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Toxicology Research

Brian G Lake
A large number of nongenotoxic chemicals have been shown to increase the incidence of liver tumours in rats and/or mice by a mode of action (MOA) involving activation of the constitutive androstane receptor (CAR). Studies with the model CAR activator phenobarbital (PB) and its sodium salt (sodium phenobarbital; NaPB) have demonstrated that the key and associative events for rat and mouse liver tumour formation include CAR activation, increased hepatocyte replicative DNA synthesis (RDS), induction of cytochrome P450 CYP2B subfamily enzymes, liver hypertrophy, increased altered hepatic foci and hepatocellular adenomas/carcinomas...
July 1, 2018: Toxicology Research
Tomoya Yamada
Rodent carcinogenicity studies are useful for screening for human carcinogens but they are not perfect. Some modes of action (MOAs) lead to cancers in both experimental rodents and humans, but others that lead to cancers in rodents do not do so in humans. Therefore, analysing the MOAs by which chemicals produce tumours in rodents and determining the relevance of such tumour data for human risk are critical. Recently, experimental data were obtained as case examples of an evaluation of the human relevance of pyrethroid (metofluthrin and momfluorothrin)- and pyrethrins-induced liver tumours in rats based on MOA...
July 1, 2018: Toxicology Research
James E Klaunig, Xilin Li, Zemin Wang
Non-alcoholic fatty liver disease is a major cause of chronic liver pathology in humans. Fatty liver disease involves the accumulation of hepatocellular fat in hepatocytes that can progress to hepatitis. Steatohepatitis is categorized into alcoholic (ASH) or non-alcoholic (NASH) steatohepatitis based on the etiology of the insult. Both pathologies involve an initial steatosis followed by a progressive inflammation of the liver and eventual hepatic fibrosis (steatohepatitis) and cirrhosis. The involvement of pharmaceuticals and other chemicals in the initiation and progression of fatty liver disease has received increased study...
July 1, 2018: Toxicology Research
Andrew G Smith, John R Foster
The haem biosynthetic pathway is of fundamental importance for cellular metabolism both for the erythroid and nonerythroid tissues. There are several genetic variants of the pathway in the human population that cause dysfunction of one or other of the enzymes resulting in porphyrias of varying severity. Serious chronic hepatic and systemic diseases may result. Some of these can be precipitated by exposure to drugs including hormones, barbiturates and antibiotics, as well as alcohol and particular chlorinated aromatic chemicals...
July 1, 2018: Toxicology Research
Robert L Smith, Samuel M Cohen, Shoji Fukushima, Nigel J Gooderham, Stephen S Hecht, F Peter Guengerich, Ivonne M C M Rietjens, Maria Bastaki, Christie L Harman, Margaret M McGowen, Sean V Taylor
The safety assessment of a flavour substance examines several factors, including metabolic and physiological disposition data. The present article provides an overview of the metabolism and disposition of flavour substances by identifying general applicable principles of metabolism to illustrate how information on metabolic fate is taken into account in their safety evaluation. The metabolism of the majority of flavour substances involves a series both of enzymatic and non-enzymatic biotransformation that often results in products that are more hydrophilic and more readily excretable than their precursors...
July 1, 2018: Toxicology Research
Jonathan Moggs, RĂ©mi Terranova
Pleiotropic xenobiotics can trigger dynamic alterations in mammalian chromatin structure and function but many of these are likely non-adverse and simply reflect short-term changes in DNA transactions underlying normal homeostatic, adaptive and protective cellular responses. However, it is plausible that a subset of xenobiotic-induced perturbations of somatic tissue or germline epigenomes result in delayed-onset and long-lasting adverse effects, in particular if they occur during critical stages of growth and development...
July 1, 2018: Toxicology Research
Ian Kimber, Alan Poole, David A Basketter
Sensitisation of the respiratory tract to chemicals resulting in respiratory allergy and allergic asthma is an important occupational health problem, and presents toxicologists with no shortage of challenges. A major issue is that there are no validated or, even widely recognised, methods available for the identification and characterisation of chemical respiratory allergens, or for distinguishing respiratory allergens from contact allergens. The first objective here has been review what is known (and what is not known) of the mechanisms through which chemicals induce sensitisation of the respiratory tract, and to use this information to construct a hybrid Adverse Outcome Pathway (AOP) that combines consideration of both skin and respiratory sensitisation...
