Annual Meeting of the Japanese Society of Toxicology
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The 40th Annual Meeting of the Japanese Society of Toxicology
Displaying 1-50 of 368 articles from this issue
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President’s Invited Lecture
  • The Development of Histamine H4 Receptor Antagonists
    Robin L. Thurmond
    Session ID: IL
    Published: 2013
    Released on J-STAGE: August 14, 2013
    DOIhttps://doi.org/10.14869/toxpt.40.1.0.1.0
    CONFERENCE PROCEEDINGS FREE ACCESS
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    The histamine H4 receptor was first reported over ten years ago and has become an attractive target for the development of drugs for the treatment of inflammation, pruritus, allergy and asthma. The H4 receptor mediates chemotaxis and cytokine release of mast cells, eosinophils, monocytes, dendritic cells and T cells. In addition, histamine released from mast cells or from other cell types can influence T cell polarization via activation of the H4 receptor. The receptor also mediates T cell activity in vivo and has a proinflammatory effect not only in models of the innate immune response, but also in models of asthma and contact dermatitis, where it mainly affects T cell responses. Extensive medicinal chemistry and pharmacology efforts have led to the development of modulators with excellent potency and selectivity for the H4 receptor. This has enabled exploration of the role of the receptor in human disease and provided candidates for clinical investigation. Several compounds have reached the clinic including JNJ 39758979 that has progressed into phase II clinical trials. This talk will highlight recent clinical and preclinical data supporting a role for the H4 receptor in human disease, as well as some of the obstacles encountered when advancing compounds with a novel mechanism into clinical studies.
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Special Lecture
  • The new toxicology of sophisticated material: Nanotoxicology and beyon
    Martin A. Philbert
    Session ID: SL-1
    Published: 2013
    Released on J-STAGE: August 14, 2013
    DOIhttps://doi.org/10.14869/toxpt.40.1.0.11.0
    CONFERENCE PROCEEDINGS FREE ACCESS
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    PEBBLE nanoplatforms are self-assembled, fluorescent probes with conserved cores that contain multiple elements for the selective localization and measurement of single analytes in a living cell. Biocompatible matrices are hydrophobic or hydrophilic and include plasticized polyvinyl chloride, decylmethacrylate, polyacrylamide or sol gels with diameters of 20?200 nm. Elements that may be embedded within the co-polymer matrix include a fluorescent sensing molecule, enzymes, sensitizers, antioxidants, dendrimeric antenna supermolecules, and magnetic/superparamagnetic chelates or nanoparticles. These possible combinations provide for a wide variety of probe functions in a range of biological specimens. Available probes include sensors for Ca2+, Mg2+, Zn2+, K+, Na+, pH, Cl-, O2, glucose, NO and E-fields. Incorporation of sensing and other elements into the biocompatible matrix provides for separation of the sensor chemistry from the biological environment, permitting the use of highly toxic, but selective sensor molecules. PEBBLE and other related nano-scale optical sensors provide for analysis of physiological processes in living cells and biological media in real time. More recent advancements in PEBBLE nanoplatforms (Dynamic NanoPlatforms: DNPs) have enabled MR imaging of orthotopic experimental brain tumors and for enhancement of visual contrast for neurosurgical resection. Data will be presented on the pharmacokinetics and the role of the reticulo-endothelial system in clearing nanomaterials from the circulation.

    Acknowledgments: This work was supported by grants from the National Cancer Institute, the WM Keck Foundation, the Department of Defense and the National Institute of Environmental Health Sciences.
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  • Integrating metabolomic and transcriptomic data into systems approaches for toxicology research
    Lois Lehman-McKeeman
    Session ID: SL-2
    Published: 2013
    Released on J-STAGE: August 14, 2013
    DOIhttps://doi.org/10.14869/toxpt.40.1.0.12.0
    CONFERENCE PROCEEDINGS FREE ACCESS
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    Systems biology provides a means to extend classical hypothesis-driven experiments from a focus on a small number of events to a more integrated understanding of the holistic response of a cell or tissue to any type of perturbation. The application of systems biology approaches requires global data sets such as those obtained from metabolomic or transcriptomic analyses. In this regard, transcriptional changes have been more widely evaluated than metabolomic profiles following toxicant exposure. However, metabolomic data ultimately reflect on the likely phenotypic consequence of altered gene expression, and represent important complementary data for determining the relevance of induction or repression of specific gene pathways. The integration of metabolomic and transcriptomic data can facilitate how we generate hypotheses, determine mechanisms of toxicity and translate the human relevance of data obtained from laboratory animals. Efforts to integrate these platforms indicate that each can inform the other, and collectively, they augment the identification of the major systemic effects of a xenobiotic or disease process. To this end, several examples will be provided of integrating data sets that lead to better definition of major biochemical events or toxic mechanisms. A very simple example is the urinary excretion of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) which differs markedly between male and female mice. TMAO is a major metabolite in females but not in males, an outcome directly attributed to expression levels of flavin monooxygenases (FMO) that form this metabolite. As another example, integrating transcriptomic and metabolomic profiling from genetically-modified models is particularly helpful in establishing the phenotype of these models (usually mice). Organic anion transporting polypeptides (Oatp) are major hepatic anion uptake transporters, and Oatp1a1 null mice are viable, fertile, and appear to have minimal alterations in hepatic gene expression patterns. However, metabolomic data indicate significant perturbations in major urinary metabolites consistent with changes in resident intestinal microflora from wildtypes. Follow up studies confirmed substantive changes in constitutive abundance of Lactobacillus species in Oatp1a1 null mice, a phenotype that may contribute to alterations in bile acid homeostasis and sensitivity to toxicants in this model. Additional examples will illustrate how metabolomic data have been used to probe transcriptional changes (or vice versa) to integrate these platforms into holistic analyses of a toxic responses.
