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Regulatory toxicology

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https://www.readbyqxmd.com/read/28934728/has-toxicity-testing-moved-into-the-21st-century-a-survey-and-analysis-of-perceptions-in-the-field-of-toxicology
#1
Virginia Zaunbrecher, Elizabeth Beryt, Daniela Parodi, Donatello Telesca, Joseph Doherty, Timothy Malloy, Patrick Allard
BACKGROUND: Ten years ago, leaders in the field of toxicology called for a transformation of the discipline and a shift from primarily relying on traditional animal testing to incorporating advances in biotechnology and predictive methodologies into alternative testing strategies (ATS). Governmental agencies and academic and industry partners initiated programs to support such a transformation, but a decade later, the outcomes of these efforts are not well understood. OBJECTIVES: We aimed to assess the use of ATS and the perceived barriers and drivers to their adoption by toxicologists and by others working in, or closely linked with, the field of toxicology...
August 30, 2017: Environmental Health Perspectives
https://www.readbyqxmd.com/read/28927750/the-challenge-of-the-application-of-omics-technologies-in-chemicals-risk-assessment-background-and-outlook
#2
Ursula G Sauer, Lize Deferme, Laura Gribaldo, Jörg Hackermüller, Tewes Tralau, Ben van Ravenzwaay, Carole Yauk, Alan Poole, Weida Tong, Timothy W Gant
This survey by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) highlights that 'omics technologies are generally not yet applied to meet standard information requirements during regulatory hazard assessment. While they are used within weight-of-evidence approaches to investigate substances' modes-of-action, consistent approaches for the generation, processing and interpretation of 'omics data are not applied. To date, no 'omics technology has been standardised or validated. Best practices for performing 'omics studies for regulatory purposes (e...
September 16, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28924161/molecular-mechanisms-involved-in-the-non-monotonic-effect-of-bisphenol-a-on-ca2-entry-in-mouse-pancreatic-%C3%AE-cells
#3
Sabrina Villar-Pazos, Juan Martinez-Pinna, Manuel Castellano-Muñoz, Paloma Alonso-Magdalena, Laura Marroqui, Ivan Quesada, Jan-Ake Gustafsson, Angel Nadal
In regulatory toxicology, the dose-response relationship is a key element towards fulfilling safety assessments and satisfying regulatory authorities. Conventionally, the larger the dose, the greater the response, following the dogma "the dose makes the poison". Many endocrine disrupting chemicals, including bisphenol-A (BPA), induce non-monotonic dose response (NMDR) relationships, which are unconventional and have tremendous implications in risk assessment. Although several molecular mechanisms have been proposed to explain NMDR relationships, they are largely undemonstrated...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28893587/current-nonclinical-testing-paradigm-enables-safe-entry-to-first-in-human-clinical-trials-the-iq-consortium-nonclinical-to-clinical-translational-database
#4
Thomas M Monticello, Thomas W Jones, Donna M Dambach, David M Potter, Michael W Bolt, Maggie Liu, Douglas A Keller, Timothy K Hart, Vivek J Kadambi
The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2×2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis...
September 8, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28892386/double-mutated-5-enol-pyruvylshikimate-3-phosphate-synthase-protein-expressed-in-mzhg0jg-corn-zea-mays-l-has-no-impact-on-toxicological-safety-and-nutritional-composition
#5
Bethany A Matthews, Karen L Launis, Patricia A Bauman, Nicole C Juba
MZHG0JG corn will offer growers the flexibility to alternate between herbicides with two different modes of action in their weed-management programs, helping to mitigate and manage the evolution of herbicide resistance in weed populations. The proteins conferring herbicide tolerence in MZHG0JG corn, double-mutated 5-enol pyruvylshikimate-3-phosphate synthase protein (mEPSPS) and phosphinothricin acetyltransferase (PAT), as well as the MZHG0JG corn event, have been assessed by regulatory authorities globally and have been determined to be safe for humans, animals, and the environment...
