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[Preclinical toxicological study of ecorsin].  


A new drug preparation ecorsin based on the dry aspen bark extract was studied for toxicological safety on a preclinical stage. The drug exhibited no toxicity upon a single administration to rats and mice (both male and female). The intragastric administration of ecorsin for 3 months to rats (at a daily dose of 50, 250, and 500 mg/kg) and rabbits (25 and 50 mg/kg) led to neither functional not morphological changes in hemopoietic and lymphoid organs, liver, kidney, heart, digestive system, and CNS. The long-term administration resulted in a partial atrophic modification of convoluted seminiferous tubules in impuberal male rats, while not affecting the testes of aged animals. The administration of ecorsin at 50, 250, and 500 mg/kg led to dose-dependent changes in some characteristics of the reproductive capacity in rats. Ecorsin did not modify the extent of allergic reactions and produced no immunotoxicant and mutagen effects. PMID:11022311

Karpova, G V; Fomina, T I; Vetoshkina, T V; Borovskaia, T G; Voronova, O L; Dubskaia, T Iu; Poluéktova, M E; Timina, E A; Smol'ianinov, E S; Turetskova, V F



Metabolomics in toxicology and preclinical research.  


Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological status of a biological system, and about the changes caused by chemicals. Metabolomics analysis is used in many fields, ranging from the analysis of the physiological status of genetically modified organisms in safety science to the evaluation of human health conditions. In toxicology, metabolomics is the -omics discipline that is most closely related to classical knowledge of disturbed biochemical pathways. It allows rapid identification of the potential targets of a hazardous compound. It can give information on target organs and often can help to improve our understanding regarding the mode-of-action of a given compound. Such insights aid the discovery of biomarkers that either indicate pathophysiological conditions or help the monitoring of the efficacy of drug therapies. The first toxicological applications of metabolomics were for mechanistic research, but different ways to use the technology in a regulatory context are being explored. Ideally, further progress in that direction will position the metabolomics approach to address the challenges of toxicology of the 21st century. To address these issues, scientists from academia, industry, and regulatory bodies came together in a workshop to discuss the current status of applied metabolomics and its potential in the safety assessment of compounds. We report here on the conclusions of three working groups addressing questions regarding 1) metabolomics for in vitro studies 2) the appropriate use of metabolomics in systems toxicology, and 3) use of metabolomics in a regulatory context. PMID:23665807

Ramirez, Tzutzuy; Daneshian, Mardas; Kamp, Hennicke; Bois, Frederic Y; Clench, Malcolm R; Coen, Muireann; Donley, Beth; Fischer, Steven M; Ekman, Drew R; Fabian, Eric; Guillou, Claude; Heuer, Joachim; Hogberg, Helena T; Jungnickel, Harald; Keun, Hector C; Krennrich, Gerhard; Krupp, Eckart; Luch, Andreas; Noor, Fozia; Peter, Erik; Riefke, Bjoern; Seymour, Mark; Skinner, Nigel; Smirnova, Lena; Verheij, Elwin; Wagner, Silvia; Hartung, Thomas; van Ravenzwaay, Bennard; Leist, Marcel



Phospholipogenic pharmaceuticals are associated with a higher incidence of histological findings than nonphospholipogenic pharmaceuticals in preclinical toxicology studies.  


While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics. PMID:22745636

Barone, Linda R; Boyer, Scott; Damewood, James R; Fikes, James; Ciaccio, Paul J



The preclinical toxicology of salmeterol hydroxynaphthoate.  


An extensive toxicology programme on salmeterol hydroxynaphthoate (Serevent), a marketed long-acting beta(2)-adrenoceptor agonist, has been carried out. The studies evaluated both the local (respiratory tract) and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential. High acute doses were well tolerated and caused no specific target organ toxicity. In repeat dose studies, animals tolerated salmeterol very well both locally and systemically. No significant effects on the respiratory tract of dogs were seen and only minor laryngeal changes, typical of those occurring with many inhaled medicines, were noted in rats. The high systemic concentrations achieved resulted in a number of changes that are considered to be the result of excessive and prolonged beta( 2)-adrenoceptor stimulation. These included tachycardia, skeletal muscle hypertrophy and minor haematological and blood biochemical changes in general toxicity studies, foetal effects in rabbit organogenesis studies and increased incidences of smooth muscle tumours of the mesovarium in the rat and of the uterus in the mouse oncogenicity studies. Salmeterol showed no evidence of any genotoxic potential. Results of the extensive toxicology programme provide good assurance of the safety for the inhaled use of salmeterol in patients; this has ben confirmed by many years of clinical experience during its development and marketing. PMID:20219844

Owen, K; Beck, S L; Damment, S J P



In Situ Mass Spectrometry Imaging and Ex Vivo Characterization of Renal Crystalline Deposits Induced in Multiple Preclinical Drug Toxicology Studies  

PubMed Central

Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development. PMID:23110069

Bjurstrom, Sivert; Goodwin, Richard J. A.; Basmaci, Elisa; Gustafsson, Ingela; Annas, Anita; Hellgren, Dennis; Svanhagen, Alexander; Andren, Per E.; Lindberg, Johan



Preclinical Pharmacology and Toxicology Studies



[Preclinical study of noopept toxicity].  


Within the framework of a preclinical investigation, the new nootrope drug noopept (N-phenyl-acetyl-L-propyl-glycine ethylate) was tested for chronic toxicity upon peroral administration in a dose of 10 or 100 mg/kg over 6 months in both male and female rabbits. The results of observations showed that noopept administered in this dose range induced no irreversible pathologic changes in the organs and systems studied and exhibited no allergenic, immunotoxic, and mutagen activity. The drug affected neither the generative function nor the antenatal or postnatal progeny development. Noopept produced a dose-dependent suppression of inflammation reaction to concanavalin A and stimulated the cellular and humoral immune response in mice. PMID:12025790

Kovalenko, L P; Smol'nikova, N M; Alekseeva, S V; Nemova, E P; Sorokina, A V; Miramedova, M G; Kurapova, S P; Sidorina, E I; Kulakova, A V; Daugel'-Dauge, N O



[Preclinical study of maxar safety].  


The results of preclinical safety evaluation of the new hepatoprotector maxar showed that this drug can be classified as a low-toxicity substance with respect to acute toxicity. No significant functional and structural changes in the systems and organs of experimental animals were observed after a 6-month administration in rats (in a dose of 300, 600, and 1200 mg/kg) and in dogs (500 mg/kg). Maxar exhibited no mutagen and allergen properties, produced no immunotoxicant action, and did not adversely affect the reproduction function. PMID:14743714

Saratikov, A S; Livshits, N S; Burchenkova, F I; Kadychagova, N G; Akhmedzhanov, R R; Bashirova, L V



Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets  

PubMed Central

Monoclonal antibodies (mAbs) and fusion proteins directed towards soluble targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 14 currently approved mAbs and fusion proteins targeted to soluble targets. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency ‘Scientific Discussions’ and United States Food and Drug Administration ‘Pharmacology/Toxicology Reviews’ and package inserts (United States Prescribing Information). Data on the following approved biopharmaceuticals were included: adalimumab, anakinra, bevacizumab, canakinumab, certolizumab pegol, denosumab, eculizumab, etanercept, golimumab, infliximab, omalizumab, ranibizumab, rilonacept and ustekinumab. Some related biopharmaceuticals in late-stage development were also included for comparison. Good concordance with human pharmacodynamics was found for both non-human primates (NHPs) receiving the human biopharmaceutical and mice receiving rodent homologues (surrogates). In contrast, there was limited concordance for human adverse effects in genetically deficient mice, mice receiving surrogates or NHPs receiving the human pharmaceutical. In summary, the results of this survey show that although both mice and NHPs have good predictive value for human pharmacodynamics, neither species have good predictive value for human adverse effects. No evidence that NHPs have superior predictive value was found. PMID:22168335

Martin, Pauline L; Bugelski, Peter J



Preclinical animal efficacy studies and drug development  

E-print Network

statistics, biased reporting etc Most of these major issues are caught during peer-review. Most journals do set of standards that will fit *all* studies. Limits to journals' power: Journals rely on peerPreclinical animal efficacy studies and drug development Most basic science journals do


Preclinical antileukemic activity, toxicology, toxicokinetics and formulation development of triptolide derivative MRx102  

PubMed Central

Purpose Triptolide induces cancer cell apoptosis by inhibiting RNA synthesis and signaling pathways like NF-?B. We compared triptolide prodrug MRx102 to triptolide to determine if it displayed comparable efficacy and improved toxicology and toxicokinetic profiles. Methods MV4–11 AML cells and cells from AML patients were analyzed for MRx102? and triptolide-induced cytotoxicity/apoptosis. MRx102 and triptolide were compared in toxicology/toxicokinetics studies in rat and dog using a new emulsion formulation. Results MRx102 induced cytotoxicity in MV4–11 cells (IC50 = 15.2 nM, 7.29 nM for triptolide) and apoptosis in cells from AML patients (EC50 = 40.6 nM and 2.13 nM for triptolide). MRx102 and triptolide induced apoptosis in CD34+CD38? AML stem/progenitor cells with a similar difference in activity (EC50, MRx102 = 40.8 nM, triptolide = 2.14 nM). In a rat toxicology comparison using a new intravenous emulsion formulation, the MRx102 MTD was 4.5 mg/kg for males, 3 mg/kg for females; the triptolide MTD was 0.63 mg/kg for males, 0.317 mg/kg for females. The MRx102 NOAEL was 1.5–3.0 mg/kg, and the triptolide NOAEL was 0.05–0.15 mg/kg. Mean plasma concentrations for both MRx102 and triptolide decreased rapidly from a high Cmax following i.v. injection. Plasma triptolide levels stabilized at a consistent level through 2 hours after MRx102 injection. Triptolide T1/2,e values for MRx102-injected rats (~0.85 to ~3.7 hours) were markedly greater than triptolide injected rats (~0.15 to ~0.39 hours), indicating more extended triptolide exposure with MRx102. MRx102 dog toxicology and toxicokinetics results are presented. Conclusions MRx102 was 20? to 60-fold safer than triptolide comparing rat NOAELs. This may be due to the improved toxicokinetic profile of MRx102 compared to triptolide using the emulsion formulation, with no high Cmax and more consistent early exposure to triptolide. PMID:24619497

Fidler, John M.; An, Jinhua; Cater, Bing Z.; Andreeff, Michael



Preclinical pharmacokinetic and toxicological evaluation of MIF-1 peptidomimetic, PAOPA: examining the pharmacology of a selective dopamine D2 receptor allosteric modulator for the treatment of schizophrenia.  


Schizophrenia is a mental illness characterized by a breakdown in cognition and emotion. Over the years, drug treatment for this disorder has mainly been compromised of orthosteric ligands that antagonize the active site of the dopamine D2 receptor. However, these drugs are limited in their use and often lead to the development of adverse movement and metabolic side effects. Allosteric modulators are an emerging class of therapeutics with significant advantages over orthosteric ligands, including an improved therapeutic and safety profile. This study investigates our newly developed allosteric modulator, PAOPA, which is a specific modulator of the dopamine D2 receptor. Previous studies have shown PAOPA to attenuate schizophrenia-like behavioral abnormalities in preclinical models. To advance this newly developed allosteric drug from the preclinical to clinical stage, this study examines the pharmacokinetic behavior and toxicological profile of PAOPA. Results from this study prove the effectiveness of PAOPA in reaching the implicated regions of the brain for therapeutic action, particularly the striatum. Pharmacokinetic parameters of PAOPA were found to be comparable to current market antipsychotic drugs. Necropsy and histopathological analyses showed no abnormalities in all examined organs. Acute and chronic treatment of PAOPA indicated no movement abnormalities commonly found with the use of current typical antipsychotic drugs. Moreover, acute and chronic PAOPA treatment revealed no hematological or metabolic abnormalities classically found with the use of atypical antipsychotic drugs. Findings from this study demonstrate a better safety profile of PAOPA, and necessitates the progression of this newly developed therapeutic for the treatment of schizophrenia. PMID:23416534

Tan, Mattea L; Basu, Dipannita; Kwiecien, Jacek M; Johnson, Rodney L; Mishra, Ram K



Preclinical pharmacology, toxicology and efficacy of sphingomyelin\\/cholesterol liposomal vincristine for therapeutic treatment of cancer  

Microsoft Academic Search

Purpose: To establish the pharmacodynamic relationships between drug biodistribution and drug toxicity\\/efficacy, a comprehensive\\u000a preclinical evaluation of sphingomyelin\\/cholesterol (SM\\/chol) liposomal vincristine and unencapsulated vincristine in mice\\u000a was undertaken. Methods: Pharmaceutically acceptable formulations of unencapsulated vincristine and liposomal vincristine at drug\\/lipid ratios of\\u000a 0.05 or 0.10 (wt\\/wt) were evaluated for toxicity, antitumor activity and pharmacokinetics following intravenous administration.\\u000a Results: Mice given

Murray S. Webb; Patricia Logan; Peter M. Kanter; Ginette St.-Onge; Karen Gelmon; Troy Harasym; Lawrence D. Mayer; Marcel B. Bally



Preclinical studies of alcohol binge drinking  

PubMed Central

Binge drinking is prevalent and has serious biomedical consequences. In children, adolescents, and young adults, it is a prominent risk factor for later development of alcohol-use disorders. Many preclinical models have been employed to study the genetic risks for and biomedical consequences of alcohol drinking. However, these models historically did not result in blood-alcohol concentrations (BACs) exceding 80 mg%; this relatively modest level is the threshold that currently defines a binge session, according to the NIAAA and CDC. Nevertheless, in alcohol-dependent rodents, binge drinking has been well documented. Key neurobiological substrates localized to brain reward and stress systems have been identified. Studies of newer models of binge drinking without dependence are reviewed here. In these models, rodents, non-human primates, and flies will drink enough to reach high BACs. They often display observable signs of intoxication. The neurobiological consequences of these episodes of binge drinking without dependence are reviewed, preliminary evidence for roles for GABA, glutamate, opioid peptides, and corticotropin releasing factor are discussed, as is the need for more work to identify the antecedents and consequences of binge drinking in both animal models and humans. PMID:21272009

Crabbe, John C.; Harris, R. Adron; Koob, George F.



Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets  

PubMed Central

Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency ‘Scientific Discussions’; and the US Food and Drug Administration ‘Pharmacology/Toxicology Reviews’ and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found. PMID:22168282

Bugelski, Peter J; Martin, Pauline L



Preclinical toxicology and tissue platinum distribution of novel oral antitumour platinum complexes: ammine/amine platinum(IV) dicarboxylates.  


The preclinical toxicology and tissue platinum distribution of a series of six orally given antitumour platinum complexes [ammine/amine platinum(IV) dicarboxylates] with structural variations of their alicyclic amine (c-C5, c-C6 or c-C7), axial dicarboxylate (CH3, C3H7 or NHC2H5) or leaving substituents (Cl2 or OCOOCO) was studied in the mouse. Platinum tissue levels measured at 48 h after a single oral dose at 0.5 of the MTD were highest in the liver (6.0-19 micrograms/g) and second highest in the kidney (2.8-12 micrograms/g), and these levels were up to 5 times higher than those reported with equi-toxic doses of i.v. cisplatin and i.v. carboplatin. Platinum levels in the lung, heart, spleen, skin, skeletal muscle and brain were all < or = 3.1 micrograms/g at this dose level. Liver platinum levels measured at 2 h, 2 days, 6 days and 10 days after a single oral dose at the MTD ranged widely (from 15 to 109 micrograms platinum/g), were related to the number of carbon atoms in the axial dicarboxylate and alicyclic amine groups (r = 0.9389) and showed a diversity of time-course profiles. Elevations of plasma ALT activity were recorded with single oral doses of JM225 and JM256 at the MTD. Accumulation of platinum in the liver with repeated oral dosing weekly for 4 consecutive weeks at 0.5 of the MTD occurred with JM269 (3.3-fold increase, P < 0.05) and JM225 (2.4-fold increase, P < 0.05), and elevated plasma ALT activity (44 +/- 33 IU/l) was recorded with repeated oral doses of JM269. JM216 was selected from this series of analogues for further study on the basis of the elevated plasma ALT activity (JM225, JM256 and JM269), liver platinum accumulation (JM269 and JM225), poor activity against human ovarian carcinoma xenografts (JM291) or severe emetogenesis (JM221) of other examples. Following a single oral dose of JM216 at the MTD, transient reductions in the WBC (nadir, 1.6 x 10(9)/l, 2 days, 74% reduction), platelet count (nadir, 613 x 10(9)/l, 10 days, 33% reduction) and bone marrow cellularity (nadir, 0.5 x 10(7) nucleated cells/femur, 4 days, 75% reduction) were found, and these had recovered by 21 days after treatment. Jejunal mucosal disaccharidase activity following single MTDs indicated that small-intestinal mucosal damage was less severe for oral JM216 (nadir maltase activity, 68% +/- 16% of control, NS) than for i.v. cisplatin (nadir maltase activity).(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8137461

McKeage, M J; Morgan, S E; Boxall, F E; Murrer, B A; Hard, G C; Harrap, K R



An Indexing Coverage Study of Toxicological Literature  

ERIC Educational Resources Information Center

The goal of this study was an appraisal of indexing coverage for the interdisciplinary field of toxicology. Information of research significance was limited to primary literature, defined as published documents containing original data from experimental work or case studies. (6 references) (Author/NH)

Montgomery, Ruth Reinke



Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology.  


Human embryonic stem cell (hESC) progenies hold great promise as surrogates for human primary cells, particularly if the latter are not available as in the case of cardiomyocytes. However, high content experimental platforms are lacking that allow the function of hESC-derived cardiomyocytes to be studied under relatively physiological and standardized conditions. Here we describe a simple and robust protocol for the generation of fibrin-based human engineered heart tissue (hEHT) in a 24-well format using an unselected population of differentiated human embryonic stem cells containing 30-40% ?-actinin-positive cardiac myocytes. Human EHTs started to show coherent contractions 5-10 days after casting, reached regular (mean 0.5 Hz) and strong (mean 100 µN) contractions for up to 8 weeks. They displayed a dense network of longitudinally oriented, interconnected and cross-striated cardiomyocytes. Spontaneous hEHT contractions were analyzed by automated video-optical recording and showed chronotropic responses to calcium and the ?-adrenergic agonist isoprenaline. The proarrhythmic compounds E-4031, quinidine, procainamide, cisapride, and sertindole exerted robust, concentration-dependent and reversible decreases in relaxation velocity and irregular beating at concentrations that recapitulate findings in hERG channel assays. In conclusion this study establishes hEHT as a simple in vitro model for heart research. PMID:22028871

Schaaf, Sebastian; Shibamiya, Aya; Mewe, Marco; Eder, Alexandra; Stöhr, Andrea; Hirt, Marc N; Rau, Thomas; Zimmermann, Wolfram-Hubertus; Conradi, Lenard; Eschenhagen, Thomas; Hansen, Arne




EPA Science Inventory

An exposure facility was designed and constructed to support health effect studies of inhaled smoke obscurants generated from light lubricating oils. Concentrations are monitored using gravimetric filter sample analysis and continuous RAM-1 aerosol monitors. Chemical consistency ...


Chemical and preclinical studies on Hedyotis diffusa with anticancer potential.  


This paper presents the chemical and preclinical anticancer research on Hedyotis diffusa Willd. in detail, one of the most renowned herbs often prescribed in the polyherbal formulas for cancer treatment in traditional Chinese medicine. Anthraquinones, flavonoids, and terpenoids constitute the majority of the 69 compounds that have been isolated and identified from H. diffusa. The anticancer effects of the methanolic, ethanolic, and aqueous extracts in various preclinical cancer models have been described. This review also summarized the anticancer activity of constituents of the herb and the mechanisms of action. All the studies suggest that H. diffusa has enormous potential in the therapy of cancer and warrants further chemical and pharmacological investigation. PMID:23600735

Niu, Yu; Meng, Qiu-Xia



Analgesia in Amphibians: Preclinical Studies and Clinical Applications  

PubMed Central

SYNOPSIS Preclinical studies of analgesia in amphibians or recommendations for clinical use of analgesics in amphibian species are extremely limited. This article briefly reviews the issues surrounding the use of analgesics in amphibians starting with common definitions of pain and analgesia when applied to non-human animals. Nociceptive and endogenous opioid systems in amphibians are reviewed and results of preclinical research on opioid and non-opioid analgesics summarized. Recommended opioid and non-opioid analgesics are summarized and practical recommendations made for their clinical use. PMID:21074701

Stevens, Craig W.



PRECLINICAL STUDY Prediction of lymph node involvement in breast cancer  

E-print Network

PRECLINICAL STUDY Prediction of lymph node involvement in breast cancer from primary tumor tissue- ther lymph node involvement in breast cancer is influenced by gene or miRNA expression of the primary tissue from a group of 96 breast cancer patients balanced for lymph node involvement using Affymetrix



PubMed Central

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.



Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs  

PubMed Central

Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting. PMID:25183392



Toxicological considerations in environmental audit studies.  


Environmental auditing has emerged as a new industrial management tool in recent years. It involves a careful examination of the organization, management procedures, product development, and equipment for environmental protection. The purpose of an environmental audit, from the toxicological point of view, is to assure that the total risk to humans, material, and environment should not increase as a result of a chemical process. The criteria to be adopted for such a safety audit are outlined. PMID:9170172

Jaffery, F N; Misra, V; Viswanathan, P N



Forensic Toxicology Certificate  

E-print Network

Forensic Toxicology Certificate What is Forensic Toxicology? Forensic toxicology is a discipline of forensic science that is concerned with the study of toxic substances or poisons. Toxicology encompasses methods and procedures from many disciplines, including chemistry, biochemistry, epidemiology

Saldin, Dilano


Resveratrol: A review of preclinical studies for human cancer prevention  

SciTech Connect

The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations.

Athar, Mohammad; Back, Jung Ho; Tang Xiuwei [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Kwang Ho [Department of Dermatology, Hallym University College of Medicine (Korea, Republic of); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892 (United States); Bickers, David R. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Arianna L. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States)], E-mail:



Accumulation of heavy metals by freshwater zooplankton - a toxicological study  

Microsoft Academic Search

So far many toxicologic studies are made earlier; we studied the acute toxicity estimation related to some specific identified freshwater zooplanktons of Paradip (Harbour City) area of Jagatsingpur District, Orissa, India which is situated on the bank of Mahanadi River. The study area is prone to heavy metal pollution because mineral based industries in relation to zinc, lead and cadmium

S. K. Baliarsingh; S. Srichandan; T. Padmavati; Subrat Naik; K. C. Sahu



Summary of Chemically Induced Pulmonary Lesions in the National Toxicology Program (NTP) Toxicology and Carcinogenesis Studies  

PubMed Central

The lung is the second most common target site of neoplasia of chemicals tested by the National Toxicology Program (NTP). Of all peer-reviewed NTP studies to date (N = 545), a total of sixty-four chemicals in sixty-six reports produced significant site-specific neoplasia in the lungs of rats and/or mice. Of the studies associated with lung tumor induction, approximately 35% were inhalation and 35% were gavage studies, with dosed-feed, dosed-water, topical, intraperitoneal, or in utero routes of chemical administration accounting for 18%, 6%, 3%, 1%, and 1% of the studies, respectively. The most commonly induced lung tumors were alveolar/bronchiolar (A/B) adenoma and/or carcinoma for both species. The most frequently observed nonneoplastic lesions included hyperplasia and inflammation in both species. The liver was the most common primary site of origin of metastatic lesions to the lungs of mice; however, skin was most often the primary site of origin of metastatic lesions to the lungs of rats. In summary, A/B adenoma and carcinoma were the most frequently diagnosed chemically induced tumors in the lungs of both rats and mice in the NTP toxicology and carcinogenesis bioassays, and hyperplasia and inflammation were the most common nonneoplastic changes observed. PMID:18441259

Dixon, Darlene; Herbert, Ronald A.; Kissling, Grace E.; Brix, Amy E.; Miller, Rodney A.; Maronpot, Robert R.



Novel technology to prepare oral formulations for preclinical safety studies.  


A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension. PMID:17942253

Niwa, Toshiyuki; Hashimoto, Naofumi



Protective efficacy of Modified Vaccinia virus Ankara in preclinical studies.  


Modified Vaccinia virus Ankara (MVA) is a tissue culture-derived, highly attenuated strain of vaccinia virus (VACV) exhibiting characteristic defective replication in cells from mammalian hosts. In the 1960s MVA was originally generated as a candidate virus for safer vaccination against smallpox. Now, MVA is widely used in experimental vaccine development targeting important infectious diseases and cancer. Versatile technologies for genetic engineering, large-scale production, and quality control facilitate R&D of recombinant and non-recombinant MVA vaccines matching today's requirements for new biomedical products. Such vaccines are attractive candidates for delivering antigens from pathogens against which no, or no effective vaccine is available, including emerging infections caused by highly pathogenic influenza viruses, chikungunya virus, West Nile virus or zoonotic orthopoxviruses. Other directions are seeking valuable vaccines against highly complex diseases such as AIDS, malaria, and tuberculosis. Here, we highlight examples of MVA candidate vaccines against infectious diseases, and review the efforts made to assess both the efficacy of vaccination and immune correlates of protection in preclinical studies. PMID:23523402

Volz, Asisa; Sutter, Gerd



Preclinical Studies of Signaling Pathways in a Mutant Mouse Model of Hormone-Refractory Prostate Cancer.  

National Technical Information Service (NTIS)

We have been investigating targeted therapies for the treatment of advanced prostate cancer using a genetically-engineered mouse model of the disease. Based on previous studies, we performed pre-clinical studies to examine the consequences of combinatoria...

C. Abate-Shen



Preclinical Studies of Signaling Pathways in a Mutant Mouse Model of Hormone-Refractory Prostate Cancer.  

National Technical Information Service (NTIS)

We have been investigating targeted therapies for the treatment of advanced prostate cancer using a genetically engineered mouse model of the disease. Based on previous studies, we performed pre-clinical studies to examine the consequences of combinatoria...

C. Abate-Shen



A crowdsourcing model for creating preclinical medical education study tools.  


During their preclinical course work, medical students must memorize and recall substantial amounts of information. Recent trends in medical education emphasize collaboration through team-based learning. In the technology world, the trend toward collaboration has been characterized by the crowdsourcing movement. In 2011, the authors developed an innovative approach to team-based learning that combined students' use of flashcards to master large volumes of content with a crowdsourcing model, using a simple informatics system to enable those students to share in the effort of generating concise, high-yield study materials. The authors used Google Drive and developed a simple Java software program that enabled students to simultaneously access and edit sets of questions and answers in the form of flashcards. Through this crowdsourcing model, medical students in the class of 2014 at the Johns Hopkins University School of Medicine created a database of over 16,000 questions that corresponded to the Genes to Society basic science curriculum. An analysis of exam scores revealed that students in the class of 2014 outperformed those in the class of 2013, who did not have access to the flashcard system, and a survey of students demonstrated that users were generally satisfied with the system and found it a valuable study tool. In this article, the authors describe the development and implementation of their crowdsourcing model for creating study materials, emphasize its simplicity and user-friendliness, describe its impact on students' exam performance, and discuss how students in any educational discipline could implement a similar model of collaborative learning. PMID:23619061

Bow, Hansen C; Dattilo, Jonathan R; Jonas, Andrea M; Lehmann, Christoph U



Preclinical safety studies of the combination moexipril hydrochloride/hydrochlorothiazide.  


The general pharmacological properties of a combination of the angiotensin converting enzyme (ACE) inhibitor moexipril hydrochloride (CAS 82586-52-5) and the thiazide diuretic hydrochlorothiazide (CAS 58-93-5, HCTZ), ratio 7.5 + 12.5, were studied in generally accepted models in vitro and in vivo. In vitro, the combination showed neither agonistic nor antagonistic activities on the isolated guinea pig trachea in concentrations up to 2 x 10(-4) g/ml. In mice, there was no effect on intestinal motility or the thiopental-induced sleeping time up to 1000 mg/kg. The only activity observed in mice was an inhibition of spontaneous motility after oral dosing with 300 and 1000 mg/kg, respectively. Both HCTZ (1-10 mg/kg) alone and the combination moexipril/HCTZ (1.6 or 4.8 mg/kg) produced dose-related increases in diuresis and electrolyte excretion in rats, however, without any potentiating effects for the drug combination. On the cardiovascular system of anaesthetised dogs, the effects observed were as expected, e.g. dose-related decrease in blood pressure. Repeated dose toxicity studies in rats and dogs revealed the kidney as target organ. This effect, based on highly exaggerated pharmacological activity, is well-known for other ACE inhibitors. No potential for teratogenic effects could be observed for the drug combination. In summary, the preclinical data indicate that the combination of moexipril and HCTZ (ratio 7.5 + 12.5) represents a safe drug without relevant side effects or gross toxicity. PMID:9608878

Gietl, R; Friehe, H; Ney, P



Preclinical safety studies on autologous cultured human skin fibroblast transplantation.  


Recently, FDA approved the clinical use of autologous fibroblasts (LAVIV™) for the improvement of nasolabial fold wrinkles in adults. The use of autologous fibroblasts for the augmentation of dermal and subcutaneous defects represents a potentially exciting natural alternative to the use of other filler materials for its long-term corrective ability and absence of allergic adverse effects proved by clinical application. However, compared to the clinical evidence, preclinical studies are far from enough. In this study, human skin-derived fibroblasts were cultured and expanded for both in vitro and in vivo observations. In vitro, the subcultured fibroblasts were divided into two groups. One set of cells underwent cell cycle and karyotype analysis at passages 5 and 10. The second group of cells was cocultured in medium with different concentrations of human skin extract D for the measurement of collagen concentration and cell count. In vivo, the subcultured fibroblasts were injected into nude mice subcutaneously. Biopsies were taken for morphology observation and specific collagen staining at 1, 2, and 3 months after injection. The results in vitro showed no significant differences in cell cycle distribution between passages 5 and 10. Cell proliferation and secretion were inhibited as the concentration of extract D increased. In vivo, the fibroblasts were remarkably denser on the experimental side with no dysplastic cells. Mitotic cells were easily observed at the end of the first month but were rare at the end of the third month. Type III collagen was detected at the end of the first month, while collagen type I was positive at the end of the second month. The content of both collagens increased as time passed. The above results indicated that the use of the autologous fibroblasts was safe, providing a basic support for clinical use of fibroblasts. PMID:23211390

Zeng, Wei; Zhang, Shuying; Liu, Dai; Chai, Mi; Wang, Jiaqi; Zhao, Yuming



Toxicology study of the high-energy plasticizer FEFO  

Microsoft Academic Search

This document contains information on the high energy plasticizer FEFO (1,1'-(methylenebis(oxy))bis(2-fluoro-2,2-dinitroethanel)). It includes interview comments from thirteen known users of the chemical through December, 1987. Included as appendices are other reference documents on FEFO. The first of these, Appendix A, is a survey on worker experiences with FEFO, Appendix B is a toxicology screening study of FEFO. Appendix C is

P. M. Swearengen; J. S. Johnson



Mouse Model for the Preclinical Study of Metastatic Disease

The successful development of new cancer therapeutics requires reliable preclinical data that are obtained from mouse models for cancer. Human tumor xenografts, which require transplantation of human tumor cells into an immune compromised mouse, represent the current standard mouse model for cancer. Since the immune system plays an important role in tumor growth, progression and metastasis, the current standard mouse model is not ideal for accurate prediction of therapeutic effectiveness in patients.


A toxicological study of gadolinium nitrate  

SciTech Connect

The sensitization study in the guinea pig did not show gadolinium nitrate to have potential sensitizing properties. Skin application studies in the rabbit demonstrated that it was cutaneously a severe irritant. This material was considered an irritant in the rabbit eye application studies. 3 refs., 1 tab.

London, J.E.



Toxicological studies of four insecticides against Musca domestica L.  


Toxicological studies of four insecticides (malathion, carbaryl, bioresmethrin, and GH 74) against Musca domestica vicinia (Ampang strain) were undertaken with particular reference to age, sex and posttreatment temperature. It was found that bioresmethrin and GH 74, both with a negative temperature coefficient, have great potential for use against houseflies. In vitro inhibitory studies of head and body esterases showed that unlike malathion and carbaryl, bioresmethrin had only negligible effect on these enzymes. The possibilities of using bioresmethrin and GH 74 for controlling the housefly problem in the Cameron Highlands, West Malaysia are discussed. PMID:818717

Yoke, O P; Sudderuddin, K I



Entomotoxicology studies the application of toxicological analysis on necrophageous insects present on human remains.  

E-print Network

Entomotoxicology studies the application of toxicological analysis on necrophageous insects present, and well-suited for routine analysis of methadone and EDDP in a single larva obtained from forensic cases. Introduction Entomotoxicology studies the application of toxicological analysis to carrion-feeding insects

Rasmont, Pierre


Ethnobotanical, phytochemical and toxicological studies of Xanthium strumarium L.  


The present study describes the ethnobotanical, phytochemical, and toxicological evaluations of Xanthium strumarium L. growing in Bangladesh. In toxicity evaluation on rats, the methanol extract of seedlings showed mortality, while both seedling and mature plant extracts raised the serum alanine transaminase and aspartate transaminase values and produced significant abnormalities in the histopathology of liver and kidney of rats. On the other hand, the aqueous soluble fraction of methanol extract of mature plant (LC50 = 0.352 microg/mL) and methanol crude extract of seedlings (LC50 = 0.656 microg/mL) demonstrated significant toxicity in the brine shrimp lethality bioassay. A total of four compounds were purified and characterized as stigmasterol (1), 11-hydroxy-11-carboxy-4-oxo-1(5),2(Z)-xanthadien-12,8-olide (2), daucosterol (3) and lasidiol-10-anisate (4). The present study suggests that X. strumarium is toxic to animal. PMID:20922910

Islam, Mohammad Rashedul; Uddin, Mohammad Zashim; Rahman, Mohammad Sharifur; Tutul, Ershad; Rahman, Mohammed Zakiur; Hassan, Md Abul; Faiz, M A; Hossain, Moazzem; Hussain, Maleeha; Rashid, Mohammad Abdur



Zebrafish as a model system to study toxicology.  


Monitoring and assessing the effects of contaminants in the aquatic eco-environment is critical in protecting human health and the environment. The zebrafish has been widely used as a prominent model organism in different fields because of its small size, low cost, diverse adaptability, short breeding cycle, high fecundity, and transparent embryos. Recent studies have demonstrated that zebrafish sensitivity can aid in monitoring environmental contaminants, especially with the application of transgenic technology in this area. The present review provides a brief overview of recent studies on wild-type and transgenic zebrafish as a model system to monitor toxic heavy metals, endocrine disruptors, and organic pollutants for toxicology. The authors address the new direction of developing high-throughput detection of genetically modified transparent zebrafish to open a new window for monitoring environmental pollutants. PMID:24307630

Dai, Yu-Jie; Jia, Yong-Fang; Chen, Na; Bian, Wan-Ping; Li, Qin-Kai; Ma, Yan-Bo; Chen, Yan-Ling; Pei, De-Sheng



MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation.  


MKT-077 (formerly known as FJ-776) is a newly synthesized, highly water-soluble ( > 200 mg/ml) rhodacyanine dye that exhibits significant antitumor activity in a variety of model systems. In culture, MKT-077 inhibits the growth of five human cancer cell lines (colon carcinoma CX-1, breast carcinoma MCF-7, pancreatic carcinoma (CRL 1420, bladder transitional cell carcinoma EJ, and melanoma LOX) but not monkey kidney CV-1, an indicator cell line for normal epithelial cells. In nude mice, MKT-077 inhibits the growth of s.c. implanted human renal carcinoma A498 and human prostate carcinoma DU145 and prolongs the survival of mice bearing i.p. implanted human melanoma LOX (tumor:control = 344%). Subcellular localization indicates that MKT-077 is taken up and retained by mitochondria, and flow cytometric analysis suggests that CX-1 cells take up MKT-077 to a much greater extent than CV-1 cells. Quantitation of MKT-077 uptake by ethanol extraction shows that CX-1 cells accumulate 65-fold more MKT-077 than do CV-1 cells. MKT-077 is the first delocalized lipophilic cation with a favorable pharmacological and toxicological profile in preclinical studies. MKT-077 is now being investigated in Phase I clinical trials. PMID:8564968

Koya, K; Li, Y; Wang, H; Ukai, T; Tatsuta, N; Kawakami, M; Shishido; Chen, L B



Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Multi-site Preclinical Biomarker Qualification Studies  

PubMed Central

Kidney toxicity accounts for a significant percentage of morbidity and drug candidate failure. Serum creatinine (SCr) and blood urea nitrogen (BUN) have been used to monitor kidney dysfunction for over a century but these markers are insensitive and non-specific. In multi-site preclinical rat toxicology studies the diagnostic performance of urinary kidney injury molecule-1 (Kim-1) was compared to traditional biomarkers as predictors of kidney tubular histopathologic changes, currently considered the “gold standard” of nephrotoxicity. In multiple models of kidney injury, urinary Kim-1 significantly outperformed SCr and BUN. The area under the receiver operating characteristic curve for Kim-1 was between 0.91 and 0.99 as compared to 0.79 to 0.9 for BUN and 0.73 to 0.85 for SCr. Thus urinary Kim-1 is the first injury biomarker of kidney toxicity qualified by the FDA and EMEA and is expected to significantly improve kidney safety monitoring. PMID:20458318

Vaidya, Vishal S.; Ozer, Josef S.; Frank, Dieterle; Collings, Fitz B.; Ramirez, Victoria; Troth, Sean; Muniappa, Nagaraja; Thudium, Douglas; Gerhold, David; Holder, Daniel J.; Bobadilla, Norma A.; Marrer, Estelle; Perentes, Elias; Cordier, Andre; Vonderscher, Jacky; Maurer, Gerard; Goering, Peter L.; Sistare, Frank D.; Bonventre, Joseph V.



A long-term toxicology study on pigs fed a combined genetically modified (GM) soy and  

E-print Network

of genetically modified (GM) crops have been approved to enter human food and animal feed since 1996, includingA long-term toxicology study on pigs fed a combined genetically modified (GM) soy and GM maize diet animal feed, toxicology, stomach inflammation, uterus weight. Introduction Genetically modified (GM

Porter, Warren P.


Recommendations for the use of preclinical models in the study and treatment of osteoarthritis1  

E-print Network

Recommendations for the use of preclinical models in the study and treatment of osteoarthritis1 R. McDougall zz, K. Pritzker xx, K. Rudolphi kk, W. van den Berg {{, T. Yaksh ## y Canadian Arthritis # Université de Montreal, Montreal, Canada yy Consumer Advisory Council, Canadian Arthritis Network, Canada zz

Buschmann, Michael


Exploratory Study of Factors Related to Educational Scores of First Preclinical Year Medical Students  

ERIC Educational Resources Information Center

The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students.…

Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarawut



Rodent treadmill for inhalation toxicological studies and respirometry  

SciTech Connect

A 10-runway treadmill was enclosed for inhalation toxicological studies of rodents under exercise exposure to environmental pollutants. The exposure system was lined with sheet stainless steel to minimize scrubbing of charged particles and reactive gases. Average metabolic gas exchange of exercising animals was derived from measurements of inlet or outlet airflow and data from an O/sub 2/ analyzer in conjunction with either a CO/sub 2/ or N/sub 2/ analyzer. An airflow rate of 400 l x min-1 ensured a response time of 1 min to reach 95% of a step change in metabolic rate and held scrubbing losses of an O/sub 3/ test atmosphere to less than 2% of treadmill inlet concentration. Gas exchange averaged for 10 rats during incremental exercise up to their highest collective performance was similar to published data for rats tested individually.

Mautz, W.J.; Phalen, R.F.; McClure, T.R.; Bufalino, C.



[Developing and standardizing experimental protocols using human iPS-derived cells to predict adverse drug reactions in pre-clinical safety studies].  


In this study, we have standardized experimental protocols to evaluate the possibility of using cells differentiated from human induced pluripotent stem cells (hiPSCs) in the pre-clinical studies for the drug approval processes. Cells differentiated from hiPSC, especially cardiomyocytes, neurons and hepatocytes, are expected to be used as new pharmacological and toxicological assay tools. Current preclinical test methods have limitations for predicting clinical adverse drug reactions. This is because of the so-called 'problem of species difference'. Drug-induced arrhythmia, cognitive impairment and hepatotoxicity which can't be predicted in pre-clinical studies are major causes of the high rate attrition of new-drug candidates in clinical studies and of withdrawal of products from the market. The development of new pre-clinical test methods using cells differentiated from hiPSCs would resolve these problems, in addition to solving the issue of "the replacement, refinement and reduction (3Rs)" of animal experiments. From 2010 to 2011, we surveyed companies belonging to the Japan Pharmaceutical Manufacturers Association (JPMA) and academic researchers about the usage of differentiated cells in their laboratories. We found that studies were performed using differentiated cells from different cell lines of hiPSC with laboratory-specific differentiation methods. The cells were cultured in various conditions and their activities were measured using different methods. This resulted in a variety of pharmacological responses of the cells. It is therefore impossible to compare reproducibility and ensure reliability of experiments using these cells. To utilize the cells in the drug approval processes, we need robust, standardized test methods to accurately reproduce these methods in all laboratories. We will then be able to compare and analyze the obtained results. Based on the survey, the Ministry of Health, Labor and Welfare funded our study. In our study, we standardize pharmacological methods among several laboratories, including our laboratory, to develop robust tests, using the same lot of cells, the same culture conditions, reference compounds, experimental protocols, and analysis methodology. In conclusion, to standardize robust test methods, we need a consistent supply of high-quality differentiated cells. Further, indexes to quantify the quality of the differentiated cells will be needed for their effective usage in the pre-clinical safety studies. PMID:24340667

Sekino, Yuko; Sato, Kaoru; Kanda, Yasunari; Ishida, Seiichi



Environmental Toxicology  

NASA Astrophysics Data System (ADS)

Environmental Toxicology is a comprehensive introductory textbook dealing with most aspects of the subject, from the molecular to the ecosystem level. Early chapters deal with basic to advanced concepts, methods and approaches. The next discusses the environmental toxicology of individual or groups of substances. The third part addresses complex issues, in which many of the concepts, approaches and substances covered in earlier parts are incorporated. The fourth part includes chapters on risk assessment, rehabilitation and regulatory toxicology. The book concludes with a summary of present and future areas of emphasis. Each chapter contains a comprehensive list of references and further reading, case studies from different jurisdictions, and student exercises.

Wright, David A.; Welbourn, Pamela



Developmental Toxicology##  

EPA Science Inventory

Developmental toxicology encompasses the study of developmental exposures, pharmacokinetics, mechanisms, pathogenesis, and outcomes potentially leading to adverse health effects. Manifestations of developmental toxicity include structural malformations, growth retardation, functi...



EPA Science Inventory

Xylene isomers and mixed xylenes were administered to male and female Sprague-Dawley rats to evaluate their effects on standard toxicological parameters rnhich included body and organ weights, hematology, serum chemistries, urinalysis and histopathological examination. n the init...


Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons from Pre-clinical Studies  

PubMed Central

Clinical implementation of spinal radiosurgery has increased rapidly in recent years but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970’s. The influences of field length, dose rate, inhomogeneous dose distributions and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in pre-clinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small and large animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Pre-clinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data is sparse, but results from guinea pig, rat and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials. PMID:21183290

Medin, Paul M.; Boike, Thomas P.



Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons From Preclinical Studies  

SciTech Connect

Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.ed [Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX (United States); Boike, Thomas P. [Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX (United States)



Nonclinical Toxicology Studies with Zidovudine: Reproductive Toxicity Studies in Rats and Rabbits  

Microsoft Academic Search

Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague–Dawley) rats and a developmental toxicity study was conducted in New Zealand white rabbits. In an additional study, reproductive outcome was characterized in female rats given ZDV before,

Jacqueline A. Greene; Kenneth M. Ayers; Paulo de Miranda



Students' perceptions about the transition to the clinical phase of a medical curriculum with preclinical patient contacts; a focus group study  

Microsoft Academic Search

BACKGROUND: Studies have shown that medical students experience the transition between preclinical and clinical training as a stressful period. They are generally frustrated by their inability to apply their knowledge to solve clinical problems in practice. Preclinical patient contacts may offer a solution to this 'shock of practice.' We studied how students who have had preclinical patient contacts perceive the

Merijn B. Godefrooij; Agnes D. Diemers; Albert J. J. A. Scherpbier



Porcine Heterotopic Composite Tissue Allograft Transplantation using A Large Animal Model for Preclinical Studies  

Microsoft Academic Search

Background: Composite tissue allograft (CTA) transplantation is currently limited by the risks of side effects resulting from long-term high-dose immunosuppression. Therefore, preclinical animal models are essential to help CTA transplanta- tion advance into clinical reality. Evidence has shown that small-animal model (rodents) immunotherapy protocols cannot be directly applied to humans. This study investigated whether a miniature porcine model is repro-

Yur-Ren Kuo; Justin M Sacks; W. P. Andrew Lee; Wen-Sheng Wu; Nai-Siong Kueh; Sheng-Fa Yao; Yuan-Cheng Chiang


Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen®  

PubMed Central

Background Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recombinant therapeutic protein widely used to treat severe neutropenia caused by myelosuppressive drugs in patients with nonmyeloid malignancies. In addition to its role in the regulation of granulopoiesis, treatment with G-CSF is considered the standard approach to mobilize CD34 positive (CD34+) mononuclear cells for reconstituting hemopoietic ability for bone marrow transplantation. An intended biosimilar filgrastim (coded BK0023) was produced in GMP conditions by E.coli fermentation according to an original recombinant process and showed physico-chemical properties and purity profile similar to Neupogen®, a commercial preparation of filgrastim. The aim of the present study was to demonstrate the comparability of BK0023 to Neupogen® in terms of both in vitro biological activities and in vivo toxicology, pharmacokinetics and pharmacodynamics. Methods Cell proliferation and radioligand binding assays were conducted in NFS-60 cells to compare the biological activity and functional interaction with the G-CSF receptor in vitro, while preclinical in vivo studies, including pharmacokinetics and pharmacodynamics after repeated dose were performed in normal and neutropenic rats. A phase I study was carried out in healthy male volunteers treated by multiple-dose subcutaneous administration of BK0023 and Neupogen® to evaluate their pharmacodynamic effects as well as their pharmacokinetic and safety profile and to demonstrate their pharmacodynamic equivalence and pharmacokinetic bioequivalence. Results The results reported in this work demonstrate that BK0023 is comparable in terms of biological activity, efficacy and safety to Neupogen®. Conclusions BK0023 has the same pharmacokinetic profile, efficacy and safety as the reference commercial filgrastim Neupogen® and therefore could be further developed to become a convenient option to treat neutropenia in oncological patients. Trial registration Trial registration number (TRN): NCT01933971. Date of registration: Sept 6th 2013. PMID:24555723



Toxicology study of the high-energy plasticizer FEFO  

SciTech Connect

This document contains information on the high energy plasticizer FEFO (1,1'-(methylenebis(oxy))bis(2-fluoro-2,2-dinitroethanel)). It includes interview comments from thirteen known users of the chemical through December, 1987. Included as appendices are other reference documents on FEFO. The first of these, Appendix A, is a survey on worker experiences with FEFO, Appendix B is a toxicology screening study of FEFO. Appendix C is a material safety data sheet on FEFO. Appendix D is an internal memorandum on personnel hazards associated with FEFO. Appendix E is a series of excerpted pages from a formerly classified document at the China Lake Naval Weapons Laboratory. Appendix F is a file on medical treatment associated with FEFO exposure. The interview comments and the appendices of related information on FEFO were provided to the LLNL Health Services Department along with Industrial Hygiene recommendations from the Safety Science Group. The response of the Health Services Director is included in this document as a preface. Taken together, the document and the medical observations provide a summary of information and recommended guidance for the safe handling of the high energy plasticizer FEFO. The material is believed to be quite biologically active by all observers. It is also believed that by correct use of strict industrial hygiene controls it can be used in large amounts with relative safety.

Swearengen, P.M.; Johnson, J.S.



Development of regional chemotherapies: feasibility, safety and efficacy in clinical use and preclinical studies  

PubMed Central

Conventional oral and intravenous chemotherapies permeate throughout the body, exposing healthy tissues to similar cytotoxic drug levels as tumors. This leads to significant dose-limiting toxicities that may prevent patients from receiving sufficient treatment to overcome cancers. Therefore, a number of locoregional drug-delivery strategies have been evaluated and implemented in preclinical studies, clinical trials and in practice, in the past decades to minimize systemic toxicities from chemotherapeutic agents and to improve treatment outcomes. Localized treatment is beneficial because many cancers, such as melanoma, peritoneal cancer and breast cancer, advance locally adjacent to the site of the primary tumors prior to their circulatory invasion. In this article, we will review the feasibility, safety and efficacy of multiple localized chemotherapies in clinical use and preclinical development. PMID:22229080

Cai, Shuang; Bagby, Taryn R; Forrest, M Laird



Reporting of preclinical tumor-graft cancer therapeutic studies  

PubMed Central

Purpose: Characterize the parameters of reporting tumor-graft experiments for oncologic drug development. Experimental Design: Using Institute of Scientific Information impact factors, we identified the most-cited medical and oncology journals with tumor-graft experiments in murine models. For each article, the characteristics of the experimental design, outcome measurements, and statistical analysis were examined. Results: We examined 145 articles describing tumor-graft experiments from October through December 2008. The articles spanned a range of disease types, animal models, treatments and delivery methods. One hundred (69%) articles were missing information needed to replicate the experiments. Outcome measurements included: tumor size (83%), biological changes (57%), and survival or cure-rate outcomes (28%). Thirty-three percent did not specify how tumor size was measured and 30% were missing the formula for evaluating volume. Only 14% utilized appropriate statistical methods. Ninety-one percent of studies were reported as positive and 7% reported with mixed positive-negative results; only 2% of studies were reported negative or inconclusive. Twenty-two articles from 2012 showed improvement in the utilization of statistical methods (35% optimal, p = 0.05) but had a similar fraction with experimental design issues (82%; p = 0.32) limiting reproducibility and 91% had positive results. Conclusions: Tumor-graft studies are reported without a set standard, often without the methodological information necessary to reproduce the experiments. The high percentage of positive trials suggests possible publication bias. Considering the widespread use of such experiments for oncologic drug development, scientists and publishers should develop experimental and publication guidelines for such experiments to ensure continued improvements in reporting. PMID:22895077

Sugar, Elizabeth; Pascoe, Adam J.; Azad, Nilofer



A Tumor-mimic Model for Evaluating the Accuracy of HIFU Preclinical Studies: An In Vivo Study  

E-print Network

A Tumor-mimic Model for Evaluating the Accuracy of HIFU Preclinical Studies: An In Vivo Study W. A of ablative technologies such as HIFU for the treatment of liver tumors in humans has been studied in animal models without tumors or in small animals like rats and rabbits with established tumors. Because

Paris-Sud XI, Université de


Analgesic and hypnotic activities of Laghupanchamula: A preclinical study  

PubMed Central

Background: In Ayurvedic classics, two types of Laghupanchamula -five plant roots (LP) have been mentioned containing four common plants viz. Kantakari, Brihati, Shalaparni, and Prinshniparni and the fifth plant is either Gokshura (LPG) or Eranda (LPE). LP has been documented to have Shothahara (anti-inflammatory), Shulanashka (analgesic), Jvarahara (antipyretic), and Rasayana (rejuvenator) activities. Aim: To evaluate the acute toxicity (in mice), analgesic and hypnotic activity (in rats) of 50% ethanolic extract of LPG (LPGE) and LPE (LPEE). Materials and Methods: LPEG and LPEE were prepared separately by using 50% ethanol following the standard procedures. A graded dose (250, 500 and 1000 mg/kg) response study for both LPEE and LPGE was carried out for analgesic activity against rat tail flick response which indicated 500 mg/kg as the optimal effective analgesic dose. Hence, 500 mg/kg dose of LPEE and LPGE was used for hot plate test and acetic acid induced writhing model in analgesic activity and for evaluation of hypnotic activity. Results: Both the extracts did not produce any acute toxicity in mice at single oral dose of 2.0 g/kg. Both LPGE and LPEE (250, 500, and 1000 mg/kg) showed dose-dependent elevation in pain threshold and peak analgesic effect at 60 min as evidenced by increased latency period in tail-flick method by 25.1-62.4% and 38.2-79.0% respectively. LPGE and LPEE (500 mg/kg) increased reaction time in hot-plate test at peak 60 min analgesic effect by 63.2 and 85.8% and reduction in the number of acetic acid-induced writhes by 55.9 and 65.8% respectively. Both potentiated pentobarbitone-induced hypnosis as indicated by increased duration of sleep in treated rats. Conclusion: The analgesic and hypnotic effects of LP formulations authenticate their uses in Ayurvedic system of Medicine for painful conditions. PMID:25364205

Ghildiyal, Shivani; Gautam, Manish K.; Joshi, Vinod K.; Goel, Raj K.



