Journal of Applied Toxicology

Cover image for Vol. 34 Issue 6

June 2014

Volume 34, Issue 6

Pages 576–732

  1. Review Articles

    1. Top of page
    2. Review Articles
    3. Research Articles
    1. Drug safety testing paradigm, current progress and future challenges: an overview (pages 576–594)

      Varun Ahuja and Sharad Sharma

      Article first published online: 29 OCT 2013 | DOI: 10.1002/jat.2935

      Early assessment of the safety of new molecules in the pharmaceutical industry is a multi-dimensional task involving predictive systems and screening approaches to aid in the optimization of lead compounds prior to their entry into the development phase. This study discusses the developments that allow toxicologists to anticipate safety problems and plan ways to address them, earlier than ever before. Today's toxicologist should collaborate with medicinal chemists, pharmacologists, and clinicians and these value-adding contributions will change traditional toxicologists from side-effect identifiers to drug development enablers.

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      Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence (pages 595–606)

      M. E. (Bette) Meek, Christine M. Palermo, Ammie N. Bachman, Colin M. North and R. Jeffrey Lewis

      Article first published online: 10 FEB 2014 | DOI: 10.1002/jat.2984

      The potential value of the mode of action (MOA)/human relevance (species concordance) framework in considering relative weight of evidence (WOE) amongst different cases and hypothesized MOA(s) is explored based on the content of several published assessments. The comparison is based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations for MOA based on experience internationally.

  2. Research Articles

    1. Top of page
    2. Review Articles
    3. Research Articles
    1. Facilitating the use of non-standard in vivo studies in health risk assessment of chemicals: a proposal to improve evaluation criteria and reporting (pages 607–617)

      Anna Beronius, Linda Molander, Christina Rudén and Annika Hanberg

      Article first published online: 30 JAN 2014 | DOI: 10.1002/jat.2991

      The purpose of this work was to propose tools that facilitate the use of non-standard toxicity studies in health risk assessment of chemicals. Criteria and guidance for evaluation of study reliability and relevance were based on requirements and recommendations identified from OECD test guidelines. A checklist for reporting such studies was also proposed. Together, these resources provide an approach to include all relevant data that may fill information gaps and reduce scientific uncertainty in health risk assessment conclusions.

    2. Mixtures of 3,4-methylenedioxymethamphetamine (ecstasy) and its major human metabolites act additively to induce significant toxicity to liver cells when combined at low, non-cytotoxic concentrations (pages 618–627)

      Diana Dias da Silva, Elisabete Silva, Félix Carvalho and Helena Carmo

      Article first published online: 14 MAY 2013 | DOI: 10.1002/jat.2885

      Combination effects between methylenedioxymethamphetamine (MDMA; ecstasy) and its metabolites methylenedioxyamphetamine, α-methyldopamine and N-methyl-α-methyldopamine were evaluated in Hep G2 cells at normal (37 ºC) and hyperthermic (40.5  ºC) incubation conditions. Joint cytotoxic effects measured as viability in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay were predicted using the concentration addition and independent action models. The combination of MDMA and its metabolites induced additive toxicity that was accurately predicted by the concentration addition model. Substantial combination effects were noted for mixtures at individually non-cytotoxic concentrations. Hyperthermic incubations dramatically increased individual and joint cytotoxicity.

    3. Nonylphenol-induced apoptotic cell death in mouse TM4 Sertoli cells via the generation of reactive oxygen species and activation of the ERK signaling pathway (pages 628–636)

      Mi-Sun Choi, Han-Jin Park, Jung-Hwa Oh, Eun-Hee Lee, Se-Myo Park and Seokjoo Yoon

      Article first published online: 16 MAY 2013 | DOI: 10.1002/jat.2886

      Nonylphenol (NP), a representative endocrine disruptor, interferes with reproductive function in aquatic organisms and animals. Although many studies have focused on apoptotic cell death by NP, the fundamental mechanism of NP on apoptosis remains poorly understood. Here, we investigated the molecular mechanism on NP-induced apoptotic cell death in mouse TM4 Sertoli cells. Our results suggest that NP induced apoptotic cell death is mediated via ROS generation and activation of the ERK signaling pathway in TM4 cells.

