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International Journal of Toxicology

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https://www.readbyqxmd.com/read/28553770/involvement-of-reactive-metabolites-of-diclofenac-in-cytotoxicity-in-sandwich-cultured-rat-hepatocytes
#1
Atsushi Kawase, Ryota Hashimoto, Mai Shibata, Hiroaki Shimada, Masahiro Iwaki
BACKGROUND AND OBJECTIVES: Diclofenac (DIC) is metabolized to reactive metabolites such as diclofenac acyl-β-d-glucuronide (DIC-AG). It is possible that such reactive metabolites could cause tissue damage by formation of covalent protein adducts and other modification of cellular proteins or by induction of immune responses against its covalent protein adducts. However, the detailed mechanisms of idiosyncratic drug-induced liver injury (DILI) have been unclear. The objective is to clarify the involvement of DIC-AG and 4'hydroxydiclofenac (4'OH-DIC) in acute DILI...
May 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28553769/editor-s-note
#2
Mary Beth Genter, Tracey Zoetis
No abstract text is available yet for this article.
May 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28553768/improving-our-understanding-of-atopic-dermatitis-will-require-research-beyond-immunology-and-dermatology
#3
Kevin J Mills
No abstract text is available yet for this article.
May 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28553738/safety-assessment-of-amino-acid-alkyl-amides-as-used-in-cosmetics
#4
Christina L Burnett, Bart Heldreth, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, F Alan Andersen
The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the product use, formulation, and safety data of 115 amino acid alkyl amides, which function as skin and hair conditioning agents and as surfactants-cleansing agents in personal care products. Safety test data on dermal irritation and sensitization for the ingredients with the highest use concentrations, lauroyl lysine and sodium lauroyl glutamate, were reviewed and determined to adequately support the safe use of the ingredients in this report. The Panel concluded that amino acid alkyl amides are safe in the present practices of use and concentration in cosmetics, when formulated to be nonirritating...
May 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28553737/safety-assessment-of-anthemis-nobilis-derived-ingredients-as-used-in-cosmetics
#5
Wilbur Johnson, Bart Heldreth, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, F Alan Andersen
Anthemis nobilis (Roman chamomile) flower extract, anthemis nobilis flower oil, anthemis nobilis flower powder, and anthemis nobilis flower water are ingredients that function as fragrance ingredients and skin-conditioning agents in cosmetic products. These ingredients are being used at concentrations up to 10% (anthemis nobilis flower water) in cosmetic products. The available data indicate that these 4 ingredients are not irritating or sensitizing. Chemical composition data and the low use concentrations suggest that systemic toxicity would not be likely if percutaneous absorption of constituents were to occur...
May 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28553736/amended-safety-assessment-of-isethionate-salts-as-used-in-cosmetics
#6
Christina L Burnett, Bart Heldreth, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, F Alan Andersen
The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) rereviewed the safety of 12 isethionate salts as used in cosmetics and concluded that these ingredients are safe in the present practices of use and concentration, when formulated to be nonirritating. These isethionate salts are reported to function mostly as surfactants and cleansing agents in cosmetic products. The Panel reviewed the available animal and clinical data as well as information from previous CIR reports. Although there are data gaps, the shared chemical core structure, expected similarities in physicochemical properties, and similar functions and concentrations in cosmetics enabled grouping these ingredients and reading across the available toxicological data to support the safety assessment of each ingredient...
May 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28481132/disruption-of-estrogen-receptor-alpha-in-rats-results-in-faster-initiation-of-compensatory-regeneration-despite-higher-liver-injury-after-carbon-tetrachloride-treatment
#7
Steven R McGreal, Karim Rumi, Michael J Soares, Benjamin L Woolbright, Hartmut Jaeschke, Udayan Apte
Estrogen receptor alpha (ESR1) is 1 of the 2 intracellular receptors for estrogen and is expressed by hepatocytes in the liver. The role of ESR1 in the regulation of toxicant-induced liver injury and compensatory regeneration is not completely clear. We investigated the role of ESR1 in liver regeneration after carbon tetrachloride (CCl4)-induced liver injury using wild type (WT) and ESR1 knockout (ESR1-KO) rats. Adult female WT and ESR1-KO rats were treated with 1 mL/kg CCl4 and euthanized over a time course of 0 to 48 hours...
May 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28403743/nonclinical-profile-of-blz-100-a-tumor-targeting-fluorescent-imaging-agent
#8
Julia Parrish-Novak, Kelly Byrnes-Blake, Narine Lalayeva, Stefanie Burleson, Janean Fidel, Rhonda Gilmore, Pamela Gayheart-Walsten, Gregory A Bricker, William J Crumb, K S Tarlo, Stacey Hansen, Valorie Wiss, Errol Malta, William S Dernell, James M Olson, Dennis M Miller
BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP...
