirements because FET is insensitive to some chemicals. It is recommended that the outlier chemicals that do not correlate between FET and AFT should be further investigated. When necessary, additional FET data should be generated. Another effort to reduce and refine AFT is incorporation of FET into the threshold approach. Furthermore, moribund as an endpoint of fish death has been introduced in revising AFT guideline to reduce the duration of suffering for refinement. This endpoint, however, needs further work on the link of moribund and death. Global regulatory acceptance of the moribund endpoint would be critical for this development. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular Mechanisms of Aldehyde Toxicity: A Chemical Perspective

PubMed Central

2015-01-01

Aldehydes are electrophilic compounds to which humans are pervasively exposed. Despite a significant health risk due to exposure, the mechanisms of aldehyde toxicity are poorly understood. This ambiguity is likely due to the structural diversity of aldehyde derivatives and corresponding differences in chemical reactions and biological targets. To gain mechanistic insight, we have used parameters based on the hard and soft, acids and bases (HSAB) theory to profile the different aldehyde subclasses with respect to electronic character (softness, hardness), electrophilic reactivity (electrophilic index), and biological nucleophilic targets. Our analyses indicate that short chain aldehydes and longer chain saturated alkanals are hard electrophiles that cause toxicity by forming adducts with hard biological nucleophiles, e.g., primary nitrogen groups on lysine residues. In contrast, α,β-unsaturated carbonyl derivatives, alkenals, and the α-oxoaldehydes are soft electrophiles that preferentially react with soft nucleophilic thiolate groups on cysteine residues. The aldehydes can therefore be grouped into subclasses according to common electronic characteristics (softness/hardness) and molecular mechanisms of toxicity. As we will discuss, the toxic potencies of these subgroups are generally related to corresponding electrophilicities. For some aldehydes, however, predictions of toxicity based on electrophilicity are less accurate due to inherent physicochemical variables that limit target accessibility, e.g., steric hindrance and solubility. The unsaturated aldehydes are also members of the conjugated type-2 alkene chemical class that includes α,β-unsaturated amide, ketone, and ester derivatives. Type-2 alkenes are electrophiles of varying softness and electrophilicity that share a common mechanism of toxicity. Therefore, exposure to an environmental mixture of unsaturated carbonyl derivatives could cause “type-2 alkene toxicity” through additive interactions

Quantitative Model of Systemic Toxicity Using ToxCast and ToxRefDB (SOT)

EPA Science Inventory

EPA’s ToxCast program profiles the bioactivity of chemicals in a diverse set of ~700 high throughput screening (HTS) assays. In collaboration with L’Oreal, a quantitative model of systemic toxicity was developed using no effect levels (NEL) from ToxRefDB for 633 chemicals with HT...

The outweigh of toxicity versus risk of recurrence for adjuvant interferon therapy: a survey in German melanoma patients and their treating physicians.

PubMed

Kähler, Katharina C; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Hauschild, Axel; Heinzerling, Lucie; Livingstone, Elisabeth; Loquai, Carmen; Müller-Brenne, Tina; Schadendorf, Dirk; Utikal, Jochen; Wagner, Tobias; Augustin, Matthias

2018-05-25

After more than two decades with interferon alfa-2a and 2b (IFN) as the only approved drugs in the adjuvant setting for melanoma, new treatment approaches like immune checkpoint inhibitors and BRAF-MEK inhibitors improve the progression free survival (PFS) and also the overall survival (OS). We compared physicians' preferences ("utilities") for health states associated with IFN therapy to their patients' preferences. Utilities describe a preference for a specific health state on a scale of 0 (as bad as death) to 1.0 (perfect health). We assessed utilities for health states associated with adjuvant IFN using the standard gamble technique in 108 physicians and 130 melanoma patients. Four IFN toxicity scenarios and three outcome scenarios were given to the participants. Both groups were asked for the 5-year disease free survival (DFS) they would need to accept the described IFN-related side effects. In both groups, utilities for melanoma relapse were significantly lower than for IFN side effects, showing that toxicity was more acceptable than relapse. Physicians indicated higher utilities for each scenario and needed lower 5-year DFS both in case of mild-to-moderate and severe side effects. Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, while physicians only required a chance of 40% and 50%, respectively. Both physicians and patients rated melanoma recurrence much lower than even severe IFN side effects. In direct comparison, physicians rated cancer-related scenarios more positively and accepted IFN toxicity for an even lower treatment benefit.

[Functional-behavioral profile of new cyclic GABA analogs in acute toxicity tests].

PubMed

Bugaeva, L I; Spasov, A A; Verovskiĭ, V E

2004-01-01

The properties of karphedone and phepyrone--new phenyl derivatives of pyrrolidone possessing nootropic activity--were studied in the course of the acute toxicity tests on rats. The drug effects were evaluated in terms of their integral influence on the state and behavior of test animals. The real therapeutic range and the profit/risk ratio of karphedone were comparable with those of the reference drug pyracetam and exceeded by a factor of 1.3 the corresponding values for phepyrone (irrespective of the LD50 values). The results give grounds for the further preclinical investigation of karphedone.

Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits

PubMed Central

Liang, H.; Brignole-Baudouin, F.; Rabinovich-Guilatt, L.; Mao, Z.; Riancho, L.; Faure, M.O.; Warnet, J.M.; Lambert, G.

2008-01-01

Purpose To evaluate and compare the toxicological profiles of two quaternary ammonium compounds (QAC), benzalkonium chloride (BAK), and cetalkonium chloride (CKC), in standard solution or cationic emulsion formulations in rabbit eyes using newly developed in vivo and ex vivo experimental approaches. Methods Seventy eyes of 35 adult male New Zealand albino rabbits were used in this study. They were randomly divided into five groups: 50 µl of phosphate-buffered saline (PBS), PBS containing 0.02% BAK or 0.002% CKC (BAK Sol and CKC Sol, respectively), and emulsion containing 0.02% BAK or 0.002% CKC (BAK Em and CKC Em, respectively) were applied to rabbit eyes 15 times at 5-min intervals. The ocular surface changes induced by these eye drops were investigated using slit-lamp examination, flow cytometry (FCM), impression cytology (IC) on conjunctiva, and corneal in vivo confocal microscopy (IVCM). Standard immunohistology in cryosections was also examined for cluster of differentiation (CD) 45+ infiltrating and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL)+ apoptotic cells. Results Clinical observations and IVCM showed that the highest toxicity was induced by BAK Sol, characterized by damaged corneal epithelium and a high level of inflammatory infiltration. BAK Em and CKC Sol presented moderate effects, and CKC Em showed the lowest toxicity with results similar to those of PBS. Conjunctival imprints analyzed by FCM showed a higher expression of RLA-DR and TNFR1 markers in BAK Sol-instilled eyes than in all other groups, especially at 4 h. Immunohistology was correlated with in vivo and ex vivo findings and confirmed this toxicity profile. A high level of infiltration of CD45+ inflammatory cells and TUNEL+ apoptotic cells was observed in limbus and conjunctiva, especially in QAC solution-receiving eyes compared to QAC emulsion-instilled eyes. Conclusions The acute administration of 15 instillations at 5 min intervals was a rapid and

Incorporation of soybean by-product okara and inulin in a probiotic soy yoghurt: texture profile and sensory acceptance.

PubMed

Bedani, Raquel; Campos, Marina M S; Castro, Inar A; Rossi, Elizeu A; Saad, Susana M I

2014-01-15

This study evaluated the effect of inulin and okara flour on textural and sensory properties of probiotic soy yoghurt (SY) throughout 28 days of storage at 4 °C. Employing a 2(2) design, four formulations of SY produced from soymilk and fermented with an ABT-4 culture (Lactobacillus acidophilus La-5, Bifidobacterium animalis Bb-12 and Streptococcus thermophilus) were studied: SY-C (control); SY-I (with inulin); SY-O (with okara); SY-IO (with inulin + okara). The addition of okara and the refrigerated storage led to significant differences in the instrumental texture parameters of SY (P < 0.05). Inulin and okara did not affect SY sensory acceptability (P > 0.05), but there was a tendency for higher scores in the presence of inulin. On the other hand, the storage period, particularly at 21 days, was unfavourable regarding the acceptance of the different SY. The results showed that the addition of okara flour and the storage were significant factors to increase firmness of the soy yoghurts. SY acceptability was not affected by the incorporation of inulin or okara. These results suggest that okara, discarded as industrial waste, may be used in probiotic soy yoghurt, helping to increase the nutritional and functional properties without altering its acceptability. © 2013 Society of Chemical Industry.

Sediment nickel bioavailability and toxicity to estuarine crustaceans of contrasting bioturbative behaviors--an evaluation of the SEM-AVS paradigm.

PubMed

Chandler, G Thomas; Schlekat, Christian E; Garman, Emily R; He, Lijian; Washburn, Katherine M; Stewart, Emily R; Ferry, John L

2014-11-04

Robust sediment quality criteria require chemistry and toxicity data predictive of concentrations where population/community response should occur under known geochemical conditions. Understanding kinetic and geochemical effects on toxicant bioavailability is key, and these are influenced by infaunal sediment bioturbation. This study used fine-scale sediment and porewater measurement of contrasting infaunal effects on carbon-normalized SEM-AVS to evaluate safe or potentially toxic nickel concentrations in a high-binding Spartina saltmarsh sediment (4%TOC; 35-45 μmol-S2-·g(-1)). Two crustaceans producing sharply contrasting bioturbation--the copepod Amphiascus tenuiremis and amphipod Leptocheirus plumulosus--were cultured in oxic to anoxic sediments with SEM[Ni]-AVS, TOC, porewater [Ni], and porewater DOC measured weekly. From 180 to 750 μg-Ni·g(-1) sediment, amphipod bioturbation reduced [AVS] and enhanced porewater [Ni]. Significant amphipod uptake, mortality, and growth-depression occurred at the higher sediment [Ni] even when [SEM-AVS]/foc suggested acceptable risk. Less bioturbative copepods produced higher AVS and porewater DOC but exhibited net population growth despite porewater [Ni] 1.3-1.7× their aqueous [Ni] LOEC. Copepod aqueous tests with/without dissolved organic matter showed significant aqueous DOC protection, which suggests porewater DOC attenuates sediment Ni toxicity. The SEM[Ni]-AVS relationship was predictive of acceptable risk for copepods at the important population-growth level.

Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays

EPA Science Inventory

Understanding potential health risks is a significant challenge for large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes chemical-target activity profiles of 976 chemicals (including failed pharmaceuticals...

Profiler Support for Operations at Space Launch Ranges

NASA Technical Reports Server (NTRS)

Merceret, Francis; Wilfong, Timothy; Lambert, Winifred; Short, David; Decker, Ryan; Ward, Jennifer

2006-01-01

Accurate vertical wind profiles are essential to successful launch or landing. Wind changes can make it impossible to fly a desired trajectory or avoid dangerous vehicle loads, possibly resulting in loss of mission. Balloons take an hour to generate a profile up to 20 km, but major wind changes can occur in 20 minutes. Wind profilers have the temporal response to detect such last minute hazards. They also measure the winds directly overhead while balloons blow downwind. At the Eastern Range (ER), altitudes from 2 to 20 km are sampled by a 50-MHz profiler every 4 minutes. The surface to 3 km is sampled by five 915-MHz profilers every 15 minutes. The Range Safety office assesses the risk of potential toxic chemical dispersion. They use observational data and model output to estimate the spatial extent and concentration of substances dispersed within the boundary layer. The ER uses 915-MHz profilers as both a real time observation system and as input to dispersion models. The WR has similar plans. Wind profilers support engineering analyses for the Space Shuttle. The 50-IVl11z profiler was used recently to analyze changes in the low frequency wind and low vertical wavenumber content of wind profiles in the 3 to 15 km region of the atmosphere. The 915-MHz profiler network was used to study temporal wind change within the boundary layer.

Gene expression profiles in rainbow trout, Onchorynchus mykiss, exposed to a simple chemical mixture.

PubMed

Hook, Sharon E; Skillman, Ann D; Gopalan, Banu; Small, Jack A; Schultz, Irvin R

2008-03-01

Among proposed uses for microarrays in environmental toxiciology is the identification of key contributors to toxicity within a mixture. However, it remains uncertain whether the transcriptomic profiles resulting from exposure to a mixture have patterns of altered gene expression that contain identifiable contributions from each toxicant component. We exposed isogenic rainbow trout Onchorynchus mykiss, to sublethal levels of ethynylestradiol, 2,2,4,4-tetrabromodiphenyl ether, and chromium VI or to a mixture of all three toxicants Fluorescently labeled complementary DNA (cDNA) were generated and hybridized against a commercially available Salmonid array spotted with 16,000 cDNAs. Data were analyzed using analysis of variance (p<0.05) with a Benjamani-Hochberg multiple test correction (Genespring [Agilent] software package) to identify up and downregulated genes. Gene clustering patterns that can be used as "expression signatures" were determined using hierarchical cluster analysis. The gene ontology terms associated with significantly altered genes were also used to identify functional groups that were associated with toxicant exposure. Cross-ontological analytics approach was used to assign functional annotations to genes with "unknown" function. Our analysis indicates that transcriptomic profiles resulting from the mixture exposure resemble those of the individual contaminant exposures, but are not a simple additive list. However, patterns of altered genes representative of each component of the mixture are clearly discernible, and the functional classes of genes altered represent the individual components of the mixture. These findings indicate that the use of microarrays to identify transcriptomic profiles may aid in the identification of key stressors within a chemical mixture, ultimately improving environmental assessment.

ToxCast: Using high throughput screening to identify profiles of biological activity

EPA Science Inventory

ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry and bioactivity profiling to predict potential for toxicity and prioritize limited testing resources (www.epa.gov/toc...

Toxic Encephalopathy

PubMed Central

Kim, Jae Woo

2012-01-01

This article schematically reviews the clinical features, diagnostic approaches to, and toxicological implications of toxic encephalopathy. The review will focus on the most significant occupational causes of toxic encephalopathy. Chronic toxic encephalopathy, cerebellar syndrome, parkinsonism, and vascular encephalopathy are commonly encountered clinical syndromes of toxic encephalopathy. Few neurotoxins cause patients to present with pathognomonic neurological syndromes. The symptoms and signs of toxic encephalopathy may be mimicked by many psychiatric, metabolic, inflammatory, neoplastic, and degenerative diseases of the nervous system. Thus, the importance of good history-taking that considers exposure and a comprehensive neurological examination cannot be overemphasized in the diagnosis of toxic encephalopathy. Neuropsychological testing and neuroimaging typically play ancillary roles. The recognition of toxic encephalopathy is important because the correct diagnosis of occupational disease can prevent others (e.g., workers at the same worksite) from further harm by reducing their exposure to the toxin, and also often provides some indication of prognosis. Physicians must therefore be aware of the typical signs and symptoms of toxic encephalopathy, and close collaborations between neurologists and occupational physicians are needed to determine whether neurological disorders are related to occupational neurotoxin exposure. PMID:23251840

[Evaluation of Brodifacoum-induced Toxicity by Metabonomics Approach Based on HPLC-TOF-MS].

PubMed

Yan, H; Zhuo, X Y; Shen, B H; Xiang, P; Shen, M

2017-06-01

To analyse the metabolic changes in urine of rats with brodifacoum intoxication, and to reveal the molecular mechanism of brodifacoum-induced toxicity on rats. By establishing a brodifacoum poisoning rats model, the urine metabolic profiling data of rats were acquired using high performance liquid chromatography-time of flight mass spectrometry （HPLC-TOF-MS）. The orthogonal partial least squares analysis-discrimination analysis （OPLS-DA） was applied for the multivariate statistics and the discovery of differential metabolites closely related to toxicity of brodifacoum. OPLS-DA score plot showed that the urinary metabolic at different time points before and after drug administration had good similarity within time period and presented clustering phenomenon. Comparing the urine samples of rats before drug administration with which after drug administration, twenty-two metabolites related to brodifacoum-induced toxicity were selected. The toxic effect of brodifacoum worked by disturbing the metabolic pathways in rats such as tricarboxylic cycle, glycolysis, sphingolipid metabolism and tryptophan metabolism, and the toxicity of brodifacoum is characterized of accumulation effect. The metabonomic method based on urine HPLC-TOF-MS can provide a novel insight into the study on molecular mechanism of brodifacoum-induced toxicity. Copyright© by the Editorial Department of Journal of Forensic Medicine

Elucidating mechanisms of toxic action of dissolved organic chemicals in oil sands process-affected water (OSPW).

PubMed

Morandi, Garrett D; Wiseman, Steve B; Guan, Miao; Zhang, Xiaowei W; Martin, Jonathan W; Giesy, John P

2017-11-01

Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface-mining oil sands industry in Alberta, Canada, and is acutely and chronically toxic to aquatic organisms. It is known that dissolved organic compounds in OSPW are responsible for most toxic effects, but knowledge of the specific mechanism(s) of toxicity, is limited. Using bioassay-based effects-directed analysis, the dissolved organic fraction of OSPW has previously been fractionated, ultimately producing refined samples of dissolved organic chemicals in OSPW, each with distinct chemical profiles. Using the Escherichia coli K-12 strain MG1655 gene reporter live cell array, the present study investigated relationships between toxic potencies of each fraction, expression of genes and characterization of chemicals in each of five acutely toxic and one non-toxic extract of OSPW derived by use of effects-directed analysis. Effects on expressions of genes related to response to oxidative stress, protein stress and DNA damage were indicative of exposure to acutely toxic extracts of OSPW. Additionally, six genes were uniquely responsive to acutely toxic extracts of OSPW. Evidence presented supports a role for sulphur- and nitrogen-containing chemical classes in the toxicity of extracts of OSPW. Copyright © 2017 Elsevier Ltd. All rights reserved.

Probing the ToxCastTM Chemical Library for Predictive Signatures of Developmental Toxicity -NLTO Poster

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesize that cell signaling pathways are primary targets for diverse environmental chemicals ...

Dielectrophoretic Field-Flow Fractionation System for Detection of Aquatic Toxicants

PubMed Central

Pui-ock, Sittisak; Ruchirawat, Mathuros; Gascoyne, Peter

2009-01-01

Dielectrophoretic field-flow fractionation (dFFF) was applied as a contact-free way to sense changes in the plasma membrane capacitances and conductivities of cultured human HL-60 cells in response to toxicant exposure. A micropatterned electrode imposed electric forces on cells in suspension in a parabolic flow profile as they moved through a thin chamber. Relative changes in the dFFF peak elution time, reflecting changes in cell membrane area and ion permeability, were measured as indices of response during the first 150 min of exposure to eight toxicants having different single or mixed modes of action (acrylonitrile, actinomycin D, carbon tetrachloride, endosulfan, N-nitroso-N-methylurea (NMU), paraquat dichloride, puromycin, and styrene oxide). The dFFF method was compared with the cell viability assay for all toxicants and with the mitochondrial potentiometric dye assay or DNA alkaline comet assay according to the mode of action of the specific agents. Except for low doses of nucleic acid-targeting agents (actinomycin D and NMU), the dFFF method detected all toxicants more sensitively than other assays, in some cases up to 105 times more sensitively than the viability approach. The results suggest the dFFF method merits additional study for possible applicability in toxicology. PMID:18788754

Subchronic oral toxicity and metabolite profiling of the p53 stabilizing agent, CP-31398, in rats and dogs.

PubMed

Johnson, William D; Muzzio, Miguel; Detrisac, Carol J; Kapetanovic, Izet M; Kopelovich, Levy; McCormick, David L

2011-11-18

CP-31398 (N'-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride) is a styrylquinazoline that stabilizes the DNA binding conformation of p53, thereby maintaining the activity of p53 as a transcription factor and tumor suppressor. In consideration of the potential use of p53 stabilizers for cancer prevention and therapy, 28-day studies (with recovery) were performed to characterize the toxicity of CP-31398 in rats and dogs. In the rat study, groups of 15 CD rats/sex received daily gavage exposure to CP-31398 at 0, 40, 80, or 160mg/kg/day (0, 240, 480, or 960mg/m(2)/day). In the dog study, groups of five beagle dogs received daily gavage exposure to CP-31398 at 0, 10, 20, or 40mg/kg/day (0, 200, 400, or 800mg/m(2)/day). The high dose of CP-31398 induced mortality in both species: seven male rats and four female rats died as a result of hepatic infarcts, and two female dogs died as a result of hepatic necrosis without evidence of thrombosis. No deaths were seen in the mid- or low-dose groups in either species. In dogs, sporadic emesis was seen in the high dose and mid dose groups, and reductions in body weight gain were observed in all drug-exposed groups. CP-31398 induced mild anemia in both species; clinical pathology data also demonstrated hepatic toxicity, renal toxicity, inflammatory reactions, and coagulopathies in rats in the high dose and mid dose groups. Treatment-related microscopic changes in high dose and mid dose rats were identified in the liver, kidney, heart, bone marrow, lung, adrenals, spleen, thymus, skeletal muscle, and ovary; microscopic changes in the liver, heart, lung, and adrenals persisted through the recovery period. In dogs, microscopic changes were identified in the central nervous system, lung, and liver; changes in all tissues remained at the end of the recovery period. The liver is the primary site of limiting toxicity for CP-31398 in rats, and is also a key site of toxicity in dogs. The

Subchronic oral toxicity and metabolite profiling of the p53 stabilizing agent, CP-31398, in rats and dogs

PubMed Central

Johnson, William D.; Muzzio, Miguel; Detrisac, Carol J.; Kapetanovic, Izet M.; Kopelovich, Levy; McCormick, David L.

2011-01-01

CP-31398 (N′-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride) is a styrylquinazoline that stabilizes the DNA binding conformation of p53, thereby maintaining the activity of p53 as a transcription factor and tumor suppressor. In consideration of the potential use of p53 stabilizers for cancer prevention and therapy, 28-day studies (with recovery) were performed to characterize the toxicity of CP-31398 in rats and dogs. In the rat study, groups of 15 CD rats/sex received daily gavage exposure to CP-31398 at 0, 40, 80, or 160 mg/kg/day (0, 240, 480, or 960 mg/m2/day). In the dog study, groups of five beagle dogs received daily gavage exposure to CP-31398 at 0, 10, 20, or 40 mg/kg/day (0, 200, 400, or 800 mg/m2/day). The high dose of CP-31398 induced mortality in both species: seven male rats and four female rats died as a result of hepatic infarcts, and two female dogs died as a result of hepatic necrosis without evidence of thrombosis. No deaths were seen in the mid- or low dose groups in either species. In dogs, sporadic emesis was seen in the high dose and mid dose groups, and reductions in body weight gain were observed in all drug-exposed groups. CP-31398 induced mild anemia in both species; clinical pathology data also demonstrated hepatic toxicity, renal toxicity, inflammatory reactions, and coagulopathies in rats in the high dose and mid dose groups. Treatment-related microscopic changes in high dose and mid dose rats were identified in the liver, kidney, heart, bone marrow, lung, adrenals, spleen, thymus, skeletal muscle, and ovary; microscopic changes in the liver, heart, lung, and adrenals persisted through the recovery period. In dogs, microscopic changes were identified in the central nervous system, lung, and liver; changes in all tissues remained at the end of the recovery period. The liver is the primary site of limiting toxicity for CP-31398 in rats, and is also a key site of toxicity in dogs. The

Modeling for influenza vaccines and adjuvants profile for safety prediction system using gene expression profiling and statistical tools

PubMed Central

Sasaki, Eita; Momose, Haruka; Hiradate, Yuki; Furuhata, Keiko; Takai, Mamiko; Asanuma, Hideki; Ishii, Ken J.

2018-01-01

Historically, vaccine safety assessments have been conducted by animal testing (e.g., quality control tests and adjuvant development). However, classical evaluation methods do not provide sufficient information to make treatment decisions. We previously identified biomarker genes as novel safety markers. Here, we developed a practical safety assessment system used to evaluate the intramuscular, intraperitoneal, and nasal inoculation routes to provide robust and comprehensive safety data. Influenza vaccines were used as model vaccines. A toxicity reference vaccine (RE) and poly I:C-adjuvanted hemagglutinin split vaccine were used as toxicity controls, while a non-adjuvanted hemagglutinin split vaccine and AddaVax (squalene-based oil-in-water nano-emulsion with a formulation similar to MF59)-adjuvanted hemagglutinin split vaccine were used as safety controls. Body weight changes, number of white blood cells, and lung biomarker gene expression profiles were determined in mice. In addition, vaccines were inoculated into mice by three different administration routes. Logistic regression analyses were carried out to determine the expression changes of each biomarker. The results showed that the regression equations clearly classified each vaccine according to its toxic potential and inoculation amount by biomarker expression levels. Interestingly, lung biomarker expression was nearly equivalent for the various inoculation routes. The results of the present safety evaluation were confirmed by the approximation rate for the toxicity control. This method may contribute to toxicity evaluation such as quality control tests and adjuvant development. PMID:29408882

Exuberant and inhibited children: Person-centered profiles and links to social adjustment.

PubMed

Dollar, Jessica M; Stifter, Cynthia A; Buss, Kristin A

2017-07-01

The current study aimed to substantiate and extend our understanding regarding the existence and developmental pathways of 3 distinct temperament profiles-exuberant, inhibited, and average approach-in a sample of 3.5-year-old children (n = 121). The interactions between temperamental styles and specific types of effortful control, inhibitory control and attentional control, were also examined in predicting kindergarten peer acceptance. Latent profile analysis identified 3 temperamental styles: exuberant, inhibited, and average approach. Support was found for the adaptive role of inhibitory control for exuberant children and attentional control for inhibited children in promoting peer acceptance in kindergarten. These findings add to our current understanding of temperamental profiles by using sophisticated methodology in a slightly older, community sample, as well as the importance of examining specific types of self-regulation to identify which skills lower risk for children of different temperamental styles. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

NMR-based metabonomics study on the effect of Gancao in the attenuation of toxicity in rats induced by Fuzi.

PubMed

Sun, Bo; Wang, Xubin; Cao, Ruili; Zhang, Qi; Liu, Qiao; Xu, Meifeng; Zhang, Ming; Du, Xiangbo; Dong, Fangting; Yan, Xianzhong

2016-12-04

Fuzi, the processed lateral root of Aconitum carmichaelii Debeaux, is a traditional Chinese medicine used for its analgesic, antipyretic, anti-rheumatoid arthritis and anti-inflammation effects; however, it is also well known for its toxicity. Gancao, the root of Glycyrrhiza uralensis Fisch., is often used concurrently with Fuzi to alleviate its toxicity. However, the mechanism of detoxication is still not well clear. In this study, the effect of Gancao on the metabolic changes induced by Fuzi was investigated by NMR-based metabonomic approaches. Fifty male Wistar rats were randomly divided into five groups (group A: control, group B: Fuzi decoction alone, group C: Gancao decoction alone, group D: Fuzi decoction and Gancao decoction simultaneously, group E: Fuzi decoction 5h after Gancao decoction) and urine samples were collected for NMR-based metabolic profiling analysis. Statistical analyses such as unsupervised PCA, t-test, hierarchical cluster, and pathway analysis were used to detect the effects of Gancao on the metabolic changes induced by Fuzi. The behavioral and biochemical characteristics showed that Fuzi exhibited toxic effects on treated rats (group B) and statistical analyses showed that their metabolic profiles were in contrast to those in groups A and C. However, when Fuzi was administered with Gancao, the metabolic profiles became similar to controls, whereby Gancao reduced the levels of trimethylamine N-oxide, betaine, dimethylglycine, valine, acetoacetate, citrate, fumarate, 2-ketoglutarate and hippurate, and regulated the concentrations of taurine and 3-hydroxybutyrate, resulting in a decrease in toxicity. Furthermore, important pathways that are known to be involved in the effect of Gancao on Fuzi, including phenylalanine, tyrosine and tryptophan biosynthesis, the synthesis and degradation of ketone bodies, and the TCA cycle, were altered in co-treated rats. Gancao treatment mitigated the metabolic changes altered by Fuzi administration in rats

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia.

PubMed

Maxwell, Rochelle R; Cole, Peter D

2017-06-01

The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

Toxic shock syndrome

MedlinePlus

Staphylococcal toxic shock syndrome; Toxic shock-like syndrome; TSLS ... Toxic shock syndrome is caused by a toxin produced by some types of staphylococcus bacteria. A similar problem, called toxic shock- ...

Risk Levels of Toxic Cyanobacteria in Portuguese Recreational Freshwaters

PubMed Central

Menezes, Carina; Dias, Elsa

2017-01-01

Portuguese freshwater reservoirs are important socio-economic resources, namely for recreational use. National legislation concerning bathing waters does not include mandatory levels or guidelines for cyanobacteria and cyanotoxins. This is an issue of concern since cyanotoxin-based evidence is insufficient to change the law, and the collection of scientific evidence has been hampered by the lack of regulatory levels for cyanotoxins in bathing waters. In this work, we evaluate the profile of cyanobacteria and microcystins (MC) in eight freshwater reservoirs from the center of Portugal, used for bathing/recreation, in order to determine the risk levels concerning toxic cyanobacteria occurrence. Three of the reservoirs did not pose a risk of MC contamination. However, two reservoirs presented a high risk in 7% of the samples according to the World Health Organization (WHO) guidelines for MC in bathing waters (above 20 µg/L). In the remaining three reservoirs, the risk concerning microcystins occurrence was low. However, they exhibited recurrent blooms and persistent contamination with MC up to 4 µg/L. Thus, the risk of exposure to MC and potential acute and/or chronic health outcomes should not be disregarded in these reservoirs. These results contribute to characterize the cyanobacterial blooms profile and to map the risk of toxic cyanobacteria and microcystins occurrence in Portuguese inland waters. PMID:29057822

Efficacy and acceptance of professional dental cleaning among nursing home residents.

PubMed

Barbe, Anna Greta; Kottmann, Hannah Elisa; Hamacher, Stefanie; Derman, Sonja Henny Maria; Noack, Michael Johannes

2018-05-13

To determine the impact of general and oral health status of nursing home residents in Germany on efficacy and acceptance of professional dental cleaning performed by a dental nurse. Participants (N = 41; mean age 83 ± 8 years) living in a nursing home were included. Personal and general health, oral health, oral hygiene habits, and needs were investigated. Individual acceptance regarding professional dental cleaning via different devices (scaler, interdental brushes, ultrasonic cleaning) was assessed, as was the efficacy of this method using after-cleaning indices. Oral health among nursing home residents was impaired and independent from dementia status. Most residents (33/41) performed oral hygiene procedures independently and showed better index values than those in need of external help. Residents requiring help with oral hygiene showed increased risk profiles (higher age, more often immobile, demented, more xerostomia). The dental cleaning procedure required a mean time of 37 ± 11 min, was widely accepted (36/41), and achieved clean results (plaque index 0.1 ± 0.5, oral hygiene index 0.2 ± 1.6, Volpe-Manhold index 0.4 ± 1.6); food residues were reduced to 0 independent from cognitive status. Regarding the cleaning methods, scalers were accepted best without difference between demented and non-demented residents. Professional dental cleaning in nursing homes is an accepted and efficacious oral hygiene procedure among nursing home residents. Professional dental cleaning is an efficacious and accepted method as a first step in line with strategies to improve oral health and should be considered in nursing home residents.

Determination of toxic metals in drinking water sources in the Chief Albert Luthuli Local Municipality in Mpumalanga, South Africa

NASA Astrophysics Data System (ADS)

Nthunya, Lebea N.; Masheane, Monaheng L.; Malinga, Soraya P.; Nxumalo, Edward N.; Mamba, Bhekie B.; Mhlanga, Sabelo D.

