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Predictive toxicology

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https://www.readbyqxmd.com/read/28335457/the-epigenetic-link-between-prenatal-adverse-environments-and-neurodevelopmental-disorders
#1
REVIEW
Marija Kundakovic, Ivana Jaric
Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf)...
March 18, 2017: Genes
https://www.readbyqxmd.com/read/28328838/development-and-validation-of-a-risk-prediction-nomogram-for-in-hospital-mortality-in-adults-poisoned-with-drugs-and-nonpharmaceutical-agents-an-observational-study
#2
Catalina Lionte, Victorita Sorodoc, Elisabeta Jaba, Alina Botezat
Acute poisoning with drugs and nonpharmaceutical agents represents an important challenge in the emergency department (ED).The objective is to create and validate a risk-prediction nomogram for use in the ED to predict the risk of in-hospital mortality in adults from acute poisoning with drugs and nonpharmaceutical agents.This was a prospective cohort study involving adults with acute poisoning from drugs and nonpharmaceutical agents admitted to a tertiary referral center for toxicology between January and December 2015 (derivation cohort) and between January and June 2016 (validation cohort)...
March 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28321487/benzene-degradation-in-a-denitrifying-biofilm-reactor-activity-and-microbial-community-composition
#3
Marcelle J van der Waals, Siavash Atashgahi, Ulisses Nunes da Rocha, Bas M van der Zaan, Hauke Smidt, Jan Gerritse
Benzene is an aromatic compound and harmful for the environment. Biodegradation of benzene can reduce the toxicological risk after accidental or controlled release of this chemical in the environment. In this study, we further characterized an anaerobic continuous biofilm culture grown for more than 14 years on benzene with nitrate as electron acceptor. We determined steady state degradation rates, microbial community composition dynamics in the biofilm, and the initial anaerobic benzene degradation reactions...
March 20, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28320775/is-it-time-to-reassess-current-safety-standards-for-glyphosate-based-herbicides
#4
REVIEW
Laura N Vandenberg, Bruce Blumberg, Michael N Antoniou, Charles M Benbrook, Lynn Carroll, Theo Colborn, Lorne G Everett, Michael Hansen, Philip J Landrigan, Bruce P Lanphear, Robin Mesnage, Frederick S Vom Saal, Wade V Welshons, John Peterson Myers
Use of glyphosate-based herbicides (GBHs) increased ∼100-fold from 1974 to 2014. Additional increases are expected due to widespread emergence of glyphosate-resistant weeds, increased application of GBHs, and preharvest uses of GBHs as desiccants. Current safety assessments rely heavily on studies conducted over 30 years ago. We have considered information on GBH use, exposures, mechanisms of action, toxicity and epidemiology. Human exposures to glyphosate are rising, and a number of in vitro and in vivo studies challenge the basis for the current safety assessment of glyphosate and GBHs...
March 20, 2017: Journal of Epidemiology and Community Health
https://www.readbyqxmd.com/read/28315380/primary-structures-and-partial-toxicological-characterization-of-two-phospholipases-a2-from-micrurus-mipartitus-and-micrurus-dumerilii-coral-snake-venoms
#5
Paola Rey-Suárez, Vitelbina Núñez, Mónica Saldarriaga-Córdoba, Bruno Lomonte
Snake venom phospholipases A2 (PLA2) share high sequence identities and a conserved structural scaffold, but show important functional differences. Only a few PLA2s have been purified and characterized from coral snake (Micrurus spp.) venoms, and their role in envenomation remains largely unknown. In this report, we describe the isolation, sequencing and partial functional characterization of two Micrurus PLA2s: MmipPLA2 from Micrurus mipartitus and MdumPLA2 from Micrurus dumerilii, two species of clinical importance in Colombia...