March 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28403742/editor-s-note
#9
Mary Beth Genter
No abstract text is available yet for this article.
March 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28403741/impact-of-acrylamide-on-calcium-signaling-and-cytoskeletal-filaments-in-testes-from-f344-rat
#10
Leslie Recio, Marvin Friedman, Dennis Marroni, Timothy Maynor, Nikolai L Chepelev
Acrylamide (AA) at high exposure levels is neurotoxic, induces testicular toxicity, and increases dominant lethal mutations in rats. RNA-sequencing in testes was used to identify differentially expressed genes (DEG), explore AA-induced pathway perturbations that could contribute to AA-induced testicular toxicity and then used to derive a benchmark dose (BMD). Male F344/DuCrl rats were administered 0.0, 0.5, 1.5, 3.0, 6.0, or 12.0 mg AA/kg bw/d in drinking water for 5, 15, or 31 days. The experimental design used exposure levels that spanned and exceeded the exposure levels used in the rat dominant lethal, 2-generation reproductive toxicology, and cancer bioassays...
March 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28403740/bisphenol-a-induces-oxidative-stress-in-bone-marrow-cells-lymphocytes-and-reproductive-organs-of-holtzman-rats
#11
Dinesh Tiwari, Geeta Vanage
Bisphenol A (BPA) is an estrogenic chemical used in the production of polycarbonate plastics and epoxy resins. Our earlier studies have demonstrated that BPA is a potent reproductive and genotoxic agent and affects the normal physiological functions. The objective of this study was to evaluate whether exposure to BPA induces oxidative stress. The male Holtzman rats were orally gavaged with BPA (0.01 mg and 5.0 mg/kg/bw) over the period of 6 days. Animals were euthanized by cervical dislocation at the end of the treatments; bone marrow cells and blood lymphocytes were aspirated; testis and epididymis were collected, immediately frozen in liquid nitrogen, and stored at -80°C...
March 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28403739/hydrogen-peroxide-and-lipopolysaccharide-differentially-affect-the-expression-of-micrornas-10a-33a-21-221-in-endothelial-cells-before-and-after-coculture-with-monocytes
#12
Atefe Ghamar Talepoor, Mehdi Kalani, Alamtaj Samsami Dahaghani, Mehrnoosh Doroudchi
Inflammation and oxidative stress are important risk factors affecting various cells in the formation of atherosclerosis. MicroRNAs (miRs) are regulators of inflammation and atherogenesis. The expressions of endothelial cell (EC)-specific miR-10a and miR-21 and monocyte-specific miR-33a and miR-221 were investigated using coculture of the ECs and monocytes upon exposure to H2O2 as an oxidative stressor, and endotoxin/lipopolysaccharide (LPS) as a microbial stressor. Human umbilical endothelial cells (HUVECs) and peripheral blood mononuclear cells (or monocytes) were cocultured in M199 complete medium and were incubated with LPS (20 ng/mL) or H2O2 (1%) for 8 hours at 37°C...