September 19, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28889778/genotoxicity-testing-progress-and-prospects-for-the-next-decade
#6
Hasan Turkez, Mehmet E Arslan, Ozlem Ozdemir
Genotoxicity and mutagenicity analyses have a significant role in the identification of hazard effects of therapeutic drugs, cosmetics, agrochemicals, industrial compounds, food additives, natural toxins and nanomaterials for regulatory purposes. To evaluate mutagenicity or genotoxicity, different in vitro and in vivo methodologies exert various genotoxicological endpoints such as point mutations, changes in number and structure of chromosomes. Areas covered: This review covered the basics of genotoxicity and in vitro/in vivo methods for determining of genetic damages...
September 10, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28889265/manganese-and-the-insulin-igf-signaling-network-in-huntington-s-disease-and-other-neurodegenerative-disorders
#7
Miles R Bryan, Aaron B Bowman
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28866265/chemical-induced-asthma-and-the-role-of-clinical-toxicological-exposure-and-epidemiological-research-in-regulatory-and-hazard-characterization-approaches
#8
Melissa J Vincent, Jonathan A Bernstein, David Basketter, Judy S LaKind, G Scott Dotson, Andrew Maier
Uncertainties in understanding all potential modes-of-action for asthma induction and elicitation hinders design of hazard characterization and risk assessment methods that adequately screen and protect against hazardous chemical exposures. To address this challenge and identify current research needs, the University of Cincinnati and the American Cleaning Institute hosted a webinar series to discuss the current state-of-science regarding chemical-induced asthma. The general consensus is that the available database, comprised of data collected from routine clinical and validated toxicological tests, is inadequate for predicting or determining causal relationships between exposures and asthma induction for most allergens...
September 1, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28865950/individual-and-combined-toxicological-effects-of-deoxynivalenol-and-zearalenone-on-human-hepatocytes-in-in-vitro-chronic-exposure-conditions
#9
Marie-Caroline Smith, Stéphanie Madec, Audrey Pawtowski, Emmanuel Coton, Nolwenn Hymery
While numerous surveys highlighted the natural co-occurrence of mycotoxins in food, data about their toxicological combined effects is still limited. This is especially the case for chronic exposure conditions, although the latter are more representative of the mycotoxin risk associated with food consumption than acute exposure. In the present study, cell viability and gene expression levels of relevant hepatocyte-specific functions were evaluated for the HepaRG human liver cell line exposed to deoxynivalenol (DON) and/or zearalenone (ZEA) during 14, 28 and 42days at three subtoxic concentrations corresponding to i) the determined average exposure dose of French adult population, ii) the tolerable daily intake established by the Joint FAO/WHO Expert Committee and iii) the maximum level permitted by the European regulation in cereals intended for direct human consumption...
September 1, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28854146/evaluation-of-the-carcinogenic-risks-at-the-influence-of-pops
#10
Aiman Nazhmetdinova, Adlet Kassymbayev, Altinay Chalginbayeva
INTRODUCTION: Kazakhstan is included in the list of environmentally vulnerable countries and Kyzylorda oblast in particular. This is due to its geographical, spatial and temporal and socioeconomic features. MATERIALS AND METHODS: As part of the program "Integrated approaches in the management of public health in the Aral region", we have carried out an expertise on many samples of natural environments and products. Samples were selected in accordance with sampling procedures according to regulatory documents by specialists of the Pesticide Toxicology Laboratory...
