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Predictive toxicology

Carlijn R Hooijmans, Rob B M de Vries, Merel Ritskes-Hoitinga, Maroeska M Rovers, Mariska M Leeflang, Joanna IntHout, Kimberley E Wever, Lotty Hooft, Hans de Beer, Ton Kuijpers, Malcolm R Macleod, Emily S Sena, Gerben Ter Riet, Rebecca L Morgan, Kristina A Thayer, Andrew A Rooney, Gordon H Guyatt, Holger J Schünemann, Miranda W Langendam
Laboratory animal studies are used in a wide range of human health related research areas, such as basic biomedical research, drug research, experimental surgery and environmental health. The results of these studies can be used to inform decisions regarding clinical research in humans, for example the decision to proceed to clinical trials. If the research question relates to potential harms with no expectation of benefit (e.g., toxicology), studies in experimental animals may provide the only relevant or controlled data and directly inform clinical management decisions...
2018: PloS One
Kaori Ambe, Kana Ishihara, Tatsuya Ochibe, Kazuyuki Ohya, Sorami Tamura, Kaoru Inoue, Midori Yoshida, Masahiro Tohkin
In silico prediction for toxicity of chemicals is required to reduce cost, time, and animal testing. However, predicting hepatocellular hypertrophy, which often affects the derivation of the No-Observed-Adverse-Effect Level in repeated dose toxicity studies, is difficult because pathological findings are diverse, mechanisms are largely unknown, and a wide variety of chemical structures exists. Therefore, a method for predicting the hepatocellular hypertrophy of diverse chemicals without complete understanding of their mechanisms is necessary...
December 22, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Jennifer M Colby, Katie L Thoren, Kara L Lynch
High-resolution mass spectrometers (HRMS), including quadrupole time of flight mass analyzers (QqTOF), are becoming more prevalent as screening tools in clinical and forensic toxicology laboratories. Among other advantages, HRMS instruments can collect untargeted, full-scan mass spectra. These datasets can be analyzed retrospectively using a combination of techniques, which can extend the drug detection capabilities. Most laboratories using HRMS in production settings perform untargeted data collection, but analyze data in a targeted manner...
January 4, 2018: Journal of Analytical Toxicology
Peter Bloomingdale, Conrad Housand, Joshua F Apgar, Bjorn L Millard, Donald E Mager, John M Burke, Dhaval K Shah
The overarching goal of modern drug development is to optimize therapeutic benefits while minimizing adverse effects. However, inadequate efficacy and safety concerns remain to be the major causes of drug attrition in clinical development. For the past 80 years, toxicity testing has consisted of evaluating the adverse effects of drugs in animals to predict human health risks. The U.S. Environmental Protection Agency recognized the need to develop innovative toxicity testing strategies and asked the National Research Council to develop a long-range vision and strategy for toxicity testing in the 21st century...
June 2017: Current Opinion in Toxicology
Ume-Kulsoom Shah, Jefferson de Oliveira Mallia, Neenu Singh, Katherine E Chapman, Shareen H Doak, Gareth J S Jenkins
The liver's role in metabolism of chemicals makes it an appropriate tissue for toxicity testing. Current testing protocols, such as animal testing and two-dimensional liver cell systems, offer limited resemblance to in vivo liver cell behaviour, in terms of gene expression profiles and metabolic competence; thus, they do not always accurately predict human toxicology. In vitro three-dimensional liver cell models offer an attractive alternative. This study reports on the development of a 3D liver model, using HepG2 cells, by a hanging-drop technique, with a focus on evaluating spheroid growth characteristics and suitability for genotoxicity testing...
January 2018: Mutation Research
Robert Burgess, Robert Davis, Deborah Edwards
Uptake of lead from soil was examined in order to establish a site-specific ecological protective concentration level for the Texas Horned Lizard (Phrynosoma cornutum) at the Former Humble Refinery in San Antonio, Texas. Soils, harvester ants, and rinse water from the ants were analyzed at 11 Texas Harvester Ant (Pogonomyrmex barbatus) mounds. Soil concentrations at the harvester ant mounds ranged from 13 to 7474 mg/kg of lead dry weight. Ant tissue sample concentrations ranged from < 0.82 to 21.17 mg/kg dry weight...
January 5, 2018: Environmental Science and Pollution Research International
Werner Höllriegl, Alexander Bauer, Bernhard Baumgartner, Barbara Dietrich, Patrice Douillard, Randolf J Kerschbaumer, Gerald Höbarth, Jeffrey S McKee, Alexander Schinagl, Frederick W K Tam, Michael Thiele, Alfred Weber, Martin Wolfsegger, Marietta Turecek, Eva-Maria Muchitsch, Friedrich Scheiflinger, Helmut Glantschnig
New therapeutic agents are needed to overcome the toxicity and suboptimal efficacy observed in current treatment of glomerulonephritis (GN). BaxB01 is a fully human monoclonal antibody targeting a disease-related immunologically distinct isoform of Macrophage migration Inhibitory Factor (MIF), designated oxidized MIF (oxMIF) and locally expressed in inflammatory conditions. We report the pharmacokinetic profile of BaxB01, and its dose and exposure-related disease-modifying activity in experimentally induced rat GN...