July 1, 2018: Toxicology Research
Emma S Walker, Ruth A Roberts
From animal research through adverse events in clinical trials to health scares around food contamination, toxicology has frequently been a focus of scientific and societal concern. As these concerns shift with each new drug, new technology or public health scare, how can toxicology stay current, relevant and ethical? Two of the biggest ethical challenges in pharmaceutical toxicology are the use of animals in testing and the high safety-related attrition rates in new drug development. Both of these require progress in the discipline that will only be driven by research funding...
July 1, 2018: Toxicology Research
Samuel M Cohen
Screening for carcinogens in general, and for the urinary bladder specifically, traditionally involves a two-year bioassay in rodents, the results of which often do not have direct relevance to humans with respect to mode of action (MOA) and/or dose response. My proposal describes a multi-step short-term (90 day) screening process that characterizes known human urinary bladder carcinogens, and identifies those reported in rodent two-year bioassays. The initial step is screening for urothelial proliferation, by microscopy or by increased Ki-67 labeling index...
July 1, 2018: Toxicology Research
Jay I Goodman
It is time to say goodbye to the standard two-year rodent bioassay. While a few, primarily genotoxic, compounds which are clearly associated with human cancer test positive in the bioassay, there is no science-based, sound foundation for presuming it provides either a valid broad (across different chemicals) capability for discerning potential human carcinogens or a valid starting point for making human risk assessment decisions. The two basic assumptions underlying the bioassay are: (1) rodent carcinogens are human carcinogens; and (2) results obtained at high doses are indicative of results that will occur at lower, environmentally relevant, doses...
July 1, 2018: Toxicology Research
Colin Berry
Recent advances in our understanding of the process of carcinogenesis in Man have required revision of our thinking about the classical initiation/promotion sequence; understanding must now encompass the roles of both genetic and epigenetic change, realisation of the importance of the variable genetic backgrounds of the tumour bearers in any group and an understanding of the importance of random genetic events over time. The behavior of tumours, once established, is more complex than has been thought. Current views of the processes involved are not modelled in toxicity testing programmes...
July 1, 2018: Toxicology Research
Lewis Smith
Introducing this themed issue dedicated to the memory of Iain Purchase and Cliff Elcombe.
July 1, 2018: Toxicology Research
Yanyan Xu, Yiwei Zhao, Xuejun Guo, Yubo Li, Yanjun Zhang
Oxaliplatin is a third generation antitumor agent, which is often used in treating advanced colorectal cancer, but the use of oxaliplatin is limited by its side effects, especially peripheral nerve toxicity. Metabonomics techniques, as a holistic analytical technique, could provide basic information on the metabolic profile of biological fluids during drug administration. In this study, we used the ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technique to analyze rat plasma samples collected seven days after oxaliplatin administration...
May 8, 2018: Toxicology Research
Qi Liang, Yujing Zhang, Ming Zeng, Lan Guan, Yuanyuan Xiao, Fang Xiao
Heavy metals such as hexavalent chromium [Cr(vi)] could induce Ca2+ overload and subsequently hepatocyte injury, and even apoptotic cell death, but the source of the increased cytosolic-free Ca2+ is still unclear. The present study aimed to explore the role of an inositol 1,4,5-trisphosphate receptor (IP3 R) - store-operated calcium channels (SOCCs) in Cr(vi)-induced Ca2+ overload and apoptosis in L-02 hepatocytes. The cytosolic-free Ca2+ concentration was evaluated using the fluorescent Ca2+ indicator Fluo-4/acetoxymethyl ester (Fluo-4/AM), while Ca2+ concentrations in the mitochondria and endoplasmic reticulum (ER) were detected using the related commercial kits...
