Journal of Applied Toxicology

Cover image for Vol. 36 Issue 9

September 2016

Volume 36, Issue 9

Pages 1073–1245

  1. Issue Information - TOC

    1. Top of page
    2. Issue Information - TOC
    3. Research articles
    1. Issue Information - TOC (pages 1073–1076)

      Version of Record online: 14 JUL 2016 | DOI: 10.1002/jat.3243

  2. Research articles

    1. Top of page
    2. Issue Information - TOC
    3. Research articles
    1. Framework for human health risk assessment of non-cancer effects resulting from short-duration and intermittent exposures to chemicals (pages 1077–1089)

      Lynne T. Haber, Reena Sandhu, Angela Li-Muller, Asish Mohapatra, Sanya Petrovic and M. E. (Bette) Meek

      Version of Record online: 14 JUN 2016 | DOI: 10.1002/jat.3345

      To aid in assessing potential noncancer health effects from short-duration and intermittent exposures, a working framework was developed utilizing a tiered approach, drawing as much as possible on existing TRVs or minor adaptations of same. Toxicokinetic and toxicodynamic considerations are included. The framework incorporates the use of TRVs based on exposure periods as similar as possible to the ‘actual’ exposure periods and application of dose averaging under limited, specified conditions.

    2. Sulfation of benzyl alcohol by the human cytosolic sulfotransferases (SULTs): a systematic analysis (pages 1090–1094)

      Lingtian Zhang, Katsuhisa Kurogi, Ming-Yih Liu, Alaina M. Schnapp, Frederick E. Williams, Yoichi Sakakibara, Masahito Suiko and Ming-Cheh Liu

      Version of Record online: 11 DEC 2015 | DOI: 10.1002/jat.3268

      The aim of the present study was to identify human cytosolic sulfotransferases (SULTs) that are capable of sulfating benzyl alcohol and to examine the sulfation in cultured human cells and human organ homogenates. A systematic analysis revealed that four human SULTs, particularly SULT1A1, were capable of sulfating benzyl alcohol. HepG2 cells were able to generate sulfated benzyl alcohol under the metabolic settings. Moreover, the homogenates of human liver and small intestine displayed strong benzyl alcohol-sulfating activity.

    3. Development and application of a human PBPK model for bromodichloromethane to investigate the impacts of multi-route exposure (pages 1095–1111)

      Elaina M. Kenyon, Christopher Eklund, Teresa Leavens and Rex A. Pegram

      Version of Record online: 9 DEC 2015 | DOI: 10.1002/jat.3269

      A refined human physiologically based pharmacokinetic (PBPK) model for bromodichloromethane (BDCM) (including new chemical-specific human parameters) was developed to evaluate the impact of BDCM exposure during showering and bathing on important measures of internal dose compared with oral exposure. Analyses demonstrated large contributions of dermal and inhalation exposure routes to an internal dose of the parent chemical reaching the systemic circulation. Thus, consideration of the contribution of multiple routes of exposure when evaluating risks from water-borne BDCM is highly desirable.

    4. Long-term exposure to high levels of decabrominated diphenyl ether inhibits CD4 T-cell functions in C57Bl/6 mice (pages 1112–1119)

      Yan Feng, Weihong Zeng, Ying Wang, Hao Shen and Yan Wang

      Version of Record online: 18 DEC 2015 | DOI: 10.1002/jat.3270

      Environmental exposure to decabrominated diphenyl ether (BDE-209) is ubiquitous and comparatively high burdens of BDE-209 have been found in occupationally environmental compartments and exposed personnel. In the present study, we observed impaired CD4 T-cell functions in mice exposed to a relatively high-dose of BDE-209 consecutively, accompanied by increased T regulatory cells in the blood. BDE-209 also suppressed the reactivity of CD4 T cells in vitro. Furthermore, antigen-specific CD4 T-cell responses to exogenous pathogens were prohibited in the exposed mice.

    5. Allopurinol induces innate immune responses through mitogen-activated protein kinase signaling pathways in HL-60 cells (pages 1120–1128)

      Akira Nakajima, Shingo Oda and Tsuyoshi Yokoi

      Version of Record online: 7 DEC 2015 | DOI: 10.1002/jat.3272

      Allopurinol is a frequent cause of severe cutaneous adverse reactions (SCARs) in humans. Although SCARs have been suspected to be immune-mediated, the mechanisms of allopurinol-induced SCARs remain unclear. In this study, we demonstrate that treatment of HL-60 cells with allopurinol significantly increased the mRNA levels of pro-inflammatory cytokines, including IL-8, MCP-1, and TNFa, through activation of MAPK signaling pathways. These results indicate that innate immune responses induced by allopurinol might be involved in the development of allopurinol-induced SCARs.