Manpower Development in Toxicology. EURO Reports and Studies, No. 9.  

ERIC Educational Resources Information Center

This report addresses the widely held view that currently available literature in toxicology is inadequate in that there is a need to identify manpower deficiencies in this field and to suggest means to correct these deficiencies. It contains a list of specific recommendations including the organization of a working group, sponsored by the World…

World Health Organization, Copenhagen (Denmark). Regional Office for Europe.


Oral Delivery of Highly Lipophilic Poorly Water-Soluble Drugs: Spray-Dried Dispersions to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a P2Y1 Antagonist.  


BMS-B is a highly lipophilic compound (clog P 7.72) with poor aqueous solubility (<10 ng/mL at pH 1 and 6.5). The compound exhibits low bioavailability in preclinical species when dosed as cosolvent solution formulations, with reduced exposure upon dose escalation. The purpose of this study was to evaluate spray-dried dispersions (SDDs) for enhancing oral exposure and enabling toxicology studies of BMS-B. SDD solids of BMS-B were prepared with 10%-25% drug in hydroxypropyl methylcellulose acetate succinate and showed an enhanced dissolution profile relative to the neat form of the compound. When dosed in rats and monkeys at 5 mg/kg, the SDD exhibited comparable exposure relative to the solution formulation. The SDD was also dosed in rats at 200 and 400 mg/kg and showed dose-proportional exposure compared to the solution formulation. Based on in vitro and in vivo data, the SDD formulation was selected for the toxicology study of BMS-B in rats. In summary, although the SDD approach could be quite challenging for highly lipophilic compounds because of the limitation on wetting and dissolution, the present study demonstrated that SDD can be applied in drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic poorly water-soluble compounds. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3924-3931, 2014. PMID:25308627

Chen, Xue-Qing; Stefanski, Kevin; Shen, Hong; Huang, Christine; Caporuscio, Christian; Yang, Wu; Lam, Patrick; Su, Ching; Gudmundsson, Olafur; Hageman, Michael



Primary hepatocyte cultures for pharmaco-toxicological studies: at the busy crossroad of various anti-dedifferentiation strategies.  


Continuously increasing understanding of the molecular triggers responsible for the onset of diseases, paralleled by an equally dynamic evolution of chemical synthesis and screening methods, offers an abundance of pharmacological agents with a potential to become new successful drugs. However, before patients can benefit of newly developed pharmaceuticals, stringent safety filters need to be applied to weed out unfavourable drug candidates. Cost effectiveness and the need to identify compound liabilities, without exposing humans to unnecessary risks, has stimulated the shift of the safety studies to the earliest stages of drug discovery and development. In this regard, in vivo relevant organotypic in vitro models have high potential to revolutionize the preclinical safety testing. They can enable automation of the process, to match the requirements of high-throughput screening approaches, while satisfying ethical considerations. Cultures of primary hepatocytes became already an inherent part of the preclinical pharmaco-toxicological testing battery, yet their routine use, particularly for long-term assays, is limited by the progressive deterioration of liver-specific features. The availability of suitable hepatic and other organ-specific in vitro models is, however, of paramount importance in the light of changing European legal regulations in the field of chemical compounds of different origin, which gradually restrict the use of animal studies for safety assessment, as currently witnessed in cosmetic industry. Fortunately, research groups worldwide spare no effort to establish hepatic in vitro systems. In the present review, both classical and innovative methodologies to stabilize the in vivo-like hepatocyte phenotype in culture of primary hepatocytes are presented and discussed. PMID:23242478

Fraczek, J; Bolleyn, J; Vanhaecke, T; Rogiers, V; Vinken, M



Toxicological screening  

PubMed Central

Toxicity testing of new compounds is essential for drug development process. The preclinical toxicity testing on various biological systems reveals the species-, organ- and dose- specific toxic effects of an investigational product. The toxicity of substances can be observed by (a) studying the accidental exposures to a substance (b) in vitro studies using cells/ cell lines (c) in vivo exposure on experimental animals. This review mainly focuses on the various experimental animal models and methods used for toxicity testing of substances. The pre-clinical toxicity testing helps to calculate “No Observed Adverse Effect Level” which is needed to initiate the clinical evaluation of investigational products. PMID:21772764

Parasuraman, S.



Toxicology Enrichment Materials  

NSDL National Science Digital Library

The series contains fact sheets on toxicology, introductory exercises to familiarize students with the study of toxicology and student assignments addressing specific issues in toxicology. The assignments are designed to enrich typical course curricula and give students practice using information from both library and internet sources.

Suzanne Conklin (Rhode Island College;)



Preclinical studies at UNC use specialized ultrasound to detect presence of cancer

In the body, tracing the twists and turns of blood vessels is difficult, but important. Vessel “bendiness” can indicate the presence and progression of cancer. This principle led UNC Lineberger Comprehensive Cancer Center scientists to a new method of using a high-resolution ultrasound to identify early tumors in preclinical studies. The method, based on vessel bendiness or “tortuosity,” potentially offers an inexpensive, non-invasive and fast method to detect cancer that could someday help doctors identify cancers when tumors are less than a centimeter in size. Their findings were published in the July 6, 2012 online issue of the journal Radiology.


Use of primary cultures of human hepatocytes in toxicology studies.  


Often results from toxicological studies using rodent models cannot be directly extrapolated to probable effects in human beings. In order to examine the genotoxic potential of chemicals in human liver cells, a human hepatocyte DNA repair assay has been defined. Procedures were optimized to prepare primary cultures of human hepatocytes from discarded surgical material. On eight different occasions human hepatocyte cultures of sufficient viability to measure DNA repair were successfully prepared by collagenase perfusion techniques. The cells were allowed to attach to plastic or collagen substrata for periods of 1.5 to 24 h and subsequently incubated with [3H]thymidine and test chemicals for periods of 18 to 24 h. Chemically induced DNA repair, measured as unscheduled DNA synthesis, was quantitated autoradiographically. The following compounds were tested: 2-acetylaminofluorene, aflatoxin B1, 2-aminobenzyl alcohol, aniline, benzo(a)pyrene, carbon tetrachloride, chloroform, 2,4-diaminotoluene, 2,6-diaminotoluene, di(2-ethylhexyl)phthalate, dimethylnitrosamine, 1,6-dinitropyrene, 2,4-dinitrotoluene, 2,6-dinitrotoluene, methyl chloride, 5-methylchrysene, mono(2-ethylhexyl)phthalate, 2-methyl-2-P-(1,2,3,4-tetrahydro-1-naphthyl)phenoxypropionic acid (nafenopin), beta-naphthylamine, nitrobenzene, 2-nitrobenzyl alcohol, 2-nitrotoluene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, unleaded gasoline, and 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy-14,643). In only one of eight cases did some of the chemicals generally regarded as genotoxic fail to give a positive response. For purposes of comparison, all test chemicals were evaluated in the in vitro rat hepatocyte DNA repair assay. Individual-to-individual variation in the DNA repair response was far greater for the human cultures than for cultures derived from rats. For only three chemicals was there a qualitative difference in the response between the rodent and the human cells; beta-naphthylamine was positive in the rat but in none of the human cultures examined, whereas the opposite was seen for 2,6-diaminotoluene and 5-methylchrysene. Clofibric acid, mono(2-ethylhexyl)phthalate, and Wy-14,643 induced enzymes indicative of peroxisomal proliferation in primary rat hepatocyte cultures, but not in two human hepatocyte cultures. These results indicate that, in general, the in vitro rat hepatocyte DNA repair assay is a valid model for predicting potential genotoxic effects in human beings. However, rodent hepatocytes may not be appropriate for assessing the potential of chemicals to elicit nongenotoxic effects in human beings such as the induction of hepatocyte peroxisomal proliferation. PMID:2917345

Butterworth, B E; Smith-Oliver, T; Earle, L; Loury, D J; White, R D; Doolittle, D J; Working, P K; Cattley, R C; Jirtle, R; Michalopoulos, G



Exploratory study of factors related to educational scores of first preclinical year medical students.  


The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students. Questionnaires were sent out to all first preclinical year medical students, with 79.8% being returned (245/307 questionnaires). Positive correlations were revealed between the premedical year grade point average (pre-MD GPA) and anatomy, physiology, and biochemistry scores (R = 0.664, 0.521, and 0.653, respectively, P < 0.001 for all) by Pearson's method. Using multiple linear regression analysis, anatomy scores could be predicted by pre-MD GPA, student satisfaction with anatomy, the percentage of expected reading, monthly earnings, reading after class and near exam time, and duration of sleeping periods near exam time (R = 0.773, R(2) = 0.598, P < 0.001). Physiology scores could be estimated by pre-MD GPA, the percentage of expected reading, monthly earnings, and percentage of those who fell asleep during class and near exam time (R = 0.722, R(2) = 0.521, P < 0.001). Biochemistry scores could be calculated by pre-MD GPA, the percentage of expected reading, motivation to study medicine, student satisfaction with biochemistry, and exam performance expectations (R = 0.794, R(2) = 0.630, P < 0.001). In conclusion, pre-MD GPA and the percentage of expected reading are factors involved in producing good academic results in the first preclinical year. Anatomy and biochemistry, but not physiology, scores are influenced by satisfaction. PMID:24585466

Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarayut




EPA Science Inventory

The study pathologist provides specialized expertise to the interpretation of the toxicity and safety of pharmaceuticals, biological agents, human and animal food additives, environmental and industrial chemicals, and medical devices in animal studies. The study pathologist's fin...


Why Toxicology?  

NSDL National Science Digital Library

One of the reasons for studying toxicology at the high school level is its relevance to everyday life. On a daily basis we are confronted with news reports about toxic chemicals in our food, water, and environment. How do we decide which of these are worth worrying about? Too often these decisions are based on misconceptions about what is "safe" and what involves too great a risk. In learning about the basic concepts of toxicology, students will become better prepared to make reasoned decisions about issues such as these. This free selection also includes the Table of Contents and Introduction.

Trautmann, Nancy M.; Team, The E.



Eritoran tetrasodium (E5564) Treatment for Sepsis: Review of Preclinical and Clinical Studies  

PubMed Central

Introduction Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS-induced inflammation by blocking toll-like receptor 4 (TLR4). Areas covered This review focuses on the rationale for the use of eritoran tetrasodium in sepsis, as well as on its pharmacokinetics, pharmacodynamics, efficacy and safety. Pre-clinical and clinical studies from a MEDLINE/PubMed literature search in August 2010 with the search terms “eritoran” and “E5564” are discussed. Expert opinion Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS, and improve survival in sepsis models. While early clinical results are promising, its efficacy and safety for treating patients with sepsis is currently under investigation. Even if the ongoing phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies will be necessary to define its clinical usage. PMID:21323610

Barochia, Amisha; Solomon, Steven; Cui, Xizhong; Natanson, Charles; Eichacker, Peter Q



Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors  

PubMed Central

Purpose Accumulating evidence supports the existence of breast cancer stem cells (BCSCs), which are characterized by their capacity to self-renew and divide indefinitely, and resistance to conventional therapies. The Notch pathway is important for stem cell renewal, and is a potential target for BCSC-directed therapy. Experimental Design Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in advanced breast cancer patients, designed to determine the maximally tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results Treatment with GSI reduced BCSCs in MC1 and BMC-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically meaningful doses of both drugs were possible, with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24?, ALDH+, and MSFE were observed in tumors of patients undergoing serial biopsies. Conclusions These preclinical data demonstrate that pharmacological inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial demonstrates feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. PMID:23340294

Schott, Anne F.; Landis, Melissa D.; Dontu, Gabriela; Griffith, Kent A.; Layman, Rachel M.; Krop, Ian; Paskett, Lacey A; Wong, Helen; Dobrolecki, Lacey E.; Froehlich, Amber M.; Paranilam, Jaya; Hayes, Daniel F.; Wicha, Max S.; Chang, Jenny C.



Toxicological study of plant extracts on termite and laboratory animals.  


Toxic activity of leaf extracts of Polygonum hydropiper L. and Pogostemon parviflorus Benth. were tested in the laboratory against tea termite, Odontotermes assamensis Holm. Both the tested extracts caused mortality of the termite. The highest toxic activity (100%) was found in the 2.0% chloroform extracts of P. hydropiper. The chloroform extract of P. hydropiper was explored for possible mammalian toxicological effects. The LD50 was 758.58 mg/kg in male albino mice. Subcutaneous injection of sub-lethal dose of extract into male mice once a week for 6 weeks failed to express any significant influence on WBC, RBC count and blood cholesterol. PMID:16161979

Rahman, I; Gogoi, Inee; Dolui, A K; Handique, Ruma



DTP | Toxicology and Pharmacology Branch (TPB)

Preclinical toxicology and pharmacology are required for decision making throughout drug discovery and development and for IND filing for clinical trials. Toxicological and pharmacological data can inform clinical trial design, such as determination of maximum tolerated dose, dose-limiting toxicities, and starting dose. With appropriate characterization, in most cases, safe operating parameters can be established for human clinical trials.


Pegylated liposomal doxorubicin: proof of principle using preclinical animal models and pharmacokinetic studies.  


Encapsulation of doxorubicin in polyethylene glycol-coated liposomes (Doxil/Caelyx [PLD]), was developed to enhance the safety and efficacy of conventional doxorubicin. The liposomes alter pharmacologic and pharmacokinetic parameters of conventional doxorubicin so that drug delivery to the tumor is enhanced while toxicity normally associated with conventional doxorubicin is decreased. In animals and humans, pharmacokinetic advantages of PLD include an increased area under the plasma concentration-time curve, longer distribution half-life, smaller volume of distribution, and reduced clearance. In preclinical models, PLD produced remission and cure against many cancers including tumors of the breast, lung, ovaries, prostate, colon, bladder, and pancreas, as well as lymphoma, sarcoma, and myeloma. It was also found to be effective as adjuvant therapy. In addition, it was found to cross the blood-brain barrier and induce remission in tumors of the central nervous system. Increased potency over conventional doxorubicin was observed and, in contrast to conventional doxorubicin, PLD was equally effective against low- and high-growth fraction tumors. The combination of PLD with vincristine or trastuzumab resulted in additive effects and possible synergy. PLD appeared to overcome multidrug resistance, possibly as the result of increased intracellular concentrations and an interaction between the liposome and P-glycoprotein function. On the basis of pharmacokinetic and preclinical studies, PLD, either alone or as part of combination therapy, has potential applications to treat a variety of cancers. PMID:15717736

Vail, David M; Amantea, Michael A; Colbern, Gail T; Martin, Francis J; Hilger, Ralf A; Working, Peter K



In silico toxicology for the pharmaceutical sciences  

Microsoft Academic Search

The applied use of in silico technologies (a.k.a. computational toxicology, in silico toxicology, computer-assisted tox, e-tox, i-drug discovery, predictive ADME, etc.) for predicting preclinical toxicological endpoints, clinical adverse effects, and metabolism of pharmaceutical substances has become of high interest to the scientific community and the public. The increased accessibility of these technologies for scientists and recent regulations permitting their use

Luis G. Valerio Jr.; Luis G



Size Distributions and Characterization of Native and Ground Samples for Toxicology Studies  

NASA Technical Reports Server (NTRS)

This slide presentation shows charts and graphs that review the particle size distribution and characterization of natural and ground samples for toxicology studies. There are graphs which show the volume distribution versus the number distribution for natural occurring dust, jet mill ground dust, and ball mill ground dust.

McKay, David S.; Cooper, Bonnie L.; Taylor, Larry A.



Extracting Respirable Particles from Lunar Regolith for Toxicology Studies B. L. Cooper1  

E-print Network

Extracting Respirable Particles from Lunar Regolith for Toxicology Studies B. L. Cooper1 , .D.S. Mc will be done using the respirable fraction of actual lunar soils (particles with physical size of less than 2 settled on the floor now floated into the air and caused eye discomfort and occasional respiratory

Perfect, Ed


Executive Function Changes before Memory in Preclinical Alzheimer’s Pathology: A Prospective, Cross-Sectional, Case Control Study  

PubMed Central

Background Early treatment of Alzheimer’s disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer’s disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology. Methods and Findings We recruited adults with probable Alzheimer’s disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer’s disease. We separated the asymptomatic group into those with (n?=?34; preclinical Alzheimer’s disease) and without (n?=?36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-? genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR?=?0.13, 95% CI?=?0.04–0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study. Conclusions Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer’s disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach. PMID:24260210

Harrington, Michael G.; Chiang, Jiarong; Pogoda, Janice M.; Gomez, Megan; Thomas, Kris; Marion, Sarah DeBoard; Miller, Karen J.; Siddarth, Prabha; Yi, Xinyao; Zhou, Feimeng; Lee, Sherri; Arakaki, Xianghong; Cowan, Robert P.; Tran, Thao; Charleswell, Cherise; Ross, Brian D.; Fonteh, Alfred N.



Nonindustry-sponsored preclinical studies on statins yield greater efficacy estimates than industry-sponsored studies: a meta-analysis.  


Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966-April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I(2) statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (-1.99; 95% CI -2.68, -1.31) versus studies sponsored by industry (-0.73; 95% CI -1.00, -0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study. PMID:24465178

Krauth, David; Anglemyer, Andrew; Philipps, Rose; Bero, Lisa



Chemical constituents and toxicological studies of leaves from Mimosa caesalpiniifolia Benth., a Brazilian honey plant  

PubMed Central

Background: Mimosa caesalpiniifolia Benth. (Leguminosae) is widely found in the Brazilian Northeast region and markedly contributes to production of pollen and honey, being considered an important honey plant in this region. Objective: To investigate the chemical composition of the ethanol extract of leaves from M. caesalpiniifolia by GC-MS after derivatization (silylation), as well as to evaluate the in vitro and in vivo toxicological effects and androgenic activity in rats. Materials and Methods: The ethanol extract of leaves from Mimosa caesalpiniifolia was submitted to derivatization by silylation and analyzed by gas chromatography-mass spectrometry (GC-MS) to identification of chemical constituents. In vitro toxicological evaluation was performed by MTT assay in murine macrophages and by Artemia salina lethality assay, and the in vivo acute oral toxicity and androgenic evaluation in rats. Results: Totally, 32 components were detected: Phytol-TMS (11.66%), lactic acid-2TMS (9.16%), ?-tocopherol-TMS (7.34%) and ?-sitosterol-TMS (6.80%) were the major constituents. At the concentrations analyzed, the ethanol extract showed low cytotoxicity against brine shrimp (Artemia salina) and murine macrophages. In addition, the extract did not exhibit any toxicological effect or androgenic activity in rats. Conclusions: The derivatization by silylation allowed a rapid identification of chemical compounds from the M. caesalpiniifolia leaves extract. Besides, this species presents a good safety profile as observed in toxicological studies, and possess a great potential in the production of herbal medicines or as for food consumption. PMID:25298660

Moncao, Nayana Bruna Nery; Costa, Luciana Muratori; Arcanjo, Daniel Dias Rufino; Araujo, Bruno Quirino; Lustosa, Maria do Carmo Gomes; Rodrigues, Klinger Antonio da Franca; Carvalho, Fernando Aecio de Amorim; Costa, Amilton Paulo Raposo; Lopes Cito, Antonia Maria das Gracas



Preclinical testing on insects predicts human haematotoxic potentials.  


The substitution of insects for laboratory animals in toxicity testing is likely to become a reality in the framework of prescreening. Haematotoxicological studies of newly developed chemicals, such as food components, drugs, etc. performed on insects can offer advantages in, for example, environmental toxicology. Reliable routine predictions should produce an increase in our knowledge of haemocyte physiology. Although the differences between human physiology and morphology and those of insects are great, the basic functions of insect haemocytes and mammalian leukocytes appear not to have changed during evolution. The use of insects in haematotoxicity assays represents a preclinical testing strategy which will lower costs, accelerate screening and offer ethical benefits. PMID:19505933

Berger, Josef



Exercise as a Potential Treatment for Drug Abuse: Evidence from Preclinical Studies  

PubMed Central

Epidemiological studies reveal that individuals who engage in regular aerobic exercise are less likely to use and abuse illicit drugs. Until recently, very few studies had examined the causal influences that mediate this relationship, and it was not clear whether exercise was effective at reducing substance use and abuse. In the past few years, several preclinical studies have revealed that exercise reduces drug self-administration in laboratory animals. These studies have revealed that exercise produces protective effects in procedures designed to model different transitional phases that occur during the development of, and recover from, a substance use disorder (e.g., acquisition, maintenance, escalation, and relapse/reinstatement of drug use). Moreover, recent studies have revealed several behavioral and neurobiological consequences of exercise that may be responsible for its protective effects in these assays. Collectively, these studies have provided convincing evidence to support the development of exercise-based interventions to reduce compulsive patterns of drug intake in clinical and at-risk populations. PMID:22347866

Smith, Mark A.; Lynch, Wendy J.



Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies.  


Preclinical models have examined the pharmacologic and pharmacodynamic activities of an anti-vascular endothelial growth factor (VEGF) humanized, monoclonal antibody, bevacizumab, and/or its murine equivalent A4.6.1. These studies found that single-agent therapy with bevacizumab/A4.6.1 resulted in tumor growth inhibition of 20 different human tumor cell lines (13 tumor types) implanted into nude mice irrespective of the route of administration or tumor location. Several of these studies also observed significant inhibition of tumor metastases. Various studies have examined the feasibility of combining anti-VEGF therapy with cytotoxic or biological agents. Combining bevacizumab/A4.6.1 with doxorubicin, topotecan, paclitaxel, docetaxel, or radiotherapy resulted in additive or synergistic tumor growth inhibition. Changes in vascular functions were frequently reported, including decreased vessel diameter, density, and permeability in response to treatment. A reduction in interstitial fluid pressure was also observed. In some studies, these improvements resulted in an increase in intratumoral uptake of chemotherapy, implying that the most effective use of anti-VEGF therapy is in combination with chemotherapy. Alternatively, combination treatment with radiation increased tumor oxygenation and tumor growth inhibition. Interestingly, anti-VEGF therapy has also been reported to reduce the development of ascites in ovarian mouse models. Finally, safety pharmacology studies with bevacizumab in cynomolgus monkeys showed that this agent is generally well tolerated with no unexpected adverse events. PMID:15705858

Gerber, Hans-Peter; Ferrara, Napoleone



Standardization of the Filovirus Plaque Assay for Use in Preclinical Studies  

PubMed Central

The filovirus plaque assay serves as the assay of choice to measure infectious virus in a cell culture, blood, or homogenized tissue sample. It has been in use for more than 30 years and is the generally accepted assay used to titrate virus in samples from animals treated with a potential antiviral therapeutic or vaccine. As these animal studies are required for the development of vaccines and therapeutics under the FDA Animal Rule, it is essential to have a standardized assay to compare their efficacies against the various filoviruses. Here, we present an evaluation of the conditions under which the filovirus plaque assay performs best for the Ebola virus Kikwit variant and the Angola variant of Marburg virus. The indicator cell type and source, inoculum volumes, length of incubation and general features of filovirus biology as visualized in the assay are addressed in terms of the impact on the sample viral titer calculations. These optimization studies have resulted in a plaque assay protocol which can be used for preclinical studies, and as a standardized protocol for use across institutions, to aid in data comparison. This protocol will be validated for use in GLP studies supporting advanced development of filovirus therapeutics and vaccines. PMID:23223188

Shurtleff, Amy C.; Biggins, Julia E.; Keeney, Ashley E.; Zumbrun, Elizabeth E.; Bloomfield, Holly A.; Kuehne, Ana; Audet, Jennifer L.; Alfson, Kendra J.; Griffiths, Anthony; Olinger, Gene G.; Bavari, Sina



Natural substances and Alzheimer's disease: from preclinical studies to evidence based medicine.  


Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID:21939756

Mancuso, Cesare; Siciliano, Raffaella; Barone, Eugenio; Preziosi, Paolo



Standardization of the filovirus plaque assay for use in preclinical studies.  


The filovirus plaque assay serves as the assay of choice to measure infectious virus in a cell culture, blood, or homogenized tissue sample. It has been in use for more than 30 years and is the generally accepted assay used to titrate virus in samples from animals treated with a potential antiviral therapeutic or vaccine. As these animal studies are required for the development of vaccines and therapeutics under the FDA Animal Rule, it is essential to have a standardized assay to compare their efficacies against the various filoviruses. Here, we present an evaluation of the conditions under which the filovirus plaque assay performs best for the Ebola virus Kikwit variant and the Angola variant of Marburg virus. The indicator cell type and source, inoculum volumes, length of incubation and general features of filovirus biology as visualized in the assay are addressed in terms of the impact on the sample viral titer calculations. These optimization studies have resulted in a plaque assay protocol which can be used for preclinical studies, and as a standardized protocol for use across institutions, to aid in data comparison. This protocol will be validated for use in GLP studies supporting advanced development of filovirus therapeutics and vaccines. PMID:23223188

Shurtleff, Amy C; Biggins, Julia E; Keeney, Ashley E; Zumbrun, Elizabeth E; Bloomfield, Holly A; Kuehne, Ana; Audet, Jennifer L; Alfson, Kendra J; Griffiths, Anthony; Olinger, Gene G; Bavari, Sina



CCD-camera-based diffuse optical tomography to study ischemic stroke in preclinical rat models  

NASA Astrophysics Data System (ADS)

Stroke, due to ischemia or hemorrhage, is the neurological deficit of cerebrovasculature and is the third leading cause of death in the United States. More than 80 percent of stroke patients are ischemic stroke due to blockage of artery in the brain by thrombosis or arterial embolism. Hence, development of an imaging technique to image or monitor the cerebral ischemia and effect of anti-stoke therapy is more than necessary. Near infrared (NIR) optical tomographic technique has a great potential to be utilized as a non-invasive image tool (due to its low cost and portability) to image the embedded abnormal tissue, such as a dysfunctional area caused by ischemia. Moreover, NIR tomographic techniques have been successively demonstrated in the studies of cerebro-vascular hemodynamics and brain injury. As compared to a fiberbased diffuse optical tomographic system, a CCD-camera-based system is more suitable for pre-clinical animal studies due to its simpler setup and lower cost. In this study, we have utilized the CCD-camera-based technique to image the embedded inclusions based on tissue-phantom experimental data. Then, we are able to obtain good reconstructed images by two recently developed algorithms: (1) depth compensation algorithm (DCA) and (2) globally convergent method (GCM). In this study, we will demonstrate the volumetric tomographic reconstructed results taken from tissuephantom; the latter has a great potential to determine and monitor the effect of anti-stroke therapies.

Lin, Zi-Jing; Niu, Haijing; Liu, Yueming; Su, Jianzhong; Liu, Hanli



Computational Toxicology  

EPA Science Inventory

?Computational toxicology? is a broad term that encompasses all manner of computer-facilitated informatics, data-mining, and modeling endeavors in relation to toxicology, including exposure modeling, physiologically based pharmacokinetic (PBPK) modeling, dose-response modeling, ...


Advances in the application of mass spectrometry to studies of drug metabolism, pharmacokinetics and toxicology  

NASA Astrophysics Data System (ADS)

Applications of mass spectrometry to studies of drug metabolism, pharmacokinetics and toxicology published from the latter part of 1988 through mid-1991 are reviewed. Current trends and future prospects for mass spectrometry in these fields are discussed, with emphasis on the value of "soft ionization" techniques, on-line LC-MS systems, tandem mass spectrometry and stable isotopes for qualitative, quantitative and mechanistic investigations.

Baillie, Thomas A.



Educational Challenges in Toxicology.  

ERIC Educational Resources Information Center

Issues and topics related to educational challenges in toxicology at all levels are discussed. They include public awareness and understanding, general approach to toxicology, quality structure-activity relationships, epidemiological studies, quantification of risk, and the types of toxicants studied. (JN)

Dixon, Robert L.



Characterization of Activin/BMP2 chimera, AB204, formulated for preclinical studies.  


AB204 is an Activin/BMP2 chimera, which has been found to exhibit a higher activity than Bone Morphogenetic Protein 2 (BMP2) in osteogenic activity. To prepare AB204 for its preclinical studies, AB204 has been characterized in various formulation buffers. We observed that AB204 purified by ion-exchange chromatography has low water solubility (2.0 mg/ml), whereas it has high water solubility (higher than 10.0 mg/ml) when purified by reverse-phase chromatography. Analysis of the purification procedures reveals that the buffer composition at the lyophilization step determines the solubility. Lyophilization from sodium acetate buffer at pH 4.5 resulted in formation of sodium hydroxide, which caused low solubility of AB204 by pH increase upon reconstitution in water. However, lyophilization from buffers, containing acetic acid or trifluoroacetic acid (TFA) rendered AB204 to be highly soluble. During the course of these analyses, we found a simple procedure to further reduce residual amount of TFA in the purified AB204. PMID:24555430

Ahn, Chihoon; Maslennikov, Innokentiy; Choi, Jung Youn; Oh, Hyosun; Cheong, Chaejoon; Choe, Senyon



Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies  

PubMed Central

Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry. PMID:16504359

Winstanley, Catharine A.; Eagle, Dawn M.; Robbins, Trevor W.



Behavioral and pharmaco-toxicological study of Papaver rhoeas L. in mice.  


A lyophilized ethanolic aqueous extract of Papaver rhoeas petals was evaluated for its behavioral and pharmaco-toxicological effects in mice and its chemical composition was studied using thin layer chromatography (TLC). In this study, chemical analysis by TLC showed that the petals contain some anthocyanins, whereas no alkaloids were detected. The toxicological effect of alcoholic and aqueous plant extract administered intraperitoneally was determined in mice. The toxicological results obtained indicated that 2000 mg/kg is LD10 and 4000 mg/kg is LD50. Behavioral and pharmacological studies of ethanolic and aqueous extract showed that the plant extract reduced locomotory, exploratory and postural behavior of mice. This was evaluated through two specific behavioral tests; a non-familiar environment test (the Staircase test) and a familiar environment test (Free exploratory test). These behavioral and pharmacological effects are more pronounced when the solvent used for extraction is 10% ethanol and is not antagonized by benzodiazepines, opioids, dopaminergic and cholinergic compounds (flumazenil, naloxone, sulpuride and atropine). The plant extract did not induce sleep in mice after treatment with an infrahypnotic dose of pentobarbital. This finding shows that the plant extract has a sedative effect at a 400 mg/kg dosage. PMID:11274828

Soulimani, R; Younos, C; Jarmouni-Idrissi, S; Bousta, D; Khallouki, F; Khalouki, F; Laila, A



Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) in Preclinical Studies of Antivascular Treatments  

PubMed Central

Antivascular treatments can either be antiangiogenic or targeting established tumour vasculature. These treatments affect the tumour microvasculature and microenvironment but may not change clinical measures like tumour volume and growth. In research on antivascular treatments, information on the tumour vasculature is therefore essential. Preclinical research is often used for optimization of antivascular drugs alone or in combined treatments. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an in vivo imaging method providing vascular information, which has become an important tool in both preclinical and clinical research. This review discusses common DCE-MRI imaging protocols and analysis methods and provides an overview of preclinical research on antivascular treatments utilizing DCE-MRI. PMID:24300371

Nielsen, Thomas; Wittenborn, Thomas; Horsman, Michael R.



A Preclinical Study of the Effects of Seabuckthorn (Hippophae rhamnoides L.) Leaf Extract on Cutaneous Wound Healing in Albino Rats  

Microsoft Academic Search

Hippophae rhamnoides L. (family Elaeagnaceae), commonly known as seabuckthorn, is a wild shrub growing at high altitude (1200-4500 meters) in adverse climatic conditions. The aim of the present study was to evaluate healing potential of seabuckthorn leaves in a preclinical study on rats using a cutaneous excision-punch wound model. Four full-thickness excision-type wounds of 8.0 mm diameter were created on

Asheesh Gupta; Ratan Kumar; Karan Pal; Pratul K. Banerjee; Ramesh C. Sawhney



Pharmacological Intervention Studies Using Mouse Models of the Inflammatory Bowel Diseases: Translating Preclinical Data into New Drug Therapies  

PubMed Central

Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose-responses and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. The failure to translate therapeutic efficacy from bench to bedside may be due, in part, to shortcomings in the design of the clinical studies; however, it is becoming clear that much of the problem resides within the preclinical studies. One potential strategy for improving our ability to identify new therapeutics that may have a reasonable chance of success in well-controlled clinical trials is to identify the most relevant mouse models IBD and pharmacologic strategies that most closely mimic the clinical situation. To begin this process, we present a critical evaluation of the different mouse models and pharmacological approaches that may be used in intervention studies as well as discuss emerging issues related to study design and data interpretation of preclinical studies. PMID:21312318

Koboziev, Iurii; Karlsson, Fridrik; Zhang, Songlin; Grisham, Matthew B.



The basics of preclinical drug development for neurodegenerative disease indications  

PubMed Central

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial. PMID:19534731

Steinmetz, Karen L; Spack, Edward G



Vitamin D analogs and bone: preclinical and clinical studies with eldecalcitol.  


Eldecalcitol [1?,25-dihydroxy-2?-(3-hydroxypropyloxy)vitamin D3] is an analog of 1?,25-dihydroxyvitamin D3 [1,25(OH)2D3], bearing a hydroxypropyloxy residue at the 2? position. In preclinical studies, eldecalcitol suppressed bone resorption to a greater extent than alfacalcidol but had a similar effect on bone formation and Ca metabolism, resulting in a greater increase in bone mineral density (BMD) in ovariectomized (OVX) rats. Histological analysis in OVX rats immediately after ovariectomy revealed that eldecalcitol reduced osteoclast number and bone resorption parameters with a decrease in bone formation parameters. Eldecalcitol also promoted focal bone formation independent of bone resorption, a process known as bone minimodeling. In clinical studies, eldecalcitol showed stronger effects than alfacalcidol in increasing BMD and reducing bone resorption markers in osteoporotic patients under vitamin D supplementation. A 3-year randomized, double-blind, active-comparator clinical trial demonstrated that once-daily 0.75??g eldecalcitol reduced vertebral fracture incidence by 26% compared with 1.0??g alfacalcidol. Eldecalcitol also reduced the incidence of wrist fractures by 71% compared with alfacalcidol. Although this may be due to the previously reported effect of vitamin D in reducing the incidence of falls, it is not known whether eldecalcitol has a stronger effect in preventing falls than alfacalcidol. Because eldecalcitol stimulates intestinal Ca absorption and improves Ca balance in addition to its skeletal effects, combination treatment with antiresorptive agents may be able to show better effects than native vitamin D and Ca supplementation in preventing fractures in osteoporotic patients. Further studies are warranted to clarify these issues. PMID:24818005

Matsumoto, Toshio; Takano, Toshiyuki; Saito, Hitoshi; Takahashi, Fumiaki



Proteomics for systems toxicology  

PubMed Central

Current toxicology studies frequently lack measurements at molecular resolution to enable a more mechanism-based and predictive toxicological assessment. Recently, a systems toxicology assessment framework has been proposed, which combines conventional toxicological assessment strategies with system-wide measurement methods and computational analysis approaches from the field of systems biology. Proteomic measurements are an integral component of this integrative strategy because protein alterations closely mirror biological effects, such as biological stress responses or global tissue alterations. Here, we provide an overview of the technical foundations and highlight select applications of proteomics for systems toxicology studies. With a focus on mass spectrometry-based proteomics, we summarize the experimental methods for quantitative proteomics and describe the computational approaches used to derive biological/mechanistic insights from these datasets. To illustrate how proteomics has been successfully employed to address mechanistic questions in toxicology, we summarized several case studies. Overall, we provide the technical and conceptual foundation for the integration of proteomic measurements in a more comprehensive systems toxicology assessment framework. We conclude that, owing to the critical importance of protein-level measurements and recent technological advances, proteomics will be an integral part of integrative systems toxicology approaches in the future. PMID:25379146

Titz, Bjoern; Elamin, Ashraf; Martin, Florian; Schneider, Thomas; Dijon, Sophie; Ivanov, Nikolai V.; Hoeng, Julia; Peitsch, Manuel C.



Alterations in the rate of binge ethanol consumption: implications for preclinical studies in mice.  


The rate at which alcohol (ethanol) is consumed has direct impact on its behavioral and subjective effects. For this reason, alterations in the pattern of ethanol consumption as a function of drinking history might be critical to the development and maintenance of alcoholism. Furthermore, because pharmacological interventions aimed at disrupting the motivation to consume ethanol are dependent on the brain/plasma concentrations present when an individual is most likely to engage in consumption of this substance, characterizing temporal drinking patterns might be useful to determine the timing of such treatments. The primary goal of the present study was to evaluate alterations in the timecourse of daily binge (drinking-in-the-dark; DID) ethanol consumption. We gave 14 daily 2 hour DID ethanol or water access sessions to male C57BL/6J (B6) mice using a state of the art volumetric drinking monitoring device. We then, primarily as a proof-of-principle, used the GABAB allosteric modulator GS39783 (GS) to determine how this compound influenced the timecourse of binge-like ethanol intake. The rate of ethanol consumption increased dramatically over sessions with the majority occurring in the first few minutes of the final session. Additionally, ethanol consumption occurring immediately following access was almost completely abolished in mice pre-treated with GS; an effect which was ethanol-specific only at this early time interval. These data characterize progressive alterations in the rate of ethanol intake using the DID model and suggest that careful consideration of prior ethanol history and timing of drug administration are warranted when interpreting results of pre-clinical drug administration studies. PMID:23742054

Linsenbardt, David N; Boehm, Stephen L




EPA Science Inventory

Lung tissue slices are model systems for the study of pulmonary metabolism. Because of the speed and simplicity of slice preparation, lung slices have been used in studies of oxygen, amino acid, carbohydrate and lipid utilization and adenine nucleotide metabolism. Dose-response c...


40 CFR 159.165 - Toxicological and ecological studies.  

Code of Federal Regulations, 2010 CFR

...higher incidence or frequency. (iv) In a different species, strain, sex, or generation of test organism. (v) By a different route of exposure. (2) Acute oral, acute dermal, acute inhalation or skin and eye irritation studies...




EPA Science Inventory

The purpose of these studies was to develop novel methods to investigate the biological fate of inhaled ozone and other oxygen-containing pollutants in animal and human tissues using the heavy isotope of oxygen, oxygen-18 (18O). Methods were developed which facilitated the conver...


Assessing Immunological Function in Toxicological Studies of Avian Wildlife  

Microsoft Academic Search

SYNOPSIS. Laboratory and field studies have demonstrated that the immune system is sensitive to environ- mental contaminants. Testing protocols have been developed to screen for immunotoxic effects and elucidate mechanisms of toxicity in laboratory rodents. Similar methods have been applied to wildlife species in captivity and the wild. Several epizootics in wildlife have been associated with elevated exposure to contam-




The zoapatle IV--toxicological and clinical studies.  


The zoapatle aqueous crude extract has been used in Mexico for the last 5 centuries for the induction of labor, treatment of post-partum bleeding problems, and as a menses inducer. Today, it is sold in street markets, and its long documented history of use by humans could be taken as indirect evidence of a lack of toxicity. Rigorous pharmacological and clinical studies described here, fully confirm the empirical observations. PMID:6851559

Southam, L; Pedrón, N; Ponce-Monter, H; Girón, H; Estrada, A; Lozoya, X; Enríquez, R G; Bejar, E; Gallegos, A J




Microsoft Academic Search

Toxicity of the aqueous extracts of raw and processed larva of Cirina forda (Westwood) administered orally were studied in white albino mice and albino rats. Preliminary investigation showed that the raw extract was toxic to mice, showing sign of irritability and muscular tremor. An LD50 value of 7,000mg\\/kg body weight was obtained for the raw extract using mice. The effects



[Synthesis, chemical and toxicological study of a new benzimidazol derivative].  


Hydatidosis is a cosmopolitan parasitic disease that remains a real public health problem in highly endemic countries. Surgery is the mainstay treatment, but with significant morbidity and mortality. In addition, contraindications for surgery emphasize the importance of developing effective medications. Currently, albendazole is the main anti-hydatid agent used worldwide. It has proven efficacy but limited bioavailability due to weak absorption. In order to improve the bioavailability of this molecule we synthesized an ester of albendazole, which exhibits a totally modified solubility compared with the princeps compound. This synthesis was achieved with an output of 75%. The structure of the synthetic product was established by IR spectrometry and by proton nuclear magnetic resonance. A careful toxicity study revealed that this product has little toxicity when administered intraperitoneally and orally in mice, with a lethal dose 50 of 2,500 mg/kg per os and 2,250 mg/kg intraperitoneally, values comparable to those of albendazole. This in vitro parasitological study demonstrated that the chemical changes introduced on the albendazole molecule had no effect on its antiparasitic activity. PMID:19298890

Ansar, M; Zellou, A; Faouzi, M E A; Zahidi, A; Serroukh, S; Lmimouni, B E; Cherrah, Y; Taoufik, J



Streams of Coal or Streams of Death? A Toxicology Case Study  

NSDL National Science Digital Library

Mary Beth was raised in Western Pennsylvania, an area where thousands of abandoned coal mines have led to extensive contamination of streams and associated ground waters. Aquatic life has clearly suffered, but the health effects on people living along the waterways have not been so clear. In working through this interrupted case study, students consider the biological consequences for Mary Beth’s family by analyzing selected research articles. Originally developed for an upper level toxicology course, it would also be appropriate for a cancer biology course and could easily be adapted for a course in science and society or environmental studies.

Niedziela, Linda



Inhalation developmental toxicology studies: Gallium arsenide in mice and rats  

SciTech Connect

Gallium arsenide is a crystalline compound used extensively in the semiconductor industry. Workers preparing solar cells and gallium arsenide ingots and wafers are potentially at risk from the inhalation of gallium arsenide dust. The potential for gallium arsenide to cause developmental toxicity was assessed in Sprague- Dawley rats and CD-1 (Swiss) mice exposed to 0, 10, 37, or 75 mg/m{sup 3} gallium arsenide, 6 h/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and {approx}30 positively mated rats or {approx}24 positively mated mice. Mice were exposed on 4--17 days of gestation (dg), and rats on 4--19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. Gallium and arsenic concentrations were determined in the maternal blood and uterine contents of the rats (3/group) at 7, 14, and 20 dg. 37 refs., 11 figs., 30 tabs.

Mast, T.J.; Greenspan, B.J.; Dill, J.A.; Stoney, K.H.; Evanoff, J.J.; Rommereim, R.L.



Subchronic Toxicological Study of Two Artemisinin Derivatives in Dogs  

PubMed Central

The objective of our study was to profile and compare the systematic changes between orally administered artesunate and intramuscularly injected artemether at a low dose over a 3-month period (92 consecutive days) in dogs. Intramuscular administration of 6 mg kg-1 artemether induced a decreased red blood cell (RBC) count (anemia), concurrent extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. We also observed a prolonged QT interval and neuropathic changes in the central nervous system, which demonstrated the cortex and motor neuron vulnerability, but no behavioral changes. Following treatment with artesunate, we observed a decreased heart rate, which was most likely due to cardiac conduction system damage, as well as a deceased RBC count, extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. However, in contrast to treatment with artemether, neurotoxicity was not observed following treatment with artesunate. In addition, ultra-structural examination by transmission electron microscopy showed mitochondrial damage following treatment with artesunate. These findings demonstrated the spectrum of toxic changes that result upon treatment with artesunate and artemether and show that the prolonged administration of low doses of these derivatives result in diverse toxicity profiles. PMID:24739881

Yin, Ji-ye; Wang, He-mei; Wang, Quan-jun; Dong, Yan-sheng; Han, Gang; Guan, Yong-biao; Zhao, Ke-yong; Qu, Wen-sheng; Yuan, Ye; Gao, Xiao-xin; Jing, Shu-fang; Ding, Ri-gao



Subchronic toxicological study of two artemisinin derivatives in dogs.  


The objective of our study was to profile and compare the systematic changes between orally administered artesunate and intramuscularly injected artemether at a low dose over a 3-month period (92 consecutive days) in dogs. Intramuscular administration of 6 mg kg-1 artemether induced a decreased red blood cell (RBC) count (anemia), concurrent extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. We also observed a prolonged QT interval and neuropathic changes in the central nervous system, which demonstrated the cortex and motor neuron vulnerability, but no behavioral changes. Following treatment with artesunate, we observed a decreased heart rate, which was most likely due to cardiac conduction system damage, as well as a deceased RBC count, extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. However, in contrast to treatment with artemether, neurotoxicity was not observed following treatment with artesunate. In addition, ultra-structural examination by transmission electron microscopy showed mitochondrial damage following treatment with artesunate. These findings demonstrated the spectrum of toxic changes that result upon treatment with artesunate and artemether and show that the prolonged administration of low doses of these derivatives result in diverse toxicity profiles. PMID:24739881

Yin, Ji-ye; Wang, He-mei; Wang, Quan-jun; Dong, Yan-sheng; Han, Gang; Guan, Yong-biao; Zhao, Ke-yong; Qu, Wen-sheng; Yuan, Ye; Gao, Xiao-xin; Jing, Shu-fang; Ding, Ri-gao



Inhalation developmental toxicology studies: Teratology study of tetrahydrofuran in mice and rats: Final report  

SciTech Connect

Tetrahydrofuran (THF), a four-carbon cyclic ether, is widely used as an industrial solvent. Although it has been used in large quantities for many years, few long-term toxicology studies, and no reproductive or developmental studies, have been conducted on THF. This study addresses the potential for THF to cause developmental toxicity in rodents by exposing Sprague-Dawley rats and Swiss (CD-1) mice to 0, 600, 1800, or 5000 ppm tetrahydrofuran (THF) vapors, 6 h/day, 7 dy/wk. Each treatment group consisted of 10 virgin females (for comparison), and approx.33 positively mated rats or mice. Positively mated mice were exposed on days 6--17 of gestation (dg), and rats on 6--19 dg. The day of plug or sperm detection was designated as O dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded and live fetuses were examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 27 refs., 6 figs., 23 tabs.

Mast, T.J.; Evanoff, J.J.; Stoney, K.H.; Westerberg, R.B.; Rommereim, R.L.; Weigel, R.J.



Temple study's pre-clinical data shows Angiocidin effective against leukemia

Angiocidin, a novel tumor-inhibiting protein, has been shown to reduce acute myeloid leukemia (AML) cells in mice by almost two-thirds in pre-clinical experiments. A researcher from Temple University’s School of Medicine who discovered Angiocidin, presented the findings during the American Society of Hematology’s national meeting in Atlanta on Dec. 9. Temple University is home to the Fox Chase Cancer Center.


Biological basis of sex differences in drug abuse: preclinical and clinical studies  

Microsoft Academic Search

.   The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review,\\u000a we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie\\u000a these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men;

Wendy J. Lynch; Megan E. Roth; Marilyn E. Carroll



Intra-arterial hepatic chemotherapy with pirarubicin. Preclinical and clinical studies.  


Intra-arterial hepatic chemotherapy (IAHC) with adriamycin (ADM) has not increased its therapeutic index. For our preclinical studies, we selected pirarubicin (THP), an ADM derivative with faster cellular uptake. In rabbits with VX2 tumor in the liver we compared plasmatic and cellular pharmacokinetics of ADM and THP after i.v. and IAH therapy. For ADM, there were no differences in plasma and heart concentrations, with only a slight increase in tumoral levels after IAH compared to i.v. administration; on the other hand, with IAH THP, there was important reduction in systemic exposure with a major increase in tumoral drug distribution. In the phase I study, involving nine patients with implanted catheters, the starting dose of THP was 30 mg/m2 with a 10 mg/m2 intrapatient escalation every 3 weeks in the absence of toxicity. Pharmacokinetics were compared for i.v. and IAH administration in seven patients. The limiting toxicity was neutropenia and the maximal tolerated dose (MTD) ranged from 50 to 110 mg/m2. Moderate nausea-vomiting (grade 1-2) and alopecia (grade 1) occurred at the MTD. No arterial occlusion, gastroduodenal ulcer, hepatitis, or sclerosing cholangitis were seen. In the phase II study, in colorectal cancer patients (CRC) with metastasis confined to the liver, patients were enrolled until June 1990. THP (40 min infusion every 3 weeks) was initiated at 60 mg/m2 with 10 mg/m2 increment until grade 2 hematotoxicity. The median MTD was 85 mg/m2 (range of 60-120 mg/m2), and the median number of cycles was 7 (range of 2-11) with cumulated doses from 180 to 1,030 mg/m2. Grade 2-4 neutropenia was reached in 15 patients. Other toxicities included two arterial occlusions, one episode of gastritis, but no hepatic toxicity and no heart failure. Antitumor effect (in 18 patients) included 1 CR, 5 PR, 3 MR, 6 NC, and 3 PD. The median survival was 18+ months and 1-year survival was 73% +/- 12%. Seven patients had extrahepatic progression at this time. In conclusion, besides 5-FU or Fudr, THP is active in IAHC (probably in relation with high local extraction) on CRC liver metastases usually unresponsive to ADM. It can be given in an outpatient setting with minimal toxicity. PMID:2291452

Rougier, P; Munck, J N; Elias, D; Herait, P; Bognel, C; Gosse, C; Lasser, P




EPA Science Inventory

This report includes the results of five toxicological studies of pesticide compounds conducted by the Institute for Medical Research and Occupational Health, Zagreb, Yugoslavia. In the first study, the reactions of two groups of esterases (cholinesterases and arylesterases) with...