May 8, 2018: Toxicology Research
Yurie Funakoshi, Ayako Azuma, Mizuki Ishikawa, Satoru Itsuki, Yasuaki Tamura, Kaori Kanemaru, Shogo Hirai, Yasuo Oyama
Many businesses thrive by producing health supplements from agricultural products, as exemplified by the production of functional (or health) foods using plants traditionally cultivated in rural areas. Dyes, such as indican, indigo, indoxyl, and indirubin, present in dye plants, possess antibacterial, antifungal, and antiproliferative activities. However, these effects may also lead to cytotoxicity. Thus, studies on normal mammalian cells are necessary to identify cytotoxicity and prevent adverse effects of functional foods that contain these dyes...
May 8, 2018: Toxicology Research
Erten Akbel, Damla Arslan-Acaroz, Hasan Huseyin Demirel, Ismail Kucukkurt, Sinan Ince
The present study was planned to evaluate the protective role of resveratrol (Res) against subchronic malathion exposure in rats over four weeks. In total, 48 Wistar rats were used and divided equally into six groups. The groups were designed as the control group (received only a rodent diet and tap water), the corn oil group (0.5 ml corn oil by the oral route), and the malathion group (100 mg kg-1 day-1 by the oral route). Other three groups received malathion (100 mg kg-1 day-1 ) plus Res (5, 10, and 20 mg kg-1 day-1 , respectively) by the oral route...
May 8, 2018: Toxicology Research
Boris V Krivoshiev, Gerrit T S Beemster, Katrien Sprangers, Bart Cuypers, Kris Laukens, Ronny Blust, Steven J Husson
The flame retardant, 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide (DOPO), has been receiving great interest given its superior fire protection properties, and its predicted low level of persistence, bioaccumulation, and toxicity. However, empirical toxicological data that are essential for a complete hazard assessment are severely lacking. In this study, we attempted to identify the potential toxicological modes of action by transcriptome (RNA-seq) profiling of the human liver hepatocellular carcinoma cell line, HepG2...
May 8, 2018: Toxicology Research
Samar Sakr, Hanan Hassanien, Megan Jean Bester, Sandra Arbi, Azza Sobhy, Heba El Negris, Vanessa Steenkamp
The aim of this study was to evaluate the protective effect of folate against methomyl-induced toxicity on the kidneys and testes of male rats. Adult male albino rats were divided into four groups; Group I served as the control (vehicle), Group II received folic acid (1.1 mg per kg b.wt.), Group III methomyl (1 mg per kg b.wt.) and Group IV folic acid and methomyl. Treatments were administered via oral gavage on a daily basis for 14 weeks. Thereafter blood samples were collected and serum creatinine, testosterone and total antioxidant capacity (TAC) were determined...
May 8, 2018: Toxicology Research
Shaohui Cui, Yueying Wang, Yan Gong, Xiao Lin, Yinan Zhao, Defu Zhi, Quan Zhou, Shubiao Zhang
As effective non-viral vectors of gene therapy, cationic lipids still have the problem of toxicity, which has become one of the main bottlenecks for their applications. The toxicity of cationic lipids is strongly connected to the headgroup structures. In this article, we studied the cytotoxicity of two cationic lipids with a quaternary ammonium headgroup (CDA14) and a tri-peptide headgroup (CDO14), respectively, and with the same linker bond and hydrophobic domain. The IC50 values of CDA14 and CDO14 against NCI-H460 cells were 109...
May 8, 2018: Toxicology Research
Meiying Wu, Yuting Jiang, Mingyuan Liu, Yu Shang, Jing An
The amino polycyclic aromatic hydrocarbons (amino-PAHs) were frequently detected in PM2.5 , and it was suggested that they contributed to the harmful health effects associated with PM2.5 . However, the process through which amino-PAHs induce oxidative stress responses as well as the pro-inflammatory processes along with the associated mechanisms is still not well-known. In this study, oxidative stress level, Nrf2/ARE anti-oxidative defense responses, oxidative damages and cytokine expressions were investigated in the A549 cell line after it was treated with typical airborne amino-PAHs including 1-aminopyrene (1-AP) and 3-aminofluoranthene (3-AF)...
May 8, 2018: Toxicology Research
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