December 20, 2017: European Journal of Pharmacology
Yan Han, Jinghua Zhao, Ruili Huang, Menghang Xia, Daojing Wang
The new strategy for chemical toxicity testing and modeling is to use in vitro human cell-based assays in conjunction with quantitative high-throughput screening (qHTS) technology, to identify molecular mechanisms and predict in vivo responses. Stem cells are more physiologically relevant than immortalized cell lines because of their unique proliferation and differentiation potentials. We established a robust two stem cells-two lineages assay system, encompassing human mesenchymal stem cells (hMSCs) along osteogenesis and human induced pluripotent stem cells (hiPSCs) along hepatogenesis...
December 20, 2017: Journal of Proteome Research
Marco Vinceti, Annalisa Chiari, Marcel Eichmüller, Kenneth J Rothman, Tommaso Filippini, Carlotta Malagoli, Jennifer Weuve, Manuela Tondelli, Giovanna Zamboni, Paolo F Nichelli, Bernhard Michalke
BACKGROUND: Little is known about factors influencing progression from mild cognitive impairment to Alzheimer's dementia. A potential role of environmental chemicals and specifically of selenium, a trace element of nutritional and toxicological relevance, has been suggested. Epidemiologic studies of selenium are lacking, however, with the exception of a recent randomized trial based on an organic selenium form. METHODS: We determined concentrations of selenium species in cerebrospinal fluid sampled at diagnosis in 56 participants with mild cognitive impairment of nonvascular origin...
December 19, 2017: Alzheimer's Research & Therapy
Katerine S Saili, Todd J Zurlinden, Andrew J Schwab, Aymeric Silvin, Nancy C Baker, E Sidney Hunter, Florent Ginhoux, Thomas B Knudsen
The blood-brain barrier (BBB) serves as a gateway for passage of drugs, chemicals, nutrients, metabolites, and hormones between vascular and neural compartments in the brain. Here, we review BBB development with regard to the microphysiology of the neurovascular unit (NVU) and the impact of BBB disruption on brain development. Our focus is on modeling these complex systems. Extant in silico models are available as tools to predict the probability of drug/chemical passage across the BBB; in vitro platforms for high-throughput screening and high-content imaging provide novel data streams for profiling chemical-biological interactions; and engineered human cell-based microphysiological systems provide empirical models with which to investigate the dynamics of NVU function...
December 1, 2017: Birth Defects Research
Christina T Holt, Kenneth L McCall, Gary Cattabriga, Chunhao Tu, Elenna K Smalley, Stephanie D Nichols
BACKGROUND: This study evaluates complete state data from controlled substance prescribing trends in the prescription monitoring program (PMP) database and their association with the risk of prescription drug overdose death. SUMMARY: Maine PMP records of individuals who died of prescription overdose deaths between 2006 and 2010 were selected (n = 690). For each subject, an age, gender, and residence matched cohort of PMP users in a 50: 1 ratio was identified (n = 34,500)...
December 14, 2017: Pharmacology
Joshua Seth Eaton, Paul E Miller, Ellison Bentley, Sara M Thomasy, Christopher J Murphy
PURPOSE: To present a semiquantitative ocular scoring system comprising elements and criteria that address many of the limitations associated with systems commonly used in preclinical studies, providing enhanced cross-species applicability and predictive value in modern ocular drug and device development. METHODS: Revisions to the ocular scoring systems of McDonald-Shadduck and Hackett-McDonald were conducted by board-certified veterinary ophthalmologists at Ocular Services On Demand (OSOD) over the execution of hundreds of in vivo preclinical ocular drug and device development studies and general toxicological investigations...
December 2017: Journal of Ocular Pharmacology and Therapeutics
Stacey A McCaffrey, Ryan A Black, Albert J Villapiano, Robert N Jamison, Stephen F Butler
Objective: The Current Opioid Misuse Measure (COMM) is a commonly used self-report instrument to identify and monitor aberrant opioid-related behavior in chronic pain patients on opioid therapy. However, the length of the COMM may limit its clinical utility. Additionally, this paper-and-pencil screener requires hand scoring, which increases paperwork and staff burden. Therefore, the current study presents development of the "COMM-9," a brief electronically administered form of the COMM...
December 11, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
Hai V Pham-The, Nguyen-Hai Nam, Doan-Viet Nga, Dang Thanh Hai, Karel Dieguez-Santana, Yovani Marrero-Poncee, Juan A Castillo-Garit, Gerardo M Casanola-Martin, Huong Le-Thi-Thu
Quantitative Structure - Activity Relationship (QSAR) modeling has been widely used in medicinal chemistry and computational toxicology for many years. Today, as the amount of data on chemicals is increasing dramatically, QSAR methods have become pivotal for the purpose of handling the data, identifying a decision, and gathering useful information from data processing. The advances in this field have paved a way for numerous alternative approaches that require deep mathematics in order to enhance the learning capability of QSAR models...
