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neuronal stem cells during proliferation and differentiation. hNPCs (ENstem A) cells were expanded in serum free Millipore proliferation expansion medium (MEM) and differentiated in HyClone neural differentiation medium (HDM). Cells were incubated for 72 hours in either MEM or HDM with CP (0-20 μg/mL). Dose-dependent decreases of cell viability were observed in both cells cultured in proliferation MEM and differentiation HDM medium, with significantly greater effects of CP on cells in HDM (78%+/-3.2%) than in the MEM (85%+/- 4%) at concentrations of CP 20ug/mL. Cells grow under differentiating conditions were more sensitive to CP. Protein expression of 18 epigenetic markers including 6 acetyl Histone H3 antibodies, 6 methyl Histone H3 antibodies and 6 HDAC antibodies were examined. We observed dose-dependent increases in phospho-Histone H3 (Ser10) in differentiating cells (about 5 fold increase at 10μg/ml), with no changes in proliferating cells. Significant increases in Acetyl-Histone H3 (Lys18) were shown during proliferation, but no significant changes were observed in this epigenetic marker during differentiation. Dose-dependent increases in di-methyl-histone H3 (Lys79) were shown during differentiation with less change during proliferation. Our results suggest that CP exposure in differentiating hNPCs resulted in significant alteration in expression of several epigenetic markers associated with transcriptional activation while exposure of cells to CP during proliferation showed fewer changes in these epigenetic factors. Differential alterations of epigenetic markers during proliferation and differentiation may provide cell stage specific mechanistic clues for examining effects on neural development.Supported by OCE- 0434087, P01ES009601, P50ES012762 and P30ES07033 and RD-83170901. 2521 IN VITRO ALGIMATRIX 3D CELL CULTURE SYSTEM, AN ALTERNATIVE TO MAMMALIAN MODELS FOR NON-SMALL CELL LUNG CANCER. M. Sachdeva 1 , A. R. Patel 1 , M. Chougule 1 and A. Sams 2 . 1 Pharmacy, Florida A&M University, Tallahassee, FL and 2 Invitrogen Corporation, Carlsbad, CA. Objective: Fundamental investigations of human biology and development of therapeutics, commonly rely on 2D cell culture systems in-vitro that do not accurately recapitulate the living tissues. There is growing recognition of the need to incorporate the 3D cell culture paradigm towards invitro toxicology models, reduce animal testing, reduce cost to identify new drug candidates and minimize product development time. AlgiMatrix® sponge (Invitrogen Corporation, CA) is a non toxic and biodegradable material made from alginate that maintains normal cell characteristics and morphology. The main objective of the current study was to appraise the AlgiMatrix cell culture system as a 3D invitro tumor model and to ascertain the anticancer activity of Docetaxel and Doxorubicin. Methods: Cell titration was done to optimize seeding density and to determine the optimal incubation time for the formation of spheroids. On day 4, 9 & 13, the number and average size of the spheroids were determined using inverted phase contrast microscopy and imaging software. Further optimized cell density was used to determine the IC50 & IC90 values of drugs. The alamarBlue® assay was performed to determine the number of viable cells in control & treatment wells. Results: Optimized seeding density and incubation time was found to be 0.15 & 0.25 million H460 cells/well and 14 days respectively. Total number of cells obtained by alamarBlue® assay on 14th day was 38.64 ± 4.94 & 42.92 ± 3.29 million cells/well for 0.15 & 0.25 million seeded cells respectively for 6 well plate. Total number of cells obtained by alamarBlue® assay on 14th day was 70.86 ± 9.25 & 117.83 ± 14.37 thousand cells/well for 15 & 25 thousand seeded cells respectively for 96 well plate. The IC50 & IC90 concentration of the docetaxel was found to be 193.19 μM & 290.47 μM when ascertained with 0.15 million cells/well. Conclusion: These results strongly support that the AlgiMatrix 3D Cell Culture System may be used as an in-vitro tumor model and to evaluate cytotoxicity of anticancer drugs. 