Attempted and Successful Compensation in Preclinical and Early Manifest Neurodegeneration - A Review of Task fMRI Studies  

PubMed Central

Several models of neural compensation in healthy aging have been suggested to explain brain activity that aids to sustain cognitive function. Applying recently suggested criteria of “attempted” and “successful” compensation, we reviewed existing literature on compensatory mechanisms in preclinical Huntington’s disease (HD) and amnestic mild cognitive impairment (aMCI). Both disorders constitute early stages of neurodegeneration ideal for examining compensatory mechanisms and developing targeted interventions. We strived to clarify whether compensation criteria derived from healthy aging populations can be applied to early neurodegeneration. To concentrate on the close coupling of cognitive performance and brain activity, we exclusively addressed task fMRI studies. First, we found evidence for parallels in compensatory mechanisms between healthy aging and neurodegenerative disease. Several studies fulfilled criteria of attempted compensation, while reports of successful compensation were largely absent, which made it difficult to conclude on. Second, comparing working memory studies in preclinical HD and aMCI, we identified similar compensatory patterns across neurodegenerative disorders in lateral and medial prefrontal cortex. Such patterns included an inverted U-shaped relationship of neurodegeneration and compensatory activity spanning from preclinical to manifest disease. Due to the lack of studies systematically targeting all criteria of compensation, we propose an exemplary study design, including the manipulation of compensating brain areas by brain stimulation. Furthermore, we delineate the benefits of targeted interventions by non-invasive brain stimulation, as well as of unspecific interventions such as physical activity or cognitive training. Unambiguously detecting compensation in early neurodegenerative disease will help tailor interventions aiming at sustained overall functioning and delayed clinical disease onset.

Scheller, Elisa; Minkova, Lora; Leitner, Mathias; Kloppel, Stefan



Preclinical and Pilot Clinical Studies of Docetaxel Chemoradiation for Stage III Non-Small-Cell Lung Cancer  

SciTech Connect

Purpose: Local and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for Stage III non-small-cell lung cancer. We conducted preclinical studies of docetaxel's cytotoxic and radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low-dose radiosensitizing docetaxel CRT. Methods and Materials: A preclinical study was conducted in human lung cancer cell lines NCI 520 and A549. Cells were treated with two concentrations of docetaxel for 3 h and then irradiated immediately or after a 24-h delay. A clonogenic survival assay was conducted and analyzed for cytotoxic effects vs. radiosensitizing effects of docetaxel. A pilot clinical study was designed based on preclinical study findings. Twenty-two patients were enrolled with a median follow-up of 4 years. Induction chemotherapy consisted of 75 mg/m{sup 2} of docetaxel and 75 mg/m{sup 2} of cisplatin on Day 1 and 150 mg/m{sup 2} of recombinant human granulocyte colony-stimulating factor on Days 2 through 10. Concurrent CRT was started 3 to 6 weeks later with twice-weekly docetaxel at 10 to 12 mg/m{sup 2} and daily delayed radiation in 1.8-Gy fractions to 64.5 Gy for gross disease. Results: The preclinical study showed potent cytotoxic effects of docetaxel and subadditive radiosensitizing effects. Delaying radiation resulted in more cancer cell death. The pilot clinical study resulted in a median survival of 32.6 months for the entire cohort, with 3- and 5-year survival rates of 50% and 19%, respectively, and a distant metastasis-free survival rate of 61% for both 3 and 5 years. A pattern-of-failure analysis showed 75% chest failures and 36% all-distant failures. Therapy was well tolerated with Grade 3 esophagitis observed in 23% of patients. Conclusions: One-cycle full-dose docetaxel/cisplatin induction chemotherapy with recombinant human granulocyte colony-stimulating factor followed by pulsed low-dose docetaxel CRT is promising with regard to its antitumor activity, low rates of distant failure, and low toxicity, suggesting that this regimen deserves further investigation.

Chen Yuhchyau, E-mail: [Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY (United States); Pandya, Kishan J. [Department of Medical Oncology, University of Rochester Medical Center, Rochester, NY (United States); Hyrien, Ollivier [Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY (United States); Keng, Peter C.; Smudzin, Therese; Anderson, Joy [Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY (United States); Qazi, Raman; Smith, Brian [Department of Medical Oncology, University of Rochester Medical Center, Rochester, NY (United States); Watson, Thomas J. [Division of Cardiothoracic Surgery, University of Rochester Medical Center, Rochester, NY (United States); Feins, Richard H. [Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC (United States); Johnstone, David W. [Division of Cardiothoracic Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Lebanon)



Environmental Toxicology  

Microsoft Academic Search

Environmental Toxicology is a comprehensive introductory textbook dealing with most aspects of the subject, from the molecular to the ecosystem level. Early chapters deal with basic to advanced concepts, methods and approaches. The next discusses the environmental toxicology of individual or groups of substances. The third part addresses complex issues, in which many of the concepts, approaches and substances covered

David A. Wright; Pamela Welbourn



Retinal electrophysiology for toxicology studies: applications and limits of ERG in animals and ex vivo recordings.  


Assessing retinal drug toxicity is becoming increasingly important as different molecules are now developed for the treatment of neurodegenerative diseases and vascular disorders. In pharmacology and toxicology, the electroretinogram (ERG) and the multielectrode array (MEA) recording techniques can be used to quantify the possible side effects of retino-active xenobiotics. Toxicity testing requires the use of rodent as well as non-rodent models for extrapolation to the human model when determining risk and safety. Animal species differ in their retinal anatomo-physiology: most rodents used in toxicology studies are essentially nocturnal species, whereas the non-rodent laboratory species normally used (e.g. dogs, pigs and monkeys) are diurnal. The ratio between the photoreceptor populations which varies from species to species, should be considered when designing the experiment protocol and the interpretation. The described ERG procedures are designed to comply with all applicable good laboratory practice standards. Use of these procedures should yield an acceptable level of intra- and inter-subject variability for compiling a historical database, and for detecting possible retinal toxicity in animal studies. They could therefore be used as specific and standardized tools for screening of potential retinotoxic molecules in drug discovery and development in order to compare methods and results with those obtained in human electrophysiological assessments. Recording of ganglion cell light responses on ex vivo retina with the MEA technique can further demonstrate how retino-active xenobiotics affect retinal visual information processing by eliminating potential obstacles related to bioavailability and blood barrier permeability. PMID:18294830

Rosolen, Serge Georges; Kolomiets, Bogdan; Varela, Oscar; Picaud, Serge



Green toxicology.  


Historically, early identification and characterization of adverse effects of industrial chemicals was difficult because conventional toxicological test methods did not meet R&D needs for rapid, relatively inexpensive methods amenable to small amounts of test material. The pharmaceutical industry now front-loads toxicity testing, using in silico, in vitro, and less demanding animal tests at earlier stages of product development to identify and anticipate undesirable toxicological effects and optimize product development. The Green Chemistry movement embraces similar ideas for development of less toxic products, safer processes, and less waste and exposure. Further, the concept of benign design suggests ways to consider possible toxicities before the actual synthesis and to apply some structure/activity rules (SAR) and in silico methods. This requires not only scientific development but also a change in corporate culture in which synthetic chemists work with toxicologists. An emerging discipline called Green Toxicology (Anastas, 2012) provides a framework for integrating the principles of toxicology into the enterprise of designing safer chemicals, thereby minimizing potential toxicity as early in production as possible. Green Toxicology`s novel utility lies in driving innovation by moving safety considerations to the earliest stage in a chemical`s lifecycle, i.e., to molecular design. In principle, this field is no different than other subdisciplines of toxicology that endeavor to focus on a specific area - for example, clinical, environmental or forensic toxicology. We use the same principles and tools to evaluate an existing substance or to design a new one. The unique emphasis is in using 21st century toxicology tools as a preventative strategy to "design out" undesired human health and environmental effects, thereby increasing the likelihood of launching a successful, sustainable product. Starting with the formation of a steering group and a series of workshops, the Green Toxicology concept is currently spreading internationally and is being refined via an iterative process. PMID:25061898

Maertens, Alexandra; Anastas, Nicholas; Spencer, Pamela J; Stephens, Martin; Goldberg, Alan; Hartung, Thomas



Novel pre-clinical methodologies for pharmacokinetic drug-drug interaction studies: spotlight on "humanized" animal models.  


Abstract Poly-therapy is common due to co-occurrence of several ailments in patients, leading to the elevated possibility of drug-drug interactions (DDI). Pharmacokinetic DDI often accounts for severe adverse drug reactions in patients resulting in withdrawal of drug from the market. Hence, the prediction of DDI is necessary at pre-clinical stage of drug development. Several human tissue and cell line-based in vitro systems are routinely used for screening metabolic and transporter pathways of investigational drugs and for predicting their clinical DDI potentials. However, ample constraints are associated with the in vitro systems and sometimes in vitro-in vivo extrapolation (IVIVE) fail to assess the risk of DDI in clinic. In vitro-in vivo correlation model in animals combined with human in vitro studies may be helpful in better prediction of clinical outcome. Native animal models vary remarkably from humans in drug metabolizing enzymes and transporters, hence, the interpretation of results from animal DDI studies is difficult. With the advent of modern molecular biology and engineering tools, novel pre-clinical animal models, namely, knockout rat/mouse, transgenic rat/mouse with humanized drug metabolizing enzymes and/or transporters and chimeric rat/mouse with humanized liver are developed. These models nearly simulate human-like drug metabolism and help to validate the in vivo relevance of the in vitro human DDI data. This review briefly discusses the application of such novel pre-clinical models for screening various type of DDI along with their advantages and limitations. PMID:25270219

Jaiswal, Swati; Sharma, Abhisheak; Shukla, Mahendra; Vaghasiya, Kalpesh; Rangaraj, Nagarjun; Lal, Jawahar



The toxicological evaluation of realistic emissions of source aerosols study: statistical methods.  


The Toxicological Evaluation of Realistic Emissions of Source Aerosols (TERESA) study involved withdrawal, aging, and atmospheric transformation of emissions of three coal-fired power plants. Toxicological evaluations were carried out in rats exposed to different emission scenarios with extensive exposure characterization. Data generated had multiple levels of resolution: exposure, scenario, and constituent chemical composition. Here, we outline a multilayered approach to analyze the associations between exposure and health effects beginning with standard ANOVA models that treat exposure as a categorical variable. The model assessed differences in exposure effects across scenarios (by plant). To assess unadjusted associations between pollutant concentrations and health, univariate analyses were conducted using the difference between the response means under exposed and control conditions and a single constituent concentration as the predictor. Then, a novel multivariate analysis of exposure composition and health was used based on Random Forests(™), a recent extension of classification and regression trees that were applied to the outcome differences. For each exposure constituent, this approach yielded a nonparametric measure of the importance of that constituent in predicting differences in response on a given day, controlling for the other measured constituent concentrations in the model. Finally, an R(2) analysis compared the relative importance of exposure scenario, plant, and constituent concentrations on each outcome. Peak expiratory flow (PEF) is used to demonstrate how the multiple levels of the analysis complement each other to assess constituents most strongly associated with health effects. PMID:21913820

Coull, Brent A; Wellenius, Gregory A; Gonzalez-Flecha, Beatriz; Diaz, Edgar; Koutrakis, Petros; Godleski, John J



Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence.  


Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium amoenum. For several of the plants studied, conclusions need to be tempered due to methodological issues such as small sample sizes, brief intervention durations and non-replication. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata and Citrus aurantium. Bacopa monnieri has shown anxiolytic effects in people with cognitive decline. The therapeutic application of psychotropic plant-based treatments for anxiety disorders is also discussed, specifically Psychotria viridis and Banisteriopsis caarti (ayahuasca), Psilocybe spp. and cannabidiol-enriched (low tetrahydrocannabinol (?(9)-THC)) Cannabis spp. PMID:23653088

Sarris, Jerome; McIntyre, Erica; Camfield, David A



The Humanized NOD/SCID Mouse as a Preclinical Model to Study the Fate of Encapsulated Human Islets  

PubMed Central

Despite encouraging results in animal models, the transplantation of microencapsulated islets into humans has not yet reached the therapeutic level. Recent clinical trials using microencapsulated human islets in barium alginate showed the presence of dense fibrotic overgrowth around the microcapsules with no viable islets. The major reason for this is limited understanding of what occurs when encapsulated human islets are allografted. This warrants the need for a suitable small animal model. In this study, we investigated the usefulness of NOD/SCID mice reconstituted with human PBMCs (called humanized NOD/SCID mice) as a preclinical model. In this model, human T cell engraftment could be achieved, and CD45+ cells were observed in the spleen and peripheral blood. Though the engrafted T cells caused a small fibrotic overgrowth around the microencapsulated human islets, this failed to stop the encapsulated islets from functioning in the diabetic recipient mice. The ability of encapsulated islets to survive in this mouse model might partly be attributed to the presence of Th2 cytokines IL-4 and IL-10, which are known to induce graft tolerance. In conclusion, this study showed that the hu-NOD/SCID mouse is not a suitable preclinical model to study the allograft rejection mechanisms of encapsulated human islets. As another result, the maintained viability of transplanted islets on the NOD/SCID background emphasized a critical role of protective mechanisms in autoimmune diabetes transplanted subjects due to specific immunoregulatory effects provided by IL-4 and IL-10. PMID:20703439

Vaithilingam, Vijayaganapathy; Oberholzer, Jose; Guillemin, Gilles J.; Tuch, Bernard E.



Toxicology and Carcinogenesis Studies of Hydrochlorothiazide (CAS No. 58-93-5) in F344/N Rats and B6C3Fl Mice (Feed Studies).  

National Technical Information Service (NTIS)

Hydrochlorothiazide is a diuretic active at the distal convoluted tubule and collecting duct. Toxicology and carcinogenesis studies were conducted by feeding diets containing hydrochlorothiazide (USP grade, greater than 98% pure) to groups of F344/N rats ...

J. R. Bucher



Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease.  


Visualizing the neuropathological hallmarks amyloid plaques and neurofibrillary tangles of Alzheimer's disease in vivo using positron emission tomography (PET) or single photon emission computed tomography will be of great value in diagnosing the individual patient and will also help in our understanding of the disease. The successful introduction of [(11)C]PIB as a PET tracer for the amyloid plaques less than 10 years ago started an intensive research, and numerous new compounds for use in molecular imaging of the amyloid plaques have been developed. The candidates are based on dyes like thioflavin T, Congo red and chrysamine G, but also on other types such as benzoxazoles, curcumin and stilbenes. In the present review, we present methods of the radiochemistry and preclinical evaluation as well as the main properties of some of these compounds. PMID:22226025

Svedberg, Marie M; Rahman, Obaidur; Hall, Håkan



Therapeutic vaccination in chronic hepatitis B: preclinical studies in the woodchuck.  


Recommended treatment of chronic hepatitis B with interferon-? and/or nucleos(t)ide analogues does not lead to a satisfactory result. Induction of HBV-specific T cells by therapeutic vaccination or immunotherapies may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients did not result in effective control of HBV infection, suggesting that new formulations of therapeutic vaccines are needed. The woodchuck (Marmota monax) is a useful preclinical model for developing the new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments with nucleos(t)ide analogues, DNA vaccines, and protein vaccines were tested in the woodchuck model. In this paper we summarize the available data concerning therapeutic immunization and gene therapy using recombinant viral vectors approaches in woodchucks, which show encouraging results. In addition, we present potential innovations in immunomodulatory strategies to be evaluated in this animal model. PMID:21188201

Kosinska, Anna D; Zhang, Ejuan; Lu, Mengji; Roggendorf, Michael



Implications of the stability behavior of zinc oxide nanoparticles for toxicological studies  

NASA Astrophysics Data System (ADS)

The increasing use of zinc oxide (ZnO) nanoparticles in sunscreens and other cosmetic products demands a risk assessment that has to be done in toxicological studies. Such investigations require profound knowledge of the behavior of ZnO in cell culture media. The current study was performed to get well-dispersed suspensions of a hydrophilic (ZnO-hydro) and a lipophilic coated (ZnO-lipo) ZnO nanomaterial for use in in vitro tests. Therefore, systematic tests were carried out with common dispersants (phosphate, lecithin, proteins) to elucidate chemical and physical changes of ZnO nanoparticles in water and physiological solutions (PBS, DMEM). Non-physiological stock suspensions were prepared using ultrasonication. Time-dependent changes of pH, conductivity, zeta potential, particle size and dissolution were recorded. Secondly, the stock suspensions were added to physiological media with or without albumin (BSA) or serum (FBS), to examine characteristics such as agglomeration and dissolution. Stable stock suspensions were obtained using phosphate as natural and physiological electrostatic stabilizing agent. Lecithin proved to be an effective wetting agent for ZnO-lipo. Although the particle size remained constant, the suspension changed over time. The pH increased as a result of ZnO dissolution and formation of zinc phosphate complexes. The behavior of ZnO in physiological media was found to depend strongly on the additives used. Applying only phosphate as additive, ZnO-hydro agglomerated within minutes. In the presence of lecithin or BSA/serum, agglomeration was inhibited. ZnO dissolution was higher under physiological conditions than in the stock suspension. Serum especially promoted this process. Using body-related dispersants (phosphate, lecithin) non-agglomerating stock suspensions of hydrophilic and lipophilic ZnO were prepared as a prerequisite to perform meaningful toxicological investigation. Both nanomaterials showed a non-negligible dissolution behavior that strongly depended on the surrounding conditions. Agglomeration of ZnO particles in physiological media is a complex function of particle coating, used dispersants and serum proteins if supplemented. The present study gives a clear guideline how to prepare and handle suspensions with ZnO for in vitro testing and allows the correlation between the chemical-physical particles behavior with findings from toxicological tests.

Meißner, Tobias; Oelschlägel, Kathrin; Potthoff, Annegret



Ovarian toxicity and carcinogenicity in eight recent national toxicology program studies  

SciTech Connect

Ovarian toxicity and/or carcinogenicity has been documented for at least eight chemicals recently tested in National Toxicity Program prechronic and chronic rodent studies. The chemicals that yielded treatment-related ovarian lesions were 1,3-butadiene, 4-vinylcyclohexene, vinylcylohexene deipoxide, nitrofurantoin, nitrofurazone, benzene,, and tricresylphosphate. Typical nonneoplastic ovarian changes included hypoplasia, atrophy, follicular necrosis, and tubular hyperplasia. The most commonly observed treatment-related neoplasms were granulosa cell tumors and benign mixed tumors. A relationship between antecedent ovarian hypoplasia, atrophy, and hyperplasia and subsequent ovarian neoplasia is supported by some of these National Toxicology Program studies. Pathologic changes in other tissues such as the adrenal glands and uterus were associated with the treatment-related ovarian changes.

Maronpot, R.R.



Toxicological Profiles  

NSDL National Science Digital Library

The Federal Agency for Toxic Substances and Disease Registry (ATSDR) produces "toxicological profiles" for hazardous substances found at National Priorities List (NPL) sites. These hazardous substances are ranked based on frequency of occurrence at NPL sites, toxicity, and potential for human exposure. Toxicological profiles are developed from a priority list of 275 substances. This site contains a wealth of information, including analytical methods, regarding these very important substances.



Spaceflight Toxicology  

NASA Technical Reports Server (NTRS)

This viewgraph presentation provides a review of NASA Johnson Space Center's Toxicology program. The mission of this program is to protect crews from toxic exposures during spaceflight. The presentation reviews some of the health hazards. A toxicological hazard level chart is presented that reviews the rating of hazard level, irritancy, systemic effects and containability. The program also participates in the Lunar Airborne Dust Toxicity Advisory Group.

Meyers, Valerie




EPA Science Inventory

A number of interesting and unusual lesions have been diagnosed in zebrafish that have been evaluated from toxicological studies or submitted as cases to the Diagnostic Service at Oregon State University. Lesions were observed in various wild-type and mutant lines of zebrafish an...


Toxicological studies on silver nanoparticles: challenges and opportunities in assessment, monitoring and imaging  

PubMed Central

Silver nanoparticles (Ag NPs) are becoming increasingly prevalent in consumer products as antibacterial agents. The increased use of Ag NP-enhanced products may lead to an increase in toxic levels of environmental silver, but regulatory control over the use or disposal of such products is lagging due to insufficient assessment on the toxicology of Ag NPs and their rate of release into the environment. In this article we discuss recent research on the transport, activity and fate of Ag NPs at the cellular and organismic level, in conjunction with traditional and recently established methods of nanoparticle characterization. We include several proposed mechanisms of cytotoxicity based on such studies, as well as new opportunities for investigating the uptake and fate of Ag NPs in living systems. PMID:21793678

Stensberg, Matthew Charles; Wei, Qingshan; McLamore, Eric Scott; Porterfield, David Marshall; Wei, Alexander; Sepulveda, Marla Soledad



Oral toxicological studies of pueraria flower extract: acute toxicity study in mice and subchronic toxicity study in rats.  


Kudzu has been widely used as an herbal medicine in China. The root of the kudzu is also well known as an antipyretic and analgesic in treatment of the common cold, while its flower has been used to treat alcohol intoxication, alcohol abuse, and dysentery. Pueraria flower extract (PFE) is a hot water extract derived from the flower of the kudzu, Pueraria thomsonii Benth. (Fabaceae), oral intake of which exhibits anti-obesity properties in mice and humans. In this study, we conducted acute and subchronic toxicity studies for an evaluation of safety. In the acute study, PFE (5 g/kg body weight) was orally administered to ddY mice. For 14 d after administration, no deaths or abnormal changes were observed in general signs, body weight (BW), or food consumption, and no abnormal findings were observed in the major organs and tissues of either males or females at necropsy. The oral LD50 of PFE was therefore estimated to be higher than 5 g/kg BW. In the subchronic study, PFE was mixed into the diet in place of powdered CRF-1 and administered at concentrations of 0% (control), 0.5%, 1.5%, and 5.0% to male and female Sprague-Dawley rats for 90 d. No mortality or toxicological changes were observed during the experimental period. Blood biochemical, hematological, and urinary parameters revealed no toxicologically significant changes. Furthermore, no anatomical or histopathological changes due to PFE were observed. The no-observed adverse-effect-level of PFE was thus estimated to be 5.0% in the diet (male: 3.0 g/kg BW/d; female: 3.5 g/kg BW/d). PMID:24245900

Takano, Akira; Kamiya, Tomoyasu; Tsubata, Masahito; Ikeguchi, Motoya; Takagaki, Kinya; Kinjo, Junei



Recent studies in the behavioral toxicology of ELF electric and magnetic fields  

SciTech Connect

Behavioral responses to ELF electric and magnetic fields are reviewed starting with the simple sensory awareness or detection by an animal and moving on through more-complicated behavioral responses such as behavior that averts exposure. The literature selected in this review is taken primarily from the area of behavioral toxicology. As such, it does not review work on specialized response systems to ELF fields. The most notable of these omitted specialized response systems are electroreception, which occurs in a number of fish species, and homing/navigation and communication of the location of food that occurs in several species of birds and in honeybees, respectively. The toxicologic orientation of most researches that evaluate the effects of exposure to ELF electric and magnetic fields has been influenced primarily by the missions of DOE and the power industry programs to determine the health effects of power frequency (50- and 60-Hz) electric and magnetic fields. Because of these large programmatic efforts, most of the recent research has in fact been done at 50 or 60 Hz. In the context of the above limitations, remarkably few robust behavioral effects have been reported. Those that have been reported probably relate to an animal's perception of the electric field, although there are some exceptions to this generalization. The apparent lack of deleterious effects in animals is consistent with recent studies on humans that have been conducted in the UK. With this in mind, it is tempting to conclude that exposure to an ELF field is a rather innocuous event and, other than possible mini-shocks, is without hazard. 43 references.

Lovely, R.H.



Implementing preclinical study findings to protocol design: translational studies with alloreactive CTL for gliomas  

PubMed Central

We are accruing patients to a Phase I dose escalation cellular therapy trial (, NCT01144247) involving intratumoral placement of alloreactive cytotoxic T lymphocytes (alloCTL) for recurrent gliomas. The trial is being conducted to confirm the findings of a prior pilot study that indicated this adjuvant therapy may be beneficial in extending survival of recurrent WHO grade III gliomas. To reduce costs of the cellular therapy, we tested a number of synthetic tissue culture media and found the AIM-V growth medium superior for their growth. We also moved the production of the alloCTL from artificial capillary systems to less expensive tissue culture bags. To standardize alloCTL infusates used for therapy, release criteria of ?60% CD3+ and ?60% viability were established that consistently translated to a 4 hr cytotoxicity of ?30% at a 30:1 effector to target ratio. To allow time for completion of quality control testing and transport to the infusion site, we determined that 30,000 IU of human recombinant Interleukin-2 in the cellular infusates sufficiently retained cell viability and cytotoxicity to allow a 10 hr expiration time to be placed on the infusates. We identified a cytotoxic T cell subset, CD3+/CD8+/CD69+, that demonstrated upregulated IFN-? production upon exposure to relevant target cells. The phenotypic identification of this T cell subset was indicative of robust in vitro cytotoxic function and thus will be followed to determine if it correlates with patient immune response to treatment. Finally, other therapeutic agents routinely used for glioma treatment were integrated into an analysis of alloCTL cytotoxic functionality. Temozolomide and bevacizumab do not adversely affect cytotoxic function of the alloCTL in the short-term, thus providing rationale for further investigating combinatorial chemo-immunotherapy for gliomas. PMID:22347526

Hickey, Michelle J; Malone, Colin C; Erickson, Kate E; Gomez, German G; Young, Emma L; Liau, Linda M; Prins, Robert M; Kruse, Carol A



[Classification of results of studying blood plasma with laser correlation spectroscopy based on semiotics of preclinical and clinical states].  


The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented. PMID:9848161

Ternovo?, K S; Kryzhanovski?, G N; Musi?chuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F



Reproducibility of results in preclinical studies: a perspective from the bone field.  


The biomedical research enterprise-and the public support for it-is predicated on the belief that discoveries and the conclusions drawn from them can be trusted to build a body of knowledge which will be used to improve human health. As in all other areas of scientific inquiry, knowledge and understanding grow by layering new discoveries upon earlier ones. The process self-corrects and distills knowledge by discarding false ideas and unsubstantiated claims. Although self-correction is inexorable in the long-term, in recent years biomedical scientists and the public alike have become alarmed and deeply troubled by the fact that many published results cannot be reproduced. The chorus of concern reached a high pitch with a recent commentary from the NIH Director, Francis S. Collins, and Principal Deputy Director, Lawrence A. Tabak, and their announcement of specific plans to enhance reproducibility of preclinical research that relies on animal models. In this invited perspective, we highlight the magnitude of the problem across biomedical fields and address the relevance of these concerns to the field of bone and mineral metabolism. We also suggest how our specialty journals, our scientific organizations, and our community of bone and mineral researchers can help to overcome this troubling trend. © 2014 American Society for Bone and Mineral Research. PMID:24916175

Manolagas, Stavros C; Kronenberg, Henry M



The Optimal Partnership of Radiation and Immunotherapy: from Preclinical Studies to Clinical Translation  

PubMed Central

The main role of the immune system is to restore tissue homeostasis when altered by pathogenic processes, including neoplastic transformation. Immune-mediated tumor rejection has been recognized as an extrinsic tumor suppressor mechanism that tumors need to overcome to progress. By the time a tumor becomes clinically apparent it has successfully escaped immune control by establishing an immunosuppressive microenvironment. Ionizing radiation applied locally to a tumor alters these tumor-host interactions. Accumulating evidence indicates that standard therapeutic doses of radiation have the potential to recover tumor immunogenicity and convert the tumor into an in situ personalized vaccine. Radiotherapy induces an immunogenic tumor cell death promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. In addition, radiotherapy stimulates chemokine-mediated recruitment of effector T cells to the tumor, and cellular recognition and killing by T cells that is facilitated by upregulation of major histocompatibility antigens, NKG2D ligands, adhesion molecules and death receptors. Despite these effects, radiotherapy alone is only rarely capable of generating enough proinflammatory signals to sufficiently overcome suppression, as it can also activate immunosuppressive factors. However, our group and others have shown that when combined with targeted immunotherapy agents radiotherapy significantly contributes to a therapeutically effective anti-tumor immune response. To illustrate this partnership between radiation and immunotherapy we will discuss as an example our experience in preclinical models and the molecular mechanisms identified. Additionally, the clinical translation of these combinations will be discussed. PMID:24937779

Demaria, Sandra; Pilones, Karsten A.; Vanpouille-Box, Claire; Golden, Encouse B.; Formenti, Silvia C.




E-print Network

toxicology § Environmental toxicology § Food/Nutritional toxicology § Genetic toxicology § ImmunologicalGRADUATE GROUP IN MOLECULAR TOXICOLOGY 2013 - 2014 University of California, Berkeley #12;#12;General Information The Interdepartmental Graduate Group in Molecular Toxicology administers the Ph


A new mathematical approach for the estimation of the AUC and its variability under different experimental designs in preclinical studies.  


The aim of the present work was to develop a new mathematical method for estimating the area under the curve (AUC) and its variability that could be applied in different preclinical experimental designs and amenable to be implemented in standard calculation worksheets. In order to assess the usefulness of the new approach, different experimental scenarios were studied and the results were compared with those obtained with commonly used software: WinNonlin® and Phoenix WinNonlin®. The results do not show statistical differences among the AUC values obtained by both procedures, but the new method appears to be a better estimator of the AUC standard error, measured as the coverage of 95% confidence interval. In this way, the new proposed method demonstrates to be as useful as WinNonlin® software when it was applicable. PMID:21268234

Navarro-Fontestad, Carmen; González-Álvarez, Isabel; Fernández-Teruel, Carlos; Bermejo, Marival; Casabó, Vicente Germán



Author's personal copy Toxicology 286 (2011) 6974  

E-print Network

for Disease Control and Prevention, Atlanta, GA 30341, USA b Reproductive Toxicology Branch, Toxicity toxicologic studies suggested that TCC could impair mam- malian reproduction by reducing birth weight and survival rate in rats (Nolen and Dierckman,

Hammock, Bruce D.


Genetic engineering of murine CD8+ and CD4+ T cells for pre-clinical adoptive immunotherapy studies  

PubMed Central

T-cell-receptor (TCR) gene therapy enables for the rapid creation of antigen-specific T cells from mice of any strain and represents a valuable tool for pre-clinical immunotherapy studies. Here, we describe the superiority of gamma-retroviral vectors compared to lentiviral vectors for transduction of murine T cells and surprisingly illustrate robust gene-transfer into phenotypically naïve/memory-stem cell (CD62Lhi/CD44low) and central memory (CD62Lhi/CD44hi) CD8+ T cells using murine-stem-cell-based gamma-retroviral vectors (MSGV1). We created MSGV1 vectors for a MHC-class I restricted T-cell receptor (TCR) specific for the melanocyte-differentiation antigen, gp100 (MSGV1-pmel-1), and a MHC-class II restricted TCR specific for tyrosinase-related-protein-1 (MSGV1-TRP-1), and found that robust gene expression required codon optimization of TCR sequences for the pmel-1 TCR. To test for functionality, we adoptively transferred TCR-engineered T cells into mice bearing B16 melanomas and observed delayed growth of established tumors with pmel-1TCR engineered CD8+ T cells and significant tumor regression with TRP-1 TCR transduced CD4+ T cells. We simultaneously created lentiviral vectors encoding the pmel-1TCR, but found that these vectors mediated low TCR expression in murine T cells, but robust gene expression in other murine and human cell lines. These results indicate that preclinical murine models of adoptive immunotherapies are more practical using gamma-retroviral rather than lentiviral vectors. PMID:21499127

Kerkar, Sid P; Sanchez-Perez, Luis; Yang, Shicheng; Borman, Zachary; Muranski, Pawel; Ji, Yun; Chinnasamy, Dhanalakshmi; Kaiser, Andrew DM; Hinrichs, Christian; Klebanoff, Christopher A; Scott, Christopher; Gattinoni, Luca; Morgan, Richard A; Rosenberg, Steven A; Restifo, Nicholas P



Toxicologic evaluation of Dichrostachys glomerata extract: subchronic study in rats and genotoxicity tests.  


In western Cameroon, edible fruits and seeds from the plant Dichrostachys glomerata are commonly used as spices. Extract from the fruit pods has been reported as a good natural source of antioxidants and may provide health benefits. The objective of the present study was to investigate potential adverse effects, if any, of D. glomerata fruit pod extract (Dyglomera™) in a subchronic toxicity study and in genotoxicity studies. In the toxicity study, Sprague Dawley rats (20/sex/group) were gavaged with D. glomerata extract at dose levels of 0, 100, 1000 and 2500 mg/kg body weight (bw)/day for 90-days. Dyglomera™ administration did not result in mortality or show treatmentrelated changes in clinical signs of toxicity, body weights, body weight gain or feed consumption. Similarly, no toxicologically significant treatment-related changes in hematological, clinical chemistry, urine analysis parameters, and organ weights were noted. Macroscopic and microscopic examinations did not reveal treatment-related abnormalities. Mutagenic and clastogenic potentials as evaluated by Ames assay, in vitro and in vivo chromosomal aberration test and in vivo micronucleus test did not reveal any genotoxicity of the extract. The results of subchronic toxicity study supports the no-observed-adverse-effect level (NOAEL) for D. glomerata extract as 2500 mg/kg bw/day, the highest dose tested. PMID:24713264

Kothari, Shil C; Shivarudraiah, Prasad; Venkataramaiah, Suresh Babu; Gavara, Swapna; Arumugam, Shri Natrajan; Soni, Madhu G



Physical and chemical characterization of mn phosphate/sulfate mixture used in an inhalation toxicology study.  


The use of methylcyclopentadienyl manganese tricarbonyl (MMT) in unleaded gasoline has given rise to numerous debates on the potential public health risk associated with manganese emissions. In fact, combustion products are mainly Mn phosphate, Mn sulfate, and Mn phosphate/sulfate mixture. Our research group did several inhalation studies in order to assess the toxicity of each Mn species. The objective of this study is to determine the physical and the chemical characteristics of a mixture of Mn phosphate/sulfate used in one of these inhalation toxicology studies. First, the mixture was analyzed by X-ray diffraction in order to obtain the specific peak of Mn phosphate and Mn sulfate. These peaks were used as reference. Second, samples of the mixture were collected on filters in the inhalation chamber at a concentration level of 3000 microg/m(3). They were analyzed by scanning electron microscopy (SEM), analytical transmission electron microscopy (ATEM), and x-ray energy-dispersive spectrometry (EDS) to show their size, morphology, and chemical composition. Results indicate that 33% of the particles were found to be agglomerated, while free particles accounted for 44% for Mn phosphate and 23% for Mn sulfate. PMID:15204770

Beaupré, Linda A; Salehi, Fariba; Zayed, Joseph; Plamondon, Philippe; L'Espérance, Gilles



Aerospace Toxicology and Microbiology  

NASA Technical Reports Server (NTRS)

Toxicology dates to the very earliest history of humanity with various poisons and venom being recognized as a method of hunting or waging war with the earliest documentation in the Evers papyrus (circa 1500 BCE). The Greeks identified specific poisons such as hemlock, a method of state execution, and the Greek word toxos (arrow) became the root of our modern science. The first scientific approach to the understanding of poisons and toxicology was the work during the late middle ages of Paracelsus. He formulated what were then revolutionary views that a specific toxic agent or "toxicon" caused specific dose-related effects. His principles have established the basis of modern pharmacology and toxicology. In 1700, Bernardo Ramazzini published the book De Morbis Artificum Diatriba (The Diseases of Workers) describing specific illnesses associated with certain labor, particularly metal workers exposed to mercury, lead, arsenic, and rock dust. Modern toxicology dates from development of the modern industrial chemical processes, the earliest involving an analytical method for arsenic by Marsh in 1836. Industrial organic chemicals were synthesized in the late 1800 s along with anesthetics and disinfectants. In 1908, Hamilton began the long study of occupational toxicology issues, and by WW I the scientific use of toxicants saw Haber creating war gases and defining time-dosage relationships that are used even today.

James, John T.; Parmet, A. J.; Pierson, Duane L.



The Route to Drug Development Preclinical  

E-print Network

The Route to Drug Development Preclinical Studies in rodents (and other animal species) looking pancreas after every meal, making us feel full. After pre-clinical testing on rats, the team, led by Dr John McMichael Centre on 020 8383 8082. Is this the end of obesity? First time in human trials begin


Recent studies in the behavioral toxicology of ELF electric and magnetic fields.  


Behavioral responses to ELF electric and magnetic fields are reviewed starting with the simple sensory awareness or detection by an animal and moving on through more-complicated behavioral responses such as behavior that averts exposure. The literature selected in this review is taken primarily from the area of behavioral toxicology. As such, it does not review work on specialized response systems to ELF fields. The most notable of these omitted specialized response systems are electroreception, (see Kalmijn, this volume), which occurs in a number of fish species, and homing/navigation and communication of the location of food that occurs in several species of birds and in honeybees, respectively. The toxicologic orientation of most researches that evaluate the effects of exposure to ELF electric and magnetic fields has been influenced primarily by the "missions" of DOE and the power industry programs to determine the health effects of power frequency (50- and 60-Hz) electric and magnetic fields. Because of these large programmatic efforts, most of the recent research has in fact been done at 50 or 60 Hz. In the context of the above limitations, remarkably few robust behavioral effects have been reported. Those that have been reported probably relate to an animal's perception of the electric field, although there are some exceptions to this generalization. The apparent lack of deleterious effects in animals is consistent with recent studies on humans that have been conducted in the UK. With this in mind, it is tempting to conclude that exposure to an ELF field is a rather innocuous event and, other than possible mini-shocks, is without hazard. However, if this is the case, then what sense are we to make of reports of altered neural function (other than behavior) that result from exposure to ELF fields (e.g., suppressed melatonin and SNAT activity in the rat pineal; efflux of calcium ions from brain cortices; histological change in the cerebellum and hippocampus following perinatal exposure, etc.)? Are these neural effects no more than "noise" to the behaving organism? Possible reasons form the disparity between cell biology, neurochemistry, and behavior have been presented in this chapter, and based on the hypothesized reasons for the existing disparity, a number of experiments were suggested. PMID:3278329

Lovely, R H



Unscheduled deoxyribonucleic acid (DNA) synthesis assays for toxicological studies. May 1977-March 1990 (A Bibliography from the NTIS data base). Report for May 1977-March 1990  

SciTech Connect

This bibliography contains citations concerning the unscheduled DNA synthesis (UDS) assay for toxicological studies. UDS assays provide very sensitive measures of damage to DNA by detecting induction of DNA synthesis in non-S-phase cells. UDS toxicological studies analyzing gamma radiation, drugs, pesticides, nerve gas, jet engine fuels, ultraviolet light, chlorated organic compounds, and aromatic compounds are discussed. UDS studies using both human and animal tissue cultures are described. (Contains 57 citations fully indexed and including a title list.)

Not Available



Studies on the Toxicological Effects of PFOA and PFOS on Rats Using Histological Observation and Chemical Analysis  

Microsoft Academic Search

As an emerging class of environmentally persistent and bioaccumulative contaminants, perfluorinated compounds (PFCs), especially\\u000a perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), have been ubiquitously found in the environment. Increasing\\u000a evidence shows that the accumulated levels of PFCs in animals and the human body might cause potential impairment to their\\u000a health. In the present study, toxicological effects of PFOA and PFOS

Lin Cui; Qun-fang Zhou; Chun-yang Liao; Jian-jie Fu; Gui-bin Jiang



Toxicological studies of "Chondrokola Rosh", an Ayurvedic preparation on liver function tests of rats.  


Chondrokola Rosh (CKR) is a traditional metallic Ayurvedic preparation widely used by the rural and ethnic people of Bangladesh in dysuria. It is a preparation of various roasted metals (Hg and Cu), non-metal (sulphur and Mica) and medicinal herbs. Considering the controversy over the risk of toxic heavy metals in Ayurvedic herbo-mineral preparations, toxicological parameters on liver functions were investigated. A single dose of 100mg/kg body weight of the preparation was administered orally to the rats of both sexes for ninety days. In this evaluation a statistically significant (p<0.001) increase of serum albumin levels in male (17%) and female (15%) rat groups were observed. On the other hand, the plasma bilirubin level was decreased 50% and 28% respectively in both rats groups. But no remarkable differences were observed in plasma protein, sGPT, sGOT and ALP activities from their corresponding control values. This study showed that CKR had no remarkable toxic effect on liver of the animals despite the presence of traces of transformed heavy metals. PMID:22754071

Nasrin, S; Bachar, S C; Choudhuri, M S K



Preclinical study of using multiphoton microscopy to diagnose liver cancer and differentiate benign and malignant liver lesions  

NASA Astrophysics Data System (ADS)

Recently, the miniaturized multiphoton microscopy (MPM) and multiphoton probe allow the clinical use of multiphoton endoscopy for diagnosing cancer via ``optical biopsy''. The purpose of this study was to establish MPM optical diagnostic features for liver cancer and evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis. Firstly, we performed a pilot study to establish the MPM diagnostic features by investigating 60 surgical specimens, and found that high-resolution MPM images clearly demonstrated apparent differences between benign and malignant liver lesions in terms of their tissue architecture and cell morphology. Cancer cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, were identified by MPM images, which were comparable to hematoxylin-eosin staining images. Secondly, we performed a blinded study to evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis by investigating another 164 specimens, and found that the sensitivity, specificity, and accuracy of MPM diagnosis was 96.32%, 96.43%, and 96.34%, respectively. In conclusion, it is feasible to use MPM to diagnose liver cancer and differentiate benign and malignant liver lesions. This preclinical study provides the groundwork for further using multiphoton endoscopy to perform real-time noninvasive ``optical biopsy'' for liver lesions in the near future.

Yan, Jun; Zhuo, Shuangmu; Chen, Gang; Wu, Xiufeng; Zhou, Dong; Xie, Shusen; Jiang, Jiahao; Ying, Mingang; Jia, Fan; Chen, Jianxin; Zhou, Jian



The minipig in toxicology.  


The use of pigs (Sus scrofa) in biomedical research is well established in particular in surgical and physiological research. For years both pigs and minipigs have been used in pharmacology and toxicology to answer specific questions when the more conventional species have been found unsuitable. The development of minipigs has resulted in strains of more manageable size than the domestic pig. Because of their well-accepted physiological and other similarities to humans, minipigs are becoming increasingly attractive toxicological and pharmacological models. There are several strains of minipigs (Göttingen, Yucatan, Sinclair, Hanford and other). This presentation is based on experience primarily with the Göttingen minipigs. In toxicology in Europe minipigs have become very popular for pharmaceutical studies in place of dogs and primates. Minipigs have been shown to be sensitive to a wide variety of drugs and chemicals. It has become obvious that minipigs can be used for all routes of administration, and in many cases are preferable to dogs or primates for metabolic or pharmacological reasons. There are advantages over the traditional non-rodent species in relation to specific responses to particular drug classes. Their use in general toxicology testing employing the continuous intravenous infusion, dermal or inhalation route has been described in detail in the literature. Background data on toxicological endpoints (ophthalmology, clinical pathology, ECG, organ weight, histopathology and reproduction parameters) have been well-established allowing studies to be interpreted. In the context of this conference, histopathology and toxicopathology data of spontaneous or drug-induced origin are available in the scientific literature. Now there is good supply of high-quality minipigs of known disease status. There are advantages over the traditional non-rodent species in relation to the ethical difficulties of use of animals in biomedical research. Consequently, there are scientific, economic and sociological reasons that make minipigs good toxicological and pharmacological models. The principal disadvantage is that toxicity testing in minipigs may require more test compound than the traditional species. PMID:16725317

Svendsen, Ove



Preclinical studies of N3-O-toluyl-fluorouracil-loaded lipid-based nanosuspensions in H22-bearing mice  

PubMed Central

Purpose N3-O-toluyl-fluorouracil (TFU) is a potential antitumor prodrug of 5-fluorouracil (5-FU), but its poor solubility has limited its use in clinic. This study aimed to improve the bioavailability of TFU by preparing TFU-loaded lipid-based nanosuspensions (TFU-LNS) and perform a preclinical evaluation. Methods TFU-LNS were prepared through high-pressure homogenization and were lyophilized afterwards. For in vitro test, the physicochemical properties and cytotoxicity against HegG2 cells were conducted. For in vivo evaluation, the pharmacokinetics, tissue distribution, and antitumor efficacy were investigated in H22-bearing Kunming mice. Results TFU showed different degradability in four media; in particular, nearly all of it converted to an equimolar amount of 5-FU in blank plasma of Wistar rats. The lyophilized TFU-LNS had a mean particle size of 180.03±3.11 nm and zeta potential of ?8.02±1.43 mV and showed no discernible changes after storage at 4°C for 3 months. In the in vivo antitumor study, the antitumor efficacy of TFU-LNS was consistent with that of 5-FU injection. Furthermore, TFU-LNS released a lower concentration of 5-FU in heart and kidney throughout the tissue distribution studies. Conclusion TFU-LNS exhibited convincing antitumor activity and easy scale-up opportunity, which suggests that TFU-LNS might be a promising drug delivery system for cancer therapy. PMID:24920908

Zhang, Juan; Li, Min; Liu, Zhihong; Wang, Lili; Liu, Yongjun; Zhang, Na



Photodynamic therapy with the phthalocyanine photosensitizer Pc 4: The case experience with preclinical mechanistic and early clinical-translational studies  

SciTech Connect

Photodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancers. PDT involves either local or systemic administration of a photosensitizing drug, which preferentially localizes within the tumor, followed by illumination of the involved organ with light, usually from a laser source. Here, we provide a selective overview of our experience with PDT at Case Western Reserve University, specifically with the silicon phthalocyanine photosensitizer Pc 4. We first review our in vitro studies evaluating the mechanism of cell killing by Pc 4-PDT. Then we briefly describe our clinical experience in a Phase I trial of Pc 4-PDT and our preliminary translational studies evaluating the mechanisms behind tumor responses. Preclinical work identified (a) cardiolipin and the anti-apoptotic proteins Bcl-2 and Bcl-xL as targets of Pc 4-PDT, (b) the intrinsic pathway of apoptosis, with the key participation of caspase-3, as a central response of many human cancer cells to Pc 4-PDT, (c) signaling pathways that could modify apoptosis, and (d) a formulation by which Pc 4 could be applied topically to human skin and penetrate at least through the basal layer of the epidermis. Clinical-translational studies enabled us to develop an immunohistochemical assay for caspase-3 activation, using biopsies from patients treated with topical Pc 4 in a Phase I PDT trial for cutaneous T-cell lymphoma. Results suggest that this assay may be used as an early biomarker of clinical response.

Miller, Janine D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Baron, Elma D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Louis-Stokes VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106 (United States); Scull, Heather [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Hsia, Andrew [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Berlin, Jeffrey C. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Department of Chemistry, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States)] (and others)



A critique of biomarkers in environmental toxicology: A case study in birds  

SciTech Connect

The authors have been testing the hypothesis that exposure to elevated levels of 2,3,7,8-TCDD and similarly-acting compounds derived from pulp mill effluent adversely affects the reproductive capacity of colonies of great blue herons and double crested cormorants in the local area. Their objectives included developing quantitative TCDD dose-response curves for various toxicologically relevant endpoints in birds, with the goal of finding an appropriate environmental biomarker of dioxin exposure and toxicity. Potential biomarkers studied included ethoxyresorufin O-deethylase (EROD) as a measure of cytochrome P-450 1-A activity, and various hormonally-relevant end-points as measures of dioxin toxicity. The animal model used was the newly hatched chick, after in ovo exposure either in the laboratory or from the environment. Because the TEQ approach is based to a large extent on the use of in vitro and in vivo biomarkers, this study provides a useful example of one of the simplest in vivo models. The authors were able to construct hepatic EROD dose-response curves from the environmentally exposed heron and cormorant chicks, and from TCDD egg injections both early and late in the incubation period. Domestic chicken and pigeons were used as control species. The EROD induction data from the late injection pigeon study was very helpful for predicting appropriate doses for use in the early injection experiments, and for the wild avian species. However, the data was too limited to use for accurately predicting such endpoints as mortality, or effects at the lower end of the dose-response curves. Using various toxic equivalency factors, TEQs for the environmental data were calculated, and compared to the laboratory derived dose-response curves for TCDD. Using specific examples from this environmental case study, the strengths and weaknesses of the use of biomarkers and the TEQ approach will be discussed.

Bellward, G.D. [Univ. of British Columbia, Vancouver, British Columbia (Canada)



Forensic toxicology  

Microsoft Academic Search

\\u000a Forensic toxicology has developed as a forensic science in recent years and is now widely used to assist in death investigations,\\u000a in civil and criminal matters involving drug use, in drugs of abuse testing in correctional settings and custodial medicine,\\u000a in road and work-place safety, in matters involving environmental pollution, as well as in sports doping. Drugs most commonly\\u000a targeted

Olaf H. Drummer


Common Handling Procedures Conducted in Preclinical Safety Studies Result in Minimal Hepatic Gene Expression Changes in Sprague-Dawley Rats  

PubMed Central

Gene expression profiling is a tool to gain mechanistic understanding of adverse effects in response to compound exposure. However, little is known about how the common handling procedures of experimental animals during a preclinical study alter baseline gene expression. We report gene expression changes in the livers of female Sprague-Dawley rats following common handling procedures. Baseline gene expression changes identified in this study provide insight on how these changes may affect interpretation of gene expression profiles following compound exposure. Rats were divided into three groups. One group was not subjected to handling procedures and served as controls for both handled groups. Animals in the other two groups were weighed, subjected to restraint in Broome restrainers, and administered water via oral gavage daily for 1 or 4 days with tail vein blood collections at 1, 2, 4, and 8 hours postdose on days 1 and 4. Significantly altered genes were identified in livers of animals following 1 or 4 days of handling when compared to the unhandled animals. Gene changes in animals handled for 4 days were similar to those handled for 1 day, suggesting a lack of habituation. The altered genes were primarily immune function related genes. These findings, along with a correlating increase in corticosterone levels suggest that common handling procedures may cause a minor immune system perturbance. PMID:24551150

Werner, Jon; Everds, Nancy; Di Palma, Chris; Chen, Yuan; Higgins-Garn, Marnie; Tran, Sandra; Afshari, Cynthia A.; Hamadeh, Hisham K.



Chimeric rodents with humanized liver: bridging the preclinical/clinical trial gap in ADME/toxicity studies.  