December 11, 2017: Current Topics in Medicinal Chemistry
Laura Depalo, Alberto Lanzoni, Antonio Masetti, Edison Pasqualini, Giovanni Burgio
Conventional insecticide assays, which measure the effects of insecticide exposure on short-term mortality, overlook important traits, including persistence of toxicity or sub-lethal effects. Therefore, such approaches are especially inadequate for prediction of the overall impact of insecticides on beneficial arthropods. In this study, the side effects of four modern insecticides (chlorantraniliprole, emamectin benzoate, spinosad, and spirotetramat) on Adalia bipunctata (L.) (Coleoptera: Coccinellidae) were evaluated under laboratory conditions by exposition on treated potted plants...
December 5, 2017: Journal of Economic Entomology
Slobodan P Rendic, F Peter Guengerich
The paper presents development and use of offline and Web-searchable human and other species metabolism databases. A search of the databases presented will produce basic information on metabolic reactions or transporter systems published on specific drug or other chemical, kinetic values, as well as structure of the metabolites. In addition, searching enables comparison of the data between different species models. The data cover time the period until 2008, and the current Web-searchable database [19] is updated quarterly each year and over the period until October 2017...
December 7, 2017: Current Drug Metabolism
Elisabet Berggren, Andrew White, Gladys Ouedraogo, Alicia Paini, Andrea-Nicole Richarz, Frederic Y Bois, Thomas Exner, Sofia Leite, Leo A van Grunsven, Andrew Worth, Catherine Mahony
We describe and illustrate a workflow for chemical safety assessment that completely avoids animal testing. The workflow, which was developed within the SEURAT-1 initiative, is designed to be applicable to cosmetic ingredients as well as to other types of chemicals, e.g. active ingredients in plant protection products, biocides or pharmaceuticals. The aim of this work was to develop a workflow to assess chemical safety without relying on any animal testing, but instead constructing a hypothesis based on existing data, in silico modelling, biokinetic considerations and then by targeted non-animal testing...
November 2017: Computational Toxicology
Seul Min Choi, Tae Hyun Roh, Duck Soo Lim, Sam Kacew, Hyung Sik Kim, Byung-Mu Lee
A risk assessment of benzalkonium chloride (BAC) was conducted based upon its toxicological profile and exposure evaluation. Since 1935, BAC has been used in a wide variety of products such as disinfectants, preservatives, and sanitizers. It is well-established that BAC is not genotoxic nor does it display tumorigenic potential, but safety concerns have been raised in local usage such as for ocular and intranasal applications. The Foundation of Korea Cosmetic Industry Institute (KCII) reported that in a hair conditioner manufactured as a cosmetic or personal product in South Korea, BAC was present at concentrations of 0...
December 6, 2017: Journal of Toxicology and Environmental Health. Part B, Critical Reviews
Shannon M Bell, Xiaoqing Chang, John F Wambaugh, David G Allen, Mike Bartels, Kim L R Brouwer, Warren M Casey, Neepa Choksi, Stephen S Ferguson, Grazyna Fraczkiewicz, Annie M Jarabek, Alice Ke, Annie Lumen, Scott G Lynn, Alicia Paini, Paul S Price, Caroline Ring, Ted W Simon, Nisha S Sipes, Catherine S Sprankle, Judy Strickland, John Troutman, Barbara A Wetmore, Nicole C Kleinstreuer
In vitro chemical safety testing methods offer the potential for efficient and economical tools to provide relevant assessments of human health risk. To realize this potential, methods are needed to relate in vitro effects to in vivo responses, i.e., in vitro to in vivo extrapolation (IVIVE). Currently available IVIVE approaches need to be refined before they can be utilized for regulatory decision-making. To explore the capabilities and limitations of IVIVE within this context, the U.S. Environmental Protection Agency Office of Research and Development and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods co-organized a workshop and webinar series...
December 1, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Wei-Chun Chou, Chin-Yu Hsu, Chia-Chi Ho, Jui-Hua Hsieh, Hung-Che Chiang, Tsui-Chun Tsou, Yu-Cheng Chen, Pinpin Lin
Polycyclic aromatic hydrocarbons (PAHs) are widely distributed throughout the atmosphere as mixtures attached to ambient particulate matter (PM). PAHs usually elicit similar toxicological pathways but do so with varying levels of efficacy. In this study, we utilized high-throughput screening (HTS) in vitro data of PAHs to predict health risks associated with coarse and fine PM. PM samples with 22 PAH compounds obtained from residential areas close to industrial parks in central Taiwan were analyzed. On the basis of the PM-bound PAH concentrations and their activities reported in HTS assays, we developed a probabilistic model for estimating cumulative exposure of humans to PAHs...
December 1, 2017: Environmental Science & Technology
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