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Regulatory toxicology

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
Zachary T Bitzer, Reema Goel, Samantha M Reilly, Ryan J Elias, Alexey Silakov, Jonathan Foulds, Joshua Muscat, John P Richie
BACKGROUND: Flavoring chemicals, or flavorants, have been used in electronic cigarettes (e-cigarettes) since their inception; however, little is known about their toxicological effects. Free radicals present in e-cigarette aerosols have been shown to induce oxidative stress resulting in damage to proliferation, survival, and inflammation pathways in the cell. Aerosols generated from e-liquid solvents alone contain high levels of free radicals but few studies have looked at how these toxins are modulated by flavorants...
March 13, 2018: Free Radical Biology & Medicine
Wasco Wruck, James Adjaye
Induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs) differentiated into hepatocyte-like cells (HLCs) provide a defined and renewable source of cells for drug screening, toxicology and regenerative medicine. We previously reprogrammed human fetal foreskin fibroblast cells (HFF1) into iPSCs employing an episomal plasmid-based integration-free approach, this iPSC-line and the hESC lines H1 and H9 were used to model hepatogenesis in vitro. Biochemical characterisation confirmed glycogen storage, ICG uptake and release, urea and bile acid production, as well as CYP3A4 activity...
March 13, 2018: Scientific Data
Kenneth A Schafer, John Eighmy, James D Fikes, Wendy G Halpern, Renee R Hukkanen, Gerald G Long, Emily K Meseck, Daniel J Patrick, Michael S Thibodeau, Charles E Wood, Sabine Francke
The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should be assigned based only on the extent (i.e., amount and complexity) of the morphologic change in the examined tissue section(s) and be clearly defined in the pathology report for critical lesions impacting study interpretation. However, the level of detail provided and criteria by which severity grades are assigned can vary, which can lead to inappropriate comparisons and confusion when evaluating pathology results...
January 1, 2018: Toxicologic Pathology
Russell S Thomas, Richard S Paules, Anton Simeonov, Suzanne C Fitzpatrick, Kevin M Crofton, Warren M Casey, Donna L Mendrick
The traditional approaches to toxicity testing have posed multiple challenges for evaluating the safety of commercial chemicals, pesticides, food additives/contaminants, and medical products.The challenges include number of chemicals that need to be tested, time and resource intensive nature of traditional toxicity tests, and unexpected adverse effects that occur in pharmaceutical clinical trials despite the extensive toxicological testing.Over a decade ago, the U.S. Environmental Protection Agency (EPA), National Toxicology Program (NTP), National Center for Advancing Translational Sciences (NCATS), and the Food and Drug Administration (FDA) formed a federal consortium for "Toxicology in the 21st Century" (Tox21) with a focus on developing and evaluating in vitro high-throughput screening (HTS) methods for hazard identification and providing mechanistic insights...
March 8, 2018: ALTEX
Kevin McAdam, James Murphy, Alison Eldridge, Christopher Proctor, Clive Meredith
The concept of a risk continuum for tobacco and nicotine products has been proposed, which differentiates products according to their propensity to reduce toxicant exposure and risk. Cigarettes are deemed the most risky and medicinal nicotine the least. We assessed whether a Reduced-Toxicant Prototype (RTP) cigarette could sufficiently reduce exposure to toxicants versus conventional cigarettes to be considered a distinct category in the risk continuum. We present findings from both pre-clinical and clinical studies in order to examine the potential for reduced smoke toxicant emissions to lower health risks associated with cigarette smoking...
March 8, 2018: Regulatory Toxicology and Pharmacology: RTP
Apurva Patange, Daniela Boehm, Michelle Giltrap, Peng Lu, P J Cullen, Paula Bourke
Generation of wastewater is one of the main environmental sustainability issues across food sector industries. The constituents of food process effluents are often complex and require high energy and processing for regulatory compliance. Wastewater streams are the subject of microbiological and chemical criteria, and can have a significant eco-toxicological impact on the aquatic life. Thus, innovative treatment approaches are required to mitigate environmental impact in an energy efficient manner. Here, dielectric barrier discharge atmospheric cold plasma (ACP) was evaluated for control of key microbial indicators encountered in food industry effluent...