2522 MICROPATTERNED PRIMARY HEPATOCYTE CO- CULTURES FOR DRUG METABOLISM AND TOXICITY STUDIES. S. Khetani, A. Moore, S. Krzyzewski, J. Gaffney, C. Kanchagar, J. Shi and J. McGeehan. Research and Development, Hepregen, Medford, MA. Sponsor: D. Keller. Primary hepatocytes display a precipitous decline in phenotypic functions when cultured in a sandwich of extracellular matrix proteins (i.e. collagen, Matrigel). We describe a human liver model with precise microscale cytoarchitecture and optimal stromal interactions (micropatterned co-cultures) that displays stable functions for several weeks in vitro. Micropatterned co-cultures were coupled with miniaturization strategies (i.e. 24- and 96-well format) and optimized for the screening of genotype-specific and clinically- relevant drug disposition and coupled DILI using standard end-points (i.e. ATP depletion, mitochondrial activity) as well as high content imaging. We have investigated the toxicity of several hepatotoxins (i.e. Troglitazone, Tolcapone) in our model under both acute (hours to days) and 540 SOT 2011 ANNUAL MEETING chronic (weeks) dosing regimens and show concordance with preclinical and clinical findings. Since metabolism is an important determinant of the overall disposition of drugs and the profile of metabolites can have an impact on efficacy and safety, the utility of micropatterned co-cultures for prediction of compound clearance and generation of human metabolites was evaluated. Micropatterned co-cultures classified compounds based on rates of clearance and generated metabolites arising from both phase 1 and 2 reactions (single and sequential). Transporter assays (uptake and efflux) could be performed on micropatterned co-cultures towards simultaneous assessment of the interplay of drug transport, metabolism and toxicity. Long-term drug-drug interaction studies (i.e. enzyme induction and inhibition) have also been explored and results indicate that micropatterned co-cultures are able to recapitulate clinical outcomes. In the future, miniaturized micropatterned co-cultures may find utility in the development of several classes of therapeutic compounds (drugs, biologics), in evaluating the injury potential of environmental toxicants, in fundamental investigations of liver physiology, and in personalized medicine for liver disease. 2523 ASSESSING CHRONIC TOXICITY OF FIALURIDINE IN A MICROPATTERNED HEPATOCYTE CO- CULTURE MODEL. S. Krzyzewski 1 , S. Khetani 1 and S. Barros 2 . 1 Research and Development, Hepregen, Medford, MA and 2 Alnylam Pharmaceuticals, Cambridge, MA. Fialuridine (FIAU), a nucleoside drug for the treatment of hepatitis B, failed in clinical trials due to mitochondrial toxicity. FIAU toxicity is difficult to replicate in sandwich cultures of primary hepatocytes as their phenotypic functions display a precipitous decline. We have utilized microfabrication tools to develop a human liver model with precise microscale cytoarchitecture and optimal stromal interactions (micropatterned co-cultures) that displays phenotypic stability for several weeks in vitro. Micropatterned co-cultures from 2 donors were dosed twice over 4 days with FIAU, uridine and 4 other related drug analogues up to 100 uM. Human hepatocytes in this model experienced significant dose- and time-dependent toxicity with FIAU incubation as assessed by mitochondrial activity, morphology, albumin secretion, urea synthesis and CYP3A4 activity. FIAU was the most toxic to human hepatocytes as compared to the other analogues when all endpoints were considered. There were donor dependent differences in the magnitude of toxicity as well as the rank ordering of the compounds. On the other hand, rat hepatocytes did not exhibit the same extent of toxicity upon FIAU incubation as did human hepatocytes in micropatterned co-cultures, consistent with preclinical animal toxicity data. We then dosed micropatterned co-cultures with either human or rat hepatocytes with fresh compounds in culture medium every 2 days for 3 weeks at doses up to 10 uM. Our results indicated that CYP3A4 activity was the most sensitive functional marker as compared to albumin secretion and urea synthesis to distinguish the effects of FIAU over the other drugs at doses as low as 1 uM. In the rat model, urea secretion was down-regulated by as much as 50% with FIAU and other compounds upon chronic administration. Mechanistic investigations are ongoing to distinguish the species-specific effects of FIAU in micropatterned co-cultures. In the future, micropatterned co-cultures may serve as a robust model system to evaluate the chronic effects of compounds on the liver. 