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(ARE/EpRE). Transcription factor Nrf2 is essential for the coordinated induction of cellular defense enzymes through ARE/EpRE. Detailed analysis of the regulatory mechanisms governing Nrf2 activity led to the identification of Keap1 that represses the Nrf2 activity by binding to the N-terminal Neh2 domain. Electrophiles liberate Nrf2 from the repression by Keap1 and provoke the nuclear accumulation of Nrf2, demonstrating that the Nrf2-Keap1 system acts as a sensor for xenobiotic and oxidative stress. The two-site substrate recognition model proposed for the Keap1-Nrf2 system describes the regulation of nuclear accumulation of Nrf2 by a Cul3- Keap1 E3 ubiquitin ligase-dependent mechanism. We have tested this model through structure biology, mouse/zebrafish genetics and human cancer analyses. Keap1 forms homodimer resembling a cherry-bob. The Keap1-DC domain binds to the Neh2 domain of Nrf2. Binding of both high affinity ETGE and low affinity DLG motifs in the Neh2 to two DC domains of the Keap1 homodimer allows correct positioning of the ubiquitin-target lysine residues within α-helix of the Neh2 domain for efficient ubiquitination. Oxidative or electrophilic stress modifies reactive cysteines of Keap1. We surmise that these modifications lead to alteration of the local conformation and result in the Keap1 dysfunction. The Nrf2 inducers can be categorized into several classes based on the interacting cysteine residues, and this observation suggests that multiple sensor functions reside within Keap1. The Nrf2- Keap1 system opens a new avenue to the understanding of the signal transduction and regulatory processes underlying the stress response and cancer progression. 1788 NRF2 IN TOXICOLOGY: FROM MONOFUNCTIONAL INDUCERS TO THERAPY. C. D. Klaassen. Pharmacology, University Kansas Medical Center, Kansas City, KS. In the late 1980s, Paul Talalay pioneered the idea that some inducers had little effect on phase-I enzymes but induced phase-II enzymes. In retrospect, this concept of monofunctional inducers explained many confounding results in toxicology, such as the protective effect of butylated hydroxyanisole against acetaminophen hepatotoxicity and the observation that oltipraz diminished aflatoxin-induced carcinogenicity. In 1990, Cecil Pickett’s group reported that induction of glutathione S-transferases (GSTs) was dependent on an antioxidant response element (ARE) found in genes, and in 1997 Yamamoto and colleagues discovered that Nrf2 was the transcription factor necessary for the induction. Thus, many monofunctional inducers are now referred to as Nrf2 activators, which induce genes containing AREs. Our work on Nrf2 began in the late 1980s when Jie Liu came to my laboratory from China with several compounds extracted from Chinese herbal medicines. He tested 16 of these chemicals for hepatoprotective effects and determined one chemical, oleanolic acid, was the most effective. In fact, oleanolic acid protected against nine different hepatotoxicants with seemingly different pathways of producing toxicity. Michael Sporn and his group synthesized many derivatives of oleanolic acid, and eventually 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO- Im) emerged as the most potent derivative. We now know that Nrf2 activators increase not only the GSTs and other phase-II enzymes, but also glutathione synthesis enzymes, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, microsomal epoxide hydrolase, and various enzymes that detoxify reactive oxygen species, all of which cumulatively produce robust anti-oxidant and anti-inflammatory effects. Thus, it is not surprising that activators of the Nrf2 pathway, like oleanolic acid, can protect against the toxicity of many chemicals. It is interesting to note that another derivative of oleanolic acid (CDDO-Me, bardoxolone methyl) is in Phase 2 clinical trials as an activator of the Nrf2 pathway for the treatment of chronic kidney disease in diabetic patients. (NIH DK-081461) 1789 NRF2: NOT JUST FOR PHASE 2 ENZYMES ANYMORE. T. W. Kensler 1, 2 . 1 Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA and 2 Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. Evaluation of the role of the Nrf2 signaling pathway on cytoprotection has focused predominantly on the regulation of phase 2 enzymes involved in the detoxication of toxins and their reactive intermediates such as glucuronosyl transferases and glutathione transferases. While these enzymes are important modifiers of toxicological responses, recent evidence highlights a much broader role for Nrf2-regulated genes in promoting cell survival. Not only is the detoxication of reactive oxygen and electrophilic metabolites enhanced, but so are mechanisms for the recognition, repair or removal of damaged macromolecules through up-regulation of nucleotide excision repair and proteasome systems. Moreover, a link to facilitated tissue repair has been observed with the observation that Nrf2 regulates the expression of Notch1, a transcription factor influencing stem cell fate. This presentation will discuss the expanding role of the Nrf2 pathway as an adaptive stress response against reactive intermediates and their macromolecular damage, and for promoting tissue repair and regeneration. 384 SOT 2011 ANNUAL MEETING 1790 GAIN OF NRF2 FUNCTION AS A TARGET FOR ANTICANCER THERAPY? S. Biswal and A. Singh. Johns Hopkins University, Baltimore, MD. Sponsor: D. Zhang. Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it for proteasomal degradation. We recently reported that NRF2-KEAP1 interactions are deregulated in lung cancer (mostly adenocarcinomas) and prostate cancer, through a variety of complementary mechanisms. Somatic alterations in Keap1 gene were detected in a high percentage of the cancer cell lines and primary lung and prostate tumors. In addition to mutations, we found novel transcriptional and post transcriptional mechanisms of KEAP1 inactivation such as promoter methylation and aberrant splicing. Silencing of Nrf2 expression, by constitutive expression of short hairpin RNA targeting Nrf2 in lung and prostate cancer cells, induced generation of ROS, suppressed tumor growth and resulted in increased sensitivity to chemotherapeutic drug-induced cell death in vitro and in vivo. Gain of NRF2 function in cancer cells also confers radioresistance. Furthermore, KEAP1 inactivation accelerates oncogenic K-RAS-induced lung tumorigenesis whereas loss of NRF2 function suppresses K-RAS driven lung tumor growth in mice models. Preliminary studies have indicated that high NRF2 activity in cancer cells upregulates the glucose flux through central pentose phosphate pathway and tricarboxylic acid cycle leading to increased ribose synthesis, de novo fatty acid synthesis, and energy metabolism, which in turn promotes cellular proliferation and tumorigenesis. This presentation will focus on presenting evidence that gain of NRF2 function in cancer helps tumor cells to exploit the NRF2 dependent cytoprotective and metabolic pathways for maintaining their tumorigenic potential and survival against cytotoxic chemotherapeutic agents and radiation therapy. (This work was supported by NIH grants P50CA058184, P30ES038819, R01CA140492 and FAMRI) 1791 GETTING CAUGHT IN THE WEB OF NRF2. D. D. Zhang. Pharmacology and Toxicology, University of Arizona, Tucson, AZ. During the last couple of years, crosstalk between the Nrf2 pathway and other important pathways has emerged. Our group has identified two separate branches that converge with the Nrf2 pathway, the p53-p21(Cip1/WAF1) pathway and the autophagy pathway. Crosstalk is mediated by the direct interaction between p21 and Nrf2, and Keap1 with p62, respectively. This presentation will consist of two parts. In part 1, I will present molecular and genetic evidence suggesting that the previously suggested antioxidant function of p53 or p21 is mediated through activation of the Nrf2 pathway. Mechanistically, p21 is able to stabilize Nrf2 by competing away Keap1, thus, activating the Nrf2-mediated antioxidant response. Therefore, the interaction between Nrf2 and p21 represents a fine-tuning mechanism between life and death according to the level of stress. In part 2, a novel mechanism of Nrf2 activation by autophagy deficiency through a direct interaction between Keap1 and p62 will be presented. In response to stress, cells can utilize several cellular processes, such as autophagy, a bulk-lysosomal degradation pathway, to mitigate damages and increase the chances of cell survival. Deregulation of autophagy causes upregulation of p62 and the formation of p62-containing aggregates, which are associated with neurodegenerative diseases and cancer. Accumulation of endogenous p62 or ectopic expression of p62 sequesters Keap1 into aggregates, resulting in the inhibition of Keap1-mediated Nrf2 ubiquitination and its subsequent degradation by the proteasome. In contrast, overexpression of mutated p62, which loses its ability to interact with Keap1, had no effect on Nrf2 stability, demonstrating that p62mediated Nrf2 upregulation is Keap1-dependent. These findings demonstrate that autophagy deficiency activates the Nrf2 pathway in a non-canonical cysteine-independent mechanism. 1792 APPROACHES FOR INCORPORATING NON- CHEMICAL STRESSORS INTO CUMULATIVE RISK ASSESSMENTS. C. V. Rider 1 and J. Simmons 2 . 1 Toxicology Branch, NIEHS-NTP, Research Triangle Park, NC and 2 Pharmacokinetics Branch, ISTD, NHEERL, ORD, U.S. EPA, Research Triangle Park, NC. Realistic human exposures are comprised of multiple chemical as well as non-chemical stressors. Non-chemical stressors, such as poor diet and physiological or psychological stress, often elicit adverse effects by targeting the same signaling path-
ways as chemical stressors and, therefore, have the potential to significantly modify our responses to chemical exposures. In recent years, regulatory agencies have emphasized the need for conducting cumulative risk assessments in order to account for real-world, multi-chemical exposure scenarios; however, the incorporation of non-chemical stressors into these cumulative risk assessments represents a novel and complex challenge. Development of a systematic approach for assessing the joint action of chemical and non-chemical stressors is needed in order to prioritize nonchemical stressors for inclusion in cumulative risk assessments, determine the type of data needed to incorporate non-chemical stressors, and develop methods for assessing their contribution to overall risk. We will highlight key issues in order to provide a rational starting place for moving forward. Therefore it is important to put this issue in context, describe data needs, and propose methods for incorporating nonchemical stressors into cumulative risk assessments. Participants represent perspectives from regulatory agencies, industry, non-profit, and academia. 1793 CURRENT REGULATORY PERSPECTIVE ON INCORPORATING NON-CHEMICAL STRESSORS INTO CUMULATIVE RISK ASSESSMENTS. M. M. Mumtaz. Computational Toxicology and Methods Development Laboratory, ATSDR, Atlanta, GA. The global risk assessment community, most recently, is trying to address concerns regarding climate change and a gamut of stressors that could impact human populations and ecological systems. The U.S. Congress has passed several laws that mandate federal agencies to perform cumulative risk assessment (CRA) thus recognizing population vulnerability factors (such as diet, behaviors, genetic traits, economic status) and social characteristics as important issues to be considered in health risk assessment. As practiced, CRA is an analysis, characterization, and possible quantification of the combined risks to human health or the environment from multiple agents or stressors. CRA provides the integrating foundation for linking chemical agents or stressors across space and time. It utilizes a population perspective, incorporating vulnerability factors (i.e., susceptibility/sensitivity and differential exposure, preparedness and ability to recover) into the assessment. To address multiple stressors and complex exposure scenarios, CRA will need to use advanced risk assessment methods: kinetic models to assess target tissue dose; extrapolations of risks across doses, species, and routes; and assessment of multiple effects to account for both primary and secondary adverse health effects. Often, the lack of toxicological data reporting that leads to an inability to identify “common metrics” is the key limiting factor to performing cumulative risk assessment of multiple stressors. A perspective on the concepts/methods of CRA including the integration of stressor/chemical interactions with vulnerability factors will be presented. 