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Regulatory toxicology

Klaus P Rothenbacher, Alison M Pecquet
This article summarizes historical and recent research on the terrestrial toxicology of tetrabromobisphenol A (TBBPA). Despite its ubiquitous use and presence in the environment, little published data is available to evaluate the terrestrial ecotoxicity of TBBPA. The purposes of this paper are to enable broad access to a series of TBBPA ecotoxicity tests (nitrogen transformation, earthworm survival/reproduction, and seedling emergence/growth) that were conducted in support of regulatory risk assessments, and to summarize available research in the terrestrial toxicity of TBBPA...
May 17, 2018: Environmental Science and Pollution Research International
David V Gauvin, Zachary J Zimmermann, Joshua Yoder, Marci Harter, David Holdsworth, Quinn Kilgus, Jonelle May, Jill Dalton, Theodore J Baird
Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240) . These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies...
May 8, 2018: Journal of Pharmacological and Toxicological Methods
Norimitsu Shirai, Mark G Evans
The present article describes an occurrence of testicular microlithiasis in a cynomolgus monkey from a routine regulatory toxicology study. The monkey was from a negative control group. Microscopically, the lesion was characterized by multiple extracellular mineralized calculi within seminiferous tubular epithelia of both testes without any tissue reaction or abnormal condition such as cryptorchidism, testicular neoplasm, or hypogonadism. The present case is remarkable in that there is a paucity of reports on spontaneous testicular microlithiasis in nonhuman primates...
April 2018: Journal of Toxicologic Pathology
Manon Beekhuijzen, Steffen Schneider, Narinder Barraclough, Nina Hallmark, Alan Hoberman, Sheri Lordi, Mary Moxon, Deborah Perks, Aldert H Piersma, Susan L Makris
In recent years several OECD test guidelines have been updated and some will be updated shortly with the requirement to measure thyroid hormone levels in the blood of mammalian laboratory species. There is, however, an imperative need for clarification and guidance regarding the collection, assessment, and interpretation of thyroid hormone data for regulatory toxicology and risk assessment. Clarification and guidance is needed for 1) timing and methods of blood collection, 2) standardization and validation of the analytical methods, 3) triggers for additional measurements, 4) the need for T4 measurements in postnatal day (PND) 4 pups, and 5) the interpretation of changes in thyroid hormone levels regarding adversity...
May 2, 2018: Reproductive Toxicology
Phoebe A Stapleton, Christopher J Wingard, Timothy R Nurkiewicz, Alison C Holloway, Judith T Zelikoff, Thomas B Knudsen, Lynette K Rogers
Xenobiotic exposures affect the maternal and/or in utero environment resulting in impairments in fetal development. During the period of rapid fetal growth, developing cardiovascular systems are especially vulnerable to their environment. Furthermore, fetal exposures can evoke changes in epigenetic signatures that result in permanent modifications in gene expression. This symposium focused on the intersection between maternal and fetal exposure and the developing cardiovascular system. The impact of maternal exposures on prenatal development is of major concern for regulatory agencies given the unique vulnerability of the embryo/fetus to environmental factors, the importance of vascular biology to maternal-fetal interactions, and the adverse consequences of vascular disruption to children's health...
April 27, 2018: Reproductive Toxicology
Luca Romanelli, Maria Grazia Evandri
Solvents can be used in the manufacture of medicinal products provided their residual levels in the final product comply with the acceptable limits based on safety data. At worldwide level, these limits are set by the "Guideline Q3C (R6) on impurities: guideline for residual solvents" issued by the ICH. Diisopropyl ether (DIPE) is a widely used solvent but the possibility of using it in the pharmaceutical manufacture is uncertain because the ICH Q3C guideline includes it in the group of solvents for which "no adequate toxicological data on which to base a Permitted Daily Exposure (PDE) was found"...
April 2018: Toxicological Research
Shayne C Gad, JoAnn C L Schuh
Safety ("biocompatibility") assessment of medical devices has evolved along a different path than that of drugs, being historically governed more by the considerations and needs of engineers rather than chemists and biologists. As a result, the involvement of veterinary pathologists has been much more limited-almost entirely to evaluating tissue responses in tissues in direct contact with implanted devices. As devices have become more complex in composition, structure, placement, and use, concerns as to adverse systemic responses in patients have called for more comprehensive and thoughtful evaluations of effects throughout the body...
