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Predictive toxicology

Richard Siller, Gareth J Sullivan
Human pluripotent stem cells (hPSCs) hold tremendous promise for regenerative medicine, disease modeling, toxicology screening, and developmental biology. These applications are hindered due to inherent differences in differentiation potential observed among different hPSC lines. This is particularly true for the differentiation of hPSCs toward the endodermal lineage. Several groups have developed methods to screen hPSCs for their endodermal differentiation potential (EP). Particularly notable studies include (i) the use of WNT3A expression as a predictive biomarker, (ii) an embryoid body-based screen, and (iii) a transcriptomics-based approach...
November 15, 2017: Current Protocols in Stem Cell Biology
Jianfeng Feng, Yongfei Gao, Yijun Ji, Lin Zhu
Predicting the toxicity of chemical mixtures is difficult because of the additive, antagonistic, or synergistic interactions among the mixture components. Antagonistic and synergistic interactions are dominant in metal mixtures, and their distributions may correlate with exposure concentrations. However, whether the interaction types of metal mixtures change at different time points during toxicodynamic (TD) processes is undetermined because of insufficient appropriate models and metal bioaccumulation data at different time points...
November 10, 2017: Journal of Hazardous Materials
Natássia Caroline Resende Corrêa, Crisciele Kuligovski, Ariane Caroline Campos Paschoal, Ana Paula Ressetti Abud, Carmen Lucia Kuniyoshi Rebelatto, Lidiane Maria Boldrini Leite, Alexandra Cristina Senegaglia, Bruno Dallagiovanna, Alessandra Melo de Aguiar
With the increasing need to develop in vitro assays to replace animal use, human stem cell-derived methods are emerging and showing outstanding contributions to the toxicological screening of substances. Adult human stem cells such as adipose-derived stem cells (ADSC) and periodontal ligament stem cells (PDLSC) were used as cell substrates for a cytotoxicity assay and toxicity prediction using the neutral red uptake (NRU) assay. First, primary cell cultures from three independent donors, from each tissue source, were characterized as mesenchymal stem cells (MSC) by plastic adherence and appropriate immunophenotype for MSC markers (positive for CD90, CD73, and CD105 and negative for CD11b, CD34, CD45, HLADR, and CD19)...
November 9, 2017: Regulatory Toxicology and Pharmacology: RTP
Marcel Leist
The complex toxicological fields of repeat dose organ toxicity (RDT) and developmental and reproductive toxicity (DART) still require new concepts and approaches to achieve a fully animal-free safety assessment of chemicals. One novel approach is the generation of relevant human cell types from pluripotent stem cells, and the use of such cells for the establishment of phenotypic test methods. Due to their broad endpoints, such tests capture multiple types of toxicants, i.e. they are a readout for the activation of many adverse outcome pathways (AOPs)...
November 2017: Alternatives to Laboratory Animals: ATLA
Santiago Vilar, Eduardo Sobarzo-Sánchez, Lourdes Santana, Eugenio Uriarte
Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. We elaborated on ligand-based models, including multiple 2D and 3D QSPR/QSAR models and integrative approaches that have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability...
November 6, 2017: Current Medicinal Chemistry
Shaghayegh Ostadjoo, Paula Berton, Julia Shamshina, Robin D Rogers
The potential of the ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) to dissolve a variety of biopolymers such as cellulose and chitin, makes it an attractive candidate for scaled-up industrial utilization. In fact, the first steps towards its use at industrial scale have been taken. This increases the urgency to fill the knowledge gaps in its toxicity and environmental impact in order to predict and control its environmental fate. In this mini-review, we discuss the available literature surrounding this key IL...
November 2, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Steven M Bryce, Derek T Bernacki, Stephanie L Smith-Roe, Kristine L Witt, Jeffrey C Bemis, Stephen D Dertinger
The in vitro MultiFlow® DNA Damage assay multiplexes p53, γH2AX, phospho-histone H3, and polyploidization biomarkers into one flow cytometric analysis (Bryce et al., 2016). The work reported herein evaluated the generalizability of the method, as well as several data analytics strategies, to a range of chemical classes not studied previously. TK6 cells were exposed to each of 103 diverse chemicals, 86 of which were supplied by the National Toxicology Program (NTP) and selected based upon responses in genetic damage assays conducted under the Tox21 program...
