Toxicity-Pathway-Based Risk Assessment Preparing for Paradigm Change: A Symposium Summary (2010) / Chapter Skim
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Appendix F: Poster Abstracts
Appendix F: Poster Abstracts
Pages 84-120
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From page 84... ...
. We used a series of linked "cause-effect" functions, fitted with a likelihood approach, to describe the relationships between successive key events and the ultimate tumor response.
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From page 85... ...
Methods: Individual models of metabolic pathways are automatically merged and coupled to a template physiologically based pharmacokinetic (PBPK) model by using the GNU MCSim software.
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From page 86... ...
Isukapalli, and P.G. Georgopoulos Environmental and Occupational Health Sciences Institute, A Joint Institute of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and Rutgers University, Piscataway, NJ Oxidative stress is an important toxicity pathway that can lead to cellular injury and carcinogenesis.
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From page 87... ...
Therefore, the mathematical formulation of the toxicity pathway for oxidative stress generation includes TCE and its metabolites and considers direct exposures to the metabolites. This new model improves on existing TCE models by including a toxicity response pathway and by considering the impact of direct exposures to metabolites.
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From page 88... ...
PBPK models, BBDR models, and virtual tissues: How will they contribute to the use of toxicity pathways in risk assessment? Rory Conolly, Imran Shah, and Thomas Knudsen U.S.
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Disclaimer: Although this work was reviewed by the U.S. Environmental Protection Agency and approved for publication, it may not necessarily reflect official agency policy.
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From page 90... ...
Subramaniam2 1 Louisiana Tech University, Ruston, LA; 2U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Research Triangle Park, NC Low-dose extrapolation and accounting for human variability in susceptibility remain among the key issues in implementing the recommendations of the National Research Council report Toxicity Testing in the 21st Century: A Vision and a Strategy (NRC 2007)
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From page 91... ...
Portier4 1 Louisiana Tech University, Ruston, LA; 2U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Research Triangle Park, NC; 3Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; 4National Institute of Environmental Health Sciences, Research Triangle Park, NC The strength of recent advances in molecular toxicology arises from the potential to provide information on proximal markers of dose and on early markers of contributions from multiple pathways to diseased states.
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From page 92... ...
Because we expect that this state of affairs will continue in the foreseeable future, we support the vision of the National Research Council committee that produced Toxicity Testing in the 21st Century: A Vision and a Strategy of not recommending development of quantitative estimates of human risk from in vitro data. Rather, efforts should focus on estimating human exposure levels that would not be expected to cause perturbations in normal physiology that could result in adverse health consequences in humans.
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From page 93... ...
This need is articulated in the 2007 National Research Council report Toxicity Testing in the 21st Century: A Vision and a Strategy. Addressing the need and establishing libraries of critical toxicity pathways will provide a substantial basis for using in silico and HTS approaches to predict toxicity credibly, to support priority-setting and screening assessments, and to provide more robust scientific foundations for quantitative risk assessment.
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From page 94... ...
The second task requires the determination of the key events linking perturbations in the toxicity pathway to the resulting adverse outcome and quantitative in vivo parameter estimates for these key events relative to in vitro toxicity-pathway measurements. This poster describes EPA efforts to address the second task through the establishment of interdisciplinary teams to identify novel toxicity pathways, establish a mode of action (MOA)
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From page 95... ...
Initial computational models will likely be biologically based dose-response (BBDR) models, which focus on toxicity pathways rather than specific chemicals.
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and Weihsueh Chiu1 1 U.S. Environmental Protection Agency, National Center for Environmental Assessment, Washington, DC; 2National Institute of Environmental Health Sciences, Research Triangle Park, NC; 3Rutgers University of Medicine and Dentistry of New Jersey, Environmental Bioinformatics and Computational Toxicology Center, Piscataway, NJ; 4U.S.
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The approach for incorporating toxicogenomic data in risk assessment may be used in future chemical assessments. The draft report of this project is currently undergoing external peer review.
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Overall, we show that 2-BE induces inflammatory-response genes and propose that this response induces hemangiosarcomas through the AKT signaling pathway. Improving prediction of chemical carcinogenicity by considering multiple mechanisms and applying toxicogenomic approaches Kathryn Z
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Our findings underscore the need for methods that better reflect current knowledge, characterize a wider array of hazard traits, improve the ability to predict the potential carcinogenicity of chemicals, and are less time-consuming and costly. Disclaimer: The views expressed are those of the authors and do not necessarily reflect the policy or endorsement of their affiliated institutions, the California Environmental Protection Agency or the U.S.
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From page 100... ...
Environmental Protection Agency, National Center for Environmental Assessment, Office of Research and Development, Washington, DC Data on a chemical's mode of action (MOA) can be critical in decisions in evaluating human health risks.
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In vitro screening for chemical toxicity in a genetically diverse human model system Shannon Hatcher,1 Oksana Kosyk,1 Pamela Ross,1 Fred Wright,2 John Schwarz,2 David Dix,3 and Ivan Rusyn1 1 University of North Carolina at Chapel Hill, Department of Environmental Sciences and Engineering, Chapel Hill, NC; 2University of North Carolina at Chapel Hill, Department of Biostatistics, Chapel Hill, NC; 3U.S. Environmental Protection Agency, Research Triangle Park, NC Immortalized human lymphoblastoid cell lines have been used to demonstrate that genetic polymorphisms control gene expression, that it is possible to use cell lines from related and unrelated individuals to identify the factors that affect the phenotypes in response to xenobiotic treatment, and that there is heritability of gene-expression traits in segregating human populations.