2524 TRANSCRIPTIONAL INDUCTION OF ALDO-KETO REDUCTASES (AKRS) BY BENZO[A]PYRENE IN JURKAT CELL LINE. B. S. Barrón-Vivanco 1, 3 , E. González-Barbosa 3 , I. M. Medina-Díaz 3 , A. E. Rojas-García 3 , S. Rothenberg 1 , G. Elizondo 2 and A. Albores 1 . 1 Toxicology, Cinvestav-Ipn, México, Mexico, 2 Cell Biology, Cinvestav-Ipn, México, Mexico and 3 Laboratorio de Contaminación y Toxicología Ambiental, Universidad Autónoma de Nayarit, Tepic, Nayarit, Mexico. Polycyclic aromatic hydrocarbons (PAHs) are chemicals formed during the incomplete combustion of carbon and are carcinogenic to humans. To exert their deleterious effects, PAHs are metabolically activated; one route is through of aldo-keto reductases (AKRs). Benzo[a]pyrene (B[a]P) is considered as the most representative PAH. There are studies in human cell lines such as HepG2 and A549, where AKR mRNA over-expression was observed in response to PAHs exposure. In addition, some human studies have shown the association of AKR mRNA over-expression of some isoforms with some human pathologies like esophagus or bladder cancer and drug resistance. Despite this evidence, studies in open populations are limited because they involved tissue sampling. Thus blood is a good tissue sample candidate because it is easy to obtain and PAHs effects can be readily detected. Therefore, we used Jurkat (lymphocytes T) cell line to assess AKR mRNA levels after PAHs exposure. Jurkat cells were added with human liver S9 fraction to activate B[a]P metabolically and exposed to B[a]P (0.1 - 5.0 μM) for 3, 6, 12 and 24 h. We assessed: cells viability (trypan blue test), AKR1A1, AKR1C1, AKR1C2 and AKR1C3 iso-
forms mRNA expression levels were assessed by quantitative real-time PCR assay (rtPCR). A time-dependent variation of the mRNA expression levels was observed. The maximum expression was detected at 12 h. The observed effect was similar for the four genes studied. B[a]P treatment had no effect on the viability of cells. This is the first study to our knowledge where lymphocyte cells are used to evaluate the PAHs effect on the AKRs mRNA expression. 2525 DATACHIP/METACHIP 2.0: AN IMPROVED CHIP PLATFORM FOR 3D CELL-BASED TOXICOLOGY ASSAYS. M. Lee 1 , J. Ryan 1 , S. Brooks 1 , J. Gray 1 , D. Lee 2 , S. Jeong 2 , J. Yang 2 , B. Ku 2 , Y. Will 3 and S. Nadanaciva 3 . 1 Solidus Biosciences, Inc., San Francisco, CA, 2 Central R & D Institute, Samsung Electro-mechanics Co., Suwon, Republic of Korea and 3 Compound Safety Prediction, Pfizer Inc., Groton, CT. Several studies suggest that 3-D cell cultures are more likely than 2-D cell cultures to reflect accurate physiological responses to cytotoxic compounds. Solidus Biosciences has developed the DataChip/MetaChip platform that couples a 3-D cell culture array with a complementary array of recombinant enzymes to identify metabolism-induced toxicity. The IC50 values of many compounds not only depend on the morphology of the cultured cells, but also vary with culture conditions and the cell type used. Access to a greater number of cell culture conditions on a high-throughput format enables the generation of a larger and more-predictive portfolio of data for new chemical entities. Thus, we have optimized the architecture of both the DataChip and the MetaChip platform for metabolism-induced toxicity measurements to enable the screening of compounds against multiple cell types cultured in 3-D matrices under different conditions on a single chip platform. In the new embodiment of the DataChip, cells are immobilized within a variety of matrices on 532 elevated pillars that are then submersed in microwells of the modified complementary MetaChip. Recombinant enzymes are sequestered within matrices in the microwells to enable the in-situ generation of metabolites. Because each cell culture is immersed in media in discrete wells, multiple cell types requiring different media can be cultured on the same chip. The IC50 values of compounds known to have cytochrome P450 generated toxic metabolites, such as Troglitazone, are compared under different culture conditions for several cell types. These studies demonstrate the increased throughput and capability of the modified MetaChip/DataChip system to identify metabolism-induced toxicity at early stages in compound safety assessment. 2526 HIGH-THROUGHPUT GENE TRANSFECTION ON A THREE-DIMENSIONAL (3-D) CELL MICROARRAY PLATFORM FOR METABOLISM-INDUCED TOXICOLOGY SCREENING. S. Kwon 1 , J. Gray 2 , B. Ku 3 , J. Ryan 2 , D. Clark 4 , J. Dordick 1 and M. Lee 2 . 