November 2, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Eduard Dumitrescu, Dinusha P Karunaratne, S V Babu, Kenneth N Wallace, Silvana Andreescu
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 (SiO2 and CeO2), chemical additives (hydrogen peroxide, proline, glycine, nicotinic acid, and benzotriazole), as well as three model representative slurries and their resulting waste...
October 27, 2017: Chemosphere
Thomas Luechtefeld, Thomas Hartung
Computational prediction of toxicity has reached new heights as a result of decades of growth in the magnitude and diversity of biological data. Public packages for statistics and machine learning make model creation faster. New theory in machine learning and cheminformatics enables integration of chemical structure, toxicogenomics, simulated and physical data in the prediction of chemical health hazards, and other toxicological information. Our earlier publications have characterized a toxicological dataset of unprecedented scale resulting from the European REACH legislation (Registration Evaluation Authorisation and Restriction of Chemicals)...
2017: ALTEX
Chee M Ng, Fei Tang, Steven Seeholzer, Yixuan Zou, Diva D De León
AIMS: Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycaemia in infants and children. Exendin-(9-39), an inverse glucagon-like peptide 1 (GLP-1) agonist, is a novel therapeutic agent for HI that has demonstrated glucose-raising effect. We reported the first population pharmacokinetic (PopPK) model of the exendin-(9-39) in patients with HI and proposed the optimal dosing regimen for future clinical trials in neonates with HI. METHODS: 182 pharmacokinetic (PK) observations from 26 subjects in three clinical studies were included for constructing the PopPK model using FOCE with interaction method in NONMEM...
October 27, 2017: British Journal of Clinical Pharmacology
Richard H McKee, Rosalie Tibaldi, Moyinoluwa D Adenuga, Juan-Carlos Carrillo, Alison Margary
The European chemical control regulation (REACH) requires that data on physical/chemical, toxicological and environmental hazards be compiled. Additionally, REACH requires formal assessments to ensure that substances can be safely used for their intended purposes. For health hazard assessments, reference values (Derived No Effect levels, DNELs) are calculated from toxicology data and compared to estimated exposure levels. If the ratio of the predicted exposure level to the DNEL, i.e. the Risk Characterization Ratio (RCR), is less than 1, the risk is considered controlled; otherwise, additional Risk Management Measures (RMM) must be applied...
October 22, 2017: Regulatory Toxicology and Pharmacology: RTP
Jessica Kratchman, Bing Wang, John Fox, George Gray
This study investigated whether, in the absence of chronic noncancer toxicity data, short-term noncancer toxicity data can be used to predict chronic toxicity effect levels by focusing on the dose-response relationship instead of a critical effect. Data from National Toxicology Program (NTP) technical reports have been extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Best-fit, minimum benchmark dose (BMD), and benchmark dose lower limits (BMDLs) have been modeled for all NTP pathologist identified significant nonneoplastic lesions, final mean body weight, and mean organ weight of 41 chemicals tested by NTP between 2000 and 2012...
October 23, 2017: Risk Analysis: An Official Publication of the Society for Risk Analysis
Merilin Al Sharif, Petko Alov, Vessela Vitcheva, Antonia Diukendjieva, Mattia Mori, Bruno Botta, Ivanka Tsakovska, Ilza Pajeva
Nonalcoholic fatty liver disease (NAFLD) is considered to be the most common chronic liver disease. The discovery of natural product-based NAFLD modulators requires a more comprehensive study of their modes of action (MoAs). In this study we analysed available in the literature data for 26 naturally-derived compounds associated with experimental evidence for NAFLD alleviation and outlined potential biomolecular targets and a network of pharmacological MoAs for 12 compounds with the highest number of experimentally supported MoA key events, modulated by them...