March 8, 2018: Science of the Total Environment
Sharon Buring Stuard, Tuula Heinonen
Structure activity relationship (SAR)-based read-across is an effective approach for addressing data gaps in human health risk assessment for 'data-poor' chemicals. In read-across, available data on chemical structural analogues are used to predict the toxicity potential of the data-poor chemical. This approach has long been recognized by regulatory agencies and used by industry to evaluate the hazards of chemicals for which there are limited direct data. Construction of a scientifically robust SAR-based read-across hazard assessment is a complex and iterative process involving multiple considerations in each step...
March 10, 2018: Basic & Clinical Pharmacology & Toxicology
Filippo Zanetti, Alain Sewer, Elena Scotti, Bjoern Titz, Walter K Schlage, Patrice Leroy, Athanasios Kondylis, Gregory Vuillaume, Anita R Iskandar, Emmanuel Guedj, Keyur Trivedi, Thomas Schneider, Ashraf Elamin, Florian Martin, Nikolai V Ivanov, Stefan Frentzel, Manuel C Peitsch, Julia Hoeng
Cigarette smoke (CS) is affecting considerably the oral mucosa. Heating, instead of burning, tobacco reduces consistently the amount of toxic compounds and may exert a lower impact on oral health than combusted cigarettes. The carbon-heated tobacco product 1.2 (CHTP1.2) is a potential modified risk tobacco product (MRTP) based on heat-not-burn technology. Using a systems toxicology assessment framework, we compared the effects of exposure to CHTP1.2 aerosol with those of CS from a reference cigarette (3R4F)...
March 2, 2018: Food and Chemical Toxicology
A H Piersma, T Burgdorf, K Louekari, B Desprez, R Taalman, R Landsiedel, J Barroso, V Rogiers, C Eskes, M Oelgeschläger, M Whelan, A Braeuning, A M Vinggaard, A Kienhuis, J van Benthem, J Ezendam
This report describes the proceedings of the BfR-RIVM workshop on validation of alternative methods which was held 23 and 24 March 2017 in Berlin, Germany. Stakeholders from. governmental agencies, regulatory authorities, universities, industry and the OECD were invited to discuss current problems concerning the regulatory acceptance and implementation of alternative test methods and testing strategies, with the aim to develop feasible solutions. Classical validation of alternative methods usually involves one to one comparison with the gold standard animal study...
March 1, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Gloria R Garcia, Sean M Bugel, Lisa Truong, Sean Spagnoli, Robert L Tanguay
The aryl hydrocarbon receptor (AHR) is a conserved ligand-activated transcription factor required for proper vertebrate development and homeostasis. The inappropriate activation of AHR by ubiquitous pollutants can lead to adverse effects on wildlife and human health. The zebrafish is a powerful model system that provides a vertebrate data stream that anchors hypothesis at the genetic and cellular levels to observations at the morphological and behavioral level, in a high-throughput format. In order to investigate the endogenous functions of AHR, we generated an AHR2 (homolog of human AHR)-null zebrafish line (ahr2osu1) using the clustered, regulatory interspaced, short palindromic repeats (CRISPR)-Cas9 precision genome editing method...
2018: PloS One
Daniel L Villeneuve, Michelle M Angrish, Marie C Fortin, Ioanna Katsiadaki, Marc Leonard, Luigi Margiotta-Casaluci, Sharon Munn, Jason M O'Brien, Nathan L Pollesch, L Cody Smith, Xiaowei Zhang, Dries Knapen
Toxicological responses to stressors are more complex than the simple one biological perturbation to one adverse outcome model portrayed by individual adverse outcome pathways (AOPs). Consequently, the AOP framework was designed to facilitate de facto development of AOP networks that can aid understanding and prediction of pleiotropic and interactive effects more common to environmentally realistic, complex exposure scenarios. The present paper introduces nascent concepts related to the qualitative analysis of AOP networks...
February 28, 2018: Environmental Toxicology and Chemistry
Shweta Singh, Pronobesh Chattopadhyay, Sahindra Kumar Borthakur, Rudragoud Policegoudra
Background: Meyna spinosa (M.S) (Roxb.) ex Link and Oroxylum indicum (O.I) (Linn.) Vent, widely used traditional Northeast Indian medicinal plant used for various purposes, have not yet explored for safety profile. Objective: To investigate the safety profile of M.S (Roxb.) ex Link leaves and O.I (Linn.) Vent stem bark extracts collected from Northeast region of India. Materials and Methods: In this study, mutagenic, cytotoxic, and genotoxic and/or nontoxic potential of these two plant extracts using various toxicological investigations, as per the regulatory test guidelines, were evaluated...