2017-08-01

This study was conducted to determine the presence and levels of toxic metals on selected water sources in a rural community in Lochiel, South Africa. Collection of water samples from identified drinking water sources (open wells, community tanks, water treatment works and boreholes) was done in all seasons of the year (winter, spring, summer and autumn) between 2014 and 2015. The concentrations of identified toxic metals (cobalt, chromium, copper, lead, zinc, manganese and iron) were measured using ICP-OES. Some water sources were found to contain concentrations of toxic metals at levels slightly higher than USEPA, WHO and SANS241 set limits (e.g. manganese and cobalt), while others were found to be within the acceptable limits. This suggested that the residents residing in locations that have water sources containing toxic metals at the concentrations above the set limits are at risk and susceptible to suffer diseases caused by these toxic metals. The side effects of the metals may not be acute; however prolonged exposure to the toxic metals may result in detrimental effects since they are known to bioaccumulate in the body.

Interaction, transformation and toxicity assessment of particles and additives used in the semiconducting industry.

PubMed

Dumitrescu, Eduard; Karunaratne, Dinusha P; Babu, S V; Wallace, Kenneth N; Andreescu, Silvana

2018-02-01

Chemical mechanical planarization (CMP) is a widely used technique for the manufacturing of integrated circuit chips in the semiconductor industry. The process generates large amounts of waste containing engineered particles, chemical additives, and chemo-mechanically removed compounds. The environmental and health effects associated with the release of CMP materials are largely unknown and have recently become of significant concern. Using a zebrafish embryo assay, we established toxicity profiles of individual CMP particle abrasives (SiO 2 and CeO 2 ), chemical additives (hydrogen peroxide, proline, glycine, nicotinic acid, and benzotriazole), as well as three model representative slurries and their resulting waste. These materials were characterized before and after use in a typical CMP process in order to assess changes that may affect their toxicological profile and alter their surface chemistry due to polishing. Toxicity outcome in zebrafish is discussed in relation with the physicochemical characteristics of the abrasive particles and with the type and concentration profile of the slurry components pre and post-polishing, as well as the interactions between particle abrasives and additives. This work provides toxicological information of realistic CMP slurries and their polishing waste, and can be used as a guideline to predict the impact of these materials in the environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

In vivo cardiovascular toxicity induced by acetochlor in zebrafish larvae.

PubMed

Liu, Hongcui; Chu, Tianyi; Chen, Lili; Gui, Wenjun; Zhu, Guonian

2017-08-01

The risk of acetochlor to human health is still unclear, prompting concern over its risk, especially to pesticide suicides population, occupational population (farmers, retailers and pharmaceutical workers), and special population (young children and infants, pregnant women, older people, and those with compromised immune systems). This study was to explore the toxic effect and the possible mechanism of toxic action of acetochlor using zebrafish larvae whose toxicity profiles have been confirmed to be strikingly similar with mammalian. The result indicated that the toxic target organ of acetochlor was cardiovascular system. Thus, cardiovascular toxicity evaluation was investigated systematically. The main phenotypes of cardiovascular toxicity induced by acetochlor were bradycardia, pericardial edema, circulation defect, and thrombosis; Malformed heart was confirmed by histopathological examination. Thrombosis which maybe triggered by bradycardia was further studied using o-dianisidine for erythrocyte staining; Substantial thrombus in the caudal vein and significantly reduced heart red blood cells (RBCs) intensity which can reflect the thrombosis degree were observed in zebrafish in a concentration-dependent manner. Additionally, the mRNA expression level of Nkx2.5 and Gata4 related to induction of cardiac program were down-regulated significantly by quantitative real-time polymerase chain reaction (qRT-PCR), which could cause defects in the cardiovascular system. For the first time, our results demonstrated that acetochlor induced cardiovascular toxicity, and down-regulation of Nkx2.5 and Gata4 might be its possible molecular basis. Our data generated here might provide novel insights into cardiovascular disease risk following acetochlor exposure to human, especially to pesticide suicides population, occupational population and special population. Copyright © 2017. Published by Elsevier Ltd.

Reproductive and developmental toxicity of the components of gasoline.

PubMed Central

Skalko, R G

1993-01-01

The reproductive, developmental, and postnatal toxicity of 14 select chemicals and mixtures that are components of gasoline has been reviewed. The majority of experimental analyses have been performed as either variations of the accepted segment 2 protocol or as traditional teratology studies. Specific deficiencies in the present database have been identified and are most obvious in the evaluation of reproductive and postnatal effects. It is recommended that future studies address the continuing need for assessment in multiple species and over a range of dosages with specific emphasis on the impact of route of administration on the results obtained. PMID:8020438

Effect of diet quality on chronic toxicity of aqueous lead to the amphipod Hyalella azteca

USGS Publications Warehouse

Besser, John M.; Ivey, Chris D.; Brumbaugh, William G.; Ingersoll, Christopher G.

2016-01-01

The authors investigated the chronic toxicity of aqueous Pb to the amphipod Hyalella azteca (Hyalella) in 42-d tests using 2 different diets: 1) the yeastþcereal leafþtrout pellet (YCT) diet, fed at the uniform low ration used in standard methods for sediment toxicity tests; and 2) a new diet of diatomsþTetraMin flakes (DT), fed at increasing rations over time, that has been optimized for use in Hyalella water-only tests. Test endpoints included survival, weight, biomass, fecundity, and total young. Lethal effects of Pb were similar for the DT and YCT tests (20% lethal concentration [LC20]¼13 mg/L and 15mg/L, respectively, as filterable Pb). In contrast, weight and fecundity endpoints were not significantly affected in the DT test at Pb concentrations up to 63 mg/L, but these endpoints were significantly reduced by Pb in the YCT test—and in a 2005 test in the same laboratory with a diet of conditioned Rabbit Chow (RC-2005). The fecundity and total young endpoints from the YCT and RC-2005 tests were considered unreliable because fecundity in controls did not meet test acceptability criteria, but both of these tests still produced lower Pb effect concentrations (for weight or biomass) than the test with the DT diet. The lowest biotic ligand model–normalized effect concentrations for the 3 tests ranged from 3.7mg/L (weight 20% effect concentration [EC20] for the RC-2005 test) to 8.2 mg/L (total young EC20 for the DT test), values that would rank Hyalella as the second or third most sensitive of 13 genera in a species sensitivity distribution for chronic Pb toxicity. These results demonstrate that toxicity tests with Hyalella fed optimal diets can meet more stringent test acceptability criteria for control performance, but suggest that results of these tests may underestimate sublethal toxic effects of Pb to Hyalella under suboptimal feeding regimes.

Comparative Developmental Toxicity of Flavonoids Using an Integrative Zebrafish System

PubMed Central

Bugel, Sean M.; Bonventre, Josephine A.; Tanguay, Robert L.

2016-01-01

Flavonoids are a large, structurally diverse class of bioactive naturally occurring chemicals commonly detected in breast milk, soy based infant formulas, amniotic fluid, and fetal cord blood. The potential for pervasive early life stage exposures raises concerns for perturbation of embryogenesis, though developmental toxicity and bioactivity information is limited for many flavonoids. Therefore, we evaluated a suite of 24 flavonoid and flavonoid-like chemicals using a zebrafish embryo-larval toxicity bioassay—an alternative model for investigating developmental toxicity of environmentally relevant chemicals. Embryos were exposed to 1–50 µM of each chemical from 6 to 120 h postfertilization (hpf), and assessed for 26 adverse developmental endpoints at 24, 72, and 120 hpf. Behavioral changes were evaluated in morphologically normal animals at 24 and 72 hpf, at 120 hpf using a larval photomotor response (LPR) assay. Gene expression was comparatively evaluated for all compounds for effects on biomarker transcripts indicative of AHR (cyp1a) and ER (cyp19a1b, esr1, lhb, vtg) pathway bioactivity. Overall, 15 of 24 flavonoids elicited adverse effects on one or more of the developmental or behavioral endpoints. Hierarchical clustering and principle component analyses compared toxicity profiles and identified 3 distinct groups of bioactive flavonoids. Despite robust induction of multiple estrogen-responsive biomarkers, co-exposure with ER and GPER antagonists did not ameliorate toxicity, suggesting ER-independence and alternative modes of action. Taken together, these studies demonstrate that development is sensitive to perturbation by bioactive flavonoids in zebrafish that are not related to traditional estrogen receptor mode of action pathways. This integrative zebrafish platform provides a useful framework for evaluating flavonoid developmental toxicity and hazard prioritization. PMID:27492224

Ocular toxicities associated with targeted anticancer agents: an analysis of clinical data with management suggestions

PubMed Central

Fu, Chen; Gombos, Dan S; Lee, Jared; George, Goldy C; Hess, Kenneth; Whyte, Andrew; Hong, David S

2017-01-01

Ocular toxicities are among the most common adverse events resulting from targeted anticancer agents and are becoming increasingly relevant in the management of patients on these agents. The purpose of this study is to provide a framework for management of these challenging toxicities based on objective data from FDA labels and from analysis of the literature. All oncologic drugs approved by the FDA up to March 14, 2015, were screened for inclusion. A total of 16 drugs (12 small-molecule drugs and 4 monoclonal antibodies) were analyzed for ocular toxicity profiles based on evidence of ocular toxicity. Trials cited by FDA labels were retrieved, and a combination search in Medline, Google Scholar, the Cochrane database, and the NIH Clinical Trials Database was conducted. The majority of ocular toxicities reported were low severity, and the most common were conjunctivitis and “visual disturbances.” However, severe events including incidents of blindness, retinal vascular occlusion, and corneal ulceration occurred. The frequency and severity at which ocular toxicities occur merits a more multidisciplinary approach to managing patients with agents that are known to cause ocular issues. We suggest a standardized methodology for referral and surveillance of patients who are potentially at risk of severe ocular toxicity. PMID:28938590

Consumer profile and acceptability of cooked beef steaks with edible and active coating containing oregano and rosemary essential oils.

PubMed

Vital, Ana Carolina Pelaes; Guerrero, Ana; Kempinski, Emilia Maria Barbosa Carvalho; Monteschio, Jessica de Oliveira; Sary, Cesar; Ramos, Tatiane Rogelio; Campo, María Del Mar; Prado, Ivanor Nunes do

2018-09-01

Fresh animal products are highly perishable and characterized by a short shelf-life. Edible coatings with natural antioxidants (essential oils: EOs) could improve stability, ensure quality, and increase the shelf-life of fresh products. Due to the strong flavor of EOs, their use should consider consumer preferences and sensory acceptability. This study evaluated the effects of edible coating (with oregano and rosemary essential oil) on beef in relation to consumer preferences, besides the determination of habits of consumption and buying intentions of consumers. Acceptability scores from three clusters of consumers was described. Coating with oregano was the preferred. The higher consumer acceptance and willingness to buy this product indicate a great potential and possibility of using coatings with essential oils in fresh animal products. Copyright © 2018. Published by Elsevier Ltd.

Impact of tumour bed boost integration on acute and late toxicity in patients with breast cancer: A systematic review.

PubMed

Hamilton, Daniel George; Bale, Rebecca; Jones, Claire; Fitzgerald, Emma; Khor, Richard; Knight, Kellie; Wasiak, Jason

2016-06-01

The purpose of this systematic review was to summarise the evidence from studies investigating the integration of tumour bed boosts into whole breast irradiation for patients with Stage 0-III breast cancer, with a focus on its impact on acute and late toxicities. A comprehensive systematic electronic search through the Ovid MEDLINE, EMBASE and PubMed databases from January 2000 to January 2015 was conducted. Studies were considered eligible if they investigated the efficacy of hypo- or normofractionated whole breast irradiation with the inclusion of a daily concurrent boost. The primary outcomes of interest were the degree of observed acute and late toxicity following radiotherapy treatment. Methodological quality assessment was performed on all included studies using either the Newcastle-Ottawa Scale or a previously published investigator-derived quality instrument. The search identified 35 articles, of which 17 satisfied our eligibility criteria. Thirteen and eleven studies reported on acute and late toxicities respectively. Grade 3 acute skin toxicity ranged from 1 to 7% whilst moderate to severe fibrosis and telangiectasia were both limited to 9%. Reported toxicity profiles were comparable to historical data at similar time-points. Studies investigating the delivery of concurrent boosts with whole breast radiotherapy courses report safe short to medium-term toxicity profiles and cosmesis rates. Whilst the quality of evidence and length of follow-up supporting these findings is low, sufficient evidence has been generated to consider concurrent boost techniques as an alternative to conventional sequential techniques. Copyright © 2016 Elsevier Ltd. All rights reserved.

Toxicity characterization of urban stormwater with bioanalytical tools.

PubMed

Tang, Janet Y M; Aryal, Rupak; Deletic, Ana; Gernjak, Wolfgang; Glenn, Eva; McCarthy, David; Escher, Beate I

2013-10-01

Stormwater harvesting has become an attractive alternative strategy to address the rising demand for urban water supply due to limited water sources and population growth. Nevertheless, urban stormwater is also a major source of surface water pollution. Runoff from different urban catchments with source contributions from anthropogenic activities and various land uses causes variable contaminant profiles, thus posing a challenging task for environmental monitoring and risk assessment. A thorough understanding of raw stormwater quality is essential to develop appropriate treatment facilities for potential indirect potable reuse of stormwater. While some of the key chemical components have previously been characterized, only scarce data are available on stormwater toxicity. We benchmarked stormwater samples from urban, residential and industrial sites across various Australian capital cities against samples from the entire water cycle, from sewage to drinking water. Six biological endpoints, targeting groups of chemicals with modes of toxic action of particular relevance for human and environmental health, were investigated: non-specific toxicity (Microtox and combined algae test), the specific modes of action of phytotoxicity (combined algae test), dioxin-like activity (AhR-CAFLUX), and estrogenicity (E-SCREEN), as well as reactive toxicity encompassing genotoxicity (umuC) and oxidative stress (AREc32). Non-specific toxicity was highly variable across sites. The baseline toxicity equivalent concentrations of the most polluted samples were similar to secondary treated effluent from wastewater treatment plants. Phytotoxicity results correlated well with the measured herbicide concentrations at all sites. High estrogenicity was found in two sampling events and could be related to sewage overflow. Genotoxicity, dioxin-like activity, and oxidative stress response were evident in only three of the samples where the stormwater drain was beside a heavy traffic road

Profiling of the toxicity mechanisms of coated and uncoated silver nanoparticles to yeast Saccharomyces cerevisiae BY4741 using a set of its 9 single-gene deletion mutants defective in oxidative stress response, cell wall or membrane integrity and endocytosis.

PubMed

Käosaar, Sandra; Kahru, Anne; Mantecca, Paride; Kasemets, Kaja

2016-09-01

The widespread use of nanosilver in various antibacterial, antifungal, and antiviral products warrants the studies of the toxicity pathways of nanosilver-enabled materials toward microbes and viruses. We profiled the toxicity mechanisms of uncoated, casein-coated, and polyvinylpyrrolidone-coated silver nanoparticles (AgNPs) using Saccharomyces cerevisiae wild-type (wt) and its 9 single-gene deletion mutants defective in oxidative stress (OS) defense, cell wall/membrane integrity, and endocytosis. The 48-h growth inhibition assay in organic-rich growth medium and 24-h cell viability assay in deionized (DI) water were applied whereas AgNO3, H2O2, and SDS served as positive controls. Both coated AgNPs (primary size 8-12nm) were significantly more toxic than the uncoated (~85nm) AgNPs. All studied AgNPs were ~30 times more toxic if exposed to yeast cells in DI water than in the rich growth medium: the IC50 based on nominal concentration of AgNPs in the growth inhibition test ranged from 77 to 576mg Ag/L and in the cell viability test from 2.7 to 18.7mg Ag/L, respectively. Confocal microscopy showed that wt but not endocytosis mutant (end3Δ) internalized AgNPs. Comparison of toxicity patterns of wt and mutant strains defective in OS defense and membrane integrity revealed that the toxicity of the studied AgNPs to S. cerevisiae was not caused by the OS or cell wall/membrane permeabilization. Copyright © 2016 Elsevier Ltd. All rights reserved.

Short-Term Acceptability of the Woman's Condom among Married Couples in Shanghai

PubMed Central

Wu, Junqing; Huang, Zirong

2016-01-01

Background. The Woman's Condom, a second-generation female condom designed for acceptability, is poised for introduction in China. Method. This single-arm study was conducted among 60 couples in China in 2010 to assess acceptability of the Woman's Condom. Results. Male participants reported that ease of handling, inserting, and removing the device improved significantly from first to fourth use. Female and male participants reported that comfort during insertion, feel of lubricant during insertion, comfort/fit of outer ring during use, and overall comfort improved significantly from first to fourth use. Further, at fourth use, female participants reported significant improvement in the comfort of the feel of the condom material and lubricant. Female and male participants reported that satisfaction with stability and sensation during sex and ability to achieve orgasm improved significantly from first to fourth use. At fourth use, female participants reported statistically significant improvement in sensation compared to using nothing. A majority of participants (78%) stated that they would use the Woman's Condom in the future, primarily due to its dual protection profile. Conclusion. This study has shown that, in China, the Woman's Condom appears to be acceptable to married couples. User experience contributes to improvement in many aspects of device acceptability. PMID:27547481

Toxicity of formulants and heavy metals in glyphosate-based herbicides and other pesticides.

PubMed

Defarge, N; Spiroux de Vendômois, J; Séralini, G E

2018-01-01

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.

Influence of psychological factors on the acceptance of complete dentures.

PubMed

al Quran, F; Clifford, T; Cooper, C; Lamey, P J

2001-07-01

To assess the influence of psychological factors on the acceptance of complete dentures in a population wearing dentures judged to be clinically satisfactory. Subjects were asked to complete personality profiles and also to rate their dentures using a denture satisfaction questionnaire. The survey was conducted in the prosthetics clinic of a teaching hospital. Patients were selected from those who had new complete dentures constructed in the department within the previous two years. The personality inventory was a self-administered questionnaire comprising 240 items covering the five domains of personality. Denture satisfaction was scored on a nine item scale with four Likert type responses to each. A group of 16% consistently complained about their dentures. Statistical analysis showed that personality factors especially Neuroticism had a significant relationship with denture satisfaction. Psychological factors significantly influence denture satisfaction and profiles may provide useful in predicting potential difficult denture wearers.

Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice.

PubMed

Socała, Katarzyna; Nieoczym, Dorota; Kowalczuk-Vasilev, Edyta; Wyska, Elżbieta; Wlaź, Piotr

2017-07-01

Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. In addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD 50 value of sulforaphane in mice was estimated at 212.67mg/kg, while the TD 50 value - at 191.58mg/kg. In seizure tests, sulforaphane at the highest dose tested (200mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6Hz-induced psychomotor seizure. At doses of 10-200mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150-300mg/kg), hypothermia (at 150-300mg/kg), impairment of motor coordination (at 200-300mg/kg), decrease in skeletal muscle strength (at 250-300mg/kg), and deaths (at 200-300mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200

Video Game Acceptance: A Meta-Analysis of the Extended Technology Acceptance Model.

PubMed

Wang, Xiaohui; Goh, Dion Hoe-Lian

2017-11-01

The current study systematically reviews and summarizes the existing literature of game acceptance, identifies the core determinants, and evaluates the strength of the relationships in the extended technology acceptance model. Moreover, this study segments video games into two categories: hedonic and utilitarian and examines player acceptance of these two types separately. Through a meta-analysis of 50 articles, we find that perceived ease of use (PEOU), perceived usefulness (PU), and perceived enjoyment (PE) significantly associate with attitude and behavioral intention. PE is the dominant predictor of hedonic game acceptance, while PEOU and PU are the main determinants of utilitarian game acceptance. Furthermore, we find that respondent type and game platform are significant moderators. Findings of this study provide critical insights into the phenomenon of game acceptance and suggest directions for future research.

Comparison of in vivo toxicity, antioxidant and immunomodulatory activities of coconut, nipah and pineapple juice vinegars.

PubMed

Mohamad, Nurul Elyani; Keong Yeap, Swee; Beh, Boon Keen; Romli, Muhammad Firdaus; Yusof, Hamidah Mohd; Kristeen-Teo, Ye Wen; Sharifuddin, Shaiful Adzni; Long, Kamariah; Alitheen, Noorjahan Banu

2018-01-01

Vinegar is widely used as a food additive, in food preparation and as a food supplement. This study compared the phenolic acid profiles and in vivo toxicities, and antioxidant and immunomodulatory effects of coconut, nipah and pineapple juice vinegars, which were respectively prepared via a two-step fermentation using Saccharomyces cerevisiae 7013 INRA and Acetobacter aceti vat Europeans. Pineapple juice vinegar, which had the highest total phenolic acid content, also exhibited the greatest in vitro antioxidant capacity compared to coconut juice and nipah juice vinegars. Following acute and sub-chronic in vivo toxicity evaluation, no toxicity and mortality were evident and there were no significant differences in the serum biochemical profiles between mice administered the vinegars versus the control group. In the sub-chronic toxicity evaluation, the highest liver antioxidant levels were found in mice fed with pineapple juice vinegar, followed by coconut juice and nipah juice vinegars. However, compared to the pineapple juice and nipah juice vinegars, the mice fed with coconut juice vinegar, exhibited a higher population of CD4 + and CD8 + T-lymphocytes in the spleen, which was associated with greater levels of serum interleukin-2 and interferon-γ cytokines. Overall, the data suggested that not all vinegar samples cause acute and sub-chronic toxicity in vivo. Moreover, the in vivo immunity and organ antioxidant levels were enhanced, to varying extents, by the phenolic acids present in the vinegars. The results obtained in this study provide appropriate guidelines for further in vivo bioactivity studies and pre-clinical assessments of vinegar consumption. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity (Developing Predictive Bioactivity Signatures from ToxCasts HTS Data)

EPA Science Inventory

ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry, bioactivity profiling and toxicogenomic data to predict potential for toxicity and prioritize limited testing resour...

Predicting the aquatic toxicity mode of action using logistic regression and linear discriminant analysis.

PubMed

Ren, Y Y; Zhou, L C; Yang, L; Liu, P Y; Zhao, B W; Liu, H X

2016-09-01

The paper highlights the use of the logistic regression (LR) method in the construction of acceptable statistically significant, robust and predictive models for the classification of chemicals according to their aquatic toxic modes of action. Essentials accounting for a reliable model were all considered carefully. The model predictors were selected by stepwise forward discriminant analysis (LDA) from a combined pool of experimental data and chemical structure-based descriptors calculated by the CODESSA and DRAGON software packages. Model predictive ability was validated both internally and externally. The applicability domain was checked by the leverage approach to verify prediction reliability. The obtained models are simple and easy to interpret. In general, LR performs much better than LDA and seems to be more attractive for the prediction of the more toxic compounds, i.e. compounds that exhibit excess toxicity versus non-polar narcotic compounds and more reactive compounds versus less reactive compounds. In addition, model fit and regression diagnostics was done through the influence plot which reflects the hat-values, studentized residuals, and Cook's distance statistics of each sample. Overdispersion was also checked for the LR model. The relationships between the descriptors and the aquatic toxic behaviour of compounds are also discussed.

Facts and Fallacies in the Debate on Glyphosate Toxicity.

PubMed

Mesnage, Robin; Antoniou, Michael N

2017-01-01

The safety profile of the herbicide glyphosate and its commercial formulations is controversial. Reviews have been published by individuals who are consultants and employees of companies commercializing glyphosate-based herbicides in support of glyphosate's reapproval by regulatory agencies. These authors conclude that glyphosate is safe at levels below regulatory permissible limits. In contrast, reviews conducted by academic scientists independent of industry report toxic effects below regulatory limits, as well as shortcomings of the current regulatory evaluation of risks associated with glyphosate exposures. Two authors in particular (Samsel and Seneff) have published a series of commentaries proposing that long-term exposure to glyphosate is responsible for many chronic diseases (including cancers, diabetes, neuropathies, obesity, asthma, infections, osteoporosis, infertility, and birth defects). The aim of this review is to examine the evidential basis for these claimed negative health effects and the mechanisms that are alleged to be at their basis. We found that these authors inappropriately employ a deductive reasoning approach based on syllogism. We found that their conclusions are not supported by the available scientific evidence. Thus, the mechanisms and vast range of conditions proposed to result from glyphosate toxicity presented by Samsel and Seneff in their commentaries are at best unsubstantiated theories, speculations, or simply incorrect. This misrepresentation of glyphosate's toxicity misleads the public, the scientific community, and regulators. Although evidence exists that glyphosate-based herbicides are toxic below regulatory set safety limits, the arguments of Samsel and Seneff largely serve to distract rather than to give a rational direction to much needed future research investigating the toxicity of these pesticides, especially at levels of ingestion that are typical for human populations.

Facts and Fallacies in the Debate on Glyphosate Toxicity

PubMed Central

Mesnage, Robin; Antoniou, Michael N.

2017-01-01

The safety profile of the herbicide glyphosate and its commercial formulations is controversial. Reviews have been published by individuals who are consultants and employees of companies commercializing glyphosate-based herbicides in support of glyphosate’s reapproval by regulatory agencies. These authors conclude that glyphosate is safe at levels below regulatory permissible limits. In contrast, reviews conducted by academic scientists independent of industry report toxic effects below regulatory limits, as well as shortcomings of the current regulatory evaluation of risks associated with glyphosate exposures. Two authors in particular (Samsel and Seneff) have published a series of commentaries proposing that long-term exposure to glyphosate is responsible for many chronic diseases (including cancers, diabetes, neuropathies, obesity, asthma, infections, osteoporosis, infertility, and birth defects). The aim of this review is to examine the evidential basis for these claimed negative health effects and the mechanisms that are alleged to be at their basis. We found that these authors inappropriately employ a deductive reasoning approach based on syllogism. We found that their conclusions are not supported by the available scientific evidence. Thus, the mechanisms and vast range of conditions proposed to result from glyphosate toxicity presented by Samsel and Seneff in their commentaries are at best unsubstantiated theories, speculations, or simply incorrect. This misrepresentation of glyphosate’s toxicity misleads the public, the scientific community, and regulators. Although evidence exists that glyphosate-based herbicides are toxic below regulatory set safety limits, the arguments of Samsel and Seneff largely serve to distract rather than to give a rational direction to much needed future research investigating the toxicity of these pesticides, especially at levels of ingestion that are typical for human populations. PMID:29226121

Environmental toxicants and autism spectrum disorders: a systematic review

PubMed Central

Rossignol, D A; Genuis, S J; Frye, R E

2014-01-01

Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case–control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case–control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that

Developmental Toxicity of Zinc Oxide Nanoparticles to Zebrafish (Danio rerio): A Transcriptomic Analysis

PubMed Central

Choi, Jin Soo; Kim, Ryeo-Ok; Yoon, Seokjoo

2016-01-01

Zinc oxide nanoparticles (ZnO NPs) are being utilized in an increasing number of fields and commercial applications. While their general toxicity and associated oxidative stress have been extensively studied, the toxicological pathways that they induce in developmental stages are still largely unknown. In this study, the developmental toxicity of ZnO NPs to embryonic/larval zebrafish was investigated. The transcriptional expression profiles induced by ZnO NPs were also investigated to ascertain novel genomic responses related to their specific toxicity pathway. Zebrafish embryos were exposed to 0.01, 0.1, 1, and 10 mg/L ZnO NPs for 96 h post-fertilization. The toxicity of ZnO NPs, based on their Zn concentration, was quite similar to that in embryonic/larval zebrafish exposed to corresponding ZnSO4 concentrations. Pericardial edema and yolk-sac edema were the principal malformations induced by ZnO NPs. Gene-expression profiling using microarrays demonstrated 689 genes that were differentially regulated (fold change >1.5) following exposure to ZnO NPs (498 upregulated, 191 downregulated). Several genes that were differentially regulated following ZnO NP exposure shared similar biological pathways with those observed with ZnSO4 exposure, but six genes (aicda, cyb5d1, edar, intl2, ogfrl2 and tnfsf13b) associated with inflammation and the immune system responded specifically to ZnO NPs (either in the opposite direction or were unchanged in ZnSO4 exposure). Real-time reverse-transcription quantitative polymerase chain reaction confirmed that the responses of these genes to ZnO NPs were significantly different from their response to ZnSO4 exposure. ZnO NPs may affect genes related to inflammation and the immune system, resulting in yolk-sac edema and pericardia edema in embryonic/larval developmental stages. These results will assist in elucidating the mechanisms of toxicity of ZnO NPs during development of zebrafish. PMID:27504894

Longitudinal stability of social competence indicators in a Portuguese sample: Q-sort profiles of social competence, measures of social engagement, and peer sociometric acceptance.

PubMed

Santos, António J; Vaughn, Brian E; Peceguina, Inês; Daniel, João R

2014-03-01

This study examines the temporal stability (over 3 years) of individual differences in 3 domains relevant to preschool children's social competence: social engagement/motivation, profiles of behavior and personality attributes characteristic of socially competent young children, and peer acceptance. Each domain was measured with multiple indicators. Sociometric status categories (Asher & Dodge, 1986) and reciprocated friendships were derived from sociometric data. Composites for social competence domains were significantly associated across all time points. Within age-periods, social competence domains were associated with both sociometric and friendship status categories; however, neither sociometric status nor reciprocated friendships were stable over time. Nevertheless, analyses examining the social competence antecedents to reciprocated friendship at age-4 and age-5 suggested that more socially competent children in the prior year were more likely to have a reciprocated friendship in the current year. Popular and rejected sociometric status categories were also associated with social competence indicators in prior years, but this was most clearly seen at age-5. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Bridging the gap between high-throughput genetic and transcriptional data reveals cellular pathways responding to alpha-synuclein toxicity

PubMed Central

Yeger-Lotem, Esti; Riva, Laura; Su, Linhui Julie; Gitler, Aaron D.; Cashikar, Anil; King, Oliver D.; Auluck, Pavan K.; Geddie, Melissa L.; Valastyan, Julie S.; Karger, David R.; Lindquist, Susan; Fraenkel, Ernest

2009-01-01

Cells respond to stimuli by changes in various processes, including signaling pathways and gene expression. Efforts to identify components of these responses increasingly depend on mRNA profiling and genetic library screens, yet the functional roles of the genes identified by these assays often remain enigmatic. By comparing the results of these two assays across various cellular responses, we found that they are consistently distinct. Moreover, genetic screens tend to identify response regulators, while mRNA profiling frequently detects metabolic responses. We developed an integrative approach that bridges the gap between these data using known molecular interactions, thus highlighting major response pathways. We harnessed this approach to reveal cellular pathways related to alpha-synuclein, a small lipid-binding protein implicated in several neurodegenerative disorders including Parkinson disease. For this we screened an established yeast model for alpha-synuclein toxicity to identify genes that when overexpressed alter cellular survival. Application of our algorithm to these data and data from mRNA profiling provided functional explanations for many of these genes and revealed novel relations between alpha-synuclein toxicity and basic cellular pathways. PMID:19234470

Preclinical evaluations of norcantharidin-loaded intravenous lipid microspheres with low toxicity.

PubMed

Lin, Xia; Zhang, Bo; Zhang, Keru; Zhang, Yu; Wang, Juan; Qi, Na; Yang, Shenshen; He, Haibing; Tang, Xing

2012-12-01

The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM). Pharmacokinetics, biodistribution, antitumor efficacy and drug safety assessment (including acute toxicity, subchronic toxicity, hemolysis testing, intravenous stimulation and injection anaphylaxis) of NLM were carried out in comparison with the commercial product disodium norcantharidate injection (NI). The pharmacokinetics of NLM in rats was similar to that of NI, and a non-linear correlation was observed between AUC and dose. A comparable antitumor efficacy of NLM and NI was observed in mice inoculated with A549, BEL7402 and BCAP-37 cell lines. It was worth noting that the NLM produced a lower drug concentration in heart compared with NI, and significantly reduced the cardiac and renal toxicity. The LD(50) of NLM was twice higher than that of NI. In NLM, over 80% of NCTD was loaded in the lipid phase or bound with phospholipids. Thus, NCTD was sequestered by direct contacting with body fluids and largely avoided distribution into tissues, consequently leading to significantly reduced cardiac and renal toxicity. These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.