    4. Combination effects of amphetamines under hyperthermia - the role played by oxidative stress (pages 637–650)

      Diana Dias da Silva, Elisabete Silva and Helena Carmo

      Article first published online: 13 JUN 2013 | DOI: 10.1002/jat.2889

      The impact of hyperthermia on the cytotoxicity of combinations of MDMA and three other amphetamines often co-ingested, d-amphetamine, methamphetamine and 4-methylthioamphetamine, was evaluated. In hyperthermia (40.5 °C), amphetamine mixtures produced deleterious effects, even when individual drugs were combined at negligible concentrations. Mixture effects were accurately predicted by concentration addition model. RNS/ROS production, GSH and ATP depletion and mitochondrial impairment were strongly exacerbated under hyperthermia, emphasizing the potential increased risks of ecstasy intake, especially when hyperthermia occurs concurrently with polydrug abuse.

    5. Induction of apoptosis by antimycin A in differentiated PC12 cell line (pages 651–657)

      Xu Lanju, Xu Jing, Liu Shichang and Yang Zhuo

      Article first published online: 19 JUL 2013 | DOI: 10.1002/jat.2890

      The aim of the present study was to investigate the effect of AMA on PC12 cells in vitro. Results of the nuclear morphology and the flow cytometer indicated that AMA efficiently induced PC12 cell apoptosis. Moreover, the levels of ROS and Ca2+ increased by AMA treatment. It was found that the Ca2+ chelators and ROS scavengers could delay AMA-induced PC12 cell apoptosis. In conclusion, the present study found that AMA induced PC12 cell apoptosis through ROS and Ca2+.

    6. In vitro PFOS exposure on immune endpoints in bottlenose dolphins (Tursiops truncatus) and mice (pages 658–666)

      Jena R. Wirth, Margie M. Peden-Adams, Natasha D. White, Gregory D. Bossart and Patricia A. Fair

      Article first published online: 30 MAY 2013 | DOI: 10.1002/jat.2891

      Following in vitro exposure to environmentally relevant perfluorooctane sulfonate (PFOS) concentrations (0–5 µg ml−1) in dolphin peripheral blood leukocytes (PBLs) and adult female B6C3F1 mouse splenocytes, lymphocyte proliferation and natural cell killer activity was measured. Risk assessment using a parallelogram approach indicated that dolphin PBLs exhibited similar results to correlative field studies; mice were generally more sensitive than dolphins; dolphins were more similar to humans than mice. The parallelogram approach was predictive two-thirds of the time for dolphin response.

    7. Characterization of the components of urban particulate matter mediating impairment of nitric oxide-dependent relaxation in intrapulmonary arteries (pages 667–674)

      Arnaud Courtois, Caroline Prouillac, Isabelle Baudrimont, Céline Ohayon-Courtes, Véronique Freund-Michel, Mathilde Dubois, Mariette Lisbonne-Autissier, Roger Marthan, Jean-Pierre Savineau and Bernard Muller

      Article first published online: 23 JUL 2013 | DOI: 10.1002/jat.2909

      We have previously shown that exposure to urban particulate matter (UPM) impairs endothelial nitric oxide (NO) bioactivity in intrapulmonary arteries. Since UPM is composed of heterogeneous constituents, the present study was designed to clarify the class of pollutants being responsible for such effect. We showed that UPM-induced impairment of endothelial NO bioactivity unlikely involved a soluble factor released by vascular cells, but organic extractible and acidic-sensitive constituents of UPM. Among those constituents, endotoxin may be responsible for such impairment.

    8. Effects of water soluble PM2.5 extracts exposure on human lung epithelial cells (A549): A proteomic study (pages 675–687)

      Qingyu Huang, Jie Zhang, Siyuan Peng, Meiping Tian, Jinsheng Chen and Heqing Shen

      Article first published online: 14 AUG 2013 | DOI: 10.1002/jat.2910

      Airborne particulate matter (PM)2.5 exposure has been associated with a number of adverse health effects. However, the mechanisms underlying PM2.5 toxicity remain unclear. In the current proteomic study, 22 differentially expressed proteins responsive to water-soluble PM2.5 extract treatment in A549 cells were identified by 2-D difference gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. Furthermore, induction of apoptosis was proposed as a vital mechanism for water-soluble PM2.5 extract cytotoxicity. These results may provide useful insights into the mechanisms of PM2.5 toxicity and assist in the development of biomarkers of PM2.5 exposure.