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  • Radiation toxicology: from discovery of radiation and nuclear fission to Fukushima
    Roger O. McClellan
    Session ID: SL-3
    Published: 2013
    Released on J-STAGE: August 14, 2013
    DOIhttps://doi.org/10.14869/toxpt.40.1.0.13.0
    CONFERENCE PROCEEDINGS FREE ACCESS
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    The discovery of x-rays in 1895 initiated revolutionary advances that joined physics, biology and medicine forever. This was further emphasized with discovery in 1939 of nuclear fission which provided the basis for development of nuclear weapons and, most importantly, many peaceful applications of nuclear technology, including generation of electricity and numerous advances in medicine. Three quarters of a century of research on how external radiation exposure and internally-deposited radionuclides affect biological systems has resulted in extensive knowledge on the health effects of ionizing radiation that greatly exceeds that available on any other toxicant or class of toxicants. The core knowledge on these effects is rooted in human misfortune, detailed studies of the A-Bomb survivors by the Radiation Effects Research Foundation and other human populations that received excessive exposure to external radiation or internally-deposited radionuclides. That knowledge obtained from studying human populations has been complemented and extended by controlled exposure studies with laboratory animals and in vitro cellular and molecular studies. Extensive information has been acquired about how different radionuclides move in the environment from various sources and reach humans. An elaborate science-based system for estimation of human health risks of exposure to ionizing radiation has evolved and serves as the basis of an internationally accepted radiation protection system based on energy deposition in specific organs. This presentation will review from a historical perspective how this body of knowledge on radiation toxicology has been acquired and used to assess accidents such as occurred at the Fukushima nuclear station. Special attention will be given to the critical agricultural pathways for fallout 131I and 134-137Cs to reach humans via consumption of contaminated agricultural products principally milk and meat. The relative importance of external radiation versus irradiation from internally-deposited radionuclides entering the body via ingestion or inhalation for nuclear workers and the general population will be discussed. The nature of the relationship between radiation dose, delivered at different dose rates, and increased excess risk of cancer and other diseases will be discussed in the context of the background incidence of these diseases. The presentation will close by emphasizing the role of scientists in risk communication based on the scientific knowledge acquired over the past three-quarters of a century on the human health hazards of radiation exposure.
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  • Roles of drug transporters in the adverse reactions of drugs
    Yuichi Sugiyama
    Session ID: SL-4
    Published: 2013
    Released on J-STAGE: August 14, 2013
    DOIhttps://doi.org/10.14869/toxpt.40.1.0.14.0
    CONFERENCE PROCEEDINGS FREE ACCESS
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    Drug transporters are expressed in many tissues, such as the intestine, liver, kidney, and the brain, and play key roles in drug absorption, distribution and excretion. In this presentation, I will summarize the significant role played by drug transporters in drug disposition, focusing particularly on their roles in the adverse reactions of drugs. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side-effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The expression system of transporters is an efficient tool for screening the activity of individual transport processes. The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have an adverse effect on the therapeutic safety and efficacy of many important drugs.
    For drugs, the target molecule of which is inside the cells, the efflux transporter is the determinant for their pharmacological effect or adverse reactions even though it had negligible impact in the plasma concentrations. Because of difficulty in quantitative evaluation of the subsequent efflux process, the transporters playing key roles in the efflux process remains unclear in humans. Development of probe substrates applicable to the PET imaging will elucidate the quantitative relationship between the transport activities and drug response. Drug transporters are also important for the disposition of endogenous and food derived compounds. Metabonomic analysis has succeeded in identifying such compounds both in animals and human, which could be a good biomarker for the transporter function in vivo.References:
    1) Giacomini KM and Sugiyama Y. Membrane transporters and drug response, in “Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12th Edition”, (Brunton LL, Chabner BA, Knollman B, eds) Chapter 5, McGraw-Hill Companies, New York, NY, pp 89-122 (2011).