A Human Mixture Risk Assessment for Neurodevelopmental Toxicity Associated with Polybrominated Diphenyl Ethers Used as Flame Retardants

PubMed Central

Martin, Olwenn V.; Evans, Richard M.; Faust, Michael

2017-01-01

Background: The European Food Safety Authority recently concluded that the exposure of small children (1–3 y old) to brominated diphenyl ether (BDE)-99 may exceed acceptable levels defined in relation to neurodevelopmental toxicity in rodents. The flame retardant BDE-209 may release BDE-99 and other lower brominated BDEs through biotic and abiotic degradation, and all age groups are exposed not only to BDE-209 and -99 but also to a cocktail of BDE congeners with evidence of neurodevelopmental toxicity. The possible risks from combined exposures to these substances have not been evaluated. Objectives: We performed a congener-specific mixture risk assessment (MRA) of human exposure to combinations of BDE-209 and other BDEs based on estimated exposures via diet and dust intake and on measured levels in biologic samples. Methods: We employed the Hazard Index (HI) method by using BDE congener-specific reference doses for neurodevelopmental toxicity. Results: Our HI analysis suggests that combined exposures to polybrominated diphenyl ethers (PBDEs) may exceed acceptable levels in breastfeeding infants (0–3 mo old) and in small children (1–3 y old), even for moderate (vs. high) exposure scenarios. Our estimates also suggest that acceptable levels of combined PBDEs may be exceeded in adults whose diets are high in fish. Small children had the highest combined exposures, with some estimated body burdens that were similar to body burdens associated with developmental neurotoxicity in rodents. Conclusions: Our estimates corroborate reports from several recent epidemiological studies of associations between PBDE exposures and neurobehavioral outcomes, and they support the inclusion of BDE-209 in the persistent organic pollutant (POP) convention as well as the need for strategies to reduce exposures to PBDE mixtures, including maximum residue limits for PBDEs in food and measures for limiting the release of PBDEs from consumer waste. https://doi.org/10.1289/EHP826 PMID

The role of surface chemistry in the cytotoxicity profile of graphene.

PubMed

Majeed, Waqar; Bourdo, Shawn; Petibone, Dayton M; Saini, Viney; Vang, Kieng Bao; Nima, Zeid A; Alghazali, Karrer M; Darrigues, Emilie; Ghosh, Anindya; Watanabe, Fumiya; Casciano, Daniel; Ali, Syed F; Biris, Alexandru S

2017-04-01

Graphene and its derivative, because of their unique physical, electrical and chemical properties, are an important class of nanomaterials being proposed as foundational materials in nanomedicine as well as for a variety of industrial applications. A major limitation for graphene, when used in biomedical applications, is its poor solubility due to its rather hydrophobic nature. Therefore, chemical functionalities are commonly introduced to alter both its surface chemistry and biochemical activity. Here, we show that surface chemistry plays a major role in the toxicological profile of the graphene structures. To demonstrate this, we chemically increased the oxidation level of the pristine graphene and compared the corresponding toxicological effects along with those for the graphene oxide. X-ray photoelectron spectroscopy revealed that pristine graphene had the lowest amount of surface oxygen, while graphene oxide had the highest at 2.5% and 31%, respectively. Low and high oxygen functionalized graphene samples were found to have 6.6% and 24% surface oxygen, respectively. Our results showed a dose-dependent trend in the cytotoxicity profile, where pristine graphene was the most cytotoxic, with decreasing toxicity observed with increasing oxygen content. Increased surface oxygen also played a role in nanomaterial dispersion in water or cell culture medium over longer periods. It is likely that higher dispersity might result in graphene entering into cells as individual flakes ~1 nm thick rather than as more cytotoxic aggregates. In conclusion, changes in graphene's surface chemistry resulted in altered solubility and toxicity, suggesting that a generalized toxicity profile would be rather misleading. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Interspecies quantitative structure-activity relationships (QSARs) for eco-toxicity screening of chemicals: the role of physicochemical properties.

PubMed

Furuhama, A; Hasunuma, K; Aoki, Y

2015-01-01

In addition to molecular structure profiles, descriptors based on physicochemical properties are useful for explaining the eco-toxicities of chemicals. In a previous study we reported that a criterion based on the difference between the partition coefficient (log POW) and distribution coefficient (log D) values of chemicals enabled us to identify aromatic amines and phenols for which interspecies relationships with strong correlations could be developed for fish-daphnid and algal-daphnid toxicities. The chemicals that met the log D-based criterion were expected to have similar toxicity mechanisms (related to membrane penetration). Here, we investigated the applicability of log D-based criteria to the eco-toxicity of other kinds of chemicals, including aliphatic compounds. At pH 10, use of a log POW - log D > 0 criterion and omission of outliers resulted in the selection of more than 100 chemicals whose acute fish toxicities or algal growth inhibition toxicities were almost equal to their acute daphnid toxicities. The advantage of log D-based criteria is that they allow for simple, rapid screening and prioritizing of chemicals. However, inorganic molecules and chemicals containing certain structural elements cannot be evaluated, because calculated log D values are unavailable.

Flow Line, Durafill VS, and Dycal toxicity to dental pulp cells: effects of growth factors

PubMed Central

Furey, Alyssa; Hjelmhaug, Julie; Lobner, Doug

2010-01-01

Introduction The objective was to determine the effects of growth factor treatment on dental pulp cell sensitivity to toxicity of two composite restoration materials, Flow Line and Durafill VS, and a calcium hydroxide pulp capping material, Dycal. Methods Toxicity of the dental materials to cultures of primary dental pulp cells was determined by the MTT metabolism assay. The ability of six different growth factors to influence the toxicity was tested. Results A 24 hour exposure to either Flow Line or Durafill VS caused approximately 40% cell death, while Dycal exposure caused approximately 80% cell death. The toxicity of Flow Line and Durafill VS was mediated by oxidative stress. Four of the growth factors tested (BMP-2, BMP-7, EGF, and TGF-β) decreased the basal MTT values while making the cells resistant to Flow Line and Durafill VS toxicity, except BMP-2 which made the cells more sensitive to Flow Line. Treatment with FGF-2 caused no change in basal MTT metabolism, prevented the toxicity of Durafill VS, but increased the toxicity of Flow Line. Treatment with IGF-I increased basal MTT metabolism and made the cells resistant to Flow Line and Durafill VS toxicity. None of the growth factors made the cells resistant to Dycal toxicity. Conclusions The results indicate that growth factors can be used to alter the sensitivity of dental pulp cells to commonly used restoration materials. The growth factors BMP-7, EGF, TGF-β, and IGF-I provided the best profile of effects, making the cells resistant to both Flow Line and Durafill VS toxicity. PMID:20630288

Toxicity testing of polymer materials for dialysis equipment: reconsidering in vivo testing.

PubMed

Sauer, U G; Liebsch, M; Kolar, R

2000-01-01

In fulfilment of the aims of the European Union Biocidal Directive (Directive 98/8/EC), Technical Guidance Documents are currently being compiled. Part I of these Technical Guidance Documents covers data requirements for active substances and biocidal products. The Three Rs principle has been applied in certain parts of the toxicity and ecotoxicity testing scheme for pesticides, such as testing for acute oral toxicity, skin and eye irritation, skin sensitisation, and dermal absorption. Further recommendations on how to proceed with regard to the continuing replacement, reduction and refinement of animal experiments in this field of regulatory testing are included for consideration. In this context, besides stressing the necessity to validate and accept further alternatives, emphasis is placed on providing the possibility of waiving unnecessary tests and on the continuous evaluation of whether certain tests are needed at all. 2000 FRAME.

Wind velocity profile reconstruction from intensity fluctuations of a plane wave propagating in a turbulent atmosphere.

PubMed

Banakh, V A; Marakasov, D A

2007-08-01

Reconstruction of a wind profile based on the statistics of plane-wave intensity fluctuations in a turbulent atmosphere is considered. The algorithm for wind profile retrieval from the spatiotemporal spectrum of plane-wave weak intensity fluctuations is described, and the results of end-to-end computer experiments on wind profiling based on the developed algorithm are presented. It is shown that the reconstructing algorithm allows retrieval of a wind profile from turbulent plane-wave intensity fluctuations with acceptable accuracy.

A MicroRNA-Mediated Insulin Signaling Pathway Regulates the Toxicity of Multi-Walled Carbon Nanotubes in Nematode Caenorhabditis elegans

NASA Astrophysics Data System (ADS)

Zhao, Yunli; Yang, Junnian; Wang, Dayong

2016-03-01

The underlying mechanisms for functions of microRNAs (miRNAs) in regulating toxicity of nanomaterials are largely unclear. Using Illumina HiSeqTM 2000 sequencing technique, we obtained the dysregulated mRNA profiling in multi-walled carbon nanotubes (MWCNTs) exposed nematodes. Some dysregulated genes encode insulin signaling pathway. Genetic experiments confirmed the functions of these dysregulated genes in regulating MWCNTs toxicity. In the insulin signaling pathway, DAF-2/insulin receptor regulated MWCNTs toxicity by suppressing function of DAF-16/FOXO transcription factor. Moreover, we raised a miRNAs-mRNAs network involved in the control of MWCNTs toxicity. In this network, mir-355 might regulate MWCNTs toxicity by inhibiting functions of its targeted gene of daf-2, suggesting that mir-355 may regulate functions of the entire insulin signaling pathway by acting as an upregulator of DAF-2, the initiator of insulin signaling pathway, in MWCNTs exposed nematodes. Our results provides highlight on understanding the crucial role of miRNAs in regulating toxicity of nanomaterials in organisms.

20170921 - Development of an acute oral toxicity dataset to facilitate assessment of existing QSARs and development of new models (ASCCT)

EPA Science Inventory

Assessment of the acute toxic potential of a substance is necessary to determine the adverse effects that might occur following accidental or deliberate short-term exposure. There are no accepted in vitro approaches available and few in silico models. Until recently, there had be...

Nrf2-dependent protection against acute sodium arsenite toxicity in zebrafish

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fuse, Yuji; Nguyen, Vu Thanh; Kobayashi, Makoto, E

Transcription factor Nrf2 induces a number of detoxifying enzymes and antioxidant proteins to confer protection against the toxic effects of a diverse range of chemicals including inorganic arsenicals. Although a number of studies using cultured cells have demonstrated that Nrf2 has a cell-protective function against acute and high-dose arsenic toxicity, there is no clear in vivo evidence of this effect. In the present study, we genetically investigated the protective role of Nrf2 against acute sodium arsenite toxicity using the zebrafish Nrf2 mutant, nrf2a{sup fh318}. After treatment with 1 mM sodium arsenite, the survival of nrf2a{sup fh318} larvae was significantly shortermore » than that of wild-type siblings, suggesting that Nrf2 protected the zebrafish larvae against high-dose arsenite exposure. To understand the molecular basis of the Nrf2-dependent protection, we analyzed the gene expression profiles after arsenite exposure, and found that the genes involved in the antioxidative function (prdx1 and gclc), arsenic metabolism (gstp1) and xenobiotic elimination (abcc2) were induced in an Nrf2-dependent manner. Furthermore, pre-treatment with sulforaphane, a well-known Nrf2 activator improved the survival of zebrafish larvae after arsenic exposure. Based on these results, we concluded that Nrf2 plays a fundamental and conserved role in protection against acute sodium arsenite toxicity. - Highlights: • The role of Nrf2 under arsenite exposure was valuated using zebrafish. • Nrf2 mutant zebrafish was highly sensitive to acute arsenic toxicity. • Nrf2 induced anti-arsenic genes in response to arsenite. • Sulforaphane attenuated arsenic toxicity through Nrf2 activation. • Nrf2 system plays an important role in the defense against acute arsenic toxicity.« less

Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity.

PubMed

Hahn, Roberta Zilles; Antunes, Marina Venzon; Verza, Simone Gasparin; Perassolo, Magda Susana; Suyenaga, Edna Sayuri; Schwartsmann, Gilberto; Linden, Rafael

2018-06-22

Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient's body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of complex sampling for the clinical use of limited sampling and population pharmacokinetic models for IRI doses individualization. Copyright

In acceptance we trust? Conceptualising acceptance as a viable approach to NGO security management.

PubMed

Fast, Larissa A; Freeman, C Faith; O'Neill, Michael; Rowley, Elizabeth

2013-04-01

This paper documents current understanding of acceptance as a security management approach and explores issues and challenges non-governmental organisations (NGOs) confront when implementing an acceptance approach to security management. It argues that the failure of organisations to systematise and clearly articulate acceptance as a distinct security management approach and a lack of organisational policies and procedures concerning acceptance hinder its efficacy as a security management approach. The paper identifies key and cross-cutting components of acceptance that are critical to its effective implementation in order to advance a comprehensive and systematic concept of acceptance. The key components of acceptance illustrate how organisational and staff functions affect positively or negatively an organisation's acceptance, and include: an organisation's principles and mission, communications, negotiation, programming, relationships and networks, stakeholder and context analysis, staffing, and image. The paper contends that acceptance is linked not only to good programming, but also to overall organisational management and structures. © 2013 The Author(s). Journal compilation © Overseas Development Institute, 2013.

Zeaxanthin: Review of Toxicological Data and Acceptable Daily Intake

PubMed Central

Edwards, James A.

2016-01-01

Zeaxanthin is a nutritional carotenoid with a considerable amount of safety data based on regulatory studies, which form the basis of its safety evaluation. Subchronic OECD guideline studies with mice and rats receiving beadlet formulations of high purity synthetic zeaxanthin in the diet at dosages up to 1000 mg/kg body weight (bw)/day, and in dogs at over 400 mg/kg bw/day, produced no adverse effects or histopathological changes. In developmental toxicity studies, there was no evidence of fetal toxicity or teratogenicity in rats or rabbits at dosages up to 1000 or 400 mg/kg bw/day, respectively. Formulated zeaxanthin was not mutagenic or clastogenic in a series of in vitro and in vivo tests for genotoxicity. A 52-week chronic oral study in Cynomolgus monkeys at doses of 0.2 and 20 mg/kg bw/day, mainly designed to assess accumulation and effects in primate eyes, showed no adverse effects. In a rat two-generation study, the NOAEL was 150 mg/kg bw/day. In 2012, this dosage was used by EFSA (NDA Panel), in association with a 200-fold safety factor, to propose an Acceptable Daily Intake equivalent to 53 mg/day for a 70 kg adult. The requested use level of 2 mg/day was ratified by the EU Commission. PMID:26885380

ToxCast Profiling in a Human Stem Cell Assay for Developmental Toxicity (CompTox CoP)

EPA Science Inventory

Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are...

Applications of high throughput screening to identify profiles of biological activity relevant to carcinogenesis

EPA Science Inventory

ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry and bioactivity profiling to predict potential for toxicity and prioritize limited testing resources (www.epa.gov/toc...

Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Socała, Katarzyna, E-mail: ksocala@op.pl

Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. Inmore » addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD{sub 50} value of sulforaphane in mice was estimated at 212.67 mg/kg, while the TD{sub 50} value – at 191.58 mg/kg. In seizure tests, sulforaphane at the highest dose tested (200 mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6 Hz-induced psychomotor seizure. At doses of 10–200 mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100 mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150–300 mg/kg), hypothermia (at 150–300 mg/kg), impairment of motor coordination (at 200–300 mg/kg), decrease in skeletal muscle strength (at 250–300 mg/kg), and deaths (at 200–300 mg/kg). Moreover, blood analysis showed

Toxicity of fluoride to aquatic species and evaluation of toxicity modifying factors.

PubMed

Pearcy, Krysta; Elphick, James; Burnett-Seidel, Charlene

2015-07-01

The present study was performed to investigate the toxicity of fluoride to a variety of freshwater aquatic organisms and to establish whether water quality variables contribute substantively to modifying its toxicity. Water hardness, chloride, and alkalinity were tested as possible toxicity modifying factors for fluoride using acute toxicity tests with Hyalella azteca and Oncorhynchus mykiss. Chloride appeared to be the major toxicity modifying factor for fluoride in these acute toxicity tests. The chronic toxicity of fluoride was evaluated with a variety of species, including 3 fish (Pimephales promelas, O. mykiss, and Salvelinus namaycush), 3 invertebrates (Ceriodaphnia dubia, H. azteca, and Chironomus dilutus), 1 plant (Lemna minor), and 1 alga (Pseudokirchneriella subcapitata). Hyalella azteca was the most sensitive species overall, and O. mykiss was the most sensitive species of fish. The role of chloride as a toxicity modifying factor was inconsistent between species in the chronic toxicity tests. © 2015 SETAC.

Emerging toxicities in the treatment of non-small cell lung cancer: ocular disorders.

PubMed

Agustoni, Francesco; Platania, Marco; Vitali, Milena; Zilembo, Nicoletta; Haspinger, Eva; Sinno, Valentina; Gallucci, Rosaria; de Braud, Filippo; Garassino, Marina Chiara

2014-02-01

The treatment of advanced disease (stage IIIb and IV) of non-small cell lung cancer (NSCLC) is based on systemic treatment with platinum-based chemotherapy or biological compounds depending on the disease molecular profile. In the last few years, intensive investigational efforts in anticancer therapy have led to the registration of new active chemotherapeutic agents, combination regimens, and biological drugs, expanding choices for customizing individual treatment. However, the introduction of new drugs in the clinical setting has led to several new toxicities, creating some difficulties in daily management. Among these, ocular toxicity is generally overlooked as more common toxicities such as myelosuppression, stomatitis, diarrhea, vomiting, "hand-foot syndrome", and neurological alterations attract greater attention. Ophthalmic complications from cytotoxic chemotherapeutics are rare, transient, and of mild/moderate intensity but irreversible acute disorders are possible. The best way to prevent potential irreversible visual complications is an awareness of the potential for ocular toxicity because dose reductions or early drug cessation can prevent serious ocular complications in the majority of cases. However, given the novelty of many therapeutic agents and the complexity of ocular pathology, oncologists may be unfamiliar with these adverse effects of anticancer therapy. Although toxicities from chemotherapy are generally intense but short lasting, toxicities related to targeted drugs are often milder but longer lasting and can persist throughout treatment. Here we review the principal clinical presentations of ocular toxicity arising from chemotherapy [1-3], target therapies [4], and newly developed drugs and provide some recommendations for monitoring and management of ocular toxicity. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

PROFILE OF TOXIC RESPONSE TO SEDIMENTS USING WHOLE-ANIMAL AND IN VITRO SUBMITOCHONDRIAL PARTICLE (SMP) ASSAYS

EPA Science Inventory

A rapid bioassy for monitoring acute toxicity of wastewater, ground water, and soil and sediment extracts using submitochondrial particles (SMP) has been developed. The assay utilizes the mitochondrial electron transfer enzyme complex present in all eukaryotic cells. Prior develo...

Potentially-toxic and essential elements profile of AH1N1 patients in Mexico City

PubMed Central

Moya, Mireya; Bautista, Edgar G.; Velázquez-González, Antonio; Vázquez-Gutiérrez, Felipe; Tzintzun, Guadalupe; García-Arreola, María Elena; Castillejos, Manuel; Hernández, Andrés

2013-01-01

During spring of 2009, a new influenza virus AH1N1 spread in the world causing acute respiratory illness and death, resulting in the first influenza pandemic since 1968. Blood levels of potentially-toxic and essential elements of 40 pneumonia and confirmed AH1N1 were evaluated against two different groups of controls, both not infected with the pandemic strain. Significant concentrations of potentially-toxic elements (lead, mercury, cadmium, chromium, arsenic) along with deficiency of selenium or increased Zn/Cu ratios characterized AH1N1 cases under study when evaluated versus controlled cases. Deficiency of selenium is progressively observed from controls I (influenza like illness) through controls II (pneumonia) and finally pneumonia -AH1N1 infected patients. Cases with blood Se levels greater than the recommended for an optimal cut-off to activate glutathione peroxidase (12.5 μg/dL) recovered from illness and survived. Evaluation of this essential element in critical pneumonia patients at the National Institutes is under evaluation as a clinical trial. PMID:23422930

Raman Spectra and Cross Sections of Ammonia, Chlorine, Hydrogen Sulfide, Phosgene, and Sulfur Dioxide Toxic Gases in the Fingerprint Region 400-1400 cm-1

DTIC Science & Technology

2016-02-11

AIP ADVANCES 6, 025310 (2016) Raman spectra and cross sections of ammonia , chlorine, hydrogen sulfide, phosgene, and sulfur dioxide toxic gases in...Received 10 December 2015; accepted 3 February 2016; published online 11 February 2016) Raman spectra of ammonia (NH3), chlorine (Cl2), hydrogen...and cross sections of ammonia (NH3), chlorine (Cl2), hydrogen sulfide (H2S), phosgene (CCl2O), and sulfur dioxide (SO2) toxic gases in the fingerprint

Enzymatic redox properties of novel nitrotriazole explosives implications for their toxicity.

PubMed

Sarlauskas, Jonas; Nemeikaite-Ceniene, Ausra; Anusevicius, Zilvinas; Miseviciene, Lina; Maroziene, Audrone; Markevicius, Arvydas; Cenas, Narimantas

2004-01-01

The toxicity of conventional nitroaromatic explosives like 2,4,6-trinitrotoluene (TNT) is caused by their enzymatic free radical formation with the subsequent oxidative stress, the formation of alkylating nitroso and/or hydroxylamino metabolites, and oxyhemoglobin oxidation into methemoglobin. In order to get an insight into the mechanisms of toxicity of the novel explosives NTO (5-nitro-1,2,4-triazol-3-one) and ANTA (5-nitro-1,2,4-triazol-3-amine), we examined their reactions with the single-electron transferring flavoenzymes NADPH: cytochrome P-450 reductase and ferredoxin:NADP+ reductase, two-electron transferring flavoenzymes mammalian NAD(P)H:quinone oxidoreductase (DT-diaphorase), and Enterobacter cloacae NAD(P)H:nitroreductase, and their reactions with oxyhemoglobin. The reactivity of NTO and ANTA in the above reactions was markedly lower than that of TNT. The toxicity of NTO and ANTA in bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK) was partly prevented by desferrioxamine and the antioxidant N,N'-diphenyl-p-phenylene diamine, and potentiated by 1,3-bis-(2-chloroethyl)-1-nitrosourea. This points to the involvement of oxidative stress in their cytotoxicity, presumably to the redox cycling of free radicals. The FLK cell line cytotoxicity and the methemoglobin formation in isolated human erythrocytes of NTO and ANTA were also markedly lower than those of TNT, and similar to those of nitrobenzene. Taken together, our data demonstrate that the low toxicity of nitrotriazole explosives may be attributed to their low electron-accepting properties.

Measuring financial toxicity as a clinically relevant patient-reported outcome: The validation of the COmprehensive Score for financial Toxicity (COST).

PubMed

de Souza, Jonas A; Yap, Bonnie J; Wroblewski, Kristen; Blinder, Victoria; Araújo, Fabiana S; Hlubocky, Fay J; Nicholas, Lauren H; O'Connor, Jeremy M; Brockstein, Bruce; Ratain, Mark J; Daugherty, Christopher K; Cella, David

2017-02-01

Cancer and its treatment lead to increased financial distress for patients. To the authors' knowledge, to date, no standardized patient-reported outcome measure has been validated to assess this distress. Patients with AJCC Stage IV solid tumors receiving chemotherapy for at least 2 months were recruited. Financial toxicity was measured by the COmprehensive Score for financial Toxicity (COST) measure. The authors collected data regarding patient characteristics, clinical trial participation, health care use, willingness to discuss costs, psychological distress (Brief Profile of Mood States [POMS]), and health-related quality of life (HRQOL) as measured by the Functional Assessment of Cancer Therapy: General (FACT-G) and the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaires. Test-retest reliability, internal consistency, and validity of the COST measure were assessed using standard-scale construction techniques. Associations between the resulting factors and other variables were assessed using multivariable analyses. A total of 375 patients with advanced cancer were approached, 233 of whom (62.1%) agreed to participate. The COST measure demonstrated high internal consistency and test-retest reliability. Factor analyses revealed a coherent, single, latent variable (financial toxicity). COST values were found to be correlated with income (correlation coefficient [r] = 0.28; P<.001), psychosocial distress (r = -0.26; P<.001), and HRQOL, as measured by the FACT-G (r = 0.42; P<.001) and by the EORTC QOL instruments (r = 0.33; P<.001). Independent factors found to be associated with financial toxicity were race (P = .04), employment status (P<.001), income (P = .003), number of inpatient admissions (P = .01), and psychological distress (P = .003). Willingness to discuss costs was not found to be associated with the degree of financial distress (P = .49). The COST measure demonstrated reliability and

Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.

PubMed

Viluksela, Matti; Heikkinen, Päivi; van der Ven, Leo T M; Rendel, Filip; Roos, Robert; Esteban, Javier; Korkalainen, Merja; Lensu, Sanna; Miettinen, Hanna M; Savolainen, Kari; Sankari, Satu; Lilienthal, Hellmuth; Adamsson, Annika; Toppari, Jorma; Herlin, Maria; Finnilä, Mikko; Tuukkanen, Juha; Leslie, Heather A; Hamers, Timo; Hamscher, Gerd; Al-Anati, Lauy; Stenius, Ulla; Dervola, Kine-Susann; Bogen, Inger-Lise; Fonnum, Frode; Andersson, Patrik L; Schrenk, Dieter; Halldin, Krister; Håkansson, Helen

2014-01-01

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological

Transcriptomic and physiological analysis of common duckweed Lemna minor responses to NH4(+) toxicity.

PubMed

Wang, Wenguo; Li, Rui; Zhu, Qili; Tang, Xiaoyu; Zhao, Qi

2016-04-18

Plants can suffer ammonium (NH4 (+)) toxicity, particularly when NH4 (+) is supplied as the sole nitrogen source. However, our knowledge about the underlying mechanisms of NH4 (+) toxicity is still largely unknown. Lemna minor, a model duckweed species, can grow well in high NH4 (+) environment but to some extent can also suffer toxic effects. The transcriptomic and physiological analysis of L. minor responding to high NH4 (+) may provide us some interesting and useful information not only in toxic processes, but also in tolerance mechanisms. The L. minor cultured in the Hoagland solution were used as the control (NC), and in two NH4 (+) concentrations (NH4 (+) was the sole nitrogen source), 84 mg/L (A84) and 840 mg/L (A840) were used as stress treatments. The NH4 (+) toxicity could inhibit the growth of L. minor. Reactive oxygen species (ROS) and cell death were studied using stained fronds under toxic levels of NH4 (+). The malondialdehyde content and the activities of superoxide dismutase and peroxidase increased from NC to A840, rather than catalase and ascorbate peroxidase. A total of 6.62G nucleotides were generated from the three distinct libraries. A total of 14,207 differentially expressed genes (DEGs) among 70,728 unigenes were obtained. All the DEGs could be clustered into 7 profiles. Most DEGs were down-regulated under NH4 (+) toxicity. The genes required for lignin biosynthesis in phenylpropanoid biosynthesis pathway were up-regulated. ROS oxidative-related genes and programmed cell death (PCD)-related genes were also analyzed and indicated oxidative damage and PCD occurring under NH4 (+) toxicity. The first large transcriptome study in L. minor responses to NH4 (+) toxicity was reported in this work. NH4 (+) toxicity could induce ROS accumulation that causes oxidative damage and thus induce cell death in L. minor. The antioxidant enzyme system was activated under NH4 (+) toxicity for ROS scavenging. The phenylpropanoid pathway was stimulated under

Galleria mellonella larvae allow the discrimination of toxic and non-toxic chemicals.

PubMed

Allegra, Enrico; Titball, Richard W; Carter, John; Champion, Olivia L

2018-05-01

The acute toxicities of 19 chemicals were assessed using G. mellonella larvae. The results obtained were compared against LD50 values derived from in vitro cytotoxicity tests and against in vivo acute oral LD50 values. In general, cell culture systems overestimated the toxicity of chemicals, especially low toxicity chemicals. In contrast, toxicity testing in G. mellonella larvae was found to be a reliable predictor for low toxicity chemicals. For the 9 chemicals tested which were assigned to Globally Harmonised System (GHS) category 5, the toxicity measured in G. mellonella larvae was consistent with their GHS categorisation but cytotoxicity measured in 3T3 or NHK cells predicted 4 out of 9 chemicals as having low toxicity. A more robust assessment of the likely toxicity of chemicals in mammals could be made by taking into account their toxicities in both cell cultures and in G. mellonella larvae. Copyright © 2018 Elsevier Ltd. All rights reserved.

Toxic Warfare

DTIC Science & Technology

2002-02-01

Prepared for the United States Air Force Approved for public release; distribution unlimited Theodore Karasik Project AIR FORCE R TOXIC WARFARE...Report Documentation Page Report Date 000002002 Report Type N/A Dates Covered (from... to) - Title and Subtitle Toxic Warfare Contract Number Grant...310) 451-6915; Email: order@rand.org Library of Congress Cataloging-in-Publication Data Karasik, Theodore William. Toxic warfare / Theodore Karasik

DETECTION OF TOXICANT(S) ON BUILDING SURFACES FOLLOWING CHEMICAL ATTACK

EPA Science Inventory

A critical step prior to reoccupation of any facility following a chemical attack is monitoring for toxic compounds on surfaces within that facility. Low level detection of toxicant(s) is necessary to ensure that these compounds have been eliminated after building decontaminatio...

Multiple-sip temporal dominance of sensations associated with acceptance test: a study on special beers.

PubMed

Corrêa Simioni, Síntia Carla; Ribeiro, Michele Nayara; de Souza, Vanessa Rios; Nunes, Cleiton Antônio; Pinheiro, Ana Carla Marques

2018-03-01

In this study, we proposed the use of a multiple-sip temporal dominance of sensations (TDS) test alongside with an acceptance test over repeated consumption for the analysis of special beers, with the aim of contributing to a deeper understanding of consumer behavior regarding temporal descriptions and sensory acceptance. Consumers of special beers sequentially evaluated six sips of a particular type of beer by TDS analysis and an acceptance test was performed for each sip. Four different kinds of specialty beers were evaluated [Bohemian Pilsner (BP), Witbier (WB), Belgian Strong Ale Dubbel (BD), and Russian Imperial Stout (RS)]. In general, the descriptive profile of beers varied temporally, i.e., there was an increased dominance of bitterness and a decreased dominance of fruity, floral, toffee, and coffee attributes. Concurrently, a reduction in sensory acceptance with an increased number of sips, especially the last sip, was observed in two kinds of beers that possessed a strong flavor, BD and RS. BP and WB presented smooth attributes and low notable characteristics, which could have contributed to the maintenance of the acceptance grades as the number of sips increased. The combination of TDS and acceptance over repeated sips can be useful for obtaining detailed descriptions of products that are closer to real time consumption by consumers, and thus aids in ensuring good product performance once released. The information obtained can also help product development scientists to fine-tune product formulations and ensure acceptability.

Toxicity of seabird guano to sea urchin embryos and interaction with Cu and Pb.

PubMed

Rial, Diego; Santos-Echeandía, Juan; Álvarez-Salgado, Xosé Antón; Jordi, Antoni; Tovar-Sánchez, Antonio; Bellas, Juan

2016-02-01

Guano is an important source of marine-derived nutrients to seabird nesting areas. Seabirds usually present high levels of metals and other contaminants because the bioaccumulation processes and biotic depositions can increase the concentration of pollutants in the receiving environments. The objectives of this study were to investigate: the toxicity of seabird guano and the joint toxicity of guano, Cu and Pb by using the sea urchin embryo-larval bioassay. In a first experiment, aqueous extracts of guano were prepared at two loading rates (0.462 and 1.952 g L(-1)) and toxicity to sea-urchin embryos was tested. Toxicity was low and not dependent of the load of guano used (EC50 0.42 ± 0.03 g L(-1)). Trace metal concentrations were also low either in guano or in aqueous extracts of guano and the toxicity of extracts were apparently related to dissolved organic matter. In a second experiment, the toxicity of Cu-Pb mixtures in artificial seawater and in extracts of guano (at two loadings: 0.015 and 0.073 g L(-1)), was tested. According to individual fittings, Cu added to extracts of guano showed less toxicity than when dissolved in artificial seawater. The response surfaces obtained for mixtures of Cu and Pb in artificial seawater, and in 0.015 g L(-1) and 0.073 g L(-1) of guano, were better described by Independent Action model adapted to describe antagonism, than by the other proposed models. This implied accepting that EC50 for Cu and Pb increased with the load of guano and with a greater interaction for Cu than for Pb. Copyright © 2015 Elsevier Ltd. All rights reserved.