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This work was reviewed by the U.S. Environmental Protection Agency and approved for publication but does not necessarily reflect official agency policy.
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From page 103... ...
Enhancements include additional modules for pathway-based analysis of geneexpression data, linkages to external systems for analysis of toxicity pathways, and modules for the analysis of proteomic and metabolomic-metabonomic data. An application of ebTrack is presented that focuses on pathway analysis of gene expression after exposure to sulfur mustard (HD or SM)
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models of in vitro data on metabolism rates and partition coefficients (PCs) can potentially facilitate rapid construction of in vivo physiologically based pharmacokinetic (PBPK)
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Martin U.S. Environmental Protection Agency, Office of Research and Development, National Center for Computational Toxicology, Research Triangle Park, NC The Food Quality Protection Act of 1996 mandates that the U.S.
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Environmental Protection Agency and approved for publication, it may not necessarily reflect official agency policy. Physiologically based pharmacokinetic and pharmacodynamic model of 4-hydroxyphenylpyruvate dioxygenase inhibition by mesotrione David Kim and Timothy Pastoor Syngenta Crop Protection, Greensboro, NC Purpose: Mesotrione, a member of the triketone family, is a selective herbicide used in the control of broad-leaf weeds.
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From page 107... ...
Environmental Protection Agency, Office of Research and Development, National Center for Computational Toxicology, Research Triangle Park, NC; 2 Lockheed Martin, contractor to the National Center for Computational Toxicology, Research Triangle Park, NC Standard practice in prenatal developmental toxicology involves testing chemicals in pregnant laboratory animals of two species, typically rats and rabbits, that were exposed during organogenesis and evaluating for fetal growth retardation, structural malformations, and prenatal death just prior to term. Phenotypic heterogeneity that often follows from disruption of molecular function, cellular processes, and signaling pathways in the embryo poses a major challenge to understanding mechanisms.
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From page 108... ...
Environmental Protection Agency and approved for publication but does not necessarily reflect official agency policy. Dose-response pathway analysis for gene-expression microarrays Zhen Li,1,2 Ivan Rusyn,2,3 and Fred A
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Environmental Protection Agency, National Center for Computational Toxicology, Office of Research and Development, Research Triangle Park, NC The U.S. Environmental Protection Agency (EPA)
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Disclaimer: Although this work was reviewed by the U.S Environmental Protection Agency and approved for publication, it may not necessarily reflect official agency policy. Computational xenobiotic metabolism prediction system for toxicity assessment Fangping Mu and Helen H
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From page 111... ...
. We describe a methodology to evaluate the fundamental shape of the dose-response curve to determine whether there is nonrandom biological activity below the toxic threshold (Calabrese et al.
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Wolf1 1 U.S. Environmental Protection Agency, National Heath and Environmental Effects Research Laboratory, Research Triangle Park, NC; 2National Taiwan University, Department of Agricultural Chemistry, Taipei, Taiwan Conazoles are a common class of fungicides used to control fungal growth in the environment and in humans.
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From page 113... ...
We performed both dose-response and time-course studies in mice to develop and characterize key events in the MOA that can describe the propiconazole-induced carcinogenic process. These studies provided data on the following series of key events in the carcinogenic MOA of propiconazole: nuclear receptor activation, CYP induction, decreases in hepatic retinoic acid levels, increased oxidative stress, decreases in serum cholesterol levels, increases in mevalonic acid levels, increased cell proliferation, decreased apoptosis, and induction of in vivo mutagenicity.
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From page 114... ...
Those key events were organized into a hypothesized MOA that explains the tumorigenic response to propiconazole. The EPA cancer risk assessment guidance was used to integrate genomic data into the risk assessment.
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From page 115... ...
. The human exposure concentrations of 132, 231, 350, 647, and 1,011 ppm provided the same brain-cell concentrations at steady state as the in vitro concentrations of 5.64 µM (no-observed-adverse-effect level)
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From page 116... ...
Environmental Protection Agency, National Center for Computational Toxicology, Research Triangle Park, NC Determining the toxic potential and mode of action (MOA) of environmental chemicals is a cost- and labor-intensive endeavor that has traditionally involved the use of laboratory animals.
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From page 117... ...
The ability to define mechanisms of action has also been demonstrated in profiling a group of non-steroidal antiinflammatory drugs. When the biologically rich data are used, key signaling pathways are flagged that define the mechanisms of action that are responsible for potential toxic liabilities and adverse events.
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From page 118... ...
Environmental Protection Agency, National Center for Environmental Assessment, Office of Research and Development, Washington, DC Exposure to a toxic chemical is often reflected in the perturbation of several cellular events in which biochemicals of a given metabolic pathway are upregulated, downregulated, or unaffected. Cellular responses exhibited by both experimental animals and humans to toxic exposure are complex, but they undergo similar types of metabolic change that lead to adverse outcomes.
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From page 119... ...
In conclusion, there are many opportunities to incorporate knowledge from multiple disciplines that could be used to reduce uncertainty in the risk assessment of formaldehyde and leukemia. Disclaimer: The views expressed are those of the authors and do not necessarily reflect the views, policies, or endorsement of their affiliated institutions, the National Cancer Institute, or the U.S.
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