1. Immunocompromised mice with humanized livers were developed in the mid-1990s to allow the study of human hepatotropic viruses, which normally replicate only in higher primates. The production of the uPA/SCID mouse was the vanguard of these models and remains the most widely worked upon model for an ever increasing range of applications. 2. Since toxicology is conducted in laboratory animal species with the implicit intent of predicting the outcome of accidental, or intentional, human exposure, the potential for using an in vivo model with a humanised metabolism opens up the possibility of better predicting the human response following exposure to drugs and industrial chemicals. Chimeric humanised mice provide the tool for bridging between the non-clinical laboratory safety and metabolism studies, carried out in rodent and non-rodent species, and the first in man clinical trials. 3. Chimeric mice carrying a human liver have now been validated against a wide range of different drugs and chemical classes, and have been shown to clearly differentiate metabolically from the recipient mouse, and to show metabolic pathways more similar to those expected from human liver. 4. This review critically appraises the available animal models carrying human livers and where future developments would improve the existing systems. PMID:24320885

Foster, John R; Lund, Garry; Sapelnikova, Svetlana; Tyrrell, D Lorne; Kneteman, Norman M



Indoor and outdoor airborne particles. An in vitro study on mutagenic potential and toxicological implications  

Microsoft Academic Search

Introduction<\\/strong>Air pollution components are present as gases and as particulate matter. As particle deposition takes place in various parts of the respiratory system particulate matter may have other toxicological implications than gaseous pollutants, which all may penetrate in the lower part of the respiratory tract. In addition, suspended particulate matter represents a group of pollutants of variable physical as well

Houdt van J. J



Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics  

PubMed Central

Preclinical toxicology studies are performed prior to phase I trials with novel cancer therapeutics to identify a safe clinical starting dose and potential human toxicities. The primary aim of this study was to evaluate the ability of rodent-only toxicology studies to identify a safe phase I trial starting dose. In addition, the ability of murine studies to predict the quantitative and qualitative human toxicology of cancer therapeutics was studied. Data for 25 cancer drugs were collated for which the preclinical and clinical routes and schedules of administration were either the same (22/25), or closely matched. The maximum tolerated dose/dose lethal to 10% of mice (MTD/LD10) was identified for 24 drugs, and in patients the maximum administered dose (MAD) was associated with dose-limiting toxicity (DLT) in initial clinical trials with 20 compounds. In addition, for 13 agents, the toxicity of the drug at one-tenth the mouse MTD/LD10 was also investigated in rats, following repeated administration (20 doses). A phase I trial starting dose of one-tenth the mouse MTD/LD10 (mg m–2) was, or would have been, safe for all 25 compounds. With the exception of nausea and vomiting, which cannot be assessed in rodents, other common DLTs were accurately predicted by the murine studies (i.e. 7/7 haematological and 3/3 neurological DLTs). For two of the 13 drugs studied in rats, repeated administration of one-tenth the mouse MTD/LD10 was toxic, leading to a reduction in the phase I trial starting dose; however, one-tenth the mouse MTD/LD10 was subsequently tolerated in patients. For the 20 drugs where clinical DLT was reached, the median ratio of the human MAD to the mouse MTD/LD10 was 2.6 (range 0.2–16) and the median ratio of the clinical starting dose to the MAD was 35 (range 2.3–160). In contrast, in 13 subsequent phase I trials with 11 of the initial 25 drugs, the median ratio of the clinical starting dose to the MAD was 2.8 (range 1.6–56), emphasizing the value of early clinical data in rapidly defining the dose range for therapeutic studies. For all 25 drugs studied, rodent-only toxicology provided a safe and rapid means of identifying the phase I trial starting dose and predicting commonly encountered DLTs. This study has shown that the routine use of a non-rodent species in preclinical toxicology studies prior to initial clinical trials with cancer therapeutics is not necessary. © 1999 Cancer Research Campaign PMID:10555743

Newell, D R; Burtles, S S; Fox, B W; Jodrell, D I; Connors, T A



Inhalation developmental toxicology studies: Teratology study of 1,3-butadiene in mice: Final report  

SciTech Connect

Maternal toxicity, reproductive performance and developmental toxicology were evaluated in CD-1 mice following whole-body, inhalation exposures to 0, 40, 200 and 1000 ppM of 1,3-butadiene. The female mice, which had mated with unexposed males were exposed to the chemical for 6 hours/day on 6 through 15 dg and sacrificed on 18 dg. Maternal animals were weighed prior to mating and on 0, 6, 11 and 18 dg; the mice were observed for mortality, morbidity and signs of toxicity during exposure and examined for gross tissue abnormalities at necropsy. Live fetuses were weighed and subjected to external, visceral and skeletal examinations to detect growth retardation and morphologic anomalies. Significant concentration-related decreases were detected in a number of maternal body weight measures. There was a significant concentration-related depression of fetal body weights and placental weights. Body weights of male fetuses of all exposed groups were significantly lower than values for control fetuses; weights of female fetuses were significantly depressed in the mice exposed to 200 and 1000 ppM. In the 200- and 1000-ppM exposure groups, weights of placentas of male fetuses were significantly decreased, but placental weights of female fetuses were significantly affected only in litters exposed to the highest 1,3-butadiene concentration. This exposure regimen produced significant signs of maternal toxicity at concentrations of 200 and 1000 ppM 1,3-butadiene.

Hackett, P.L.; Sikov, M.R.; Mast, T.J.; Brown, M.G.; Buschbom, R.L.; Clark, M.L.; Decker, J.R.; Evanoff, J.J.; Rommereim, R.L.; Rowe, S.E.; Westerberg, R.B.



Toxicology 1: Toxicology and Living Systems  

NSDL National Science Digital Library

In the first lesson, Toxicology 1: Toxicology and Living Systems, students are introduced to the basic concepts and terminology of the science. Toxicology 2: Finding the Toxic Dose allows students the opportunity to conduct a toxicology experiment on a plant. Specifically, students determine the toxic dose of a chemical that will inhibit seed germination in Brassica rapa, a relative to cabbages and mustards. In the third lesson, Toxicology 3: Toxicology and Human Health, students investigate the effect of environmental tobacco smoke on human lung development. These lessons can be done in a series or they can stand alone.

American Association for the Advancement of Science (;)



Toxicological Evaluation of Realistic Emission Source Aerosols (TERESA)-power plant studies: assessment of cellular responses  

PubMed Central

The Toxicological Evaluation of Realistic Emission Source Aerosols (TERESA) project assessed primary and secondary particulate by simulating the chemical reactions that a plume from a source might undergo during atmospheric transport and added other atmospheric constituents that might interact with it. Three coal-fired power plants with different coal and different emission controls were used. Male Sprague-Dawley rats were exposed for 6 h to either filtered air or aged aerosol from the power plant. Four exposure scenarios were studied: primary particles (P); primary + secondary (oxidized) particles (PO); primary + secondary (oxidized) particles + SOA (POS); and primary + secondary (oxidized) particles neutralized + SOA (PONS). Exposure concentrations varied by scenario to a maximum concentration of 257.1 ± 10.0 µg/m3. Twenty-four hours after exposure, pulmonary cellular responses were assessed by bronchoalveolar lavage (BAL), complete blood count (CBC), and histopathology. Exposure to the PONS and POS scenarios produced significant increases in BAL total cells and macrophage numbers at two plants. The PONS and P scenarios were associated with significant increases in BAL neutrophils and the presence of occasional neutrophils and increased macrophages in the airways and alveoli of exposed animals. Univariate analyses and random forest analyses showed that increases in total cell count and macrophage cell count were significantly associated with neutralized sulfate and several correlated measurements. Increases in neutrophils in BAL were associated with zinc. There were no significant differences in CBC parameters or blood vessel wall thickness by histopathology. The association between neutrophils increases and zinc raises the possibility that metals play a role in this response. PMID:21466245

Godleski, John J.; Diaz, Edgar A.; Lemos, Miriam; Long, Mark; Ruiz, Pablo; Gupta, Tarun; Kang, Choong-Min; Coull, Brent



A comparative study of the toxicological aspects of vanadium pentoxide and vanadium oxide nanoparticles.  


Abstract Indiscriminate use of vanadium oxide nanoparticles (NPs) in steel industries and their release during combustion of fossil fuels makes it essential to study their toxic potential. Herein, we assessed the toxicological effects of two types of in-house synthesized vanadium oxide NPs in Wistar rats exposed to NPs through inhalation route. V2O5 and VO2 NPs exhibited rod and spherical symmetry, respectively with a mean diameter of 50?±?20 and 30?±?10?nm. Assessment of bronchoalveolar lavage fluid parameters demonstrated that VO2 NP-exposed animals had higher levels of lactate dehydrogenase, gamma-glutamyl transpeptidase and alkaline phosphatase as compared to V2O5 NP-exposed animals. The levels of oxidative stress markers malondialdehyde and reduced glutathione also indicated higher toxic potential of VO2 NPs. Moreover, after 7-day recovery, the levels of the above parameters were closer to normal levels only in V2O5-exposed animals. Interestingly, histopathological and immune-histopathology analysis (TNF-?) of lung tissue showed higher damage and inflammatory response in VO2 NP-exposed animals, which persisted even after 7 days of recovery period. Surprisingly, the carcinogenic potential of vanadium oxide NPs came into light which was indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay as well as the decreased levels of p53 and Bax, in lung tissue of NP-exposed animals. Notably, the physiochemical characterization of NPs, especially the shape and the size, play a central role in shaping the toxicity of these NPs and thus should be extensively evaluated for outlining the regulatory guidelines. PMID:25296879

Kulkarni, Apoorva; Kumar, Goru Santosh; Kaur, Jasmine; Tikoo, Kulbhushan



Toxicology and Carcinogenesis Studies of Dichlorvos (CAS NO. 62-73-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).  

National Technical Information Service (NTIS)

Toxicology and carcinogenesis studies of dichlorvos were conducted by administering 0, 4, or 8 mg/kg dichlorvos in corn oil by gavage 5 days per week for 103 weeks to groups of 50 F344/N rats of each sex. Groups of 50 male B6C3F1 mice were administered 0,...

P. C. Chan



Pre-Clinical Atherosclerosis due to HIV Infection: Carotid Intima-Medial Thickness Measurements from the FRAM Study  

PubMed Central

Background Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors. Methods Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors. Results For internal carotid, mean IMT was 1.17±0.50mm for HIV-infected participants and 1.06±0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm). Conclusions Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking. PMID:19455012

Grunfeld, C.; Delaney, J.A.C.; Wanke, C.; Currier, J.S.; Scherzer, R.; Biggs, M. L.; Tien, P.; Shlipak, M.; Sidney, S.; Polak, J.F.; O'Leary, D.; Bacchetti, P.; Kronmal, R.



Toxicology of Biodiesel Combustion products  

EPA Science Inventory

1. Introduction The toxicology of combusted biodiesel is an emerging field. Much of the current knowledge about biological responses and health effects stems from studies of exposures to other fuel sources (typically petroleum diesel, gasoline, and wood) incompletely combusted. ...


Choosing preclinical study models of diabetic retinopathy: key problems for consideration  

PubMed Central

Diabetic retinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR.

Mi, Xue-Song; Yuan, Ti-Fei; Ding, Yong; Zhong, Jing-Xiang; So, Kwok-Fai



A Preclinical Study Combining the DNA Repair Inhibitor Dbait with Radiotherapy for the Treatment of Melanoma1  

PubMed Central

Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of “palliative” RT (10 × 3 Gy) or “radical” RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the “palliative” protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67 days] or the “radical” protocol (TGD by 3.2-fold; median survival: 221 vs 109 days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial). PMID:25379020

Biau, Julian; Devun, Flavien; Jdey, Wael; Kotula, Ewa; Quanz, Maria; Chautard, Emmanuel; Sayarath, Mano; Sun, Jian-Sheng; Verrelle, Pierre; Dutreix, Marie



A preclinical study of the effects of seabuckthorn (Hippophae rhamnoides L.) leaf extract on cutaneous wound healing in albino rats.  


Hippophae rhamnoides L. (family Elaeagnaceae), commonly known as seabuckthorn, is a wild shrub growing at high altitude (1200-4500 meters) in adverse climatic conditions. The aim of the present study was to evaluate healing potential of seabuckthorn leaves in a preclinical study on rats using a cutaneous excision-punch wound model. Four full-thickness excision-type wounds of 8.0 mm diameter were created on the dorsal surface of rats under aseptic conditions. The aqueous lyophilized extract of seabuckthorn leaves, at doses of 0.5%, 1.0%, and 1.5% w/v prepared in propylene glycol, were applied topically twice daily for 7 days. Control animals received the vehicle alone in an identical manner. Wound granulation tissues were excised on eighth day postwounding, and the hydroxyproline, hexosamine, total protein content, and antioxidant levels were determined. Wound surface area was also measured on the eighth day before wound excision to determine wound contraction. Topical application of 1.0% seabuckthorn leaf extract statistically significantly augmented the healing process, as evidenced by increases in the content of hydroxyproline and protein as well as the reduction in wound area when compared with similar effects in response to treatment using povidone-iodine ointment (standard care). The reduced glutathione, vitamin C, superoxide dismutase, catalase, and glutathione peroxidase activities showed significant increases in seabuckthorn leaf extract-treated wounds as compared to controls. The lipid peroxide levels were significantly decreased in leaf extract-treated wounds. The results suggest that aqueous leaf extract of seabuckthorn promotes wound healing, which may be due to increased antioxidant levels in the granulation tissue. PMID:15911921

Gupta, Asheesh; Kumar, Ratan; Pal, Karan; Banerjee, Pratul K; Sawhney, Ramesh C



Some pharmacologic and toxicologic studies on rhazya stricta decne in rats, mice and rabbits  

Microsoft Academic Search

1.1. This work examines some in vivo and in vitro pharmacologic and toxicologic effects of extracts of Rhazya stricta, a medicinal plant in the United Arab Emirates.2.2.R. stricta extracts at doses of 0.1–10 mg reduced the mean arterial blood pressure (MBP) of anesthetized rats in a dose-dependent manner. The depressor effect was partially sensitive to atropine (5 ?M). Although the

M. O. M. Tanira; B. H. Ali; A. K. Bashir; I. Chandranath



Preclinical Studies and Clinical Correlation of the Effect of Alkylating Dose1  

Microsoft Academic Search

Dose-response studies were performed with the alkylating agents (nitrogen mustard, \\/V,Ar'-bis(2-chloroethyl)-AI-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and tri- methyleneiminethiophosphoramide) in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSalIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, mel phalan, and 4-HC In vitro produced low levels (6.5- to 9-fold) of drug resistance, despite

Emil Frei; Beverly A. Teicher; Sylvia A. Holden; Kathleen N. S. Cathcart; Yenyun Wang



Assessment of cell sheets derived from human periodontal ligament cells: a pre-clinical study  

Microsoft Academic Search

Periodontal-ligament-derived cells (PDL cells) have stem-cell-like properties and, when implanted into periodontal defects\\u000a in vivo, can induce periodontal regeneration including the formation of new bone, cementum, and periodontal ligament. We have\\u000a previously demonstrated that PDL cell sheets, harvested from temperature-responsive cell culture dishes, have a great potential\\u000a for periodontal regeneration. The purpose of this study has been to validate the

Kaoru Washio; Takanori Iwata; Manabu Mizutani; Tomohiro Ando; Masayuki Yamato; Teruo Okano; Isao Ishikawa



Novel sugar esters proniosomes for transdermal delivery of vinpocetine: Preclinical and clinical studies  

Microsoft Academic Search

Vinpocetine (Vin) existing oral formulations suffer poor bioavailability (?7%) since Vin undergoes a marked first-pass effect (?75%) and its absorption is dissolution rate-limited. In this study, a novel sustained release proniosomal system was designed using sugar esters (SEs) as non-ionic surfactants in which proniosomes were converted to niosomes upon skin water hydration following topical application under occlusive conditions. Different in

Hanan M. El-Laithy; Omar Shoukry; Laila G. Mahran



Revising the high-density lipoprotein targeting strategies - Insights from human and preclinical studies.  


Abstract In recent years, the high-density lipoprotein (HDL) hypothesis has been challenged. Several completed randomized clinical trials continue to fall short in demonstrating HDL, or at least HDL-cholesterol (HDL-C) levels, as being a consistent target in the prevention of cardiovascular diseases. However, population studies and findings in lipid modifying trials continue to strongly support HDL-C as a superb risk predictor. It is increasingly evident that the complexity of HDL metabolism confounds the use of HDL-C concentration as a unified target. However, important insights continue to emerge from the post hoc analyses of recently completed (i) fibrate-based FIELD and ACCORD trials, including the unexpected beneficial effect of fibrates in microvascular diseases, (ii) the niacin-based AIM-HIGH and HPS2-THRIVE studies, (iii) recombinant HDL-based as well as (iv) the completed CETP inhibitor-based trials. These together with on-going mechanistic studies on novel pathways, which include the unique roles of microRNAs, post-translational remodeling of HDL and novel pathways related to HDL modulators will provide valuable insights to guide how best to refocus and redesign the conceptual framework for selecting HDL-based targets. PMID:25115413

Nesan, Dinushan; Ng, Dominic S



AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models  

PubMed Central

Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1st or 2nd decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM. PMID:23667438

Vasireddy, Vidyullatha; Kohnke, Monika; Black, Aaron D.; Alexandrov, Krill; Zhou, Shangzhen; Maguire, Albert M.; Chung, Daniel C.; Mac, Helen; Sullivan, Lisa; Gadue, Paul; Bennicelli, Jeannette L.; French, Deborah L.; Bennett, Jean



Neural Stem Cell-Mediated Enzyme-Prodrug Therapy for Glioma: Preclinical Studies  

PubMed Central

High-grade gliomas are extremely difficult to treat because they are invasive and therefore are not curable by surgical resection; the toxicity of currently chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles that can target enzyme/prodrug therapy selectively to tumors. We have used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the tumor-localized prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, indicating that these cells are genetically and functionally stable. In vivo biodistribution studies demonstrated that these NSCs retained tumor tropism, even in mice pre-treated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor bearing, and in orthotopic glioma-bearing, immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was approximately one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, non-toxic and effective in mice. These data have led to approval of a first-inhuman study of an allogeneic NSC-mediated enzyme/prodrug targeted cancer therapy in patients with recurrent high-grade glioma. PMID:23658244

Aboody, Karen S.; Najbauer, Joseph; Metz, Marianne Z.; D'Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J.; Synold, Timothy W.; Couture, Larry A.; Blanchard, Suzette; Moats, Rex A.; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V.; Frank, Richard T.; Barish, Michael E.; Brown, Christine E.; Kim, Seung U.; Badie, Behnam; Portnow, Jana



Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trials.  


Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) transgenic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining pharmacokinetic with efficacy data. The efficacy of five currently marketed statins (atorvastatin, simvastatin, lovastatin, pravastatin, and rosuvastatin) in hypercholesterolemic patients (low-density lipoprotein ? 160 mg/dl) was ranked based on meta-analysis of published human trials. Additionally, a preclinical combined PK efficacy data set for these five statins was established in E3L mice that were fed a high-cholesterol diet for 4 weeks, followed by 6 weeks of drug intervention in which statins were supplemented to the diet. Plasma and tissue levels of the statins were determined on administration of (radiolabeled) drugs (10 mg/kg p.o.). As expected, all statins reduced plasma cholesterol in the preclinical model, but a direct correlation between cholesterol lowering efficacy of the different statins in mice and in humans did not reach statistical significance (R(2) = 0.11, P < 0.57). It is noteworthy that, when murine data were corrected for effective liver uptake of the different statins, the correlation markedly increased (R(2) = 0.89, P < 0.05). Here we show for the first time that hepatic uptake of statins is related to their cholesterol-lowering efficacy and provide evidence that combined PK and efficacy studies can substantially improve the translational value of the E3L mouse model in the case of statin treatment. This strategy may also be applicable for other classes of drugs and other preclinical models. PMID:24049060

van de Steeg, E; Kleemann, R; Jansen, H T; van Duyvenvoorde, W; Offerman, E H; Wortelboer, H M; Degroot, J



Preclinical students' experiences in early clerkships after skills training partly offered in primary health care centers: a qualitative study from Indonesia  

PubMed Central

Background Students may encounter difficulties when they have to apply clinical skills trained in their pre-clinical studies in clerkships. Early clinical exposure in the pre-clinical phase has been recommended to reduce these transition problems. The aim of this study is to explore differences in students' experiences during the first clerkships between students exclusively trained in a skills laboratory and peers for whom part of their skills training was substituted by early clinical experiences (ECE). Methods Thirty pre-clinical students trained clinical skills exclusively in a skills laboratory; 30 peers received part of their skills training in PHC centers. Within half a year after commencing their clerkships all 60 students shared their experiences in focus group discussions (FGDs). Verbatim transcripts of FGDs were analyzed using Atlas-Ti software. Results Clerkship students who had participated in ECE in PHC centers felt better prepared to perform their clinical skills during the first clerkships than peers who had only practiced in a skills laboratory. ECE in PHC centers impacted positively in particular on students’ confidence, clinical reasoning, and interpersonal communication. Conclusion In the Indonesian setting ECE in PHC centers reduce difficulties commonly encountered by medical students in the first clerkships. PMID:22640419



Novel sugar esters proniosomes for transdermal delivery of vinpocetine: preclinical and clinical studies.  


Vinpocetine (Vin) existing oral formulations suffer poor bioavailability (?7%) since Vin undergoes a marked first-pass effect (?75%) and its absorption is dissolution rate-limited. In this study, a novel sustained release proniosomal system was designed using sugar esters (SEs) as non-ionic surfactants in which proniosomes were converted to niosomes upon skin water hydration following topical application under occlusive conditions. Different in vitro aspects (encapsulation efficiency, vesicle size and shape, effect of occlusion, in vitro release, skin permeation and stability) were studied leading to an optimized formula that was assessed clinically for transdermal pharmacokinetics and skin irritation. All formulae exhibited high entrapment efficiencies, regardless of the surfactant HLB. Vesicle size analysis showed that all vesicles were in the range from 0.63 ?m to 2.52 ?m which favored efficient transdermal delivery. The extent of drug permeation through the skin from the optimized formula--containing laurate SE with shorter fatty acid chain length and high HLB--was quite high (91%) after 48 h under occlusive conditions. The extent of absorption of Vin from proniosomes was larger when compared to the oral tablet with a relative bioavailability (F(rel)) of 206%. Histopathological evaluation revealed only moderate skin irritation when using SEs compared to skin inflammation when using Tween 80. Sugar esters proniosomes may be a promising carrier for vinpocetine, especially due to their simple scaling up and their ability to control drug release. PMID:21056658

El-Laithy, Hanan M; Shoukry, Omar; Mahran, Laila G



Transoral endoscopic thyroidectomy via the tri-vestibular routes: results of a preclinical cadaver feasibility study.  


The concept of natural orifice transluminal endoscopic surgery (NOTES) is an emerging experimental alternative to conventional surgery that eliminates skin incisions using an endoscope passed through a natural orifice (e.g., mouth, urethra, or anus). This study was designed to evaluate the feasibility and safety of thyroid resection via an entirely transoral tri-vestibular route using endoscopy, and to introduce NOTES to the head and neck area of medicine. We performed ten complete endoscopic thyroid lobectomies with central lymph node dissection via a tri-vestibular approach in fresh-frozen cadavers. A 5-mm endoscope with a deflectable tip was used to visualize the surgical field. Three cannulas were inserted through the midline and bilateral incision sites in the vestibule to position the instruments and endoscope. We refined and described the surgical technique in each step using video clips. We identified and preserved neighboring critical structures during surgery. We also confirmed that there were no obvious remnant thyroid tissues and no injury to the neighboring structures after exploration. The transoral tri-vestibular approach seems to provide a good view and surgical field for endoscopic thyroidectomy. However, the transoral approach for thyroidectomy remains experimental, and the detailed surgical technique should be refined via further clinical studies. PMID:24496566

Park, Jun-Ook; Kim, Choung Soo; Song, Jee-Nam; Kim, Ju-Eun; Nam, Inn-Chul; Lee, So-Yoon; Chun, Byung-Joon; Cho, Jung-Hae; Joo, Young-Hoon; Cho, Kwang-Jae; Park, Young Hak; Kim, Min-Sik; Sun, Dong-Il



Preclinical episodes of orofacial pain symptoms and their association with healthcare behaviors in the OPPERA prospective cohort study.  

PubMed Central

The course of preclinical pain symptoms sheds light on the etiology and prognosis of chronic pain. We aimed to quantify rates of developing initial- and recurrent-symptoms of painful temporomandibular disorder (TMD) and to evaluate associations with health behaviors. In the OPPERA prospective cohort study, 2,719 people aged 18-44 years with lifetime absence of TMD when enrolled completed 25,103 quarterly (three-monthly) questionnaires during amedian 2.3-year follow-up period. Questionnaires documented TMD symptom episodes, headache, other body pain, health care attendance and analgesic usage and. Kaplan-Meier methods for clustered data estimated symptom-free survival time. Multivariable models assessed demographic variation in TMD symptom rates and evaluated associations with healthcare and analgesic use. One third of people developed TMD symptoms and for one quarter of symptomatic episodes, pain intensity was severe. Initial TMD symptoms developed at anannual rate of 18.8 episodes per 100 people. The annual rate more than doubled for first-recurrence and doubled again for second-or-subsequent recurrence such that, one year after first recurrence, 71% of people experienced second recurrence. The overall rate increased with age and was greater in African-Americans and lower in Asians relative to Whites. The probability of TMD symptoms was strongly associated with concurrent episodes of headache and body pain and with past episodes of TMD symptoms. Episodes of TMD symptoms, headache and body pain were associated with increases of ~10% in probability of analgesic usage and healthcare attendance. Yet, even when TMD, headache and body pain occurred concurrently, 27% of people neither attended healthcare nor used analgesics. PMID:23531476

Slade, Gary D.; Sanders, Anne E.; Bair, Eric; Brownstein, Naomi; Dampier, Dawn; Knott, Charles; Fillingim, Roger; Maixner, William O.; Smith, Shad; Greenspan, Joel; Dubner, Ron; Ohrbach, Richard



Irinotecan delivery by microbubble-assisted ultrasound - A pilot preclinical study  

NASA Astrophysics Data System (ADS)

Irinotecan is conventionally used for the treatment of colorectal cancer. However, its administration is associated with severe side effects. Targeted drug delivery using ultrasound (US) combined with microbubbles offers new opportunities to increase the therapeutic effectiveness of antitumor treatment and to reduce toxic exposure to healthy tissues. The objective of this study is to investigate the safety and efficacy of in-vivo delivery of irinotecan by microbubble-assisted US in human glioblastoma model (U-87 MG). In order to validate the potential of this new method in-vivo, subcutaneous tumors were implanted in the flank of nude mouse and treated when they reached a volume of 100 mm3. In the first study, the measured volumes with caliper and anatomic ultrasound imaging were compared for the monitoring and the quantification of tumor growth during 27 days. Ultrasound imaging measurements were positively correlated to caliper measurements. The tumor treatment consisted of an i.v. injection of irinotecan (20 mg/kg) followed one hour later by i.v. administration of MM1 microbubble and an US insonation using a single-element transducer operating at 1MHz (400 kPa, 10 kHz PRF 40% DC, 3 min). The therapeutic efficacy was evaluated for 39 days by measuring the tumor volume before and after treatment using a caliper and based on ultrasound images using an 18 MHz probe (Vevo 2100). Our results showed that anatomical ultrasound imaging was as efficient as caliper for the monitoring and the quantification of tumor growth. Moreover, irinotecan delivery by sonoporation induced a significant decrease of glioblastoma tumor volume and an increase of tumor-doubling time compared to the tumor treated by irinotecan alone. In conclusion, this novel therapeutic approach has promising features since it can be used to reduce the injected drug dose and to achieve a better therapeutic efficacy.

Escoffre, Jean-Michel; Novell, Anthony; Serrière, Sophie; Bouakaz, Ayache



Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment.  


Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose-response data (Gollapudi et al., 2013), here we present analyses of 1-ethyl-1-nitrosourea (ENU) and 1-methyl-1-nitrosourea (MNU) dose-response data and additional approaches for the determination of genetic toxicity point-of-departure (PoD) metrics. We previously described methods to determine the no-observed-genotoxic-effect-level (NOGEL), the breakpoint-dose (BPD; previously named Td), and the benchmark dose (BMD10 ) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non-linear slope-transition-dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL10 and BMDL1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL10 values were often lower than the other PoDs, and the distribution of BMDL10 values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making. Environ. Mol. Mutagen. 55:609-623, 2014. © 2014 Wiley Periodicals, Inc. PMID:24801602

Johnson, G E; Soeteman-Hernández, L G; Gollapudi, B B; Bodger, O G; Dearfield, K L; Heflich, R H; Hixon, J G; Lovell, D P; MacGregor, J T; Pottenger, L H; Thompson, C M; Abraham, L; Thybaud, V; Tanir, J Y; Zeiger, E; van Benthem, J; White, P A



HD047703, a New Promising Anti-Diabetic Drug Candidate: In Vivo Preclinical Studies  

PubMed Central

G-protein coupled receptor 119 (GPR119) has emerged as a novel target for the treatment of type 2 diabetes mellitus. GPR119 is involved in glucose-stimulated insulin secretion (GSIS) from the pancreatic ?-cells and intestinal cells. In this study, we identified a novel small-molecule GPR119 agonist, HD047703, which raises intracellular cAMP concentrations in pancreatic ?-cells and can be expected to potentiate glucose-stimulated insulin secretion from human GPR119 receptor stably expressing cells (CHO cells). We evaluated the acute efficacy of HD047703 by the oral glucose tolerance test (OGTT) in normal C57BL/6J mice. Then, chronic administrations of HD047703 were performed to determine its efficacy in various diabetic rodent models. Single administration of HD047703 caused improved glycemic control during OGTT in a dose-dependent manner in normal mice, and the plasma GLP-1 level was also increased. With respect to chronic efficacy, we observed a decline in blood glucose levels in db/db, ob/ob and DIO mice. These results suggest that HD047703 may be a potentially promising anti-diabetic agent.

Kim, SoRa; Kim, Dae Hoon; Kim, Young-Seok; Ha, Tae-Young; Yang, Jin; Park, Soo Hyun; Jeong, Kwang Won; Rhee, Jae-Keol



Novel transdermal delivery of Timolol maleate using sugar esters: preclinical and clinical studies.  


The feasibility of matrix controlled transdermal patch based on sugar fatty acid ester (SE) as penetration and absorption enhancer containing Timolol maleate (TM) was investigated. The influence of fatty acid type, chain length and hydrophile-lipophile balance (HLB) on the in vitro drug release as well as its permeation across hairless rat skin were studied and compared aiming to select a patch formula for clinical performance. Skin irritation induced by SE patch was evaluated by visual scoring, color reflectance measurements and non-invasive transepidermal water loss (TEWL) technique. The results indicated that among different SEs tried, laurate SE with shorter fatty acid chain length and higher HLB value significantly increased the amount of TM liberated from the patch (99+/-2.1%) and its permeation across rat skin (86+/-4.3%). The total drug permeation and flux values were approximately 5-fold greater compared to SE free patch. The extent of absorption of TM-SE patch expressed by AUC was 64% larger as compared to the oral solution with steady plasma concentration over 18 h and relative bioavailability (F(rel)) of 163%. The developed patch was well tolerated by all the subjects with only moderate skin irritation, which was recovered in 24h after patch removal. The results are very encouraging and offer an alternative approach to maintain higher, prolonged and controlled blood level profile of the drug over 18-24h. PMID:19126429

El-Laithy, Hanan M



Confidentiality in preclinical Alzheimer disease studies: when research and medical records meet.  


Clinical trials to advance the diagnosis and treatment of Alzheimer disease (AD) may expose research subjects to discrimination risks. An individual enrolled in a research study that uses positive test results from amyloid PET imaging or CSF measures of ?-amyloid 42 as inclusion criteria has biomarkers indicative of AD pathology. If insurers and employers learn this information, it could expose subjects to discrimination. Unfortunately, current legal and regulatory mechanisms are not sufficient to protect against harms that have significant consequences for subjects. Existing law that prohibits employment and insurance discrimination based on genetic status does not apply to amyloid biomarkers or any other biomarkers for neurodegenerative diseases. Gaps in legal protections fail to protect research subjects from discrimination by long-term care and disability insurers. This risk is particularly concerning because individuals with AD dementia ultimately need long-term care services. To maximize subject protections and advance valuable research, policymakers, investigators, and research institutions must address shortcomings in the design of the electronic medical record, revise laws to limit discrimination, and develop practices that inform research participants of risks associated with loss of confidentiality. PMID:24477112

Arias, Jalayne J; Karlawish, Jason



Chronic Electrical Stimulation with a Suprachoroidal Retinal Prosthesis: A Preclinical Safety and Efficacy Study  

PubMed Central

Purpose To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis. Methods Seven normally-sighted feline subjects were implanted for 96–143 days with a suprachoroidal electrode array and six were chronically stimulated for 70–105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue. Results All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11–15 k? during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses. Conclusions Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents. PMID:24853376

Nayagam, David A. X.; Williams, Richard A.; Allen, Penelope J.; Shivdasani, Mohit N.; Luu, Chi D.; Salinas-LaRosa, Cesar M.; Finch, Sue; Ayton, Lauren N.; Saunders, Alexia L.; McPhedran, Michelle; McGowan, Ceara; Villalobos, Joel; Fallon, James B.; Wise, Andrew K.; Yeoh, Jonathan; Xu, Jin; Feng, Helen; Millard, Rodney; McWade, Melanie; Thien, Patrick C.; Williams, Chris E.; Shepherd, Robert K.



Photoacoustic spectroscopy in the monitoring of breast tumor development: a pre-clinical study  

NASA Astrophysics Data System (ADS)

Breast cancer is the most frequently diagnosed cancer type and its detection at an early stage can reduce the mortality rate substantially. With the aim to detect breast cancer early, by studying tumor progression in nude mice, a pulsed laser induced photoacoustic spectroscopy set up has been designed and developed. MCF-7 cells xenografts were developed using six to eight weeks old female nude mice and tumor tissues were extracted on different days (10th, 15th and 20th Day) post injection and the corresponding photoacoustic spectra were recorded at 281nm excitation. A total of 144 time domain spectra were recorded from 36 animals belonging to the three time points (10th, 15th and 20th day post injection) and converted into frequency domains by Fast Fourier Transform (FFT) tools of the MATLAB algorithms and analyzed. The frequency patterns of the tumor masses on 10th, 15th and 20th day of tumor development showed a gradual increase in intensity at certain frequencies, 5.93 x103 Hz, 15.9 x103 Hz, 29.69 x103 Hz and 32.5 x103 Hz in the FFT patterns indicating that these frequencies were more sensitive towards tumor development. Further analysis of the data yielded a clear variation in the spectral parameters with progression of the disease suggesting that the technique may be suitable for early detection of the disease. Thus, we expect that the developed setup may be useful in assessing the different phases of tumor development which may have clinical implications.

Priya, Mallika; Rao, Bola Sadashiva Satish; Ray, Satadru; Mahato, Krishna Kishore



Preclinical studies and clinical correlation of the effect of alkylating dose.  


Dose-response studies were performed with the alkylating agents [nitrogen mustard, N,N'-bis(2-chloroethyl)-N-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and trimethyleneiminethiophosphoramide] in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSaIIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, melphalan, and 4-HC in vitro produced low levels (6.5- to 9-fold) of drug resistance, despite an intensive and prolonged treatment program. The MCF-7 sublines made resistant to CDDP and 4-HC did not exhibit cross-resistance to other alkylating agents; however, the MCF-7 subline resistant to melphalan was partially cross-resistant to nitrogen mustard, 4-HC, and CDDP. A log-linear relationship was maintained between surviving fraction of MCF-7 cells in culture and drug concentration with alkylating agents, whereas for nonalkylating agents the survival curves tended to plateau at high drug concentrations. Log-linear tumor cell kill was also obtained over a wide dosage range with several alkylating agents in murine tumors treated in vivo. Tumor cell survival assay by colony formation indicated the continuing importance of dose in the action of the drugs even at high levels of tumor cell kill. With some agents, there was a difference between the slopes of the tumor cell killing curves in vivo as compared to in vitro. Cyclophosphamide was far more potent in vitro (4-HC) than in vivo (cyclophosphamide). Trimethyleneiminethiophosphoramide and N,N'-bis(2-chloroethyl)-N-nitrosourea were both more potent in vivo than in vitro. These differences may be explained by the various metabolic patterns of these drugs. Dose of alkylating agents is clearly a crucial variable particularly where multilog tumor cell kill is the goal, and in this regard, the effect of drug dose on the tumoricidal action of the alkylating agents is substantially greater than for nonalkylating agents. PMID:3180059

Frei, E; Teicher, B A; Holden, S A; Cathcart, K N; Wang, Y Y



Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders  

PubMed Central

Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium’s therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium’s main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington’s, Alzheimer’s, and Parkinson’s diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium’s neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases. PMID:20705090

Chiu, Chi-Tso; Chuang, De-Maw



Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study)  

PubMed Central

Background The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. Hypothesis That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Animals Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. Methods The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. Results The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034). Conclusion and Clinical Importance The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome. PMID:23078651

Summerfield, NJ; Boswood, A; O'Grady, MR; Gordon, SG; Dukes-McEwan, J; Oyama, MA; Smith, S; Patteson, M; French, AT; Culshaw, GJ; Braz-Ruivo, L; Estrada, A; O'Sullivan, ML; Loureiro, J; Willis, R; Watson, P



Fiber optic fluorescence detection of low-level porphyrin concentrations in preclinical and clinical studies  

NASA Astrophysics Data System (ADS)

A significant clinical problem in the local treatment of cutaneous metastases of breast cancer (by any modality--surgery, radiation therapy or photodynainic therapy) is the fact that the disease almost always extends beyond the boundary of visible lesions in the form of microscopic deposits. These deposits may be distant from the site of visible disease but are often in close proximity to it and are manifested sooner or later by the development of recurrent lesions at the border of the treated area, thus the "marginal miss" in radiation therapy, the "rim recurrence" in photodynamic therapy, and the "incisional recurrence" following surgical excision. More intelligent use of these treatment modalities demands the ability to detect microscopic deposits of tumor cells using non-invasive methodology. In vivo fluorescence measurements have been made possible by the development of an extremely sensitive fiber optic in vivo fluorescence photometer. The instrument has been used to verify that fluorescence correlated with injected porphyrin levels in various tissues. The delivery of light to excite and detect background fluorescence as well as photosensitizer fluorescence in tissues has been accomplished using two HeNe lasers emitting at 632.8 nm and 612 nm delivered through a single quartz fiber optic. Chopping at different frequencies, contributions of fluorescence may be separated. Fluorescence is picked up via a 400 micron quartz fiber optic positioned appropriately near the target tissue. Validation of these levels was made by extraction of the drug from the tissues with resultant quantitation. Recently, an extensive study was undertaken to determine if fluorescence could be used for the detection of occult, clinically non-palpable metastases in the lymph node of rats. This unique model allowed for the detection of micrometastases in lymph nodes using very low injected doses of the photosensitizer Photofrin II. Data obtained revealed the ability to detect on the order of 50-100 cells using 0.25 mg/kg of sensitizer, a level 20 times lower than normally used for treatment of animal tumors. These results indicate that Photofrin II could be used for fluorescence detection of small metastatic tumors, while substantially reducing the major side effect of PDT; namely, prolonged photosensitivity. Results to be presented demonstrate the ability of this technique to detect microscopic deposits of malignant tumor cells in patients with metastatic breast cancer. These deposits were found in clinically negative areas of the chest wall.

Mang, Thomas S.; McGinnis, Carolyn; Khan, S.



Efficient vitreolysis by combining plasmin and sulfur hexafluoride injection in a preclinical study in rabbit eyes  

PubMed Central

Purpose To investigate the efficacy of plasmin and sulfur hexafluoride (SF6) on the vitreoretinal junction, as well as the long-term safety in the eye and effect on the recipient’s general health after application in the eye. Methods The study design included four groups of rabbits with three animals in each group. Group 1 received an intravitreal injection (IVI) of plasmin and SF6 in the right eye; group 2 received an IVI of plasmin in the right eye; group 3 received an IVI of SF6 in the right eye; and group 4 received an IVI of balanced salt solution in the right eye, which served as a normal control. Long-term safety (up to approximately three months) after plasmin and/or SF6 injection was evaluated morphologically by clinical examination, histology, and immunohistochemistry, and functionally by electroretinograms (ERGs). General health evaluations after intravitreal injection included the assessment of weight gain, food intake, body temperature, and complete blood count analysis. Results Plasmin plus SF6 injection resulted in complete posterior vitreous detachment (PVD), whereas plasmin or SF6 injection alone resulted in only partial PVD. Balanced salt solution did not induce PVD. Eighty days after intravitreal injection, there were no major differences among the eyes of the three groups of animals compared with the normal control animals upon clinical evaluation, or regarding retinal morphology and ERGs. The lenses examined remained clear for up to 80 days following the intravitreal injection of plasmin plus SF6, except one eye in the plasmin-treated group. ERGs decreased transiently one week after intravitreal injection in groups 1 through 3, but animals recovered fully to normal status afterward. General health was not affected after the injection of plasmin plus SF6. Conclusions Efficient vitreoretinal separation could be achieved, and an acceptable long-term safety profile was noted after plasmin plus SF6 injection in the eye. No major ocular toxicity or systemic toxicity was found after the injection of plasmin plus SF6. These results provide good support for the future clinical use of plasmin plus SF6 for treatment of a variety of vitreoretinopathies. PMID:23049236

Wu, Wei-Chi; Liu, Chi-Hsien; Chen, Chih-Chun; Wang, Nan-Kai; Chen, Kwan-Jen; Chen, Tun-Lu; Hwang, Yih-Shiou; Li, Lien-Min



Pediatric toxicology.  


Pediatric patients present unique concerns in the field of medical toxicology. First, there are medicines that are potentially dangerous to small children, even when they are exposed to very small amounts. Clinicians should be wary of these drugs even when young patients present with accidental ingestions of apparently insignificant amounts. Next, over-the-counter laxatives and syrup of ipecac, although not commonly considered abused substances, may be misused in both the setting of Munchausen's syndrome by proxy and in adolescents who have eating disorders. Their use should be considered in any gastrointestinal illness of uncertain origin. Finally, as the use of syrup of ipecac at home now has been discouraged by many, some have explored using activated charcoal at home as a new method of prehospital gastrointestinal decontamination. The literature examining activated charcoal and its use in this capacity is discussed. PMID:17482021

Eldridge, David L; Van Eyk, Jason; Kornegay, Chad



Efficacy of screens in removing long fibers from an aerosol stream--sample preparation technique for toxicology studies.  


Fiber dimension (especially length) and biopersistence are thought to be important variables in determining the pathogenicity of asbestos and other elongate mineral particles. In order to prepare samples of fibers for toxicology studies, it is necessary to develop and evaluate methods for separating fibers by length in the micrometer size range. In this study, we have filtered an aerosol of fibers through nylon screens to investigate whether such screens can efficiently remove the long fibers (L >20 µm, a typical macrophage size) from the aerosol stream. Such a sample, deficient in long fibers, could then be used as the control in a toxicology study to investigate the role of length. A well-dispersed aerosol of glass fibers (a surrogate for asbestos) was generated by vortex shaking a Japan Fibrous Material Research Association (JFMRA) glass fiber powder. Fibers were collected on a mixed cellulose ester (MCE) filter, imaged with phase contrast microscopy (PCM) and lengths were measured. Length distributions of the fibers that penetrated through various screens (10, 20 and 60?µm mesh sizes) were analyzed; additional study was made of fibers that penetrated through double screen and centrally blocked screen configurations. Single screens were not particularly efficient in removing the long fibers; however, the alternative configurations, especially the centrally blocked screen configuration, yielded samples substantially free of the long fibers. PMID:24417374

Ku, Bon Ki; Deye, Gregory J; Turkevich, Leonid A



Spontaneous occurrence of a distinctive renal tubule tumor phenotype in rat carcinogenicity studies conducted by the national toxicology program.  


The Toxicology Data Management System (TDMS) of the National Toxicology Program, National Institutes of Environmental Health Sciences, National Institutes of Health, was surveyed for occurrence and distribution of a distinctive renal tubule tumor type in rats. The hallmark features of this tumor included eosinophilic/amphophilic staining, large finely granular cells, and numerous vacuoles and/or minilumens. It is referred to here as the amphophilic-vacuolar (AV) variant of renal tubule tumor. Of 154 studies in which renal tubule tumors had been recorded in the standard single sections of kidney in the TDMS, there were collectively 1012 rats with renal adenomas, carcinomas, or adenocarcinomas, and of these, 100 displayed the distinctive AV morphology, representing 74 studies involving mostly the F344 rat, but also the Sprague-Dawley and Wistar strains. The AV tumors (mainly adenomas but also some carcinomas) occurred usually as solitary lesions in the affected animals. However, they were multiple and bilateral in a few cases. They were equally distributed between the sexes, did not metastasize (at least to the lung), and were not associated with chronic progressive nephropathy. The distribution of this renal tumor type was random across studies and dose groups, underscoring the likelihood that it was of spontaneous origin and not chemically induced. Accordingly, it is suggested that this distinctive renal tumor phenotype be recorded as a separate category from conventional RTT when assessing the carcinogenic potential of a test compound. PMID:18441261

Hard, Gordon C; Seely, John Curtis; Kissling, Grace E; Betz, Laura J




PubMed Central

The Toxicology Data Management System (TDMS) of the National Toxicology Program, NIEHS, NIH, was surveyed for occurrence and distribution of a distinctive renal tubule tumor type in rats. The hallmark features of this tumor included eosinophilic/amphophilic staining, large finely granular cells, and numerous vacuoles and/or minilumens. It is referred to here as the amphophilic-vacuolar (AV) variant of renal tubule tumor. Of 154 studies in which renal tubule tumors had been recorded in the standard single sections of kidney in the TDMS, there were collectively 1012 rats with renal adenomas, carcinomas or adenocarcinomas, and of these, 100 displayed the distinctive AV morphology, representing 74 studies involving mostly the F344 rat, but also the Sprague-Dawley and Wistar strains. The AV tumors (mainly adenomas but also some carcinomas) occurred usually as solitary lesions in the affected animals. However, they were multiple and bilateral in a few cases. They were equally distributed between the sexes, did not metastasize (at least to the lung), and were not associated with chronic progressive nephropathy. The distribution of this renal tumor type was random across studies and dose groups, underscoring the likelihood that it was of spontaneous origin and not chemically induced. Accordingly, it is suggested that this distinctive renal tumor phenotype be recorded as a separate category from conventional RTT when assessing the carcinogenic potential of a test compound. PMID:18441261

Hard, Gordon C; Seely, John Curtis; Kissling, Grace E; Betz, Laura J



Comparative toxicology of borates  

Microsoft Academic Search

Inorganic borates, including boric acid, Na, ammonium, K, and Zn borates generally display low acute toxicity orally, dermally,\\u000a and by inhalation. They are either not irritant or mild skin and eye irritants. Exceptions owing to physiochemical properties\\u000a do occur.\\u000a \\u000a Longer-term toxicological studies have been reported mainly on boric acid or borax where the properties are generally similar\\u000a on an equivalent

Susan A. Hubbard



Animal-free toxicology: the use of human tissue to replace the use of animals - examples from human biomonitoring and human placental transport studies.  


Human data on exposure and adverse effects are the most appropriate for human risk assessment, and modern toxicology focuses on human pathway analysis and the development of human biomarkers. Human biomonitoring and human placental transport studies provide necessary information for human risk assessment, in accordance with the legislation on chemical, medicine and food safety. Toxicology studies based on human mechanistic and exposure information can replace animal studies. These animal-free approaches can be further supplemented by new in silico methods and chemical structure-activity relationships. The inclusion of replacement expertise in the international Three Rs centres, the ongoing exploration of alternatives to animal research, and the improvement of conditions for research animals, all imply the beginning of a paradigm shift in toxicology research toward the use of human data. PMID:24512227

Knudsen, Lisbeth E



Molecular Toxicology Major Snapshot Department of Nutritional Science and Toxicology  

E-print Network

Molecular Toxicology Major Snapshot Department of Nutritional Science and Toxicology College of Natural Resources, University of California Berkeley The Department Nutritional Science and Toxicology in the College of Natural Resources at UC Berkeley offers an undergraduate major in Molecular Toxicology

Wildermuth, Mary C


Toxicological approaches to complex mixtures.  

PubMed Central

This paper reviews the role of toxicological studies in understanding the health effects of environmental exposures to mixtures. The approach taken is to review mixtures that have received the greatest emphasis from toxicology; major mixtures research programs; the toxicologist's view of mixtures and approaches to their study; and the complementary roles of toxicological, clinical, and epidemiological studies. Studies of tobacco smoke, engine exhaust, combustion products, and air pollutants comprise most of the past research on mixtures. Because of their great experimental control over subjects, exposures, and endpoints, toxicologists tend to consider a wider range of toxic interactions among mixture components and sequential exposures than is practical for human studies. The three fundamental experimental approaches used by toxicologists are integrative (studying the mixture as a whole), dissective (dissecting a mixture to determine causative constituents), and synthetic (studying interactions between agents in simple combinations). Toxicology provides information on potential hazards, mechanisms by which mixture constituents interact to cause effects, and exposure dose-effect relationships; but extrapolation from laboratory data to quantitative human health risks is problematic. Toxicological, clinical, and epidemiological approaches are complementary but are seldom coordinated. Fostering synergistic interactions among the disciplines in studying the risks from mixtures could be advantageous. PMID:7515806

Mauderly, J L



Genetic toxicology assessment of HI-6 dichloride  

SciTech Connect

The oxime HI-6 dichloride (1-(2 hydroxyiminomethyl- 1-pyridino)-3- (4-carbamoyl-1- pyridino)-2-oxapropane dichloride monohydrate) has shown to be a potent reactivator of cholinesterase activity and may have efficacy for the treatment of organo-phosphate intoxication (SIPRI, 1976; Schenk et al.; Arch Toxicol 36:71-81, 1976). As part of a pre-clinical safety assessment program, the genetic toxicology of HI-6 dichloride was evaluated in a series of assays designed to measure induction of gene mutations and chromosomal aberrations. HI-6 dichloride gave negative responses in the Salmonella mutagenicity assay and in the CHO/HGPRT gene mutation assay. Dose-dependent increases in the frequency of chromosomal aberrations when HI-6 dichloride was tested in cultured CHO cells and in cultured human peripheral blood lymphocytes. The mouse lymphoma gene mutation assay, reputed to measure both gene mutations and chromosomal deletions, was negative in the absence of metabolic activation. Depending on the criteria employed, a negative or equivocal response was seen in the presence of rat liver-derived S-9 mix. An in vivo rat bone marrow metaphase assay performed to further investigate the in vitro clastogenic responses was negative. The results from these studies indicate that HI-6 dichloride does not induce gene mutations in vitro; however, it is clastogenic in vitro but does not appear to be clastogenic in vivo.

Putman, D.; San, R.H.; Bigger, C.A.; Levine, B.S.; Jacobson-Kram, D.