Carbonyl emission and toxicity profile of diesel blends with an animal-fat biodiesel and a tire pyrolysis liquid fuel.

PubMed

Ballesteros, R; Guillén-Flores, J; Martínez, J D

2014-02-01

In this paper, two diesel fuels, an animal-fat biodiesel and two diesel blends with the animal-fat biodiesel (50vol.%) and with a tire pyrolysis liquid (TPL) fuel (5vol.%) have been tested in a 4-cylinder, 4-stroke, turbocharged, intercooled, 2.0L Nissan diesel automotive engine (model M1D) with common-rail injection system and diesel oxidation catalyst (DOC). Carbonyl emissions have been analyzed both before and after DOC and specific reactivity of carbonyl profile has been calculated. Carbonyl sampling was carried out by means of a heated line, trapping the gas in 2,4-DNPH cartridges. The eluted content was then analyzed in an HPLC system, with UV-VIS detection. Results showed, on the one hand, an increase in carbonyl emissions with the biodiesel fraction in the fuel. On the other hand, the addition of TPL to diesel also increased carbonyl emissions. These trends were occasionally different if the emissions were studied after the DOC, as it seems to be selectivity during the oxidation process. The specific reactivity was also studied, finding a decrease with the oxygen content within the fuel molecule, although the equivalent ozone emissions slightly increased with the oxygen content. Finally, the emissions toxicity was also studied, comparing them to different parameters defined by different organizations. Depending on the point of study, emissions were above or below the established limits, although acrolein exceeded them as it has the least permissive values. Copyright © 2013 Elsevier Ltd. All rights reserved.

Wind profiling based on the optical beam intensity statistics in a turbulent atmosphere.

PubMed

Banakh, Victor A; Marakasov, Dimitrii A

2007-10-01

Reconstruction of the wind profile from the statistics of intensity fluctuations of an optical beam propagating in a turbulent atmosphere is considered. The equations for the spatiotemporal correlation function and the spectrum of weak intensity fluctuations of a Gaussian beam are obtained. The algorithms of wind profile retrieval from the spatiotemporal intensity spectrum are described and the results of end-to-end computer experiments on wind profiling based on the developed algorithms are presented. It is shown that the developed algorithms allow retrieval of the wind profile from the turbulent optical beam intensity fluctuations with acceptable accuracy in many practically feasible laser measurements set up in the atmosphere.

Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays (Communities of Practice)

EPA Science Inventory

Understanding potential health risks is a significant challenge for large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes chemical-target activity profiles of 976 chemicals (including failed pharmaceuticals...

In vitro toxicity analysis of nanoscale aluminum: Particle size and shape effects

NASA Astrophysics Data System (ADS)

Palazuelos Jorganes, Maria

2007-12-01

Nanostructured materials promise to revolutionize many key areas of science and technology. As our ability to manipulate matter at the nanoscale increases, there is a need to assess the effects of these materials on human health and the environment. Materials at the nanoscale are interesting and useful because they possess properties that are different from the equivalent bulk or molecular scale. These same properties can make toxicological profiles very different from those of the same materials on a different scale. There is a rising consensus that toxicity analysis of nanomaterials should start from a thorough physicochemical characterization of the materials under investigation in order to be able to establish a proper correlation between the nanoparticles characteristics and their effects and behavior in physiological environments. This research is a clear example of the necessity of comprehensive studies when investigating the toxicity of nanomaterials. Aluminum nanoparticles are being extensively used for their very unique energetic properties. These materials offer a very promising market that is fostering many startup companies which are expected to consolidate on strong technological positions. Aluminum is generally recognized as a non-toxic material to humans and it is widely used for applications which imply direct human contact. The effect of aluminum nanoparticles in human health is still an unknown. My research consisted of an in vitro toxicity screening of aluminum materials from nano to micron size, including spherical irregularly shaped particles. Several issues relating to size, shape, detection and characterization of nanoparticles in the different environments relevant to in vitro toxicity analysis were addressed and suitable protocols were developed. Lung human epithelial cells were exposed to different concentrations of these materials and the effects were analyzed by means of various toxicity tests. Some of the materials investigated caused

Measuring Acceptance of Sleep Difficulties: The Development of the Sleep Problem Acceptance Questionnaire.

PubMed

Bothelius, Kristoffer; Jernelöv, Susanna; Fredrikson, Mats; McCracken, Lance M; Kaldo, Viktor

2015-11-01

Acceptance may be an important therapeutic process in sleep medicine, but valid psychometric instruments measuring acceptance related to sleep difficulties are lacking. The purpose of this study was to develop a measure of acceptance in insomnia, and to examine its factor structure as well as construct validity. In a cross-sectional design, a principal component analysis for item reduction was conducted on a first sample (A) and a confirmatory factor analysis on a second sample (B). Construct validity was tested on a combined sample (C). Questionnaire items were derived from a measure of acceptance in chronic pain, and data were gathered through screening or available from pretreatment assessments in four insomnia treatment trials, administered online, via bibliotherapy and in primary care. Adults with insomnia: 372 in sample A and 215 in sample B. Sample C (n = 820) included sample A and B with another 233 participants added. Construct validity was assessed through relations with established acceptance and sleep scales. The principal component analysis presented a two-factor solution with eight items, explaining 65.9% of the total variance. The confirmatory factor analysis supported the solution. Acceptance of sleep problems was more closely related to subjective symptoms and consequences of insomnia than to diary description of sleep, or to acceptance of general private events. The Sleep Problem Acceptance Questionnaire (SPAQ), containing the subscales "Activity Engagement" and "Willingness", is a valid tool to assess acceptance of insomnia. © 2015 Associated Professional Sleep Societies, LLC.

Concentration rather than dose defines the local brain toxicity of agents that are effectively distributed by convection-enhanced delivery.

PubMed

Zhang, Rong; Saito, Ryuta; Mano, Yui; Kanamori, Masayuki; Sonoda, Yukihiko; Kumabe, Toshihiro; Tominaga, Teiji

2014-01-30

Convection-enhanced delivery (CED) has been developed as a potentially effective drug-delivery strategy into the central nervous system. In contrast to systemic intravenous administration, local delivery achieves high concentration and prolonged retention in the local tissue, with increased chance of local toxicity, especially with toxic agents such as chemotherapeutic agents. Therefore, the factors that affect local toxicity should be extensively studied. With the assumption that concentration-oriented evaluation of toxicity is important for local CED, we evaluated the appearance of local toxicity among different agents after delivery with CED and studied if it is dose dependent or concentration dependent. Local toxicity profile of chemotherapeutic agents delivered via CED indicates BCNU was dose-dependent, whereas that of ACNU was concentration-dependent. On the other hand, local toxicity for doxorubicin, which is not distributed effectively by CED, was dose-dependent. Local toxicity for PLD, which is extensively distributed by CED, was concentration-dependent. Traditional evaluation of drug induced toxicity was dose-oriented. This is true for systemic intravascular delivery. However, with local CED, toxicity of several drugs exacerbated in concentration-dependent manner. From our study, local toxicity of drugs that are likely to distribute effectively tended to be concentration-dependent. Concentration rather than dose may be more important for the toxicity of agents that are effectively distributed by CED. Concentration-oriented evaluation of toxicity is more important for CED. Copyright © 2013 Elsevier B.V. All rights reserved.

How toxic is coal ash? A laboratory toxicity case study

DOE PAGES

Sherrard, Rick M.; Carriker, Neil; Greeley, Jr., Mark Stephen

2014-12-08

Under a consent agreement among the Environmental Protection Agency (EPA) and proponents both for and against stricter regulation, EPA is to issue a new coal ash disposal rule by the end of 2014. Laboratory toxicity investigations often yield conservative estimates of toxicity because many standard test species are more sensitive than resident species, thus could provide information useful to the rule-making. However, few laboratory studies of coal ash toxicity are available; most studies reported in the literature are based solely on field investigations. In this paper, we describe a broad range of toxicity studies conducted for the Tennessee Valley Authoritymore » (TVA) Kingston ash spill, results of which help provide additional perspective on the toxicity of coal ash.« less

SU-F-T-475: An Evaluation of the Overlap Between the Acceptance Testing and Commissioning Processes for Conventional Medical Linear Accelerators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morrow, A; Rangaraj, D; Perez-Andujar, A

2016-06-15

Purpose: This work’s objective is to determine the overlap of processes, in terms of sub-processes and time, between acceptance testing and commissioning of a conventional medical linear accelerator and to evaluate the time saved by consolidating the two processes. Method: A process map for acceptance testing for medical linear accelerators was created from vendor documentation (Varian and Elekta). Using AAPM TG-106 and inhouse commissioning procedures, a process map was created for commissioning of said accelerators. The time to complete each sub-process in each process map was evaluated. Redundancies in the processes were found and the time spent on each weremore » calculated. Results: Mechanical testing significantly overlaps between the two processes - redundant work here amounts to 9.5 hours. Many beam non-scanning dosimetry tests overlap resulting in another 6 hours of overlap. Beam scanning overlaps somewhat - acceptance tests include evaluating PDDs and multiple profiles but for only one field size while commissioning beam scanning includes multiple field sizes and depths of profiles. This overlap results in another 6 hours of rework. Absolute dosimetry, field outputs, and end to end tests are not done at all in acceptance testing. Finally, all imaging tests done in acceptance are repeated in commissioning, resulting in about 8 hours of rework. The total time overlap between the two processes is about 30 hours. Conclusion: The process mapping done in this study shows that there are no tests done in acceptance testing that are not also recommended to do for commissioning. This results in about 30 hours of redundant work when preparing a conventional linear accelerator for clinical use. Considering these findings in the context of the 5000 linacs in the United states, consolidating acceptance testing and commissioning would have allowed for the treatment of an additional 25000 patients using no additional resources.« less

Low-flow profiles of the Tennessee River tributaries in Georgia

USGS Publications Warehouse

Carter, R.F.; Hopkins, E.H.; Perlman, H.A.

1988-01-01

Low flow information is provided for use in an evaluation of the capacity of streams to permit withdrawals or to accept waste loads without exceeding the limits of State water quality standards. The purpose of this report is to present the results of a compilation of available low flow data in the form of tables and ' 7Q10 flow profiles ' (minimum average flow for 7 consecutive days with a 10-yr recurrence interval) (7Q10 flow plotted against distance along a stream channel) for all stream reaches of the Tennessee River tributaries where sufficient data of acceptable accuracy are available. Drainage area profiles are included for all stream basins larger than 5 sq mi, except for those in a few remote areas. This report is the fifth in a series of reports that will cover all stream basins north of the Fall Line in Georgia. It includes the parts of the Tennessee River basin in Georgia. Flow records were not adjusted for diversions or other factors that cause measured flows to represent other than natural flow conditions. The 7-day minimum flow profile was omitted for stream reaches where natural flow was known to be altered significantly. (Lantz-PTT)

Classification of baseline toxicants for QSAR predictions to replace fish acute toxicity studies.

PubMed

Nendza, Monika; Müller, Martin; Wenzel, Andrea

2017-03-22

Fish acute toxicity studies are required for environmental hazard and risk assessment of chemicals by national and international legislations such as REACH, the regulations of plant protection products and biocidal products, or the GHS (globally harmonised system) for classification and labelling of chemicals. Alternative methods like QSARs (quantitative structure-activity relationships) can replace many ecotoxicity tests. However, complete substitution of in vivo animal tests by in silico methods may not be realistic. For the so-called baseline toxicants, it is possible to predict the fish acute toxicity with sufficient accuracy from log K ow and, hence, valid QSARs can replace in vivo testing. In contrast, excess toxicants and chemicals not reliably classified as baseline toxicants require further in silico, in vitro or in vivo assessments. Thus, the critical task is to discriminate between baseline and excess toxicants. For fish acute toxicity, we derived a scheme based on structural alerts and physicochemical property thresholds to classify chemicals as either baseline toxicants (=predictable by QSARs) or as potential excess toxicants (=not predictable by baseline QSARs). The step-wise approach identifies baseline toxicants (true negatives) in a precautionary way to avoid false negative predictions. Therefore, a certain fraction of false positives can be tolerated, i.e. baseline toxicants without specific effects that may be tested instead of predicted. Application of the classification scheme to a new heterogeneous dataset for diverse fish species results in 40% baseline toxicants, 24% excess toxicants and 36% compounds not classified. Thus, we can conclude that replacing about half of the fish acute toxicity tests by QSAR predictions is realistic to be achieved in the short-term. The long-term goals are classification criteria also for further groups of toxicants and to replace as many in vivo fish acute toxicity tests as possible with valid QSAR

Toxicity of ZnO and TiO2 to Escherichia coli cells

PubMed Central

Leung, Yu Hang; Xu, Xiaoying; Ma, Angel P. Y.; Liu, Fangzhou; Ng, Alan M. C.; Shen, Zhiyong; Gethings, Lee A.; Guo, Mu Yao; Djurišić, Aleksandra B.; Lee, Patrick K. H.; Lee, Hung Kay; Chan, Wai Kin; Leung, Frederick C. C.

2016-01-01

We performed a comprehensive investigation of the toxicity of ZnO and TiO2 nanoparticles using Escherichia coli as a model organism. Both materials are wide band gap n-type semiconductors and they can interact with lipopolysaccharide molecules present in the outer membrane of E. coli, as well as produce reactive oxygen species (ROS) under UV illumination. Despite the similarities in their properties, the response of the bacteria to the two nanomaterials was fundamentally different. When the ROS generation is observed, the toxicity of nanomaterial is commonly attributed to oxidative stress and cell membrane damage caused by lipid peroxidation. However, we found that significant toxicity does not necessarily correlate with up-regulation of ROS-related proteins. TiO2 exhibited significant antibacterial activity, but the protein expression profile of bacteria exposed to TiO2 was different compared to H2O2 and the ROS-related proteins were not strongly expressed. On the other hand, ZnO exhibited lower antibacterial activity compared to TiO2, and the bacterial response involved up-regulating ROS-related proteins similar to the bacterial response to the exposure to H2O2. Reasons for the observed differences in toxicity and bacterial response to the two metal oxides are discussed. PMID:27731373

Toxicity and paralytic shellfish toxin profiles of the xanthid crabs, Lophozozymus pictor and Zosimus aeneus, collected from some Australian coral reefs.

PubMed

Llewellyn, L E; Endean, R

1989-01-01

Purification of toxic aqueous extracts from the xanthid crabs Zosimus aeneus and Lophozozymus pictor, collected from Australian waters, yielded paralytic shelfish toxins, including saxitoxin (STX), neosaxitoxin (neoSTX) and gonyautoxins 1, 2 and 4 (GTX1,2,4). No more than two paralytic shellfish toxins were found in any of the purified extracts from any specimen. Four specimens of Z. aeneus and one specimen of L. pictor each contained more toxic material than the suggested human oral lethal dose. The moult of a specimen of L. pictor was toxic, which may indicate a route in crabs for toxin removal.

Translation of Toxicity Data into CW Agent Toxicity Estimates

DTIC Science & Technology

2003-07-01

UNLIMITED UNCLASSIFIED/UNLIMITEDPrepared by Douglas R. Sommerville, PE US Army ECBC, APG, MD Dependence of Toxic Effect on Exposure Time Inhalation (IH...to longer exposure durations. Toxicity estimates for exposure durations ranging from 2 to 360 minutes have been derived for six agents (GA, GB, GD...individuals having effects greater in severity than the defining effect of the ECTYY Cn T = k Toxic load equation 5 6 Edgewood Chemical Biological Center

The taste of toxicity: A quantitative analysis of bitter and toxic molecules.

PubMed

Nissim, Ido; Dagan-Wiener, Ayana; Niv, Masha Y

2017-12-01

The role of bitter taste-one of the few basic taste modalities-is commonly assumed to signal toxicity and alert animals against consuming harmful compounds. However, it is known that some toxic compounds are not bitter and that many bitter compounds have negligible toxicity while having important health benefits. Here we apply a quantitative analysis of the chemical space to shed light on the bitterness-toxicity relationship. Using the BitterDB dataset of bitter molecules, The BitterPredict prediction tool, and datasets of toxic compounds, we quantify the identity and similarity between bitter and toxic compounds. About 60% of the bitter compounds have documented toxicity and only 56% of the toxic compounds are known or predicted to be bitter. The LD 50 value distributions suggest that most of the bitter compounds are not very toxic, but there is a somewhat higher chance of toxicity for known bitter compounds compared to known nonbitter ones. Flavonoids and alpha acids are more common in the bitter dataset compared with the toxic dataset. In contrast, alkaloids are more common in the toxic datasets compared to the bitter dataset. Interestingly, no trend linking LD 50 values with the number of activated bitter taste receptors (TAS2Rs) subtypes is apparent in the currently available data. This is in accord with the newly discovered expression of TAS2Rs in several extra-oral tissues, in which they might be activated by yet unknown endogenous ligands and play non-gustatory physiological roles. These results suggest that bitter taste is not a very reliable marker for toxicity, and is likely to have other physiological roles. © 2017 IUBMB Life, 69(12):938-946, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Large Dataset of Acute Oral Toxicity Data Created for Testing ...

EPA Pesticide Factsheets

Acute toxicity data is a common requirement for substance registration in the US. Currently only data derived from animal tests are accepted by regulatory agencies, and the standard in vivo tests use lethality as the endpoint. Non-animal alternatives such as in silico models are being developed due to animal welfare and resource considerations. We compiled a large dataset of oral rat LD50 values to assess the predictive performance currently available in silico models. Our dataset combines LD50 values from five different sources: literature data provided by The Dow Chemical Company, REACH data from eChemportal, HSDB (Hazardous Substances Data Bank), RTECS data from Leadscope, and the training set underpinning TEST (Toxicity Estimation Software Tool). Combined these data sources yield 33848 chemical-LD50 pairs (data points), with 23475 unique data points covering 16439 compounds. The entire dataset was loaded into a chemical properties database. All of the compounds were registered in DSSTox and 59.5% have publically available structures. Compounds without a structure in DSSTox are currently having their structures registered. The structural data will be used to evaluate the predictive performance and applicable chemical domains of three QSAR models (TIMES, PROTOX, and TEST). Future work will combine the dataset with information from ToxCast assays, and using random forest modeling, assess whether ToxCast assays are useful in predicting acute oral toxicity. Pre

Profile preferences of Korean American orthodontic patients and orthodontists.

PubMed

Park, Yoon S; Evans, Carla A; Viana, Grace; Anderson, Nina K; Giddon, Donald B

2006-01-01

The purpose of this study was to determine differences in preference for Korean American facial profiles among Korean American orthodontic patients with 2 levels of acculturation, Asian American orthodontists, and Caucasian orthodontists. Images of 1 male and 1 female Korean American adult were animated to move parts of the faces from an extreme retrusive position to an extreme protrusive position by using the Perceptometrics computer program. Three movies were created of the nose, lips, and chin for each image. Three groups of judges, ie, 18 Korean American orthodontic patients, 17 Asian orthodontists, and 18 Caucasian orthodontists selected the most pleasing position and the zone of acceptability as a measure of tolerance. Statistically significant differences were found between Caucasian orthodontists and Korean American orthodontic patients for the most pleasing and midpoint of acceptability positions of female nose and male chin, with no differences in the zone of acceptability position among the groups. In general, the Korean American orthodontic patients preferred a more protrusive nose on the female image and more retrusive chin on the male image than Caucasian orthodontists for the most pleasing and midpoint of acceptability positions, with similar zone of acceptability for all 3 groups.

Incidence of CNS Oxygen Toxicity with Mild Hyperoxia: A Literature and Data Review

DTIC Science & Technology

2013-04-01

multi-depth profiles.16,17 One diver reported numbness, tingling, poor concentration and dizziness after only 5 minutes. One diver reported tinnitus ...function dives,22, 24, 26, 28 the symptoms considered to be CNS oxygen toxicity during the training dives--nausea, dizziness, tinnitus ...models accumulate risk from prior exposure but do not (and cannot) consider other possible changes caused by immediate history , e.g., sensitization or

Toxic cyanobacteria and cyanotoxins in public hot springs in Saudi Arabia.

PubMed

Mohamed, Zakaria A

2008-01-01

Toxic cyanobacteria are well reported in rivers, lakes and even marine environments, but the toxin production of cyanobacteria in hot springs is largely unexplored. Therefore, the present study investigated the presence of toxic cyanobacteria and cyanotoxins in public hot springs in Saudi Arabia. The results of an enzyme-linked immunosorbent assay (ELISA) revealed that Saudi spring cyanobacterial mats contained microcystins (MCYSTs) at concentrations ranging from 468 to 512.5 microg g(-1). The Limulus amebocyte lystae (LAL) assay detected lipopolysaccharide (LPS) endotoxins in these mats at concentrations ranging from 433.3 to 506.8 EU g(-1). MCYSTs and endotoxins were also detected in spring waters at levels of 5.7 microg l(-1) and 640 EU ml(-1), respectively, exceeding WHO's provisional guideline value for MCYST-LR in drinking-water. High-performance liquid chromatography (HPLC) analysis revealed that only Oscillatoria limosa and Synechococcus lividus can produce MCYSTs with a profile consisting of MCYST-RR and -LR. Based on the LAL assay, 12 out of 17 cyanobacterial species contained LPS at concentrations ranging from 0.93 to 21.06 EU g(-1). However, not all LPS of these species were toxic to mice. This study suggests that the hot springs in the world including Saudi Arabia should be screened for toxic cyanobacteria to avoid the exposure of people recreating and bathing in spring waters to cyanobacterial toxins.

Effect of apitherapy formulations against carbon tetrachloride-induced toxicity in Wistar rats after three weeks of treatment.

PubMed

Andritoiu, Calin Vasile; Ochiuz, Lacramioara; Andritoiu, Vasile; Popa, Marcel

2014-08-29

The human body is exposed nowadays to increasing attacks by toxic compounds in polluted air, industrially processed foods, alcohol and drug consumption that increase liver toxicity, leading to more and more severe cases of hepatic disorders. The present paper aims to evaluate the influence of the apitherapy diet in Wistar rats with carbon tetrachloride-induced hepatotoxicity, by analyzing the biochemical determinations (enzymatic, lipid and protein profiles, coagulation parameters, minerals, blood count parameters, bilirubin levels) and histopathological changes at the level of liver, spleen and pancreas. The experiment was carried out on six groups of male Wistar rats. Hepatic lesions were induced by intraperitoneal injection of carbon tetrachloride (dissolved in paraffin oil, 10% solution). Two mL per 100 g were administered, every 2 days, for 2 weeks. Hepatoprotection was achieved with two apitherapy diet formulations containing honey, pollen, propolis, Apilarnil, with/without royal jelly. Biochemical results reveal that the two apitherapy diet formulations have a positive effect on improving the enzymatic, lipid, and protein profiles, coagulation, mineral and blood count parameters and bilirubin levels. The histopathological results demonstrate the benefits of the two apitherapy diet formulations on reducing toxicity at the level of liver, spleen and pancreas in laboratory animals.

Prediction of human population responses to toxic compounds by a collaborative competition.

PubMed

Eduati, Federica; Mangravite, Lara M; Wang, Tao; Tang, Hao; Bare, J Christopher; Huang, Ruili; Norman, Thea; Kellen, Mike; Menden, Michael P; Yang, Jichen; Zhan, Xiaowei; Zhong, Rui; Xiao, Guanghua; Xia, Menghang; Abdo, Nour; Kosyk, Oksana; Friend, Stephen; Dearry, Allen; Simeonov, Anton; Tice, Raymond R; Rusyn, Ivan; Wright, Fred A; Stolovitzky, Gustavo; Xie, Yang; Saez-Rodriguez, Julio

2015-09-01

The ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson's r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.

GHS additivity formula: A true replacement method for acute systemic toxicity testing of agrochemical formulations.

PubMed

Corvaro, M; Gehen, S; Andrews, K; Chatfield, R; Arasti, C; Mehta, J

2016-12-01

Acute systemic (oral, dermal, inhalation) toxicity testing of agrochemical formulations (end-use products) is mainly needed for Classification and Labelling (C&L) and definition of personal protection equipment (PPE). A retrospective analysis of 225 formulations with available in vivo data showed that: A) LD 50 /LC 50 values were above limit doses in <20.2% via oral route but only in <1% and <2.4% of cases via dermal and inhalation route, respectively; B) for each formulation the acute oral toxicity is always equal or greater than the Acute Toxicity Estimate (ATE) via the other two routes; C) the GHS (Global Harmonised System) computational method based on ATE, currently of limited acceptance, has very high accuracy and specificity for prediction of agrochemical mixture toxicity according to the internationally established classification thresholds. By integrating this evidence, an exposure- and data-based waiving strategy is proposed to determine classification and adequate PPE and to ensure only triggered animal testing is used. Safety characterisation above 2000 mg/kg body weight or 1.0 mg/L air should not be recommended, based on the agrochemical exposure scenarios. The global implementation of these tools would allow a remarkable reduction (up to 95%) in in vivo testing, often inducing lethality and/or severe toxicity, for agrochemical formulations. Copyright © 2016. Published by Elsevier Inc.

Genome-Wide Functional and Stress Response Profiling Reveals Toxic Mechanism and Genes Required for Tolerance to Benzo[a]pyrene in S. cerevisiae

PubMed Central

O’Connor, Sean Timothy Francis; Lan, Jiaqi; North, Matthew; Loguinov, Alexandre; Zhang, Luoping; Smith, Martyn T.; Gu, April Z.; Vulpe, Chris

2012-01-01

Benzo[a]pyrene (BaP) is a ubiquitous, potent, and complete carcinogen resulting from incomplete organic combustion. BaP can form DNA adducts but other mechanisms may play a role in toxicity. We used a functional toxicology approach in S. cerevisiae to assess the genetic requirements for cellular resistance to BaP. In addition, we examined translational activities of key genes involved in various stress response pathways. We identified multiple genes and processes involved in modulating BaP toxicity in yeast which support DNA damage as a primary mechanism of toxicity, but also identify other potential toxicity pathways. Gene ontology enrichment analysis indicated that DNA damage and repair as well as redox homeostasis and oxidative stress are key processes in cellular response to BaP suggesting a similar mode of action of BaP in yeast and mammals. Interestingly, toxicant export is also implicated as a potential novel modulator of cellular susceptibility. In particular, we identified several transporters with human orthologs (solute carrier family 22) which may play a role in mammalian systems. PMID:23403841

Boron-containing acids: preliminary evaluation of acute toxicity and access to the brain determined by Raman scattering spectroscopy.

PubMed

Soriano-Ursúa, Marvin A; Farfán-García, Eunice D; López-Cabrera, Yessica; Querejeta, Enrique; Trujillo-Ferrara, José G

2014-01-01

Boron-containing compounds (BCCs), particularly boron containing acids (BCAs), have become attractive moieties or molecules in drug development. It has been suggested that when functional groups with boron atoms are added to well-known drugs, the latter are conferred with greater potency and efficacy in relation to their target receptors. However, the use of BCAs in drug development is limited due to the lack of a toxicological profile. Consequently, the aim of the present study was to evaluate the acute toxicity of boric and boronic acids. Thus, a determination was made of the lethal dose (LD50) of test compounds in male CD1 mice, as well as the effective dose required to negatively affect spontaneous motor activity and to produce notable behavioral abnormalities. After treatment of animals at different doses, macroscopic observations were made from a necropsy, and Raman scattering spectroscopic studies were carried out on brain tissue samples. In general, the results show that most of the tested BCAs have very low toxicity, evidenced by the high doses required to induce notable toxic effects (greater than 100 mg/kg of body weight for all compounds, except for 3-thyenilboronic acid). Such toxic effects, presumably mediated by action on the CNS, include eye damage, gastrointestinal effects (e.g., gastric-gut dilatation and fecal retention), sedation, hypnosis and/or trembling. This preliminary toxicological profile suggests that BCAs can be considered potential therapeutic agents or moieties to be added to other compounds in the development of new drugs. Future studies are required to explore possible chronic toxicity of BCCs. Copyright © 2013 Elsevier Inc. All rights reserved.

Electronic cigarette solutions and resultant aerosol profiles.

PubMed

Herrington, Jason S; Myers, Colton

2015-10-30

Electronic cigarettes (e-cigarettes) are growing in popularity exponentially. Despite their ever-growing acceptance, their aerosol has not been fully characterized. The current study focused on evaluating e-cigarette solutions and their resultant aerosol for potential differences. A simple sampling device was developed to draw e-cigarette aerosol into a multi-sorbent thermal desorption (TD) tube, which was then thermally extracted and analyzed via a gas chromatography (GC) mass spectrometry (GC-MS) method. This novel application provided detectable levels of over one hundred fifteen volatile organic compounds (VOCs) and semivolatile organic compounds (SVOCs) from a single 40mL puff. The aerosol profiles from four commercially available e-cigarettes were compared to their respective solution profiles with the same GC-MS method. Solution profiles produced upwards of sixty four unidentified and identified (some only tentatively) constituents and aerosol profiles produced upwards of eighty two compounds. Results demonstrated distinct analyte profiles between liquid and aerosol samples. Most notably, formaldehyde, acetaldehyde, acrolein, and siloxanes were found in the aerosol profiles; however, these compounds were never present in the solutions. These results implicate the aerosolization process in the formation of compounds not found in solutions; have potential implications for human health; and stress the need for an emphasis on electronic cigarette aerosol testing. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Comparison of chronic toxicities between brachytherapy-based accelerated partial breast irradiation and whole breast irradiation using intensity modulated radiotherapy.

PubMed

Wobb, Jessica L; Shah, Chirag; Jawad, Maha S; Wallace, Michelle; Dilworth, Joshua T; Grills, Inga S; Ye, Hong; Chen, Peter Y

2015-12-01

Brachytherapy-based APBI (bAPBI) shortens treatment duration and limits dose to normal tissue. While studies have demonstrated similar local control when comparing bAPBI and whole breast irradiation using intensity modulated radiotherapy (WBI-IMRT), comparison of late side effects is limited. Here, we report chronic toxicity profiles associated with these two treatment modalities. 1034 patients with early stage breast cancer were treated at a single institution; 489 received standard-fractionation WBI-IMRT between 2000 and 2013 and 545 received bAPBI (interstitial 40%, applicator-based 60%) between 1993 and 2013. Chronic toxicity was evaluated ≥6 months utilizing CTCAE version 3.0; cosmesis was evaluated using the Harvard scale. Median follow-up was 4.6 years (range 0.1-13.4) for WBI-IMRT versus 6.7 years (range 0.1-20.1) for bAPBI (p < 0.001). Compared to WBI-IMRT, bAPBI was associated with higher rates of ≥grade 2 seroma formation (14.4% vs 2.9%, p < 0.001), telangiectasia (12.3% vs 2.1%, p = 0.002) and symptomatic fat necrosis (10.2% vs 3.6%, p < 0.001). Lower rates of hyperpigmentation were observed (5.8% vs 14.5%; p = 0.001). Infection rates were similar (3.3% vs 1.3%, p = 0.07). There was no difference between rates of fair (6.1% vs. 4.1%, p = 0.30) or poor (0.2% vs. 0.5%, p = NS) cosmesis. Mastectomy rates for local recurrence (3.1% for WBI-IMRT and 1.2% for bAPBI, p = 0.06), or for other reasons (0.8% and 0.6%, p = 0.60) were similar between groups. With 5-year follow-up, WBI-IMRT and bAPBI are associated with similar, acceptable rates of toxicity. These data further support the utilization of bAPBI as a modality to deliver adjuvant radiation in a safe and efficacious manner. Copyright © 2015 Elsevier Ltd. All rights reserved.