1 Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY, 2 Solidus Biosciences, Inc., San Francisco, CA, 3 Central R&D Institute, Samsung Electro-Mechanics Co., Suwon, Republic of Korea and 4 Department of Chemical Engineering, University of California Berkeley, Berkeley, CA. Variation in metabolic enzyme expression among segments of the human population may cause deviations from the expected pharmacokinetic profile of a drug, resulting in idiosyncratic toxicity or a lack of efficacy. Cell lines that stably express individual or combinations of metabolic enzymes are emerging tools for prediction of these rare clinical events; however, it is difficult to create and maintain a library of stable cell lines that mimics the diversity of metabolic profiles that give rise to unexpected outcomes. In addition, it is difficult to control the expression levels of each of the enzymes in stably-transfected cell lines. To address this need, we have developed a technique for simultaneously infecting an array of miniaturized 3-D cell cultures with varying concentrations of recombinant adenoviruses carrying genes for different metabolic enzymes, which generates an array of cell cultures with differentiated metabolizing capabilities. Compounds can be added to this array of cell cultures to assay the compounds and their metabolites for a variety of end points including, but not limited to, cell viability. We have demonstrated the controlled expression of individual and multiple reporter proteins (GFP and RFP) and drug-metabolizing enzymes (CYP3A4, CYP2C9, and UGT1A4) in two human liver cell lines (HepG2 and THLE-2 cells) on the chip by altering the MOI of the various recombinant adenoviruses. The microarrays of 3-D human cells expressing metabolic enzymes were tested with model compounds, such as acetaminophen, to simulate enzyme-specific hepatotoxicity. These studies demonstrate that the new chip platform can provide critical information necessary for evaluating metabolisminduced toxicity in a high-throughput manner. 2527 CELL TOXICITY AND INTERLEUKIN (IL) 8 PRODUCTION: UNIQUE RELATIONSHIP WITH ALLERGENICITY. I. Kimber1 , C. F. Portsmouth1 , R. Pendlington2 , G. Maxwell2 and R. J. Dearman1 . 1University of Manchester, Manchester, United Kingdom and 2Unilever Safety & Environmental Assurance Centre, Bedford, United Kingdom. There has been considerable interest in the development of in vitro tests for the characterisation of chemical allergens, such as the production by dendritic cell (DC)-like cell lines of cytokines. These methods are often limited by toxicity and delivery of chemical allergen in culture. We have constructed toxicity and IL-8 secretion dose response curves for a number of human cell lines (DC-like : THP-1, U937; erthyromyeloid: K562). Cells were incubated for 24h with the contact allergen dinitrochlorobenzene (DNCB) or its water soluble analogue, dinitrobenzene sulfonic acid (DNBS), or with the irritant benzenesulfonic acid (BS). All cell lines expressed IL-8 constitutively and displayed similar toxicity profiles for each of the individual chemicals. DNCB and DNBS enhanced IL-8 production at subtoxic doses (10μM and 300μM, respectively). In contrast, despite using doses that caused similar toxicity profiles to those observed for the allergens, there was no increase in IL-8 secretion recorded for BS (30 to 300mM). Cells (THP-1 and U937) were cultured with two additional allergens (dinitrothiocyanobenzene [DNTB] and dinitrofluorobenzene [DNFB]) or two irritants (1-bromobutane [1BB] and sodium lauryl sulfate [SLS]) at subtoxic and toxic doses. In addition, cells were incubated at varying osmotic pressures (ranging from 0 to 500mOsMo). Treatment with subtoxic doses of DNTB and DNFB (10μM) induced the production of IL-8 by both THP-1 and U937 cells, whereas toxic doses of 1BB and SLS (10μM and 0.3μM, respectively) were without effect. Furthermore, under conditions of hypoosmolality (100mOsMo) and hyper-osmolality (400mOsMo), both of which caused cell death, there was no marked increase in IL-8 secretion. These data reveal that the relationship between toxicity and IL-8 production is unique to allergens. Defining the signalling pathways involved may allow the identification of novel cellular biomarkers that, compared with IL-8, may offer increased sensitivity and selectivity. 