The Study about the Degradation of Nitrobenzene by Domesticated Activated Sludge and the Initial Validation of Toxicology before and after the Degradation  

Microsoft Academic Search

In this paper, the domestication of the activated sludge by which nitrobenzene can be degraded in a relatively poor nutrition is studied. The ability of activated sludge degradation of nitrobenzene is studied by degradation kinetics. The toxicology validation about the effect of activated sludge degradation of nitrobenzene is preliminarily explored. The results show that: The nitrobenzene could be the sole

Yu-bin Ji; Jin-yu Zhou; Wen-lan Li; Chang-ru Xu; Xing-jie Zhu



Studies on the metabolism and the toxicological analysis of the nootropic drug fipexide in rat urine using gas chromatography–mass spectrometry  

Microsoft Academic Search

Qualitative studies are described on the metabolism and the toxicological analysis of the nootropic fipexide (FIP) in rat urine using gas chromatography–mass spectrometry (GC–MS). FIP was extensively metabolized to 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), 4-chlorophenoxyacetic acid, 1-[2-(4-chlorophenoxy)acetyl]piperazine, N-(4-hydroxy-3-methoxy-benzyl)piperazine, piperazine, N-(3,4-methylenedioxybenzyl)ethylenediamine, and N-[2-(4-chlorophenoxy)acetyl]ethylenediamine. The authors’ systematic toxicological analysis (STA) procedure using full-scan GC–MS after acid hydrolysis of one urine aliquot, liquid-liquid extraction and acetylation

Roland F. Staack; Hans H. Maurer



An Independent Study of the Preclinical Efficacy of C2-8 in the R6/2 Transgenic Mouse Model of Huntington's Disease  

PubMed Central

Background C2-8 is a small molecule inhibitor of polyglutamine aggregation and can reduce photoreceptor neurodegeneration in a Drosophila model of Huntington's disease (HD). Further preclinical studies have shown that oral administration of C2-8 in R6/2 HD transgenic mice can penetrate into the brain, reduce mHTT-exon1 aggregation, improve motor performance and diminish striatal neuron atrophy. Objective In this independent preclinical study, we aimed to evaluate the pharmacokinetic properties and therapeutic efficacy of C2-8 intraperitoneal (IP) delivery in the R6/2 HD mouse. Methods R6/2 mice were IP injected with low dose C2-8 (10 mg/kg), high dose C2-8 (20 mg/kg), or vehicle twice daily from 3 weeks to 3 months old. Longitudinal behavioral tests (accelerating Rotarod and wire-hang) were performed to evaluate the motor deficits, and neuropathology was measured by unbiased stereology. Results We confirmed that the compound has good blood-brain-barrier penetration after acute or sub-chronic intraperitoneal delivery. Chronic treatment with C2-8 in R6/2 mice results in a significant reduction of nuclear mHTT aggregate volume in the brains, replicating a key finding of C2-8 as a polyglutamine aggregation inhibitor in vivo. However, by comparing HD mice with C2-8 treatment to those with vehicle treatment, we were unable to demonstrate significant amelioration of motor deficits using Rotarod and wire-hang tests. Moreover, we did not observe improvement in the striatal neurodegenerative pathology, as measured by brain weight, striatal volume, and striatal neuron volume in the C2-8 treated R6/2 mice. Conclusions Our study supports the practice of independent preclinical studies for novel molecules in HD therapeutic development and suggests that the use of alternative delivery strategies and full-length HD mouse models are likely needed to further assess whether the aggregate-inhibiting properties of C2-8 can be consistently translated into a preclinical benefit in HD mice. PMID:25062731

Wang, Nan; Lu, Xiao-Hong; Sandoval, Susana V.; Yang, X. William



Case study: the role of mechanistic network models in systems toxicology.  


Twenty first century systems toxicology approaches enable the discovery of biological pathways affected in response to active substances. Here, we briefly summarize current network approaches that facilitate the detailed mechanistic understanding of the impact of a given stimulus on a biological system. We also introduce our network-based method with two use cases and show how causal biological network models combined with computational methods provide quantitative mechanistic insights. Our approach provides a robust comparison of the transcriptional responses in different experimental systems and enables the identification of network-based biomarkers modulated in response to exposure. These advances can also be applied to pharmacology, where the understanding of disease mechanisms and adverse drug effects is imperative for the development of efficient and safe treatment options. PMID:23933191

Hoeng, Julia; Talikka, Marja; Martin, Florian; Sewer, Alain; Yang, Xiang; Iskandar, Anita; Schlage, Walter K; Peitsch, Manuel C



Optimization of Preclinical Animal Models  

E-print Network

Optimization of Preclinical Animal Models Steven Perrin, PhD CEO, CSO ALS Therapy Development Institute #12;Historical Issue with Pre-clinical Animal Model Development and Validation Optimized Experimental Design for Preclinical Drug Screening in the ALS Mouse Model, 2007 10 Years To Validate the Model


Swine as models in biomedical research and toxicology testing.  


Swine are considered to be one of the major animal species used in translational research, surgical models, and procedural training and are increasingly being used as an alternative to the dog or monkey as the choice of nonrodent species in preclinical toxicologic testing of pharmaceuticals. There are unique advantages to the use of swine in this setting given that they share with humans similar anatomic and physiologic characteristics involving the cardiovascular, urinary, integumentary, and digestive systems. However, the investigator needs to be familiar with important anatomic, histopathologic, and clinicopathologic features of the laboratory pig and minipig in order to put background lesions or xenobiotically induced toxicologic changes in their proper perspective and also needs to consider specific anatomic differences when using the pig as a surgical model. Ethical considerations, as well as the existence of significant amounts of background data, from a regulatory perspective, provide further support for the use of this species in experimental or pharmaceutical research studies. It is likely that pigs and minipigs will become an increasingly important animal model for research and pharmaceutical development applications. PMID:21441112

Swindle, M M; Makin, A; Herron, A J; Clubb, F J; Frazier, K S




EPA Science Inventory

TOXLINE? (TOXicology information onLINE) are the National Library of Medicines extensive collection of online bibliographic information covering the pharmacological, biochemical, physiological, and toxicological effects of drugs and other chemicals. TOXLINE and TOXLINE65 together...


Toxicological Study of Ocimum sanctum Linn Leaves: Hematological, Biochemical, and Histopathological Studies  

PubMed Central

The present study was aimed to study the acute and subacute toxicity studies with orally administered 50% ethanolic leaves extract of Ocimum sanctum Linn (OSE). In acute toxicity tests, four groups of mice (n = 6/group/sex) were orally treated with doses of 200, 600, and 2000?mg/kg, and general behavior, adverse effects, and mortality were recorded for up to 14 days. In subacute toxicity study, rats received OSE by gavage at the doses of 200, 400, and 800?mg/kg/day (n = 6/group/sex) for 28 days, and biochemical, hematological, and histopathological changes in tissues (liver, kidney, spleen, heart, and testis/ovary) were determined. OSE did not produce any hazardous symptoms or death and CNS and ANS toxicities in the acute toxicity test. Subacute treatment with OSE did not show any change in body weight, food and water consumption, and hematological and biochemical profiles. In addition, no change was observed both in macroscopic and microscopic aspects of vital organs in rats. Our result showed that Ocimum sanctum extract could be safe for human use. PMID:24616736

Gautam, M. K.; Goel, R. K.




EPA Science Inventory




EPA Science Inventory

The rodent, specifically the inbred laboratory rat, is the primary experimental animal used in toxicology testing. Despite its popularity, recent studies from our laboratory and others raise a number of questions concerning the rat's appropriateness as an animal model for toxicol...


Graduate Program Environmental Toxicology  

E-print Network

1 Graduate Program in Environmental Toxicology Graduate Student Guidelines Updated December 7, 2011 for Ph.D. Students 3. ENTOX Form 2 ­ Graduate Research Proposal #12;3 PROGRAM OF ENVIRONMENTAL TOXICOLOGY GRADUATE STUDENT GUIDELINES A. Introduction The Faculty of Environmental Toxicology welcomes you

Duchowski, Andrew T.


Recent Advances in Particulate Matter and Nanoparticle Toxicology: A Review of the In Vivo and In Vitro Studies  

PubMed Central

Epidemiological and clinical studies have linked exposure to particulate matter (PM) to adverse health effects, which may be registered as increased mortality and morbidity from various cardiopulmonary diseases. Despite the evidence relating PM to health effects, the physiological, cellular, and molecular mechanisms causing such effects are still not fully characterized. Two main approaches are used to elucidate the mechanisms of toxicity. One is the use of in vivo experimental models, where various effects of PM on respiratory, cardiovascular, and nervous systems can be evaluated. To more closely examine the molecular and cellular mechanisms behind the different physiological effects, the use of various in vitro models has proven to be valuable. In the present review, we discuss the current advances on the toxicology of particulate matter and nanoparticles based on these techniques. PMID:23865044

Nemmar, Abderrahim; Holme, J?rn A.; Rosas, Irma; Schwarze, Per E.



Methadone-Related Deaths - Epidemiological, Pathohistological, and Toxicological Traits in 10-year Retrospective Study in Vojvodina, Serbia.  


The number of methadone-related deaths (MRDs) during a 10-year period (2002-2011) in the region of Vojvodina, Serbia, was increased. The cases were evaluated according to epidemiological parameters, pathohistological findings, and toxicological screening. The majority of victims were men, aged from 20 to 38. Pathohistologically, the signs of acute focal myocardial damage were present in the heart of victims with drug abuse history shorter than 2 years, while both signs of recent and chronic focal myocardial damage were developed among victims with longer drug abuse history (2-5 years). In postmortem blood samples of 54.84% of victims, methadone was detected in combination with diazepam, both in therapeutic range. Alcohol was absent in most cases. Other detected drugs were antipsychotics and antidepressants in therapeutic concentrations. These findings raise the attention to the concomitant use of methadone and benzodiazepines with the need for further studies to clarify the mechanism of death in such cases. PMID:24502699

Mijatovi?, Vesna; Samojlik, Isidora; Ajdukovi?, Nikša; Durendi?-Brenesel, Maja; Petkovi?, Stojan



Inhalation developmental toxicology studies: Teratology study of acetone in mice and rats: Final report  

SciTech Connect

Acetone, an aliphatic ketone, is a ubiquitous industrial solvent and chemical intermediate; consequently, the opportunity for human exposure is high. The potential for acetone to cause developmental toxicity was assessed in Sprague-Dawley rats exposed to 0, 440, 2200, or 11000 ppm, and in Swiss (CD-1) mice exposed to 0, 440, 2200, and 6600 ppm acetone vapors, 6 h/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and approx.32 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 46 refs., 6 figs., 27 tabs.

Mast, T.J.; Evanoff, J.J.; Rommereim, R.L.; Stoney, K.H.; Weigel, R.J.; Westerberg, R.B.



Inhalation developmental toxicology studies: Teratology study of n-hexane in rats: Final report  

SciTech Connect

The straight chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent used in industrial, academic, and smaller commercial environments. The significant opportunity for women of child-bearing age to be exposed to this chemical prompted the undertaking of a study to assess the developmental toxicity of n-hexane in an animal model. Timed-pregnant (30 animals per group) and virgin (10 animals per group) Sprague-Dawley rats were exposed to 0 (filtered air), 200, 1000, and 5000 ppM n-hexane (99.9% purity) vapor in inhalation chambers for 20 h/day for a period of 14 consecutive days. Sperm-positive females were exposed for 6 to 19 days of gestation (dg) and virgins were exposed concurrently for 14 consecutive days. The day of sperm detection was designated as 0 dg for mated females. Adult female body weights were monitored prior to, throughout the exposure period, and at sacrifice. Uterine, placental, and fetal body weights were obtained for gravid females at sacrifice. Implants were enumerated and their status recorded as live fetus, early or late resorption, or dead. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 16 refs., 3 figs., 7 tabs.

Mast, T.J.



Inhalation developmental toxicology studies: Teratology study of methyl ethyl ketone in mice: Final report  

SciTech Connect

Methyl ethyl ketone (MEK) is a widely used industrial solvent which results in considerable human exposure. In order to assess the potential for MEK to cause developmental toxicity in rodents, four groups of Swiss (CD-1) mice were exposed to 0, 400, 1000 or 3000 ppM MEK vapors, 7 h/day, 7 dy/wk. Ten virgin females and approx.30 plug-positive females per group were exposed concurrently for 10 consecutive days (6--15 dg for mated mice). Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice on 18 dg. Uterine implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. Exposure of pregnant mice to these concentrations of MEK did not result in apparent maternal toxicity, although there was a slight, treatment-correlated increase in liver to body weight ratios which was significant for the 3000-ppM group. Mild developmental toxicity was evident at 3000-ppM as a reduction in mean fetal body weight. This reduction was statistically significant for the males only, although the relative decrease in mean fetal body weight was the same for both sexes. 17 refs., 4 figs., 10 tabs.

Mast, T.J.; Dill, J.A.; Evanoff, J.J.; Rommereim, R.L.; Weigel, R.J.; Westerberg, R.B.



Inhalation developmental toxicology studies: Teratology study of isoprene in mice and rats: Final report  

SciTech Connect

Isoprene, a reactive, branched diene, is used in large quantities in the manufacture of polyisoprene and as a copolymer in the synthesis of butyl rubber. The potential for isoprene to cause developmental toxicity was assessed in rodents, by exposing four groups each of Sprague-Dawley rats and Swiss (CD-1) mice to 0, 280, 1400, or 7000 ppM isoprene vapors, 6 h/day, 7 day/wk. Each treatment group consisted of 10 virgin females (for comparison), and approx.30 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 31 refs., 6 figs., 19 tabs.

Mast, T.J.; Evanoff, J.J.; Stoney, K.H.; Westerberg, R.B.; Rommereim, R.L.; Weigel, R.J.



Timing of Decompressive Surgery of Spinal Cord after Traumatic Spinal Cord Injury: An Evidence-Based Examination of Pre-Clinical and Clinical Studies  

PubMed Central

Abstract While the recommendations for spine surgery in specific cases of acute traumatic spinal cord injury (SCI) are well recognized, there is considerable uncertainty regarding the role of the timing of surgical decompression of the spinal cord in the management of patients with SCI. Given this, we sought to critically review the literature regarding the pre-clinical and clinical evidence on the potential impact of timing of surgical decompression of the spinal cord on outcomes after traumatic SCI. The primary literature search was performed using MEDLINE, CINAHL, EMBASE, and Cochrane databases. A secondary search strategy incorporated articles referenced in prior meta-analyses and systematic and nonsystematic review articles. Two reviewers independently assessed every study with regard to eligibility, level of evidence, and study quality. Of 198 abstracts of pre-clinical studies, 19 experimental studies using animal SCI models fulfilled our inclusion and exclusion criteria. Despite some discrepancies in the results of those pre-clinical studies, there is evidence for a biological rationale to support early decompression of the spinal cord. Of 153 abstracts of clinical studies, 22 fulfilled the inclusion and exclusion criteria. While the vast majority of the clinical studies were level-4 evidence, there were two studies of level-2b evidence. The quality assessment scores varied from 7 to 25 with a mean value of 12.41. While 2 of 22 clinical studies assessed feasibility and safety, 20 clinical studies examined efficacy of early surgical intervention to stabilize and align the spine and to decompress the spinal cord; the most common definitions of early operation used 24 and 72?h after SCI as timelines. A number of studies indicated that patients who undergo early surgical decompression can have similar outcomes to patients who received a delayed decompressive operation. However, there is evidence to suggest that early surgical intervention is safe and feasible and that it can improve clinical and neurological outcomes and reduce health care costs. Based on the current clinical evidence using a Delphi process, an expert panel recommended that early surgical intervention should be considered in all patients from 8 to 24?h following acute traumatic SCI. PMID:20001726

Furlan, Julio C.; Noonan, Vanessa; Cadotte, David W.



Identification of Prenatal Amphetamines Exposure by Maternal Interview and Meconium Toxicology in the Infant Development, Environment and Lifestyle (IDEAL) Study  

PubMed Central

The Infant Development Environment and Lifestyle (IDEAL) study is investigating the effects of prenatal methamphetamine (MAMP) exposure on infant and child development; potential concurrent exposure to cannabis and tobacco also are evaluated. Maternal self-reported drug use and/or meconium toxicology results defined drug exposure status. It is unclear how the frequency, duration and magnitude of maternal MAMP exposure affect qualitative and quantitative meconium results. Materials and Methods Interviews regarding maternal drug use were collected shortly after birth; meconium specimens were screened for amphetamines, cannabis and cotinine by immunoassay and confirmed by gas chromatography mass spectrometry (GCMS). Results The majority of MAMP- and cannabis-exposed infants were identified by maternal interview alone. Meconium tests were more likely to be positive if the mother reported MAMP and cannabis use, particularly in the third trimester. Less than half of immunoassay-positive amphetamines (31.0%) and cannabis (17.9%) meconium results were confirmed by GCMS. Tobacco exposure was equally detected by immunoassay cotinine screen and maternal report. Meconium concentrations did not correlate with maternal self-report status or trimester of use, frequency or route of MAMP use. Discussion Maternal self-report was more sensitive than meconium testing for identifying MAMP and cannabis-exposed neonates; however, the timing of drug exposure may influence meconium toxicology results. Most women ceased MAMP and cannabis use before the third trimester. In the first trimester, meconium has not yet formed, and based on our recent results for opiates and cocaine, drug use in the second trimester appears to be poorly reflected in meconium. Conclusion Low confirmation rates in meconium reinforce the need for confirmatory testing following positive screening results and additional research to identify alternative biomarkers. PMID:19935364

Gray, Teresa R.; LaGasse, Linda L.; Smith, Lynne M.; Derauf, Chris; Grant, Penny; Shah, Rizwan; Arria, Amelia M.; Della Grotta, Sheri A.; Strauss, Arthur; Haning, William F.; Lester, Barry M.; Huestis, Marilyn A.



Applications of Proteomic Technologies to Toxicology  

EPA Science Inventory

Proteomics is the large-scale study of gene expression at the protein level. This cutting edge technology has been extensively applied to toxicology research recently. The up-to-date development of proteomics has presented the toxicology community with an unprecedented opportunit...


Inhalation developmental toxicology studies of 1,3-butadiene in the rat: Final report  

SciTech Connect

Maternal toxicity, reproductive performance and developmental toxicology were evaluated in Sprague-Dawley-derived rats during and following 6 hours/day, whole-body, inhalation exposures to 0, 40, 200, and 1000 ppM of 1,3-butadiene. The female rats (Ns = 24 to 28), which had mated with unexposed males, were exposed to the chemical from 6 through 15 dg and sacrificed on 20 dg. Maternal animals were weighed prior to mating and on 0, 6, 11, 16 and 20 dg; the rats were observed for mortality, morbidity and signs of toxicity during exposure and examined for gross tissue abnormalities at necropsy. Live fetuses were weighed and subjected to external, visceral and skeletal examinations to detect growth retardation and morphologic anomalies. There were no significant differences among treatment groups in maternal body weights or extragestational weights of rats exposed to 1,3-butadiene concentrations of 40 or 200 ppM, but, in animals exposed to 1000 ppM, significantly depressed body weight gains were observed during the first 5 days of exposure and extragestational weight gains tended to be lower than control values. These results, and the absence of clinical signs of toxicity, were considered to indicate that there was no maternal toxicity at exposure levels of 200 ppM or lower. The percentage of pregnant animals and the number of litters with live fetuses were unaffected by treatment. Under the conditions of this exposure regimen, there was no evidence for a teratogenic response to 1,3-butadiene exposure.

Hackett, P.L.; Sikov, M.R.; Mast, T.J.; Brown, M.G.; Buschbom, R.L.; Clark, M.L.; Decker, J.R.; Evanoff, J.J.; Rommereim, R.L.; Rowe, S.E.; Westerberg, R.B.



[Studies of biologic activation associated with molecular receptor increase and tumor response in ChL6/L6 protocol patients; Studies in phantoms; Quantitative SPECT; Preclinical studies; and Clinical studies]. DOE annual report, 1994--95  

SciTech Connect

The authors describe results which have not yet been published from their associated studies listed in the title. For the first, they discuss Lym-1 single chain genetically engineered molecules, analysis of molecular genetic coded messages to enhance tumor response, and human dosimetry and therapeutic human use radiopharmaceuticals. Studies in phantoms includes a discussion of planar image quantitation, counts coincidence correction, organ studies, tumor studies, and {sup 90}Y quantitation with Bremsstrahlung imaging. The study on SPECT discusses attenuation correction and scatter correction. Preclinical studies investigated uptake of {sup 90}Y-BrE-3 in mice using autoradiography. Clinical studies discuss image quantitation verses counts from biopsy samples, S factors for radiation dose calculation, {sup 67}Cu imaging studies for lymphoma cancer, and {sup 111}In MoAb imaging studies for breast cancer to predict {sup 90}Y MoAb therapy.

DeNardo, S.J.



The basics of preclinical drug development for neurodegenerative disease indications  

Microsoft Academic Search

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The

Karen L Steinmetz; Edward G Spack



Contrasting gray and white matter changes in preclinical Huntington disease  

E-print Network

Contrasting gray and white matter changes in preclinical Huntington disease An MRI study DD ABSTRACT Background: In Huntington disease (HD), substantial striatal atrophy precedes clinical motor of view; GM gray matter; HD Huntington disease; MRI magnetic resonance imaging; pre-HD preclinical HD

Aron, Adam


Validation of murine and human placental explant cultures for use in sex steroid and phase II conjugation toxicology studies.  


Human primary placental explant culture is well established for cytokine signaling and toxicity, but has not been validated for steroidogenic or metabolic toxicology. The technique has never been investigated in the mouse. We characterized human and mouse placental explants for up to 96h in culture. Explant viability (Lactate dehydrogenase) and sex steroid levels were measured in media using spectrophotometry and ELISA, respectively. Expression and activities of the steroidogenic (3?-hydroxysteroid dehydrogenase, Cytochrome P45017A1, Cytochrome P45019), conjugation (UDP-glucuronosyltransferase, sulfotransferase (SULT)), and regeneration (?-glucuronidase, arylsulfatase C (ASC)) enzymes were determined biochemically in tissues with fluorimetric and spectrophotometric assays, and western blot. Explants were viable up to 96h, but progesterone, estrone, and 17?-estradiol secretion decreased. Steroidogenic enzyme expression and activities were stable in mouse explants and similar to levels in freshly isolated tissues, but were lower in human explants than in fresh tissue (P<0.01). Human and mouse explants exhibited significantly less conjugation after 96h, SULT was not detected in the mouse, and neither explants had active ASC, although proteins were expressed. Mouse explants may be useful for steroid biochemistry and endocrine disruption studies, but not metabolic conjugation. In contrast, human explants may be useful for studying conjugation for <48h, but not for steroid/endocrine studies. PMID:25283089

Sato, Brittany L; Ward, Monika A; Astern, Joshua M; Kendal-Wright, Claire E; Collier, Abby C



Toxicological studies of a leachable stabilizer di-n-butyltin dilaurate(DBTL): effects on hepatic drug metabolizing enzyme activities.  


Toxicological studies of a leachable stabilizer Di-n-butyltin dilaurate (DBTL) were undertaken. Effects of DBTL after 15 days oral exposure to rats were studied on brain and liver enzyme activities. A significant decrease in body weight gain of DBTL exposed rats were observed. No effect was observed in the activities of brain enzymes, succinic dehydrogenase, adenosine triphosphatase, acetylcholine esterase and monoamine oxidase. In liver, DBTL treatment resulted in a significant decrease in the activities of microsomal enzymes glucose-6-phosphatase, aminopyrine-N-demethylase, benzphetamine-N-demethylase, aniline hydroxylase, benzo(a)pyrene hydroxylase and also on cytochrome P-450 content, whereas no difference in the activities of mitochondrial enzymes, succinic dehydrogenase, Mg2+-adenosine triphosphatase as well as in the activity of lysosomal enzyme acid phosphatase was observed. Duration of exposure dependent increase in pentabarbital induced sleeping time was also observed. DBTL treatment produced an induction in heme oxygenase activity whereas the activity of -aminolevulinic acid synthetase remained unaltered. The results demonstrate that DBTL significantly affects the biotransformation mechanism and heme metabolism of hepatocytes. PMID:7261948

Mushtaq, M; Mukhtar, H; Datta, K K; Tandon, S G; Seth, P K



Management of ErbB2-positive breast cancer: insights from preclinical and clinical studies with lapatinib.  


The management of human epidermal growth factor receptor 2-positive (ErbB2+) breast cancer is challenging; patients with ErbB2+ breast tumors have more aggressive disease and a poor prognosis. The increasing incidence of breast cancer in Asia and the limitations of existing treatments pose additional challenges. In this review, we summarize the preclinical and clinical evidence that indicates how lapatinib, a novel inhibitor that targets the human epidermal growth factor receptor (ErbB1) and ErbB2 may help clinicians address four particularly challenging issues in the management of ErbB2+ breast cancer. These issues are: (i) trastuzumab therapy failure, (ii) development of central nervous system metastases, (iii) minimizing toxicity and (iv) selecting the most appropriate partners (chemotherapy and non-chemotherapy) for combination therapy with lapatinib. Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab. Lapatinib, in combination with non-chemotherapeutic agents, such as letrozole, may also provide a chemotherapy-free treatment option for postmenopausal patients with estrogen receptor-positive/ErbB2+ metastatic breast cancer. Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer. Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases. Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer. PMID:20542996

Vogel, Charles; Chan, Arlene; Gril, Brunilde; Kim, Sung-Bae; Kurebayashi, Junichi; Liu, Li; Lu, Yen-Shen; Moon, Hanlim




EPA Science Inventory

The National Toxicology Program (NTP) was established in 1978 by the Department of Health and Human Services (DHHS) to coordinate toxicological testing programs within the department, strengthen the science base in toxicology; develop and validate improved testing methods; and pr...


NTP Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in F344/N Rats (Feed Studies).  


Oxazepam and related benzodiazepine drugs are used in the treatment of anxiety. All benzodiazepines currently in use share a number of effects, including sedation, hypnosis, decreased anxiety, muscle relaxation, amnesia, and anticonvulsant activity. Oxazepam and four other benzodiazepines (chlordiazepoxide, chlorazepate, diazepam, and flurazepam) were nominated for study by the Food and Drug Administration (FDA) and by the NIEHS based on their widespread use, use by pregnant women, and the lack of adequate rodent carcinogenicity studies. Oxazepam was evaluated in 14-week and 2-year studies by the NTP, and Technical Report No. 443 contains the results of the studies performed with the Swiss-Webster and B6C3F1 strains of mice. Studies with rats were not initiated at the same time as the mouse studies because adequate carcinogenicity studies of oxazepam with the Sprague-Dawley rat strain had been submitted to the FDA. Subsequently, because of the marked neoplastic responses found in the two mouse strains, the NTP initiated 2-year studies of oxazepam with the F344/N rat. Groups of male and female F344/N rats were exposed to oxazepam (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells, and mouse peripheral blood samples were analyzed for the frequency of micronucleated normochromatic erythrocytes. 2-YEAR STUDY: Groups of 50 male and 50 female F344/N rats were fed diets containing 0, 625, 2,500, or 5,000 ppm oxazepam for up to 105 weeks. A stop-exposure group of 50 males and 50 females received 10,000 ppm oxazepam in feed for 26 weeks, after which animals received undosed feed for the remainder of the 2-year study. The continuous-exposure concentrations resulted in average daily doses of 25, 100, or 250 mg oxazepam/kg body weight to males and 25, 110, or 220 mg/kg to females. Stop- exposure males and females received an average daily dose of 630 mg/kg during the exposure period. Survival, Body Weights, and Clinical Findings: All 5,000 ppm continuous-exposure and 10,000 ppm stop-exposure males died before the end of the study. Survival of 2,500 ppm continuous-exposure males and females was significantly less than that of the controls. The mean body weight gains of 2,500 and 5,000 ppm males and females were less than those of the controls throughout the study. The mean body weights of 10,000 ppm stop-exposure males were generally less than those of the controls throughout the study; those of 10,000 ppm stop-exposure females were less than those of the controls during the exposure portion of the study but increased steadily after the cessation of dosing at week 27. Feed consumption by exposed groups was similar to that by the controls after week 1 of the study. Treatment-related eye/nasal discharge, hyperactivity when handled, and/or ataxia were observed in exposed male and female rats on or about day 2 of exposure but were no longer apparent after day 7. Plasma Oxazepam Determinations: Plasma oxazepam concentrations were measured at the end of the study. The concentrations ranged from approximately 0.5 (625 ppm males) to 2.8 &mgr;g/mL (5,000 ppm females). Pathology Findings: In the standard histopathologic evaluation, the incidence of renal tubule adenoma was slightly increased in male rats exposed to 2,500 ppm and was at the upper limit of the historical control range for this neoplasm in 2-year NTP feed studies. In an extended evaluation (step section) of the kidneys of male rats, the incidences of renal tubule adenoma occurred with a positive trend in exposed groups. In standard and step sections (combined), male rats exposed to 2,500 or 5,000 ppm showed a significant increase in the incidences of renal tubule adenoma and hyperplasia. In addition, the incidences of renal tubule adenoma and hyperplasia were significantly increased in the 10,000 ppm stop-exposure group. The incidences of nephropathy in continuously exposed female rats were significantly greater than in the controls, and the severity of nephropathy increased wis



Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study  

NASA Astrophysics Data System (ADS)

Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore



Preclinical profile of cabazitaxel  

PubMed Central

First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel. In conclusion, the demonstrated activity of cabazitaxel in tumors with innate or acquired resistance to docetaxel, CNS tumors, and pediatric tumors made this agent a candidate for further clinical evaluation in a broader range of patient populations compared with first-generation taxanes. PMID:25378905

Vrignaud, Patricia; Semiond, Dorothée; Benning, Veronique; Beys, Eric; Bouchard, Hervé; Gupta, Sunil



Toxicology ontology perspectives.  


The field of predictive toxicology requires the development of open, public, computable, standardized toxicology vocabularies and ontologies to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. In this article we review ontology developments based on a set of perspectives showing how ontologies are being used in predictive toxicology initiatives and applications. Perspectives on resources and initiatives reviewed include OpenTox, eTOX, Pistoia Alliance, ToxWiz, Virtual Liver, EU-ADR, BEL, ToxML, and Bioclipse. We also review existing ontology developments in neighboring fields that can contribute to establishing an ontological framework for predictive toxicology. A significant set of resources is already available to provide a foundation for an ontological framework for 21st century mechanistic-based toxicology research. Ontologies such as ToxWiz provide a basis for application to toxicology investigations, whereas other ontologies under development in the biological, chemical, and biomedical communities could be incorporated in an extended future framework. OpenTox has provided a semantic web framework for the implementation of such ontologies into software applications and linked data resources. Bioclipse developers have shown the benefit of interoperability obtained through ontology by being able to link their workbench application with remote OpenTox web services. Although these developments are promising, an increased international coordination of efforts is greatly needed to develop a more unified, standardized, and open toxicology ontology framework. PMID:22562487

Hardy, Barry; Apic, Gordana; Carthew, Philip; Clark, Dominic; Cook, David; Dix, Ian; Escher, Sylvia; Hastings, Janna; Heard, David J; Jeliazkova, Nina; Judson, Philip; Matis-Mitchell, Sherri; Mitic, Dragana; Myatt, Glenn; Shah, Imran; Spjuth, Ola; Tcheremenskaia, Olga; Toldo, Luca; Watson, David; White, Andrew; Yang, Chihae



Preclinical Cardiorenal Interrelationships in Essential Hypertension  

PubMed Central

A diseased heart causes numerous adverse effects on kidney function, and vice versa renal disease can significantly impair cardiac function. Beyond these heart-kidney interrelationships at the clinical level, a reciprocal association has been suggested to exist even in the early stages of those organs' dysfunction. The aim of the present review is to provide evidence of the presence of a preclinical cardiorenal syndrome in the particular setting of essential hypertension, focusing on the subsequent hypertensive sequelae on heart and kidneys. In particular, a plethora of studies have demonstrated not only the predictive role of kidney damage, as expressed by either decreased glomerular filtration or increased urine albumin excretion, for adverse left ventricular functional and structural adaptations but also preclinical heart disease, i.e. left ventricular hypertrophy that is associated with deterioration of renal function. Notably, these reciprocal interactions seem to exist even at the level of microcirculation, since both coronary flow reserve and renal hemodynamics are strongly related with clinical and preclinical renal and cardiac damage, respectively. In this preclinical setting, common pathophysiological denominators, including the increased hemodynamic load, sympathetic and renin-angiotensin system overactivity, increased subclinical inflammatory reaction, and endothelial dysfunction, account not only for the reported associations between overt cardiac and renal damage but also for the parallel changes that occur in coronary and renal microcirculation. PMID:23946723

Tsioufis, Costas; Tsiachris, Dimitrios; Kasiakogias, Alexandros; Dimitriadis, Kyriakos; Petras, Dimitris; Goumenos, Dimitris; Siamopoulos, Konstantinos; Stefanadis, Christodoulos




EPA Science Inventory

Among the many promised and potential applications of embryonic stem cells, in vitro toxicology is one area in which ES cells have already proven their utility. In 2003, the Embryonic Stem Cell Test (EST) protocol was validated in Europe as an in vitro alternative to live animal...


Metabolic profiling studies on the toxicological effects of realgar in rats by {sup 1}H NMR spectroscopy  

SciTech Connect

The toxicological effects of realgar after intragastrical administration (1 g/kg body weight) were investigated over a 21 day period in male Wistar rats using metabonomic analysis of {sup 1}H NMR spectra of urine, serum and liver tissue aqueous extracts. Liver and kidney histopathology examination and serum clinical chemistry analyses were also performed. {sup 1}H NMR spectra and pattern recognition analyses from realgar treated animals showed increased excretion of urinary Kreb's cycle intermediates, increased levels of ketone bodies in urine and serum, and decreased levels of hepatic glucose and glycogen, as well as hypoglycemia and hyperlipoidemia, suggesting the perturbation of energy metabolism. Elevated levels of choline containing metabolites and betaine in serum and liver tissue aqueous extracts and increased serum creatine indicated altered transmethylation. Decreased urinary levels of trimethylamine-N-oxide, phenylacetylglycine and hippurate suggested the effects on the gut microflora environment by realgar. Signs of impairment of amino acid metabolism were supported by increased hepatic glutamate levels, increased methionine and decreased alanine levels in serum, and hypertaurinuria. The observed increase in glutathione in liver tissue aqueous extracts could be a biomarker of realgar induced oxidative injury. Serum clinical chemistry analyses showed increased levels of lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase as well as increased levels of blood urea nitrogen and creatinine, indicating slight liver and kidney injury. The time-dependent biochemical variations induced by realgar were achieved using pattern recognition methods. This work illustrated the high reliability of NMR-based metabonomic approach on the study of the biochemical effects induced by traditional Chinese medicine.

Wei Lai; Liao Peiqiu; Wu Huifeng [Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 (China); Li Xiaojing [Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 (China)], E-mail:; Pei Fengkui [Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 (China)], E-mail:; Li Weisheng; Wu Yijie [Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 (China)



Use of genetic toxicology data in U.S. EPA risk assessment: the mercury study report as an example.  

PubMed Central

Assessment of human health risks of environmental agents has often been limited to consideration of the potential for the agent to cause cancer or general systemic toxicity after long-term exposure. The U.S. Environmental Protection Agency (U.S. EPA) is increasingly moving toward the development of integrated assessments, which consider all potential health end points including developmental toxicity, neurotoxicity, immunotoxicity, reproductive effects, and germ cell mutagenicity. The U.S. EPA has a responsibility to assess risks to nonhuman species or ecosystems when appropriate data are available. An example of a recent integrated human health and ecological risk assessment can be found in the U.S. EPA Mercury Study Report to Congress. This report covers the following topics in separate volumes: an inventory of anthropogenic mercury emissions in the United States; an exposure assessment using measured and predicted values and including indirect dietary exposure; an evaluation of human health risks; an assessment of ecologic risk wherein water criteria are presented for several wildlife species; an overall integrated characterization of human and nonhuman risk; and a discussion of risk management considerations. In the evaluation of human health risk, genetic toxicology data were considered for three forms of mercury: elemental, inorganic (divalent), and methylmercury. These data were used in judgments of two types of potential health effects (carcinogenicity and germ cell mutagenicity). In assessment of potential carcinogenicity of inorganic and methylmercury, genetic toxicity data were key. Data for clastogenicity in the absence of mutagenicity supported the characterization of inorganic and methylmercury as materials that produce carcinogenic effects only at high, toxic doses. The evidence for clastogenicity, coupled with information on metabolism and distribution, resulted in a judgment of a moderate degree of concern (or weight of evidence) that inorganic mercury can act as a human germ cell mutagen. For methylmercury, the degree of concern for germ cell mutagenicity is high. PMID:8781402

Schoeny, R



Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated Born-normalization and in vivo preclinical study of cancer.  


Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets. PMID:24880378

Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric



Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated born-normalization and in vivo preclinical study of cancer  

NASA Astrophysics Data System (ADS)

Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets.

Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric



A pharmacokinetic study of ethyl glucuronide in blood and urine: Applications to forensic toxicology  

Microsoft Academic Search

This pharmacokinetic study investigated the kinetics of ethanol and its metabolite ethyl glucuronide (EtG) in blood and urine during the whole time course of absorption and elimination. There are few previous studies on the kinetics of EtG in blood, and we wanted to evaluate whether such knowledge could yield valuable information regarding the time of ethanol ingestion in forensic cases,

Gudrun Høiseth; Jean Paul Bernard; Ritva Karinen; Lene Johnsen; Anders Helander; Asbjørg S. Christophersen; Jørg Mørland



A toxicological study of 1,2,4-triazole-5-one  

SciTech Connect

The acute oral LD/sub 50/ values for 1,2,4-triazole-5-one (TO) are greater than 5g/kg. According to classical guidelines, the material would be considered only slightly toxic or practically nontoxic in both rats and mice. The sensitization study in the guinea pig did not show TO to have potential sensitizing effects. Skin application studies on the rabbit demonstrated it was cutaneously nonirritating. This material was also nonirritating in the rabbit eye application studies. 4 refs., 1 tab.

London, J.




EPA Science Inventory

Acute oral LD50 and 30-day dietary subacute LC50 studies of 10 selected pesticides were evaluated in microtine rodents. As a means to developing new animal model systems, four species of microtine rodents including Microtus ochrogaster (MO), Microtus canicaudus (MC), Microtus pen...



EPA Science Inventory

Arsenic (As) is a common environmental toxicant and known human carcinogen. Epidemiological studies link As exposure to various disorders and cancers. However, the molecular mechanisms for As toxicity and carcinogenicity are not completely known. The cDNA microarray, a high-th...



EPA Science Inventory

Heart rate variability (HRV) is a measure of cardiac pacing dynamics that has recently garnered a great deal of interest in environmental health studies. While the use of these measures has become popular, much uncertainty remains in the interpretation of results, both in terms ...


Toward a Checklist for Exchange and Interpretation of Data froma Toxicology Study  

EPA Science Inventory

With the advent of toxicogenomics came the need to share data across interdisciplinary teams and to deposit data associated with publications into public data repositories. Within a single institution, many variables associated with a study are standardized, for instance diet, an...


Toxicological significance of dihydrodiol metabolites  

SciTech Connect

Dihydrodiols are often found as the major organic-extractable metabolites of various olefinic or aromatic xenobiotics in many biological samples. Studies on the chemistry of dihydrodiol metabolites have provided insight into the pharmacokinetic behavior and the mode of action of the parent compound. The toxicology of dihydrodiol is more complex than what can be deduced solely on the basis of diminished bioavailability of the epoxide precursor, and the increased hydrophilicity associated with the dihydrodiol moiety. Dihydrodiols can be intrinsically toxic and may even represent metabolically activated species. Some of the dihydrodiol metabolites may still retain sufficient lipophilic character to serve again as substrates for microsomal oxygenases. Because of the tremendous chemical and biological diversity that existed among the various dihydrodiols, more mechanistic studies are needed to examine the toxicological properties of these compounds. It may be premature to conclude dihydrodiol formation as purely a detoxification route for xenobioties.

Hsia, M.T.



Toxicological Evaluation of Realistic Emission Source Aerosols (TERESA)--Power plant studies: assessment of breathing pattern  

PubMed Central

Our approach to study multi-pollutant aerosols isolates a single emissions source, evaluates the toxicity of primary and secondary particles derived from this source, and simulates chemical reactions that occur in the atmosphere after emission. Three U.S. coal-fired power plants utilizing different coals and with different emission controls were evaluated. Secondary organic aerosol (SOA) derived from ?-pinene and/or ammonia was added in some experiments. Male Sprague-Dawley rats were exposed for 6 h to filtered air or different atmospheric mixtures. Scenarios studied at each plant included the following: primary particles (P); secondary (oxidized) particles (PO); oxidized particles + SOA (POS); and oxidized and neutralized particles + SOA (PONS); additional control scenarios were also studied. Continuous respiratory data were obtained during exposures using whole body plethysmography chambers. Of the 12 respiratory outcomes assessed, each had statistically significant changes at some plant and with some of the 4 scenarios. The most robust outcomes were found with exposure to the PO scenario (increased respiratory frequency with decreases in inspiratory and expiratory time); and the PONS scenario (decreased peak expiratory flow and expiratory flow at 50%). PONS findings were most strongly associated with ammonium, neutralized sulfate, and elemental carbon (EC) in univariate analyses, but only with EC in multivariate analyses. Control scenario O (oxidized without primary particles) had similar changes to PO. Adjusted R2 analyses showed that scenario was a better predictor of respiratory responses than individual components, suggesting that the complex atmospheric mixture was responsible for respiratory effects. PMID:21639693

Diaz, Edgar A.; Lemos, Miriam; Coull, Brent; Long, Mark S.; Rohr, Annette C.; Ruiz, Pablo; Gupta, Tarun; Kang, Choong-Min; Godleski, John J.



Toxicological and cytogenetic assessment of a Salacia oblonga extract in a rat subchronic study.  


Salacia oblonga holds potential as a natural method to mitigate the blood glucose response for people with diabetes by inhibiting the activity of intestinal alpha-glucosidases. As part of a safety evaluation of novel ingredients for use in blood glucose control, the toxicity of a S. oblonga root extract (SOE) was evaluated in a subchronic 90-day feeding study in rats. An in vivo-in vitro rat peripheral blood lymphocyte chromosomal aberrations assay was added at termination of the subchronic rat study to examine cultured lymphocytes for possible chromosomal aberration induction. This was conducted due to a previous weak; although reproducible, positive chromosomal aberrations response in cultured peripheral blood human lymphocytes after acute in vitro treatment with SOE. The present study results indicate that SOE was negative for the induction of chromosomal aberrations in cultured rat peripheral blood lymphocytes after 90 consecutive days of treatment with SOE. The no observable adverse effect level (NOAEL) was determined to be 2,500 mg/kg/day following daily subchronic oral gavage administrations to rats. PMID:17566623

Flammang, A M; Erexson, G L; Mirwald, J M; Henwood, S M




PubMed Central

Lactate dehydrogenase (LDH) release is frequently used as an end-point for cytotoxicity studies. We have been unable to measure LDH release during studies using para-aminophenol (PAP) in LLC-PK1 cells. When LLC-PK1 cells were incubated with either PAP (0–10 mM) or menadione (0–1000 ?M), viability was markedly reduced when assessed by alamar Blue or total LDH activity but not by release of LDH into the incubation medium. In addition, we incubated cells with PAP or menadione and compared LDH activity using two different assays. Both assays confirmed our observation of decreased LDH activity in cell lysates without corresponding increases in LDH activity in incubation media. Using purified LDH and 10 mM PAP, we that PAP produced loss of LDH activity that was inversely proportional to the amount of LDH initially added. In additional experiments, we incubated 0.5 units of LDH for 1 h with varying concentrations of PAP, menadione, hydrogen peroxide (H2O2) or cisplatin. All four chemicals produced concentration-dependent decreases in LDH activity. In previous experiments, inclusion of antioxidants such as reduced glutathione (GSH) and ascorbate protected cells from PAP toxicity. GSH (1 mM) preserved LDH activity in the presence of toxicants while ascorbate (1 mM) only prevented LDH loss induced by PAP. These studies suggest that LDH that is released into the incubation medium is susceptible to degradation when reactive chemicals are present. PMID:17079110

Kendig, Derek M.; Tarloff, Joan B.



Computational Toxicology (S)  

EPA Science Inventory

The emerging field of computational toxicology applies mathematical and computer models and molecular biological and chemical approaches to explore both qualitative and quantitative relationships between sources of environmental pollutant exposure and adverse health outcomes. Th...


Toxicological Sciences Online  

NSDL National Science Digital Library

The journal Toxicological Sciences is now available online, thanks to a combined effort of the Society for Toxicology and Stanford University's HighWire Press. Toxicological Sciences publishes "research articles that are broadly relevant to assessing the potential adverse health effects resulting from exposure of human or animals to chemicals, drugs, natural products, or synthetic materials." Manuscripts are published in "all areas of toxicology" including descriptive, mechanistic, interpretive, theoretical, experimental, and observational investigations. The full text (.pdf format) of all articles is available online starting 1999, with abstracts from 1998. The Society has yet to announce when the free trial period will end, but at present, the site allows free access to all online materials, as well as a free sample issue.



Preclinical Dose-Finding Study With a Liver-Tropic, Recombinant AAV-2/8 Vector in the Mouse Model of Galactosialidosis  

PubMed Central

Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients. PMID:22008912

Hu, Huimin; Gomero, Elida; Bonten, Erik; Gray, John T; Allay, Jim; Wu, Yanan; Wu, Jianrong; Calabrese, Christopher; Nienhuis, Arthur; d'Azzo, Alessandra



Preclinical dose-finding study with a liver-tropic, recombinant AAV-2/8 vector in the mouse model of galactosialidosis.  


Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients. PMID:22008912

Hu, Huimin; Gomero, Elida; Bonten, Erik; Gray, John T; Allay, Jim; Wu, Yanan; Wu, Jianrong; Calabrese, Christopher; Nienhuis, Arthur; d'Azzo, Alessandra



Preclinical studies with the anti-CD19-saporin immunotoxin BU12-SAPORIN for the treatment of human-B-cell tumours.  

PubMed Central

The immunotoxin BU12-SAPORIN was constructed by covalently coupling the single-chain ribosome-inactivating protein saporin to the anti-CD19 monoclonal antibody BU12 via a disulphide linker using the heterobifunctional reagent SPDP. The immunoreactivity and specificity of BU12-SAPORIN was identical to that of unmodified native BU12 antibody. BU12-SAPORIN was selectively cytotoxic in vitro in a dose-dependent manner for the CD19+ human common acute lymphoblastic leukaemia (cALL) cell line NALM-6 but exhibited no toxicity for the CD19- T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2. The survival of severe combined immunodeficient (SCID) mice with disseminated NALM-6 leukaemia was significantly prolonged compared with sham-treated control animals by a course of therapy with BU12-SAPORIN but not with the irrelevant anti-CD7 immunotoxin HB2-SAPORIN. BU12-SAPORIN had no therapeutic effect in SCID mice with disseminated CD19- HSB-2 leukaemia. These preclinical studies have clearly demonstrated the selective cytotoxicity of BU12-SAPORIN for CD19+ target cells both in vitro and in vivo. This, taken together with the lack of expression of the CD19 molecule by any normal life-sustaining tissue and its ubiquitous and homogeneous expression by the majority of cALL and B-NHL cells, provides the rationale for undertaking a phase I trial of systemic therapy with BU12-SAPORIN. Images Figure 1 PMID:8519647

Flavell, D. J.; Flavell, S. U.; Boehm, D. A.; Emery, L.; Noss, A.; Ling, N. R.; Richardson, P. R.; Hardie, D.; Wright, D. H.



Preclinical Evaluation of HIV Eradication Strategies in the Simian Immunodeficiency Virus-Infected Rhesus Macaque: A Pilot Study Testing Inhibition of Indoleamine 2,3-Dioxygenase  

PubMed Central

Abstract Even in the setting of maximally suppressive antiretroviral therapy (ART), HIV persists indefinitely. Several mechanisms might contribute to this persistence, including chronic inflammation and immune dysfunction. In this study, we have explored a preclinical model for the evaluation of potential interventions that might serve to eradicate or to minimize the level of persistent virus. Given data that metabolic products of the inducible enzyme indoleamine 2,3-dioxygeanse (IDO) might foster inflammation and viral persistence, chronically simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques were treated with the IDO inhibitor 1-methyl tryptophan (1mT). Orally administered 1mT achieved targeted plasma levels, but did not impact tryptophan metabolism or decrease viral RNA or DNA in plasma or in intestinal tissues beyond levels achieved by ART alone. Animals treated with 1mT showed no difference in the levels of T cell activation or differentiation, or in the kinetics or magnitude of viral rebound following cessation of ART. Notwithstanding these negative results, our observations suggest that the chronically SIV-infected rhesus macaque on suppressive ART can serve as a tractable model in which to test and to prioritize the selection of other potential interventions designed to eradicate HIV in vivo. In addition, this model might be used to optimize the route and dose by which such interventions are administered and the methods by which their effects are monitored. PMID:22924680

Dunham, Richard M.; Gordon, Shari N.; Vaccari, Monica; Piatak, Michael; Huang, Yong; Deeks, Steven G.; Lifson, Jeffrey; Franchini, Genoveffa



Toxicological impact studies based on Escherichia coli bacteria in ultrafine ZnO nanoparticles colloidal medium.  


We report here preliminary studies of biocidal effects and cellular internalization of ZnO nanoparticles on Escherichia coli bacteria. ZnO nanoparticles were synthesized in di(ethylene glycol) (DEG) medium by forced hydrolysis of ionic Zn2+ salts. Particle size and shape were controlled by addition of small molecules and macromolecules such as tri-n-octylphosphine oxide, sodium dodecyl sulfate, polyoxyethylene stearyl ether, and bovine serum albumin. Transmission electron microscopy (TEM) and X-ray diffraction analyses were used to characterize particle structure, size, and morphology. Bactericidal tests were performed in Luria-Bertani medium on solid agar plates and in liquid systems with different concentrations of small and macromolecules and also with ZnO nanoparticles. TEM analyses of bacteria thin sections were used to study biocidal action of ZnO materials. The results confirmed that E. coli cells after contact with DEG and ZnO were damaged showing a Gram-negative triple membrane disorganization. This behavior causes the increase of membrane permeability leading to accumulation of ZnO nanoparticles in the bacterial membrane and also cellular internalization of these nanoparticles. PMID:16608300

Brayner, Roberta; Ferrari-Iliou, Roselyne; Brivois, Nicolas; Djediat, Shakib; Benedetti, Marc F; Fiévet, Fernand



Toxicological study and oxidative stress evaluation for safety assessment of xylanase preparations in wistar rats.  


Acute and 90-day subchronic oral toxicity studies were conducted to establish the safety evaluation of xylanases preparations. A potential oxidative stress evaluation was also performed through testing the generation of oxidative radicals, depletion of antioxidants via oxidative modification of lipids, proteins and DNA of organ cells. During the subchronic oral toxicity study, no mortality was observed, obvious treatment-related clinical signs and urinalysis parameters were in normal range. Differences in some hematological parameters, biochemistry, relative organ weight, and histopathology examinations between the treated group and the control group were not judged to be adverse. Our results indicated that the no-observed-adverse-effect level for xylanases was 1,500 TXU/kg/day and the plasma antioxidant assays showed that these xylanases did not produce free-radicals nor oxidative injuries. On the basis of the bacterial reverse mutation assay data, it is concluded that the expressed xylanase in Pichia pastoris do not present any mutagenic potential when tested in relevant genotoxicological assays. PMID:25044497

Driss, Dorra; Soudani, Najla; Boudawara, Tahia; Zeghal, Najiba; Chaabouni, Semia Ellouze



Therapeutic and toxicologic studies in a murine model of invasive pulmonary aspergillosis.  


