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concentrations in plasma or liver tissue. This two compartment model was compared with a 10-compartment model composed of 5 sequential blood compartments each connected to a liver tissue compartment. Gor some compounds the two models gave very similar results, but differences were observed for compounds with high active uptake. The multicompartment liver model is an approximation for the dispersion or tube models. The majority of the analyses have been for published human intravenous plasma profiles, but modeling for the rat has been completed for a more limited set of compounds. In addition to modeling the in vivo data to obtain estimates for the various processes, in vitro data from human liver microsomes and sandwich cultured hepatocytes have been used. Comparisons of predictions for plasma concentration profiles based upon in vitro results have been made to estimate in vitro to in vivo extrapolation factors. The in vitro to in vivo extrapolation factors vary for the different processes being scaled. The analyses demonstrate the value of capturing mechanistic biological processes in pharmacokinetic modeling to improve the ability to predict pharmacokinetic disposition. 939 A NOVEL PREDICTIVE PLATFORM FOR DILI: A COMBINATION OF IN SILICO AND IN VITRO METHODS TO PREDICT TOXICITY MECHANISMS IN VIVO. S. Das, R. Kumar, S. Raghavan and K. Subramanian. Strand Life Sciences, Bangalore, India. Prediction of hepatotoxicity is still a challenge in the drug development process. Currently available methods are inadequate both for extrapolation of rodent information to humans as well as in predicting the likelihood of idiosyncratic liver injury. Species used in preclinical toxicity do not usually possess underlying aberrations leading to idiosyncratic toxicity observed in humans in the clinic. We have developed a dynamic systems model of the rat liver to predict DILI. The metabolic network modeled integrates the biology behind different types of drug induced toxicity. Important biological processes involved in fat metabolism (steatosis), energy homeostasis (necrosis), oxidative stress (oxidative damage) are modeled quantitatively. A set of differential equations predict changes in metabolite concentrations The model was first validated by comparing model predictions under conditions of normal liver homeostasis and DILI with observations published in the literature. We then used the model to generate hypotheses for the mechanism behind idiosyncratic toxicity caused by the anti-diabetic drug troglitazone. Sensitivity analysis of the metabolic network identified a set of enzymes that are predicted to be key players in causing different types of DILI. In vitro measurements of these enzyme rates, using a primary hepatocyte system, in absence and presence of well-known hepatotoxic drugs, are used as input to the model. Model simulated outputs of toxicity for each drug matched well with the associated toxic phenotype reported in the literature. The validation of this combinatorial (in silico and in vitro) approach using known hepatotoxic drugs e.g. Diclofenac, Cyclosporin, Tamoxifen, etc. yielded additional novel mechanistic insights. The purpose of study is to develop a generalized liver toxicity prediction platform integrating in vitro and in silico approaches. Such an approach allows us to predict toxicity, generate mechanistic insights, and mechanism specific biomarkers. 940 APPLICATIONS OF A COMPUTATIONAL MODEL FOR PREDICTING DRUG INDUCED LIVER INJURY (DILI). B. A. Howell 1 , R. Kumar 3 , L. Wennerberg 3 , Y. Yang 2 , R. Ho 3 , A. Harrill 1 , C. L. Kurtz 1 , M. E. Andersen 2 , H. J. Clewell 2 , S. Q. Siler 3 and P. B. Watkins 1 . 1 Drug Safety Sciences, The Hamner Institutes, Research Triangle Park, NC, 2 Chemical Safety Sciences, The Hamner Institutes, Research Triangle Park, NC and 3 Entelos, Inc., Foster City, CA. Drug-induced liver injury (DILI) is the adverse drug event that most frequently leads to termination of clinical development programs and regulatory actions on drugs. We have developed a predictive model based on physiological processes involved in DILI, focusing initially on acetaminophen toxicity. A physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition and metabolism of APAP. Reactive metabolite production and subsequent covalent protein binding are characterized. Glutathione (GSH) depletion and synthesis, oxidative stress, mitochondrial dysfunction, and the cell life cycle, including regeneration and death, are modeled. The model accurately reproduced APAP pharmacokinetic measures and GSH depletion/recovery for rats, mice, and humans, and this explained much of the variation in species specific susceptibility to APAP induced DILI. In-depth comparisons were also made between rats and mice with regard to their