A MicroRNA-Mediated Insulin Signaling Pathway Regulates the Toxicity of Multi-Walled Carbon Nanotubes in Nematode Caenorhabditis elegans

PubMed Central

Zhao, Yunli; Yang, Junnian; Wang, Dayong

2016-01-01

The underlying mechanisms for functions of microRNAs (miRNAs) in regulating toxicity of nanomaterials are largely unclear. Using Illumina HiSeqTM 2000 sequencing technique, we obtained the dysregulated mRNA profiling in multi-walled carbon nanotubes (MWCNTs) exposed nematodes. Some dysregulated genes encode insulin signaling pathway. Genetic experiments confirmed the functions of these dysregulated genes in regulating MWCNTs toxicity. In the insulin signaling pathway, DAF-2/insulin receptor regulated MWCNTs toxicity by suppressing function of DAF-16/FOXO transcription factor. Moreover, we raised a miRNAs-mRNAs network involved in the control of MWCNTs toxicity. In this network, mir-355 might regulate MWCNTs toxicity by inhibiting functions of its targeted gene of daf-2, suggesting that mir-355 may regulate functions of the entire insulin signaling pathway by acting as an upregulator of DAF-2, the initiator of insulin signaling pathway, in MWCNTs exposed nematodes. Our results provides highlight on understanding the crucial role of miRNAs in regulating toxicity of nanomaterials in organisms. PMID:26984256

Peer Acceptance of Children with Language and Communication Impairments in a Mainstream Primary School: Associations with Type of Language Difficulty, Problem Behaviours and a Change in Placement Organization

ERIC Educational Resources Information Center

Laws, Glynis; Bates, Geraldine; Feuerstein, Maike; Mason-Apps, Emily; White, Catherine

2012-01-01

This research investigated peer acceptance of children with language and communication impairments attending a language resource base attached to a mainstream school. Compared to other children in their mainstream peer groups, peer acceptance was poor. Peer rejection was more common for children with profiles consistent with an autistic spectrum…

Stable Spheromaks with Profile Control

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, T K; Jayakumar, R

A spheromak equilibrium with zero edge current is shown to be stable to both ideal MHD and tearing modes that normally produce Taylor relaxation in gun-injected spheromaks. This stable equilibrium differs from the stable Taylor state in that the current density j falls to zero at the wall. Estimates indicate that this current profile could be sustained by non-inductive current drive at acceptable power levels. Stability is determined using the NIMROD code for linear stability analysis. Non-linear NIMROD calculations with non-inductive current drive could point the way to improved fusion reactors.

Chinese Nurses' Acceptance of PDA: A Cross-Sectional Survey Using a Technology Acceptance Model.

PubMed

Wang, Yanling; Xiao, Qian; Sun, Liu; Wu, Ying

2016-01-01

This study explores Chinese nurses' acceptance of PDA, using a questionnaire based on the framework of Technology Acceptance Model (TAM). 357 nurses were involved in the study. The results reveal the scores of the nurses' acceptance of PDA were means 3.18~3.36 in four dimensions. The younger of nurses, the higher nurses' title, the longer previous usage time, the more experienced using PDA, and the more acceptance of PDA. Therefore, the hospital administrators may change strategies to enhance nurses' acceptance of PDA, and promote the wide application of PDA.

Integrated analysis of drug-induced gene expression profiles predicts novel hERG inhibitors.

PubMed

Babcock, Joseph J; Du, Fang; Xu, Kaiping; Wheelan, Sarah J; Li, Min

2013-01-01

Growing evidence suggests that drugs interact with diverse molecular targets mediating both therapeutic and toxic effects. Prediction of these complex interactions from chemical structures alone remains challenging, as compounds with different structures may possess similar toxicity profiles. In contrast, predictions based on systems-level measurements of drug effect may reveal pharmacologic similarities not evident from structure or known therapeutic indications. Here we utilized drug-induced transcriptional responses in the Connectivity Map (CMap) to discover such similarities among diverse antagonists of the human ether-à-go-go related (hERG) potassium channel, a common target of promiscuous inhibition by small molecules. Analysis of transcriptional profiles generated in three independent cell lines revealed clusters enriched for hERG inhibitors annotated using a database of experimental measurements (hERGcentral) and clinical indications. As a validation, we experimentally identified novel hERG inhibitors among the unannotated drugs in these enriched clusters, suggesting transcriptional responses may serve as predictive surrogates of cardiotoxicity complementing existing functional assays.

Integrated Analysis of Drug-Induced Gene Expression Profiles Predicts Novel hERG Inhibitors

PubMed Central

Babcock, Joseph J.; Du, Fang; Xu, Kaiping; Wheelan, Sarah J.; Li, Min

2013-01-01

Growing evidence suggests that drugs interact with diverse molecular targets mediating both therapeutic and toxic effects. Prediction of these complex interactions from chemical structures alone remains challenging, as compounds with different structures may possess similar toxicity profiles. In contrast, predictions based on systems-level measurements of drug effect may reveal pharmacologic similarities not evident from structure or known therapeutic indications. Here we utilized drug-induced transcriptional responses in the Connectivity Map (CMap) to discover such similarities among diverse antagonists of the human ether-à-go-go related (hERG) potassium channel, a common target of promiscuous inhibition by small molecules. Analysis of transcriptional profiles generated in three independent cell lines revealed clusters enriched for hERG inhibitors annotated using a database of experimental measurements (hERGcentral) and clinical indications. As a validation, we experimentally identified novel hERG inhibitors among the unannotated drugs in these enriched clusters, suggesting transcriptional responses may serve as predictive surrogates of cardiotoxicity complementing existing functional assays. PMID:23936032

Thermal Stress and Toxicity

EPA Science Inventory

Elevating ambient temperature above thermoneutrality exacerbates toxicity of most air pollutants, insecticides, and other toxic chemicals. On the other hand, safety and toxicity testing of toxicants and drugs is usually performed in mice and rats maintained at subthermoneutral te...

Single oral dose toxicity test of blue honeysuckle concentrate in mice.

PubMed

Kim, Hyung-Soo; Park, Sang-In; Choi, Seung-Hoon; Song, Chang-Hyun; Park, Soo-Jin; Shin, Yong-Kook; Han, Chang-Hyun; Lee, Young Joon; Ku, Sae-Kwang

2015-03-01

The objective of this study was to obtain single oral dose toxicity information for concentrated and lyophilized powder of blue honeysuckle (Lonicera caerulea L., Caprifoliaceae; BHcL) in female and male ICR mice to aid in the process of developing natural origin medicinal ingredients or foods following proximate analysis and phytochemical profile measurement. The proximate analysis revealed that BHcL had an energy value of 3.80 kcal/g and contained 0.93 g/g of carbohydrate, 0.41 g/g of sugar, 0.02 g/g of protein, and 0.20 mg/g of sodium. BHcL did not contain lipids, including saturated lipids, trans fats, or cholesterols. Further, BHcL contained 4.54% of betaine, 210.63 mg/g of total phenols, 159.30 mg/g of total flavonoids, and 133.57 mg/g of total anthocyanins. Following administration of a single oral BHcL treatment, there were no treatment-related mortalities, changes in body weight (bw) or organ weight, clinical signs, necropsy or histopathological findings up to 2,000 mg/kg bw, the limited dosage for rodents of both sexes. We concluded that BHcL is a practically non-toxic material in toxicity potency.

Single Oral Dose Toxicity Test of Blue Honeysuckle Concentrate in Mice

PubMed Central

Park, Sang-In; Choi, Seung-Hoon; Song, Chang-Hyun; Park, Soo-Jin; Shin, Yong-Kook; Han, Chang-Hyun; Lee, Young Joon; Ku, Sae-Kwang

2015-01-01

The objective of this study was to obtain single oral dose toxicity information for concentrated and lyophilized powder of blue honeysuckle (Lonicera caerulea L., Caprifoliaceae; BHcL) in female and male ICR mice to aid in the process of developing natural origin medicinal ingredients or foods following proximate analysis and phytochemical profile measurement. The proximate analysis revealed that BHcL had an energy value of 3.80 kcal/g and contained 0.93 g/g of carbohydrate, 0.41 g/g of sugar, 0.02 g/g of protein, and 0.20 mg/g of sodium. BHcL did not contain lipids, including saturated lipids, trans fats, or cholesterols. Further, BHcL contained 4.54% of betaine, 210.63 mg/g of total phenols, 159.30 mg/g of total flavonoids, and 133.57 mg/g of total anthocyanins. Following administration of a single oral BHcL treatment, there were no treatment-related mortalities, changes in body weight (bw) or organ weight, clinical signs, necropsy or histopathological findings up to 2,000 mg/kg bw, the limited dosage for rodents of both sexes. We concluded that BHcL is a practically non-toxic material in toxicity potency. PMID:25874034

Accelerating Information Retrieval from Profile Hidden Markov Model Databases.

PubMed

Tamimi, Ahmad; Ashhab, Yaqoub; Tamimi, Hashem

2016-01-01

Profile Hidden Markov Model (Profile-HMM) is an efficient statistical approach to represent protein families. Currently, several databases maintain valuable protein sequence information as profile-HMMs. There is an increasing interest to improve the efficiency of searching Profile-HMM databases to detect sequence-profile or profile-profile homology. However, most efforts to enhance searching efficiency have been focusing on improving the alignment algorithms. Although the performance of these algorithms is fairly acceptable, the growing size of these databases, as well as the increasing demand for using batch query searching approach, are strong motivations that call for further enhancement of information retrieval from profile-HMM databases. This work presents a heuristic method to accelerate the current profile-HMM homology searching approaches. The method works by cluster-based remodeling of the database to reduce the search space, rather than focusing on the alignment algorithms. Using different clustering techniques, 4284 TIGRFAMs profiles were clustered based on their similarities. A representative for each cluster was assigned. To enhance sensitivity, we proposed an extended step that allows overlapping among clusters. A validation benchmark of 6000 randomly selected protein sequences was used to query the clustered profiles. To evaluate the efficiency of our approach, speed and recall values were measured and compared with the sequential search approach. Using hierarchical, k-means, and connected component clustering techniques followed by the extended overlapping step, we obtained an average reduction in time of 41%, and an average recall of 96%. Our results demonstrate that representation of profile-HMMs using a clustering-based approach can significantly accelerate data retrieval from profile-HMM databases.

Toxicity and bioaccumulation of sediment-associated contaminants using freshwater invertebrates: A review of methods and applications

USGS Publications Warehouse

Ingersoll, C.G.; Ankley, G.T.; Benoit, D.A.; Brunson, E.L.; Burton, G.A.; Dwyer, F.J.; Hoke, R.A.; Landrum, P.F.; Norberg-King, T. J.; Winger, P.V.

1995-01-01

This paper reviews recent developments in methods for evaluating the toxicity and bioaccumulation of contaminants associated with freshwater sediments and summarizes example case studies demonstrating the application of these methods. Over the past decade, research has emphasized development of more specific testing procedures for conducting 10-d toxicity tests with the amphipod Hyalella azteca and the midge Chironomus tentans. Toxicity endpoints measured in these tests are survival for H. azteca and survival and growth for C. tentans. Guidance has also been developed for conducting 28-d bioaccumulation tests with the oligochaete Lumbriculus variegatus, including determination of bioaccumulation kinetics for different compound classes. These methods have been applied to a variety of sediments to address issues ranging from site assessments to bioavailability of organic and inorganic contaminants using field-collected and laboratory-spiked samples. Survival and growth of controls routinely meet or exceed test acceptability criteria. Results of laboratory bioaccumulation studies with L. variegatus have been confirmed with comparisons to residues (PCBs, PAHs, DDT) present from synoptically collected field populations of oligochaetes. Additional method development is currently underway to develop chronic toxicity tests and to provide additional data-confirming responses observed in laboratory sediment tests with natural benthic populations.

Handbook of acute toxicity of chemicals to fish and aquatic invertebrates : summaries of toxicity tests conducted at Columbia National Fisheries Research Laboratory, 1965-78

USGS Publications Warehouse

Johnson, W. Waynon; Finley, Mack T.

1980-01-01

Acute toxicity is a major subject of research at Columbia National Fisheries Research Laboratory for evaluating the impact of toxic chemicals on fishery resources. The Laboratory has played a leading role in developing research technology for toxicity testing and data interpretation. In 1965-78, more than 400 chemicals were tested against a variety of invertebrates and fish species representative of both cold- and warm-water climates.The use of acute toxicity tests for assessing the potential hazard of chemical contaminants to aquatic organisms is well documented (Boyd 1957; Henderson et al. 1960; Sanders and Cope 1966; Macek and McAllister 1970). Static acute toxicity tests provide rapid and (within limits) reproducible concentration-response curves for estimating toxic effects of chemicals on aquatic organisms. These tests provide a database for determining relative toxicity of a large number of chemicals to a variety of species and for estimating acute effects of chemical spills on natural aquatic systems; they also assist in determining priority and design of additional toxicity studies.Acute toxicity tests usually provide estimates of the exposure concentration causing 50% mortality (LC50) to test organisms during a specified period of time. For certain invertebrates, the effective concentration is based on immobilization, or some other identifiable endpoint, rather than on lethality. The application of the LC50 has gained acceptance among toxicologists and is generally the most highly rated test for assessing potential adverse effects of chemical contaminants to aquatic life (Brungs and Mount 1978; American Institute for Biological Sciences 1978a).The literature contains numerous papers dealing with the acute toxicity of chemicals to freshwater organisms. However, there is a tremendous need for a concise compendium of toxicity data covering a large variety of chemicals and test species. This Handbook is a compilation of a large volume of acute toxicity data

Evaluation of ability of reference toxicity tests to identify stress in laboratory populations of the amphipod Hyalella azteca

USGS Publications Warehouse

McNulty, E.W.; Dwyer, F.J.; Ellersieck, Mark R.; Greer, E.I.; Ingersoll, C.G.; Rabeni, C.F.

1999-01-01

Standard methods for conducting toxicity tests imply that the condition of test organisms can be established using reference toxicity tests. However, only a limited number of studies have evaluated whether reference toxicity tests can actually be used to determine if organisms are in good condition at the start of a test. We evaluated the ability of reference toxicants to identify stress associated with starvation in laboratory populations of the amphipod Hyalella azteca using acute toxicity tests and four reference toxicants: KCl, CdCl2, sodium pentachlorophenate (NaPCP), and carbaryl. Stress associated with severe starvation was observed with exposure of amphipods to carbaryl or NaPCP but not with exposure to KCl or CdCl2 (i.e., lower LC50 with severe starvation). Although the LC50s for NaPCP and carbaryl were statistically different between starved and fed amphipods, this difference may not be biologically significant given the variability expected in acute lethality tests. Stress associated with sieving, heat shock, or cold shock of amphipods before the start of a test was not evident with exposure to carbaryl or KCl as reference toxicants. The chemicals evaluated in this study provided minimal information about the condition of the organisms used to start a toxicity test. Laboratories should periodically perform reference toxicity tests to assess the sensitivity of life stages or strains of test organisms. However, use of other test acceptability criteria required in standard methods such as minimum survival, growth, or reproduction of organisms in the control treatment at the end of a test, provides more useful information about the condition of organisms used to start a test compared to data generated from reference toxicity tests.

Dose–response relationships in gene expression profiles in rainbow trout, Oncorhyncus mykiss, exposed to ethynylestradiol

PubMed Central

Hook, Sharon E.; Skillman, Ann D.; Small, Jack A.; Schultz, Irvin R.

2008-01-01

Determining how gene expression profiles change with toxicant dose will improve the utility of arrays in identifying biomarkers and modes of toxic action. Isogenic rainbow trout, Oncorhyncus mykiss, were exposed to 10, 50 or 100 ng/L ethynylestradiol (a xeno-estrogen) for 7 days. Following exposure hepatic RNA was extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon/Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNAs. Transcript expression in treated vs control fish was analyzed via Genespring (Silicon Genetics) to identify genes with altered expression, as well as to determine gene clustering patterns that can be used as “expression signatures”. Array results were confirmed via qRT PCR. Our analysis indicates that gene expression profiles varied somewhat with dose. Established biomarkers of exposure to estrogenic chemicals, such as vitellogenin, vitelline envelope proteins, and the estrogen receptor alpha, were induced at every dose. Other genes were dose specific, suggesting that diffierent doses induce distinct physiological responses. These findings demonstrate that cDNA microarrays could be used to identify both toxicant class and relative dose. PMID:16725192

Dose-response relationships in gene expression profiles in rainbow trout, Oncorhyncus mykiss, exposed to ethynylestradiol.

PubMed

Hook, Sharon E; Skillman, Ann D; Small, Jack A; Schultz, Irvin R

2006-07-01

Determining how gene expression profiles change with toxicant dose will improve the utility of arrays in identifying biomarkers and modes of toxic action. Isogenic rainbow trout, Oncorhyncus mykiss,were exposed to 10, 50 or 100 ng/L ethynylestradiol (a xeno-estrogen) for 7 days. Following exposure hepatic RNA was extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon/Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNAs. Transcript expression in treated vs control fish was analyzed via Genespring (Silicon Genetics) to identify genes with altered expression, as well as to determine gene clustering patterns that can be used as "expression signatures". Array results were confirmed via qRT PCR. Our analysis indicates that gene expression profiles varied somewhat with dose. Established biomarkers of exposure to estrogenic chemicals, such as vitellogenin, vitelline envelope proteins, and the estrogen receptor alpha, were induced at every dose. Other genes were dose specific, suggesting that different doses induce distinct physiological responses. These findings demonstrate that cDNA microarrays could be used to identify both toxicant class and relative dose.

Aluminum Toxicity-Induced Alterations of Leaf Proteome in Two Citrus Species Differing in Aluminum Tolerance.

PubMed

Li, Huan; Yang, Lin-Tong; Qi, Yi-Ping; Guo, Peng; Lu, Yi-Bin; Chen, Li-Song

2016-07-21

Seedlings of aluminum-tolerant 'Xuegan' (Citrus sinensis) and Al-intolerant 'sour pummelo' (Citrus grandis) were fertigated for 18 weeks with nutrient solution containing 0 and 1.2 mM AlCl₃·6H₂O. Al toxicity-induced inhibition of photosynthesis and the decrease of total soluble protein only occurred in C. grandis leaves, demonstrating that C. sinensis had higher Al tolerance than C. grandis. Using isobaric tags for relative and absolute quantification (iTRAQ), we obtained more Al toxicity-responsive proteins from C. sinensis than from C. grandis leaves, which might be responsible for the higher Al tolerance of C. sinensis. The following aspects might contribute to the Al tolerance of C. sinensis: (a) better maintenance of photosynthesis and energy balance via inducing photosynthesis and energy-related proteins; (b) less increased requirement for the detoxification of reactive oxygen species and other toxic compounds, such as aldehydes, and great improvement of the total ability of detoxification; and (c) upregulation of low-phosphorus-responsive proteins. Al toxicity-responsive proteins related to RNA regulation, protein metabolism, cellular transport and signal transduction might also play key roles in the higher Al tolerance of C. sinensis. We present the global picture of Al toxicity-induced alterations of protein profiles in citrus leaves, and identify some new Al toxicity-responsive proteins related to various biological processes. Our results provide some novel clues about plant Al tolerance.

Pre-clinical toxicity of a combination of berberine and 5-aminosalicylic acid in mice.

PubMed

Li, Yan-Hong; Zhang, Man; Fu, Hai-Bo; Xiao, Hai-Tao; Bian, Zhao-Xiang

2016-11-01

Our previous study demonstrated that a combination of alternative medicine berberine and conventional 5-aminosalicylic acid (5-ASA) showed promise to be a novel therapeutic strategy for ulcerative colitis (UC). This present study aims to sketch the pre-clinical toxicity profile of this combination (1:10 dose ratio) on mice. In acute toxicity test, the determined median lethal dose (LD 50 ) was 278.7 mg/kg berberine plus 2787 mg/kg 5-ASA. The results from subacute toxicity test demonstrated that no toxic signs of clinical symptoms, no significant changes in hematological or biochemical parameters were detected in mice treated with 14 + 140, 28 + 280 or 56 + 560 mg/kg of berberine plus 5-ASA treatment. Histological examinations revealed that accompanied with an increase in spleen weight, frequently recorded enlargement and white pulp hyperplasia of spleen were detected in mice when exposed to three doses of combination treatments. Further in vitro assessment suggested that the spleen toxicity was originated from berberine by its inhibition in cell viability and cell proliferation of lymphocytes. The results of this study indicate that the combination of berberine and 5-ASA shows a slight toxic effect on spleen, suggesting that this combination should be used with caution for patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of N′-nitrosodimethylamine on red blood cell rheology and proteomic profiles of brain in male albino rats

PubMed Central

Ahmad, Areeba; Fatima, Ravish; Maheshwari, Veena; Ahmad, Riaz

2011-01-01

We investigated the effects of N'-nitrosodimethylamine (NDMA) induced toxicity on red blood cell rheology in male rats and identified bands in proteomic profiles of brain which can be used as novel markers. Polyacrylamide gel electrophoresis (PAGE) profiles exhibited constitutive as well as induced expression of the polypeptides. Remarkably, the molecular weight range of the polypeptides (8–150 kDa) corresponded to that of the family of heat shock proteins. Our results revealed significant changes in blood parameters and showed the presence of acanthocytes, tear drop cells, spicules and cobot rings in the treated categories. Lactate dehydrogenase and esterase zymograms displayed a shift to anaerobic metabolism generating hypoxia-like conditions. This study strongly suggests that NDMA treatment causes acute toxicity leading to cell membrane destruction and alters protein profiles in rats. It is therefore recommended that caution should be exercised in using NDMA to avoid risks, and if at all necessary strategies should be designed to combat such conditions. PMID:22058653

Mefloquine use, psychosis, and violence: A retinoid toxicity hypothesis

PubMed Central

Mawson, Anthony R.

2013-01-01

Mefloquine use has been linked to severe gastrointestinal and neuropsychiatric adverse effects, including cognitive disturbances, anxiety, depression, psychosis, and violence. The adverse effects of the drug are thought to result from the secondary consequences of hepatocellular injury; in fact, mefloquine is known to cause a transient, anicteric chemical hepatitis. However, the mechanism of mefloquine-associated liver damage and the associated neuropsychiatric and behavioral effects of the drug are not well understood. Mefloquine and other 8-amino-quinolines are the only antimalarial drugs that target the liver-stage malaria parasites, which selectively absorb vitamin A from the host. Vitamin A is also stored mainly in the liver, in potentially poisonous concentrations. These observations suggest that both the therapeutic effectiveness of mefloquine and its adverse effects are related to the ability of the 8-aminoquinolines to alter the metabolism of retinoids (vitamin A and its congeners). Several lines of evidence support the hypothesis that mefloquine neurotoxicity and other adverse effects reflect an endogenous form of hypervitaminosis A due to a process involving: mefloquine-induced dehydrogenase inhibition; the accumulation of retinoids in the liver; retinoid-induced hepatocellular damage; the spillage of stored retinoids into the circulation; and the transport of these compounds to the gut and brain in toxic concentrations. The retinoid hypothesis could be tested clinically by comparing cases of mefloquine toxicity and untreated controls in terms of retinoid profiles (retinol, retinyl esters, percent retinyl esters, and retinoic acid). Subject to such tests, retinoid profiling could provide an indicator for assessing mefloquine-associated adverse effects. PMID:23852388

Mefloquine use, psychosis, and violence: a retinoid toxicity hypothesis.

PubMed

Mawson, Anthony

2013-07-15

Mefloquine use has been linked to severe gastrointestinal and neuropsychiatric adverse effects, including cognitive disturbances, anxiety, depression, psychosis, and violence. The adverse effects of the drug are thought to result from the secondary consequences of hepatocellular injury; in fact, mefloquine is known to cause a transient, anicteric chemical hepatitis. However, the mechanism of mefloquine-associated liver damage and the associated neuropsychiatric and behavioral effects of the drug are not well understood. Mefloquine and other 8-amino-quinolines are the only antimalarial drugs that target the liver-stage malaria parasites, which selectively absorb vitamin A from the host. Vitamin A is also stored mainly in the liver, in potentially poisonous concentrations. These observations suggest that both the therapeutic effectiveness of mefloquine and its adverse effects are related to the ability of the 8-aminoquinolines to alter the metabolism of retinoids (vitamin A and its congeners). Several lines of evidence support the hypothesis that mefloquine neurotoxicity and other adverse effects reflect an endogenous form of hypervitaminosis A due to a process involving: mefloquine-induced dehydrogenase inhibition; the accumulation of retinoids in the liver; retinoid-induced hepatocellular damage; the spillage of stored retinoids into the circulation; and the transport of these compounds to the gut and brain in toxic concentrations. The retinoid hypothesis could be tested clinically by comparing cases of mefloquine toxicity and untreated controls in terms of retinoid profiles (retinol, retinyl esters, percent retinyl esters, and retinoic acid). Subject to such tests, retinoid profiling could provide an indicator for assessing mefloquine-associated adverse effects.

Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity.

PubMed

Jabir, Rafid Salim; Naidu, Rakesh; Annuar, Muhammad Azrif Bin Ahmad; Ho, Gwo Fuang; Munisamy, Murali; Stanslas, Johnson

2012-12-01

Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

Controlled loading of cryoprotectants (CPAs) to oocyte with linear and complex CPA profiles on a microfluidic platform.

PubMed

Heo, Yun Seok; Lee, Ho-Joon; Hassell, Bryan A; Irimia, Daniel; Toth, Thomas L; Elmoazzen, Heidi; Toner, Mehmet

2011-10-21

Oocyte cryopreservation has become an essential tool in the treatment of infertility by preserving oocytes for women undergoing chemotherapy. However, despite recent advances, pregnancy rates from all cryopreserved oocytes remain low. The inevitable use of the cryoprotectants (CPAs) during preservation affects the viability of the preserved oocytes and pregnancy rates either through CPA toxicity or osmotic injury. Current protocols attempt to reduce CPA toxicity by minimizing CPA concentrations, or by minimizing the volume changes via the step-wise addition of CPAs to the cells. Although the step-wise addition decreases osmotic shock to oocytes, it unfortunately increases toxic injuries due to the long exposure times to CPAs. To address limitations of current protocols and to rationally design protocols that minimize the exposure to CPAs, we developed a microfluidic device for the quantitative measurements of oocyte volume during various CPA loading protocols. We spatially secured a single oocyte on the microfluidic device, created precisely controlled continuous CPA profiles (step-wise, linear and complex) for the addition of CPAs to the oocyte and measured the oocyte volumetric response to each profile. With both linear and complex profiles, we were able to load 1.5 M propanediol to oocytes in less than 15 min and with a volumetric change of less than 10%. Thus, we believe this single oocyte analysis technology will eventually help future advances in assisted reproductive technologies and fertility preservation.

Automated Lab-on-a-Chip Technology for Fish Embryo Toxicity Tests Performed under Continuous Microperfusion (μFET).

PubMed

Zhu, Feng; Wigh, Adriana; Friedrich, Timo; Devaux, Alain; Bony, Sylvie; Nugegoda, Dayanthi; Kaslin, Jan; Wlodkowic, Donald

2015-12-15

The fish embryo toxicity (FET) biotest has gained popularity as one of the alternative approaches to acute fish toxicity tests in chemical hazard and risk assessment. Despite the importance and common acceptance of FET, it is still performed in multiwell plates and requires laborious and time-consuming manual manipulation of specimens and solutions. This work describes the design and validation of a microfluidic Lab-on-a-Chip technology for automation of the zebrafish embryo toxicity test common in aquatic ecotoxicology. The innovative device supports rapid loading and immobilization of large numbers of zebrafish embryos suspended in a continuous microfluidic perfusion as a means of toxicant delivery. Furthermore, we also present development of a customized mechatronic automation interface that includes a high-resolution USB microscope, LED cold light illumination, and miniaturized 3D printed pumping manifolds that were integrated to enable time-resolved in situ analysis of developing fish embryos. To investigate the applicability of the microfluidic FET (μFET) in toxicity testing, copper sulfate, phenol, ethanol, caffeine, nicotine, and dimethyl sulfoxide were tested as model chemical stressors. Results obtained on a chip-based system were compared with static protocols performed in microtiter plates. This work provides evidence that FET analysis performed under microperfusion opens a brand new alternative for inexpensive automation in aquatic ecotoxicology.

Different Toxicity of Cetuximab and Panitumumab in Metastatic Colorectal Cancer Treatment: A Systematic Review and Meta-Analysis.

PubMed

Petrelli, Fausto; Ardito, Raffaele; Ghidini, Antonio; Zaniboni, Alberto; Ghidini, Michele; Barni, Sandro; Tomasello, Gianluca

2018-01-01

Over the last few years only one large randomized phase III study has tried to prospectively assess the safety of cetuximab and panitumumab in a head-to-head comparison. Despite the similar overall toxicity profile, cetuximab and panitumumab retain peculiar safety characteristics that deserve to be deeply investigated. We conducted a systematic review for randomized trials in PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, and EMBASE using the terms ("cetuximab" or "panitumumab") AND ("colorectal cancer" OR "colorectal carcinoma"). Data of adverse events were aggregated to obtain pooled incidence rates of prespecified adverse events. Incidence of skin toxicities was the primary outcome. A χ2 test was used for comparisons of proportions and an odds ratio (OR) was calculated for comparison. A total of 38 studies were included for analysis. Cetuximab was associated with fewer G3-4 skin toxicities (OR = 0.62, 95% CI 0.53-0.62; p < 0.001), slightly more frequent G3-4 acne-like rash (OR = 1.24, 95% CI 1.04-1.48; p = 0.04), and paronychia (OR 1.36, 95% CI 1.1-1.7), but fewer cases of skin fissures (OR = 0.64, 95% CI 0.44-0.93; p = 0.02) and pruritus (OR = 0.45, 95% CI 0.35-0.58; p < 0.001) than PANI. In conclusion, this meta-analysis shows that cetuximab- and panitumumab-based chemotherapy have different toxicity profiles in terms of the rate of severe adverse events. © 2018 S. Karger AG, Basel.

Toxicity and taste: unequal chemical defences in a mimicry ring.

PubMed

Winters, Anne E; Wilson, Nerida G; van den Berg, Cedric P; How, Martin J; Endler, John A; Marshall, N Justin; White, Andrew M; Garson, Mary J; Cheney, Karen L

2018-06-13

Mimicry of warning signals is common, and can be mutualistic when mimetic species harbour equal levels of defence (Müllerian), or parasitic when mimics are undefended but still gain protection from their resemblance to the model (Batesian). However, whether chemically defended mimics should be similar in terms of toxicity (i.e. causing damage to the consumer) and/or unpalatability (i.e. distasteful to consumer) is unclear and in many studies remains undifferentiated. In this study, we investigated the evolution of visual signals and chemical defences in a putative mimicry ring of nudibranch molluscs. First, we demonstrated that the appearance of a group of red spotted nudibranchs molluscs was similar from the perspective of potential fish predators using visual modelling and pattern analysis. Second, using phylogenetic reconstruction, we demonstrated that this colour pattern has evolved multiple times in distantly related individuals. Third, we showed that these nudibranchs contained different chemical profiles used for defensive purposes. Finally, we demonstrated that although levels of distastefulness towards Palaemon shrimp remained relatively constant between species, toxicity levels towards brine shrimp varied significantly. We highlight the need to disentangle toxicity and taste when considering chemical defences in aposematic and mimetic species, and discuss the implications for aposematic and mimicry signal evolution. © 2018 The Author(s).

Long-term toxic effects of deltamethrin and fenvalerante in soil.