Invasive pulmonary aspergillosis remains problematic in immunocompromised patient populations. We studied potential therapeutic options in a murine model of pulmonary aspergillosis in triamcinolone-suppressed DBA/2 mice infected intranasally with conidia from Aspergillus fumigatus. Mice were treated with liposomal-amphotericin B (AmBi; AmBisome), lipid-complexed amphotericin B (ABLC; Abelcet), voriconazole (VCZ), micafungin (MICA), caspofungin (CAS) or deoxycholate amphotericin B (AMBd) given alone or in combination. Monotherapy with AmBi, ABLC, AMBd, CAS or MICA had activity in prolonging survival; however, only AMBd or CAS reduced fungal burden in the lungs and kidneys. Combinations of AmBi plus CAS or MICA prolonged survival, but were not better than monotherapy. VCZ was ineffective and AMBd plus CAS showed a possible antagonism. AmBi or ABLC at higher dosages, or loading-doses of AmBi resulted in reduced survival. Histopathology showed increased incidence of serious renal and mild hepatic toxicity in triamcinolone-treated mice given an amphotericin B regimen compared to no or only triamcinolone (minimal renal changes occurred with CAS or VCZ with or without triamcinolone); suggestive of combined toxicity of triamcinolone and the amphotericin B in AmBi or ABLC. Infected treated mice showed progressive pulmonary disease including abscesses, angioinvasion and abundant intralesional fungi. High loading-doses of AmBi were associated with nephrosis and damage to other tissues. No monotherapy or combination regimen showed superiority for the treatment of pulmonary aspergillosis in corticosteroid suppressed mice and the potential for combined drug toxicity was enhanced in these mice. High dosages of lipid-formulated amphotericin B also proved unsatisfactory. Additional studies are needed to evaluate improved treatment. PMID:21539507

Clemons, Karl V; Schwartz, Julie A; Stevens, David A



Toxicological studies of shale oils, some of their components, and commercial products.  

PubMed Central

Estonian shale oil contains about 25--30% phenols, and their action determines the toxicity of shale oils. The clinical symptoms of intoxication are rather similar, regardless of route of administration. Due to neurotropic action, the coordination of movements is impaired, and clonic and tetanic convulsions, paresis and paralysis of extremities, and narcosis are observed. In subacute and chronic toxicity tests, dysfunction of the central nervous system was found. In long-term (4--6 month) experiments, changes in liver and kidney function were found. Shale oil has gonadotropic activity and causes changes in the sexual cycle as well as diminution of the number of primordial folicles in the ovaries or a decrease in the quantity of normal spermatogonia in testicular germinal epithelium. Shale oils produce local irritation of skin and mucous membranes. Shale oil can induce sensitization of the organism after repeated administration. The results of acute intoxication tests have proved that volatile and nonvolatile phenol fractions, isomeric dimethylphenols, and 5-methylresorcinol, must be characterized as moderately toxic substances; the LD50 ranges from 501 to 1500 mg/kg. The clinical symptoms of acute toxication are similar for all studied phenols (restlessness, unsteadiness, clonic tremor, paresis and paralysis of extremities, and death). In spite of the moderate toxicity of phenols in acute experiments, repeated administration of small doses can cause different changes in the nervous system and internal organs of experimental animals. For all the phenols studied, the maximum allowable concentration in water was limited by their effect on the organoleptic properties of water. The nonactive dose for warm-blooded animals is from 100 to 3000 times the threshold limit value of phenols on the basis of their organoleptic properties. The effect of commercial products of oil shale industry is generally determined by the toxicity of the main components: water-soluble oil shale phenols. PMID:571802

Veldre, I A; Janes, H J



Systems toxicology study of doxorubicin on rats using ultra performance liquid chromatography coupled with mass spectrometry based metabolomics  

Microsoft Academic Search

A metabolomics-based systems toxicology approach was used to profile the urinary metabolites for the toxicity related processes\\u000a and pathogenesis induced by doxorubicin (DOX) to rats. Endogenous metabolite profiles were obtained with ultra performance\\u000a liquid chromatography-mass spectrometry (UPLC-MS) for rats receiving different single dosages of DOX (5, 10 or 20 mg\\/kg) prior\\u000a and at three time points after dosage. Principal components analysis

Jiangshan Wang; Theo Reijmers; Lijuan Chen; Rob Van Der Heijden; Mei Wang; Shuangqing Peng; Thomas Hankemeier; Guowang Xu; Jan Van Der Greef



Proof of Hazard and Proof of Safety in Toxicological Studies Using Simultaneous Confidence Intervals for Differences and Ratios to Control  

Microsoft Academic Search

Simultaneous confidence interval for differences or ratios to control are described for both the proof of hazard and the proof of safety for the typical design in toxicology including several doses and a control. For most endpoints the direction of harmfulness is a priori known; therefore one-sided confidence intervals for Gaussian distributed endpoints, proportions, and poly-k-adjusted tumor rates are used.

Ludwig A. Hothorn; Mario Hasler



The identification of complex interactions in epidemiology and toxicology: a simulation study of boosted regression trees  

PubMed Central

Background There is a need to evaluate complex interaction effects on human health, such as those induced by mixtures of environmental contaminants. The usual approach is to formulate an additive statistical model and check for departures using product terms between the variables of interest. In this paper, we present an approach to search for interaction effects among several variables using boosted regression trees. Methods We simulate a continuous outcome from real data on 27 environmental contaminants, some of which are correlated, and test the method’s ability to uncover the simulated interactions. The simulated outcome contains one four-way interaction, one non-linear effect and one interaction between a continuous variable and a binary variable. Four scenarios reflecting different strengths of association are simulated. We illustrate the method using real data. Results The method succeeded in identifying the true interactions in all scenarios except where the association was weakest. Some spurious interactions were also found, however. The method was also capable to identify interactions in the real data set. Conclusions We conclude that boosted regression trees can be used to uncover complex interaction effects in epidemiological studies. PMID:24993424



Toxicological studies for some agricultural waste extracts on mosquito larvae and experimental animals  

PubMed Central

Objective To evaluate some agricultural waste extracts as insecticide and their effects on enzyme activities in liver and kidney of male mice. Methods The insecticidal activity of five tested compounds (one crude extract and 4 waste compounds) was bioassay against the 3rd instars of the Culex pipiens (Cx. pipiens) larvae in the laboratory. The LC50 values of eucalyptol, apricot kernel, Rice bran, corn, black liquor and white liquor are 91.45, 1 166.1, 1 203.3, 21 449.65, 4 025.78 and 6 343.18 ppm, respectively. Selection of the compounds for the subsequent studies was not only dependent on LC50 values but also on the persistence of these wastes products on large scale. Results White and black liquor did not produce any gross effect at 200 mg/Kg body weight. No apparent toxic symptoms were observed in tested animals during the whole period of the experiment which run out for 14 days. No statistically significance was observed in the enzyme cholinesterase activity, the activities of liver enzymes and kidney function in treated mice with black and white liquors. While, no and slight inhibition was observed after the 2 weeks of treatment period with deltamethrin and fenitrothion reached to about 24% in plasma cholinesterase enzyme activity. Significantly increase in the activities of liver enzymes and kidney function in treated mice with deltamethrin and fenitrothion. Conclusions Black liquor can be used efficiently to control Cx. pipiens larvae under laboratory condition. Environmental problem caused by rice straw can be solved by converting the waste material to beneficial natural selective insecticide. PMID:23569971

El-Maghraby, Somia; Nawwar, Galal A; Bakr, Reda FA; Helmy, Nadia; Kamel, Omnia MHM



Toxicology as a nanoscience? – Disciplinary identities reconsidered  

PubMed Central

Toxicology is about to establish itself as a leading scientific discipline in addressing potential health effects of materials on the nanosize level. Entering into a cutting-edge field, has an impact on identity-building processes within the involved academic fields. In our study, we analyzed the ways in which the entry into the field of nanosciences impacts on the formation of disciplinary identities. Using the methods of qualitative interviews with particle toxicologists in Germany, Holland, Switzerland and the USA, we could demonstrate that currently, toxicology finds itself in a transitional phase. The development of its disciplinary identity is not yet clear. Nearly all of our interview partners stressed the necessity of repositioning toxicology. However, they each suggested different approaches. While one part is already propagandizing the establishment of a new discipline – 'nanotoxicology'- others are more reserved and are demanding a clear separation of traditional and new research areas. In phases of disciplinary new-orientation, research communities do not act consistently. Rather, they establish diverse options. By expanding its disciplinary boundaries, participating in new research fields, while continuing its previous research, and only vaguely defining its topics, toxicology is feeling its way into the new fields without giving up its present self-conception. However, the toxicological research community is also discussing a new disciplinary identity. Within this, toxicology could develop from an auxiliary into a constitutive position, and take over a basic role in the cognitive, institutional and social framing of the nanosciences. PMID:16646961

Kurath, Monika; Maasen, Sabine



Evaluation of diethylnitrosamine- or hepatitis B virus X gene-induced hepatocellular carcinoma with 18F-FDG PET/CT: A preclinical study.  


The aim of this study was to evaluate whether the development of hepatocellular carcinoma (HCC) in murine models resembles tumor progression in humans, using non?invasive molecular imaging methods. Murine HCC models were generated by treating mice with diethylnitrosamine (DEN) or by the transgenic expression of hepatitis B virus X (HBx) protein (HBx-Tg model). Tumor development was detected using 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The histopathological changes and expression of glucose transporter 1 (Glut1) and hexokinase 2 (HK2) were evaluated using hematoxylin and eosin and immunohistochemical staining, respectively. Tumor lesions as small as 1 mm in diameter were detected by MRI. Tumor development was monitored using 18F-FDG PET/CT at 6.5?10 months after DEN treatment or 11?20 months after birth of the HBx-Tg model mice. A correlation study between the 18F-FDG uptake levels and expression levels of HK2 and Glut1 in developed HCC showed a high 18F-FDG uptake in poorly differentiated HCCs that expressed high levels of HK2, in contrast to that in well-differentiated tumors. The progression of primary HCCs resembling human HCC in murine models was detected and monitored by 18F-FDG PET/CT. The correlation between tumor size and SUVmax was verified in the two HCC models. To the best of our knowledge, this is the first study to demonstrate that in vivo 18F-FDG uptake varies in HCCs according to differentiation grade in a preclinical study. PMID:25371060

Park, Ju Hui; Kang, Joo Hyun; Lee, Yong Jin; Kim, Kwang Il; Lee, Tae Sup; Kim, Kyeong Min; Park, Ji Ae; Ko, Yin Ohk; Yu, Dae-Yeul; Nahm, Sang-Soep; Jeon, Tae Joo; Park, Young-Seo; Lim, Sang Moo



The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies  

Microsoft Academic Search

Epidemiologic studies indicate that children exposed to early adverse experiences are at increased risk for the development of depression, anxiety disorders, or both. Persistent sensitization of central nervous system (CNS) circuits as a consequence of early life stress, which are integrally involved in the regulation of stress and emotion, may represent the underlying biological substrate of an increased vulnerability to

Christine Heim; Charles B. Nemeroff



Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein Ee4\\/4 homozygotes: a replication study  

Microsoft Academic Search

In a previous cross-sectional study of 100 asymptomatic individuals aged 49–69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4\\/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998

Richard J. Caselli; David Osborne; Eric M. Reiman; Joseph G. Hentz; Carolyn J. Barbieri; Ann M. Saunders; John Hardy; Neill R. Graff-Radford; Geri R. Hall; Gene E. Alexander



Adjuvant Anticholinesterase Therapy for the Management of Epilepsy-Induced Memory Deficit: A Critical Pre-clinical Study.  


Epilepsy is one of the major neurological disorders still awaiting safer drugs with improved antiepileptic effect and lesser side effects. Apart from epilepsy itself, AEDs also have been shown to induce cognitive impairment in patients with epilepsy. There are limited data for the treatment of this menace. As cholinergic approach has widely been practiced for the restoration of memory in various neurodegenerative disorders, this study was envisaged to evaluate add on effect of acetylcholinesterase inhibitor (tacrine) with phenytoin in pentylenetetrazole-kindling-induced learning and memory deficit in mice. In this study, mice were kindled using subconvulsive dose of pentylenetetrazole (35 mg/kg, i.p.; at interval of 48 ± 2 hr) and successfully kindled animals were divided into different groups and treated with vehicle, phenytoin and phenytoinin in combination with tacrine (0.3 mg/kg), atropine (1 mg/kg) and tacrine + atropine. Effect of different interventions on learning and memory was evaluated using elevated plus maze and passive shock avoidance on days 5, 10, 15 and 20. Phenytoin-treated kindled animals were associated with learning and memory deficit, while tacrine supplementation improved memory deficit with increased seizure severity score. Atropine treatment significantly reversed the protective effect of tacrine. Neurochemical findings also support the behavioural finding of the study. Our results suggest the use of anticholinesterases, with better seizure tolerance, for the management of cognitive impairment of epilepsy, as adjunct therapy. PMID:24890882

Mishra, Awanish; Goel, Rajesh Kumar



Toxicology of deoxynivalenol (vomitoxin).  


Trichothecene mycotoxins are a group of structurally similar fungal metabolites that are capable of producing a wide range of toxic effects. Deoxynivalenol (DON, vomitoxin), a trichothecene, is prevalent worldwide in crops used for food and feed production, including in Canada and the United States. Although DON is one of the least acutely toxic trichothecenes, it should be treated as an important food safety issue because it is a very common contaminant of grain. This review focuses on the ability of DON to induce toxicologic and immunotoxic effects in a variety of cell systems and animal species. At the cellular level, the main toxic effect is inhibition of protein synthesis via binding to the ribosome. In animals, moderate to low ingestion of toxin can cause a number of as yet poorly defined effects associated with reduced performance and immune function. The main overt effect at low dietary concentrations appears to be a reduction in food consumption (anorexia), while higher doses induce vomiting (emesis). DON is known to alter brain neurochemicals. The serotoninergic system appears to play a role in mediation of the feeding behavior and emetic response. Animals fed low to moderate doses are able to recover from initial weight losses, while higher doses induce more long-term changes in feeding behavior. At low dosages of DON, hematological, clinical, and immunological changes are also transitory and decrease as compensatory/adaptation mechanisms are established. Swine are more sensitive to DON than mice, poultry, and ruminants, in part because of differences in metabolism of DON, with males being more sensitive than females. The capacity of DON to alter normal immune function has been of particular interest. There is extensive evidence that DON can be immunosuppressive or immunostimulatory, depending upon the dose and duration of exposure. While immunosuppression can be explained by the inhibition of translation, immunostimulation can be related to interference with normal regulatory mechanisms. In vivo, DON suppresses normal immune response to pathogens and simultaneously induces autoimmune-like effects which are similar to human immunoglobulin A (IgA) nephropathy. Other effects include superinduction of cytokine production by T helper cells (in vitro) and activation of macrophages and T cells to produce a proinflammatory cytokine wave that is analogous to that found in lipopolysaccharide-induced shock (in vivo). To what extent the elevation of cytokines contributes to metabolic effects such as decreased feed intake remains to be established. Although these effects have been largely characterized in the mouse, several investigations with DON suggest that immunotoxic effects are also likely in domestic animals. Further toxicology studies and an assessment of the potential of DON to be an etiologic agent in human disease are warranted. PMID:8637056

Rotter, B A; Prelusky, D B; Pestka, J J



Biodegradation of Rubine GFL by Galactomyces geotrichum MTCC 1360 and subsequent toxicological analysis by using cytotoxicity, genotoxicity and oxidative stress studies.  


Galactomyces geotrichum MTCC 1360 showed 87?% decolorization of the azo dye Rubine GFL (50 mg l(-1)) within 96 h at 30 °C and pH 7.0 under static conditions, with significant reduction of chemical oxygen demand (67?%) and total organic carbon (59?%). Examination of oxidoreductive enzymes, namely laccase, tyrosinase and azo reductase, confirmed their role in decolorization and degradation of Rubine GFL. Biodegradation of Rubine GFL into different metabolites was confirmed using high-performance TLC, HPLC, Fourier transform IR spectroscopy and GC-MS analysis. During toxicological studies, cell death was observed in Rubine GFL-treated Allium cepa root cells. Toxicological studies before and after microbial treatment were done with respect to cytotoxicity, genotoxicity, oxidative stress, antioxidant enzyme status, protein oxidation and lipid peroxidation using root cells of A. cepa. The analysis with A. cepa showed that the dye exerts oxidative stress and subsequently has a toxic effect on the root cells, whereas its metabolites are less toxic. Phytotoxicity studies revealed the less toxic nature of the metabolites as compared with Rubine GFL. PMID:22723285

Waghmode, Tatoba R; Kurade, Mayur B; Kabra, Akhil N; Govindwar, Sanjay P



Targeting therapy of hepatocellular carcinoma with doxorubicin prodrug PDOX increases anti-metastatic effect and reduces toxicity: a preclinical study  

PubMed Central

Background This study was to investigate the effects and safety of cathepsin B-cleavable doxorubicin (DOX)-prodrug (PDOX) for targeting therapy of metastatic human hepatocellular carcinoma (HCC) using DOX as a positive control drug. Methods The orthotopic nude mice model of highly metastatic HCC was established and the animals were randomized and treated with PDOX, DOX and saline, respectively. Hematology, biochemistry and tumor markers were studied. At autopsy, liver tumor weight and size, ascites, abdominal lymph nodes metastases, experimental peritoneal carcinomatosis index (ePCI), and tumor-host body weight ratio were investigated. Immunohistochemical studies and western blotting were done to investigate key molecules involved in the mechanism of action. Results Compared with Control, both PDOX and DOX could similarly and significantly reduce liver tumor weight and tumor volume by over 40%, ePCI values, retroperitoneal lymph node metastases and lung metastases and serum AFP levels (P?



Preclinical Study of Treatment Response in HCT-116 Cells and Xenografts with 1H-decoupled 31P MRS  

PubMed Central

The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G2/M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G2/M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton (1H)-decoupled phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p = 0.0004) and inorganic phosphate (p = 0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83±5% G2/M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5±1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39±10% apoptosis. In vivo 1H-decoupled 31P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies. PMID:21994185

Darpolor, Moses M.; Kennealey, Peter T.; Carl Le, H; Zakian, Kristen L.; Ackerstaff, Ellen; Rizwan, Asif; Chen, Jin-Hong; Sambol, Elliot B.; Schwartz, Gary K.; Singer, Samuel; Koutcher, Jason A.



Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: a replication study.  


In a previous cross-sectional study of 100 asymptomatic individuals aged 49-69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998 to 2000, 80 asymptomatic residents of Maricopa County, AZ were recruited through newspaper ads. 20 apoE-e4/4 homozygotes, 20 e3/4 heterozygotes, and 40 e4 noncarriers were matched (1:1:2) by age, gender, and years of education. All had normal neurologic and psychiatric examinations, including Folstein minimental status exam (MMSE) and Hamilton depression scale, and underwent a battery of neuropsychological tests identical to those in our previous study. The groups were well-matched for age (55.9+/-5.9 years), gender (60% women), and education (15.9+/-2.2 years), and were demographically similar to our previous cohort. Complex figure test recall was lower in e3/4 heterozygotes than noncarriers, but there was no significant difference between e4/4 homozygotes and noncarriers. There were no other significant differences in mean test scores between groups, but Wechsler adult intelligence scale-revised (WAIS-R) digit span showed a significant negative correlation with age in the e4/4 homozygote group relative to e4 noncarriers (p=0.008) as we had found in our previous study. In conclusion, we found a significant negative correlation of WAIS-R digit span with age in apoE-e4/4 homozygotes relative to e4 noncarriers in two separate cohorts, possibly reflecting an age-related effect on frontal lobe function in this genetic subgroup. PMID:11535238

Caselli, R J; Osborne, D; Reiman, E M; Hentz, J G; Barbieri, C J; Saunders, A M; Hardy, J; Graff-Radford, N R; Hall, G R; Alexander, G E



Preclinical Safety of the Root Extract of Polygala tenuifolia Willdenow in Sprague-Dawley Rats and Beagle Dogs  

PubMed Central

The root of Polygala tenuifolia Willdenow has been used for the treatment of insomnia, depression, and amnesia. However, the toxicological properties of the herb have been overlooked, because it has been used for a long time for various purposes. In this study, we evaluated the preclinical safety of the root extract in rats and beagle dogs. First, the acute oral toxicity was tested in both rats and dogs. In the rats, only one female of 2?g/kg died, but no treatment-related death or clinical and gross findings were observed after the administration. No toxicological changes or mortalities related to the test substance were also observed after the administration in the dogs. Although vomiting, discoloration, or hemorrhage was found in some dogs, there were no serious abnormalities. Second, the subchronic toxicity was investigated in the rats. Two animals were found dead in the female group of 1,000?mg/kg/day, but there were no abnormal findings associated with the test substance. There also were no adverse effects on the clinical signs, body weight, and hematological and biochemical findings. Therefore, our results showed that the acute or subchronic toxicity of the root extract of Polygala tenuifolia might not be toxic to rats and dogs.

Shin, Ki Young; Won, Beom Young; Ha, Hyun Jee; Yun, Yeo Sang; Lee, Hyung Gun



Utilization management in toxicology.  


Recent upward trends in the prevalence of abuse of prescription drugs and illicit substances have resulted in increased demands for toxicology testing to support the emergency department and drug treatment in pain management programs. This review will discuss the challenges faced by clinical laboratories to manage the utilization of toxicology tests, particularly those ordered in managing poisoned patients in the emergency department and chronic pain patients on opioid therapy. Optimal utilization of toxicology tests to support the emergency department relies on selecting the appropriate tests for the patient, and the availability of the results in a timely fashion. Two tiers of toxicology testing systems with different requirements for turnaround time will be discussed. In patients with chronic pain urine drug testing, including screening and confirmation testing are used extensively in pain management to monitor patient compliance. A thorough understanding of the performance characteristics of the test methodologies and drug metabolism is a key to making a proper analytical and clinical interpretation of the test results and will contribute to effective utilization of these tests. In addition, the reimbursement system is an important factor in the decision making process for test selection utilization as significant costs can be incurred by both payers and patients. Collaboration, trust, and effective communication among clinicians, patients, and clinical laboratory professionals are essential for effective utilization of toxicology testing. PMID:24091099

Zhang, Yan; Kwong, Tai C



A Preclinical Study of the Safety and Efficacy of Occlusin Trade-Mark-Sign 500 Artificial Embolization Device in Sheep  

SciTech Connect

Introduction: This study evaluated the safety, effectiveness, and biodegradation of a new embolic agent, Occlusin Trade-Mark-Sign 503 Artificial Embolization Device (OCL 503). The agent consists of biodegradable poly-lactic-co-glycolic acid microspheres (150-212 {mu}m) coated with type I bovine collagen and was compared with Embosphere{sup Registered-Sign} Microspheres (300-500 {mu}m) in this controlled study of uterine artery embolization (UAE) in sheep. Methods: Unilateral UAE was performed in 32 adult ewes randomly assigned. Vessels were embolized to effective stasis. The cohort was divided into four groups, which were sacrificed at 1, 3, 6, and 12 months. Results: Both agents were 100% effective in achieving stasis. At 6 months, all OCL 503-treated arteries were occluded, the microspheres degraded with time, and at 12 months all four animals examined demonstrated recanalization. OCL 503 was found in the untreated uterine artery in one animal with no other evidence of non target embolization. In the Embosphere-treated group, all vessels remained occluded and microspheres were detected in the contralateral uterine artery in 6 of 15 examined vessels and in 10 vaginal, 2 ovarian, and 1 vesical artery. No procedural-related complications were seen in either group. Conclusions: OCL 503 is as effective an embolic agent as Embosphere{sup Registered-Sign} Microspheres when embolizing ovine uterine arteries and resorbs with time, allowing recanalization of the treated arteries. No device-related issues or adverse events were observed.

Owen, Richard J., E-mail: [University of Alberta, Radiology and Diagnostic Imaging, Walter C. Mackenzie Health Sciences Centre (Canada); Nation, Patrick N. [University of Alberta, Laboratory Medicine and Pathology, Walter C. Mackenzie Health Sciences Centre (Canada); Polakowski, Robert [BioLipids Inc (Canada); Biliske, Jennifer A. [University of Alberta, Biological Sciences, CW405, Biological Sciences Building (Canada); Tiege, Paul B. [University of Alberta, Lipid Products Research Alberta (LiPRA), 410 Agriculture/Forestry Centre (Canada); Griffith, Irwin J. [IMBiotechnologies Ltd (Canada)



Fluorine-18-fluorodeoxygglucose-guided breast cancer surgery with a positron-sensitive probe: Validation in preclinical studies  

SciTech Connect

In this study, the feasibility of utilizing 2-deoxy-2-fluoro-d-glucose (FDG) in conjunction with a positron-sensitive intraoperative probe to guide breast tumor excision was investigated. The probe was constructed with a plastic scintillator tip coupled to a photomultiplier tube with fiber optic cable. Anticipated resolution degradation was evaluated by measurement of line spread functions in the presence of background radiation. Realistic photon background distributions were simulated with a human torso phantom and a cardiac insert. The relationship between resolution and energy threshold was measured to find the optimal discriminator settings. In addition, probe sensitivity as a function of energy threshold was determined for various size-simulated tumors. Finally, the ability to localize breast cancers in vivo was tested in a rodent model. Mammary rat tumors implanted in Lewis rats were examined after injection with FDG; these results were correlated with those of histologic analyses. Measurements of line spread functions indicated that resolution could be maximized in a realistic background photon environment by increasing the energy threshold to levels at or above the Compton continuum edge (340 keV). At this setting, the probe`s sensitivity was determined to be 58 and 11 cps/{mu}Ci for 3.18- and 6.35-mm diameter simulated tumors, respectively. Probe readings correlated well with histologic results; the probe was generally able to discriminate between tumor and normal tissue. This study indicates that breast cancer surgery guided by a positron-sensitive probe warrants future evaluation in breast-conserving surgery of patients with breast cancer. 23 refs., 5 figs.

Raylman, R.R.; Fisher, S.J.; Brown, R.S.; Ethier, S.P.; Wahl, R.L. [Univ. of Michigan Medical Center, Ann Arbor, MI (United States)



177Lu-EC0800 combined with the antifolate pemetrexed: preclinical pilot study of folate receptor targeted radionuclide tumor therapy.  


Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor has been identified as specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folate-based radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect in reducing undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate (177)Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of (177)Lu-EC0800 and PMX on the viability of folate receptor-positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI < 0.8). In an in vivo study, tumor-bearing mice were treated with (177)Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of (177)Lu-EC0800 with PMXther resulted in a two- to four-fold enhanced tumor growth delay and a prolonged survival of KB and IGROV-1 tumor-bearing mice, as compared to the combination with PMXsubther or untreated control mice. PMXsubther protected the kidneys from undesired side effects of (177)Lu-EC0800 (20 MBq) by reducing the absorbed radiation dose. Intact kidney function was shown by determination of plasma parameters and quantitative single-photon emission computed tomography using (99m)Tc-DMSA. Our results confirmed the anticipated dual role of PMX. Its unique features resulted in an improved antitumor effect of folate-based radionuclide therapy and prevented undesired radio-nephrotoxicity. PMID:24030631

Reber, Josefine; Haller, Stephanie; Leamon, Christopher P; Müller, Cristina



Child and Adolescent Behavior Inventory (CABI): A New Instrument for Epidemiological Studies and Pre-Clinical Evaluation  

PubMed Central

Background: Some questionnaires have already been elaborated to collect information from parents of children and adolescents, both as preparation for clinical evaluation and for screening and epidemiological studies. Here a new questionnaire, the CABI, is proposed, and it is validated in a population of 8-10 year-old children. Compared to existing questionnaires, the CABI has been organized so as to be of medium length, with items concerning the most significant symptoms indicated by the DSM-IV-TR for the pertinent disorders, and covering a wider range than existing instruments. There is no charge for its use. Methods: The answers of the parents of 302 children in the last 3 years of primary school provided the normative data. A discriminant validation was done for internalizing and externalizing disorders and as a comparison with self-administered anxiety and depression scales. Exploratory factor analysis and internal consistency were also performed. Results: Distribution of scores on the main scales in the normal population shows positive skewness, with the most frequent score being zero. A highly discriminant capability was found in regard to the sample of children with internalizing and externalizing disorders, with high correlation with the self-administered anxiety and depression scales. Conclusion: The CABI appears to be capable, at least for 8-10 year-old children, of effectively discriminating those with pathological symptoms from those without. Compared with the widely- used CBCL, it has the advantages of a lower number of items, which should facilitate parental collaboration especially in epidemiological studies, and of being free of charge. PMID:23539369

Cianchetti, Carlo; Pittau, Andrea; Carta, Valeria; Campus, Grazia; Littarru, Roberta; Ledda, Maria Giuseppina; Zuddas, Alessandro; Fancello, Giuseppina Sannio



A comparative study of students' performance in preclinical physiology assessed by multiple choice and short essay questions.  


This study was designed to compare the performance of medical students in physiology when assessed by multiple choice questions (MCQs) and short essay questions (SEQs). The study also examined the influence of factors such as age, sex, O/level grades and JAMB scores on performance in the MCQs and SEQs. A structured questionnaire was administered to 264 medical students' four months before the Part I MBBS examination. Apart from personal data of each student, the questionnaire sought information on the JAMB scores and GCE O' Level grades of each student in English Language, Biology, Chemistry, Physics and Mathematics. The physiology syllabus was divided into five parts and the students were administered separate examinations (tests) on each part. Each test consisted of MCQs and SEQs. The performance in MCQs and SEQs were compared. Also, the effects of JAMB scores and GCE O/level grades on the performance in both the MCQs and SEQs were assessed. The results showed that the students performed better in all MCQ tests than in the SEQs. JAMB scores and O' level English Language grade had no significant effect on students' performance in MCQs and SEQs. However O' level grades in Biology, Chemistry, Physics and Mathematics had significant effects on performance in MCQs and SEQs. Inadequate knowledge of physiology and inability to present information in a logical sequence are believed to be major factors contributing to the poorer performance in the SEQs compared with MCQs. In view of the finding of significant association between performance in MCQs and SEQs and GCE O/level grades in science subjects and mathematics, it was recommended that both JAMB results and the GCE results in the four O/level subjects above may be considered when selecting candidates for admission into the medical schools. PMID:11713989

Oyebola, D D; Adewoye, O E; Iyaniwura, J O; Alada, A R; Fasanmade, A A; Raji, Y



In silico toxicology for the pharmaceutical sciences  

SciTech Connect

The applied use of in silico technologies (a.k.a. computational toxicology, in silico toxicology, computer-assisted tox, e-tox, i-drug discovery, predictive ADME, etc.) for predicting preclinical toxicological endpoints, clinical adverse effects, and metabolism of pharmaceutical substances has become of high interest to the scientific community and the public. The increased accessibility of these technologies for scientists and recent regulations permitting their use for chemical risk assessment supports this notion. The scientific community is interested in the appropriate use of such technologies as a tool to enhance product development and safety of pharmaceuticals and other xenobiotics, while ensuring the reliability and accuracy of in silico approaches for the toxicological and pharmacological sciences. For pharmaceutical substances, this means active and impurity chemicals in the drug product may be screened using specialized software and databases designed to cover these substances through a chemical structure-based screening process and algorithm specific to a given software program. A major goal for use of these software programs is to enable industry scientists not only to enhance the discovery process but also to ensure the judicious use of in silico tools to support risk assessments of drug-induced toxicities and in safety evaluations. However, a great amount of applied research is still needed, and there are many limitations with these approaches which are described in this review. Currently, there is a wide range of endpoints available from predictive quantitative structure-activity relationship models driven by many different computational software programs and data sources, and this is only expected to grow. For example, there are models based on non-proprietary and/or proprietary information specific to assessing potential rodent carcinogenicity, in silico screens for ICH genetic toxicity assays, reproductive and developmental toxicity, theoretical prediction of human drug metabolism, mechanisms of action for pharmaceuticals, and newer models for predicting human adverse effects. How accurate are these approaches is both a statistical issue and challenge in toxicology. In this review, fundamental concepts and the current capabilities and limitations of this technology will be critically addressed.

Valerio, Luis G., E-mail: Luis.Valerio@fda.hhs.go [Science and Research Staff, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak 51 Room 4128, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002 (United States)



Determination of doxorubicin and its metabolites in rat serum and bile by LC: application to preclinical pharmacokinetic studies.  


A simple, accurate and precise high-performance liquid chromatographic method was developed and validated for the simultaneous determination of doxorubicin and its three metabolites, including doxorubicinol, doxorubicinolone and doxorubicinone, in rat serum and bile. Following a single protein precipitation step, chromatographic separation was accomplished using a C-18 column with a mobile phase consisting of 50 mM sodium phosphate buffer-acetonitrile-1-propanol (65:25:2, v/v), pH 2.0. The analytes were measured by fluorescence detection with excitation wavelength of 480 nm and emission wavelength of 560 nm. The lower limits of quantitation were 10 ng/ml for doxorubicin, and 5 ng/ml for the three metabolites. The calibration curves were linear over a concentration range of 10-2500 ng/ml for doxorubicin, and 5-1250 ng/ml for its three metabolites. The average recoveries were greater than 89% for all analytes. The within-day and between-day coefficients of variation were generally less than 13%. Doxorubicin and its metabolites were stable in the precipitated serum and bile samples at room temperature in darkness for at least 48 h. This method permitted the analysis of samples without the presence of the anticoagulant sodium citrate and thus was applied to serum and bile samples collected from rats that were administered doxorubicin intravenously in a pharmacokinetic study. PMID:12408897

Zhou, Qingyu; Chowbay, Balram



Preclinical studies relating to the use of thiotepa in the high-dose setting alone and in combination.  


In vitro and in vivo studies with N,N',N''-triethylene-thiophosphoramide (thiotepa) alone and in combination with cyclophosphamide (CTX) were carried out using the MCF-7 human breast carcinoma cell line and the EMT6 mouse mammary carcinoma cell line. In vitro, survival curves were essentially linear. The cytotoxicity of thiotepa toward MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with a 3-log greater cell kill at 500 mumol with cells that were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate in the presence of a reduced nicotinamide adenine dinucleotide phosphate-regenerating system resulted in an eightfold increase in cytotoxicity toward the MCF-7 cells over a wide range of drug concentrations. The thiotepa metabolite N,N',N''-triethylenephosphoramide (TEPA) was significantly less cytotoxic toward the MCF-7 cells than was thiotepa. Simultaneous and immediately sequential treatments with thiotepa and CTX produced supra-additive cell killing of both cell lines, although the magnitude of the supra-additivity was greater in the MCF-7 cell line than in the EMT6 cell line. These drugs Vppeared to be equally effective as thiol-depleting agents. By DNA alkaline elution, there was a pattern of increasing DNA cross-linking similar to the increasing levels of cytotoxicity of this drug combination as the concentrations of thiotepa increased. In the EMT6 tumor in vivo, the maximally tolerated combination therapy (5 mg/kg x 6, thiotepa, and 100 mg/kg x 3, CTX) produced about 25 days of tumor growth delay, which was not significantly different than expected for additivity of the individual drugs. The survival of EMT6 tumor cells after treatment of the animals with the various single doses of thiotepa and CTX was assayed. Tumor cell killing by thiotepa produced a very steep, linear survival curve through 5 logs with increasing dose. The tumor cell survival cure for CTX to 500 mg/kg had linear tumor cell kill through almost 4 logs. In vivo modeling of quasicontinuous exposure (3 intraperitoneal over 9 hours) versus pulse (single-dose) administration of thiotepa and CTX compared EMT6 tumor cell survival with survival of bone marrow as a representative sensitive normal tissue. With CTX, there was a considerable increase in the therapeutic index (killing of tumor cells/killing of colony forming units-granulocyte macrophage) when the same total dose of drug was administered in multiple injections versus a single injection. For thiotepa, smaller increases in therapeutic index were also observed with the multiple-injection schedule.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2106164

Teicher, B A; Holden, S A; Eder, J P; Herman, T S; Antman, K H; Frei, E




EPA Science Inventory

The report on metal toxicology contains reviews on twenty-three metals. These have been written for inclusion in a Handbook on the Toxicology of Metals: Environmental and Occupational Aspects which is being prepared by the Scientific Committee on the Toxicology of Metals of the P...


Bridging the preclinical - clinical gap  

Microsoft Academic Search

TO THE EDITOR: Basic or preclinical research in addiction has moved on enormou- sly in the last decade, but in order for clinical research to benefit there need to be new efforts in translational research. We can approach this question in a number of ways. The first is to use well-established but indirect technologies, such as challenge tests. In these,

David J. Nutt; Anne Lingford-Hughes; Mark Daglish; Tim Williams; Lindsay Taylor; Sue Wilson; Simon Davies; Jan Melichar; Judy Myles


Advances in Preclinical SPECT Instrumentation  

PubMed Central

Preclinical SPECT imaging of rodents is both in demand and very demanding. The need for high spatial resolution in combination with good sensitivity has given rise to considerable innovation in the areas of detectors, collimation, acquisition geometry, and image reconstruction. Some of the developments described herein are beginning to carry over into clinical imaging as well. PMID:22586145

Peterson, Todd E.; Shokouhi, Sepideh



Toxicology of chlorofluorocarbon replacements.  

PubMed Central

Chlorofluorocarbons (CFCs) are stable in the atmosphere and may reach the stratosphere. They are cleaved by UV-radiation in the stratosphere to yield chlorine radicals, which are thought to interfere with the catalytic cycle of ozone formation and destruction and deplete stratospheric ozone concentrations. Due to potential adverse health effects of ozone depletion, chlorofluorocarbon replacements with much lower or absent ozone depleting potential are developed. The toxicology of these compounds that represent chlorofluorohydrocarbons (HCFCs) or fluorohydrocarbons (HFCs) has been intensively studied. All compounds investigated (1, 1-dichloro-1-fluoroethane [HCFC-141b], 1,1,1,2-tetrafluoroethane [HFC-134a], pentafluoroethane [HFC-125], 1-chloro- 1,2,2,2-tetrafluoroethane [HCFC-124], and 1,1-dichloro-2,2,2-trifluoroethane [HCFC-123]) show only a low potential for skin and eye irritation. Chronic adverse effects on the liver (HCFC-123) and the testes (HCFC-141b and HCFC-134a), including tumor formation, were observed in long-term inhalation studies in rodents using very high concentrations of these CFC replacements. All CFC replacements are, to varying extents, biotransformed in the organism, mainly by cytochrome P450-catalyzed oxidation of C-H bonds. The formed acyl halides are hydrolyzed to give excretable carboxylic acids; halogenated aldehydes that are formed may be further oxidized to halogenated carboxylic acids or reduced to halogenated alcohols, which are excretory metabolites in urine from rodents exposed experimentally to CFC replacements. The chronic toxicity of the CFC replacements studied is unlikely to be of relevance for humans exposed during production and application of CFC replacements. PMID:8722112

Dekant, W



Preclinical safety profile of sildenafil  

Microsoft Academic Search

Sildenafil citrate, marketed as Viagra®, for the treatment of erectile dysfunction, has a proven record of safety in humans as predicted by the results of extensive pharmacological and toxicological testing in animals and in vitro, and confirmed by pharmacokinetic exposure data. The aim of this paper is to review succinctly the main findings resulting from these experiments. Daily doses of

D Abbott; P Comby; C Charuel; P Graepel; G Hanton; B Leblanc; A Lodola; L Longeart; G Paulus; C Peters; J Stadler




EPA Science Inventory

This paper discusses the need for the Society of Toxicology (SOT) to develop a policy for ethical research in humans, and a review for publication of these studies. Observations on human beings have been the foundation upon which toxicologic knowledge has been built since the in...


Toxicology, an STS Approach.  

ERIC Educational Resources Information Center

Presented are activities suggested through Project L.A.B.S. that involve the topic of toxicology. Activities include suggested research, the risk benefit seesaw, human-made compounds, legislation, a historical perspective, and health. A suggested readings list is provided. (KR)

Wagner, Richard



Toxicology and Chemical Safety.  

ERIC Educational Resources Information Center

Topics addressed in this discussion of toxicology and chemical safety include routes of exposure, dose/response relationships, action of toxic substances, and effects of exposure to chemicals. Specific examples are used to illustrate the principles discussed. Suggests prudence in handling any chemicals, whether or not toxicity is known. (JN)

Hall, Stephen K.



Synovial fluid: an alternative toxicologic specimen?  


Although blood is the most commonly used specimen in forensic toxicology, it is not always available. In those cases, alternative samples are sought on which to perform toxicology testing. The current study assessed the usefulness of synovial fluid for postmortem cocaine and opiate/opioid testing. One hundred four cases were sampled, with 98 cases being tested representing 24 negative controls and 74 cases positive for cocaine, benzoylecgonine, morphine, 6-monoacetylmorphine, hydrocodone, and/or oxycodone. Synovium demonstrated excellent correlation and predictability when compared with blood, although it was not as sensitive for 6-monoacetylmorphine as either vitreous or urine. The authors recommend further study to assess the usefulness of synovial fluid in postmortem toxicology to include the evaluation of its utilize for more drugs and the development of further assays to use its potential even in limited quantities. PMID:24781403

Deking, Janine; Hargrove, Veronica M; Molina, D Kimberley



Toxicological characterization of the landfill leachate prior/after chemical and electrochemical treatment: a study on human and plant cells.  


In this research, toxicological safety of two newly developed methods for the treatment of landfill leachate from the Piškornica (Croatia) sanitary landfill was investigated. Chemical treatment procedure combined chemical precipitation with CaO followed by coagulation with ferric chloride and final adsorption by clinoptilolite. Electrochemical treatment approach included pretreatment with ozone followed by electrooxidation/electrocoagulation and final polishing by microwave irradiation. Cell viability of untreated/treated landfill leachate was examined using fluorescence microscopy. Cytotoxic effect of the original leachate was obtained for both exposure periods (4 and 24 h) while treated samples showed no cytotoxic effect even after prolonged exposure time. The potential DNA damage of the untreated/treated landfill leachate was evaluated by the comet assay and cytokinesis-block micronucleus (CBMN) assay using either human or plant cells. The original leachate exhibited significantly higher comet assay parameters compared to negative control after 24 h exposure. On the contrary, there was no significant difference between negative control and chemically/electrochemically treated leachate for any of the parameters tested. There was also no significant increase in either CBMN assay parameter compared to the negative control following the exposure of the lymphocytes to the chemically or electrochemically treated landfill leachate for both exposure periods while the original sample showed significantly higher number of micronuclei, nucleoplasmic bridges and nuclear buds for both exposure times. Results suggest that both methods are suitable for the treatment of such complex waste effluent due to high removal efficiency of all measured parameters and toxicological safety of the treated effluent. PMID:23790829

Garaj-Vrhovac, Vera; Oreš?anin, Višnja; Gajski, Goran; Geri?, Marko; Ruk, Damir; Kollar, Robert; Radi? Brkanac, Sandra; Cvjetko, Petra



Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.  


Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 ?g) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 ?g), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 ?g VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated. PMID:24291725

Yue, X; Hariri, D J; Caballero, B; Zhang, S; Bartlett, M J; Kaut, O; Mount, D W; Wüllner, U; Sherman, S J; Falk, T



Subsite awareness in neuropathology evaluation of National Toxicology Program (NTP) studies: a review of select neuroanatomical structures with their functional significance in rodents.  


This review article is designed to serve as an introductory guide in neuroanatomy for toxicologic pathologists evaluating general toxicity studies. The article provides an overview of approximately 50 neuroanatomical subsites and their functional significance across 7 transverse sections of the brain. Also reviewed are 3 sections of the spinal cord, cranial and peripheral nerves (trigeminal and sciatic, respectively), and intestinal autonomic ganglia. The review is limited to the evaluation of hematoxylin and eosin-stained tissue sections, as light microscopic evaluation of these sections is an integral part of the first-tier toxicity screening of environmental chemicals, drugs, and other agents. Prominent neuroanatomical sites associated with major neurological disorders are noted. This guide, when used in conjunction with detailed neuroanatomic atlases, may aid in an understanding of the significance of functional neuroanatomy, thereby improving the characterization of neurotoxicity in general toxicity and safety evaluation studies. PMID:24135464

Rao, Deepa B; Little, Peter B; Sills, Robert C



Toxicologic methods: controlled human exposures.  

PubMed Central

The assessment of risk from exposure to environmental air pollutants is complex, and involves the disciplines of epidemiology, animal toxicology, and human inhalation studies. Controlled, quantitative studies of exposed humans help determine health-related effects that result from breathing the atmosphere. The major unique feature of the clinical study is the ability to select, control, and quantify pollutant exposures of subjects of known clinical status, and determine their effects under ideal experimental conditions. The choice of outcomes to be assessed in human clinical studies can be guided by both scientific and practical considerations, but the diversity of human responses and responsiveness must be considered. Subjects considered to be among the most susceptible include those with asthma, chronic obstructive lung disease, and cardiovascular disease. New experimental approaches include exposures to concentrated ambient air particles, diesel engine exhaust, combustion products from smoking machines, and experimental model particles. Future investigations of the health effects of air pollution will benefit from collaborative efforts among the disciplines of epidemiology, animal toxicology, and human clinical studies. PMID:10931779

Utell, M J; Frampton, M W



Evaluation Of Microdosing Strategies For Studies In Preclinical Drug Development: Demonstration Of Linear Pharmacokinetics In Dogs Of A Nucleoside Analogue Over A 50-Fold Dose Range  

SciTech Connect

The technique of accelerator mass spectrometry (AMS) was validated successfully and utilized to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across sub-pharmacological (microdose) and pharmacological dose ranges in an animal model, prior to initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as LC-MS/MS and liquid scintillation counting analyses. Thus, Compound A displayed multiphasic kinetics and possessed low plasma clearance (4.4 mL/min/kg), a long terminal elimination half-life (19.4 hr) and high oral bioavailability (82%). Currently there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus sub-pharmacological doses employing microdosing strategies. The present study thus provides the first description of the pharmacokinetics of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A were similar following dosing at 0.02 mg/kg as at 1 mg/kg, indicating that in the case of Compound A, the kinetics of absorption, distribution and elimination in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even following a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques. The applications of accelerator mass spectrometry (AMS) are broad ranging and vary from studying environmental and ecological issues such as the isotopic composition of the atmosphere, soil and water (Hughen et al., 2000; Beck et al., 2001; Keith-Roach et al., 2001; Mironov et al., 2002), to archaeology and volcanology (Stafford et al., 1984; Vogel et al., 1990; Smith et al., 1999) to its use as a bioanalytical tool for nutritional research (Buchholz et al., 1999; Deuker et al., 2000; Weaver and Liebman, 2002). Biomedical applications of AMS and its use in the arena of pharmaceutical research also have been detailed in review articles (Barker and Garner, 1999; Garner, 2000; Turteltaub and Vogel, 2000). To date, most studies on the metabolism and disposition of xenobiotics by AMS have focused on how carcinogens bind to DNA and proteins to form adducts (Turteltaub et al., 1990, 1997; Frantz et al., 1995; Dingley et al., 1999; Li et al., 2003). Its application to the field of pharmaceutical sciences has been limited to a few studies (Kaye et al., 1997; Young et al., 2001; Garner et al., 2002). However, the pharmaceutical industry is becoming increasingly aware of the potential benefits that may accrue from the ultra high sensitivity afforded by AMS in terms of evaluating the pharmacokinetics of lead drug candidates in early development. Specifically, AMS allows administration of sub-pharmacological doses (microdoses) of carbon-14 or tritium-labeled investigational drugs to animals or humans at radiologically insignificant levels with the goal of obtaining preliminary information regarding the absorption, distribution, metabolism, and excretion of test compounds (Turteltaub and Vogel, 2000). An unresolved issue, however, is whether the pharmacokinetics determined following a microdose are representative of those following a conventional (pharmacological) dose (Lappin and Garner, 2003). This paper examines the linearity of kinetics of an antiviral nucleoside analogue, Compound A, across sub-pharmacological and pharmacological dose ranges in the dog prior to initiation of a human microdose study. The specific objectives of this study, therefore, were (1) to assess the pharmacokinetics of Compound A in dogs by a conventional dosing approach utilizing LC-MS/MS for sample analysis, (2) to assess the pharmacokinetics of Compound A in dogs by the microdose approach utilizing AMS for sample ana

Sandhu, P; Vogel, J S; Rose, M J; Ubick, E A; Brunner, J E; Wallace, M A; Adelsberger, J K; Baker, M P; Henderson, P T; Pearson, P G; Baillie, T A



Environmental Toxicology: Testing and Screening  

E-print Network

Assessment (OTA) is preparing a study on the Toxic Substances Control Act (TSCA) to evaluate the Existing Chemicals Program. The purpose of the Chemical Testing and Screening Workshop was to identify the present and future methods of screening and testing of commercial chemicals using nine specific endpoints, one being environmental toxicology (i. e., ecological effects assessment). This chapter addresses the state of the science by responding to several specific questions asked by the OTA (e.g., “what are the best tests available to identify a chemical of concern and to evaluate its toxicity?’?. This chapter concludes that basic screening and testing methods are already being applied by EPA/OPPT, especially by the use of structure-activity relationships (SARs/QSARs) for ecotoxicity screening purposes, and by the use of rapid and inexpensive tests to actually assess ecotoxicity. Areas for improving existing methods include sorting priorities to assess chemical exposure information and SARs/QSARs for avian species, plants, earthworms, and sediment dwelling organisms. One of nine specified topics of interest addressed at the Office of Technology Assessment (OTA) Workshop was the testing and screening methods used by the U.S. Environmental Protection Agency (EPA) and others to assess environmental toxicology. Methods for “environmental toxicology ” were understood to mean screening and testing methodologies used to assess potential ecological effects on organisms found in the environment from TSCA-regulated chemicals. The Toxic Substances Control Act of 1976 (TSCA) provided the EPA Office of Pollution Prevention and Toxics (OPPT) with authority to require development of adequate data for assessing the risk to human health and the natural environment from industrial chemicals identified as having risk potential. “Protection of the environ-

Maurice Zeeman; Anne Fairbrother; Joseph W. Gorsuch


A longitudinal study assessing lens thickness changes in the eye of the growing beagle using ultrasound scanning: relevance to age of dogs in regulatory toxicology studies.  