ability to re-synthesize GSH after GSH depletion. The use of N-acetyl-cysteine (NAC) as a treatment for APAP overdose was incorporated into the model, and treatment times were analyzed and compared to standard clinical practices to predict optimal NAC use. Finally, the model was used to successfully predict the species differences in hepatotoxicity of methapyrilene using in vitro to in vivo ex- 200 SOT 2011 ANNUAL MEETING trapolation. The absorption, distribution, and metabolism of methapyrilene were estimated from the physical characteristics of the compound and in vitro metabolism. The model correctly predicted that rats would be less sensitive to acetaminophen than mice or humans, but most sensitive to methapyrilene. A parametric search for in silico rats, mice, and humans susceptible to methapyrilene DILI predicted that methapyrilene would cause very little hepatotoxicity in humans clinically. This finding agrees with clinical reports. 941 DEVELOPMENT OF A PBPK/PD MODEL FOR ACETAMINOPHEN TOXICITY IN RATS. Y. Yang, B. Howell, M. Yoon, M. Andersen and H. J. Clewell. The Hamner Institutes for Health Sciences, Research Triangle Park, NC. A whole-body physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for acetaminophen (APAP) and its metabolites in the rat was developed to quantitatively describe the processes that determine APAP hepatotoxicity. The key features of the model include metabolic activation of APAP by cytochrome P450s, detoxication of APAP via sulfate and glucuronide conjugation, and binding of the reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) to hepatic glutathione (GSH) and cellular macromolecules. Both sulfate and glucuronide conjugation was described using Michaelis Menten equations. Sulfation was modeled as a high affinity, low capacity pathway, while glucuronidation was described as a low affinity, high capacity pathway. A description of the depletion of the cofactor for sulfation (PAPS) and its precursor inorganic sulfate was required to properly simulate APAP-sulfate concentrations in the rat blood. Enterohepatic recirculation of the conjugates was also included. The net production of NAPQI is determined by the balance between the bioactivation via cytochrome P450s and the detoxification by conjugation with GSH. The model also describes the resulting depletion and recovery of GSH by incorporating a feed-back regulation of GSH synthesis. The model successfully simulated concentration-time profiles of APAP, sulfate and glucuronide conjugates of APAP after oral, intraperitoneal, and intravenous (iv) administrations ranging from 37.5 to 1000 mg/kg doses. The dosedependent changes in hepatic GSH concentrations after IV dose were also well described. This model will contribute to better understanding of the mechanism of APAP hepatotoxicity by providing a tool for predicting the time-course of reactive metabolite formation and glutathione depletion in studies measuring hepatic damage and repair. 942 USING ZEBRAFISH TO STUDY BENZO(A)PYRENE- MEDIATED CHANGES IN DNA METHYLATION STATUS DURING DEVELOPMENT. X. Fang 1 , C. Thornton 1 , B. E. Scheffler 2 and K. L. Willett 1 . 1 Department of Pharmacology and Toxicology, the University of Mississippi, University, MS and 2 Genomics and Bioinformatics Research Unit, USDA Mid South Area Genomics Laboratory, Stoneville, MS. DNA methylation is one of the epigenetic mechanisms to control gene expression and is vulnerable to in utero or early-life environmental toxicant exposures. Constitutively, we confirmed that zygote demethylation is conserved in zebrafish and characterized dynamic CpG methylation patterns in 5 genes (vasa, Ras-association domain family member 1 (RASSF1), telomerase reverse transcriptase (TERT), c-Myc and c-Jun). Direct waterborne benzo(a)pyrene (BaP) treatment at 100 μg/L from ~2 to 96 hours post fertilization (hpf) to zebrafish embryos significantly decreased global cytosine 5’ methylation by 55% and gene-specifically reduced promoter CpG methylation in vasa by 17.2%. Future study will measure the vasa mRNA expression to determine correlated altered expression. However, BaP did not change CpG island methylation in RASSF1, TERT, c-Myc and c-Jun at 96 hpf. To study the mechanisms of demethylaion, mRNA expression and enzyme activity of 2 methylation related enzymes, DNA methyltransferase 1 (DNMT1) and glycine N-methyltransferase (GNMT), were measured constitutively and after treatment. BaP exposure at 1, 10 or 100 μg/L did not change DNMT1 and GNMT mRNA expression at 48, 60 or 96 hpf or nuclear total DNMT and cytosolic GNMT enzyme activity at 96 hpf. In summary, BaP is a potential epigenetic modifier for global and gene specific DNA methylation status in zebrafish embryos and the alteration is possibly not mediated by affecting DNMT1 and GNMT expression. (Support: NIEHS R01ES012710).