PubMed

Song, Yufang; Kai, Jianrong; Song, Xueying; Zhang, Wei; Li, Lingling

2015-05-30

In this study, the long-term toxic effects of pyrethroids on the earthworm Eisenia fetida were evaluated. Earthworms were exposed to moist filter paper and soil for 14 days to evaluate the survival, exposed to soil for 56 days to assess the reproductive success and for 28 days to identify the cytotoxicity. Results showed that the earthworm survival rate decreased with increasing the concentration of either deltamethrin or fenvalerate in both filter paper test and soil test. No worms survived at 602.15 μg cm(-2) of deltamethrin and 0.86 μg cm(-2) of fenvalerate in the filter paper test, however 100-125 mg kg(-1) of both chemicals resulted in the maximum mortality of 90% in the soil test. The CYP3A4 enzyme activity responded significantly to deltamethrin and fenvalerante in soil at low concentration levels, however, the toxicity response of worms under the long-term exposure conflicted with the degradation of deltamethrin and fenvalerate in soil, indicating the possible formation of more toxic pyrethroid metabolites. This study gave an insight into the toxicological effects profile of pyrethroids for a better risk assessment of pyrethroids deltamethrin and fenvalerante in soil. Copyright © 2015 Elsevier B.V. All rights reserved.

Texture and acceptability of goat meat frankfurters processed with 3 different sources of fat.

PubMed

Bratcher, C L; Dawkins, N L; Solaiman, S; Kerth, C R; Bartlett, J R

2011-05-01

The objective of this research was to evaluate the texture and consumer acceptability of goat meat frankfurter formulations with no added fat (NAF), beef fat (BF), or canola oil (CO). Consumer sensory evaluation, fat, and moisture and texture profile analyses were performed on goat meat frankfurters produced with the fat sources BF, CO, and NAF. For sensory evaluations, NAF was less tender (P = 0.007; 4.90 vs. 4.11 and 4.35 for BF and CO, respectively) and the flavor was liked less (P = 0.004; 4.59 vs. 3.83 and 4.30 for BF and CO, respectively); BF was scored as the juiciest (P = 0.003; 3.86 vs. 4.49 and 4.58 for CO and NAF, respectively); and CO had the least amount of flavor (P = 0.029; 3.65 vs. 3.12 and 3.10 for BF and NAF, respectively). Moisture was least (P < 0.001) in CO (46.59%), followed by BF (48.57%) and NAF (55.80%). The amount of fat was not different (P = 0.761) in BF (24.36%) or CO (24.43%) but was less (P < 0.001) in NAF (9.06%), as expected. The NAF had the most protein (P < 0.001; 34.14%), followed by CO (27.98%) and BF (26.07%). For texture profile analyses, NAF had the least hardness value (P = 0.008; 3.92 vs. 4.48 and 4.40 for BF and CO, respectively) and least chewiness value (P = 0.026; 2.89 vs. 3.39 and 3.29 for BF and CO, respectively). Beef fat and CO were not different for hardness (P = 0.596) or chewiness (P = 0.530). No differences were observed in springiness (P = 0.954) or resilience (P = 0.561). The sensory panelists tended to prefer BF for overall acceptability. Results from these data revealed that value-added goat meat products received acceptable sensory scores; therefore, continued research and development will greatly expand the knowledge of goat meat and increase the acceptance of value-added products.

Toxicity Studies on Antiradiation Agents.

DTIC Science & Technology

1979-03-01

Mice 193-403 WI 2823 Acute Oral and IP Toxicity in Guinea Pigs 193-404 WR 2823 14-Day IV Toxicity in Rats 193-405 WI 2823 Acute IV Toxicity in Dogs ...193-406 W 2823 14-Day Subacute IV Toxicity in Dogs 193-407 WI 2721 28-Day Oral Toxicity in Monkeys 193-408 WI 2529 Acute Oral Toxicity in Mice 193-409... Dogs 193-415 WI 149, 024 Acute IV Toxicity in Monkeys 193-416 WI 149, 024 2-Week IV Toxicity in Dogs 193-417 WI 149, 024 2-Week Toxicity in Monkeys 193

Age and Acceptance of Euthanasia.

ERIC Educational Resources Information Center

Ward, Russell A.

1980-01-01

Study explores relationship between age (and sex and race) and acceptance of euthanasia. Women and non-Whites were less accepting because of religiosity. Among older people less acceptance was attributable to their lesser education and greater religiosity. Results suggest that quality of life in old age affects acceptability of euthanasia. (Author)

Developmental Toxicity

EPA Science Inventory

This chapter provides an overview the developmental toxicity resulting from exposure to perfluorinated alkyl acids (PFAAs). The majority of studies of PFAA-induced developmental toxicity have examined effects of perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA) a...

Influence of surfactants and humic acids on Artemia Franciscana's embryonic phospho-metabolite profile as measured by 31P NMR.

PubMed

Deese, Rachel D; Weldeghiorghis, Thomas K; Haywood, Benjamin J; Cook, Robert L

2017-05-01

Surfactants, such as triton X-100 (Tx-100), cetylpyridinium chloride (CPC), and sodium dodecyl sulfate (SDS) are known to be toxic to Artemia Franciscana (Artemia) - an organism, frequently used to monitor the health of the aquatic environment. The phospho-metabolite profile of a living organism is often indicative of imbalances that may have been caused by environmental stressors, such as surfactants. This study utilizes in vivo 31 P NMR to monitor temporal changes in the phospho-metabolite profile of Artemia caused by Tx-100, CPC, and SDS and the ability of humic acid (HA) to mitigate the toxicity of these surfactants. It was found that, while Tx-100 does not have any effect on the phospho-metabolite profile, both CPC and SDS cause a complete retardation in growth of the phosphodiester (PDE) peak in the 31 P NMR spectrum, which is indicative of the inhibited cell replication. This growth inhibition was independently verified by the decreased guanosine triphosphate (GTP) concentration in the CPC and SDS-exposed Artemia. In addition, upon introduction of HA to the CPC and SDS-exposed Artemia, an increase of PDE peak over time is indicative of HA mitigating toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhalational mold toxicity: fact or fiction? A clinical review of 50 cases.

PubMed

Khalili, Barzin; Montanaro, Marc T; Bardana, Emil J

2005-09-01

Three well-accepted mechanisms of mold-induced disease exist: allergy, infection, and oral toxicosis. Epidemiologic studies suggest a fourth category described as a transient aeroirritation effect. Toxic mold syndrome or inhalational toxicity continues to cause public concern despite a lack of scientific evidence that supports its existence. To conduct a retrospective review of 50 cases of purported mold-induced toxic effects and identify unrecognized conditions that could explain presenting symptoms; to characterize a subgroup with a symptom complex suggestive of an aeroirritation-mediated mechanism and compare this group to other diagnostic categories, such as sick building syndrome and idiopathic chemical intolerance; and to discuss the evolution of toxic mold syndrome from a clinical perspective. Eighty-two consecutive medical evaluations were analyzed of which 50 met inclusion criteria. These cases were critically reviewed and underwent data extraction of 23 variables, including demographic data, patient symptoms, laboratory, imaging, and pulmonary function test results, and an evaluation of medical diagnoses supported by medical record review, examination, and/or test results. Upper respiratory tract, lower respiratory tract, systemic, and neurocognitive symptoms were reported in 80%, 94%, 74%, and 84% of patients, respectively. Thirty patients had evidence of non-mold-related conditions that explained their presenting complaints. Two patients had evidence of allergy to mold allergens, whereas 1 patient exhibited mold-induced psychosis best described as toxic agoraphobia. Seventeen patients displayed a symptom complex that could be postulated to be caused by a transient mold-induced aeroirritation. The clinical presentation of patients with perceived mold-induced toxic effects is characterized by a disparate constellation of symptoms. Close scrutiny revealed a number of preexisting diagnoses that could plausibly explain presenting symptoms. The pathogenesis

Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism.

PubMed

Shiraki, Ayako; Saito, Fumiyo; Akane, Hirotoshi; Akahori, Yumi; Imatanaka, Nobuya; Itahashi, Megu; Yoshida, Toshinori; Shibutani, Makoto

2016-01-01

We previously found that developmental hypothyroidism changed the expression of genes in the rat hippocampal dentate gyrus, a brain region where adult neurogenesis is known to occur. In the present study, we performed brain region-specific global gene expression profiling in an adult rat hypothyroidism model to see if it reflected the developmental neurotoxicity we saw in the developmental hypothyroidism model. Starting when male rats were 5 weeks old, we administered 6-propyl-2-thiouracil at a doses of 0, 0.1 and 10 mg kg(-1) body weight by gavage for 28 days. We selected four brain regions to represent both cerebral and cerebellar tissues: hippocampal dentate gyrus, cerebral cortex, corpus callosum and cerebellar vermis. We observed significant alterations in the expression of genes related to neural development (Eph family genes and Robo3) in the cerebral cortex and hippocampal dentate gyrus and in the expression of genes related to myelination (Plp1 and Mbp) in the hippocampal dentate gyrus. We observed only minor changes in the expression of these genes in the corpus callosum and cerebellar vermis. We used real-time reverse-transcription polymerase chain reaction to confirm Chrdl1, Hes5, Mbp, Plp1, Slit1, Robo3 and the Eph family transcript expression changes. The most significant changes in gene expression were found in the dentate gyrus. Considering that the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28-day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrus may also detect possible developmental neurotoxic effects. Copyright © 2015 John Wiley & Sons, Ltd.

Non-animal Replacements for Acute Toxicity Testing.

PubMed

Barker-Treasure, Carol; Coll, Kevin; Belot, Nathalie; Longmore, Chris; Bygrave, Karl; Avey, Suzanne; Clothier, Richard

2015-07-01

Current approaches to predicting adverse effects in humans from acute toxic exposure to cosmetic ingredients still heavily necessitate the use of animals under EU legislation, particularly in the context of the REACH system, when cosmetic ingredients are also destined for use in other industries. These include the LD50 test, the Up-and-Down Procedure and the Fixed Dose Procedure, which are regarded as having notable scientific deficiencies and low transferability to humans. By expanding on previous in vitro tests, such as the animal cell-based 3T3 Neutral Red Uptake (NRU) assay, this project aims to develop a truly animal-free predictive test for the acute toxicity of cosmetic ingredients in humans, by using human-derived cells and a prediction model that does not rely on animal data. The project, funded by Innovate UK, will incorporate the NRU assay with human dermal fibroblasts in animal product-free culture, to generate an in vitro protocol that can be validated as an accepted replacement for the currently available in vivo tests. To date, the project has successfully completed an assessment of the robustness and reproducibility of the method, by using sodium lauryl sulphate (SLS) as a positive control, and displaying analogous results to those of the original studies with mouse 3T3 cells. Currently, the testing of five known ingredients from key groups (a surfactant, a preservative, a fragrance, a colour and an emulsifier) is under way. The testing consists of initial range-finding runs followed by three valid runs of a main experiment with the appropriate concentration ranges, to generate IC50 values. Expanded blind trials of 20 ingredients will follow. Early results indicate that this human cell-based test holds the potential to replace aspects of in vivo animal acute toxicity testing, particularly with reference to cosmetic ingredients. 2015 FRAME.

Probing the ToxCastTM Chemical Library for Predictive Signatures of Developmental Toxicity - Poster at Teratology Society Annual Meeting

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesize that cell signaling pathways are primary targets for diverse environmental chemicals ...

Status of acute systemic toxicity testing requirements and data uses by U.S. regulatory agencies.

PubMed

Strickland, Judy; Clippinger, Amy J; Brown, Jeffrey; Allen, David; Jacobs, Abigail; Matheson, Joanna; Lowit, Anna; Reinke, Emily N; Johnson, Mark S; Quinn, Michael J; Mattie, David; Fitzpatrick, Suzanne C; Ahir, Surender; Kleinstreuer, Nicole; Casey, Warren

2018-04-01

Acute systemic toxicity data are used by a number of U.S. federal agencies, most commonly for hazard classification and labeling and/or risk assessment for acute chemical exposures. To identify opportunities for the implementation of non-animal approaches to produce these data, the regulatory needs and uses for acute systemic toxicity information must first be clarified. Thus, we reviewed acute systemic toxicity testing requirements for six U.S. agencies (Consumer Product Safety Commission, Department of Defense, Department of Transportation, Environmental Protection Agency, Food and Drug Administration, Occupational Safety and Health Administration) and noted whether there is flexibility in satisfying data needs with methods that replace or reduce animal use. Understanding the current regulatory use and acceptance of non-animal data is a necessary starting point for future method development, optimization, and validation efforts. The current review will inform the development of a national strategy and roadmap for implementing non-animal approaches to assess potential hazards associated with acute exposures to industrial chemicals and medical products. The Acute Toxicity Workgroup of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), U.S. agencies, non-governmental organizations, and other stakeholders will work to execute this strategy. Copyright © 2018 Elsevier Inc. All rights reserved.

Scenario-targeted toxicity assessment through multiple endpoint bioassays in a soil posing unacceptable environmental risk according to regulatory screening values.

PubMed

Rodriguez-Ruiz, A; Etxebarria, J; Boatti, L; Marigómez, I

2015-09-01

Lanestosa is a chronically polluted site (derelict mine) where the soil (Lanestosa (LA) soil) exceeds screening values (SVs) of regulatory policies in force (Basque Country; Europe) for Zn, Pb and Cd. A scenario-targeted toxicity assessment was carried out on the basis of a multi-endpoint bioassay approach. Acute and chronic toxicity bioassays were conducted with selected test species (Vibrio fischeri, Dictyostelium discoideum, Lactuca sativa, Raphanus sativus and Eisenia fetida) in combination with chemical analysis of soils and elutriates and with bioaccumulation studies in earthworms. Besides, the toxicity profile was compared with that of the mine runoff (RO) soil and of a fresh artificially polluted soil (LAAPS) resembling LA soil pollutant profile. Extractability studies in LA soil revealed that Pb, Zn and Cd were highly available for exchange and/or release into the environment. Indeed, Pb and Zn were accumulated in earthworms and LA soil resulted to be toxic. Soil respiration, V. fischeri, vegetative and developmental cycles of D. discoideum and survival and juvenile production of E. fetida were severely affected. These results confirmed that LA soil had unacceptable environmental risk and demanded intervention. In contrast, although Pb and Zn concentrations in RO soil revealed also unacceptable risk, both metal extractability and toxicity were much lower than in LA soil. Thus, within the polluted site, the need for intervention varied between areas that posed dissimilar risk. Besides, since LAAPS, with a high exchangeable metal fraction, was the most toxic, ageing under in situ natural conditions seemingly contributed to attenuate LA soil risk. As a whole, combining multi-endpoint bioassays with scenario-targeted analysis (including leaching and ageing) provides reliable risk assessment in soils posing unacceptable environmental risk according to SVs, which is useful to optimise the required intervention measures.

Validation of the "Security Needs Assessment Profile" for measuring the profiles of security needs of Chinese forensic psychiatric inpatients.

PubMed

Siu, B W M; Au-Yeung, C C Y; Chan, A W L; Chan, L S Y; Yuen, K K; Leung, H W; Yan, C K; Ng, K K; Lai, A C H; Davies, S; Collins, M

Mapping forensic psychiatric services with the security needs of patients is a salient step in service planning, audit and review. A valid and reliable instrument for measuring the security needs of Chinese forensic psychiatric inpatients was not yet available. This study aimed to develop and validate the Chinese version of the Security Needs Assessment Profile for measuring the profiles of security needs of Chinese forensic psychiatric inpatients. The Security Needs Assessment Profile by Davis was translated into Chinese. Its face validity, content validity, construct validity and internal consistency reliability were assessed by measuring the security needs of 98 Chinese forensic psychiatric inpatients. Principal factor analysis for construct validity provided a six-factor security needs model explaining 68.7% of the variance. Based on the Cronbach's alpha coefficient, the internal consistency reliability was rated as acceptable for procedural security (0.73), and fair for both physical security (0.62) and relational security (0.58). A significant sex difference (p=0.002) in total security score was found. The Chinese version of the Security Needs Assessment Profile is a valid and reliable instrument for assessing the security needs of Chinese forensic psychiatric inpatients. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Are acute toxicity testing and the three Rs rule reconcilable? Example of the lethal dose 50 determination].

PubMed

Dorandeu, Fr; Lallement, G

2003-11-01

Toxicity assessment and demonstration of innocuousness of chemical compounds have been part of the research studies conducted in the fields of pharmacy, agriculture and chemical industry for years. Acute systemic toxicity studies are an important element of the safety evaluation. They remain compulsory for regulatory purposes and important for the public opinion that does not accept the risk anymore. Evolutions of the ethics in animal experiments foster a necessary reduction of the number of animals involved in this type of experiments, following the well-known principle of the three Rs rule of Russell and Burch (1959) (Reduction, refinement and replacement). These two views seem in contradiction. Using the example of acute toxicity testing and focusing on the now very criticized parameter lethal dose 50, we will present approaches, including statistical ones, that a toxicologist can use, when free to choose, to keep on conducting the indispensable in vivo studies while abiding by ethical recommendations.

Assessment of toxicological profiles of the municipal wastewater effluents using chemical analyses and bioassays.

PubMed

Smital, Tvrtko; Terzic, Senka; Zaja, Roko; Senta, Ivan; Pivcevic, Branka; Popovic, Marta; Mikac, Iva; Tollefsen, Knut Erik; Thomas, Kevin V; Ahel, Marijan

2011-05-01

The hazardous chemical contamination of untreated wastewater and secondary effluent from the wastewater treatment plant (WWTP) of the city of Zagreb, Croatia was comprehensively characterized using large-volume solid-phase extraction (SPE) and silica gel fractionation, followed by a detailed analysis of the resulting extracts by a combination of chemical and bioassay methods. Over 100 individual contaminants or closely related-contaminant groups were identified by high-resolution gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-QTOF). Ecotoxicity profiling of the investigated samples, including cytotoxicity, chronic toxicity and EROD activity; inhibition of the multixenobiotic resistance (MXR), genotoxicity and estrogenic potential, revealed the most significant contribution of toxic compounds to be present in polar fractions. Wastewater treatment using conventional activated sludge process reduced the initial toxicity of raw wastewater to various extents, ranging from 28% for algal toxicity to 73.2% for an estrogenic activity. The most efficient toxicity removal was observed for the polar compounds. Copyright © 2010 Elsevier Inc. All rights reserved.

Behavioral, clinical, and pathological characterization of acid metalliferous water toxicity in mallards

USGS Publications Warehouse

Isanhart, J.P.; Wu, H.; Pandher, K.; MacRae, R.K.; Cox, S.B.; Hooper, M.J.

2011-01-01

From September to November 2000, United States Fish and Wildlife Service biologists investigated incidents involving 221 bird deaths at 3 mine sites located in New Mexico and Arizona. These bird deaths primarily involved passerine and waterfowl species and were assumed to be linked to consumption of acid metalliferous water (AMW). Because all of the carcasses were found in or near pregnant leach solution ponds, tailings ponds, and associated lakes or storm water retention basins, an acute-toxicity study was undertaken using a synthetic AMW (SAMW) formulation based on the contaminant profile of a representative pond believed to be responsible for avian mortalities. An acute oral-toxicity trial was performed with a mixed-sex group of mallards (Anas platyrhynchos). After a 24-h pretreatment food and water fast, gorge drinking was evident in both SAMW treatment and control groups, with water consumption rates greatest during the initial drinking periods. Seven of nine treated mallards were killed in extremis within 12 h after the initiation of dose. Total lethal doses of SAMW ranged from 69.8 to 270.1 mL/kg (mean ?? SE 127.9 ?? 27.1). Lethal doses of SAMW were consumed in as few as 20 to 40 min after first exposure. Clinical signs of SAMW toxicity included increased serum uric acid, aspartate aminotransferase, creatine kinase, potassium, and P levels. PCV values of SAMW-treated birds were also increased compared with control mallards. Histopathological lesions were observed in the esophagus, proventriculus, ventriculus, and duodenum of SAMW-treated mallards, with the most distinctive being erosion and ulceration of the kaolin of the ventriculus, ventricular hemorrhage and/or congestion, and duodenal hemorrhage. Clinical, pathological, and tissue-residue results from this study are consistent with literature documenting acute metal toxicosis, especially copper (Cu), in avian species and provide useful diagnostic profiles for AMW toxicity or mortality events. Blood and

Behavioral, clinical, and pathological characterization of acid metalliferous water toxicity in mallards

USGS Publications Warehouse

Isanhart, John P.; Wu, Hongmei; Pandher, Karamjeet; MacRae, Russell K.; Cox, Stephen B.; Hooper, Michael J.

2011-01-01

From September to November 2000, United States Fish and Wildlife Service biologists investigated incidents involving 221 bird deaths at 3 mine sites located in New Mexico and Arizona. These bird deaths primarily involved passerine and waterfowl species and were assumed to be linked to consumption of acid metalliferous water (AMW). Because all of the carcasses were found in or near pregnant leach solution ponds, tailings ponds, and associated lakes or storm water retention basins, an acute-toxicity study was undertaken using a synthetic AMW (SAMW) formulation based on the contaminant profile of a representative pond believed to be responsible for avian mortalities. An acute oral-toxicity trial was performed with a mixed-sex group of mallards (Anas platyrhynchos). After a 24-h pretreatment food and water fast, gorge drinking was evident in both SAMW treatment and control groups, with water consumption rates greatest during the initial drinking periods. Seven of nine treated mallards were killed in extremis within 12 h after the initiation of dose. Total lethal doses of SAMW ranged from 69.8 to 270.1 mL/kg (mean ± SE 127.9 ± 27.1). Lethal doses of SAMW were consumed in as few as 20 to 40 min after first exposure. Clinical signs of SAMW toxicity included increased serum uric acid, aspartate aminotransferase, creatine kinase, potassium, and P levels. PCV values of SAMW-treated birds were also increased compared with control mallards. Histopathological lesions were observed in the esophagus, proventriculus, ventriculus, and duodenum of SAMW-treated mallards, with the most distinctive being erosion and ulceration of the kaolin of the ventriculus, ventricular hemorrhage and/or congestion, and duodenal hemorrhage. Clinical, pathological, and tissue-residue results from this study are consistent with literature documenting acute metal toxicosis, especially copper (Cu), in avian species and provide useful diagnostic profiles for AMW toxicity or mortality events. Blood and

Behavioral, clinical, and pathological characterization of acid metalliferous water toxicity in mallards.

PubMed

Isanhart, John P; Wu, Hongmei; Pandher, Karamjeet; MacRae, Russell K; Cox, Stephen B; Hooper, Michael J

2011-11-01

From September to November 2000, United States Fish and Wildlife Service biologists investigated incidents involving 221 bird deaths at 3 mine sites located in New Mexico and Arizona. These bird deaths primarily involved passerine and waterfowl species and were assumed to be linked to consumption of acid metalliferous water (AMW). Because all of the carcasses were found in or near pregnant leach solution ponds, tailings ponds, and associated lakes or storm water retention basins, an acute-toxicity study was undertaken using a synthetic AMW (SAMW) formulation based on the contaminant profile of a representative pond believed to be responsible for avian mortalities. An acute oral-toxicity trial was performed with a mixed-sex group of mallards (Anas platyrhynchos). After a 24-h pretreatment food and water fast, gorge drinking was evident in both SAMW treatment and control groups, with water consumption rates greatest during the initial drinking periods. Seven of nine treated mallards were killed in extremis within 12 h after the initiation of dose. Total lethal doses of SAMW ranged from 69.8 to 270.1 mL/kg (mean ± SE 127.9 ± 27.1). Lethal doses of SAMW were consumed in as few as 20 to 40 min after first exposure. Clinical signs of SAMW toxicity included increased serum uric acid, aspartate aminotransferase, creatine kinase, potassium, and P levels. PCV values of SAMW-treated birds were also increased compared with control mallards. Histopathological lesions were observed in the esophagus, proventriculus, ventriculus, and duodenum of SAMW-treated mallards, with the most distinctive being erosion and ulceration of the kaolin of the ventriculus, ventricular hemorrhage and/or congestion, and duodenal hemorrhage. Clinical, pathological, and tissue-residue results from this study are consistent with literature documenting acute metal toxicosis, especially copper (Cu), in avian species and provide useful diagnostic profiles for AMW toxicity or mortality events. Blood and

Dactinomycin and Vincristine Toxicity in the Treatment of Childhood Cancer: A Retrospective Study from the Children’s Oncology Group

PubMed Central

Langholz, Bryan; Skolnik, Jeffrey M.; Barrett, Jeffrey S.; Renbarger, Jamie; Seibel, Nita L.; Zajicek, Anne; Arndt, Carola A.S.

2011-01-01

Background Dactinomycin (AMD) and vincristine (VCR) have been used for the treatment of childhood cancer over the past 40 years but evidence-based dosing guidance is lacking. Methods Patient AMD and VCR dose and drug-related adverse event (AE) information from four rhabdomyosarcoma (RMS) and two Wilms tumor (WT) studies were assembled. Statistical modeling was used to account for differences in AE data collection across studies, develop rate models for grade 3/4 CTCAE v3 hepatic- (AMD) and neuro- (AMD) toxicity, assess variation in toxicity rates over age and other factors, and predict toxicity risk under current dosing guidelines. Results For the same dose/body size, AMD toxicity rates were higher in patients <1 year than older patients and VCR toxicity rates increased with age. The statistical model provided estimates for AMD and VCR toxicity risk under current dosing schedules and indicated that patients of smaller body size were at lower risk of VCR toxicity than larger patients of the same age. The rate of AMD toxicity was highest early in treatment and was lower in patients who tolerated initial AMD without toxicity. Conclusion The observed decrease in AMD toxicity rate with cumulative dose may indicate sensitivity in a subgroup of patients while the observed increase in VCR toxicity risk with age may indicate changing sensitivity to VCR. Current dosing practices result in a fairly uniform toxicity profile within age group. However, PK/PD studies should be done to provide further provide further information on best dosing guidelines. PMID:21671362

Toxic metal(loid)-based pollutants and their possible role in autism spectrum disorder.

PubMed

Bjørklund, Geir; Skalny, Anatoly V; Rahman, Md Mostafizur; Dadar, Maryam; Yassa, Heba A; Aaseth, Jan; Chirumbolo, Salvatore; Skalnaya, Margarita G; Tinkov, Alexey A

2018-06-11

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, verbal and non-verbal communication, and stereotypic behaviors. Many studies support a significant relationship between many different environmental factors in ASD etiology. These factors include increased daily exposure to various toxic metal-based environmental pollutants, which represent a cause for concern in public health. This article reviews the most relevant toxic metals, commonly found, environmental pollutants, i.e., lead (Pb), mercury (Hg), aluminum (Al), and the metalloid arsenic (As). Additionally, it discusses how pollutants can be a possible pathogenetic cause of ASD through various mechanisms including neuroinflammation in different regions of the brain, fundamentally occurring through elevation of the proinflammatory profile of cytokines and aberrant expression of nuclear factor kappa B (NF-κB). Due to the worldwide increase in toxic environmental pollution, studies on the role of pollutants in neurodevelopmental disorders, including direct effects on the developing brain and the subjects' genetic susceptibility and polymorphism, are of utmost importance to achieve the best therapeutic approach and preventive strategies. Copyright © 2018 Elsevier Inc. All rights reserved.

Toxicity, toxicokinetics and biodistribution of dextran stabilized Iron oxide Nanoparticles for biomedical applications.

PubMed

Remya, N S; Syama, S; Sabareeswaran, A; Mohanan, P V

2016-09-10

Advancement in the field of nanoscience and technology has alarmingly raised the call for comprehending the potential health effects caused by deliberate or unintentional exposure to nanoparticles. Iron oxide magnetic nanoparticles have an increasing number of biomedical applications and hence a complete toxicological profile of the nanomaterial is therefore a mandatory requirement prior to its intended usage to ensure safety and to minimize potential health hazards upon its exposure. The present study elucidates the toxicity of in house synthesized Dextran stabilized iron oxide nanoparticles (DINP) in a regulatory perspective through various routes of exposure, its associated molecular, immune, genotoxic, carcinogenic effects and bio distribution profile. Synthesized ferrite nanomaterials were successfully coated with dextran (<25nm) and were physicochemically characterized and subjected to in vitro and in vivo toxicity evaluations. The results suggest that surface coating of ferrite nanoparticles with dextran helps in improvising particle stability in biological environments. The nanoparticles do not seem to induce oxidative stress mediated toxicological effects, nor altered physiological process or behavior changes or visible pathological lesions. Furthermore no anticipated health hazards are likely to be associated with the use of DINP and could be concluded that the synthesized DINP is nontoxic/safe to be used for biomedical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

UPLC/ESI-QTOF-MS-based metabolomics survey on the toxicity of triptolide and detoxication of licorice.

PubMed

Wang, Zhuo; Liu, Jian-Qun; Xu, Jin-Di; Zhu, He; Kong, Ming; Zhang, Guo-Hua; Duan, Su-Min; Li, Xiu-Yang; Li, Guang-Fu; Liu, Li-Fang; Li, Song-Lin

2017-06-01

Triptolide (TP) from Tripterygium wilfordii has been demonstrated to possess anti-inflammatory, immunosuppressive, and anticancer activities. TP is specially used for the treatment of awkward rheumatoid arthritis, but its clinical application is confined by intense side effects. It is reported that licorice can obviously reduce the toxicity of TP, but the detailed mechanisms involved have not been comprehensively investigated. The current study aimed to explore metabolomics characteristics of the toxic reaction induced by TP and the intervention effect of licorice water extraction (LWE) against such toxicity. Obtained urine samples from control, TP and TP + LWE treated rats were analyzed by UPLC/ESI-QTOF-MS. The metabolic profiles of the control and the TP group were well differentiated by the principal component analysis and orthogonal partial least squares-discriminant analysis. The toxicity of TP was demonstrated to be evolving along with the exposure time of TP. Eight potential biomarkers related to TP toxicity were successfully identified in urine samples. Furthermore, LWE treatment could attenuate the change in six of the eight identified biomarkers. Functional pathway analysis revealed that the alterations in these metabolites were associated with tryptophan, pantothenic acid, and porphyrin metabolism. Therefore, it was concluded that LWE demonstrated interventional effects on TP toxicity through regulation of tryptophan, pantothenic acid, and porphyrin metabolism pathways, which provided novel insights into the possible mechanisms of TP toxicity as well as the potential therapeutic effects of LWE against such toxicity. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Mixture toxicity of wood preservative products in the fish embryo toxicity test.

PubMed

Coors, Anja; Dobrick, Jan; Möder, Monika; Kehrer, Anja

2012-06-01

Wood preservative products are used globally to protect wood from fungal decay and insects. We investigated the aquatic toxicity of five commercial wood preservative products, the biocidal active substances and some formulation additives contained therein, as well as six generic binary mixtures of the active substances in the fish embryo toxicity test (FET). Median lethal concentrations (LC50) of the single substances, the mixtures, and the products were estimated from concentration-response curves and corrected for concentrations measured in the test medium. The comparison of the experimentally observed mixture toxicity with the toxicity predicted by the concept of concentration addition (CA) showed less than twofold deviation for all binary mixtures of the active substances and for three of the biocidal products. A more than 60-fold underestimation of the toxicity of the fourth product by the CA prediction was detected and could be explained fully by the toxicity of one formulation additive, which had been labeled as a hazardous substance. The reason for the 4.6-fold underestimation of toxicity of the fifth product could not be explained unambiguously. Overall, the FET was found to be a suitable screening tool to verify whether the toxicity of formulated wood preservatives can reliably be predicted by CA. Applied as a quick and simple nonanimal screening test, the FET may support approaches of applying component-based mixture toxicity predictions within the environmental risk assessment of biocidal products, which is required according to European regulations. Copyright © 2012 SETAC.

Systematic and comprehensive investigation of the toxicity of curcuminoid‑essential oil complex: A bioavailable turmeric formulation.