March 14, 2017: Biochimie
https://www.readbyqxmd.com/read/28304357/clinical-prediction-of-suicide-and-undetermined-death-a-pseudo-prospective-clinical-and-medico-legal-study-of-substance-abusers
#6
Louise Brådvik, Mats Berglund, Arne Frank, Peter Löwenhielm
This study examines aspects of prediction of suicide and death of undetermined intent. We investigated all consecutive, autopsied patients between 1993 and 1997 who had been in contact with the Addiction Centre in Malmö from 1968 onwards. The staff was asked, shortly after autopsy but before they knew of the manner of death, if they thought the patient had committed suicide. The case records were blindly evaluated, and toxicological autopsy findings for alcohol in blood samples investigated. The specificity of prediction was 83% and significantly more often correct than the sensitivity, which was only 45% for suicide and for suicide/death of undetermined intent (93% versus 39%)...
March 17, 2017: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/28303741/weight-of-the-evidence-evaluation-of-2-4-d-potential-for-interactions-with-the-estrogen-androgen-and-thyroid-pathways-and-steroidogenesis
#7
B H Neal, J Bus, M S Marty, K Coady, A Williams, J Staveley, J C Lamb
A comprehensive weight-of-the-evidence evaluation of 2,4-dichlorophenoxyacetic acid (2,4-D) was conducted for potential interactions with the estrogen, androgen and thyroid pathways and with steroidogenesis. This assessment was based on an extensive database of high quality in vitro, in vivo ecotoxicological and in vivo mammalian toxicological studies. Epidemiological studies were also considered. Toxicokinetic data provided the basis for determining rational cutoffs above which exposures were considered irrelevant to humans based on exceeding thresholds for saturation of renal clearance (TSRC); extensive human exposure and biomonitoring data support that these boundaries far exceed human exposures and provide ample margins of exposure...
March 2, 2017: Critical Reviews in Toxicology
https://www.readbyqxmd.com/read/28302026/drug-metabolism-in-preclinical-drug-development-a-survey-of-the-discovery-process-toxicology-and-computational-tools
#8
Naiem T Issa, Henri Wathieu, Abiola Ojo, Stephen W Byers, Sivanesan Dakshanamurthy
Increased R & D spending and high failure rates exist in drug development, due in part to inadequate prediction of drug metabolism and its consequences in the human body. Hence, there is a need for computational methods to supplement and complement current biological assessment strategies. In this review, we provide an overview of drug metabolism in pharmacology, and discuss the current in vitro and in vivo strategies for assessing drug metabolism in preclinical drug development. We highlight computational tools available to the scientific community for the in silico prediction of drug metabolism, and examine how these tools have been implemented to produce drug-target signatures relevant to metabolic routes...
March 15, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28285123/preclinical-predictors-that-the-orthosteric-mglu2-3-receptor-antagonist-ly3020371-will-not-engender-ketamine-associated-neurotoxic-motor-cognitive-subjective-or-abuse-liability-related-effects
#9
J M Witkin, J A Monn, J Li, B Johnson, D L McKinzie, X-S Wang, B A Heinz, R Li, P L Ornstein, S C Smith, C H Mitch, D O Calligaro, S Swanson, D Allen, K Phillips, G Gilmour
The novel mGlu2/3 receptor antagonist, LY3020371 has been shown to produce antidepressant-like effects comparable to that of the clinically-effective antidepressant ketamine. In the present study, we investigated whether LY3020371 would be predicted to be free of the side-effects and safety pharmacology issues associated with ketamine. In contrast to ketamine, LY3020371 produced small increases in locomotion and did not impair motor performance on an inverted. Ketamine, but not LY3020371, increased dopamine efflux in the nucleus accumbens of rats...
March 8, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28274809/behaviour-of-chemical-respiratory-allergens-in-novel-predictive-methods-for-skin-sensitisation
#10
David Basketter, Alan Poole, Ian Kimber
Asthma resulting from sensitisation of the respiratory tract to chemicals is an important occupational health issue, presenting many toxicological challenges. Most importantly there are no recognised predictive methods for respiratory allergens. Nevertheless, it has been found that all known chemical respiratory allergens elicit positive responses in assays for skin sensitising chemicals. Thus, chemicals failing to induce a positive response in skin sensitisation assays such as the local lymph node assay (LLNA) lack not only skin sensitising activity, but also the potential to cause respiratory sensitisation...