1794 A CONCEPTUAL FRAMEWORK FOR CHARACTERIZING FACTORS THAT INFLUENCE EXPOSURES TO CHEMICAL AND NON-CHEMICAL STRESSORS. P. S. Price. Toxicology & Environmental Research & Consulting, The Dow Chemical Company, Midland, MI. All communities are exposed to multiple stressors. Characterizing the magnitude of the stressors and their cumulative impact presents major challenges to the exposure assessor. Individuals’ exposures to chemicals are known to vary over time (longitudinal variation) and to vary from individual-to-individual (interindividual variation). Non-chemical stressors can be expected to have similar levels of longitudinal and interindividual variation. In addition, vast amounts of data on a community (demographics, economics, meteorology, geography, etc.) are often available but the value of the data and how it can be best used to predict the occurrence and intensity of stressors is unclear. To address these challenges, we propose to extend a system developed for categorizing data on the relationships between individual and community characteristics and chemical stressors (LifeLine, 2005) to non-chemical stressors. This system, 1) organizes individuals’ and the community’s characteristics into six categories, fixed, progressive, episodic, cyclic, and ephemeral, and 2) defines how each of the six types of variation influences other types and ultimately the patterns of individual’s exposure. Once organized, the factors can be used to assist in the analysis of temporal, geographic, and demographic patterns of stressors and adverse effects in a community. More importantly, this system can be used in the development of person-oriented models (POM) of stressors (Price and Chaisson, 2005). Such models can be used to integrate data from diverse sources in a transparent and internally consistent manner to clarify associations, make predictions of causation, and develop strategies for mitigation. 1795 ISSUES WITH QUANTIFICATION OF THE JOINT IMPACT OF CHEMICAL AND NON-CHEMICAL STRESSORS FOR ENVIRONMENTAL HEALTH RISK ASSESSMENT. R. C. Hertzberg. Biomathematics Consulting, Atlanta, GA. Sponsor: C. Rider. The joint impact of exposure to chemicals and nonchemical stressors is complicated by both a lack of consistent exposure metrics and lack of quantitative exposure-response relationships. Many nonchemical factors are known to impact health, although often with rough descriptions. Heat impairs judgment, socioeconomic status affects psychological stress, and vibration alters cardiovascular function. In addition, some evidence of interactions exists, including noise and solvents jointly affecting hearing, chemical exposure affecting susceptibility to disease, and anxiety enhancing chemical toxicity. Potential exists for adapting approaches for chemical mixtures, including weight-of-evidence categories, hazard ranking formulas, and the Superfund hazard index. Ways of expressing known or suspected nonchemical exposures in quantitative terms will be explored, and some commonly used joint toxicity approaches and formulas will be discussed in terms of implications for toxicologic interaction. Examples will represent environmental and occupational scenarios. 1796 COMPARATIVE DIETARY RISK ASSESSMENT: AN ALGORITHM WITH INCORPORATION OF CULTURAL BENEFITS OR STRESSORS. M. L. Dourson. Toxicology Excellence for Risk Assessment (TERA), Cincinnati, OH. Analyses of fish throughout the United States confirm the presence of chemical contaminants. In many cases the concentrations of these contaminants have been high enough to warrant the posting of fish consumption advisories by state and local authorities. In virtually all cases, these advisories are based solely on the potential adverse effects posed by the contaminants in fish. Yet medical practice and recent publications suggest that the health benefits of eating—-even contaminated—-fish may outweigh the potential risks caused the by the presence of these contaminants. Furthermore, cultural and personal perceptions affect the choice of fish in our diet. A framework for comparing the risks from chemical contaminants in fish, the health benefits from fish consumption, and the cultural and personal perceptions in fish consumption choices is proposed. Data limitations and assumptions used to develop the framework are highlighted. 1797 EXTENDING PULMONARY TOXICITY FINDINGS FOR NANOMATERIALS. D. Warheit 2 and P. Sayre 1 . 1 U.S. EPA, Washington, DC and 2 DuPont, Providence, RI. As the diversity of manufactured nanomaterials continues to increase, associated exposures may pose concerns for human health. Subchronic inhalation studies are often needed to evaluate the possible effects related to longer-term inhalation exposures. However, since all nanomaterials cannot be tested in this manner, additional methods need to be developed for use by industry screening at the research and development phase, and/or for regulatory review as part of a commercial submission. One such method is to consider extending the pulmonary toxicity findings from one material within a class of nanomaterial types to other materials within that same class. This may not be possible for the majority of eclectic particle-types within most nanoscale-related categories. However, there exists well-developed pulmonary toxicity testing data for two classes of materials—those for nano titania and multi-walled carbon nanotubes (MWCNTs). The hazard data were generated for these two classes by utilizing standardized regulatory guideline methodologies, which make such predictions for closely-related materials approachable. Additional methodologies which may facilitate broader-based conclusions or assist in screening include use of other in vivo-based testing approaches such as those involving shorter-term inhalation, or aspiration/intratracheal instillation protocols. We will highlight different perspectives, consistent with our panel of experts diverse backgrounds which are needed to address this complex need. In addition, we will offer the latest findings on the pulmonary toxicity of nano titania and MWCNTs. In addition, viewpoints will be offered on how generalizable the findings are to other types of titania and MWCNTs, given differing physicochemical properties, methods of particle generation and delivery, and current perspectives on modes of actions. Insights will be presented on how such data can be utilized in applications such as pre-screening, and establishment of protective levels for workers. We believe that the dialogue between the panelists and the audience will facilitate the identification of areas of agreement, and key information needs, in order to further develop these approaches. SOT 2011 ANNUAL MEETING 385
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The Toxicologist Supplement to Toxi
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The Toxicologist Supplement to Toxi
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1 BIODEGRADABLE MATERIALS FOR TISSU
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that genetic toxicology data are ge
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well-orchestrated lung inflammation
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scribed in the literature. We have
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years ago). We will illustrate how
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involved in the biodegradation proc
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stem cells but rather a treatment i
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additional compound showed agreemen
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82 COMPARISON OF 3H-THYMIDINE INCOR
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irritants. While in practice these
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alleles are especially vulnerable t
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109 CD4+ T CELL INTRINSIC TNF RECEP
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118 TO STUDY THE SIGNAL TRANSDUCTIO
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PAHs, such as dioxins, are prevalen
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containing substituents and/or hydr
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146 COMPUTATIONAL MODELING FOR QT P
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suggest that the combination of too
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164 TRANSLOCATOR PROTEIN (18 KDA) (
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function as a metal binding protein
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laboratory has demonstrated that NR
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known. The aim of this study was to
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from 5 to 28 days in duration) in e
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positive cells, caspase-3 activatio
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creased level in the 46 kDa preproe
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invasiveness at concentrations repr
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thracene (DMBA,50 μg in acetone, a
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247 CO-CARCINOGENESIS OF N, N- DIET
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sponds to the endosomal dsRNA that
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ODD in both WT (maximum 177% of con
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Lastly, using p53siRNA cells, p53 w
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its receptor Mpl to exert its funct
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294 LOW LEVEL OF LEAD CAN INDUCE PH
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lunar surface presented potential h
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lar about cellular export mechanism
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DNA in the kidney medulla, grandula
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5.00 and 7.50 mg/kg/day by oral gav
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events and carcinogenesis. Here we
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tinization of cells of the hair fol
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358 CHARACTERIZATION OF GENOME-WIDE
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RNAi were also performed to identif
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376 A FUNCTIONAL CROSSTALK BETWEEN
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UGT1A gene induction, while this re
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tivity, specifically peroxisome pro
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and cytotoxic effects; however, its
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histone deacetylase that is necessa
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ment. Paradoxically, buthionine sul
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drug leflunomide and its major (A77
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442 GENE EXPRESSION AND MORPHOLOGIC
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451 INHIBITION OF THE MITOCHONDRIAL
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460 SULFORAPHANE PREVENTS ACETAMINO
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drophilic/lipophilic balance. Other
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pharmacokinetic and toxicological p
