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Regulatory toxicology

Hesham Dahshan, Ayman Mohamed Megahed, Amr Mohamed Mohamed Abd-Elall, Mahdy Abdel-Goad Abd-El-Kader, Ehab Nabawy, Mariam Hassan Elbana
BACKGROUND: Persistent organic pollutants represent about 95 % of the industrial sector effluents in Egypt. Contamination of the River Nile water with various pesticides poses a hazardous risk to both human and environmental compartments. Therefore, a large scale monitoring study was carried on pesticides pollution in three geographical main regions along the River Nil water stream, Egypt. METHODS: Organochlorine and organophosphorus pesticides were extracted by liquid-liquid extraction and analyzed by GC-ECD...
2016: Journal of Environmental Health Science & Engineering
W Michael Peden
Revision of the International Council for Harmonization (ICH) S1 guidance for rat carcinogenicity studies to be more selective of compounds requiring a 2-year rat carcinogenicity study has been proposed following extensive evaluation of rat carcinogenicity and chronic toxicity studies by industry and drug regulatory authorities. To inform the ICH S1 expert working group in their potential revision of ICH S1, a prospective evaluation study was initiated in 2013, in which sponsors would assess the pharmacologic and toxicologic findings present in the chronic toxicity studies and predict a positive or negative carcinogenicity outcome using a weight of evidence argument (a carcinogenicity assessment document [CAD])...
October 17, 2016: Toxicologic Pathology
Rachael A Smith, Michael St J Warne, Kerrie Mengersen, Ryan D R Turner
Pollutant loads are a means for assessing regulatory compliance and setting targets to reduce pollution entering receiving waterbodies. However, a pollutant load is often comprised of multiple chemicals, which may exert joint toxicity on biota. When the ultimate goal for assessing pollutant loads is to protect ecosystems from adverse effects of toxicants, then the total pollutant load needs to be calculated based on the principles of mixture toxicology. In this paper, an improved method is proposed to convert a pollutant load to a toxicity-based load (toxic load) using a modified toxic equivalency factor (TEF) derivation method...
October 15, 2016: Integrated Environmental Assessment and Management
Roshan Ashoor, Dong Lee, Alvan Cheng, Bart Jessen, Wenhu Huang
PURPOSE: PF-06653157 is a bifunctional antagonist monoclonal antibody (mAb) that targets human VEGF-A ligand and PDGF-Rβ. With the advent of PF-06653157 as an angiogenesis inhibitor and potential treatment for angiogenesis deregulation diseases, a relevant toxicology species is needed for toxicity and efficacy studies. Investigative studies were conducted to validate the mAb dual antagonist properties in a human system and determine its cross-reactive pharmacology in nonhuman cells. METHODS: Sequence alignment was used to determine percent sequence identity of VEGF and PDGF receptors and ligands; qualitative reverse transcription polymerase chain reaction (qRT-PCR) was used to determine the presence of PDGF-Rβ on cells of interest...
October 13, 2016: Journal of Ocular Pharmacology and Therapeutics
Paul M D Foster
Regulatory studies of developmental and reproductive toxicity (DART) studies have remained largely unchanged for decades, with exposures occurring at various phases of the reproductive cycle and toxicity evaluations at different ages/times depending on the study purpose. The National Toxicology Program has conducted studies examining the power to detect adverse effects where there is a prenatal exposure, but evaluations occur postnatally. In these studies, examination is required of only 1 male and female pup from each litter beyond weaning...
October 5, 2016: Toxicologic Pathology
Elias M Oziolor, Karel De Schamphelaere, Cole W Matson
The regulatory decision-making process regarding chemical safety is most often informed by evidence based on ecotoxicity tests that consider growth, reproduction and survival as end-points, which can be quantitatively linked to short-term population outcomes. Changes in these end-points resulting from chemical exposure can cause alterations in micro-evolutionary forces (mutation, drift, selection and gene flow) that control the genetic composition of populations. With multi-generation exposures, anthropogenic contamination can lead to a population with an altered genetic composition, which may respond differently to future stressors...
