Journal of Applied Toxicology

Cover image for Journal of Applied Toxicology

August 2009

Volume 29, Issue 6

Pages 459–550

  1. Reviews

    1. Top of page
    2. Reviews
    3. Research Articles
    4. Toxicological Update
    1. Minireview: does in-vitro testing of oximes help predict their in-vivo action after paraoxon exposure? (pages 459–469)

      D. E. Lorke and G. A. Petroianu

      Article first published online: 14 JUL 2009 | DOI: 10.1002/jat.1457

      This article summarizes in vitro data on cholinesterase inhibitory activity (IC50), reactivation potency (slope of IC50 shift tan a) and lipophilicity/ hydrophilicity (LogP) obtained for conventional and experimental oximes in human and rat blood exposed to the organophosphorous compound paraoxon. In vitro values are correlated with in vivo results (LD50, relative risk of death after paraoxon and oxime exposure). In vitro IC50 testing in rat blood has a very good predictive value for in vivo toxicity (LD50) in rats. Strongly hydrophilic oximes (LogP in low negatives) tend to be less toxic, whereas in vitro assessment of reactivation capacity (tan a) has limited practical significance.

  2. Research Articles

    1. Top of page
    2. Reviews
    3. Research Articles
    4. Toxicological Update
    1. MCF-7 human mammary adenocarcinoma cells exhibit augmented responses to human insulin on a collagen IV surface (pages 470–477)

      Nicolai Listov-Saabye, Marianne Blirup Jensen, Benedicte Kiehr, Erik W. Hansen, Jette E. Svendsen, Anders Lundby, Gitte-Mai Nelander Holm and Martin B. Oleksiewicz

      Article first published online: 31 MAR 2009 | DOI: 10.1002/jat.1428

      We developed an insulin mitogenicity assay in MCF-7 human mammary adenocarcinoma cells. With MCF-7 cells on a collagen IV surface, fold mitogenic responses and dynamic range and steepness of dose-response curves was increased. AspB10 insulin was significantly more mitogenic than native human insulin, validating the ability of the assay to identify hypermitogenic human insulin analogues. This optimized MCF-7 assay is of relevance for in vitro toxicological testing and carcinogenicity safety assessment of new insulin compounds.

    2. In vitro investigations related to the hypothesis that Lipoatrophia semicircularis finds its origin in electro-stimulation (pages 478–482)

      Luc Verschaeve and Annemarie Maes

      Article first published online: 31 MAR 2009 | DOI: 10.1002/jat.1430

      Lipoatrophia semicircularis is an idiopathic condition characterized by semicircular impressions of the skin, usually at the front and sides of both thighs. It is characterized by atrophy of the subcutaneous adipocytes whereas the skin and muscles remain normal. We have previously presented the hypothesis that this condition has probably a multifactorial origin from which electro stimulation of the adipocytes is crucial. In the present study we present data from in vitro cellular studies that further support our hypothesis.

    3. Effect of five acetylcholinesterase reactivators on tabun-intoxicated rats: induction of oxidative stress versus reactivation efficacy (pages 483–488)

      Miroslav Pohanka, Jana Zdarova Karasova, Kamil Musilek, Kamil Kuca and Jiri Kassa

      Article first published online: 31 MAR 2009 | DOI: 10.1002/jat.1432

      Oxime reactivators HI-6, obidoxime, trimedoxime, K347 and K628 were investigated as drugs designed for treatment of tabun intoxication in rat model. Activities cholinesterases were measured as markers of reactivation efficacy. An estimation of low molecular weight antioxidants levels using cyclic voltammetry was the second examination parameter. The evaluation of cholinesterases activity showed good reactivation potency of the all tested reactivators for blood cholinesterases. Commercially available reactivator HI-6 and newly synthesized K628 caused oxidative stress.

    4. Both DNA damage and mitochondrial dysfunction are involved in novel oxadiazolo[3,4-d]pyrimidine nucleoside derivatives-induced cancer cell death (pages 489–495)

      Hai-liang Liu, Jing-jing Xu, Xiao-min Dai, Jing-Bo Shi, Song Xu, Jing Gao, Qi-zheng Yao and Feng Liu

      Article first published online: 23 APR 2009 | DOI: 10.1002/jat.1433

      Eight novel oxdiazolo[3,4-d]pyrimidine nucleoside derivatives (I-VIII) were synthesized to investigate their antitumor effects and possible mechanisms. Four human cancer cell lines including Hela, ECA109, HepG2 and A459 cells were used. Compounds VI and VIII showed significant inhibition on cancer cell proliferation by MTT assay and IC50 values were around 30–70 mmol l-1. Both compounds could release nitric oxide (NO), led to a significant intracellular free Ca2+ overloading and resulted in mitochondrial dysfunction, showing a decrease in mitochondrial membrane potential in HepG2 cells in a dose-dependent manner.

    5. Phytoglycoprotein (75 kDa) isolated from Cudrania tricuspidata Bureau inhibits expression of interleukin-4 in the presence of di (2-ethylhexyl) phthalate via modulation of p38 mitogen-activated protein kinase in primary-cultured mouse thymocytes (pages 496–504)

      Phil-Sun Oh and Kye-Taek Lim

      Article first published online: 20 APR 2009 | DOI: 10.1002/jat.1434

      The purpose of this study is to determine the inhibitory effect of a glycoprotein isolated from Cudrania tricuspidata Bureau (CTB glycoprotein) on di(2-ethylhexyl) phthalate (DEHP)-induced differentiation of T helper (Th) type 2 cells in primary cultured thymocytes. The results obtained from this study revealed that the CTB glycoprotein in the presence of DEHP produces an antioxidative activity against intracellular reactive oxygen species production in cells.