2528 SCREENING DRUG-INDUCED MITOCHONDRIAL TOXICITY USING A HIGH-THROUGHPUT DUAL- PARAMETER CELL BASED ASSAY. J. Hynes2 , C. Carey2 , S. Kirwan2 , R. Swiss1 and Y. Will1 . 1Compound Safety Prediction, Pfizer Global Research & Development, Groton, CT and 2Luxcel Biosciences, Cork, Ireland. Recent years have seen a growing appreciation of the importance of the mitochondrion as a site for off-target drug effects. This in turn has prompted the development of a variety of in vitro plate-based mitochondrial toxicity assays, including measuring oxygen consumption in isolated rat liver mitochondria and quantifying the differential ATP depletion rates of aerobically poised versus conventionally cultured HepG2 cells. Both assays identify similar compounds, but each assay also identifies a unique set of compounds. To investigate if a cell-based metabolic assessment could be used to address shed light on this phenomenon, a 384 well assay capable of simultaneous monitoring of both glycolytic flux and oxygen consumption was developed. Cell-based analysis addresses the risk of over prediction which exists with an isolated organelle while also allowing confirmation of mitochondrial dysfunction by observing modulation of both oxygen consumption and glycolytic flux. HL60s were chosen over an adherent cell model as they exhibit similar sensitivity to mitochondrial impairment while also removing the requirement for pre-plating, thereby simplifying workflows. The approach was initially validated using a small compound set and subsequently used to screen a library of 200 compounds across a 10 point dilution series. A small subset of compounds is flagged by all three assays with isolated mitochondrial analysis flagging more than ATP depletion. The vast majority of compounds flagged by either assay are detected by cell-based metabolic analysis; however this approach appears to be more sensitive, confirming metabolic perturbations for a larger number of compounds, albeit typically above 125uM. These data suggest that over-prediction using isolated mitochondria is not a significant problem, but also points to the fact that additional retrospective analysis is required to allow such cell-based metabolic analyses to be correctly interpreted. 2529 USING MULTIPLE ASSAYS TO ASSESS DRUG- INDUCED MITOCHONDRIAL TOXICITY IN EARLY TOXICOLOGY TESTING. R. Swiss, P. Rana and Y. Will. Compound Safety Prediction, Pfizer Global Research & Development, Groton, CT. Drug-induced mitochondrial dysfunction has been shown to contribute to organ toxicity and late stage attrition. Therefore, testing for drug-induced mitochondrial dysfunction pre-clinically is vitally important. We compared two separate assays to SOT 2011 ANNUAL MEETING 541
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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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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
Page 375 and 376:
isk assessment. However, unique cha
Page 377 and 378:
model of APAP metabolism and glutat
Page 379 and 380:
logically & morphologically similar
Page 381 and 382:
posure, blood chemistry was analyze
Page 383 and 384:
elated to oxidative stress by measu
Page 385 and 386:
ostasis), but work is needed to tra
Page 387 and 388:
tokine products during carcinogenes
Page 389 and 390:
ways as chemical stressors and, the
Page 391 and 392:
toxicity of nanomaterials relates s
Page 393 and 394:
1815 MEASURING COMPOUND SELECTIVITY
Page 395 and 396:
1825 EFFECTS OF METABOLISM BY INTES
Page 397 and 398:
cyanoacetic acid increased 2-3 fold
Page 399 and 400:
1845 IS THE PROMISCUITY OF THE ARYL
Page 401 and 402:
crorarray analysis. RT-PCR results
Page 403 and 404:
are a family of phase-II biotransfo
Page 405 and 406:
ous labs. As a result of positive s
Page 407 and 408:
down the doses may produce more tox
Page 409 and 410:
spectively. Below 100 mg/l of gemfi
Page 411 and 412:
1900 GENERATION OF PRECISION CUT LI
Page 413 and 414:
iomarkers or observation of lesions
Page 415 and 416:
creased reticulocytes and lymphocyt
Page 417 and 418:
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: launched with the aim of developing
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 595 and 596:
Author Index (Continued) The numera
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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