October 3, 2016: Ecotoxicology
David Azzopardi, Kharishma Patel, Tomasz Jaunky, Simone Santopietro, Oscar M Camacho, John McAughey, Marianna Gaça
Electronic cigarettes (E-cigarettes) are a potential means of addressing the harm to public health caused by tobacco smoking by offering smokers a less harmful means of receiving nicotine. As e-cigarettes are a relatively new phenomenon, there are limited scientific data on the longer-term health effects of their use. This study describes a robust in vitro method for assessing the cytotoxic response of e-cigarette aerosols that can be effectively compared with conventional cigarette smoke. This was measured using the regulatory accepted Neutral Red Uptake assay modified for air-liquid interface (ALI) exposures...
July 2016: Toxicology Mechanisms and Methods
Gary M Williams, Marilyn Aardema, John Acquavella, Sir Colin Berry, David Brusick, Michele M Burns, Joao Lauro Viana de Camargo, David Garabrant, Helmut A Greim, Larry D Kier, David J Kirkland, Gary Marsh, Keith R Solomon, Tom Sorahan, Ashley Roberts, Douglas L Weed
The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is "probably carcinogenic to humans" (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC's assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies...
September 2016: Critical Reviews in Toxicology
Maurice Whelan, Chantra Eskes
Validation is essential for the translation of newly developed alternative approaches to animal testing into tools and solutions suitable for regulatory applications. Formal approaches to validation have emerged over the past 20 years or so and although they have helped greatly to progress the field, it is essential that the principles and practice underpinning validation continue to evolve to keep pace with scientific progress. The modular approach to validation should be exploited to encourage more innovation and flexibility in study design and to increase efficiency in filling data gaps...
2016: Advances in Experimental Medicine and Biology
Glyn N Stacey, Sandra Coecke, Anna-Bal Price, Lyn Healy, Paul Jennings, Anja Wilmes, Christian Pinset, Magnus Ingelman-Sundberg, Jochem Louisse, Simone Haupt, Darren Kidd, Andrea Robitski, Heinz-Georg Jahnke, Gilles Lemaitre, Glenn Myatt
Quality control of cell cultures used in new in vitro toxicology assays is crucial to the provision of reliable, reproducible and accurate toxicity data on new drugs or constituents of new consumer products. This chapter explores the key scientific and ethical criteria that must be addressed at the earliest stages of developing toxicology assays based on human pluripotent stem cell (hPSC) lines. It also identifies key considerations for such assays to be acceptable for regulatory, laboratory safety and commercial purposes...
2016: Advances in Experimental Medicine and Biology
Rebecca A Clewell, Patrick D McMullen, Yeyejide Adeleye, Paul L Carmichael, Melvin E Andersen
The field of toxicity testing for non-pharmaceutical chemicals is in flux with multiple initiatives in North America and the EU to move away from animal testing to mode-of-action based in vitro assays. In this arena, there are still obstacles to overcome, such as developing appropriate cellular assays, creating pathway-based dose-response models and refining in vitro-in vivo extrapolation (IVIVE) tools. Overall, it is necessary to provide assurances that these new approaches are adequately protective of human and ecological health...
2016: Advances in Experimental Medicine and Biology
Rodger D Curren, Albrecht Poth, Hans A Raabe
New toxicology test methods, especially those using in vitro methods, are continually being developed. Some are used by industry for screening purposes; others are eventually validated for regulatory use. However, for a new test method to be firmly adopted by industry it must be readily available, generally through an in-house industry laboratory, an academic laboratory, or a contract research organization. Regardless of the type of laboratory which intends to implement the test method, certain steps must be taken to ascertain that the method that is put into place is reproducible and performs identically to the test method that was published or has undergone validation...
2016: Advances in Experimental Medicine and Biology
Thomas Bartels, Kerstin Wäse, Martin Heinrichs, Manuela Stolte, Nigel Roome, Petra Scherer, Klaus Lindauer
The toxicological profile of insulins is exclusively due to exaggerated pharmacology resulting in hypoglycemic findings. Insulin analogues displaying modifications and aimed at improving pharmacokinetics do not induce different toxicity. The main target is the brain displaying neuronal necrosis. Wallerian degeneration of nerves occurs rarely after severe hypoglycemia. These findings are of potential human relevance; nevertheless, these changes are induced in normoglycemic animals whereas diabetic patients suffer from hyperglycemia...