943 GENOME-WIDE DNA METHYLATION DIFFERENCES BETWEEN LATE-ONSET ALZHEIMER’S DISEASE AND COGNITIVELY NORMAL CONTROLS IN THE HUMAN FRONTAL CORTEX. K. Bakulski 1 , D. C. Dolinoy 1 , M.A.Sartor 1 , H. L. Paulson 2 , A. P. Lieberman 2 , R. L. Albin 2 , H. Hu 1, 2 andL.S.Rozek 2 . 1 School of Public Health, University of Michigan, Ann Arbor, MI and 2 Medical School, University of Michigan, Ann Arbor, MI. Sporadic cases of late-onset Alzheimer’s disease (LOAD) are the most globally prevalent form of dementia, resulting in significant public health and economic burdens. Discordant twin studies highlight the non-Mendelian characteristics of LOAD and prompt a further look at its potential environmental etiology. Primate studies demonstrate early life exposure to the heavy metal lead influences brain βamyloid deposition, a major hallmark of Alzheimer’s disease (AD), as well as DNA methyltransferase activity in late life. This foundational human study investigates DNA methylation differences between LOAD cases and controls, so that future work may associate environmental exposures with LOAD-specific epigenetic change. In 24 human post-mortem frontal cortex tissues from LOAD and cognitively normal age- and gender-matched subjects, quantitative DNA methylation was measured at 27,578 CpG sites spanning 14,475 genes via the Illumina Infinium HumanMethylation27 BeadArray. Based on parallel linear models with empirical Bayes methods, 958 CpG sites representing 928 unique genes were significantly associated with disease status. The top gene hit was recently implicated in Amyloid Precursor Protein post-translational processing, supporting a role for epigenetic change in AD pathology. Over 3,500 CpG sites were associated with an age-specific epigenetic drift, highlighting the importance of age adjustment in statistical modeling of disease methylation in late life. Future studies will evaluate cumulative lead exposure, as determined by ICP-MS lead levels in the occipital bone, to investigate the association between lead and LOAD-specific epigenetic change as a potential toxicological mechanism of disease. In human, relevant LOAD-disease tissue, this study demonstrates significant discordant DNA methylation and invites additional research associating environmental exposures. 944 EPIGENETIC CHANGES DURING CO- CARCINOGENESIS OF N, N-DIETHYLNITROSAMINE AND CARBON TETRACHLORIDE IN MOUSE LIVER. K. Kutanzi 1 , I. Koturbash 1 , T. Uehara 2 , O. Kosyk 2 , I. Pogribny 1 and I. Rusyn 2 . 1 National Center for Toxicological Research, U.S. FDA, Jefferson, AR and 2 Department of Environmental Sciences and Engineering, UNC, Chapel Hill, NC. Global genomic hypomethylation and transcriptional silencing of cancer-related genes induced by promoter CpG island hypermethylation are important epigenetic events during human and rodent hepatocarcinogenesis. In human hepatocellular carcinoma, which develops mostly under conditions of liver fibrosis and cirrhosis, both global DNA methylation levels and gene-specific methylation status in tumorous and adjacent non-tumorous tissues have been established as important for tumor development and predictors of recurrence and overall patient survival. In animal models of experimental chemical-induced liver carcinogenesis, the role of fibrosis and epigenetic alterations is less understood. This study aimed to examine the epigenetic alterations caused by fibrosis and fibrosis-promoted tumor development in the mouse liver. Male B6C3F1 mice were treated with either a single dose (1 mg/kg) of N,N-diethylnitrosamine (DEN) or PBS at 15 days of age. Carbon tetrachloride (CCl4) treatment (0.2 ml/kg; i.p.; 2/week) was started at 8 weeks of age and continued for 9 or 14 weeks. CCl4 treatment led to a severe bridging fibrosis with nodule-like features, which was accompanied by liver inflammation and steatosis. DEN treatment resulted in few histopathological changes except for the formation of pre-neoplastic foci. Loss of global DNA methylation and methylation of the repetitive DNA elements (i.e., LINE-1) in non-tumorous liver tissue was observed in CCl4 and CCL4+DEN (22 weeks of age) groups. At the same time, methylation-specific PCR showed progressive hyper-methylation of the promoters of p16(Ink4a), Rassf1a and Mgmt genes. This study provides evidence that progressive liver fibrosis is not only acting as a tumor promoter after DEN-initiation, but also has an effect on epigenetic modifications of the DNA which may also play a role in the mechanism of chemical-induced liver carcinogenesis in the mouse. 945 AH RECEPTOR INHIBITS GENE EXPRESSION OF DELETED IN LIVER CANCER (DLC1) THROUGH REGULATION OF MICRORNA IN MOUSE LIVER CELLS. Y. Tian 1 , S. Ke 1 , M. Huang 2 , B. Zhou 1 and Z. Zhou 2 . 