March 6, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28274094/calculation-of-a-first-in-man-dose-of-7-o-succinyl-macrolactin-a-based-on-allometric-scaling-of-data-from-mice-rats-and-dogs
#11
Keumhan Noh, Wonku Kang
7-O-succinyl macrolactin A (SMA) exerts several pharmacological effects including anti-bacterial, anti-inflammation, and anticancer activities. Recently, SMA has been extensively evaluated as an anti-cancer drug. Thus, the objectives of the present study were to characterise the pharmacokinetics of SMA via both non-compartmental and compartmental analysis in mice, rats, and dogs, and to derive an appropriate first-in-man dose based on allometric scaling of the animal data. The time courses of plasma SMA concentrations after intravenous administration to rats and dogs were analysed retrospectively, as were data collected after intraperitoneal SMA injection in mice...
March 10, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28259702/in-vitro-cardiotoxicity-assessment-of-environmental-chemicals-using-an-organotypic-human-induced-pluripotent-stem-cell-derived-model
#12
Oksana Sirenko, Fabian A Grimm, Kristen R Ryan, Yasuhiro Iwata, Weihsueh A Chiu, Frederick Parham, Jessica A Wignall, Blake Anson, Evan F Cromwell, Mamta Behl, Ivan Rusyn, Raymond R Tice
An important target area for addressing data gaps through in vitro screening is the detection of potential cardiotoxicants. Despite the fact that current conservative estimates relate at least 23% of all cardiovascular disease cases to environmental exposures, the identities of the causative agents remain largely uncharacterized. Here, we evaluate the feasibility of a combinatorial in vitro/in silico screening approach for functional and mechanistic cardiotoxicity profiling of environmental hazards using a library of 69 representative environmental chemicals and drugs...
March 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28254378/cell-and-tissue-based-in-vitro-models-for-improving-the-development-of-oral-inhalation-drug-products
#13
Marius Hittinger, Nicole Schneider-Daum, Claus-Michael Lehr
The interplay of costs and ethics has increased the need for adequate models mimicking the human in vivo situation drastically. An adequate model has the ability to generate data which are predictive for a certain aspect of the human response, for example for the bioavailability. This review highlights how in vitro models can enrich pulmonary drug delivery research with more detailed insights in cellular and non-cellular barriers, allowing for faster improvements and significant innovations of inhalation drug products...
February 27, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28247928/advancing-alternatives-analysis-the-role-of-predictive-toxicology-in-selecting-safer-chemical-products-and-processes
#14
Timothy Malloy, Virginia Zaunbrecher, Elizabeth Beryt, Richard Judson, Raymond Tice, Patrick Allard, Ann Blake, Ila Cote, Hilary Godwin, Lauren Heine, Patrick Kerzic, Jakub Kostal, Gary Marchant, Jennifer McPartland, Kelly Moran, Andre Nel, Oladele Oguseitan, Mark Rossi, Kristina Thayer, Joel Tickner, Margaret Whittaker, Ken Zarker
Alternatives analysis (AA) is a method used in regulation and product design to identify, assess, and evaluate the safety and viability of potential substitutes for hazardous chemicals. It requires toxicological data for the existing chemical and potential alternatives. Predictive toxicology uses in silico and in vitro approaches, computational models, and other tools to expedite toxicological data generation in more cost-effective manner than traditional approaches. This article briefly reviews the challenges associated with using predictive toxicology in regulatory AA, then presents four recommendations for its advancement...
March 1, 2017: Integrated Environmental Assessment and Management
https://www.readbyqxmd.com/read/28244128/a-quantitative-in-silico-model-for-predicting-skin-sensitization-using-a-nearest-neighbours-approach-within-expert-derived-structure-activity-alert-spaces
#15
Steven J Canipa, Martyn L Chilton, Rachel Hemingway, Donna S Macmillan, Alun Myden, Jeffrey P Plante, Rachael E Tennant, Jonathan D Vessey, Thomas Steger-Hartmann, Janet Gould, Jedd Hillegass, Sylvain Etter, Benjamin P C Smith, Angela White, Paul Sterchele, Ann De Smedt, Devin O'Brien, Rahul Parakhia
Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU. A Nearest Neighbours in silico model was developed using an in-house dataset of 1096 murine local lymph node (LLNA) studies...