October 2016: Toxicologic Pathology
Achim Aigner, Roland Buesen, Tim Gant, Nigel Gooderham, Helmut Greim, Jörg Hackermüller, Bruno Hubesch, Madeleine Laffont, Emma Marczylo, Gunter Meister, Jay S Petrick, Reza J Rasoulpour, Ursula G Sauer, Kerstin Schmidt, Hervé Seitz, Frank Slack, Tokuo Sukata, Saskia M van der Vies, Jan Verhaert, Kenneth W Witwer, Alan Poole
The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that ncRNA expression profiling data requires careful evaluation to determine the utility of specific ncRNAs as biomarkers. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify possibly suitable ncRNAs and areas of toxicology where ncRNA expression profiling could address prevailing scientific deficiencies...
September 20, 2016: Regulatory Toxicology and Pharmacology: RTP
Kerry L Dearfield, B Bhaskar Gollapudi, Jeffrey C Bemis, R Daniel Benz, George R Douglas, Rosalie K Elespuru, George E Johnson, David J Kirkland, Matthew J LeBaron, Albert P Li, Francesco Marchetti, Lynn H Pottenger, Emiel Rorije, Jennifer Y Tanir, Veronique Thybaud, Jan van Benthem, Carole L Yauk, Errol Zeiger, Mirjam Luijten
For several decades, regulatory testing schemes for genetic damage have been standardized where the tests being utilized examined mutations and structural and numerical chromosomal damage. This has served the genetic toxicity community well when most of the substances being tested were amenable to such assays. The outcome from this testing is usually a dichotomous (yes/no) evaluation of test results, and in many instances, the information is only used to determine whether a substance has carcinogenic potential or not...
September 21, 2016: Environmental and Molecular Mutagenesis
Clara Hartmanshenn, Megerle Scherholz, Ioannis P Androulakis
Personalized medicine strives to deliver the 'right drug at the right dose' by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses...
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
Mark J Selby, John J Engelhardt, Robert J Johnston, Li-Sheng Lu, Minhua Han, Kent Thudium, Dapeng Yao, Michael Quigley, Jose Valle, Changyu Wang, Bing Chen, Pina M Cardarelli, Diann Blanset, Alan J Korman
The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade...
2016: PloS One
Thomas H Broschard, Susanne Glowienke, Uma S Bruen, Lee M Nagao, Andrew Teasdale, Cheryl L M Stults, Kim L Li, Laurie A Iciek, Greg Erexson, Elizabeth A Martin, Douglas J Ball
Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers. Details of these approaches may differ depending on the nature of the final drug product...
August 26, 2016: Regulatory Toxicology and Pharmacology: RTP
Peter J Boogaard, Juan-Carlos Carrillo, Linda G Roberts, Graham F Whale
Gas-to-liquid (GTL) products are synthetic hydrocarbons produced from natural gas using a Fischer-Tropsch process. This process yields a synthetic crude oil that consists of saturated hydrocarbons, primarily linear alkanes, with increasing amounts of branched (methyl-groups) alkanes as the chains get longer. In addition, small amounts of cycloalkanes (branched cyclopentanes and cyclohexanes) may be formed as the polymerization reaction prolongs. This synthetic crude can subsequently be refined to a range of products very similar to petroleum refining...
August 25, 2016: Critical Reviews in Toxicology
Giuseppe Felice Mangiatordi, Domenico Alberga, Cosimo Damiano Altomare, Angelo Carotti, Marco Catto, Saverio Cellamare, Domenico Gadaleta, Gianluca Lattanzi, Francesco Leonetti, Leonardo Pisani, Angela Stefanachi, Daniela Trisciuzzi, Orazio Nicolotti
Computational methods have advanced toxicology towards the development of target-specific models based on a clear cause-effect rationale. However, the predictive potential of these models presents strengths and weaknesses. On the good side, in silico models are valuable cheap alternatives to in vitro and in vivo experiments. On the other, the unconscious use of in silico methods can mislead end-users with elusive results. The focus of this review is on the basic scientific and regulatory recommendations in the derivation and application of computational models...
September 2016: Molecular Informatics
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