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489 USE OF ‘OMICS DATA TO IMPROVE
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498 APPLICATION OF AGE-SPECIFIC ADJ
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507 A DOSE VOLUME TOLERABILITY STUD
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involved the use of an acute inflam
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sorption in the gastrointestinal (G
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(ABC) transporters actively transpo
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545 BEHAVIORAL EFFECTS OF REPIN IN
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a blood pressure phenotype that res
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and inhalation exposure system that
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and lethality associated with these
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position, on vascular reactivity an
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therefore more accurate and reprodu
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commercial chrysotile product that
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elative to their controls. ST-depre
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ats. The majority of the studies fo
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in the China Jintan Child Cohort St
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corneum thickness, cellular epiderm
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645 EVALUATION OF THE IN VITRO EPIS
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654 TCDD ADSORBED ONTO NATURAL AND
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tion revealed no test article-relat
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671 INFLAMMATION AND TISSUE DAMAGE
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model, ethanol was found to inhibit
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689 ENHANCED SUPPRESSIVE FUNCTION O
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NAC + LPS yielded different levels
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707 LIFE-STAGE PBPK MODELS FOR MULT
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downstream of the apical endpoint o
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726 UPDATED ALUMINUM PHARMACOKINETI
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global parameter sensitivity analys
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and renal inflammation induced by 2
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754 PLASMA, URINE, AND TISSUE CONCE
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cently characterized transporter OA
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exposure system was developed from
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lood cell mass and decrease in urin
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practical alternatives to MC in non
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imals dosed with 167 mg/kg THU alon
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and organ weights, clinical signs a
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yet is induced in most bladder and
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830 RISK ASSESSMENT OF THE SPILL: C
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knowledgebase creation. Results are
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852 UNDERSTANDING STRUCTURAL AND PH
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for integrating epidemiology and an
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motor activity, including age of th
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y partial purification of urine (fr
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pacity for self-renewal and may dif
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sue. The depth of our analysis led
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910 IMPLEMENTING CALIFORNIA’S GRE
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concentrations in six tissues and b
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934 THE FDA’S LIVER TOXICITY KNOW
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943 GENOME-WIDE DNA METHYLATION DIF
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membrane localization and subsequen
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trols, respectively. Subtoxic and t
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survival using both smoking regimes
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as non-, weak, moderate, or strong
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988 NNK-INDUCED CYTOKINE ALTERATION
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group (one-way ANOVA, p90 % viabili
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ered as an organ involved in xenobi
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Transport of CPZ across the Caco-2
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estrous cycle and sexual behavior d
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mRNA expression levels. Collectivel
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1043 THE EFFECTS OF ENDOCRINE DISRU
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1052 MONO-2-ETHYLHEXYL PHTHALATE IN
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Results: MC was variable within and
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UtSMCs. Phosphorylation of FoxO1 wa
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nonpregnant and pregnant diabetic m
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1089 PFOA-INDUCED LIVER EFFECTS IN
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events in the liver. AZD9056 was ev
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The peppermint oil caused a concent
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OA did not affect food consumption.