February 28, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28243641/-q-sars-to-predict-environmental-toxicities-current-status-and-future-needs
#16
Mark T D Cronin
The current state of the art of (Quantitative) Structure-Activity Relationships ((Q)SARs) to predict environmental toxicity is assessed along with recommendations to develop these models further. The acute toxicity of compounds acting by the non-polar narcotic mechanism of action can be well predicted, however other approaches, including read-across, may be required for compounds acting by specific mechanisms of action. The chronic toxicity of compounds to environmental species is more difficult to predict from (Q)SARs, with robust data sets and more mechanistic information required...
February 28, 2017: Environmental Science. Processes & Impacts
https://www.readbyqxmd.com/read/28242142/retrospective-mining-of-toxicology-data-to-discover-multispecies-and-chemical-class-effects-anemia-as-a-case-study
#17
Richard S Judson, Matthew T Martin, Grace Patlewicz, Charles E Wood
Predictive toxicity models rely on large amounts of accurate in vivo data. Here, we analyze the quality of in vivo data from the U.S. EPA Toxicity Reference Database (ToxRefDB), using chemical-induced anemia as an example. Considerations include variation in experimental conditions, changes in terminology over time, distinguishing negative from missing results, observer and diagnostic bias, and data transcription errors. Within ToxRefDB, we use hematological data on 658 chemicals tested in one or more of 1738 studies (subchronic rat or chronic rat, mouse, or dog)...
February 24, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28239160/insights-into-the-molecular-mechanisms-of-polygonum-multiflorum-thunb-induced-liver-injury-a-computational-systems-toxicology-approach
#18
Yin-Yin Wang, Jie Li, Zeng-Rui Wu, Bo Zhang, Hong-Bin Yang, Qin Wang, Ying-Chun Cai, Gui-Xia Liu, Wei-Hua Li, Yun Tang
An increasing number of cases of herb-induced liver injury (HILI) have been reported, presenting new clinical challenges. In this study, taking Polygonum multiflorum Thunb (PmT) as an example, we proposed a computational systems toxicology approach to explore the molecular mechanisms of HILI. First, the chemical components of PmT were extracted from 3 main TCM databases as well as the literature related to natural products. Then, the known targets were collected through data integration, and the potential compound-target interactions (CTIs) were predicted using our substructure-drug-target network-based inference (SDTNBI) method...
February 27, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28228010/selective-fusion-of-heterogeneous-classifiers-for-predicting-substrates-of-membrane-transporters
#19
Naeem Shaikh, Mahesh Sharma, Prabha Garg
Membrane transporters play a crucial role in determining fate of administered drugs in a biological system. Early identification of plausible transporters for a drug molecule can provide insights into its therapeutic, pharmacokinetic, and toxicological profiles. In the present study, predictive models for classifying small molecules into substrates and nonsubstrates of various pharmaceutically important membrane transporters were developed using quantitative structure-activity relationship (QSAR) and proteochemometric (PCM) approaches...
March 6, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28217795/understanding-the-microscopic-binding-mechanism-of-hydroxylated-and-sulfated-polybrominated-diphenyl-ethers-with-transthyretin-by-molecular-docking-molecular-dynamics-simulations-and-binding-free-energy-calculations
#20
Huiming Cao, Yuzhen Sun, Ling Wang, Chunyan Zhao, Jianjie Fu, Aiqian Zhang
Polybrominated diphenyl ethers (PBDEs), one typical type of persistent environmental contaminant, have toxicological effects such as disrupting thyroid homeostasis in the human body. The high binding affinities of hydroxylated metabolites of PBDEs (OH-PBDEs) with transthyretin (TTR) were considered to be one major reason for their extraordinary capacity of passing through the blood-brain barrier via competitive thyroid hormone (T4) transport protein binding. Recent findings showed that sulfated PBDEs can be formed in human liver cytosol as phase-II metabolites...
February 20, 2017: Molecular BioSystems
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