January 1, 2018: Toxicologic Pathology
Glenn J Myatt, Ernst Ahlberg, Yumi Akahori, David Allen, Alexander Amberg, Lennart T Anger, Aynur Aptula, Scott Auerbach, Lisa Beilke, Phillip Bellion, Romualdo Benigni, Joel Bercu, Ewan D Booth, Dave Bower, Alessandro Brigo, Natalie Burden, Zoryana Cammerer, Mark T D Cronin, Kevin P Cross, Laura Custer, Magdalena Dettwiler, Krista Dobo, Kevin A Ford, Marie C Fortin, Samantha E Gad-McDonald, Nichola Gellatly, Véronique Gervais, Kyle P Glover, Susanne Glowienke, Jacky Van Gompel, Steve Gutsell, Barry Hardy, James S Harvey, Jedd Hillegass, Masamitsu Honma, Jui-Hua Hsieh, Chia-Wen Hsu, Kathy Hughes, Candice Johnson, Robert Jolly, David Jones, Ray Kemper, Michelle O Kenyon, Marlene T Kim, Naomi L Kruhlak, Sunil A Kulkarni, Klaus Kümmerer, Penny Leavitt, Bernhard Majer, Scott Masten, Scott Miller, Janet Moser, Moiz Mumtaz, Wolfgang Muster, Louise Neilson, Tudor I Oprea, Grace Patlewicz, Alexandre Paulino, Elena Lo Piparo, Mark Powley, Donald P Quigley, M Vijayaraj Reddy, Andrea-Nicole Richarz, Patricia Ruiz, Benoit Schilter, Rositsa Serafimova, Wendy Simpson, Lidiya Stavitskaya, Reinhard Stidl, Diana Suarez-Rodriguez, David T Szabo, Andrew Teasdale, Alejandra Trejo-Martin, Jean-Pierre Valentin, Anna Vuorinen, Brian A Wall, Pete Watts, Angela T White, Joerg Wichard, Kristine L Witt, Adam Woolley, David Woolley, Craig Zwickl, Catrin Hasselgren
The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies...
April 17, 2018: Regulatory Toxicology and Pharmacology: RTP
Charles A Pittinger, Alison M Pecquet
This paper summarizes the historical and recent research on the aquatic toxicology and bioconcentration potential of tetrabromobisphenol A (TBBPA), a major flame retardant in electronics. Historical studies on TBBPA are presented in detail, and are compared with more recent research. The historical studies have not been published to date, though they were pivotal in regulatory assessments by the European Union, Canada, and the USA. These assessments have enabled the use of TBBPA as a flame retardant in electronic applications, to the present...
April 18, 2018: Environmental Science and Pollution Research International
Shruti Shukla, Jong Suk Lee, Vivek K Bajpai, Shivraj Hariram Nile, Yun Suk Huh, Young-Kyu Han, Myunghee Kim
Meju, a cooked and fermented soy bean based food product, is used as a major ingredient in Korean traditional fermented foods such as Doenjang. We developed a novel type of Meju using single and combined extracts of Allium sativum (garlic clove), Nelumbo nucifera (lotus leaves), and Ginkgo biloba (ginkgo leaves) at 1% and 10% concentrations to improve the safety of Meju-based fermented products. Biogenic amines (BAs) in protein-rich fermented food products pose considerable toxical risks. The objective of this study was to investigate the effects of adding selected plant extracts in Meju samples during fermentation...
April 10, 2018: Food and Chemical Toxicology
Tommaso Prosdocimi, Luca Mollica, Stefano Donini, Marta S Semrau, Anna Paola Lucarelli, Egidio Aiolfi, Andrea Cavalli, Paola Storici, Silvana Alfei, Chiara Brullo, Olga Bruno, Emilio Parisini
Selected members of the large rolipram-related GEBR family of phosphodiesterase-4 (PDE4) inhibitors have been shown to facilitate long term potentiation (LTP) and improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, little if any structure-activity relationship studies have so far been carried out in order to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone...
April 13, 2018: Biochemistry
Manish K Dubey, Mohd Aamir, Manish S Kaushik, Saumya Khare, Mukesh Meena, Surendra Singh, Ram S Upadhyay
Out of the various mycotoxigenic food and feed contaminant, the fungal species belonging to Penicillium genera, particularly Penicillium roqueforti is of great economic importance, and well known for its crucial role in the manufacturing of Roquefort and Gorgonzola cheese. The mycotoxicosis effect of this mold is due to secretion of several metabolites, of which PR toxin is of considerable importance, with regard to food quality and safety challenges issues. The food products and silages enriched with PR toxin could lead into damage to vital internal organs, gastrointestinal perturbations, carcinogenicity, immunotoxicity, necrosis, and enzyme inhibition...
2018: Frontiers in Pharmacology
Randi B Gombos, Ana Gonzalez, Mariana Manrique, Dhan Chand, David Savitsky, Benjamin Morin, Ekaterina Breous-Nystrom, Christopher Dupont, Rebecca A Ward, Cornelia Mundt, Benjamin Duckless, Hao Tang, Mark A Findeis, Andrea Schuster, Jeremy D Waight, Dennis Underwood, Christopher Clarke, Gerd Ritter, Taha Merghoub, David Schaer, Jedd D Wolchok, Marc van Dijk, Jennifer S Buell, Jean-Marie Cuillerot, Robert Stein, Elise E Drouin, Nicholas S Wilson
CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with other immunomodulatory antibodies...