1 Program of Toxicology, Texas A&M University, College Station, TX and 2 School of Public Health, Fudan University, Shanghai, China. Dioxin and related compounds have been shown to promote hepatocarcinogenesis in rodent. Although the mechanism for the tumor promotion activity of dioxin is not clear, the activity is dependent on the aryl hydrocarbon receptor (AhR). MicroRNA, together with other non-protein coding RNA have recently been found to possess critical functions for physiological and pathophysiological processes including carcinogenesis. In order to understand the mechanism of cancer promotion by dioxin we analyzed microRNA profiles in the mouse hepatocytes exposed to dioxin (10 nM, 24 hr). By surveying the microRNA regulated by AhR, we have identified a novel AhR target DLC1 (deleted in liver cancer 1) whose expression was regulated at post-transcriptional level by AhR complex. We found that activation of AhR by TCDD significantly suppressed the mRNA of DLC1 which is critical for hepatocarcinogenesis. The inhibition of DLC1 expression by dioxin is mediated by the AhR complex as both AhR and the AhR partner protein ARNT were required for the suppression of DLC1 by dioxin. The 3’UTR of DLC1 harbors several target sites of dioxin-induced microRNA. The reporter gene directed by the 3’ UTR of DLC1 is responsive to dioxin treatment in a AhR-dependent manner. These results collectively suggest that DLC1 is an important target for ligand-activated AhR and AhR-regulated DLC1 gene expression may be important for the liver cancer promoting activity of dioxin and related toxic compounds (Supported in part by ES 09859 from NIEHS). 946 INTER-STRAIN DIFFERENCES IN SUSCEPTIBILITY TO 1, 3-BUTADIENE-INDUCED DNA DAMAGE, EPIGENETIC AFFECTS AND HEPATOTOXICITY. I. Pogribny 1 , K. Igor 1 , A. Scherhag 1 , J. Sorrentino 2 , S. Kennet 2 , W. Bodnar 2 , S. A. James 2 , B. A. Frederick 1 and R. Ivan 2 . 1 National Center for Toxicological Research, Jefferson, AR and 2 University of North Carolina, Chapel Hill, NC. 1,3-Butadiene (BD) is a major industrial chemical and a common environmental contaminant which is classified as carcinogenic to humans. Both genetic and epigenetic factors may influence individual susceptibility to environmental toxicants and it has been suggested that BD exposure may yield variable adverse health outcomes in humans. In order to model the inter-individual differences in genetic and epigenetic effects of BD, we used a panel of inbred mouse strains (NOD/LtJ, CAST/EiJ, A/J, WSB/EiJ, PWK/PhJ, C57BL/6J and 129S/SvImJ) exposed to 0 or 625 ppm BD for 6 hours/day, 5 days/week for 2 weeks. The goals of this study were to compare the magnitude of inter-individual differences in BD toxicity between individual inbred strains of mice, and to investigate possible mechanisms of the effects on DNA damage, epigenetic alterations and hepatotoxicity. In CAST/EiJ strain, liver levels of N-7-(2,3,4-trihydroxybut-1-yl)guanine adducts in DNA were about 2fold lower than in other strains. Epigenetic effects were evident at the level of both DNA and histones. Global loss of hepatic DNA methylation was observed in PWK/PhJ, C57BL/6J, and 129S/SvImJ mice, with the greatest effect being detected in C57BL/6J mice. Loss of trimethylation of H3 lysines 9 and 27, and H4 lysine 20 was found in C57BL/6J mice, while the opposite effect was detected in CAST/EiJ mice. Interestingly, gene expression analysis demonstrated altered expression of genes that are indicators of liver toxicity in C57BL/6J mice only. These findings demonstrate that significant epigenetic events occur following BD and suggest that the differences in inter-individual susceptibility to BD exposure may be determined by variations in epigenetic response. 947 ALTERED DNA METHYLATION PATTERNS IN INDIVIDUALS WITH ARSENICOSIS. L. Smeester 1 , J. Rager 1 , L. Zhang 6 , X. Guan 3 , N. Smith 1 , G. Garcia-Vargas 4 , L. Del Razo 5 , Z. Drobna 2 , H. Kelkar 3 , G. Schroth 6 , M. Styblo 2 and R. Fry 1 . 1 Environmental Sciences and Engineering, Gillings School of Global Public Health UNC-Chapel Hill, Chapel Hill, NC, 2 Nutrition, Gillings School of Global Public Health UNC-Chapel Hill, Chapel Hill, NC, 3 Center for Bioinformatics, UNC- Chapel Hill, Chapel Hill, NC, 4 Faculty of Medicine, Juarez University of Durango State, Juarez, Mexico, 5 Department of Toxicology, CINVESTAV-IPN, Mexico City, Mexico and 6 Illumina, Inc., Hayward, CA. Inorganic arsenic (iAs) is a documented carcinogen and an environmental toxicant, poisoning tens of millions of people worldwide through drinking water. Individuals exposed chronically to iAs are susceptible to arsenicosis, or arsenic poisoning. Such SOT 2011 ANNUAL MEETING 201