The lens is formed in utero with new secondary lens fibres added as outer layers throughout life in a growth pattern characteristic of the species. This study examined the time course of beagle lens growth to better understand the optimal starting age of dogs for safety studies to support adult versus paediatric indications, and to assess the feasibility of non-invasively monitoring lens growth with high frequency ultrasound. Ultrasound scanning was performed in six female beagle dogs using the Vevo770. All dogs were imaged in B-mode using local anaesthetic but without sedation. Imaging was carried out every 2 weeks from 8 to 22 weeks of age and then monthly until 62 weeks of age. The dogs tolerated the procedure well. The lens was visible in all dogs and measuring the lens thickness with high frequency ultrasound demonstrated good analytical reproducibility [Root Mean Square (RMS)?=?3.13%]. No differences between the left and right eye existed and lens thickness correlated with body weight. The highest weekly growth rate was before 12 weeks of age. A statistically significant difference between monthly thickness was detected until 42 weeks of age at which point growth reached a plateau. During the experiment, lenses grew by 29.7% reaching an average thickness of 6.4 mm?±?0.03. By 10 months of age (the typical age used for routine toxicological evaluation), beagles have reached a plateau in lens growth that is analogous to human adults. Where lens is a target organ of concern it is suggested that beagles under 6 months old may be a better model for determining paediatric safety. Copyright © 2014 John Wiley & Sons, Ltd. PMID:24436247

Maynard, Juliana; Sykes, Angela; Powell, Helen; Healing, Guy; Scott, Marietta; Holmes, Andrew; Ricketts, Sally-Ann; Stewart, Jane; Davis, Stewart



Toxicological Profile Information Sheet  

NSDL National Science Digital Library

The Agency for Toxic Substances and Disease Registry (ATSDR) is continually assembling toxicological profiles for hazardous substances. This site contains 256 online profiles listed alphabetically by chemical name. Each profile begins with a non-technical public health statement discussing the chemical, its environmental and health effects, and risk of human exposure. A more technical version of this information can also be downloaded in Adobe Acrobat (.pdf) format.



History of wildlife toxicology  

Microsoft Academic Search

The field of wildlife toxicology can be traced to the late nineteenth and early twentieth centuries. Initial reports included\\u000a unintentional poisoning of birds from ingestion of spent lead shot and predator control agents, alkali poisoning of waterbirds,\\u000a and die-offs from maritime oil spills. With the advent of synthetic pesticides in the 1930s and 1940s, effects of DDT and\\u000a other pesticides

Barnett A. Rattner



Research Models in Developmental Behavioral Toxicology.  

ERIC Educational Resources Information Center

Developmental models currently used by child behavioral toxicologists and teratologists are inadequate to address current issues in these fields. Both child behavioral teratology and toxicology scientifically study the impact of exposure to toxic agents on behavior development: teratology focuses on prenatal exposure and postnatal behavior…

Dietrich, Kim N.; Pearson, Douglas T.


Transgenic Fish as Models in Environmental Toxicology  

Microsoft Academic Search

Historically, fish have played significant roles in assessing potential risks associated with exposure to chemical con- tamination in aquatic environments. Considering the contri- butions of transgenic rodent models to biomedicine, it is reasoned that the development of transgenic fish could enhance the role of fish in environmental toxicology. Application of transgenic fish in environmental studies remains at an early stage,

Richard N. Winn


Mining environmental toxicology information: web resources  

Microsoft Academic Search

Environmental toxicology is the study of the ecological effects of anthropogenic substances released into the environment. It is a relatively diverse field addressing impacts to aquatic and terrestrial organisms and communities. The determination of potential risk associated with toxic agents is of interest to government regulators, industry, researchers, private organizations and citizen groups. In assessing the ecological risk associated with

Christine L Russom



Toxicological screening of seven Nigerian mushrooms  

Microsoft Academic Search

Toxicological studies were carried out on seven Nigerian mushrooms, namely, Chlorophyllum molybditis (Mayer ex. fr.) Masse, Cortinarius melliolens Fries, Lentinus subnudus Berk, Pleurotus tuber-regium (Fries) Singer, Termitomyces robustus (Beeli) Heim, Tricholoma lobayensis Heim and Volvariella esculenta (Mass) Singer. Amatoxin spot test and Chromatographic screening of the mushrooms revealed the absence of amatoxins and phallotoxins. None of the mushroom extracts tested

Isola O. Fasidi; Mukaila Kadiri




EPA Science Inventory

Toxicology studies were conducted with the mono-, di-, and pentachlorophenols (CP). Chlorophenols (except PC) demonstrate a relatively low order of toxicity. The order of toxicity in mice and rats (most to least) is: PCP > tetra CPs > mono CPs > tri CPs > di CPs. Short-term (14 d...


Preclinical Alzheimer disease and risk of falls  

PubMed Central

Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify A?42, tau, and phosphorylated tau. Methods: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/A?42 and CSF phosphorylated tau/A?42, after adjustment for common fall risk factors. Results: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01–6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. Conclusions: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes. PMID:23803314

Roe, Catherine M.; Grant, Elizabeth A.; Hollingsworth, Holly; Benzinger, Tammie L.; Fagan, Anne M.; Buckles, Virginia D.; Morris, John C.



Ramucirumab: preclinical research and clinical development  

PubMed Central

Ramucirumab (IMC-1121B, LY3009806), a fully humanized monoclonal antibody directed against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), is a new therapeutic option that selectively inhibits the human VEGFR-2 with a much greater affinity than its natural ligands. Based on the promising results of both preclinical and early clinical studies, ramucirumab has been tested in different tumor types either alone or in combination with chemotherapy. While it has recently been granted its first US Food and Drug Administration approval for use as a single agent in patients with advanced or metastatic gastric cancer or gastroesophageal junction carcinoma, its role for metastatic breast cancer or advanced non-small-cell lung cancer is still debated. The aims of this review are to recall and discuss the most significant preclinical and clinical studies that led to the development of ramucirumab and to present the results of the randomized clinical trials that have tested its efficacy in different malignancies, including gastric and lung cancer. PMID:25378934

Aprile, Giuseppe; Rijavec, Erika; Fontanella, Caterina; Rihawi, Karim; Grossi, Francesco



42 CFR 493.1213 - Condition: Toxicology.  

Code of Federal Regulations, 2011 CFR

...STANDARDS AND CERTIFICATION LABORATORY REQUIREMENTS Quality System for Nonwaived Testing ...Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology, the laboratory must meet the...



42 CFR 493.1213 - Condition: Toxicology.  

Code of Federal Regulations, 2013 CFR

...STANDARDS AND CERTIFICATION LABORATORY REQUIREMENTS Quality System for Nonwaived Testing ...Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology, the laboratory must meet the...



42 CFR 493.1213 - Condition: Toxicology.  

Code of Federal Regulations, 2012 CFR

...STANDARDS AND CERTIFICATION LABORATORY REQUIREMENTS Quality System for Nonwaived Testing ...Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology, the laboratory must meet the...



42 CFR 493.1213 - Condition: Toxicology.  

Code of Federal Regulations, 2010 CFR

...STANDARDS AND CERTIFICATION LABORATORY REQUIREMENTS Quality System for Nonwaived Testing ...Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology, the laboratory must meet the...



Reprint Library for Toxicology Data Bank  

ERIC Educational Resources Information Center

The Industrial Toxicology Research Center, Lucknow, India, maintains a register of toxicology and provides its research workers with current information mainly through its collection of reprints. (Author)

Agarwal, S. N.; Khan, R. R.



PREVENT Cancer Preclinical Drug Development Program

The PREVENT Cancer Drug Development Program is a National Cancer Institute-supported pipeline to bring new cancer preventing interventions and biomarkers through preclinical development towards clinical trials.


Textile dye degradation by bacterial consortium and subsequent toxicological analysis of dye and dye metabolites using cytotoxicity, genotoxicity and oxidative stress studies.  


The present study aims to evaluate Red HE3B degrading potential of developed microbial consortium SDS using two bacterial cultures viz. Providencia sp. SDS (PS) and Pseudomonas aeuroginosa strain BCH (PA) originally isolated from dye contaminated soil. Consortium was found to be much faster for decolorization and degradation of Red HE3B compared to the individual bacterial strain. The intensive metabolic activity of these strains led to 100% decolorization of Red HE3B (50 mg l(-1)) with in 1h. Significant induction of various dye decolorizing enzymes viz. veratryl alcohol oxidase, laccase, azoreductase and DCIP reductase compared to control, point out towards their involvement in overall decolorization and degradation process. Analytical studies like HPLC, FTIR and GC-MS were used to scrutinize the biodegradation process. Toxicological studies before and after microbial treatment was studied with respect to cytotoxicity, genotoxicity, oxidative stress, antioxidant enzyme status, protein oxidation and lipid peroxidation analysis using root cells of Allium cepa. Toxicity analysis with A. cepa signifies that dye Red HE3B exerts oxidative stress and subsequently toxic effect on the root cells where as biodegradation metabolites of the dye are relatively less toxic in nature. Phytotoxicity studies also indicated that microbial treatment favors detoxification of Red HE3B. PMID:21144656

Phugare, Swapnil S; Kalyani, Dayanand C; Patil, Asmita V; Jadhav, Jyoti P



Screening for pre-clinical disability in different residential settings  

PubMed Central

Background Preventing disability and offering effective interventions to older people during early decline in function is most likely to be effective if those most at risk of progressive disablement are able to be identified. Similarly the ability to easily identify a group with similar functional profile from disparate sectors of the community is of significant benefit to researchers. This study aimed to (1) describe the use of a pre-clinical disability screening tool to select a functionally comparable group of older men and women with early functional limitation from different settings, and (2) explore factors associated with function and disability. Methods Self-reported function and disability measured with the Late-Life Function and Disability Instrument along with a range of physical performance measurements were compared across residential settings and gender in a sample of 471 trial participants identified as pre-clinically disabled after being screened with the Fried pre-clinical disability tool. Factors that might lie on the pathway to progressive disablement were identified using multiple linear regression analysis. Results We found that a sample population, screened for pre-clinical disability, had a functional status and disability profile reflecting early functional limitation, regardless of residential setting or gender. Statistical models identified a range of factors associated with function and disability which explained a greater degree of the variation in function, than disability. Conclusions We selected a group of people with a comparable function and disability profile, consistent with the pre-clinical stage of disability, from a sample of older Australian men and women from different residential settings using the Fried pre-clinical disability screening tool. The results suggest that the screening tool can be used with greater confidence for research, clinical and population health purposes. Further research is required to examine the validity of the tool. These findings offer insight into the type of impairment factors characterising early functional loss that could be addressed through disability prevention initiatives. Trial Registration ACTRN01206000431527 PMID:20678235



Toxicology: Old Art, New Science.  

ERIC Educational Resources Information Center

Examines the need for a science of toxicology and training at both the undergraduate and graduate levels in response to legislation controlling drugs, food additives and toxic substances in the work environment, and concern about effects on man. Stresses need for putting toxicology on a scientific base with adequate funding. (JM)

Timbrell, John A.



Meal-feeding rodents and toxicology research.  


Most laboratory rodents used for toxicology studies are fed ad libitum, with unlimited access to food. As a result, ad libitum-fed rodents tend to overeat. Research demonstrates that ad libitum-fed rodents are physiologically and metabolically different from rodents fed controlled amounts of food at scheduled times (meal-fed). Ad libitum-fed rodents can develop hypertriglyceridemia, hypercholesterolemia, diet-induced obesity, nephropathy, cardiomyopathy, and pituitary, pancreatic, adrenal, and thyroid tumors, conditions likely to affect the results of toxicology research studies. In contrast, meal-feeding synchronizes biological rhythms and leads to a longer life span, lower body weight, lower body temperature, hypertrophy of the small intestine, and synchronization of hepatic and digestive enzymes. The circadian rhythms present in nearly all living organisms are entrained by light intensity and food intake, and peripheral clocks in all organs of the body, especially the GI tract and liver, are particularly sensitive to food intake. Feeding schedule has been demonstrated to alter the toxicity and metabolism of drugs including sodium valproate, chloral hydrate, acetaminophen, gentamicin, and methotrexate. Feeding schedule alters the expression of genes that code for Phase I, II, and III proteins, thereby altering the rate and amplitude of drug disposition. Rhythms of plasma insulin and glucagon that fluctuate with food ingestion are also altered by feeding schedule; ad libitum feeding promotes hyperinsulinemia which is a precursor for developing diabetes. The emerging field of chronopharmacology, the interaction of biological rhythms and drugs, will lead to optimizing the design and delivery of drugs in a manner that matches biological rhythms, but it is wise for toxicology researchers to consider feeding schedule when designing these experiments. It has been 10 years since the Society for Toxicologic Pathology voiced its position that feeding schedule is an important variable that should be controlled in toxicology experiments, and research continues to underscore this position. PMID:22642213

Carey, Gale B; Merrill, Lisa C



78 FR 38982 - Availability of Draft Toxicological Profiles  

Federal Register 2010, 2011, 2012, 2013

...OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [Docket...Toxicological Profiles AGENCY: Agency for Toxic Substances and Disease Registry (ATSDR...and studies on the health effects of toxic substances'' under CERCLA Section...



FORUM Concise Review: Gene Expression Applied to Toxicology  

Microsoft Academic Search

Toxicogenomics and toxicogenetics are the application of genomics and genetics, respectively, to toxicology. The major focus of toxicogenetics is the study of differential gene expres- sion induced as an adaptation or \\

Spencer Farr; Robert T. Dunn



NTP Report on Toxicology Study of Senna (CAS No. 8013-11-4) in C57BL/6NTac Mice and Toxicology and Carcinogenesis Study of Senna in Genetically Modified C3B6.129F1/Tac-Trp53(tm1Brd) N12 Haploinsuffient Mice. Feed Studies.  

National Technical Information Service (NTIS)

The National Toxicology Program (NTP) is an interagency program within the Public Health Service (PHS) of the Department of Health and Human Services (HHS) and is headquartered at the National Institute of Environmental Health Sciences of the National Ins...



Translational toxicology: a developmental focus for integrated research strategies  

PubMed Central

Background Given that toxicology studies the potential adverse effects of environmental exposures on various forms of life and that clinical toxicology typically focuses on human health effects, what can and should the relatively new term of "translational toxicology" be taken to mean? Discussion Our assertion is that the core concept of translational toxicology must incorporate existing principles of toxicology and epidemiology, but be driven by the aim of developing safe and effective interventions beyond simple reduction or avoidance of exposure to prevent, mitigate or reverse adverse human health effects of exposures. The field of toxicology has now reached a point where advances in multiple areas of biomedical research and information technologies empower us to make fundamental transitions in directly impacting human health. Translational toxicology must encompass four action elements as follows: 1) Assessing human exposures in critical windows across the lifespan 2) Defining modes of action and relevance of data from animal models 3) Use of mathematical models to develop plausible predictions as the basis for 4) Protective and restorative human health interventions. The discussion focuses on the critical window of in-utero development. Summary Exposure assessment, basic toxicology and development of certain categories of mathematical models are not new areas of research; however overtly integrating these in order to conceive, assess and validate effective interventions to mitigate or reverse adverse effects of environmental exposures is our novel opportunity. This is what we should do in translational toxicology so that we have a portfolio of interventional options to improve human health that include both minimizing exposures and specific preventative/restorative/mitigative therapeutics. PMID:24079609




SciTech Connect

This report provides a detailed account of a two year chronic inhalation study of methyl bromide toxicity in B6C3Fl mice conducted for the National Toxicology Program. Mice were randomized into three dose groups (10, 33 and 100 ppm methyl bromide) and one control group (0 ppm) per sex and exposed 5 days/week, 6 hours/day, for a total of 103 weeks. Endpoints included body weight; clinical signs and mortality, and at 6, 15 and 24 months of exposure, animals were sacrificed for organ weights, hematology and histopathology. In addition, a subgroup of animals in each dosage group was monitored for neurobehavioral and neuropathological changes. After only 20 weeks of exposure, 48% of the males and 12% of the females in the 100 ppm group had died. Exposures were terminated in that group and the surviving mice were observed for the duration of the study. Exposure of B6C3Fl mice to methyl bromide, even for only 20 weeks, produced significant changes in growth rate, mortality, organ weights and neurobehavioral functioning. These changes occurred in both males and females, but were more pronounced in males.




Emerging approaches in predictive toxicology.  


Predictive toxicology plays an important role in the assessment of toxicity of chemicals and the drug development process. While there are several well-established in vitro and in vivo assays that are suitable for predictive toxicology, recent advances in high-throughput analytical technologies and model systems are expected to have a major impact on the field of predictive toxicology. This commentary provides an overview of the state of the current science and a brief discussion on future perspectives for the field of predictive toxicology for human toxicity. Computational models for predictive toxicology, needs for further refinement and obstacles to expand computational models to include additional classes of chemical compounds are highlighted. Functional and comparative genomics approaches in predictive toxicology are discussed with an emphasis on successful utilization of recently developed model systems for high-throughput analysis. The advantages of three-dimensional model systems and stem cells and their use in predictive toxicology testing are also described. Environ. Mol. Mutagen. 55:679-688, 2014. © 2014 Wiley Periodicals, Inc. PMID:25044351

Zhang, Luoping; McHale, Cliona M; Greene, Nigel; Snyder, Ronald D; Rich, Ivan N; Aardema, Marilyn J; Roy, Shambhu; Pfuhler, Stefan; Venkatactahalam, Sundaresan



[Preclinical safety investigation of GB-115 dipeptide].  


Preclinical safety investigations of newly synthesized dipeptide compound GB-115 (amide N-phenylhexanoyl-glycyl-L-tryptophan), an antagonist of cholecystokinin receptors, were performed. No animals were lost after GB-115 acute oral administration at a maximum dose of 6000 mg/kg in mice and at 3500 mg/kg in rats. GB-115 administered per os during 6 months in rabbits and rats (both males and females) at the doses of 0.1 and 10 mg/kg induced no irreversible pathological changes in organs and systems studied. The tested dipeptide exhibited no allergenic, immunotoxic and mutagenic activity, and did not affect generative function and the antenatal and postnatal development of progeny. GB-115 at a dose of 10 mg/kg produced suppression of the inflammatory reaction to concanavalin A. PMID:20726348

Sorokina, A V; Alekseeva, S V; Nemova, E P; Kovalenko, L P; Smol'nikova, N M; Shipaeva, E V; Shreder, O V; Miroshkina, I A; Diukova, S A; Daugel'-Dauge, N O; Kulakova, A V; Kolik, L G; Durnev, A D; Seredenin, S B



Complex effects of two presumably antagonistic endocrine disrupting compounds on the goldfish Carassius aumtus: a comprehensive study with multiple toxicological endpoints.  


We studied the effects of endocrine disrupting compounds nonylphenol (NP) and letrozole (LE) on the male goldfish Carassius aumtus. Exposure to NP (20 ?g l(-1)) alone caused a significant up-regulation in the expression of aromatase, estrogen receptors and vitellogenin (VTG) genes, an increase in hepatic and plasma VTG concentration, but no obvious testicular impairment. Exposure to LE (1 mg kg(-1)) alone resulted in a significant decline in aromatase activity, reduced levels of plasma 17?-estradiol (E2), and enhanced sperm maturation. Co-exposure with LE (1 mg kg(-1)) could only partially affect some of the estrogenic effects caused by NP (20 ?g l(-1)) (i.e. expression of hepatic and brain estrogen receptor genes, hepatic VTG concentration), but inhibit other estrogenic effects (i.e. brain and testicular aromatase activity, plasma E2). In addition, co-exposure resulted in impairment of liver mitochondria (i.e. detachment of ridges from the membrane, and uneven distribution of the cytoplasm with clusters of glycogen granules), but did not cause significant damage to the testes (i.e. the morphology, the spermatogonia and spermatozoa densities). Our results clearly showed that nonylphenol and letrozole co-exposure could induce profound effects on fish, and highlighted the importance of adopting multiple toxicological endpoints when evaluating the combined effects of endocrine disrupting compounds. PMID:24974122

Wu, Fengxia; Lin, Li; Qiu, Jian-Wen; Chen, Hao; Weng, Shaoping; Luan, Tiangang



Isolation and fractionation of gill cells from freshwater (Lasmigona costata) and seawater (Mesodesma mactroides) bivalves for use in toxicological studies with copper.  


Gills cells of the freshwater mussel Lasmigona costata and the seawater clam Mesodesma mactroides were isolated (mussel: chemical dissociation; clam: mechanical dissociation) and fractionated (Percoll gradient) into Fractions I and II. Mitochondrial dyes (DASPEI: mussel; MitoTracker(®): clam) and Na(+), K(+)-ATPase activity measurement were used to distinguish between cells of Fractions I and II. For mussel and clam, 80.5 ± 1.5 and 48.3 ± 3.2 % of cells were in Fraction II, respectively. For both species, cells of Fraction II had higher fluorescence emission and higher enzyme activity than those of Fraction I, being characterized as 'cells rich in mitochondria'. Cells of Fraction II were kept in saline solutions approximating the ionic composition of hemolymph either under control conditions (no Cu addition) or exposed (3 h) to copper (Cu: 5, 9 and 20 ?g Cu/L). Cell viability and Cu and Na(+) content were measured. For both species, Cu content was higher and Na(+) content was lower in cells exposed to 20 ?g Cu/L. Furthermore, a strong negative correlation was observed between cell Na(+) and Cu content in the two bivalve species, indicating a possible competition between Cu and Na(+) for ion-transporting mechanisms or binding sites at gill cells of Fraction II. Considering that Cu is an ionoregulatory toxicant in aquatic invertebrates, these preliminary toxicological data support the idea of using isolated gill cells rich in mitochondria to study the mechanisms underlying the acute toxicity of waterborne Cu in freshwater and marine bivalves. PMID:24081614

Nogueira, Lygia S; Wood, Chris M; Gillis, Patricia L; Bianchini, Adalto



Analysis of Statistical Methods Currently used in Toxicology Journals.  


Statistical methods are frequently used in toxicology, yet it is not clear whether the methods employed by the studies are used consistently and conducted based on sound statistical grounds. The purpose of this paper is to describe statistical methods used in top toxicology journals. More specifically, we sampled 30 papers published in 2014 from Toxicology and Applied Pharmacology, Archives of Toxicology, and Toxicological Science and described methodologies used to provide descriptive and inferential statistics. One hundred thirteen endpoints were observed in those 30 papers, and most studies had sample size less than 10, with the median and the mode being 6 and 3 & 6, respectively. Mean (105/113, 93%) was dominantly used to measure central tendency, and standard error of the mean (64/113, 57%) and standard deviation (39/113, 34%) were used to measure dispersion, while few studies provide justifications regarding why the methods being selected. Inferential statistics were frequently conducted (93/113, 82%), with one-way ANOVA being most popular (52/93, 56%), yet few studies conducted either normality or equal variance test. These results suggest that more consistent and appropriate use of statistical method is necessary which may enhance the role of toxicology in public health. PMID:25343012

Na, Jihye; Yang, Hyeri; Bae, SeungJin; Lim, Kyung-Min



Analysis of Statistical Methods Currently used in Toxicology Journals  

PubMed Central

Statistical methods are frequently used in toxicology, yet it is not clear whether the methods employed by the studies are used consistently and conducted based on sound statistical grounds. The purpose of this paper is to describe statistical methods used in top toxicology journals. More specifically, we sampled 30 papers published in 2014 from Toxicology and Applied Pharmacology, Archives of Toxicology, and Toxicological Science and described methodologies used to provide descriptive and inferential statistics. One hundred thirteen endpoints were observed in those 30 papers, and most studies had sample size less than 10, with the median and the mode being 6 and 3 & 6, respectively. Mean (105/113, 93%) was dominantly used to measure central tendency, and standard error of the mean (64/113, 57%) and standard deviation (39/113, 34%) were used to measure dispersion, while few studies provide justifications regarding why the methods being selected. Inferential statistics were frequently conducted (93/113, 82%), with one-way ANOVA being most popular (52/93, 56%), yet few studies conducted either normality or equal variance test. These results suggest that more consistent and appropriate use of statistical method is necessary which may enhance the role of toxicology in public health. PMID:25343012

Na, Jihye; Yang, Hyeri



Overview of inhalation toxicology.  

PubMed Central

The development of inhalation toxicology as a distinct discipline can be traced back well over one hundred years. The technology has advanced in terms of materials and designs used to construct inhalation chambers and the equipment used to generate controlled test atmospheres of a wide variety of gases, vapors, dusts, and droplets. Consideration of metered dose inhalers, a relatively recent concern, has led to the design of new equipment for administering this unique dosage form. The parameters used to evaluate inhalation toxicity are similar to those used for any other route of administration. In addition, there are some unique procedures for early screening of pulmonary toxicity, especially within a series of related chemicals. Images FIGURE 1. FIGURE 3. FIGURE 7. FIGURE 8. PMID:2200660

Dorato, M A



Resource Guide to Careers in Toxicology  

NSDL National Science Digital Library

This is a career guide which answers the following questions on careers in toxicology: 1) What is Toxicology?, 2) Why Consider a Career in Toxicology?, 3) What Do Toxicologists Do?, 4) Where Do Toxicologists Work?, 5) Regional Distribution of Toxicology Jobs, 6) How Much Do Toxicologists Earn?, 7) How Do I Prepare for a Career in Toxicology? A link is also provided to academic and post-doctoral programs and web sites.

Society of Toxicology (;)



Phase I Study of Paclitaxel and Uracil plus Tegafur Combination in Patients with Pretreated Metastatic Breast Cancer: Drug Sequencing Based on Preclinical Modelling Studies  

Microsoft Academic Search

Objective: Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC. Methods: Pacl was infused at a fixed dose

A. Passardi; R. Maltoni; C. Milandri; L. Cecconetto; I. Massa; W. Zoli; A. Tesei; F. Fabbri; O. Nanni; D. Amadori




EPA Science Inventory

Cheminformatics and data models, are providing the underpinning for the large public HTS efforts of the NIH Molecular Libraries Initiative, as well as new toxicity-targeted HTS programs within the EPA and the NIEHS National Toxicology Program....



EPA Science Inventory

The book contains the proceedings of a symposium entitled Behavioral Toxicology: An Emerging Discipline, held in conjunction with the Southwest Psychological Association meetings, April 30, 1976 in Albuquerque, New Mexico. Authors of formal presentations later reviewed and enlarg...


EXTOXNET: The Extension Toxicology Network  

NSDL National Science Digital Library

A cooperative effort of University of California-Davis, Oregon State University, Michigan State University, Cornell University, and the University of Idaho, EXTOXNET (the Extension Toxicology Network) is an online resource providing "objective, science-based information about pesticides" and other toxic chemicals. First-time viewers will find useful information in the FAQ section, which covers health effects and risks, diet and cancer, food safety, drinking water, garden chemicals, and other topics. Also available at the site is the University of California at Davis's Environmental Toxicology Newsletter. The heart of the site, however, is the searchable database, which provides extensive profiles of pesticides, toxicology information briefs, toxicology issues of concern, and fact sheets. Although still under construction, the database of pesticide profiles includes trade name(s), regulatory status, chemical class, formulation, toxicological effects, ecological effects (on birds, aquatic organisms, etc.), environmental fate, physical properties, exposure guidelines, basic manufacturer, and references. For toxicology students, researchers, or the general public, this is a well-written and useful resource.



Toxicology and carcinogenesis studies of tetralin (CAS No. 119-64-2) in F344/N rats and B6C3F1 mice (inhalation studies).  


Tetralin is used as an industrial solvent primarily for naphthalene, fats, resins, oils, and waxes; as a solvent and stabilizer for shoe polishes and floor waxes; as a solvent for pesticides, rubber, asphalt, and aromatic hydrocarbons (e.g., anthracene); as a dye solvent carrier in the textile industry; as a substitute for turpentine in lacquers, paints, and varnishes; in paint thinners and as a paint remover; in alkali-resistant lacquers for cleaning printing ink from rollers and type; as a constituent of motor fuels and lubricants; for the removal of naphthalene in gas distribution systems; and as an insecticide for clothes moths. Tetralin was nominated by the National Cancer Institute for carcinogenicity and disposition studies because of its structure, high production volume, and high potential for worker and consumer exposure. Male and female F344/N rats and B6C3F1 mice were exposed to tetralin (at least 97% pure) by inhalation for 2 weeks, 3 months, or 2 years; male NCI Black Reiter (NBR) rats were exposed to tetralin by inhalation for 2 weeks. Male NBR rats do not produce 2u-globulin; the NBR rats were included to study the relationship of 2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male (F344/N and NBR) and five female (F344/N) rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 12 exposures. All rats survived to the end of the studies. The final mean body weight of female rats exposed to 120 ppm and mean body weight gains of female rats exposed to 30 ppm or greater were significantly less than those of the chamber controls. Final mean body weights of exposed groups of male NBR rats and mean body weight gains of all exposed groups of male rats were significantly less than those of the chamber controls. Dark-stained urine was observed in all 120 ppm rats. Squinting, weeping, or matted fur around the eyes were noted in the majority of F344/N rats exposed to 120 ppm. The 2u-globulin concentrations in the kidney of male F344/N rats were significantly greater in all exposed groups than in the chamber control group. The absolute kidney weight of 60 ppm females and the relative kidney weights of male F344/N rats exposed to 30 ppm or greater and female rats exposed to 15 ppm or greater were significantly increased. The absolute liver weight of 120 ppm NBR male rats and the relative liver weights of male and female rats exposed to 60 or 120 ppm were significantly increased. In the nose, the incidences of mononuclear cell cellular infiltration were generally significantly increased in all exposed groups of rats, and incidences of olfactory epithelium degeneration and glandular hypertrophy occurred in all male F344/N rats exposed to 120 ppm. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 13 exposures. All mice survived to the end of the study. Mean body weights of male and female mice were similar to those of the chamber controls. Dark-stained urine was observed in most of the exposed mice. The absolute and relative liver weights of 60 and 120 ppm males and 30 and 120 ppm females and the relative liver weights of 60 ppm females were significantly greater than those of the chamber controls. In the nose, the incidences of olfactory epithelium atrophy were significantly increased in 60 and 120 ppm males and females. Glandular dilatation occurred in all 120 ppm females, and glandular hyperplasia occurred in all 120 ppm males and females. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. The same exposure concentrations were given to additional groups of 10 male and



Studies on the toxicological effect of the aqueous extract of the fresh, dried and boiled berries of Solanum aculeastrum Dunal in male Wistar rats  

Microsoft Academic Search

The toxicological effect of the aqueous extract of fresh, dried and boiled berries of Solanum aculeastrum Dunal at 1, 10 and 25 mg\\/kg body weight was investigated in male Wistar rats for 28 days. The parameters used were the body weight of the animals and absolute weights of the organs, haematological parameters, renal and liver functional endpoints. The animals gained

OM Aboyade; MT Yakubu; DS Grierson; AJ Afolayan



NTP Toxicology and Carcinogenesis Studies of Coumarin (CAS No. 91-64-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).  


Coumarin is the basic structure of numerous naturally occurring compounds with important and diverse physiological activities. More than a thousand coumarin derivatives have been described, varying from simple coumarins containing alkyl and hydroxyl side chains to complex coumarins with benzoyl, furanoyl, pyranoyl, or alkylphosphorothionyl substituents. Coumarin and 3,4-dihydrocoumarin were nominated by the Food and Drug Administration and the National Cancer Institute for study because of the widespread use of coumarin in perfumes, cosmetics, and other products as a fragrance, continued interest in coumarin compounds as flavor-enhancing agents for foods, and the interest in structure-activity relationships of this important group of compounds. Coumarin is believed to be metabolized to a 3,4-epoxide intermediate, which may be responsible for its toxic effects, while 3,4-dihydrocoumarin, which lacks the 3,4-double bond, is not considered likely to form an epoxide intermediate. Toxicity and carcinogenicity studies were conducted by administering coumarin (97% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and B6C3F1 mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats received coumarin in corn oil by gavage at doses of 0, 25, 50, 100, 200, or 400 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All female rats and four male rats receiving 400 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female rats were similar to those of the controls. There were no clinical signs of organ-specific toxicity, and there was no evidence of impaired blood coagulation from measurements of capillary clotting time or prothrombin and activated partial thromboplastin time. 16-DAY STUDY IN MICE: Groups of five male and five female mice received coumarin in corn oil by gavage at doses of 0, 40, 75, 150, 300, or 600 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All mice receiving 600 mg/kg, two male mice receiving 300 mg/kg, and one male mouse receiving 75 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female mice were similar to those of the controls. Clinical findings of inactivity, excessive lacrimation, piloerection, bradypnea, ptosis, or ataxia were observed in some mice from the 300 and 600 mg/kg groups within the first several hours after dosing. Capillary clotting time and platelet counts of dosed mice were similar to those of controls. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received coumarin in corn oil by gavage at doses of 0,19, 38, 75,150, or 300 mg per kg body weight. Three male and three female rats receiving 300 mg/kg died. The mean body weight gains and final mean body weights of male rats that received 150 and 300 mg/kg were significantly lower than those of the controls. There were no clinical signs related to specific organ toxicity. Male and female rats receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin, and dose-related increases in erythrocyte counts. Serum levels of total bilirubin and one or more cytoplasmic enzymes including alanine aminotransferase, aspartate aminotransferase, ornithine carbamoyltransferase, and/or sorbitol dehydrogenase in males and females receiving 300 mg/kg were higher than those of controls. The absolute and relative liver weights of male and female rats that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular degeneration and necrosis, chronic active inflammation, and bile duct hyperplasia were observed in the liver of rats receiving 150 or 300 mg/kg. The high dose selected for the 2-year study was 100 mg/kg, which was just below the level at which mortality, lower final mean body weio



NTP Toxicology and Carcinogenesis Studies of Isobutene (CAS No. 115-11-7) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).  


Isobutene is produced during the fractionation of refinery gases or through the catalytic cracking of methyl-t-butyl ether. Isobutene is primarily used to produce diisobutylene, trimers, butyl rubber, and other polymers. In addition, it is used in the production of isooctane, high-octane aviation gasoline, methyl-t-butyl ether, and copolymer resins with butadiene and acrylonitrile. Isobutene was selected for evaluation because of the potential for human exposure due to its large production volume and the lack of adequate data on its carcinogenic potential. The toxicity and carcinogenicity of isobutene were determined in male and female F344/N rats and B6C3F1 mice exposed to isobutene (greater than 98% pure) by inhalation for 14 weeks or 2 years. The mutagenicity of isobutene was assessed in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed by inhalation for 14 weeks. 14-WEEK STUDIES: Groups of 10 male and 10 female F344/N rats and B6C3F1 mice were exposed to isobutene at concentrations of 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm 6 hours per day, 5 days per week, for 14 weeks. Concentrations greater than 8,000 ppm isobutene were not used because of the danger of explosion. All rats and mice survived to the end of the study. The final mean body weights and body weight gains of all exposed groups were similar to those of the chamber controls. No exposure-related gross lesions were observed in male or female rats or mice at necropsy. Microscopically, minimal hypertrophy of goblet cells lining the nasopharyngeal duct in the most caudal nose section was observed in some rats in each exposed group of males and females. 2-YEAR STUDIES: Based on the lack of significant exposure-related toxicologic effects in the 14-week rat and mouse studies, 8,000 ppm was selected as the highest exposure concentration in the 2-year studies. Concentrations of 0, 500, 2,000, and 8,000 ppm were selected for rats and mice with the 500 and 2,000 ppm selection based on published metabolic elimination rates for Sprague-Dawley rats and B6C3F1 mice. Rats: Groups of 50 male and 50 female F344/N rats were exposed to isobutene at concentrations of 0, 500, 2,000, or 8,000 ppm 6 hours per day, 5 days per week, for 105 weeks. Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of exposed groups were generally similar to those of the chamber controls throughout the study. 2-Hydroxyisobutyric Acid - Biomarker of Exposure 2-Hydroxyisobutyric acid (HIBA), the major urinary metabolite of isobutene, was measured in the urine of male and female rats as an indicator of isobutene exposure at 6, 12, and 18 months. The amount of HIBA excreted increased with increasing exposure concentration. However, when HIBA concentration was normalized to isobutene exposure concentration, the relative amount of HIBA excreted decreased with increasing exposure concentration, implying nonlinear kinetics. Pathology Findings: The incidence of thyroid gland follicular cell carcinoma in male rats exposed to 8,000 ppm was increased compared to the chamber control group and exceeded the historical control range. The incidences of hyaline degeneration of the olfactory epithelium were marginally increased in exposed rats; however, the severities of hyaline degeneration increased with increasing exposure concentration in males and females. Mice: Groups of 50 male and 50 female B6C3F1 mice were exposed to isobutene at concentrations of 0, 500, 2,000, or 8,000 ppm 6 hours per day, 5 days per week, for 105 weeks. Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of exposed mice were generally similar to those of the chamber controls throughout the study except for female mice exposed to 2,000 or 8,000 ppm, which weighed slightly less than chamber controls from about week 52 until week 92. 2-Hydroxyisobutyric Acid - Biomarker of Exposure: HIBA was measured in the urine of male and female mice as an indicator of isobutene exposure at 6, 12t



Simple high-performance liquid chromatography-fluorescence detection method for plasma, kidney and liver of rat as a tool for toxicology studies.  


A fast and simple HPLC-FLD (high-performance liquid chromatography-fluorescence detection) analytical method has been developed and validated for the determination of ochratoxin A in rat plasma, kidney and liver. The extraction method, calibration curves and chromatographic conditions are common for the three matrices. Plasma and homogenized tissue samples (250 microL) were extracted with ethanol (400 microL) and trichloroacetic acid 20% (w/v) (50 microL). Supernatants were directly injected into the HPLC system, analyzed on a 5-microm (25 cm x 0.4 cm) Tracer Extrasil ODS2 column using FLD (excitation wavelength=225 nm, emission wavelength=461 nm). The mobile phase was 29:29:42 (v/v) methanol-acetonitrile-sodium acetate. The small volume of sample needed which allows the obtaining of ochratoxin A levels in individual tissue samples from small animals and the wide range of concentrations that could be analyzed make this method easy to apply in toxicology and toxicokinetic studies of this mycotoxin, even in low dose carcinogenic studies. This method was linear and selective for all the matrices. Precision and accuracy were always <10% and recovery was very efficient in each case. Limits of detection and quantification were also calculated in plasma (1 and 8.4 microg/L), kidney (14.3 and 55.8 microg/kg) and liver (4.1 and 52.8 microg/kg). Stability of the tissue homogenates was assured for at least 10 months at -80 degrees C. The method has been successfully applied to the analysis of rat samples after 7 days of ochratoxin A (0.5mg/kg b.w. dissolved in an aqueous NaHCO(3) solution) administration by oral gavage. PMID:19027908

Vettorazzi, Ariane; Gonzalez-Peñas, Elena; Arbillaga, Leire; Corcuera, Laura-Ana; López de Cerain, Adela



Leukotrienes as Modifiers of Preclinical Atherosclerosis?  

PubMed Central

Preclinical atherosclerosis represents a crucial period associated with several pathophysiological reactions in the vascular wall. Failure to diagnose preclinical atherosclerosis at this stage misses a major opportunity to prevent the long-term consequences of this disease. Surrogate biological and structural vascular markers are available to determine the presence and the extension of preclinical vascular injury in the general population. Examples of surrogate markers are carotid intima media thickness and biomarkers including high-sensitivity C-reactive protein, cell adhesion molecules and matrix metalloproteinases, and leukotrienes. Recently, leukotrienes have been implicated as mediators, biomarkers, and possible therapeutic targets in the context of subclinical atherosclerosis. The aim of this short paper is to focus on the relation between preclinical atherosclerosis and leukotrienes, with particular attention to the recent development on the use of leukotriene modifiers in the treatment of atherosclerosis. PMID:22645425

Riccioni, Graziano; Back, Magnus



Multiscale Toxicology- Building the Next Generation Tools for Toxicology  

SciTech Connect

A Cooperative Research and Development Agreement (CRADA) was established between Battelle Memorial Institute (BMI), Pacific Northwest National Laboratory (PNNL), Oak Ridge National Laboratory (ORNL), Brookhaven National Laboratory (BNL), Lawrence Livermore National Laboratory (LLNL) with the goal of combining the analytical and synthetic strengths of the National Laboratories with BMI?s expertise in basic and translational medical research to develop a collaborative pipeline and suite of high throughput and imaging technologies that could be used to provide a more comprehensive understanding of material and drug toxicology in humans. The Multi-Scale Toxicity Initiative (MSTI), consisting of the team members above, was established to coordinate cellular scale, high-throughput in vitro testing, computational modeling and whole animal in vivo toxicology studies between MSTI team members. Development of a common, well-characterized set of materials for testing was identified as a crucial need for the initiative. Two research tracks were established by BMI during the course of the CRADA. The first research track focused on the development of tools and techniques for understanding the toxicity of nanomaterials, specifically inorganic nanoparticles (NPs). ORNL?s work focused primarily on the synthesis, functionalization and characterization of a common set of NPs for dissemination to the participating laboratories. These particles were synthesized to retain the same surface characteristics and size, but to allow visualization using the variety of imaging technologies present across the team. Characterization included the quantitative analysis of physical and chemical properties of the materials as well as the preliminary assessment of NP toxicity using commercially available toxicity screens and emerging optical imaging strategies. Additional efforts examined the development of high-throughput microfluidic and imaging assays for measuring NP uptake, localization, and toxicity in vitro. The second research track within the MSTI CRADA focused on the development of ex vivo animal models for examining druginduced cardiotoxicity. ORNL's role in the second track was limited initially, but was later expanded to include the development of microfluidic platforms that might facilitate the translation of Cardiac 'Microwire' technologies developed at the University of Toronto into a functional platform for drug screening and predictive assessment of cardiotoxicity via highthroughput measurements of contractility. This work was coordinated by BMI with the Centre for the Commercialization of Regenerative Medicine (CCRM) and the University of Toronto (U Toronto). This partnership was expanded and culminated in the submission of proposal to Work for Others (WFO) agencies to explore the development of a broader set of microphysiological systems, a so call human-on-a-chip, that could be used for toxicity screening and the evaluation of bio-threat countermeasures.

Retterer, S. T. [ORNL] [ORNL; Holsapple, M. P. [Battelle Memorial Institute] [Battelle Memorial Institute



New cast for a new era: preclinical cancer drug development revisited  

PubMed Central

Molecularly targeted agents promise to revolutionize therapeutics by reducing morbidity and mortality in patients with cancer. However, despite an urgent need for more effective anticancer compounds, current preclinical drug evaluations largely fail to satisfy the demand. New preclinical strategies, including the improvement of sophisticated mouse models and co-clinical study designs, are being used to augment the predictive value of animal-based translational cancer research. Here, we review the development of successful preclinical antineoplastic agents, their associated limitations, and alternative methods to predict clinical outcomes. PMID:23999436

Herter-Sprie, Grit S.; Kung, Andrew L.; Wong, Kwok-Kin



The toxicology of chemosterilants  

PubMed Central

Sterilization of males can in certain circumstances be more efficient than killing as a method for control of insects and perhaps other pests. A number of chemicals (chemosterilants) show promise of producing sexual sterility in insects without some of the practical limitations of radiation. The most important compounds are alkylating agents. These have little immediate pharmacological action, but are notable for their selective action against haematopoietic and some other proliferating tissues. A number of alkylating agents have been shown to be mutagens in insects, bacteria, fungi, and higher plants; carcinogens in mammals; and teratogens in insects, birds, and mammals. Some produce sexual sterility, possibly in mammals as well as in insects, at doses too low to produce the other effects. Some have an established reputation as drugs for palliative treatment of leukaemia and other neoplasms. The development of insect sterilization as a vector control technique has been handicapped in part by lack of scientific information on the acute and long-term hazards that might be associated with the use of chemosterilants. In this paper the author brings together the available knowledge on the toxicology of the alkylating agents. PMID:14278008

Hayes, Wayland J.



Avian toxicologic diagnosis  

USGS Publications Warehouse

This chapter describes the sources and pathophysiology of some potential poisons that affect birds and summarizes useful laboratory tests. The diagnosis of poisoning in birds, as in mammals, requires a complete and accurate history, careful observation of clinical signs, and a thorough necropsy evaluation. Appropriate sample handling and analysis, based on consultation with the diagnostic toxicologist, are critical (Table 19--1). Veterinary toxicology laboratories are becoming increasingly specialized, with only certain laboratories capable of analyzing for drug residues or anticoagulants, for example. Although a local laboratory may not be able to fulfill a specific test request, they may recommend an alternative laboratory or may be willing to forward the sample. As a general rule in suspect poisoning cases, large tissue samples of liver, kidney, brain, and subcutaneous fat and of crop, proventriculus, and ventriculus contents should be collected at necropsy and frozen. Appropriate samples should be submitted frozen, with the remainder held in the freezer for possible later testing. A second set of tissues should be placed in 10% formalin for histopathologic examination.

Sigurdson, C. J.; Franson, J. C.



The toxicology of chlorine.  


Chlorine is a reactive gas used by humanity for over two centuries. Exposure to chlorine has occurred in a number of situations, including as a chemical warfare agent, in industrial and domestic exposures, and as a result of accidents and spills. The toxicology of chlorine is related almost entirely to effects in the respiratory system. A consistent symptomology occurs in both animals and humans. This ranges from sensory irritation, to irritation and bronchospasm, to cellular changes to bronchioles and alveoli, to development of pulmonary disease. While full recovery from such injuries remains the most likely outcome, there is little doubt that permanent loss of function is possible in severe cases. In all industrial applications of chlorine, occupational exposures to chlorine should be controlled to at least the recommended exposure standard. However, a focus of activity on ensuring that excursions (such as leaks or "gassing" incidents) above these values do not occur is likely to be more beneficial. Treatment of chlorine exposure is essentially symptomatic, with the efficacy of some treatments (such as corticosteroid therapy) still not well established. PMID:11161660

Winder, C



Preclinical formulations: insight, strategies, and practical considerations.  


A lot of resources and efforts have been directed to synthesizing potentially useful new chemical entities (NCEs) by pharmaceutical scientists globally. Detailed physicochemical characterization of NCEs in an industrial setup begins almost simultaneously with preclinical testing. Most NCEs possess poor water solubility posing bioavailability issues during initial preclinical screening, sometimes resulting in dropping out of an NCE with promising therapeutic activity. Selection of right formulation approach for an NCE, based on its physicochemical properties, can aid in improving its solubility-related absorption and bioavailability issues. The review focuses on preclinical formulations stressing upon different preclinical formulation strategies and deciphers the understanding of formulation approaches that could be employed. It also provides detailed information related to a vast pool of excipients available today, which is of immense help in designing preclinical formulations. Few examples mentioned, throw light on key aspects of preclinical formulation development. The review will serve as an important guide for selecting the right strategy to improve bioavailability of NCEs for academic as well as industrial formulation scientists. PMID:24920522

Shah, Sanket M; Jain, Ankitkumar S; Kaushik, Ritu; Nagarsenker, Mangal S; Nerurkar, Maneesh J



The discovery of rivaroxaban: translating preclinical assessments into clinical practice  

PubMed Central

Direct oral anticoagulants that target a single coagulation factor (such as factor Xa or thrombin) have been developed in recent years in an attempt to address some of the limitations of traditional anticoagulants. Rivaroxaban is an oral, direct factor Xa inhibitor that inhibits free and clot-bound factor Xa and factor Xa in the prothrombinase complex. Preclinical studies demonstrated a potent anticoagulant effect of rivaroxaban in plasma as well as the ability of this agent to prevent and treat venous and arterial thrombosis in animal models. These studies led to an extensive phase I clinical development program that investigated the pharmacological properties of rivaroxaban in humans. In these studies, rivaroxaban was shown to exhibit predictable pharmacokinetics and pharmacodynamics and to have no clinically relevant interactions with many commonly prescribed co-medications. The pharmacodynamic effects of rivaroxaban (for example, inhibition of factor Xa and prolongation of prothrombin time) were closely correlated with rivaroxaban concentrations in plasma. The encouraging findings from preclinical and early clinical studies were expanded upon in large, randomized phase III studies, which demonstrated the clinical efficacy and safety of rivaroxaban in a broad spectrum of patients. This article provides an overview of the discovery and development of rivaroxaban, describing the pharmacodynamic profile established in preclinical studies and the optimal translation to clinical studies in healthy subjects and patient populations. PMID:24324436

Kubitza, Dagmar; Perzborn, Elisabeth; Berkowitz, Scott D.



Toxicological evaluation of ammonium perfluorobutyrate in rats: Twenty-eight-day and ninety-day oral gavage studies  

EPA Science Inventory

Sequential 28-day and 90-day oral toxicity studies were performed in male and female rats with ammonium perfluorobutyrate (NH4+PFBA) at doses up to 150 and 30 mg/kg/d, respectively. Ammonium perfluorooctanoate was used as a comparator at a dose of 30 mg/kg/d in the 28-d study. Fe...


An approach to feeding high-percentage fish diets to mice for human and wildlife toxicology studies  

Microsoft Academic Search

Experimental feeding of sport fish to rodents has been an important tool for the study of biological effects induced by a contaminated fish diet. Most rodent feeding studies have used low-to-moderate levels of tissue from large fish species incorporated into diets fed to rats and have given little consideration to issues of diet palatability or nutrition. There are currently no

Christopher M. Somers; Eduardo V. Valdes; James S. Quinn



Various aspects of piscine toxicology.  


In opposition to toxicology of mammals piscine toxicology is closely connected with the conditions of external environment. The aquatic environment is necessary for embryonic development and after hatching during short or long-lasting larval period of most fish species. An aquatic environment is polluted by many industrial and agricultural wastes. Ammonia as a toxic and common compound in water have negative influence for aquaculture especially in intensive fish culture, recirculation system and hatchery facilities. Acute toxicity of ammonia was investigated in carp Cyprinus carpio L. and developmental stages of chub Squalius cephalus L. Changes in the peripheral blood characteristics and hemopoietic tissues of carp occurred after exposition to ammonia in acute tests and 3, 5 and 10 weeks sublethal concetration. The observed increase of the concentration of most amino acids in fish intoxicated with amonia suggests that the process reflects detoxication of ammonia which takes place both in the brain and muscles after 3 weeks of exposition. Phenol intoxication tests induced considerable unfavorable changes in the blood and dystrophic and necrobiotic lesions in tissues of fish leading to dysfunction both hemopoietic and reproductive processes.In study on fish reproduction disruptors the influence of oxygenated polycyclic hydrocarbons (17-?-estradiol, 4,7-dihydroxyisoflavone, 1,6-dihydroxynaphthalene and 1,5-dihydroxynaphthalene) and oxygenated monocyclic hydrocarbons (phenol, 4-n-heptylphenol, 4-n-buthylphenol, 4-sec-buthylphenol; 4-tert-buthylphenol) was assessed using histopathological methods. It was established that examined oxygenated aromatic hydrocarbons both natural (17-?-estradiol and 4,7-dihydroxyisoflavone) and synthetic can disrupt the differentiation of primary and secondary sex traits in pikeperch Sander lucioperca L. The chronic activity of these "biomimetics of estrogen" can lead to the disappearance of natural fish population. In vivo and in vitro tests were used to exam dibutyl phthalate and butyl benzyl phthalate impact on the development of the reproductive system of pikeperch. Additional as multigenerational studies are needed to clarify influence long term exposure of fish to environmental concentrations of endocrine disrupting chemicals.Hydrogen peroxide used in fish therapy is known to be toxic for sensitive species. In our work safe concentrations and exposure times was evaluated for ide Leuciscus idus L. and pike Esox lucius L. fry. The intensity of lesions in gills, skin, pseudobranch and thymus of exposed fish were connected with the time of bath.Actually anesthetics are routinely required during stressful procedures with fish, but data regarding the safety of individual anesthetics to different fish species are still few and insufficient. The influence of clove oil, MS-222 and 2-phenoxyaethanol anesthesia on fish organism was investigated in our faculty with cooperation with Research Institute of Fish Culture and Hydrobiology, Vodnany, Czech Republic. PMID:21217882

Wlasow, Teresa; Demska-Zakes, Krystyna; Gomulka, Piotr; Jarmolowicz, Sylwia



UNCORRECTED 3 Molluscs as multidisciplinary models in environment toxicology  

E-print Network

c Toxicology Program, Duke University, Durham, North Carolina, United States 9 d Environmental and multidisciplinary research 13 approaches in the field of environmental toxicology. Molluscs are effective models. 19 Keywords: Multidisciplinary toxicology models; Molluscs; Imposex; Environmental toxicology

McClellan-Green, Patricia



EPA Science Inventory

Current approaches in Reproductive Toxicology encompass a broad spectrum. This review article summarizes several of these approaches, based on presentations at the Symposium on Reproductive ToxicologY in Michigan. here are multiple targets for toxicological injury in the developi...