    6. Discrimination of skin sensitizers from non-sensitizers by interleukin-1α and interleukin-6 production on cultured human keratinocytes (pages 1129–1136)

      Daun Jung, Jeong-Hwan Che, Kyung-Min Lim, Young-Jin Chun, Yong Heo and Seung Hyeok Seok

      Version of Record online: 22 DEC 2015 | DOI: 10.1002/jat.3274

      In vitro testing methods for classifying sensitizers could be valuable alternatives to in vivo sensitization testing using animal models, such as themurine local lymph node assay (LLNA) and the guinea pigmaximization test (GMT), but there remains a need for in vitro methods that are more accurate and simpler to distinguish skin sensitizers from non-sensitizers. Thus, the aim of our study was to establish an in vitro assay as a screening tool for detecting skin sensitizers using the human keratinocyte cell line, HaCaT.

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      Systems toxicology of chemically induced liver and kidney injuries: histopathology-associated gene co-expression modules (pages 1137–1149)

      Jerez A. Te, Mohamed Diwan M. AbdulHameed and Anders Wallqvist

      Version of Record online: 4 JAN 2016 | DOI: 10.1002/jat.3278

      We proposed a protocol for selecting gene co-expression modules associated with chemical-induced injuries that classify 11 liver and eight kidney histopathology endpoints based on dose-dependent activation of the identified modules. We showed that the activation of the modules for a particular chemical exposure correlated with the severity of histopathological damage and could distinguish different types of organ-specific injuries. The generated modules provide a link between toxic chemical exposures, different molecular initiating events among underlying molecular pathways, and resultant organ damage.

    8. Integrated decision strategies for skin sensitization hazard (pages 1150–1162)

      Judy Strickland, Qingda Zang, Nicole Kleinstreuer, Michael Paris, David M. Lehmann, Neepa Choksi, Joanna Matheson, Abigail Jacobs, Anna Lowit, David Allen and Warren Casey

      Version of Record online: 6 FEB 2016 | DOI: 10.1002/jat.3281

      The Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) evaluated a non-animal decision strategies to predict skin sensitization. Machine learning approaches integrated in vitro, in chemico and in silico data and six physicochemical properties for 120 substances to predict murine local lymph node assay (LLNA) outcomes. The seven models with the highest accuracy used a support vector machine with different combinations of predictor variables. The models outperformed individual non-animal methods and test batteries. This suggests that computational approaches are promising tools to effectively integrate data to identify potential skin sensitizers without animal testing.

    9. Combined toxicity of heavy metal mixtures in liver cells (pages 1163–1172)

      Xialu Lin, Yuanliang Gu, Qi Zhou, Guochuan Mao, Baobo Zou and Jinshun Zhao

      Version of Record online: 10 FEB 2016 | DOI: 10.1002/jat.3283

      Human exposure through air, water and food normally involves a mixture consisting of multiple metals. In this study, eight common heavy metals (Pb, Cd, Hg, Cu, Zn, Mn, Cr, Ni) that cause environmental contamination were selected to investigate the combined toxicity of different metal mixtures in HL7702 cells. Synergistic, antagonistic or additive effects of the toxicity were observed in different metal mixtures. These results suggest that the combined effects should be considered in the risk assessment of heavy metal co-exposure.

    10. Diurnal activity patterns as a sensitive behavioural outcome in fish: effect of short-term exposure to treated sewage and a sub-lethal PPCP mixture (pages 1173–1182)

      Steven D. Melvin, David R. Buck and Larelle D. Fabbro

      Version of Record online: 9 FEB 2016 | DOI: 10.1002/jat.3284

      Diurnal activity patterns occur in many fish species and are sensitive to changes in natural factors. We exposed the mosquitofish (Gambusia holbrooki) to treated sewage and a mixture of Pharmaceuticals and Personal Care Products (PPCPs) identified in the wastewater, and quantified outcomes on diurnal rhythms. Daytime activity was abolished in male fish exposed to sewage and the mixture, whereas female activity was only significantly reduced with the PPCP mixture. Results demonstrate that diurnal activities provide a sensitive indication of sub-lethal toxicity in fish exposed to environmental pollutants.