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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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Page 155 and 156: NAC + LPS yielded different levels
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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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vitro with this potentially insect-
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their performance on toxicological
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need for a better understanding of
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1577 AN IN VITRO MODEL SYSTEM FOR A
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gene expression post-transcriptiona
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1595 GENE EXPRESSION PROFILE OF RAT
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to confirm a hepatotoxic property o
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1613 AN INVESTIGATION OF THE CLEARA
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its nuclear translocation was reduc
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were collected from TK animals at d
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egulated targets were selected for
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U/L after tetracycline. Minocycline
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peri-pubertal FasL-/- mice show a d
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showed similar levels of apoptosis
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1676 TWO BIOMARKERS FOR EVALUATION
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motifs selected. This system was ap
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1693 VOC SERUM LEVELS IN THE GENERA
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1702 DOES THE CLOCK MAKE THE POISON
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those with high nickel content are
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isk assessment. However, unique cha
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model of APAP metabolism and glutat
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logically & morphologically similar
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posure, blood chemistry was analyze
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elated to oxidative stress by measu
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ostasis), but work is needed to tra
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tokine products during carcinogenes
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ways as chemical stressors and, the
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toxicity of nanomaterials relates s
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1815 MEASURING COMPOUND SELECTIVITY
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1825 EFFECTS OF METABOLISM BY INTES
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cyanoacetic acid increased 2-3 fold
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1845 IS THE PROMISCUITY OF THE ARYL
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crorarray analysis. RT-PCR results
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are a family of phase-II biotransfo
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ous labs. As a result of positive s
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down the doses may produce more tox
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spectively. Below 100 mg/l of gemfi
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1900 GENERATION OF PRECISION CUT LI
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iomarkers or observation of lesions
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creased reticulocytes and lymphocyt
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statistically significant interacti
Page 419 and 420:
monize sample preparation and analy
Page 421 and 422:
NPC and sinonasal cancer in neighbo
Page 423 and 424:
showed incidences of lung and nasal
Page 425 and 426:
utylbenzenes, exhibited most simila
Page 427 and 428:
1975 DIFFERENTIAL MODULATION OF CYP
Page 429 and 430:
organic As to MMA(V) and a lower ca
Page 431 and 432:
ole in invasion and metastasis of c
Page 433 and 434:
3T3-L1 cells to low-levels of arsen
Page 435 and 436:
2011 IDENTIFICATION OF A NOVEL VX M
Page 437 and 438:
This work was supported by Cooperat
Page 439 and 440:
2029 EFFICACY OF ENDOTRACHEAL ADMIN
Page 441 and 442:
Diazepam injections and its combina
Page 443 and 444:
2047 ESTERASE ACTIVITIES AND HEMOST
Page 445 and 446:
nanoparticle-induced toxicity progr
Page 447 and 448:
house, were iv infused into rats ov
Page 449 and 450:
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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