    9. Obese mice are resistant to eosinophilic airway inflammation induced by diesel exhaust particles (pages 688–694)

      Rie Yanagisawa, Eiko Koike, Takamichi Ichinose and Hirohisa Takano

      Article first published online: 18 SEP 2013 | DOI: 10.1002/jat.2925

      We investigated the differences in susceptibility to DEP-induced airway inflammation between obese mice (db/db) and lean mice (db/+m). DEP exposure results in eosinophilic airway inflammation via generation of Th2 cytokines, chemokines, and soluble ICAM-1 in db/+m mice; whereas in db/db mice, there was mild neutrophilic inflammation with attenuation of eosinophilic infiltration in the lungs. Obesity can affect the susceptibility to DEP-related airway inflammation, presumably because of differences in systemic and local inflammatory responses between obese and lean individuals.

    10. Circulating microRNAs as biomarkers of retinal toxicity (pages 695–702)

      Qinghai Peng, Wenhu Huang and Annette John-Baptiste

      Article first published online: 30 SEP 2013 | DOI: 10.1002/jat.2930

      Despite attrition due to retinal toxicity during drug development there are no early reliable predictive biomarkers of retinal toxicity. Currently the technologies for assessing retinopathy are limited to inconvenient visual behavioral tests, invasive electroretinograms or terminal histopathology. To address this gap, we explored several retinal enriched miRNAs in rats ex vivo and in vivo with pan-CDK inhibitors to assess these miRNAs in plasma. Although they need additional confirmatory evaluation, results provide promise for further testing using other retinal toxicants.

    11. Xenobiotic metabolism induction and bulky DNA adducts generated by particulate matter pollution in BEAS-2B cell line: geographical and seasonal influence (pages 703–713)

      Capucine Lepers, Véronique André, Mona Dergham, Sylvain Billet, Anthony Verdin, Guillaume Garçon, Dorothée Dewaele, Fabrice Cazier, François Sichel and Pirouz Shirali

      Article first published online: 30 SEP 2013 | DOI: 10.1002/jat.2931

      Particulate matter (PM) toxicity is of growing interest, but the link between chemical composition and toxicity remains unclear. We studied 6 native PM samples from various origins on BEAS-2B cell line. Cells exposure resulted in CYP1A1 and CYP1B1 genes induction, followed by an increase in EROD activity leading to bulky DNA-adducts. We showed that adducts level is only partly explained by PM content in polycyclic aromatic hydrocarbons, and that inorganic compounds may promote adducts formation by supporting CYPs activity.

    12. Toxic effects of a modified montmorillonite clay on the human intestinal cell line Caco-2 (pages 714–725)

      Sara Maisanaba, Daniel Gutiérrez-Praena, Silvia Pichardo, F. Javier Moreno, María Jordá, Ana M. Cameán, Susana Aucejo and Ángeles Jos

      Article first published online: 9 OCT 2013 | DOI: 10.1002/jat.2945

      The increasing used of montmorillonite based clays in the development of reinforced food contact materials makes necessary to study the toxicological aspects of these materials. In the present study, the cytotoxic effects of a non-modified clay (Cloisite® Na+) and an organoclay (Cloisite® 30B) have been investigated in the intestinal cell line Caco-2. Only Cloisite® 30B showed cytotoxicity. In order to elucidate the toxic mechanisms underlying these effects, apoptosis, oxidative stress and genotoxicity biomarkers as well as ultrastructural alterations were studied.

    13. Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis (pages 726–732)

      John D. Clarke, Tatiana Sharapova, April D. Lake, Eric Blomme, Jonathan Maher and Nathan J. Cherrington

      Article first published online: 12 NOV 2013 | DOI: 10.1002/jat.2960

      The methionine choline-deficient diet (MCD) is a frequently used hepatotoxicity animal model of non-alcoholic steatohepatitis (NASH) that induces hepatic transaminase (ALT, AST) elevations and hepatobiliary histological changes similar to those observed in human NASH. Liver-specific microRNA-122 (miR-122) has recently been proposed as a sensitive and specific circulating biomarker of hepatic injury. This study shows that miR-122 serum levels are elevated earlier than transaminases and may be useful as a sensitive biomarker for the early detection of NAFLD-associated liver injury.