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1126 PERSISTENT DEVELOPMENTAL ARYLH
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1135 BACH2 BINDING TO Prdm1 AS A ME
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The purpose of this project was to
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one marrow. Since Chk1 is an attrac
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1163 THE MRNA AND MIRNA PROFILE OF
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have now compared the IC50 values b
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1181 ELUCIDATION OF FACTORS DETERMI
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enced by pre-exposure to cigarette
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if abnormal PF was associated with
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weight (P=0.016) and small for gest
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portant cause of death, compared to
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posure groups. However, the differe
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Naphthalene is routinely analyzed i
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1245 SEASONAL CHARACTERIZATION OF H
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1255 URINARY T, T MUCONIC ACID LEVE
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modating a reliable data evaluation
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enzoquinone generate ROS and arylat
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teins (e.g. C3, 4, and 5, APOB, VDB
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1293 TRANSFORMING GROWTH FACTOR BET
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mation was decreased to the same le
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1312 EVALUATION OF THE SENSITIVITY
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luted OFR and CRL. Culture media ex
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urinary TCPy levels, blood and brai
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activity. The dose-response curves
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mice, each with 4 dose groups. One
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exposure to both ATR and DACT has a
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third tetratricopeptide repeats (TP
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7d. 28d after TMT injury there was
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subunits. Each cell type was treate
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1394 COMPARATIVE EFFECTS OF METHYLM
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1403 GENOTOXICITY AND PRE-NEOPLASTI
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vated only in high-dose-treated ani
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1421 DOSE-RESPONSE OF NAPHTHALENE-I
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cisplatin; 1.2-, 1.9- and 2.9-fold
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Day 11 and started to recover on Da
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1448 DEVELOPMENT OF A METHOD FOR QU
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1457 GLOBAL GENE PROFILING REVEALS
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cluding mouse and human macrophage,
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model of lung inflammation and host
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1484 NANOTOXICOLOGY AND NANOHEALTH
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throughput in vitro approach was us
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1502 IMMUNOLOGICAL ASPECTS OF AN AN
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(CIA) and the Streptococcal cell wa
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sitizers were 100% concordant among
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1530 MINIMAL RISK LEVELS FOR STYREN
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ical groups in the field of regulat
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2029 EFFICACY OF ENDOTRACHEAL ADMIN
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Diazepam injections and its combina
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2047 ESTERASE ACTIVITIES AND HEMOST
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nanoparticle-induced toxicity progr