November 4, 2017: Toxicology and Applied Pharmacology
Jelena Ivanova, Shiju Zhang, Rong-Lin Wang, Heiko L Schoenfuss
Many organisms, including the fathead minnow (Pimephales promelas), a toxicological model organism, establish social hierarchies. The social rank of each male in a population is under the control of the hypothalamic-pituitary-gonadal (HPG) axis mainly through regulation of circulating androgen concentrations, which in turn drive the expression of secondary sex characteristics (SSCs). As dominant and subordinate males in an exposure study are initially under different physiological conditions (i.e., differing plasma androgen concentrations), we proposed that they belong to different subpopulations in the context of exposure to compounds that may interact with the HPG axis...
2017: PloS One
Haixia Lin, Laura E Ewing, Igor Koturbash, Bill J Gurley, Isabelle R Miousse
MicroRNAs (miRNAs) are short regulatory RNAs that are involved in various biological processes that regulate gene expression posttranscriptionally. Changes in miRNA expression can be detected in many physiological and pathological events, such as liver injury. Drug induced liver injury is a life threatening condition that frequently requires organ transplantation. Hepatotoxicity is also one of the major causes of drug failure in clinical trials and of drug withdrawal from the market. The profiling of miRNA expression shows great promise in monitoring liver injury, in the prediction of outcome in patients, and in the identification of liver-reactive compounds in toxicological assessment...
October 16, 2017: Food and Chemical Toxicology
Xuefang Liang, April Feswick, Denina Simmons, Christopher J Martyniuk
Molecular initiating events and downstream transcriptional/proteomic responses provide valuable information for adverse outcome pathways, which can be used predict the effects of chemicals on physiological systems. There has been a paucity of research that addresses sex-specific expression profiling in toxicology and due to cost, time, and logistical considerations, sex as a variable has not been widely considered. In response to this deficiency, federal agencies in the United States, Canada, and Europe have highlighted the importance of including sex as a variable in scientific investigations...
October 13, 2017: Journal of Proteomics
Sandrine F Chebekoue, Kannan Krishnan
Many substances in workplace do not have occupational exposure limits. The threshold of toxicological concern (TTC) principle is part of the hierarchy of approaches useful in occupational health risk assessment. The aim of this study was to derive occupational TTCs (OTTCs) reflecting the airborne concentrations below which no significant risk to workers would be anticipated. A reference dataset consisting of the 8-h threshold limit values-Time-Weighted Average for 280 organic substances was compiled. Each substance was classified into low (class I), intermediate (class II), or high (class III) hazard categories as per Cramer rules...
November 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Frank Alexander, Sebastian Eggert, Joachim Wiest
Sensor-based cellular microphysiometry is a technique that allows non-invasive, label-free, real-time monitoring of living cells that can greatly improve the predictability of toxicology testing by removing the influence of biochemical labels. In this work, the Intelligent Mobile Lab for In Vitro Diagnostics (IMOLA-IVD) was utilized to perform cellular microphysiometry on 3D multicellular spheroids. Using a commercial 3D printer, 3 × 3 microwell arrays were fabricated to maintain nine previously cultured HepG2 spheroids on a single BioChip...
October 14, 2017: Cytotechnology
Ryan A Black, Stacey A McCaffrey, Albert J Villapiano, Robert N Jamison, Stephen F Butler
Objective: Although the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) has become a widely used screener for aberrant opioid-related behavior in adults, the length of the instrument may limit its utility. The purpose of the current study was to develop a short form of the SOAPP-R by retaining as few items as possible while maximizing predictive accuracy. Methods: Participants (N = 555), recruited from pain clinics, completed the 24-item SOAPP-R and participated in a five-month follow-up visit to evaluate aberrant drug-related behaviors...
August 11, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
Daniela Trisciuzzi, Domenico Alberga, Kamel Mansouri, Richard Judson, Ettore Novellino, Giuseppe Felice Mangiatordi, Orazio Nicolotti
We present a practical and easy-to-run in silico workflow exploiting a structure-based strategy making use of docking simulations to derive highly predictive classification models of the androgenic potential of chemicals. Models were trained on a high-quality chemical collection comprising 1689 curated compounds made available within the CoMPARA consortium from the US Environmental Protection Agency and were integrated with a two-step applicability domain whose implementation had the effect of improving both the confidence in prediction and statistics by reducing the number of false negatives...
October 26, 2017: Journal of Chemical Information and Modeling
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