    11. Evaluation of kidney injury biomarkers in rat amniotic fluid after gestational exposure to cadmium (pages 1183–1193)

      Tania Jacobo-Estrada, Mariana Cardenas-Gonzalez, Mitzi Santoyo-Sánchez, Benjamín Parada-Cruz, Esther Uria-Galicia, Laura Arreola-Mendoza and Olivier Barbier

      Version of Record online: 27 JAN 2016 | DOI: 10.1002/jat.3286

      Cadmium effects in fetal kidneys have not been widely studied, and no study has used early biomarkers for the detection of prenatal kidney injury. Pregnant Wistar rats were exposed to cadmium during gestation. Biomarkers of kidney injury were quantified in amniotic fluid (AF) samples, and fetal kidneys were processed for histological examination. Cadmium increased the levels of some biomarkers. Histological findings confirmed kidney alterations. In conclusion, kidney injury biomarkers in AF may be used to detect cadmium-induced fetal kidney damage.

    12. Phenotypic and biomarker evaluation of zebrafish larvae as an alternative model to predict mammalian hepatotoxicity (pages 1194–1206)

      Sandra Verstraelen, Bernard Peers, Walid Maho, Karen Hollanders, Sylvie Remy, Pascale Berckmans, Adrian Covaci and Hilda Witters

      Version of Record online: 4 MAR 2016 | DOI: 10.1002/jat.3288

      Zebrafish phenotypic assays have shown promise to assess human hepatotoxicity, though scoring of liver morphology remains subjective and difficult to standardize. Liver toxicity in zebrafish larvae at 5 days was assessed using gene expression as the biomarker approach, complementary to phenotypic analysis and analytical data on compound uptake. This approach aimed to contribute to improved hepatotoxicity prediction, with the goal of identifying biomarker(s) as a step towards the development of transgenic models for prioritization.

    13. Depth-dependent stratum corneum permeability in human skin in vitro (pages 1207–1213)

      John Jay P. Cadavona, Hanjiang Zhu, Xiaoying Hui, Eui-Chang Jung and Howard I. Maibach

      Version of Record online: 3 FEB 2016 | DOI: 10.1002/jat.3289

      The stratum corneum (SC) concentration–thickness profiles were determined for four model chemicals on intact and adhesive tape-stripped skin samples to clarify whether SC is a homogeneous barrier for chemical transport. Data analysis with the diffusion equation of Fick's second law permitted the chemical diffusion coefficient in SC. Results suggested the depth-dependency of SC permeability to panthenol, benzoic acid and butenafine; variation of the diffusion coefficient from the SC surface to the deeper layers agreed with a change in the diffusion coefficient over time in intact skin.

    14. Development of a quantitative morphological assessment of toxicant-treated zebrafish larvae using brightfield imaging and high-content analysis (pages 1214–1222)

      Samantha Deal, John Wambaugh, Richard Judson, Shad Mosher, Nick Radio, Keith Houck and Stephanie Padilla

      Version of Record online: 29 FEB 2016 | DOI: 10.1002/jat.3290

      We developed a Computational Malformation Index that provides an objective manner for rapid phenotypic brightfield assessment of individual zebrafish larva in a developmental assay. By combining the use of high-content imaging with a very abbreviated human visual assessment, each larva can be quickly assessed for both detailed features as well as in-life parameters. Further, stability of these high-content measurements and the index performance were verified using a test set of zebrafish treated with two reference chemicals.

    15. n-butylparaben induces male reproductive disorders via regulation of estradiol and estrogen receptors (pages 1223–1234)

      Linyuan Zhang, Sijin Ding, Peihuan Qiao, Li Dong, Miao Yu, Chong Wang, Ming Zhang, Lixia Zhang, Yimin Li, Ning Tang and Bing Chang

      Version of Record online: 17 FEB 2016 | DOI: 10.1002/jat.3291

      Exposure to exogenous hormones during fetal or neonatal life leads to adverse reproductive outcomes. In this study, we investigated the possible mechanisms of reproductive disorders induced by n-butylparaben in utero and lactation in rats, which indicated that altered synthesis and metabolism of T and E2, the expressions of ERα and epigenetic hypomethylation of ERα contributed to the reproductive disorders. It is the first time to elucidate the possible mechanisms of reproductive disorders induced by n-butylparaben as a xenoestrogenic chemical.

    16. Effects of in vitro exposure to butylparaben and di-(2 ethylhexyl) phthalate, alone or in combination, on ovarian function (pages 1235–1245)

      Marina T. Guerra, Hayley C. Furlong, Wilma G. Kempinas and Warren G. Foster

      Version of Record online: 2 MAY 2016 | DOI: 10.1002/jat.3335

      We evaluated the effects of Di-(2-ethylhexyl) phthalate (DEHP) and Butylparaben (BP), alone and in combination, on isolated mouse preantral follicle and human granulosa cell (hGC) cultures to study direct effects on follicle growth and ovarian steroidogenesis. Our results suggest that DEHP and BP adversely affect steroidogenesis from the preanatral stage onward and the effects of these chemicals are both stage-dependent and modified by co-exposure.