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house, were iv infused into rats ov
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een explored. This study investigat
Page 451 and 452:
croscopic analysis revealed that on
Page 453 and 454:
egg yolk collected from turtles inh
Page 455 and 456:
consistency of results in both expe
Page 457 and 458:
2111 CYTOCHROME P450 3A5 GENOTYPE I
Page 459 and 460:
esidues of organophosphates or thei
Page 461 and 462:
manganism. Recent work from our lab
Page 463 and 464:
Aβ1-40 in CSF and hippocampus in P
Page 465 and 466:
2147 CATALASE MANIPULATIONS MODIFY
Page 467 and 468:
ation based on real-world exposure
Page 469 and 470:
NPs. Aggregation of citrate-stabili
Page 471 and 472:
2175 THE ROLE OF SURFACE CHEMISTRY
Page 473 and 474:
seen rapid uptake in biological ima
Page 475 and 476:
effect on uterine weight or vaginal
Page 477 and 478:
dicating widespread exposure. While
Page 479 and 480:
components into the liver parenchym
Page 481 and 482:
2223 ISOLATION AND DETECTION OF RIC
Page 483 and 484:
stored (-20 celsius degree). The co
Page 485 and 486:
2241 DDA, A BIOMARKER FOR ENVIRONME
Page 487 and 488:
2249 INTERACTION BETWEEN DIETARY SE
Page 489 and 490:
2258 PHARMACOKINETICS, EXCRETION BA
Page 491 and 492:
2267 SENSITIVE AND SPECIFIC FLUORES
Page 493 and 494:
2276 METABOLISM AND DISPOSITION OF
Page 495 and 496:
ment of hypertension in companion a
Page 497 and 498:
for the propyl series can be used f
Page 499 and 500:
2304 IN VITRO EXPOSURE AND EVALUATI
Page 501 and 502:
2313 THE SYNERGISTIC EFFECT OF SODI
Page 503 and 504:
genes that play a crucial role in M
Page 505 and 506:
2330 THE ROLE OF TRANSFORMING GROWT
Page 507 and 508:
ined following up to 96 h continuou
Page 509 and 510:
effect doses obtained with the rat
Page 511 and 512:
diated transcriptional response of
Page 513 and 514:
docrine disruptor activities of EDC
Page 515 and 516:
individuals. Week 6 results were qu
Page 517 and 518:
functionality of photosystem II and
Page 519 and 520:
wild mice (Mus musculus) from areas
Page 521 and 522:
2406 TOXICITY AND BIOACCUMULATION O
Page 523 and 524:
Isocitric acid is the acid in the h
Page 525 and 526:
2425 EFFECTS OF FUMONISINS IN ETHAN
Page 527 and 528:
centration(μg/g) were: 5.1-95.3; 2
Page 529 and 530:
2445 AUTOPHAGY IN DEVELOPMENT: A LI
Page 531 and 532:
sures to inhaled Mn in dust. Nevert
Page 533 and 534:
2466 CRITICAL EVALUATION OF ANIMAL
Page 535 and 536:
elationships predict that resting r
Page 537 and 538:
2489 COMPARATIVE TOXICITY OF BIODIE
Page 539 and 540:
2497 TRANSCRIPTIONAL REGULATION OF
Page 541 and 542:
2506 TOXICOLOGICAL CONSIDERATIONS O
Page 543 and 544:
launched with the aim of developing
Page 545 and 546:
forms mRNA expression levels were a
Page 547 and 548:
2534 CUTANEOUS WOUND HEALING IN THE
Page 549 and 550:
wells (0, 1, 5, 10, 25, 50, 100, an
Page 551 and 552:
2553 AN ORGANOTYPIC MICROLIVER PLAT
Page 553 and 554:
serum-free media. At 24 hrs, the gr
Page 555 and 556:
2572 INCREASED ARSENIC BIOACCESSIBI
Page 557 and 558:
nology to develop improved methods.
Page 559 and 560:
tuna, swordfish, or mako shark (3.5
Page 561 and 562:
nificantly reduce circulating thyro
Page 563 and 564:
grouped into 9 observation periods
Page 565 and 566:
histopathological or biochemical ev
Page 567 and 568:
exhibited a hyperactive phenotype,
Page 569 and 570:
the search of effective drugs for e
Page 571 and 572:
2644 COVALENT BINDING OF 14 C 2-MET
Page 573 and 574:
aries targeting all transcription f
Page 575 and 576:
(p 9 weeks) and CSC phenotype acqui
Page 577 and 578:
2673 IMMUNE-MEDIATED VASCULAR INJUR
Page 579 and 580:
for risk identification and charact
Page 581 and 582:
to control toxicant delivery in tob
Page 583 and 584:
Author Index (Continued) The numera
Page 585 and 586:
Page 587 and 588:
Page 589 and 590:
Page 591 and 592:
Page 593 and 594:
Page 595 and 596:
Page 597 and 598:
Page 599 and 600:
Page 601 and 602:
Page 603 and 604:
Page 605 and 606:
Page 607 and 608:
Page 609 and 610:
Page 611 and 612:
Keyword Index (Continued) Arsenite
Page 613 and 614:
Keyword Index (Continued) Covalent
Page 615 and 616:
Keyword Index (Continued) flow cyto
Page 617 and 618:
Keyword Index (Continued) innate im
Page 619 and 620:
Keyword Index (Continued) nanoparti
Page 621 and 622:
Keyword Index (Continued) preservat
Page 623 and 624:
Keyword Index (Continued) Thrombocy
Page 625 and 626:
Toxicological Sciences The Official
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