PubMed

Aggarwal, Madan L; Chacko, Karampendethu M; Kuruvilla, Binu T

2016-01-01

Curcumin, the active component present in Curcuma longa of the family Zingiberaceae, has a number of pharmacological effects, including potential anti‑inflammatory activity. One of the major limitations of curcumin/turmeric extract is its poor absorption through the gastrointestinal tract. Several approaches have been adopted to increase the bioavailability of curcumin, including loading curcumin into liposomes or nanoparticles, complexation with phospholipids, addition of essential oils and synthesizing structural analogues of curcumin. In the present study, the toxicity and safety of one such bioavailable turmeric formulation, curcuminoid‑essential oil complex (CEC), the toxicity profile of which has not been reported, were examined using in vivo and in vitro models, as per the guidelines of the Organisation for Economic Co-operation and Development. Investigations of acute toxicity study were performed in rats and mice, and the results revealed no signs and symptoms or toxicity or mortality in any of the animals at the maximum recommended dose level of 5,000 mg/kg body weight. The repeated administration of CEC for 90 days in Wistar rats at a dose of 1,000 mg/kg body weight did not induce any observable toxic effects, compared with corresponding control animals. Mutagenicity/genotoxicity investigations were also performed using a bacterial reverse mutation assay (Ames test), a mammalian bone marrow chromosome aberration test and a mammalian erythrocyte micronucleus test in mice. CEC was found to be non‑mutagenic in all three mutagenic investigations. Consequently, the present study indicated that CEC elicited no toxic effects in animals or in vitro. Therefore, following investigations of acute toxicity, repeated dose toxicity and mutagenicity, CEC was deemed a safe, non‑toxic pharmacological formulation.

Implication of global environmental changes on chemical toxicity-effect of water temperature, pH, and ultraviolet B irradiation on acute toxicity of several pharmaceuticals in Daphnia magna.

PubMed

Kim, Jungkon; Park, Jeongim; Kim, Pan-Gyi; Lee, Chulwoo; Choi, Kyunghee; Choi, Kyungho

2010-04-01

Global environmental change poses emerging environmental health challenges throughout the world. One of such threats could be found in chemical safety in aquatic ecosystem. In the present study, we evaluated the effect of several environmental factors, such as water pH, temperature and ultraviolet light on the toxicity of pharmaceutical compounds in water, using freshwater invertebrate Daphnia magna. Seven pharmaceuticals including ibuprofen, acetaminophen, lincomycin, ciprofloxacin, enrofloxacin, chlortetracycline and sulfathiazole were chosen as test compounds based on their frequent detection in water. The experimental conditions of environmental parameters were selected within the ranges that could be encountered in temperate environment, i.e., water temperature (15, 21, and 25 degrees C), pH (7.4, 8.3, and 9.2), and UV-B light intensity (continuous irradiation of 15.0 microW/cm(2)). For acetaminophen, enrofloxacin and sulfathiazole, decrease in water pH generally led to increase of acute lethal toxicity, which could be explained by the unionized fraction of pharmaceuticals. Increase of water temperature enhanced the acute toxicity of the acetaminophen, enrofloxacin and chlortetracycline, potentially due to alteration in toxicokinetics of chemicals as well as impact on physiological mechanisms of the test organism. The presence of UV-B light significantly increased the toxicity of sulfathiazole, which could be explained by photo-modification of this chemical that lead to oxidative stress. Under the UV light, however, acute toxicity of enrofloxacin decreased, which might be due to photo-degradation. Since changing environmental conditions could affect exposure and concentration-response profile of environmental contaminants, such conditions should be identified and evaluated in order to better manage ecosystem health under changing global environment.

[Immunological adjuvants. Determinant factors in the efficacy-toxicity ratio of the contemporary vaccines].

PubMed

Batista-Duharte, Alexander; Lastre, Miriam; Pérez, Oliver

2014-02-01

To achieve effective and safe vaccines for the prevention of not yet controlled or re-emergent infectious diseases, one of the more importance aspects is to have immunological adjuvants that allow inducing a protective immune response with an appropriate safety profile. Since 1926 the aluminium compounds have been used as adjuvants for human vaccines, and only in the last 10 years have some new products been registered. Although there an enormous quantity of proposed candidates, the toxicity is the main factor that has limited their introduction into the clinic. In this work the mechanism of action are updated, and the toxicity of the immunological adjuvants are revised, especially those that have obtained clinical approval or are close to getting it. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Gene Transcription, Metabolite and Lipid Profiling in Eco-Indicator Daphnia magna Indicate Diverse Mechanisms of Toxicity by Legacy and Emerging Flame-Retardants

EPA Science Inventory

The use of chemical flame-retardants (FR) in consumer products has steadily increased over the last 30 years. Toxicity data exist for legacy FRs such as pentabromodiphenyl ether (pentaBDE), but less is known about effects of new formulations. To address this issue, the toxicity o...

The protection of glycyrrhetinic acid (GA) towards acetaminophen (APAP)-induced toxicity partially through fatty acids metabolic pathway.

PubMed

Yang, Hua; Jiang, Tingshu; Li, Ping; Mao, Qishan

2015-09-01

Acetaminophen (APAP)-induced liver toxicity remains the key factor limiting the clinical application of APAP, and herbs are the important sources for isolation of compounds preventing APAP-induced toxicity. To investigate the protection mechanism of glycyrrhetinic acid towards APAP-induced liver damage using metabolomics method. APAP-induced liver toxicity model was made through intraperitoneal injection (i.p.) of APAP (400 mg/kg). Glycyrrhetinic acid was dissolved in corn oil, and intraperitoneal injection (i.p.) of glycyrrhetinic acid (500 mg/kg body weight) was performed for 20 days before the injection of APAP. UPLC-ESI-QTOF MS was employed to analyze the metabolomic profile of serum samples. The pre-treatment of glycyrrhetinic acid significantly protected APAP-induced toxicity, indicated by the histology of liver, the activity of ALT and AST. Metabolomics showed that the level of palmtioylcarnitine and oleoylcarnitine significantly increased in serum of APAP-treated mice, and the pre-treatment with GA can prevent this elevation of these two fatty acid-carnitines. Reversing the metabolism pathway of fatty acid is an important mechanism for the protection of glycyrrhetinic acid towards acetaminophen-induced liver toxicity.

Toxicity profile of ethanolic extract of Azadirachta indica stem bark in male Wistar rats.

PubMed

Ashafa, Anofi Omotayo Tom; Orekoya, Latifat Olubukola; Yakubu, Musa Toyin

2012-10-01

To investigate the toxic implications of ethanolic stem bark extract of Azadirachta indica (A. indica) at 50, 100, 200 and 300 mg/kg body weight in Wistar rats. Fifty male rats of Wistar strains were randomly grouped into five (A-E) of ten animals each. Animals in Group A (control) were orally administered 1 mL of distilled water on daily basis for 21 days while those in Groups B-E received same volume of the extract corresponding to 50, 100, 200 and 300 mg/kg body weight. The extract did not significantly (P>0.05) alter the levels of albumin, total protein, red blood cells and factors relating to it whereas the white blood cell, platelets, serum triacylglycerol and high-density lipoprotein cholesterol decreased significantly (P<0.05). In contrast, the final body weights, absolute weights of the liver, kidney, lungs and heart as well as their organ-body weight ratios, serum globulins, total and conjugated bilirubin, serum cholesterol, low-density lipoprotein cholesterol and computed atherogenic index increased significantly. The spleen-body weight ratio, alkaline phosphatase, alanine and aspartate transaminases, sodium, potassium, calcium, feed and water intake were altered at specific doses. Overall, the alterations in the biochemical parameters of toxicity have consequential effects on the normal functioning of the organs of the animals. Therefore, the ethanolic extract of A. indica stem bark at the doses of 50, 100, 200 and 300 mg/kg body weight may not be completely safe as an oral remedy and should be taken with caution if absolutely necessary.

Factor Structure and Reliability of the Dutch Version of Seven Scales of the Communication Profile for the Hearing Impaired (CPHI)

ERIC Educational Resources Information Center

Mokkink, Lidwine B.; Knol, Dirk L.; Zekveld, Adriana A.; Goverts, S. Theo; Kramer, Sophia E.

2009-01-01

Purpose: Seven scales of the Communication Profile for the Hearing Impaired (CPHI; M. E. Demorest & S. A. Erdman, 1987) were translated into Dutch: Maladaptive Behavior, Verbal Strategies, and Nonverbal Strategies (within the area of Communication Strategies) and Self-Acceptance, Acceptance of Loss, Stress, and Withdrawal (within the area of…

Weathering and aging of 2,4,6-trinitrotoluene in soil increases toxicity to potworm Enchytraeus crypticus.

PubMed

Kuperman, Roman G; Checkai, Ronald T; Simini, Michael; Phillips, Carlton T; Kolakowski, Jan E; Kurnas, Carl W

2005-10-01

Energetic materials are employed in a wide range of commercial and military activities and often are released into the environment. Scientifically based ecological soil-screening levels (Eco-SSLs) are needed to identify contaminant explosive levels in soil that present an acceptable ecological risk. Insufficient information for 2,4,6-trinitrotoluene (TNT) to generate Eco-SSLs for soil invertebrates necessitated toxicity testing. We adapted the standardized Enchytraeid Reproduction Test and selected Enchytraeus crypticus for these studies. Tests were conducted in Sassafras sandy loam soil, which supports relatively high bioavailability of TNT. Weathering and aging procedures for TNT amended to test soil were incorporated into the study design to produce toxicity data that better reflect the soil exposure conditions in the field compared with toxicity in freshly amended soils. This included exposing hydrated TNT-amended soils in open glass containers in the greenhouse to alternating wetting and drying cycles. Definitive tests showed that toxicity for E. crypticus adult survival and juvenile production was increased significantly in weathered and aged soil treatments compared with toxicity in freshly amended soil based on 95% confidence intervals. The median effect concentration and 20% effective concentration for reproduction were 98 and 77 mg/kg, respectively, for TNT freshly amended into soil and 48 and 37 mg/kg, respectively, for weathered and aged TNT soil treatments. These findings of increased toxicity to E. crypticus in weathered and aged TNT soil treatments compared with exposures in freshly amended soils show that future investigations should include a weathering and aging component to generate toxicity data that provide more complete information on ecotoxicological effects of energetic contaminants in soil.

ToxPi Prioritization and Profiling of 1060 ToxCast Chemicals Across Multiple Sectors of Toxicological Concern

EPA Science Inventory

The Toxicological Prioritization Index (ToxPi™) framework was developed as a decision-support tool to aid in the prioritization of chemicals for integrated toxicity testing. ToxPi consolidates information from multiple domains - including ToxCast™ in vitro bioactivity profiles (a...

FBX aqueous chemical dosimeter for measurement of virtual wedge profiles.

PubMed

Semwal, Manoj K; Bansal, Anil K; Thakur, Pradeep K; Vidyasagar, Pandit B

2008-10-24

We investigated the ferrous sulfate-benzoic acid-xylenol orange (FBX) aqueous chemical dosimeter for measurement of virtual (dynamic) wedge profiles on a linear accelerator. The layout for irradiation of the FBX-filled tubes mimicked a conventional linear detector array geometry. A comparison of the resulting measurements with film-measured profiles showed that, in the main beam region, the difference between the FBX system and the film system was within +/-2% and that, in the penumbra region, the difference varied from +/-1 mm to +/-2.5 mm in terms of positional equivalence, depending on the size of the dosimeter tubes. We thus believe that the energy-independent FBX dosimetry system can measure virtual wedge profiles with reasonable accuracy at reasonable cost. However, efficiency improvement is required before this dosimetry system can be accepted into routine practice.

LIMS user acceptance testing.

PubMed

Klein, Corbett S

2003-01-01

Laboratory Information Management Systems (LIMS) play a key role in the pharmaceutical industry. Thorough and accurate validation of such systems is critical and is a regulatory requirement. LIMS user acceptance testing is one aspect of this testing and enables the user to make a decision to accept or reject implementation of the system. This paper discusses key elements in facilitating the development and execution of a LIMS User Acceptance Test Plan (UATP).

Intra-articular administration of lidocaine plus adrenaline in dogs: Pharmacokinetic profile and evaluation of toxicity in vivo and in vitro.

PubMed

Di Salvo, A; Chiaradia, E; della Rocca, G; Mancini, F; Galarini, R; Giusepponi, D; De Monte, V; Cagnardi, P; Marenzoni, M L; Bufalari, A

2016-02-01

The aim of this study was to evaluate the safety of intra-articular (IA) lidocaine plus adrenaline for improving peri-operative analgesia in anaesthetized dogs undergoing arthroscopy of the elbow. A solution of lidocaine (L) 1.98% plus adrenaline 1:100.000 was administered via the IA route and its safety evaluated in terms of cardio-, neuro-, and chondro-toxicity. No bradycardia or hypotension was recorded from induction to the last observational time point. Signs of toxicity of the nervous system could have been masked by the general anaesthesia but lidocaine concentrations detected in the blood were lower than those thought to be capable of producing toxicity. The assessment of in vitro chondrotoxicity showed a dose- and time-dependent effect of lidocaine on the viability of articular cells. Adrenaline appeared to reduce the chondrotoxicity of 1% lidocaine, following an exposure of up to 30 min. Copyright © 2015 Elsevier Ltd. All rights reserved.

Identification of gene expression profiling associated with erlotinib-related skin toxicity in pancreatic adenocarcinoma patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caba, Octavio, E-mail: ocaba@ujaen.es

Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that showed activity against pancreatic ductal adenocarcinoma (PDAC). The drug's most frequently reported side effect as a result of EGFR inhibition is skin rash (SR), a symptom which has been associated with a better therapeutic response to the drug. Gene expression profiling can be used as a tool to predict which patients will develop this important cutaneous manifestation. The aim of the present study was to identify which genes may influence the appearance of SR in PDAC patients. The study included 34 PDAC patients treated with erlotinib: 21 patientsmore » developed any grade of SR, while 13 patients did not (controls). Before administering any chemotherapy regimen and the development of SR, we collected RNA from peripheral blood samples of all patients and studied the differential gene expression pattern using the Illumina microarray platform HumanHT-12 v4 Expression BeadChip. Seven genes (FAM46C, IFITM3, GMPR, DENND6B, SELENBP1, NOL10, and SIAH2), involved in different pathways including regulatory, migratory, and signalling processes, were downregulated in PDAC patients with SR. Our results suggest the existence of a gene expression profiling significantly correlated with erlotinib-induced SR in PDAC that could be used as prognostic indicator in this patients. - Highlights: • Skin rash (SR) is the most characteristic side effect of erlotinib in PDAC patients. • Erlotinib-induced SR has been associated with a better clinical outcome. • Gene expression profiling was used to determine who will develop this manifestation. • 7 genes involved in different pathways were downregulated in PDAC patients with SR. • Our profile correlated with erlotinib-induced SR in PDAC could be used for prognosis.« less

Aluminum Toxicity-Induced Alterations of Leaf Proteome in Two Citrus Species Differing in Aluminum Tolerance

PubMed Central

Li, Huan; Yang, Lin-Tong; Qi, Yi-Ping; Guo, Peng; Lu, Yi-Bin; Chen, Li-Song

2016-01-01

Seedlings of aluminum-tolerant ‘Xuegan’ (Citrus sinensis) and Al-intolerant ‘sour pummelo’ (Citrus grandis) were fertigated for 18 weeks with nutrient solution containing 0 and 1.2 mM AlCl3·6H2O. Al toxicity-induced inhibition of photosynthesis and the decrease of total soluble protein only occurred in C. grandis leaves, demonstrating that C. sinensis had higher Al tolerance than C. grandis. Using isobaric tags for relative and absolute quantification (iTRAQ), we obtained more Al toxicity-responsive proteins from C. sinensis than from C. grandis leaves, which might be responsible for the higher Al tolerance of C. sinensis. The following aspects might contribute to the Al tolerance of C. sinensis: (a) better maintenance of photosynthesis and energy balance via inducing photosynthesis and energy-related proteins; (b) less increased requirement for the detoxification of reactive oxygen species and other toxic compounds, such as aldehydes, and great improvement of the total ability of detoxification; and (c) upregulation of low-phosphorus-responsive proteins. Al toxicity-responsive proteins related to RNA regulation, protein metabolism, cellular transport and signal transduction might also play key roles in the higher Al tolerance of C. sinensis. We present the global picture of Al toxicity-induced alterations of protein profiles in citrus leaves, and identify some new Al toxicity-responsive proteins related to various biological processes. Our results provide some novel clues about plant Al tolerance. PMID:27455238

TOXICITY CHARACTERIZATION PROCEDURES FOR ORGANIC TOXICANTS IN BULK SEDIMENTS

EPA Science Inventory

We have been pursuing development of toxicant characterization, isolation, and identification procedures for organic toxicants that can be applied in the context of 10-d solid-phase sediment tests measuring survival and growth of freshwater in the context of 10-d solid-phase sedi...

Prevalidation of the ex-vivo model PCLS for prediction of respiratory toxicity.

PubMed

Hess, A; Wang-Lauenstein, L; Braun, A; Kolle, S N; Landsiedel, R; Liebsch, M; Ma-Hock, L; Pirow, R; Schneider, X; Steinfath, M; Vogel, S; Martin, C; Sewald, K

2016-04-01

In acute inhalation toxicity studies, animals inhale substances at given concentrations. Without additional information, however, appropriate starting concentrations for in-vivo inhalation studies are difficult to estimate. The goal of this project was the prevalidation of precision-cut lung slices (PCLS) as an ex-vivo alternative to reduce the number of animals used in inhalation toxicity studies. According to internationally agreed principles for Prevalidation Studies, the project was conducted in three independent laboratories. The German BfR provided consultancy in validation principles and independent support with biostatistics. In all laboratories, rat PCLS were prepared and exposed to 5 concentrations of 20 industrial chemicals under submerged culture conditions for 1h. After 23 h post-incubation, toxicity was assessed by measurement of released lactate dehydrogenase and mitochondrial activity. In addition, protein content and pro-inflammatory cytokine IL-1α were measured. For all endpoints IC50 values were calculated if feasible. For each endpoint test acceptance criteria were established. This report provides the final results for all 20 chemicals. More than 900 concentration-response curves were analyzed. Log10[IC50 (μM)], obtained for all assay endpoints, showed best intra- and inter-laboratory consistency for the data obtained by WST-1 and BCA assays. While WST-1 and LDH indicated toxic effects for the majority of substances, only some of the substances induced an increase in extracellular IL-1α. Two prediction models (two-group classification model, prediction of LC50 by IC50) were developed and showed promising results. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Local Control and Toxicity in a Large Cohort of Central Lung Tumors Treated With Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Modh, Ankit; Rimner, Andreas; Williams, Eric

2014-12-01

Purpose: Stereotactic body radiation therapy (SBRT) in central lung tumors has been associated with higher rates of severe toxicity. We sought to evaluate toxicity and local control in a large cohort and to identify predictive dosimetric parameters. Methods and Materials: We identified patients who received SBRT for central tumors according to either of 2 definitions. Local failure (LF) was estimated using a competing risks model, and multivariate analysis (MVA) was used to assess factors associated with LF. We reviewed patient toxicity and applied Cox proportional hazard analysis and log-rank tests to assess whether dose-volume metrics of normal structures correlated with pulmonarymore » toxicity. Results: One hundred twenty-five patients received SBRT for non-small cell lung cancer (n=103) or metastatic lesions (n=22), using intensity modulated radiation therapy. The most common dose was 45 Gy in 5 fractions. Median follow-up was 17.4 months. Incidence of toxicity ≥ grade 3 was 8.0%, including 5.6% pulmonary toxicity. Sixteen patients (12.8%) experienced esophageal toxicity ≥ grade 2, including 50% of patients in whom PTV overlapped the esophagus. There were 2 treatment-related deaths. Among patients receiving biologically effective dose (BED) ≥80 Gy (n=108), 2-year LF was 21%. On MVA, gross tumor volume (GTV) was significantly associated with LF. None of the studied dose-volume metrics of the lungs, heart, proximal bronchial tree (PBT), or 2 cm expansion of the PBT (“no-fly-zone” [NFZ]) correlated with pulmonary toxicity ≥grade 2. There were no differences in pulmonary toxicity between central tumors located inside the NFZ and those outside the NFZ but with planning target volume (PTV) intersecting the mediastinum. Conclusions: Using moderate doses, SBRT for central lung tumors achieves acceptable local control with low rates of severe toxicity. Dosimetric analysis showed no significant correlation between dose to the lungs, heart, or NFZ

Sediment Toxicity Identification Evaluation

EPA Science Inventory

Approach combining chemical manipulations and aquatic toxicity testing, generally with whole organisms, to systematically characterize, identify and confirm toxic substances causing toxicity in whole sediments and sediment interstitial waters. The approach is divided into thre...

FDA-approved drugs that protect mammalian neurons from glucose toxicity slow aging dependent on cbp and protect against proteotoxicity.

PubMed

Lublin, Alex; Isoda, Fumiko; Patel, Harshil; Yen, Kelvin; Nguyen, Linda; Hajje, Daher; Schwartz, Marc; Mobbs, Charles

2011-01-01

Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications.

Predictors of Toxicity After Image-guided High-dose-rate Interstitial Brachytherapy for Gynecologic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Larissa J.; Viswanathan, Akila N., E-mail: aviswanathan@lroc.harvard.edu

2012-12-01

Purpose: To identify predictors of grade 3-4 complications and grade 2-4 rectal toxicity after three-dimensional image-guided high-dose-rate (HDR) interstitial brachytherapy for gynecologic cancer. Methods and Materials: Records were reviewed for 51 women (22 with primary disease and 29 with recurrence) treated with HDR interstitial brachytherapy. A single interstitial insertion was performed with image guidance by computed tomography (n = 43) or magnetic resonance imaging (n = 8). The median delivered dose in equivalent 2-Gy fractions was 72.0 Gy (45 Gy for external-beam radiation therapy and 24 Gy for brachytherapy). Toxicity was reported according to the Common Toxicity Criteria for Adversemore » Events. Actuarial toxicity estimates were calculated by the Kaplan-Meier method. Results: At diagnosis, the median patient age was 62 years and the median tumor size was 3.8 cm. The median D90 and V100 were 71.4 Gy and 89.5%; the median D2cc for the bladder, rectum, and sigmoid were 64.6 Gy, 61.0 Gy, and 52.7 Gy, respectively. The actuarial rates of all grade 3-4 complications at 2 years were 20% gastrointestinal, 9% vaginal, 6% skin, 3% musculoskeletal, and 2% lymphatic. There were no grade 3-4 genitourinary complications and no grade 5 toxicities. Grade 2-4 rectal toxicity was observed in 10 patients, and grade 3-4 complications in 4; all cases were proctitis with the exception of 1 rectal fistula. D2cc for rectum was higher for patients with grade 2-4 (68 Gy vs 57 Gy for grade 0-1, P=.03) and grade 3-4 (73 Gy vs 58 Gy for grade 0-2, P=.02) rectal toxicity. The estimated dose that resulted in a 10% risk of grade 2-4 rectal toxicity was 61.8 Gy (95% confidence interval, 51.5-72.2 Gy). Discussion: Image-guided HDR interstitial brachytherapy results in acceptable toxicity for women with primary or recurrent gynecologic cancer. D2cc for the rectum is a reliable predictor of late rectal complications. Three-dimensional-based treatment planning should be performed to

Evaluation of aquatic toxicities of chromium and chromium-containing effluents in reference to chromium electroplating industries.

PubMed

Baral, A; Engelken, R; Stephens, W; Farris, J; Hannigan, R

2006-05-01

This study evaluated aquatic toxicities of chromium and chromium-containing laboratory samples representative of effluents from chromium electroplating industries, and compared the aquatic environmental risks of hexavalent and trivalent chromium electroplating operations. Trivalent chromium electroplating has emerged as an acceptable alternative to hazardous hexavalent chromium electroplating. This process substitution has reduced the human health impact in the workplace and minimized the production of hazardous sludge regulated under the Resource Conservation and Recovery Act (RCRA). The thrust behind this research was to investigate whether trivalent chromium electroplating operations have lower adverse impacts on standardized toxicity test organisms. Ceriodaphnia dubia and Pimephales promelas were used to investigate toxicities of trivalent chromium (Cr (III)), hexavalent chromium (Cr (VI)), and industrial effluents. In agreement with previous studies, Cr (III) was found to be less toxic than Cr (VI). Despite having several organic and inorganic constituents in the effluents obtained from trivalent chromium plating baths, they exhibited less adverse effects to C. dubia than effluents obtained from hexavalent chromium electroplating baths. Thus, transition from hexavalent to trivalent chromium electroplating processes may be justified. However, because of the presence of organic constituents such as formate, oxalate, and triethylene glycol in effluents, trivalent chromium electroplating operations may face additional regulatory requirements for removal of total organic carbon.

Genome-wide transcriptome profiling of black poplar (Populus nigra L.) under boron toxicity revealed candidate genes responsible in boron uptake, transport and detoxification.

PubMed

Yıldırım, Kubilay; Uylaş, Senem

2016-12-01

Boron (B) is an essential nutrient for normal growth of plants. Despite its low abundance in soils, it could be highly toxic to plants in especially arid and semi-arid environments. Poplars are known to be tolerant species to B toxicity and accumulation. However, physiological and gene regulation responses of these trees to B toxicity have not been investigated yet. Here, B accumulation and tolerance level of black poplar clones were firstly tested in the current study. Rooted cutting of these clones were treated with elevated B toxicity to select the most B accumulator and tolerant genotype. Then we carried out a microarray based transcriptome experiment on the leaves and roots of this genotype to find out transcriptional networks, genes and molecular mechanisms behind B toxicity tolerance. The results of the study indicated that black poplar is quite suitable for phytoremediation of B pollution. It could resist 15 ppm soil B content and >1500 ppm B accumulation in leaves, which are highly toxic concentrations for almost all agricultural plants. Transcriptomics results of study revealed totally 1625 and 1419 altered probe sets under 15 ppm B toxicity in leaf and root tissues, respectively. The highest induction were recorded for the probes sets annotated to tyrosine aminotransferase, ATP binding cassette transporters, glutathione S transferases and metallochaperone proteins. Strong up regulation of these genes attributed to internal excretion of B into the cell vacuole and existence of B detoxification processes in black poplar. Many other candidate genes functional in signalling, gene regulation, antioxidation, B uptake and transport processes were also identified in this hyper B accumulator plant for the first time with the current study. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A Systematic Review Comparing the Acceptability, Validity and Concordance of Discrete Choice Experiments and Best-Worst Scaling for Eliciting Preferences in Healthcare.

PubMed

Whitty, Jennifer A; Oliveira Gonçalves, Ana Sofia

2018-06-01

The aim of this study was to compare the acceptability, validity and concordance of discrete choice experiment (DCE) and best-worst scaling (BWS) stated preference approaches in health. A systematic search of EMBASE, Medline, AMED, PubMed, CINAHL, Cochrane Library and EconLit databases was undertaken in October to December 2016 without date restriction. Studies were included if they were published in English, presented empirical data related to the administration or findings of traditional format DCE and object-, profile- or multiprofile-case BWS, and were related to health. Study quality was assessed using the PREFS checklist. Fourteen articles describing 12 studies were included, comparing DCE with profile-case BWS (9 studies), DCE and multiprofile-case BWS (1 study), and profile- and multiprofile-case BWS (2 studies). Although limited and inconsistent, the balance of evidence suggests that preferences derived from DCE and profile-case BWS may not be concordant, regardless of the decision context. Preferences estimated from DCE and multiprofile-case BWS may be concordant (single study). Profile- and multiprofile-case BWS appear more statistically efficient than DCE, but no evidence is available to suggest they have a greater response efficiency. Little evidence suggests superior validity for one format over another. Participant acceptability may favour DCE, which had a lower self-reported task difficulty and was preferred over profile-case BWS in a priority setting but not necessarily in other decision contexts. DCE and profile-case BWS may be of equal validity but give different preference estimates regardless of the health context; thus, they may be measuring different constructs. Therefore, choice between methods is likely to be based on normative considerations related to coherence with theoretical frameworks and on pragmatic considerations related to ease of data collection.

Toxicity Assessment of the Xanthid Crab Demania cultripes from Cebu Island, Philippines

PubMed Central

Asakawa, Manabu; Gomez-Delan, Gloria; Tsuruda, Shintaro; Shimomura, Michitaka; Shida, Yasuo; Taniyama, Shigeto; Barte-Quilantang, Mercy; Shindo, Jo

2010-01-01

Several cases of poisoning resulting in human fatalities and stemming from the ingestion of coral reef crabs have been reported from the Indo-Pacific region. We assessed the toxicity of the unidentified xanthid crab collected from the Camotes Sea off the eastern coast of Cebu Island, central Visayas region of Philippines from the food hygienic point of view. All seven specimens, which were identified with Demania cultripes, collected in 2006 were toxic to mice irrespective of the season of collection and induced paralytic symptoms typical of tetrodotoxin (TTX) and paralytic shellfish poison (PSP). The activity was expressed in mouse unit (MU) being defined as the amount of TTX to kill a 20 g ddY male mice in 30 min after i.p. injection. Toxicity scores for viscera and appendages of specimens were 18.2 ± 16.0 (mean ± S.D.) and 4.4 ± 2.6 MU/g, respectively. The highest individual toxicity scores observed for viscera and appendages were 52.1 and 7.7 MU/g, respectively. The frequency of toxic samples was 100%. Toxin profiles as determined by high-performance liquid chromatography-fluorescent detection analysis (HPLC-FLD) revealed that TTX was the main toxic principle accounting for about 90% of the total toxicity along with 4-epi TTX and 4,9-anhydroTTX. Furthermore, gas chromatography-mass spectrometry (GC-MS) analysis revealed mass fragment ion peaks at m/z 376, 392 and 407, which were characteristic of the quinazoline skeleton (C9-base) specific to TTX. In addition, only a small amount of PSP containing gonyautoxins1–4 and hydroxysaxitoxin was detected. To our knowledge, this is the first report presenting evidence of occurrence of TTX and PSP in the xanthid crab D. cultripes inhabiting waters surrounding Cebu Island. From food hygienic point of view, people in coastal areas should be warned of the potential hazard of this crab in order to prevent its intentional or accidental consumption. PMID:21209702

Distribution of toxic alkaloids in tissues from three herbal medicine Aconitum species using laser micro-dissection, UHPLC-QTOF MS and LC-MS/MS techniques.

PubMed

Jaiswal, Yogini; Liang, Zhitao; Ho, Alan; Wong, LaiLai; Yong, Peng; Chen, Hubiao; Zhao, Zhongzhen

2014-11-01

Aconite poisoning continues to be a major type of poisoning caused by herbal drugs in many countries. Nevertheless, despite its toxic characteristics, aconite is used because of its valuable therapeutic benefits. The aim of the present study was to determine the distribution of toxic alkaloids in tissues of aconite roots through chemical profiling. Three species were studied, all being used in traditional Chinese Medicine (TCM) and traditional Indian medicine (Ayurveda), namely: Aconitum carmichaelii, Aconitum kusnezoffii and Aconitum heterophyllum. Laser micro-dissection was used for isolation of target microscopic tissues, such as the metaderm, cortex, xylem, pith, and phloem, with ultra-high performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS) employed for detection of metabolites. Using a multi-targeted approach through auto and targeted LC-MS/MS, 48 known compounds were identified and the presence of aconitine, mesaconitine and hypaconitine that are the biomarkers of this plant was confirmed in the tissues. These results suggest that the three selected toxic alkaloids were exclusively found in A. carmichaelii and A. kusnezoffii. The most toxic components were found in large A. carmichaelii roots with more lateral root projections, and specifically in the metaderm, cork and vascular bundle tissues. The results from metabolite profiling were correlated with morphological features to predict the tissue specific distribution of toxic components and toxicity differences among the selected species. By careful exclusion of tissues having toxic diester diterpenoid alkaloids, the beneficial effects of aconite can still be retained and the frequency of toxicity occurrences can be greatly reduced. Knowledge of tissue-specific metabolite distribution can guide users and herbal drug manufacturers in prudent selection of relatively safer and therapeutically more effective parts of the root. The information provided from

Management of pulmonary toxicity associated with targeted anticancer therapies.