January 2018: Pharmacognosy Magazine
Zahoor Ul Hassan, Roda Al Thani, Fathy A Atia, Saeed Al Meer, Quirico Migheli, Samir Jaoua
The present study was conducted to explore the occurrence of mycotoxins in commercial baby foods in Doha-Qatar. LCMS/MS- and HPLC-based analysis of baby food (n=67) for 12 mycotoxins, confirmed the presence of aflatoxin M1 (AFM1, 33%), ochratoxin A (OTA, 31%), deoxynivalenol (DON, 27%), aflatoxin B1 (AFB1, 22%), fumonisin B2 (FB2, 10%), zearalenone (ZEN, 4%) and T-2 toxin (2%). Noodles exhibited the maximum contamination percentage, with 33% of the samples being contaminated above the EU maximum limits, for at least one mycotoxin...
February 28, 2018: Food Additives & Contaminants. Part B, Surveillance
Anna Bal-Price, Helena T Hogberg, Kevin M Crofton, Mardas Daneshian, Rex E FitzGerald, Ellen Fritsche, Tuula Heinonen, Susanne Hougaard Bennekou, Stefanie Klima, Aldert H Piersma, Magdalini Sachana, Timothy J Shafer, Andrea Terron, Florianne Monnet-Tschudi, Barbara Viviani, Tanja Waldmann, Remco H S Westerink, Martin F Wilks, Hilda Witters, Marie-Gabrielle Zurich, Marcel Leist
Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing...
February 23, 2018: ALTEX
Jacques Descotes, Linda Allais, Philippe Ancian, Henrik Duelund Pedersen, Claire Friry-Santini, Antonio Iglesias, Tina Rubic-Schneider, Hollie Skaggs, Peter Vestbjerg
There is a growing need to consider non-rodent species for the immunological safety evaluation of drug candidates. The EU Framework-6 RETHINK Project demonstrated that the Göttingen Minipig is a relevant animal model for regulatory toxicology studies. Extensive knowledge on the immune system of domestic pigs is available and fewer differences from humans have been identified as compared to other species, such as mice or non-human primates. Minipig data are too scarce to allow for claiming full immunological comparability with domestic pigs...
February 23, 2018: Regulatory Toxicology and Pharmacology: RTP
Antonio Pietroiusti, Helene Stockmann-Juvala, Francesca Lucaroni, Kai Savolainen
The use of engineered nanomaterials (ENM) has grown after the turn of the 21st century. Also, the production of ENM has globally grown, and exposure of workers especially via the lungs to ENM has increased. This review tackles with effects of ENM on workers' health because occupational environment is the main source of exposure to ENM. Assessment of exposure to ENM is demanding, and today there are no occupational exposure level (OEL) for ENM. This is partly due to challenges of such measurements, and in part to the unknown causality between ENM metrics and effects...
February 23, 2018: Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology
Tatiana Heid Furley, Julie Brodeur, Helena C Silva de Assis, Pedro Carriquiriborde, Katia R Chagas, Jone Corrales, Marina Denadai, Julio Fuchs, Renata Mascarenhas, Karina Sb Miglioranza, Diana Margarita Miguez Caramés, José Maria Navas, Danaythi Nugegoda, Estela Planes, Ignacio Alejandro Rodriguez-Jorquera, Martha Orozco-Medina, Alistair Ba Boxall, Murray A Rudd, Bryan W Brooks
The Global Horizon Scanning Project (GHSP) is an innovative initiative that aims to identify important global environmental quality research needs. Here we report 20 key research questions from Latin America (LA). Members of the Society of Environmental Toxicology and Chemistry (SETAC) LA and other scientists from LA were asked to submit research questions that would represent priority needs to address in the region. One hundred questions were received, then partitioned among categories, examined, and some rearranged during a workshop in Buenos Aires, Argentina...
February 22, 2018: Integrated Environmental Assessment and Management
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