2018: PloS One
Silvia Casati
The concept of Integrated Approaches to Testing and Assessment (IATA) has been advanced by the Organisation for Economic Cooperation and Development (OECD) member countries to enable a progressive shift from traditional chemical assessments largely based on the observation of the adverse effect in animal models, using individual methods or pre-defined batteries of standard toxicity tests, to assessment strategies integrating diverse lines of evidence. The flexible nature of IATA allows the inclusion of mechanistic data generated with non-animal testing methods and with new technologies (e...
March 31, 2018: Basic & Clinical Pharmacology & Toxicology
Harald F Krug, Nils Bohmer, Dana Kühnel, Clarissa Marquardt, Katja Nau, Christoph Steinbach
Nanotechnology is closely related to the tailored manufacturing of nanomaterials for a huge variety of applications. However, such applications with newly developed materials are also a reason for concern. The DaNa2.0 project provides information and support for these issues on the web in condensed and easy-to-understand wording. Thus, a key challenge in the field of advanced materials safety research is access to correct and reliable studies and validated results. For nanomaterials, there is currently a continuously increasing amount of publications on toxicological issues, but criteria to evaluate the quality of these studies are necessary to use them e...
March 29, 2018: Nanomaterials
Louise Sladen, Rommel Matheson, Kevin Norton, Aileen Milne
INTRODUCTION: Assessment of effects of potential drug candidates on the respiratory system is part of the regulatory preclinical safety assessment conducted prior to first in human trials (FTIH). Commonly, this is carried out utilizing head out plethysmography (HOP) or whole body plethysmography (WBP) which record only ventilatory parameters. When dosing via the inhaled route a more thorough respiratory assessment, including a direct measure of airway mechanics, is desirable. The aim of the present work was to improve the strategy for respiratory safety testing by a) evaluating a telemetered pleural pressure - HOP (PP-HOP) model and b) evaluating a crossover study design protocol in the WBP model to reduce variability and animal usage...
March 23, 2018: Journal of Pharmacological and Toxicological Methods
Christian Riebeling, Andreas Luch, Tewes Tralau
Driven by the fast paced development of complex test systems in vitro, mass spectrometry and omics we finally have the tools to unravel the molecular events that underlie toxicological adversity. Yet, timely regulatory adaptation of these new tools continues to pose major challenges even for organs readily accessible such as skin. The reasons for this encompass a need for conservatism as well as the need of tests to serve an existing regulatory framework rather than to produce scientific knowledge. It is important to be aware of this in order to align regulatory skin toxicity with the 3R-principles more readily...
March 25, 2018: Experimental Dermatology
Sumee Khanal, Priyanka Singh, Svetlana L Avlasevich, Dorothea K Torous, Jeffrey C Bemis, Stephen D Dertinger
Regulatory guidance documents stress the value of assessing multiple tissues and the most appropriate endpoints when evaluating chemicals for in vivo genotoxic potential. However, conducting several independent studies to consider multiple endpoints and/or tissue compartments is resource intensive. Furthermore, conventional approaches for scoring genotoxicity endpoints are slow, tedious, and less objective than what would be considered ideal. In an effort to address these issues with current practices, we attempted to i) employ flow cytometry-based methods to score liver micronuclei, blood micronuclei, and blood Pig-a gene mutation, and ii) integrate the endpoints into a common general toxicology study design-the rat 28-day repeat dose study...
April 2018: Mutation Research
Tetsuya Suzuki, Kyomu Matsumoto, Masamitsu Honma, Takehiko Nohmi
In regulatory genetic toxicology, it is an axiom that there is no threshold for genotoxicity of chemicals, such that genotoxic chemicals may impose carcinogenic risk on humans even at very low doses. This paradigm is counterintuitive, however, because humans possess a number of self-defense mechanisms that may suppress the genotoxicity at these low doses and therefore manifest a practical threshold. DNA polymerase zeta (Pol ζ) is a specialized Pol that plays an important role in DNA synthesis across DNA damage, thereby modulating cell survival and genotoxicity...
April 2018: Mutation Research
Maria Grazia Mascolo, Stefania Perdichizzi, Monica Vaccari, Francesca Rotondo, Cristina Zanzi, Sandro Grilli, Martin Paparella, Miriam N Jacobs, Annamaria Colacci
The development of alternative methods to animal testing is a priority in the context of regulatory toxicology. Carcinogenesis is a field where the demand for alternative methods is particularly high. The standard rodent carcinogenicity bioassay requires a large use of animals, high costs, prolonged duration, and shows several limitations, which can affect the comprehension of the human relevance of animal carcinogenesis. The Cell Transformation Assay has long been debated as a possible in vitro test to study carcinogenesis...
March 15, 2018: Carcinogenesis
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