PubMed

Teuwen, Laure-Anne; Van den Mooter, Tom; Dirix, Luc

2015-01-01

Targeted anticancer therapies act by interfering with defined molecular entities and/or biologic pathways. Because of their more specific mechanism of action, adverse events (AEs) on healthy tissues are intended to be minimal, resulting in a different toxicity profile from that observed with conventional cytotoxic chemotherapy. Pulmonary AEs are rare but potentially life-threatening and it is, therefore, critical to recognize early on and manage appropriately. In this review, we aim to offer an overview of both more frequent and rare pulmonary AEs caused by targeted anticancer therapies and discuss possible treatment algorithms. Anti-vascular endothelial growth factor, anti-human epidermal growth factor receptor and anti-CD20 therapy will be reviewed, as well as immune checkpoint inhibitors, anaplastic lymphoma kinase inhibitors and mammalian target of rapamycin inhibitors. Novel agents used in the treatment of cancer have specific side-effects, the result of allergic reactions, on-target and off-target effects. Clinical syndromes associated with pulmonary toxicity vary from bronchospasms, hypersensitivity reactions, pneumonitis, acute respiratory distress, lung bleeding, pleural effusion to pneumothorax. Knowledge of risk factors, a high index of suspicion and a complete diagnostic work-up are essential for limiting the risk of these events becoming life threatening. The development of treatment algorithms is extremely helpful in managing these events. It is probable that these toxicities will be even more frequent with the introduction of combination therapies with the obvious challenge of discerning the responsible agent.

A toxicity profile of osteoprotegerin in the cynomolgus monkey.

PubMed

Smith, Brenda B; Cosenza, Mary Ellen; Mancini, Audrey; Dunstan, Colin; Gregson, Richard; Martin, Steven W; Smith, Susan Y; Davis, Harold

2003-01-01

Osteoprotegerin (OPG) is a novel secreted glycoprotein of the tumor necrosis factor (TNF) receptor superfamily that acts as an antiresorptive agent inhibiting osteoclast maturation. OPG acts by competitively inhibiting the association of the OPG ligand with the RANK receptor on osteoclasts and osteoclast precursors. This inhibition of osteoclasts can lead to excess accumulation of newly synthesized bone and cartilage in vivo. The purpose of this study was to investigate the potential toxicity of a human recombinant form of OPG in the young cynomolgus monkey. OPG was administered by intravenous (i.v.) or subcutaneous (s.c.) injection three times per week for either 4 or 13 weeks. There were no deaths during the study, no clinical signs related to treatment, no effect on body weight, appetence, or ophthalmology. No toxicologically relevant changes in routine laboratory investigations, organ weights, or gross or histopathological findings were observed. Serum ionized calcium and phosphorus were decreased at all dose levels. Evaluations were performed to monitor biochemical markers of bone resorption (N-telopeptide [NTx], deoxypyridinoline [DPD]), bone formation (skeletal alkaline phosphatase [sALP], osteocalcin [OC]), parathyroid hormone [PTH], and bone density of the proximal tibia and distal radius in vivo. Dose-related decreases in NTx and/or DPD were observed at each dose level, with up to a 90% decrease in NTx noted for animals treated i.v. or s.c. at 15 mg/kg. Similar decreases were observed for sALP and OC. PTH was increased for animals treated at 5 and 15 mg/kg (i.v. or s.c.). Trabecular bone density was increased for the majority of males and females treated i.v. or s.c. at 15 mg/kg and males treated i.v. at 5 mg/kg. Microscopic examination of the sternebrae revealed corresponding increases in bone. Decreases in markers of bone turnover, and corresponding increases in bone density, were consistent with the pharmacological action of OPG as an osteoclast

A toxicity reduction evaluation for an oily waste treatment plant exhibiting episodic effluent toxicity.

PubMed

Erten-Unal, M; Gelderloos, A B; Hughes, J S

1998-07-30

A Toxicity Reduction Evaluation (TRE) was conducted on the oily wastewater treatment plant (Plant) at a Naval Fuel Depot. The Plant treats ship and ballast wastes, berm water from fuel storage areas and wastes generated in the fuel reclamation plant utilizing physical/chemical treatment processes. In the first period of the project (Period I), the TRE included chemical characterization of the plant wastewaters, monitoring the final effluent for acute toxicity and a thorough evaluation of each treatment process and Plant operating procedures. Toxicity Identification Evaluation (TIE) procedures were performed as part of the overall TRE to characterize and identify possible sources of toxicity. Several difficulties were encountered because the effluent was saline, test organisms were marine species and toxicity was sporadic and unpredictable. The treatability approach utilizing enhancements, improved housekeeping, and operational changes produced substantial reductions in the acute toxicity of the final effluent. In the second period (Period II), additional acute toxicity testing and chemical characterization were performed through the Plant to assess the long-term effects of major unit process improvements for the removal of toxicity. The TIE procedures were also modified for saline wastewaters to focus on suspected class of toxicants such as surfactants. The TRE was successful in reducing acute toxicity of the final effluent through process improvements and operational modifications. The results indicated that the cause of toxicity was most likely due to combination of pollutants (matrix effect) rather than a single pollutant.

Biomarkers of Exposure to Toxic Substances: Volume 4: Metabonomics Biomarkers to Liver and Organ Damage

DTIC Science & Technology

2009-05-01

examined the urinary metabolite profiles from rats following a single exposure to the kidney toxicants D- serine, puromycin, hippuric acid and...15. SUBJECT TERMS Amphotericin B, bioinformatics, cell cycle regulation, clinical, clustering analysis, D-serine, glomerular injury, hippuric acid ...puromycin, hippuric acid and amphotericin B at various doses, and as a function of time post-dose. In toxicology, such dose-time metabonomics studies are

Use of the Zebrafish Larvae as a Model to Study Cigarette Smoke Condensate Toxicity

PubMed Central

Ellis, Lee D.; Soo, Evelyn C.; Achenbach, John C.; Morash, Michael G.; Soanes, Kelly H.

2014-01-01

The smoking of tobacco continues to be the leading cause of premature death worldwide and is linked to the development of a number of serious illnesses including heart disease, respiratory diseases, stroke and cancer. Currently, cell line based toxicity assays are typically used to gain information on the general toxicity of cigarettes and other tobacco products. However, they provide little information regarding the complex disease-related changes that have been linked to smoking. The ethical concerns and high cost associated with mammalian studies have limited their widespread use for in vivo toxicological studies of tobacco. The zebrafish has emerged as a low-cost, high-throughput, in vivo model in the study of toxicology. In this study, smoke condensates from 2 reference cigarettes and 6 Canadian brands of cigarettes with different design features were assessed for acute, developmental, cardiac, and behavioural toxicity (neurotoxicity) in zebrafish larvae. By making use of this multifaceted approach we have developed an in vivo model with which to compare the toxicity profiles of smoke condensates from cigarettes with different design features. This model system may provide insights into the development of smoking related disease and could provide a cost-effective, high-throughput platform for the future evaluation of tobacco products. PMID:25526262

Developmental toxicity in flounder embryos exposed to crude oils derived from different geographical regions.

PubMed

Jung, Jee-Hyun; Lee, Eun-Hee; Choi, Kwang-Min; Yim, Un Hyuk; Ha, Sung Yong; An, Joon Geon; Kim, Moonkoo

2017-06-01

Crude oils from distinct geographical regions have distinct chemical compositions, and, as a result, their toxicity may be different. However, developmental toxicity of crude oils derived from different geographical regions has not been extensively characterized. In this study, flounder embryos were separately exposed to effluents contaminated by three crude oils including: Basrah Light (BLO), Pyrenees (PCO), and Sakhalin Vityaz (SVO), in addition to a processed fuel oil (MFO-380), to measure developmental toxicity and for gene expressions. Each oil possessed a distinct chemical composition. Edema defect was highest in embryos exposed to PCO and MFO-380 that both have a greater fraction of three-ring PAHs (33% and 22%, respectively) compared to BLO and SVO. Observed caudal fin defects were higher in embryos exposed to SVO and MFO-380, which are both dominated by naphthalenes (81% and 52%, respectively). CYP1A gene expressions were also highest in embryos exposed to SVO and MFO-380. Higher incidence of cardiotoxicity and lower nkx 2.5 expression were detected in embryos exposed to PCO. Unique gene expression profiles were observed in embryos exposed to crude oils with distinct compositions. This study demonstrates that crude oils of different geographical origins with different compositional characteristics induce developmental toxicity to different degrees. Copyright © 2017 Elsevier Inc. All rights reserved.

Use of the zebrafish larvae as a model to study cigarette smoke condensate toxicity.

PubMed

Ellis, Lee D; Soo, Evelyn C; Achenbach, John C; Morash, Michael G; Soanes, Kelly H

2014-01-01

The smoking of tobacco continues to be the leading cause of premature death worldwide and is linked to the development of a number of serious illnesses including heart disease, respiratory diseases, stroke and cancer. Currently, cell line based toxicity assays are typically used to gain information on the general toxicity of cigarettes and other tobacco products. However, they provide little information regarding the complex disease-related changes that have been linked to smoking. The ethical concerns and high cost associated with mammalian studies have limited their widespread use for in vivo toxicological studies of tobacco. The zebrafish has emerged as a low-cost, high-throughput, in vivo model in the study of toxicology. In this study, smoke condensates from 2 reference cigarettes and 6 Canadian brands of cigarettes with different design features were assessed for acute, developmental, cardiac, and behavioural toxicity (neurotoxicity) in zebrafish larvae. By making use of this multifaceted approach we have developed an in vivo model with which to compare the toxicity profiles of smoke condensates from cigarettes with different design features. This model system may provide insights into the development of smoking related disease and could provide a cost-effective, high-throughput platform for the future evaluation of tobacco products.

DISTRIBUTED STRUCTURE-SEARCHABLE TOXICITY ...

EPA Pesticide Factsheets

The ability to assess the potential genotoxicity, carcinogenicity, or other toxicity of pharmaceutical or industrial chemicals based on chemical structure information is a highly coveted and shared goal of varied academic, commercial, and government regulatory groups. These diverse interests often employ different approaches and have different criteria and use for toxicity assessments, but they share a need for unrestricted access to existing public toxicity data linked with chemical structure information. Currently, there exists no central repository of toxicity information, commercial or public, that adequately meets the data requirements for flexible analogue searching, SAR model development, or building of chemical relational databases (CRD). The Distributed Structure-Searchable Toxicity (DSSTox) Public Database Network is being proposed as a community-supported, web-based effort to address these shared needs of the SAR and toxicology communities. The DSSTox project has the following major elements: 1) to adopt and encourage the use of a common standard file format (SDF) for public toxicity databases that includes chemical structure, text and property information, and that can easily be imported into available CRD applications; 2) to implement a distributed source approach, managed by a DSSTox Central Website, that will enable decentralized, free public access to structure-toxicity data files, and that will effectively link knowledgeable toxicity data s

Gene expression profiling as an initial approach for mechanistic studies of toxicity and tumorigenicity of herbal plants and herbal dietary supplements.

PubMed

Guo, Lei; Mei, Nan; Xia, Qingsu; Chen, Tao; Chan, Po-Chuen; Fu, Peter P

2010-01-01

Dietary supplements are consumed by more than 300 million people worldwide, and herbal dietary supplements represent the most rapidly growing portion of this industry. Even though adverse health effects of many herbal dietary supplements have been reported, safety assurances are not being addressed adequately. Toxicological data on the identification of genotoxic and tumorigenic ingredients in many raw herbs are also lacking. Currently, more than 30 herbal dietary supplements and active ingredients have been selected by the National Toxicology Program (NTP) for toxicity and tumorigenicity studies. Due to the complexity of the chemical components present in plant extracts, there are no established methodologies for determining the mechanisms of toxicity (particularly tumorigenicity) induced by herbs, such as Gingko biloba leaf extract (GBE) and other herbal plant extracts. Consequently, the understanding of toxicity of herbal dietary supplements remains limited. We have proposed that application of DNA microarrays could be a highly practical initial approach for revealing biological pathways and networks associated with toxicity induced by herbal dietary supplements and the generation of hypotheses to address likely mechanisms. The changes in expression of subsets of genes of interest, such as the modulation of drug metabolizing genes, can be analyzed after treatment with an herbal dietary supplement. Although levels of gene expression do not represent fully the levels of protein activities, we propose that subsequent biochemical and genomic experiments based on these initial observations will enable elucidation of the mechanisms leading to toxicity, including tumorigenicity. This review summarizes the current practices of microarray analysis of gene expressions in animals treated with herbal dietary supplements and discusses perspectives for the proposed strategy.

Toxic Hazards Research Unit

NASA Technical Reports Server (NTRS)

Macewen, J. D.; Vernot, E. H.

1971-01-01

The activities of the Toxic Hazards Research Unit (THRU) for the period of June 1970 through May 1971 reviewed. Modification of the animal exposure facilities primarily for improved human safety but also for experimental integrity and continuity are discussed. Acute toxicity experiments were conducted on hydrogen fluoride (HF), hydrogen chloride (HCl), nitrogen dioxide (NO2), and hydrogen cyanide (HCN) both singly and in combination with carbon dioxide (CO). Additional acute toxicity experiments were conducted on oxygen difluoride (OF2) and chlorine pentafluoride (ClF5). Subacute toxicity studies were conducted on methylisobutylketone and dichloromethane (methylene dichloride). The interim results of further chronic toxicity experiments on monomethylhydrazine (MMH) are also described.

Precooked bran-enriched wheat flour using extrusion: dietary fiber profile and sensory characteristics.

PubMed

Gajula, H; Alavi, S; Adhikari, K; Herald, T

2008-05-01

The effect of precooking by extrusion processing on the dietary fiber profile of wheat flour substituted with 0%, 10%, 20%, and 30% wheat bran was evaluated. Depending on the level of bran, total dietary fiber (TDF) and soluble dietary fiber (SDF) in uncooked flours ranged from 4.2% to 17.2% and 1.5% to 2.4%, respectively. Precooking by extrusion significantly increased SDF in flours (by 22% to 73%); although in most cases it also led to a significant decrease in TDF. Cookies and tortillas produced from uncooked and precooked flours with 0% and 20% substituted bran were evaluated for consumer acceptability using a 9-point hedonic scale. With a few exceptions, all cookies had scores ranging from 6 to 7 ("like slightly" to "like moderately") for each attribute, including overall acceptability, appearance, texture, crumbliness, and flavor. Tortillas were rated for the same attributes except for crumbliness, which was replaced with chewiness. In most cases, tortilla scores ranged from 5 to 7 ("neither like nor dislike" to "like moderately"). Consumer acceptability scores of cookies from uncooked flour did not change significantly with increase in bran substitution from 0% to 20%. However, consumer scores for tortillas did decrease significantly with increase in bran level. Extrusion precooking of the flours did not improve the consumer acceptability of cookies and tortillas; however, it did improve their dietary fiber profile by increasing the SDF significantly.

Can YAG screen accept LEReC bunch train?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seletskiy, S.; Thieberger, P.; Miller, T.

2016-05-18

LEReC RF diagnostic beamline is supposed to accept 250 us long pulse trains of 1.6 MeV – 2.6 MeV (kinetic energy) electrons. This beamline is equipped with YAG profile monitor. Since we are interested in observing only the last macro bunch in the train, one of the possibilities is to install a fast kicker and a dedicated dump upstream of the YAG screen (and related diagnostics equipment). This approach is expensive and challenging from engineering point of view. Another possibility is to send the whole pulse train to the YAG screen and to use a fast gated camera (such asmore » Imperex B0610 with trigger jitter under 60ns) to observe the image from the last pulse only. In this paper we study the feasibility of the last approach.« less

Difference in volatile profile between pericarp tissue and locular gel in tomato fruit

USDA-ARS?s Scientific Manuscript database

Aroma, a complex mixture of volatile compounds, plays an important role in the perception and acceptability of tomato products by consumers. Numerous studies have reported volatile profiles in tomatoes based on measurement of the whole fruit or pericarp tissue, however, little is understood regardin...

Current use and acceptability of novel diagnostic tests for active tuberculosis: a worldwide survey

PubMed Central

Amicosante, Massimo; D’Ambrosio, Lia; Munoz, Marcela; Mello, Fernanda Carvalho de Queiroz; Tebruegge, Marc; Chegou, Novel Njweipi; Seghrouchni, Fouad; Centis, Rosella; Goletti, Delia; Bothamley, Graham; Migliori, Giovanni Battista

2017-01-01

ABSTRACT Objective: To determine the current use and potential acceptance (by tuberculosis experts worldwide) of novel rapid tests for the diagnosis of tuberculosis that are in line with World Health Organization target product profiles. Methods: A multilingual survey was disseminated online between July and November of 2016. Results: A total of 723 individuals from 114 countries responded to the survey. Smear microscopy was the most commonly used rapid tuberculosis test (available to 90.9% of the respondents), followed by molecular assays (available to 70.7%). Only a small proportion of the respondents in middle- and low-income countries had access to interferon-gamma-release assays. Serological and lateral flow immunoassays were used by more than a quarter (25.4%) of the respondents. Among the respondents who had access to molecular tests, 46.7% were using the Xpert assay overall, that proportion being higher in lower middle-income countries (55.6%) and low-income countries (76.6%). The data also suggest that there was some alignment of pricing for molecular assays. Respondents stated they would accept novel rapid tuberculosis tests if available, including molecular assays (acceptable to 86.0%) or biomarker-based serological assays (acceptable to 81.7%). Simple biomarker-based assays were more commonly deemed acceptable in middle- and low-income countries. Conclusions: Second-generation molecular assays have become more widely available in high- and low-resource settings. However, the development of novel rapid tuberculosis tests continues to be considered important by tuberculosis experts. Our data also underscore the need for additional training and education of end users. PMID:29160384

Current use and acceptability of novel diagnostic tests for active tuberculosis: a worldwide survey.

PubMed

Amicosante, Massimo; D'Ambrosio, Lia; Munoz, Marcela; Mello, Fernanda Carvalho de Queiroz; Tebruegge, Marc; Chegou, Novel Njweipi; Seghrouchni, Fouad; Centis, Rosella; Goletti, Delia; Bothamley, Graham; Migliori, Giovanni Battista

2017-01-01

To determine the current use and potential acceptance (by tuberculosis experts worldwide) of novel rapid tests for the diagnosis of tuberculosis that are in line with World Health Organization target product profiles. A multilingual survey was disseminated online between July and November of 2016. A total of 723 individuals from 114 countries responded to the survey. Smear microscopy was the most commonly used rapid tuberculosis test (available to 90.9% of the respondents), followed by molecular assays (available to 70.7%). Only a small proportion of the respondents in middle- and low-income countries had access to interferon-gamma-release assays. Serological and lateral flow immunoassays were used by more than a quarter (25.4%) of the respondents. Among the respondents who had access to molecular tests, 46.7% were using the Xpert assay overall, that proportion being higher in lower middle-income countries (55.6%) and low-income countries (76.6%). The data also suggest that there was some alignment of pricing for molecular assays. Respondents stated they would accept novel rapid tuberculosis tests if available, including molecular assays (acceptable to 86.0%) or biomarker-based serological assays (acceptable to 81.7%). Simple biomarker-based assays were more commonly deemed acceptable in middle- and low-income countries. Second-generation molecular assays have become more widely available in high- and low-resource settings. However, the development of novel rapid tuberculosis tests continues to be considered important by tuberculosis experts. Our data also underscore the need for additional training and education of end users.

Using machine learning and quantum chemistry descriptors to predict the toxicity of ionic liquids.

PubMed

Cao, Lingdi; Zhu, Peng; Zhao, Yongsheng; Zhao, Jihong

2018-06-15

Large-scale application of ionic liquids (ILs) hinges on the advancement of designable and eco-friendly nature. Research of the potential toxicity of ILs towards different organisms and trophic levels is insufficient. Quantitative structure-activity relationships (QSAR) model is applied to evaluate the toxicity of ILs towards the leukemia rat cell line (ICP-81). The structures of 57 cations and 21 anions were optimized by quantum chemistry. The electrostatic potential surface area (S EP ) and charge distribution area (S σ-profile ) descriptors are calculated and used to predict the toxicity of ILs. The performance and predictive aptitude of extreme learning machine (ELM) model are analyzed and compared with those of multiple linear regression (MLR) and support vector machine (SVM) models. The highest R 2 and the lowest AARD% and RMSE of the training set, test set and total set for the ELM are observed, which validates the superior performance of the ELM than that of obtained by the MLR and SVM. The applicability domain of the model is assessed by the Williams plot. Copyright © 2018 Elsevier B.V. All rights reserved.

Proton Therapy for Spinal Ependymomas: Planning, Acute Toxicities, and Preliminary Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amsbaugh, Mark J.; Grosshans, David R., E-mail: dgrossha@mdanderson.org; McAleer, Mary Frances

2012-08-01

Purpose: To report acute toxicities and preliminary outcomes for pediatric patients with ependymomas of the spine treated with proton beam therapy at the MD Anderson Cancer Center. Methods and Materials: Eight pediatric patients received proton beam irradiation between October 2006 and September 2010 for spinal ependymomas. Toxicity data were collected weekly during radiation therapy and all follow-up visits. Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0. Results: All patients had surgical resection of the tumor before irradiation (7 subtotal resection and 1 gross total resection). Six patients had World Health Organization Grade I ependymomas,more » and two had World Health Organization Grade II ependymomas. Patients had up to 3 surgical interventions before radiation therapy (range, 1-3; median, 1). Three patients received proton therapy after recurrence and five as part of their primary management. The entire vertebral body was treated in all but 2 patients. The mean radiation dose was 51.1 cobalt gray equivalents (range, 45 to 54 cobalt gray equivalents). With a mean follow-up of 26 months from the radiation therapy start date (range, 7-51 months), local control, event-free survival, and overall survival rates were all 100%. The most common toxicities during treatment were Grade 1 or 2 erythema (75%) and Grade 1 fatigue (38%). No patients had a Grade 3 or higher adverse event. Proton therapy dramatically reduced dose to all normal tissues anterior to the vertebral bodies in comparison to photon therapy. Conclusion: Preliminary outcomes show the expected control rates with favorable acute toxicity profiles. Proton beam therapy offers a powerful treatment option in the pediatric population, where adverse events related to radiation exposure are of concern. Extended follow-up will be required to assess for late recurrences and long-term adverse effects.« less

Global transcriptomic profiling using small volumes of whole blood: a cost-effective method for translational genomic biomarker identification in small animals.

PubMed

Fricano, Meagan M; Ditewig, Amy C; Jung, Paul M; Liguori, Michael J; Blomme, Eric A G; Yang, Yi

2011-01-01

Blood is an ideal tissue for the identification of novel genomic biomarkers for toxicity or efficacy. However, using blood for transcriptomic profiling presents significant technical challenges due to the transcriptomic changes induced by ex vivo handling and the interference of highly abundant globin mRNA. Most whole blood RNA stabilization and isolation methods also require significant volumes of blood, limiting their effective use in small animal species, such as rodents. To overcome these challenges, a QIAzol-based RNA stabilization and isolation method (QSI) was developed to isolate sufficient amounts of high quality total RNA from 25 to 500 μL of rat whole blood. The method was compared to the standard PAXgene Blood RNA System using blood collected from rats exposed to saline or lipopolysaccharide (LPS). The QSI method yielded an average of 54 ng total RNA per μL of rat whole blood with an average RNA Integrity Number (RIN) of 9, a performance comparable with the standard PAXgene method. Total RNA samples were further processed using the NuGEN Ovation Whole Blood Solution system and cDNA was hybridized to Affymetrix Rat Genome 230 2.0 Arrays. The microarray QC parameters using RNA isolated with the QSI method were within the acceptable range for microarray analysis. The transcriptomic profiles were highly correlated with those using RNA isolated with the PAXgene method and were consistent with expected LPS-induced inflammatory responses. The present study demonstrated that the QSI method coupled with NuGEN Ovation Whole Blood Solution system is cost-effective and particularly suitable for transcriptomic profiling of minimal volumes of whole blood, typical of those obtained with small animal species.

[The Profile of Leisure Activities, a promising instrument in occupational therapy].

PubMed

Dutil, Elisabeth; Bier, Nathalie; Gaudreault, Céline

2007-10-04

Although the benefits of leisure activities are well known, few instruments have been specifically designed to measure a person's engagement in their leisure activities and to assess the personal or environmental factors affecting their capacity to participate in leisure activities. The purpose of this paper is to present the steps leading to the development of the Profil du Loisir between 1990 and 2002. The planning, construction, and validation of the tool were done according to the steps suggested by Benson and Clark (1982). The first versions were tested by occupational therapists on individuals with traumatic brain injuries. The validation led to the development of the final version (3.0). The inter-rater reliability of the instrument was rated from acceptable (kappa 0.21-0.4) to very good (0.61-0.80) and the test-retest reliability was rated from acceptable to moderate (0.41-0.60). The Profil du Loisir is a promising tool that invites occupational therapists to systematically consider and assess client leisure time in their practice.

Estimation of toxicity using the Toxicity Estimation Software Tool (TEST)

EPA Science Inventory

Tens of thousands of chemicals are currently in commerce, and hundreds more are introduced every year. Since experimental measurements of toxicity are extremely time consuming and expensive, it is imperative that alternative methods to estimate toxicity are developed.

Wearable Activity Tracker Use Among Australian Adolescents: Usability and Acceptability Study

PubMed Central

Timperio, Anna; Brown, Helen; Ball, Kylie; Macfarlane, Susie; Lai, Samuel K; Richards, Kara; Mackintosh, Kelly A; McNarry, Melitta A; Foster, Megan; Salmon, Jo

2018-01-01

Background Wearable activity trackers have the potential to be integrated into physical activity interventions, yet little is known about how adolescents use these devices or perceive their acceptability. Objective The aim of this study was to examine the usability and acceptability of a wearable activity tracker among adolescents. A secondary aim was to determine adolescents’ awareness and use of the different functions and features in the wearable activity tracker and accompanying app. Methods Sixty adolescents (aged 13-14 years) in year 8 from 3 secondary schools in Melbourne, Australia, were provided with a wrist-worn Fitbit Flex and accompanying app, and were asked to use it for 6 weeks. Demographic data (age, sex) were collected via a Web-based survey completed during week 1 of the study. At the conclusion of the 6-week period, all adolescents participated in focus groups that explored their perceptions of the usability and acceptability of the Fitbit Flex, accompanying app, and Web-based Fitbit profile. Qualitative data were analyzed using pen profiles, which were constructed from verbatim transcripts. Results Adolescents typically found the Fitbit Flex easy to use for activity tracking, though greater difficulties were reported for monitoring sleep. The Fitbit Flex was perceived to be useful for tracking daily activities, and adolescents used a range of features and functions available through the device and the app. Barriers to use included the comfort and design of the Fitbit Flex, a lack of specific feedback about activity levels, and the inability to wear the wearable activity tracker for water-based sports. Conclusions Adolescents reported that the Fitbit Flex was easy to use and that it was a useful tool for tracking daily activities. A number of functions and features were used, including the device’s visual display to track and self-monitor activity, goal-setting in the accompanying app, and undertaking challenges against friends. However

One- and two-dimensional dopant/carrier profiling for ULSI

NASA Astrophysics Data System (ADS)

Vandervorst, W.; Clarysse, T.; De Wolf, P.; Trenkler, T.; Hantschel, T.; Stephenson, R.; Janssens, T.

1998-11-01

Dopant/carrier profiles constitute the basis of the operation of a semiconductor device and thus play a decisive role in the performance of a transistor and are subjected to the same scaling laws as the other constituents of a modern semiconductor device and continuously evolve towards shallower and more complex configurations. This evolution has increased the demands on the profiling techniques in particular in terms of resolution and quantification such that a constant reevaluation and improvement of the tools is required. As no single technique provides all the necessary information (dopant distribution, electrical activation,..) with the requested spatial and depth resolution, the present paper attempts to provide an assessment of those tools which can be considered as the main metrology technologies for ULSI-applications. For 1D-dopant profiling secondary ion mass spectrometry (SIMS) has progressed towards a generally accepted tool meeting the requirements. For 1D-carrier profiling spreading resistance profiling and microwave surface impedance profiling are envisaged as the best choices but extra developments are required to promote them to routinely applicable methods. As no main metrology tool exist for 2D-dopant profiling, main emphasis is on 2D-carrier profiling tools based on scanning probe microscopy. Scanning spreading resistance (SSRM) and scanning capacitance microscopy (SCM) are the preferred methods although neither of them already meets all the requirements. Complementary information can be extracted from Nanopotentiometry which samples the device operation in more detail. Concurrent use of carrier profiling tools, Nanopotentiometry, analysis of device characteristics and simulations is required to provide a complete characterization of deep submicron devices.

A review of toxicity and mechanisms of individual and mixtures of heavy metals in the environment.

PubMed

Wu, Xiangyang; Cobbina, Samuel J; Mao, Guanghua; Xu, Hai; Zhang, Zhen; Yang, Liuqing

2016-05-01

The rational for the study was to review the literature on the toxicity and corresponding mechanisms associated with lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As), individually and as mixtures, in the environment. Heavy metals are ubiquitous and generally persist in the environment, enabling them to biomagnify in the food chain. Living systems most often interact with a cocktail of heavy metals in the environment. Heavy metal exposure to biological systems may lead to oxidation stress which may induce DNA damage, protein modification, lipid peroxidation, and others. In this review, the major mechanism associated with toxicities of individual metals was the generation of reactive oxygen species (ROS). Additionally, toxicities were expressed through depletion of glutathione and bonding to sulfhydryl groups of proteins. Interestingly, a metal like Pb becomes toxic to organisms through the depletion of antioxidants while Cd indirectly generates ROS by its ability to replace iron and copper. ROS generated through exposure to arsenic were associated with many modes of action, and heavy metal mixtures were found to have varied effects on organisms. Many models based on concentration addition (CA) and independent action (IA) have been introduced to help predict toxicities and mechanisms associated with metal mixtures. An integrated model which combines CA and IA was further proposed for evaluating toxicities of non-interactive mixtures. In cases where there are molecular interactions, the toxicogenomic approach was used to predict toxicities. The high-throughput toxicogenomics combines studies in genetics, genome-scale expression, cell and tissue expression, metabolite profiling, and bioinformatics.

Children's Ability to Recognise Toxic and Non-Toxic Fruits

ERIC Educational Resources Information Center

Fancovicova, Jana; Prokop, Pavol

2011-01-01

Children's ability to identify common plants is a necessary prerequisite for learning botany. However, recent work has shown that children lack positive attitudes toward plants and are unable to identify them. We examined children's (aged 10-17) ability to discriminate between common toxic and non-toxic plants and their mature fruits presented in…

Characterization and toxicity of citral incorporated with nanostructured lipid carrier.

PubMed

Nordin, Noraini; Yeap, Swee Keong; Zamberi, Nur Rizi; Abu, Nadiah; Mohamad, Nurul Elyani; Rahman, Heshu Sulaiman; How, Chee Wun; Masarudin, Mas Jaffri; Abdullah, Rasedee; Alitheen, Noorjahan Banu

2018-01-01

The nanoparticle as a cancer drug delivery vehicle is rapidly under investigation due to its promising applicability as a novel drug delivery system for anticancer agents. This study describes the development, characterization and toxicity studies of a nanostructured lipid carrier (NLC) system for citral. Citral was loaded into the NLC using high pressure homogenization methods. The characterizations of NLC-citral were then determined through various methods. Based on Transmission Electron Microscope (TEM) analysis, NLC-Citral showed a spherical shape with an average diameter size of 54.12 ± 0.30 nm and a polydipersity index of 0.224 ± 0.005. The zeta potential of NLC-Citral was -12.73 ± 0.34 mV with an entrapment efficiency of 98.9 ± 0.124%, and drug loading of 9.84 ± 0.041%. Safety profile of the formulation was examined via in vitro and in vivo routes to study its effects toward normal cells. NLC-Citral exhibited no toxic effects towards the proliferation of mice splenocytes. Moreover, no mortality and toxic signs were observed in the treated groups after 28 days of treatment. There were also no significant alterations in serum biochemical analysis for all treatments. Increase in immunomodulatory effects of treated NLC-Citral and Citral groups was verified from the increase in CD4/CD3 and CD8/CD3 T cell population in both NLC-citral and citral treated splenocytes. This study suggests that NLC is a promising drug delivery system for citral as it has the potential in sustaining drug release without inducing any toxicity.