    2) Kusuhara H, Maeda K and Sugiyama Y “Impact of Drug Transporters in the Pharmacological and Adverse Reactions of Drugs” pp563-598 In New Horizons in Predictive Toxicology: Current Status and Application, Ed. by Wilson AGE (2011)
    3) Yoshida K, Maeda K, Sugiyama Y. Hepatic and Intestinal Drug Transporters: Prediction of Pharmacokinetic Effects Caused by Drug-Drug Interactions and Ge etic Polymorphisms. Annu Rev Pharmacol Toxicol. 53: 581-612 (2013)
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  • The translational knowledge cycle: innovations in moving science from discovery to application
    Syril D. Pettit
    Session ID: SL-5
    Published: 2013
    Released on J-STAGE: August 14, 2013
    DOIhttps://doi.org/10.14869/toxpt.40.1.0.15.0
    CONFERENCE PROCEEDINGS FREE ACCESS
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    The current era of ‘big data’, the promise of the sequenced genome, advances in green chemistry-all contribute to unique opportunities to apply innovative science to improve human and environmental health. Traditional scientific disciplinary lines are being replaced with interdisciplinary approaches. As a result, there is a growing interest in collaboration across groups that were once competitive. These collaborations take the form of public-private and private-private partnerships and are creating a new and energized research environment. However, these new approaches must seek to meet challenges of emerging and chronic diseases, growing environmental impacts associated with population growth and industrialization, and economic and resource limitations for novel research.
    HESI, a global scientific foundation based in Washington, DC, has initiated a new program called CITE (Combining Interdisciplinary and Translational Expertise). This effort has engaged participants from a broad range of disciplines (agricultural sciences, environmental sciences, drug development and safety, chemical development and safety, economics, foundation management, entrepreneurship, regulatory science, philanthropy, and academic research management among others) to identify opportunities to move science from discovery to application more efficiently. This presentation will identify some of the opportunities for improving this process that were identified through the HESI CITE initiative and the next steps that will be taken to address these recommendations. The discussion will also include examples of how HESI’s current scientific portfolio and process help to optimize the flow and management of knowledge as part of translational science implementation.
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  • Advancing regulatory science to enhance medical product development and public health
    William Slikker, Jr, Weida Tong
    Session ID: SL-6
    Published: 2013
    Released on J-STAGE: August 14, 2013
    DOIhttps://doi.org/10.14869/toxpt.40.1.0.16.0
    CONFERENCE PROCEEDINGS FREE ACCESS
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    The FDA’s new initiative on advancing regulatory science embraces the increased adoption of emerging technologies such as pharmacogenomics (PGx) and bioinformatics in regulatory application. These technologies are complex in nature and individual groups often do not have the resources to pursue biological qualification of biomarkers and validation of these technologies individually, thus slowing the realization in regulatory application. The FDA has developed the Voluntary eXploratory Data Submission (VXDS) program as a framework outside traditional regulatory interactions for sponsors and FDA to develop expertise, tools, and processes appropriate for regulatory interpretation of PGx data, and ultimately determine the utility, shortcomings, and needs for development and application of PGx. The program identifies considerable work in progress and controversies to be resolved before consensus is achieved on the most appropriate and valid methods at a refined and advanced level. The VXDS is thus being undertaken in parallel with ongoing research aimed at determining the best scientific practices in using exploratory data. An important parallel research effort is the MicroArray Quality Control (MAQC) project that is an FDA-led, community-wide effort aimed at developing consensus among stakeholders for optimizing the reproducibility of technologies, standardizing data analysis practices, and allowing re-analysis of the data by sharing the results across the research community. Both VXDS and MAQC programs have had to grapple with formidable difficulties in data management, analyses, and interpretation, resulting in the establishment of the new Division of Bioinformatics and Biostatistics at the FDA’s National Center for Toxicological Research (NCTR), which has developed a suite of bioinformatics tools including ArrayTrack as an efficient and adaptable bioinformatics environment to support regulatory science. Realizing that we are entering the 21st century as consumer products are increasingly globalized, regulatory science needs a strategy to develop a global path to expedite the translation of basic science innovation to regulatory application. With this goal in mind, we established the Global Summit on Regulatory Science (GSRS) which fosters the development of sustainable regulatory systems that promote global public health through scientific exchange, training and research collaborations. Importantly, we have developed a Global Coalition of Regulatory Research Scientists (GSRSR); this is an international coalition with an objective of facilitating education, scientific training and scientific exchange in the field of regulatory science. All these aforementioned efforts are designed to enhance our capability to expedite the translation of cutting edge technologies into comprehensive approaches to advance regulatory science and public health.
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Educational Lecture
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