August 30, 2017: Reviews on Environmental Health
https://www.readbyqxmd.com/read/28819176/use-of-biocompatible-sorafenib-gold-nanoconjugates-for-reversal-of-drug-resistance-in-human-hepatoblatoma-cells
#11
Sandeep Kumar Vishwakarma, Priyanka Sharmila, Avinash Bardia, Lakkireddy Chandrakala, N Raju, G Sravani, B V S Sastry, Md Aejaz Habeeb, Aleem Ahmed Khan, Marshal Dhayal
The present study identifies the potential of highly biocompatible SF-GNP nano-conjugate to enhance the chemotherapeutic response to combat drug resistance in cancer cells. We developed a stable colloidal suspension of sorafenib-gold nanoconjugate (SF-GNP) of <10 nm size in aqueous medium for reverting the cancer drug resistance in SF-resistant HepG2 cells in a 3D ex-vivo model system. In-vivo biocompatibility assay of SF-GNPs showed absence of systemic toxicological effects including hematological, biochemical and histological parameters...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28817646/genetic-dissection-of-endothelial-transcriptional-activity-of-zebrafish-aryl-hydrocarbon-receptors-ahrs
#12
Wade W Sugden, Roberto C Leonardo-Mendonça, Darío Acuña-Castroviejo, Arndt F Siekmann
The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix transcription factor conserved across phyla from flies to humans. Activated by a number of endogenous ligands and environmental toxins, studies on AHR function and gene regulation have largely focused on a toxicological perspective relating to aromatic hydrocarbons generated by human activities and the often-deleterious effects of exposure on vertebrates mediated by AHR activation. A growing body of work has highlighted the importance of AHR in physiologic processes, including immune cell differentiation and vascular patterning...
2017: PloS One
https://www.readbyqxmd.com/read/28796812/toxicological-and-bio-distribution-profile-of-a-gm-csf-expressing-double-targeted-chimeric-oncolytic-adenovirus-oncos-102-support-for-clinical-studies-on-advanced-cancer-treatment
#13
Lukasz Kuryk, Lotta Vassilev, Tuuli Ranki, Akseli Hemminki, Aila Karioja-Kallio, Onerva Levälampi, Antti Vuolanto, Vincenzo Cerullo, Sari Pesonen
The purpose of this work was to carry out preclinical toxicity and bio-distribution studies required for regulatory approval of a clinical trial application for Phase I clinical studies of ONCOS-102 (Ad5/3-D24-GM-CSF) for therapy of advanced cancers (NCT01598129). The study design, route of administration and dosage differs from the clinical protocol and in more detail, investigate bio-distribution and toxicological profile of ONCOS-102 treatment in animal model. The study was carried out in 300 hamsters divided into nine test groups-three bio-distribution groups and six groups for analysis of toxicity...
2017: PloS One
https://www.readbyqxmd.com/read/28772059/optical-projection-tomography-with-a-tissue-clearing-agent-for-developmental-and-reproductive-toxicology-studies
#14
Alexander W Magsam, Michael Johnson, Thomas Villani, Mark C Pierce
BACKGROUND: Developmental and reproductive toxicology (DART) testing represents an expensive and time-consuming stage in determining the toxicological profile of new chemical entities. Within DART studies, morphological evaluation of fetal skeletons for developmental abnormalities typically requires 7 to 14 days. Current processing techniques involve digestion of soft tissue using a strong base (KOH), followed by qualitative assessment of the remaining skeletal tissue by a fetal morphologist...
August 3, 2017: Birth defects research
https://www.readbyqxmd.com/read/28760446/in-vitro-to-in-vivo-extrapolation-of-effective-dosimetry-in-developmental-toxicity-testing-application-of-a-generic-pbk-modelling-approach
#15
Styliani Fragki, Aldert H Piersma, Emiel Rorije, Marco J Zeilmaker
Incorporation of kinetics to quantitative in vitro to in vivo extrapolations (QIVIVE) is a key step for the realization of a non-animal testing paradigm, in the sphere of regulatory toxicology. The use of Physiologically-Based Kinetic (PBK) modelling for determining systemic doses of chemicals at the target site is accepted to be an indispensable element for such purposes. Nonetheless, PBK models are usually designed for a single or a group of compounds and are considered demanding, with respect to experimental data needed for model parameterization...