    6. Immunohistochemical studies on early stage of hepatic damage induced by subacute inhalation of toluene vapor in rats (pages 505–509)

      Takako Gotohda, Akiyoshi Nishimura and Kyoji Morita

      Article first published online: 23 APR 2009 | DOI: 10.1002/jat.1435

      Toxic effect of toluene inhalation on rat liver was examined by analyzing the expression of histological markers. Toluene inhalation enhanced the expression of heat shock proteins, cytochrome P4502E1, α-smooth muscle actin, collagen, glucocorticoid receptors and leptin receptors in the liver. The direct exposure to toluene caused the damage to human hepatoma HepG2 cells in culture. Thus, toluene inhalation may primarily induce the hepatic damage, and then secondarily exacerbated by the activation of systemic processes possibly connected with glucocorticoids and leptin.

    7. Differential developmental toxicities of di-n-hexyl phthalate and dicyclohexyl phthalate administered orally to rats (pages 510–521)

      Anne-Marie Saillenfait, Frédéric Gallissot and Jean-Philippe Sabaté

      Article first published online: 23 APR 2009 | DOI: 10.1002/jat.1436

      The developmental toxic potential of the two plasticizers, di-n-hexyl phthalate (DnHP) and dicyclohexyl phthalate (DCHP), was determined in Sprague-Dawley rats following administration by gavage, on days 6 to 20 of gestation, at doses of 0, 250, 500, or 750 mg kg–1. DnHP produced an increased incidence of embryonic loss and of fetuses with malformations, but not DCHP. There was evidence that both phthalates could alter the development of the male reproductive system, DnHP being much more potent than DCHP.

    8. S-allylcysteine attenuates renal injury by altering the expressions of iNOS and matrix metallo proteinase-2 during cyclosporine-induced nephrotoxicity in Wistar rats (pages 522–530)

      Vinayagam Magendiramani, Syed Umesalma, Srinivasan Kalayarasan, Ponnuraj Nagendraprabhu, Jagadeesan Arunkumar and Ganapasam Sudhandiran

      Article first published online: 23 APR 2009 | DOI: 10.1002/jat.1437

      Cyclosporine A (CsA) is used for the prevention of allograft rejection in solid organ transplantation and immune-mediated diseases. Reactive oxygen species-induced oxidative stress is implicated in CsA-induced renal injury. In the present work we studied the effect of S-allylcysteine (SAC) on CsA-induced nephrotoxicity. We observed elevation of serum marker enzymes, levels of kidney markers, lipid peroxidation along with abnormal levels of enzymic and non-enzymic antioxidants in the kidneys of the rats. SAC exhibits its protective effect by altering the expressions of NF-κB, iNOS and MMP-2.

    9. Silver ion-induced suicidal erythrocyte death (pages 531–536)

      Mentor Sopjani, Michael Föller, Judith Haendeler, Friedrich Götz and Florian Lang

      Article first published online: 14 MAY 2009 | DOI: 10.1002/jat.1438

      In mammalian cells, silver ions trigger apoptosis by stimulation of mitochondrial cytochrome c release. The present study explored the effect of AgNO3 on eryptosis, the suicidal death of erythrocytes, cells devoid of mitochondria. Eryptosis is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure at the cell surface. A 48 hours exposure to AgNO3 significantly enhanced the percentage of PS-exposing cells, decreased cell volume and decreased cytosolic ATP. Ag+-induced eryptosis was inhibited by staurosporine and NO-donator nitroprusside.

    10. Evaluation of cytotoxic concentration–time response in A549 cells exposed to respirable α-quartz (pages 537–544)

      Carla Fanizza, Anna Maria Fresegna, Raffaele Maiello, Emilia Paba and Delia Cavallo

      Article first published online: 14 MAY 2009 | DOI: 10.1002/jat.1440

      In this study cytotoxic concentration-time response in human lung epithelial cell line (A549) exposed to respirable α-quartz (SRM1878a, NIST) was evaluated using scanning electron microscope, fluorescence microscopic analysis of apoptotic morphology and LDH release as cytotoxicity indicator tests. Results showed that exposure to crystalline silica produced concentration- and time-dependent cell surface morphological changes in A549. An apoptosis induction particularly after 48h exposure and a significant LDH release in cells exposed to higher concentrations of α-quartz for 24 or 48h occurred.

  3. Toxicological Update

    1. Top of page
    2. Reviews
    3. Research Articles
    4. Toxicological Update
    1. Updating the skin sensitization in vitro data assessment paradigm in 2009 (pages 545–550)

      David A. Basketter and Ian Kimber

      Article first published online: 29 MAY 2009 | DOI: 10.1002/jat.1443

      There is a common view that multiple in vitro assays will be needed for replacement of the in vivo tests for skin sensitization, so a strategy for data integration will be required. There has been at one previous attempt to develop a framework for integration of information from different sources to reach informed decisions about skin sensitisation potential and potency. In the light of recent developments and initiatives, it is timely to revisit this paradigm to develop recommendations for modification and refinement.