March 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28592157/correlation-between-nasal-epithelial-injury-and-in-vitro-cytotoxicity-using-a-series-of-small-molecule-protein-tyrosine-phosphatase-1b-inhibitors-investigated-for-reversal-of-leptin-resistance-in-obesity
#13
Alan P Brown, Chandrassegar Saravanan, Patrick Devine, Maria Magnifico, Jiaping Gao, Valerie Beaulieu, Fupeng Ma, Kayo Yasoshima, David Barnes-Seeman, Ken Yamada
This research provides a cautionary example when evaluating changes in behavioral end points with respect to postulated pharmacologic activity. Various small molecule substrate mimetic protein tyrosine phosphatase 1B (PTP1B) inhibitors were investigated as pharmacologic agents for decreasing food consumption using intranasal (IN) dosing as a means for direct nose-to-brain delivery along the olfactory/trigeminal nerve pathways. Although food consumption was decreased in diet-induced obese (DIO) mice, nasal discharge was observed...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28583045/recommendations-for-clinical-pathology-data-generation-interpretation-and-reporting-in-target-animal-safety-studies-for-veterinary-drug-development
#14
William Siska, Aradhana Gupta, Lindsay Tomlinson, Niraj Tripathi, Barbara von Beust
Clinical pathology testing is routinely performed in target animal safety studies in order to identify potential toxicity associated with administration of an investigational veterinary pharmaceutical product. Regulatory and other testing guidelines that address such studies provide recommendations for clinical pathology testing but occasionally contain outdated analytes and do not take into account interspecies physiologic differences that affect the practical selection of appropriate clinical pathology tests...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28578602/why-do-promising-therapies-stall-in-development-and-how-can-we-move-them-forward
#15
Craig D Wegner, Andrew Goodwin, Jon C Cook, Krishna Allamneni, Jane Sohn, Maralee McVean
There are many reasons that molecules fail to progress to market and various principles of risk-benefit decisions that can help drive the molecule through development. This symposium included discussions on global strategies involved in pushing promising molecules to market, what to do when a molecule stalls in its progress to market, and options for rescuing the molecule and pushing it forward again. Innovative partnerships that bring stalled drugs back into clinical development were also addressed. A regulatory perspective on common reasons for a molecule to fail in its forward progress was presented...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28553733/tg-rash2-mice-and-not-cbyb6f1-mice-should-be-used-for-28-day-dose-range-finding-studies-prior-to-26-week-tg-rash2-carcinogenicity-studies
#16
Madhav G Paranjpe, Jessica Belich, Tom J Vidmar, Reem H Elbekai, Marie McKeon, Caren Brown
Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28535735/clenbuterol-attenuates-herg-channel-by-promoting-the-mature-channel-degradation
#17
Ling Luo, Peijing Hu, Changqing Miao, Aiqun Ma, Tingzhong Wang
Clenbuterol, a β2-selective adrenergic receptor agonist, is illicitly used in weight loss and performance enhancement and animal production. Increasing evidence demonstrates that clenbuterol induces various kinds of arrhythmias and QTc interval prolongation. However, little is known about the underlying mechanism. Most drugs are associated with QTc prolongation through interfering with human ether-a-go-go-related gene (hERG) K(+) channels. The present study aims to investigate the effects and underlying mechanisms of clenbuterol on the hERG channel...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28481133/oral-1-generation-rat-reproduction-study-of-isobornyl-acetate-an-evaluation-through-sexual-maturity-in-the-f1-generation
#18
Valerie T Politano, Elise M Lewis, Alan M Hoberman, Robert M Diener, Anne Marie Api, Atish Patel
Reproductive toxicity of isobornyl acetate (IA), a widely used fragrance ingredient, was investigated in a 1-generation reproduction study in which 25 Crl: CD (Sprague-Dawley) rats/sex/group were gavaged with dosages of 0 (corn oil vehicle), 30, 100, or 300 mg/kg/d during premating, mating, gestation, and lactation. After weaning, 25 F1 generation pups/sex/dosage group were randomly selected for evaluation until sexual maturity. The following parameters were evaluated in P generation males and females: viability, clinical signs, body weights, feed consumption, mating and fertility, organ weights, gross and microscopic observations, sperm assessments (motility and concentration), natural delivery and litter observations, and ovarian follicle counts...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28466692/dna-methylation-changes-in-tbx3-in-a-mouse-model-exposed-to-polybrominated-diphenyl-ethers
#19
Takashi Shimbo, June K Dunnick, Amy Brix, Deepak Mav, Ruchir Shah, John D Roberts, Paul A Wade
DE-71, a commercial mixture of polybrominated diphenyl ethers widely used in flame retardants, is a pervasive environmental contaminant due to its continuing release from waste material and its long half-life in humans. Although the genotoxic potential of DE-71 appears to be low based on bacterial mutagenicity, it remains a public health concern due to its reported involvement in tumor development. Molecular mechanisms by which DE-71 influences tumor incidence or progression remain understudied. We used liver carcinoma tissue from mice exposed to DE-71 to test the hypothesis that epigenetic alterations consistent with tumor development, specifically DNA methylation, result from long-term DE-71 exposure...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28466691/salt-selection-matters-differential-renal-toxicity-with-mdv1634-maleate-versus-mdv1634-2hcl
#20
Mausumee Guha, Linh Nguyen, Florence Poitout-Belissent, Agathe Bedard, Kavita Raman
Salt forms of pharmaceutical compounds can have unique pharmacokinetic and toxicity properties. MDV1634 was evaluated for neurology indication and also demonstrated blood pressure (BP)-lowering effects in nonclinical studies. During the chemistry manufacturing campaign, 2 salt forms, dihydrochloride (2HCl) and maleate (MAL), which improved chemical stability and water solubility of the free base were identified. MDV1634.MAL showed better chemical attributes and was evaluated in toxicology studies for further development...
January 1, 2017: International Journal of Toxicology
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