October 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28757310/recommendations-for-harmonization-of-data-collection-and-analysis-of-developmental-neurotoxicity-endpoints-in-regulatory-guideline-studies-proceedings-of-workshops-presented-at-society-of-toxicology-and-joint-teratology-society-and-neurobehavioral-teratology
#16
REVIEW
Abby A Li, Larry P Sheets, Kathleen Raffaele, Virginia Moser, Angela Hofstra, Alan Hoberman, Susan L Makris, Robert Garman, Brad Bolon, Wolfgang Kaufmann, Roland Auer, Edmund Lau, Thomas Vidmar, Wayne J Bowers
The potential for developmental neurotoxicity (DNT) of environmental chemicals may be evaluated using specific test guidelines from the US Environmental Protection Agency or the Organisation for Economic Cooperation and Development (OECD). These guidelines generate neurobehavioral, neuropathological, and morphometric data that are evaluated by regulatory agencies globally. Data from these DNT guideline studies, or the more recent OECD extended one-generation reproductive toxicity guideline, play a pivotal role in children's health risk assessment in different world areas...
July 27, 2017: Neurotoxicology and Teratology
https://www.readbyqxmd.com/read/28751261/getting-a-molecule-into-the-clinic-nonclinical-testing-and-starting-dose-considerations
#17
Paul Baldrick
Examination of content of 35 Investigator Brochures (IBs) for small molecules (including some for oncology) used to support First-In-Human studies over a 2 year period (2014-2016) showed that a mean of 37 nonclinical studies were performed per molecule with pharmacology, ADME and toxicology testing contributing 43%, 32% and 24% of the studies, respectively. Examination of 11 IBs for biopharmaceuticals (monoclonal antibodies) over the same time frame showed that the mean number of nonclinical studies was 17 studies per molecule with pharmacology, ADME and toxicology testing contributing 82%, 6% and 12% of the studies, respectively...
July 24, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28749665/summary-of-the-acs-symposium-on-public-health-perspectives-of-mycotoxins-in-food
#18
Lauren S Jackson, Dojin Ryu
A symposium entitled "Public Health Perspectives of Mycotoxins in Food" was held at the 251st American Chemical Society (ACS) Meeting in March 2016 in San Diego, CA, and was sponsored by the ACS Division of Agricultural and Food Chemistry. The purpose of the symposium was to convene the leading mycotoxin researchers throughout the world to discuss the current state of knowledge as well as research needs with respect to evaluating the toxicological properties of mycotoxins and ways to detect, control, and reduce human and animal exposure to these natural toxins...
August 23, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28748456/nonclinical-development-of-combination-drugs
#19
Alberto Lodola
We define "combination drugs" as "fixed-dose combinations" (FDCs), that is, two or more drugs (marketed or not) combined in a single pill or two or more separate drugs packaged together. FDCs have been available commercially for many years but only relatively recently have nonclinical development guidelines been released by a number of regulatory authorities and the World Health Organization; as yet there are no ICH guidelines specific to combination drugs. In general however, the ICH guidelines for monotherapy development provide a framework for FDC development...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28714573/assessment-of-the-dna-damaging-potential-of-environmental-chemicals-using-a-quantitative-high-throughput-screening-approach-to-measure-p53-activation
#20
Kristine L Witt, Jui-Hua Hsieh, Stephanie L Smith-Roe, Menghang Xia, Ruili Huang, Jinghua Zhao, Scott S Auerbach, Junguk Hur, Raymond R Tice
Genotoxicity potential is a critical component of any comprehensive toxicological profile. Compounds that induce DNA or chromosomal damage often activate p53, a transcription factor essential to cell cycle regulation. Thus, within the US Tox21 Program, we screened a library of ∼10,000 (∼8,300 unique) environmental compounds and drugs for activation of the p53-signaling pathway using a quantitative high-throughput screening assay employing HCT-116 cells (p53(+/+) ) containing a stably integrated β-lactamase reporter gene under control of the p53 response element (p53RE)...
August 2017: Environmental and Molecular Mutagenesis
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