Arsenic Exposure and Toxicology: A Historical Perspective  

PubMed Central

The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve. PMID:21750349

Hughes, Michael F.; Beck, Barbara D.; Chen, Yu; Lewis, Ari S.; Thomas, David J.



Arsenic exposure and toxicology: a historical perspective.  


The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve. PMID:21750349

Hughes, Michael F; Beck, Barbara D; Chen, Yu; Lewis, Ari S; Thomas, David J



Toxicological evaluation of ammonium perfluorobutyrate in rats: Twenty-eight-day and ninety-day oral gavage studies  

Microsoft Academic Search

Sequential 28-day and 90-day oral toxicity studies were performed in male and female rats with ammonium perfluorobutyrate (NH4+PFBA) at doses up to 150 and 30mg\\/kg-d, respectively. Ammonium perfluorooctanoate was used as a comparator at a dose of 30mg\\/kg-d in the 28-day study. Female rats were unaffected by NH4+PFBA. Effects in males included: increased liver weight, slight to minimal hepatocellular hypertrophy;

John L. Butenhoff; James A. Bjork; Shu-Ching Chang; David J. Ehresman; George A. Parker; Kaberi Das; Christopher Lau; Paul H. Lieder; François M. van Otterdijk; Kendall B. Wallace


Evaluation of the Association between Persistent Organic Pollutants (POPs) and Diabetes in Epidemiological Studies: A National Toxicology Program Workshop Review  

PubMed Central

Background: Diabetes is a major threat to public health in the United States and worldwide. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health. Objective: We assessed the epidemiologic literature for evidence of associations between persistent organic pollutants (POPs) and type 2 diabetes. Methods: Using a PubMed search and reference lists from relevant studies or review articles, we identified 72 epidemiological studies that investigated associations of persistent organic pollutants (POPs) with diabetes. We evaluated these studies for consistency, strengths and weaknesses of study design (including power and statistical methods), clinical diagnosis, exposure assessment, study population characteristics, and identification of data gaps and areas for future research. Conclusions: Heterogeneity of the studies precluded conducting a meta-analysis, but the overall evidence is sufficient for a positive association of some organochlorine POPs with type 2 diabetes. Collectively, these data are not sufficient to establish causality. Initial data mining revealed that the strongest positive correlation of diabetes with POPs occurred with organochlorine compounds, such as trans-nonachlor, dichlorodiphenyldichloroethylene (DDE), polychlorinated biphenyls (PCBs), and dioxins and dioxin-like chemicals. There is less indication of an association between other nonorganochlorine POPs, such as perfluoroalkyl acids and brominated compounds, and type 2 diabetes. Experimental data are needed to confirm the causality of these POPs, which will shed new light on the pathogenesis of diabetes. This new information should be considered by governmental bodies involved in the regulation of environmental contaminants. PMID:23651634

Novak, Raymond F.; Anderson, Henry A.; Birnbaum, Linda S.; Blystone, Chad; DeVito, Michael; Jacobs, David; Köhrle, Josef; Lee, Duk-Hee; Rylander, Lars; Rignell-Hydbom, Anna; Tornero-Velez, Rogelio; Turyk, Mary E.; Boyles, Abee L.; Thayer, Kristina A.; Lind, Lars



NTP Toxicology and Carcinogenesis Studies of Diethanolamine (CAS No. 111-42-2) in F344/N Rats and B6C3F1 Mice (Dermal Studies).  


Diethanolamine is widely used in the preparation of diethanolamides and diethanolamine salts of long-chain fatty acids that are formulated into soaps and surfactants used in liquid laundry and dishwashing detergents, cosmetics, shampoos, and hair conditioners. Diethanolamine is also used in textile processing, in industrial gas purification to remove acid gases, as an anticorrosion agent in metalworking fluids, and in preparations of agricultural chemicals. Aqueous diethanolamine solutions are used as solvents for numerous drugs that are administered intravenously. Diethanolamine was selected for evaluation because its large-scale production and pattern of use indicate the potential for widespread human exposure. Male and female F344/N rats and B6C3F1 mice received dermal applications of diethanolamine in 95% ethanol for 2 years. Genetic toxicology studies were performed in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and B6C3F1 mouse peripheral blood erythrocytes. RATS: Groups of 50 male rats were administered 0, 16, 32, or 64 mg diethanolamine/kg body weight in ethanol dermally for 2 years. Groups of 50 female rats were administered 0, 8, 16, or 32 mg/kg in ethanol dermally for 2 years. Survival, Body Weights, and Clinical Findings Survival of vehicle control and dosed male and female rats was similar. Mean body weights of 64 mg/kg males were less than those of the vehicle controls beginning week 8, and mean body weights of females were generally similar to those of the vehicle control group. The only clinical finding attributed to diethanolamine administration was irritation of the skin at the site of application. Pathology Findings: Minimal to mild nonneoplastic lesions occurred at the site of application in the epidermis of dosed male and female rats. The incidence of acanthosis in 64 mg/kg males, the incidences of hyperkeratosis in 32 and 64 mg/kg males and in all dosed female groups, and the incidences of exudate in 64 mg/kg males and in all dosed female groups were greater than those in the controls. The incidences and severities of nephropathy were significantly increased in dosed female rats compared to the vehicle controls. MICE: Groups of 50 male and 50 female mice were administered 0, 40, 80, or 160 mg diethanolamine/kg body weight in ethanol dermally for 2 years. Survival, Body Weights, and Clinical Findings Survival of dosed male groups was similar to that of the vehicle control group; survival of dosed female groups was significantly less than that of the vehicle control group. Mean body weights of 80 and 160 mg/kg males were less than those of the vehicle controls after weeks 88 and 77, respectively. Mean body weights of dosed groups of females were generally less than those of the vehicle controls during the second year of the study. Pathology Findings: In male mice, the incidences of hepatocellular adenoma and of hepatocellular adenoma or carcinoma (combined) in all dosed groups and of hepatocellular carcinoma and hepatoblastoma in 80 and 160 mg/kg males were significantly increased compared to the vehicle controls. The incidences of hepatocellular neoplasms were significantly greater in dosed groups of female mice than in the vehicle control group. The incidences of hepatocellular neoplasms in all dosed groups of males and females exceeded the historical control ranges. Nonneoplastic hepatocyte changes were seen only in dosed male and female mice. Changes consisted of cytoplasmic alteration and syncytial alteration. The incidences of renal tubule adenoma in males occurred with a positive trend; however, the incidences of carcinoma and hyperplasia did not follow this pattern. An extended evaluation of kidney step sections revealed additional adenomas and hyperplasias in all dosed groups. The combined analysis of single and step sections indicated a dose-related increase in the incidences of renal tubule hyperplasia and renal tubule adenoma or carcinoma (combined), and an increase in the incidences of renal tubule adenoma in male mice. Incidences of thyroidt



Gordon Research Conference on Genetic Toxicology  

SciTech Connect

Genetic toxicology represents a study of the genetic damage that a cell can incur, the agents that induce such damage, the damage response mechanisms available to cells and organisms, and the potential consequences of such damage. Genotoxic agents are abundant in the environment and are also induced endogenously. The consequences of such damage can include carcinogenesis and teratogenesis. An understanding of genetic toxicology is essential to carry out risk evaluations of the impact of genotoxic agents and to assess how individual genetic differences influence the response to genotoxic damage. In recent years, the importance of maintaining genomic stability has become increasingly recognized, in part by the realization that failure of the damage response mechanisms underlies many, if not all, cancer incidence. The importance of these mechanisms is also underscored by their remarkable conservation between species, allowing the study of simple organisms to provide significant input into our understanding of the underlying mechanisms. It has also become clear that the damage response mechanisms interface closely with other aspects of cellular metabolism including replication, transcription and cell cycle regulation. Moreover, defects in many of these mechanisms, as observed for example in ataxia telangiectasia patients, confer disorders with associated developmental abnormalities demonstrating their essential roles during growth and development. In short, while a decade ago, a study of the impact of DNA damage was seen as a compartmentalized area of cellular research, it is now appreciated to lie at the centre of an array of cellular responses of crucial importance to human health. Consequently, this has become a dynamic and rapidly advancing area of research. The Genetic Toxicology Gordon Research Conference is biannual with an evolving change in the emphasis of the meetings. From evaluating the nature of genotoxic chemicals, which lay at the centre of the early conferences, the emphasis has moved to understanding how cells and organisms respond to the different forms of genotoxic damage incurred. By understanding these mechanisms, the risk to humans can be more rationally assessed and evaluated. More recently, the format of the meetings have aimed to facilitate input from the range of disciplines that can now provide insight into the field. This evolution in emphasis has been continued in the format of the proposed 2003 meeting. In the last Genetic Toxicology Gordon Conference (2001), the aim was to integrate studies on genetic toxicology at the structural, molecular and cellular level with those involving mice and humans (2 micron to Man). In the 2003 conference, we aim to integrate the approaches from 2 micron to man together with approaches where our basic knowledge has been exploited in an applied context (2 micron to Man to manipulation).

Project Director Penelope Jeggo



Multiscale Toxicology - Building the Next Generation Tools for Toxicology  

SciTech Connect

A Cooperative Research and Development Agreement (CRADA) was sponsored by Battelle Memorial Institute (Battelle, Columbus), to initiate a collaborative research program across multiple Department of Energy (DOE) National Laboratories aimed at developing a suite of new capabilities for predictive toxicology. Predicting the potential toxicity of emerging classes of engineered nanomaterials was chosen as one of two focusing problems for this program. PNNL’s focus toward this broader goal was to refine and apply experimental and computational tools needed to provide quantitative understanding of nanoparticle dosimetry for in vitro cell culture systems, which is necessary for comparative risk estimates for different nanomaterials or biological systems. Research conducted using lung epithelial and macrophage cell models successfully adapted magnetic particle detection and fluorescent microscopy technologies to quantify uptake of various forms of engineered nanoparticles, and provided experimental constraints and test datasets for benchmark comparison against results obtained using an in vitro computational dosimetry model, termed the ISSD model. The experimental and computational approaches developed were used to demonstrate how cell dosimetry is applied to aid in interpretation of genomic studies of nanoparticle-mediated biological responses in model cell culture systems. The combined experimental and theoretical approach provides a highly quantitative framework for evaluating relationships between biocompatibility of nanoparticles and their physical form in a controlled manner.

Thrall, Brian D.; Minard, Kevin R.; Teeguarden, Justin G.; Waters, Katrina M.



National Particle Component Toxicity (NPACT) Initiative: integrated epidemiologic and toxicologic studies of the health effects of particulate matter components.  


Particulate matter (PM*), an ambient air criteria pollutant, is a complex mixture of chemical components; particle sizes range from nanometer-sized molecular clusters to dust particles that are too large to be aspirated into the lungs. Although particle composition is believed to affect health risks from PM exposure, our current health-based air quality standards for PM are limited to (1) the mass concentrations of PM2.5 (particles 2.5 microm or smaller in aerodynamic diameter), which are largely attributable to combustion products; and (2) PM10 (10 microm or smaller), which includes larger-sized mechanically generated dusts. Both of these particle size fractions are regulated under the National Ambient Air Quality Standards (NAAQS) and both have been associated with excess mortality and morbidity. We conducted four studies as part of HEI's integrated National Particle Component Toxicity (NPACT) Initiative research program. Since 1999, the Chemical Speciation Network (CSN), managed by the U.S. Environmental Protection Agency (U.S; EPA), has routinely gathered air monitoring data every third or sixth day for the concentrations of numerous components of PM2.5. Data from the CSN enabled us to conduct a limited time-series epidemiologic study of short-term morbidity and mortality (Ito study); and a study of the associations between long-term average pollutant concentrations and annual mortality (Thurston study). Both have illuminated the roles of PM2.5 chemical components and source-related mixtures as potentially causal agents. We also conducted a series of 6-month subchronic inhalation exposure studies (6 hours/day, 5 days/week) of PM2.5 concentrated (nominally) 10 x from ambient air (CAPs) with apolipoprotein E-deficient (ApoE(-/-)) mice (a mouse model of atherosclerosis) (Chen study). The CAPs studies were conducted in five different U.S. airsheds; we measured the daily mass concentrations of PM2.5, black carbon (BC), and 16 elemental components in order to identify their sources and their roles in eliciting both short- and long-term health-related responses. In addition, from the same five air-sheds we collected samples of coarse (PM10-2.5), fine (PM2.5-0.2), and ultrafine (PM0.2) particles. Aliquots of these samples were administered to cells in vitro and to mouse lungs in vivo (by aspiration) in order to determine their comparative acute effects (Gordon Study). The results of these four complementary studies, and the overall integrative analyses, provide a basis for guiding future research and for helping to determine more targeted emission controls for the PM components most hazardous to acute and chronic health. Application of the knowledge gained in this work may therefore contribute to an optimization of the public health benefits of future PM emission controls. The design of each NPACT study conducted at NYU was guided by our scientific hypotheses, which were based on our reviews of the background literature and our experience in conducting studies of associations between ambient PM and health-related responses. These hypotheses guided the development and conduct of the four studies. Hypothesis 1. Coarse, fine, and ultrafine PM are each capable of producing acute health effects of public health concern, but the effects may differ according to particle size and composition. (Applies to all studies.) Hypothesis 2. Long-term PM2.5 exposures are closely associated with chronic health effects. (Applies to studies 1 and 4.) Hypothesis 3. The source-apportionment techniques that we have developed and refined in recent years provide a useful basis for identifying major categories of sources of PM in ambient air and specific chemical components that have the greatest impacts on a variety of acute and chronic health effects. (Applies to all studies.) Hypothesis 4. The health effects due to ambient PM exposures can best be seen in sensitive subgroups within overall human populations and in animal models of such populations. (Applies to studies 1, 3, and 4.) Overall, the studies have demonstrated that the toxicity of PM is d

Lippmann, Morton; Chen, Lung-Chi; Gordon, Terry; Ito, Kazuhiko; Thurston, George D



[Toxicological evaluation in the childhood].  


Intoxications in infancy require urgent medical treatment within national health systems. In our country they represent 0.3% of paediatric urgencies. Most of them are accidental intoxications but is not infrequent to find some related to child abuse or to suicidal intentions, especially in adolescence. The objectives of the study are to evaluate both clinical health care and medical legal aspects in intoxications in infancy. Medical assistance is described and it includes clinical diagnosis, typology of the more common toxics, percentages and referral to social work and emergency care equipment units of the Ministry of Social Welfare and the Department of Health or, where appropriate, directly to prosecutors and courts for their intervention. In cases of detection of alcohol, drugs or medication in infants, the importance of the correct interpretation of the results of toxicological findings is discussed. Several studies for the interpretation of results concerning the detection of these toxics are reported. Both legal aspects and the forensic medical opinion are assessed. The findings will be analysed by the judicial authority in order to circumscribe responsibilities or to take appropriate decisions concerning the protection of infants' interests. In conclusion intoxication in infancy can lead to legal proceedings requiring specific actions for their protection. Both physicians and hospitals must comply with the legal requirement of the submission to the court of judicial parties. On the other hand, this information is an interesting step toward reinforcing public health surveillance. PMID:24913753

Arroyo, Amparo; Rodrigo, Carlos; Teresa Marrón, M




EPA Science Inventory

A multi-year study in the C-111 canal and associated sites in Florida Bay was undertaken in order to determine the potential contaminant risk that exists in South Florida. After examining extensive surface water data, as well as sediment, tissue, and semi-permeable membrane devic...



EPA Science Inventory

Four laboratories, two in Czechoslovakia (Brno and Prague) and two in USSR (Moscow and Duschanbe), participated in the International Program On Chemical Safety's (IPCS) Collaborative Study to evaluate the utility of the most commonly used plant test systems, including the Arabido...


Comparative toxicological studies of distillery effluent treatments such as UASB reactor followed by an oxidizer unit using Cyprinus carpio fish  

Microsoft Academic Search

The aim of the present study was to evaluate the acute toxicity of anaerobically treated distillery effluent and oxidized effluent on freshwater fish, Cyprinus carpio. The untreated distillery effluent (Sample A) was treated with up?flow anaerobic sludge blanket (UASB) reactor (Sample B) and followed by an oxidizer system (Sample C and D) under optimized conditions. The comparative acute toxicity of

Vandana Patil; Vikram Ghole



Combining Mass Spectrometry and Toxicology for a Multi-Country European Epidemiologic Study on Drinking Water Disinfection By-Products.  

EPA Science Inventory

The HiWATE (Health Impacts of long-term exposure to disinfection by-products in drinking WATEr) project is the first systematic analysis that combines the epidemiology on adverse pregnancy outcomes with analytical chemistry and analytical biology in the European Union. This study...


Combining Mass Spectrometry and Toxicology for a Multi-Country European Epidemiologic Study on Drinking Water Disinfection By-Products  

EPA Science Inventory

The HiWATE (Health Impacts of long-term exposure to disinfection by-products in drinking WATEr) project is the first systematic analysis that combines the epidemiology on adverse pregnancy outcomes with analytical chemistry and analytical biology in the European Union. This study...


Evaluation of potential health effects of 10 kHz magnetic fields: A short-term mouse toxicology study  

SciTech Connect

A high-frequency inductive power distribution (HID) technology has been developed that generates sinusoidal magnetic fields at a frequency of 10 kHz. In typical industrial applications, field intensities in the order of 0.2 mT can be expected between the current-carrying coils. Because the possible health effects of 10 kHz sinusoidal magnetic fields of this type had never been investigated, a broad evaluation of possible effects on animal health was made in a preliminary 14 day acute study and in a 90 day subchromic study using male and female B6C3F1 mice. Exposures were at 0.08, 0.28, and 1.0 mT vs a background exposure of 3.7 {micro}T and were essentially continuous. These studies failed to demonstrate any health effects that can be clearly related to the magnetic field exposure. No changes in animal behavior or indications of morbidity were detected during the initial exposure to the fields. There were no significant differences in body weight between exposed and unexposed (control) mice at any time int h study, and the clinical chemistry and hematology parameters were essentially unchanged. Although minor differences in some clinical chemistry and hematology parameters were seen between control and exposure groups, the lack of exposure dependence, the lack of consistency between sexes, and the lack of correspondence with the results of the two studies all suggest that these were chance associations. Even if the changes were real, the magnitude of the changes was very small and does not indicate serious biological effects. Finally, all organs were macroscopically and microscopically normal except for isolated, generally mild, histological lesions and lesions that were ascribed to fighting among males. There was no obvious association with field intensity.

Robertson, I.G.C.; Wilson, W.R.; Dawson, B.V.; Zwi, L.J.; Green, A.W.; Boys, J.T. [Univ. of Auckland (New Zealand)] [Univ. of Auckland (New Zealand)



Preclinical safety profile of sildenafil.  


Sildenafil citrate, marketed as Viagra, for the treatment of erectile dysfunction, has a proven record of safety in humans as predicted by the results of extensive pharmacological and toxicological testing in animals and in vitro, and confirmed by pharmacokinetic exposure data. The aim of this paper is to review succinctly the main findings resulting from these experiments. Daily doses of sildenafil, within and far beyond the human therapeutic range, were given to dogs and rodents for up to 1 and 2 y, respectively. Plasma analyses were conducted to determine the exposure to sildenafil. We found species-specific effects in dogs (Beagle pain syndrome), mice (marked intestinal dilatation) and rats (adaptive reversible hepatocellular hypertrophy associated with secondary thyroid hypertrophy). All these effects in rodents and dogs have no relevance to humans. Morphometric thickness measurements of the retinal layers carried out in response to clinical observations of visual disturbances in humans indicated no difference between treated and control rats and dogs after up to 24 months of treatment. There was no evidence of histopathologic damage to any structures of the visual pathway. Sildenafil had no effects on fertility, no teratogenic potential, was not genotoxic and has no carcinogenic potential. In rats and dogs, safety ratios were 40:1 and 28:1, respectively, in terms of exposure over 24 h (AUC24 h) and 19:1 and 8:1, respectively, in terms of peak plasma concentration (Cmax). These safety ratios illustrate the separation between exposure to sildenafil of animals at large nontoxic doses and the much smaller human therapeutic exposure. This profile highlights the very low risk of human toxicity for sildenafil. The favourable results of the nonclinical safety evaluation of sildenafil in established animal models have been confirmed by many years of clinical experience during the development and marketing of sildenafil. PMID:15057260

Abbott, D; Comby, P; Charuel, C; Graepel, P; Hanton, G; Leblanc, B; Lodola, A; Longeart, L; Paulus, G; Peters, C; Stadler, J



Preclinical humanized mouse model with ectopic ovarian tissues  

PubMed Central

The aim of the present study was to establish human ovarian stroma within the mouse subcutaneously, in order for the resulting stroma to serve as a useful preclinical tool to study the progression of human ovarian cancer in a humanized ovarian microenvironment. Normal human ovarian tissues were subcutaneously implanted into severe combined immunodeficient (SCID) mice and then the implants were identified by immunohistochemistry. The implants became vascularized and retained their original morphology for about 4 weeks following implantation. Immunohistochemical staining for cytokeratin-7 confirmed the ovarian origin of the epithelial cells. CD34 staining demonstrated human-derived vessels. Positive estrogen receptor and partially-positive progesterone receptor staining indicated the estrogen and progesterone dependence of the implants. Only vascular pericytes expressed ?-smooth muscle actin, indicating the normal ovarian origin of the xenografts. Human ovarian tissue successfully survived in SCID mice and retained its original properties. This humanized mouse model may be used as preclinical tool to investigate ovarian cancer. PMID:25120592




Toxicology and carcinogenesis studies of methylphenidate hydrochloride (Cas No. 298-59-9) in F344/N rats and B6C3F1 mice (feed studies). Technical report series  

SciTech Connect

Toxicology and carcinogenicity studies were conducted by administration of methylphenidate hydrochloride in feed to groups of 70 F344/N rats of each sex at doses of 0, 100, 500, or 1,0000 ppm and to groups of 70 B6C3F1 mice of each sex at doses of 0, 50, 250, or 500 ppm. Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of methylphenidate hydrochloride in male or female F344/N rats receiving 100, 500, or 1,000 ppm. There was some evidence of carcinogenic activity in male and female B6C3F1 mice, based on the occurrence of hepatocellular neoplasms. Treatment of female rats with methylphenidate hydrochloride was associated with a decrease in the incidence of mammary gland fibroadenomas. Administration of methylphenidate hydrochloride to male and female mice resulted in increased incidence of eosinophilic foci in the liver.




NTP technical report on the toxicology and carcinogenesis studies of benzethonium chloride (Cas No. 121-54-0) in F344/N rats and B6C3F1 mice (dermal studies). Technical report series  

SciTech Connect

Toxicology and carcinogenicity studies were conducted by dermal administration of benzethonium chloride to groups of 60 F344/N rats and 60 B6C3F1 mice of each sex at doses of 0, 0.15, 0.5, or 1.5 mg/kg body weight. Benzethonium chloride was administered to rats in ethanol 5 days per week and doses were adjusted weekly according to the average body weights of the groups. Under the conditions of these 2 year dermal studies, there was no evidence of carcinogenic activity of benzethonium chloride in male or female F344/N rats or in male or female B6C3F1 mice. Exposure of rats and mice to benzethonium chloride by dermal application in ethanol for 2 years resulted in epithelial hyperplasia in male and female rats and mice and sebaceous gland hyperplasia and ulcers in female rats at the site of application.




Biochemical degradation pathway of textile dye Remazol red and subsequent toxicological evaluation by cytotoxicity, genotoxicity and oxidative stress studies  

Microsoft Academic Search

Remazol red (RR), a monochloro sulphonated azo dye was degraded up to 97% within 20 min at 40 °C and pH 7 at dye concentration 50 mg l?1 by Pseudomonas aeruginosa BCH. Examination of enzyme status exposed the involvement of various oxidoreductive enzymes viz. laccase, veratryl alcohol oxidase and NADH-DCIP reductase. Analytical studies viz. HPTLC, HPLC, FTIR and GC-MS carried out with dye and

Shekhar B. Jadhav; Swapnil S. Phugare; Pratibha S. Patil; Jyoti P. Jadhav



Toxicological evaluation of potassium perfluorobutanesulfonate in a 90-day oral gavage study with Sprague–Dawley rats  

Microsoft Academic Search

Perfluorobutanesulfonate (PFBS) is a surfactant and degradation product of substances synthesized using perfluorobutanesulfonyl fluoride. A 90-day rat oral gavage study has been conducted with potassium PFBS (K+PFBS). Rats were dosed with K+PFBS at doses of 60, 200, and 600mg\\/kg-day body weight. The following endpoints were evaluated: clinical observations, food consumption, body weight, gross and microscopic pathology, clinical chemistry, and hematology.

Paul H. Lieder; Shu-Ching Chang; Raymond G. York; John L. Butenhoff



Recovery of contaminated wetland soils at the Savannah River Site by natural rainfall: An experimental, toxicological study  

SciTech Connect

This study was conducted at the Department of Energy Savannah River Site in South Carolina. Seepage basins at the SRS F-Area received liquid effluent from the 1950s to 1988. This effluent was typically acidic, containing high amounts of total dissolved ions, low levels of tritium and other radioactive elements, and trace levels of various heavy metals. Sodium (from NaOH), and aluminum (from soil matrix reduction due to acid leachate) were at particularly high levels in the outcropping water. The effluent gradually seeped down to the water table and subsequently outcropped along the edge of a forested wetland bordering Four Mile Creek. A laboratory study was conducted to evaluate the potential for natural remediation of contaminated wetland soils by rainfall. Contaminated soils were collected and leached repeatedly with rainwater. After 6 leachings the leachate was observed to be non-toxic to lettuce seedlings, whereas the initial leachate was very toxic. These results suggest that more detailed studies on leaching as a remediation technique would be beneficial. 6 refs., 2 figs., 3 tabs.

Loehle, C.



Virtual tissues in toxicology.  


New approaches are vital for efficiently evaluating human health risk of thousands of chemicals in commerce. In vitro models offer a high-throughput approach for assaying chemical-induced molecular and cellular changes; however, bridging these perturbations to in vivo effects across chemicals, dose, time, and species remains challenging. Technological advances in multiresolution imaging and multiscale simulation are making it feasible to reconstruct tissues in silico. In toxicology, these "virtual" tissues (VT) aim to predict histopathological outcomes from alterations of cellular phenotypes that are controlled by chemical-induced perturbations in molecular pathways. The behaviors of thousands of heterogeneous cells in tissues are simulated discretely using agent-based modeling (ABM), in which computational "agents" mimic cell interactions and cellular responses to the microenvironment. The behavior of agents is constrained by physical laws and biological rules derived from experimental evidence. VT extend compartmental physiologic models to simulate both acute insults as well as the chronic effects of low-dose exposure. Furthermore, agent behavior can encode the logic of signaling and genetic regulatory networks to evaluate the role of different pathways in chemical-induced injury. To extrapolate toxicity across species, chemicals, and doses, VT require four main components: (a) organization of prior knowledge on physiologic events to define the mechanistic rules for agent behavior, (b) knowledge on key chemical-induced molecular effects, including activation of stress sensors and changes in molecular pathways that alter the cellular phenotype, (c) multiresolution quantitative and qualitative analysis of histologic data to characterize and measure chemical-, dose-, and time-dependent physiologic events, and (d) multiscale, spatiotemporal simulation frameworks to effectively calibrate and evaluate VT using experimental data. This investigation presents the motivation, implementation, and application of VT with examples from hepatotoxicity and carcinogenesis. PMID:20574905

Shah, Imran; Wambaugh, John



Study of a possible magnetite biosignature in Martian meteorite ALH84001: Implications for the biological toxicology of Mars  

NASA Astrophysics Data System (ADS)

"Why do we have such a longstanding fascination with Mars? Very simply put, it's about life. The search for life elsewhere in our Solar System has been a major driver for exploring Mars, pretty much since we began seriously looking at that planet."1 The major objective of this work is to describe signs of possible life, that is biosignatures, in rocks from Mars if indeed they are present. Biosignatures are specific identifiable properties that result from living things; they may be implanted in the environment and may persist even if the living thing is no longer present. Over 100 mineral biosignatures have been discussed in the literature; however, only one, magnetite, is addressed by this study. Magnetite is found in many rock types on earth and in meteorites. Previous studies of terrestrial magnetite have used few properties, such as size and chemical composition, to determine one of the modes of origins for magnetite (e.g., biogenic, inorganic). This study has established a rigorous set of six criteria for the identification of intracellularly precipitated biogenic magnetite. These criteria have been applied to a subpopulation of magnetites embedded within carbonates in Martian meteorite ALH84001. These magnetites are found to be chemically and physically indistinguishable from those produced by magnetotactic bacteria strain MV-1, hence, they were likely formed by biogenic processes on ancient Mars. These criteria may be also used to distinguish origins for magnetites from terrestrial samples with complex or unknown histories. The presence of purported past life on early Mars suggests that, if life once began it may still exist today, possibly in oases in the Martian subsurface. Future manned missions should consider potential hazards of an extant biological environment(s) on Mars. 1 Quote attributed to Jack Farmer of Arizona State University in discussing NASA's program of Mars Exploration (see "Deciphering Mars: Follow the Water," Astrobiology Magazine Sept. 12, 2005)

Thomas-Keprta, Kathie Louise


An In Vivo Toxicological Study Upon Shallomin, the Active Antimicrobial Constitute of Persian Shallot (Allium hirtifolium, Boiss) Extract  

PubMed Central

Background Previous studies have shown that shallomin, one of the active constituents of Persian shallot, has a broad range of antimicrobial properties. Objectives The safety of shallomin must be established before it can be used in clinical applications. Therefore, the aim of the present study was to evaluate the acute toxic effects of shallomin and to estimate its lethal dose low (LDLo) value. Materials and Methods Two series of experiments were performed: In the first series, we used functional testing to assess the acute toxic effects of shallomin on the blood, liver, and kidney and examined histopathological changes in the liver, kidney, lung, and heart, following 7 days of daily intraperitoneal administration of 3 standard doses (10, 20, and 30 µg/g body weight of mice). In the second series, the LDLo value was estimated by determining daily mortality in mice after 7-day administration of escalating doses of shallomin (10 to 240 µg/g body weight of mice). Results The results showed that shallomin (at the anticipated in vivo doses), unlike the placebo (ethanol), did not produce any adverse effects on the tested organs. The LDLo value was observed to be 160 µg/g body weight; this value is 8- to 32-times the anticipated in vivo dose that produces antimicrobial effects under in vitro conditions against various pathogenic organisms. Conclusions In conclusion, the results of the present study show that shallomin is a relatively safe agent, although its use needs to be carefully monitored. Further in vivo chronic toxicity tests need to be performed to establish the therapeutic potential of shallomin as an antimicrobial agent. PMID:24624146

Amin, Mansor; Pipelzadeh, Mohammad Hassan; Mehdinejad, Manijeh; Rashidi, Iran



Prenatal antidepressant exposure: clinical and preclinical findings.  


Pharmacological treatment of any maternal illness during pregnancy warrants consideration of the consequences of the illness and/or medication for both the mother and unborn child. In the case of major depressive disorder, which affects up to 10-20% of pregnant women, the deleterious effects of untreated depression on the offspring can be profound and long lasting. Progress has been made in our understanding of the mechanism(s) of action of antidepressants, fetal exposure to these medications, and serotonin's role in development. New technologies and careful study designs have enabled the accurate sampling of maternal serum, breast milk, umbilical cord serum, and infant serum psychotropic medication concentrations to characterize the magnitude of placental transfer and exposure through human breast milk. Despite this progress, the extant clinical literature is largely composed of case series, population-based patient registry data that are reliant on nonobjective means and retrospective recall to determine both medication and maternal depression exposure, and limited inclusion of suitable control groups for maternal depression. Conclusions drawn from such studies often fail to incorporate embryology/neurotransmitter ontogeny, appropriate gestational windows, or a critical discussion of statistically versus clinically significant. Similarly, preclinical studies have predominantly relied on dosing models, leading to exposures that may not be clinically relevant. The elucidation of a defined teratological effect or mechanism, if any, has yet to be conclusively demonstrated. The extant literature indicates that, in many cases, the benefits of antidepressant use during pregnancy for a depressed pregnant woman may outweigh potential risks. PMID:24567054

Bourke, Chase H; Stowe, Zachary N; Owens, Michael J



Toxicology Studies on Lewisite and Sulfur Mustard Agents: Subchronic Toxicity of Sulfur Mustard (HD) In Rats Final Report  

SciTech Connect

Occupational health standards have not been established for sulfur mustard [bis(2- chlorethyl)-sulfide], a strong alkylating agent with known mutagenic properties. Seventytwo Sprague-Dawley rats of each sex, 6-7 weeks old, were divided into six groups (12/group/ sex) and gavaged with either 0, 0.003 , 0.01 , 0.03 , 0.1 or 0.3 mg/kg of sulfur mustard in sesame oil 5 days/week for 13 weeks. No dose-related mortality was observed. A significant decrease (P ( 0.05) in body weight was observed in both sexes of rats only in the 0.3 mg/kg group. Hematological evaluations and clinical chemistry measurements found no consistent treatment-related effects at the doses studied. The only treatment-related lesion associated with gavage exposure upon histopathologic evaluation was epithelial hyperplasia of the forestomach of both sexes at 0.3 mg/kg and males at 0.1 mg/kg. The hyperplastic change was minimal and characterized by cellular disorganization of the basilar layer, an apparent increase in mitotic activity of the basilar epithelial cells, and thickening of the epithelial layer due to the apparent increase in cellularity. The estimated NOEL for HD in this 90-day study is 0.1 mg/kg/day when administered orally.

Sasser, L. B.; Miller, R. A.; Kalkwarf, D, R.; Buschbom, R. L.; Cushing, J. A.



A comparative study on the relationship between various toxicological endpoints in Caenorhabditis elegans exposed to organophosphorus insecticides.  


The toxicity of 10 organophophorus (OP) insecticides-acephate, dimethoate, dichlorvos, dicrotophos, monocrotophos, methamidophos, phosphamidon, omethoate, phosdrin, and trichlorfon-was evaluated in Caenorhabditis elegans using lethality, movement, and acetylcholinesterase (AChE) activity as the endpoints after a 4-hr- exposure period. The OP insecticides tested showed LC50 values ranging from 0.039 mM (for dichlorovs) to 472.8 mM (for methamidophos). The order of toxicity for lethality and movement was not significantly different when tested using the rank order correlation coefficient. AChE activity was markedly affected by all the OP insecticide exposures that caused significant inhibition in movement, indicating that the mechanism of toxicity of OP insecticides in C. elegans is the same as in higher animals. All OP insecticides induced greater than 50% inhibition of AChE at the lowest tested OP insecticide concentration resulting in inhibition in movement. While a significant correlation was evident between LC50 values in C. elegans and the LD50 values in rats for the 10 OP insecticides studied, a correlation was not evident between EC50 values in C. elegans and LD50 values in rats. Overall, the two endpoints, LC50 and movement, were more reliable and easier to perform than measurement of AChE activity in C. elegans for determining the toxicity of OP insecticides. Further, ranking of these endpoints with respect to the OP insecticides studied indicates that these parameters in C. elegans are predictive of OP insecticides mammalian neurotoxicity. PMID:18569613

Rajini, P S; Melstrom, Paul; Williams, Phillip L



Toxicological evaluation of potassium perfluorobutanesulfonate in a 90-day oral gavage study with Sprague-Dawley rats.  


Perfluorobutanesulfonate (PFBS) is a surfactant and degradation product of substances synthesized using perfluorobutanesulfonyl fluoride. A 90-day rat oral gavage study has been conducted with potassium PFBS (K+PFBS). Rats were dosed with K+PFBS at doses of 60, 200, and 600mg/kg-day body weight. The following endpoints were evaluated: clinical observations, food consumption, body weight, gross and microscopic pathology, clinical chemistry, and hematology. In addition, functional observation battery and motor activity assessments were made. Histological examination included tissues in control and 600 mg/kg-day groups. Additional histological examinations were performed on nasal cavities and turbinates, stomachs, and kidneys in the 60 and 200 mg/kg-day groups. No treatment-related mortality, body weight, or neurological effects were noted. Chromorhinorrhea (perioral) and urine-stained abdominal fur were observed in males at 600mg/kg-day. Red blood cell counts, hemoglobin, and hematocrit values were reduced in males receiving 200 and 600mg/kg-day; however, there were no adverse histopathological findings in bone marrow. Total protein and albumin were lower in females at 600mg/kg-day. There were no significant changes in clinical chemistry in either sex. All rats appeared normal at sacrifice. Microscopic changes were observed only at the highest dose in the stomach. These changes consisted of hyperplasia with some necrosis of the mucosa with some squamous metaplasia. These effects likely were due to a cumulative direct irritation effect resulting from oral dosing with K+PFBS. Histopathological changes were also observed in the kidneys. The changes observed were minimal-to-mild hyperplasia of the epithelial cells of the medullary and papillary tubules and the ducts in the inner medullary region. There were no corresponding changes in kidney weights. Clinical chemistry parameters related to kidney function were unchanged. These kidney findings are likely due to a response to high concentration of K+PFBS in tubules and ducts and represent a minimal-to-mild effect. Microscopic changes of an equivocal and uncertain nature were observed in the nasal mucosa and were likely attributable to the route of dosing (oral gavage). The NOAEL for the female rat in this study was 600 mg/kg-day (highest dose of study). The NOAEL for the male rat was 60 mg/kg-day based on hematological effects. PMID:18992301

Lieder, Paul H; Chang, Shu-Ching; York, Raymond G; Butenhoff, John L



Establishment of patient-derived non-small cell lung cancer xenograft models with genetic aberrations within EGFR, KRAS and FGFR1: useful tools for preclinical studies of targeted therapies  

PubMed Central

Background Patient-derived tumor xenograft models have been established and increasingly used for preclinical studies of targeted therapies in recent years. However, patient-derived non-small cell lung cancer (NSCLC) xenograft mouse models are relatively few in number and are limited in their degree of genetic characterization and validation. In this study, we aimed to establish a variety of patient-derived NSCLC models and characterize these for common genetic aberrations to provide more informative models for preclinical drug efficacy testing. Methods NSCLC tissues from thirty-one patients were collected and implanted into immunodeficient mice. Established xenograft models were characterized for common genetic aberrations, including detection of gene mutations within EGFR and KRAS, and genetic amplification of FGFR1 and cMET. Finally, gefitinib anti-tumor efficacy was tested in these patient-derived NSCLC xenograft models. Results Ten passable patient-derived NSCLC xenograft models were established by implantation of NSCLC specimens of thirty-one patients into immunodeficient mice. Genetic aberrations were detected in six of the models, including one model with an EGFR activating mutation (Exon19 Del), one model with KRAS mutation, one model with both KRAS mutation and cMET gene amplification, and three models with FGFR1 amplification. Anti-tumor efficacy studies using gefitinib demonstrated that the EGFR activating mutation model had superior sensitivity and that the KRAS mutation models were resistant to gefitinib. The range of gefitinib responses in the patient-derived NSCLC xenograft models were consistent with the results reported from clinical trials. Furthermore, we observed that patient-derived NSCLC models with FGFR1 gene amplification were insensitive to gefitinib treatment. Conclusions Ten patient-derived NSCLC xenograft models were established containing a variety of genetic aberrations including EGFR activating mutation, KRAS mutation, and FGFR1 and cMET amplification. Gefitinib anti-tumor efficacy in these patient-derived NSCLC xenografts containing EGFR and KRAS mutation was consistent with the reported results from previous clinical trials. Thus, data from our panel of patient-derived NSCLC xenograft models confirms the utility of these models in furthering our understanding of this disease and aiding the development of personalized therapies for NSCLC patients. PMID:23842453



Designed Synthesis of CeO2 Nanorods and Nanowires for Studying Toxicological Effects of High Aspect Ratio Nanomaterials  

PubMed Central

While it has been shown that high aspect ratio nanomaterials like carbon nanotubes and TiO2 nanowires can induce toxicity by acting as fiber-like substances that damage the lysosome, it is not clear what the critical lengths and aspect ratios are that induce this type of toxicity. To answer this question, we synthesized a series of cerium oxide (CeO2) nanorods and nanowires with precisely controlled lengths and aspect ratios. Both phosphate and chloride ions were shown to play critical roles in obtaining these high aspect ratio nanostructures. High resolution TEM analysis shows that single crystalline CeO2 nanorods/nanowires were formed along the [211] direction by an “oriented attachment” mechanism, followed by Ostwald ripening. The successful creation of a comprehensive CeO2 nanorod/nanowire combinatorial library allows, for the first time, the systematic study of the effect of aspect ratio on lysosomal damage, cytoxicity and IL-1? production by the human myeloid cell line (THP-1). This in vitro toxicity study demonstrated that at lengths ?200 nm and aspect ratios ? 22, CeO2 nanorods induced progressive cytotoxicity and pro-inflammatory effects. The relatively low “critical” length and aspect ratio were associated with small nanorod/nanowire diameters (6–10 nm), which facilitates the formation of stacking bundles due to strong van der Waals and dipole-dipole attractions. Our results suggest that both length and diameter components of aspect ratio should be considered when addressing the cytotoxic effects of long aspect ratio materials. PMID:22564147

Ji, Zhaoxia; Wang, Xiang; Zhang, Haiyuan; Lin, Sijie; Meng, Huan; Sun, Bingbing; George, Saji; Xia, Tian; Nel, Andre E.; Zink, Jeffrey I.



A toxicological study of inhalable particulates in an industrial region of Lanzhou City, northwestern China: Results from plasmid scission assay  

NASA Astrophysics Data System (ADS)

The city of Lanzhou in northwestern China experiences serious air pollution episodes in the form of PM10 that is characterized by having high levels of heavy metals. The Xigu District represents the industrial core area of Lanzhou City and is denoted by having the largest petrochemical bases in western China. This study investigates heavy metal compositions and oxidative potential of airborne PM10 (particulate matter with aerodynamic diameter of 10 ?m or less) collected in Xigu District in the summer and winter of 2010. An in vitro plasmid scission assay (PSA) was employed to study the oxidative potential of airborne PM10 and inductively coupled plasma-mass spectrometry (ICP-MS) was used to examine heavy metal compositions. Transmission electron microscopy coupled with energy-dispersive X-ray spectrometry (TEM/EDX) was used to investigate elemental compositions and mixing states of PM10. The average mass concentrations of PM10 collected in Xigu District were generally higher than the national standard for daily PM10 (150 ?g/m3). Cr, Zn, Pb and Mn were the most abundant metals in the intact whole particles of PM10. Zn, Mn and As was the most abundant metal in the water-soluble fraction, while Cr, Pb, and V existed primarily in insoluble forms. TD20 values (i.e. toxic dosage of PM10 causing 20% of plasmid DNA damage) varied considerably in both winter and summer (from 19 ?g/mL to >1000 ?g/mL) but were typically higher in summer, suggesting that the winter PM10 exhibited greater bioreactivity. In addition, the PM10 collected during a dust storm episode had a highest TD20 value and thus the least oxidative damage to supercoiled plasmid DNA, while the particles collected on a hazy day had a lowest TD20 value and thus the highest oxidative damage to supercoiled plasmid DNA. The particles collected on the first day after snow fall and on a day of cold air intrusion exhibited minor oxidative potential (i.e. caused limited DNA damage). The water-soluble Zn, Mn, As, and Cu displayed a significant negative correlation with TD20 values, suggesting that these heavy metals were responsible for the increase of oxidative potential. The high mass concentration of PM10 and resulting high oxidative potential in Xigu District may be due to the constant low wind speed and high relative humidity, particularly in winter. Finally, TEM analysis suggested that the oxidative potential of PM10 may be associated with its degree of internal mixing, whereby the heterogeneous assortment of soot, mineral and metals created a highly reactive moiety.

Xiao, Zhenghui; Shao, Longyi; Zhang, Ning; Wang, Jing; Chuang, Hsiao-Chi; Deng, Zhenzhen; Wang, Zhen; BéruBé, Kelly



Update of the Stroke Therapy Academic Industry Roundtable Preclinical Recommendations  

PubMed Central

The initial Stroke Therapy Academic Industry Roundtable (STAIR) recommendations published in 1999 were intended to improve the quality of preclinical studies of purported acute stroke therapies. Although recognized as reasonable, they have not been closely followed nor rigorously validated. Substantial advances have occurred regarding the appropriate quality and breadth of preclinical testing for candidate acute stroke therapies for better clinical translation. The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate. The updated STAIR recommendations include: the fundamentals of good scientific inquiry should be followed by eliminating randomization and assessment bias, a priori defining inclusion/exclusion criteria, performing appropriate power and sample size calculations, and disclosing potential conflicts of interest. After initial evaluations in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions such as hypertension, diabetes, and hypercholesterolemia. Another consideration is the use of clinically relevant biomarkers in animal studies. Although the recommendations cannot be validated until effective therapies based on them emerge from clinical trials, it is hoped that adherence to them might enhance the chances for success. PMID:19246690

Fisher, Marc; Feuerstein, Giora; Howells, David W.; Hurn, Patricia D.; Kent, Thomas A.; Savitz, Sean I.; Lo, Eng H.



Unsuitability of the northern bobwhite as a model species for the assessment of reproductive behavior in toxicological studies.  


The northern bobwhite (Colinus virginianus) is used in numerous wildlife toxicity studies, however no published reports could be located that mention the measurement of reproductive behavior in this species. Changes in reproductive behavior can be potentially more sensitive to environmental contaminant exposures and less resilient than more traditional physiological responses. Male bobwhite copulatory behaviors were measured similarly to those that are well established for use in Japanese quail (Coturnix japonica). Time to initiate mating, time to achieve a successful copulation, the number of mating attempts, and the number of successful copulations were recorded daily for four consecutive days over a period of 3 min for each male/female pair of birds per day. When females were introduced to male cages, males were more occupied with shows of aggression towards neighboring males than attempts to mate with the female sharing their space. Only one male successfully mated with a female over the entire 4 days of the test. Future attempts at assessing reproductive behavior in this species may be more successful if birds are separated from the rest of the group when paired. The Japanese quail seems to be a more appropriate species for overall reproductive tests due to: willingness of males to copulate in the presence of other males, consistent egg laying ability, and the short time required for embryonic development and reproductive maturity. PMID:19778231

Quinn, Michael J; McFarland, Craig A; Johnson, Mark S



Preclinical Models for Neuroblastoma: Establishing a Baseline for Treatment  

PubMed Central

Background Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system. Principal Findings Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a “standard of care” chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents. Significance The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer. PMID:21559450

Federico, Sara; Bradley, Cori L.; Brennan, Rachel; Zhang, Jiakun; Johnson, Melissa D.; Sedlacik, Jan; Inoue, Madoka; Zhang, Ziwei M.; Frase, Sharon; Rehg, Jerold E.; Hillenbrand, Claudia M.; Finkelstein, David; Calabrese, Christopher; Dyer, Michael A.; Lahti, Jill M.



Metabolomics in Toxicology and Preclinical Research, a t4 Workshop Report  

EPA Science Inventory

Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological condition of the test system, and of changes affected by anthropogenic chemicals. Metabolomic analysis is used in many fields, ranging...


Science: Aquatic Toxicology Matures, Gains Importance.  

ERIC Educational Resources Information Center

Reviews recent advances in aquatic toxicology, whose major goal is to protect diverse aquatic organisms and whole ecological communities from the dire effects of man-made chemicals. Current legislation is reviewed. Differences in mammalian and aquatic toxicology are listed, and examples of research in aquatic toxicology are discussed. (CS)

Dagani, Ron



Predictive Toxicology of cobalt ferrite nanoparticles: comparative in-vitro study of different cellular models using methods of knowledge discovery from data  

PubMed Central

Background Cobalt-ferrite nanoparticles (Co-Fe NPs) are attractive for nanotechnology-based therapies. Thus, exploring their effect on viability of seven different cell lines representing different organs of the human body is highly important. Methods The toxicological effects of Co-Fe NPs were studied by in-vitro exposure of A549 and NCIH441 cell-lines (lung), precision-cut lung slices from rat, HepG2 cell-line (liver), MDCK cell-line (kidney), Caco-2 TC7 cell-line (intestine), TK6 (lymphoblasts) and primary mouse dendritic-cells. Toxicity was examined following exposure to Co-Fe NPs in the concentration range of 0.05 -1.2 mM for 24 and 72 h, using Alamar blue, MTT and neutral red assays. Changes in oxidative stress were determined by a dichlorodihydrofluorescein diacetate based assay. Data analysis and predictive modeling of the obtained data sets were executed by employing methods of Knowledge Discovery from Data with emphasis on a decision tree model (J48). Results Different dose–response curves of cell viability were obtained for each of the seven cell lines upon exposure to Co-Fe NPs. Increase of oxidative stress was induced by Co-Fe NPs and found to be dependent on the cell type. A high linear correlation (R2=0.97) was found between the toxicity of Co-Fe NPs and the extent of ROS generation following their exposure to Co-Fe NPs. The algorithm we applied to model the observed toxicity belongs to a type of supervised classifier. The decision tree model yielded the following order with decrease of the ranking parameter: NP concentrations (as the most influencing parameter), cell type (possessing the following hierarchy of cell sensitivity towards viability decrease: TK6 > Lung slices > NCIH441 > Caco-2?=?MDCK > A549 > HepG2?=?Dendritic) and time of exposure, where the highest-ranking parameter (NP concentration) provides the highest information gain with respect to toxicity. The validity of the chosen decision tree model J48 was established by yielding a higher accuracy than that of the well-known “naive bayes” classifier. Conclusions The observed correlation between the oxidative stress, caused by the presence of the Co-Fe NPs, with the hierarchy of sensitivity of the different cell types towards toxicity, suggests that oxidative stress is one possible mechanism for the toxicity of Co-Fe NPs. PMID:23895432