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post fertilization (hpf) for 5 days when they were scored for acute lethality and developmental defects. Six hpf embryos were treated with compound and RNA isolated for RT-PCR at 10 or 24 hpf to confirm downstream canonical Wnt target inhibition (Axin2 and Cyclin D1) using RPL13a as an endogenous control. Non-canonical Wnt Planar Cell pathway VANGL2 expression was also measured. FH535, a transcriptional Wnt pathway inhibitor, suppressed Axin2 and Cyclin D1 expression at 10 and 24 hpf. IWR-1, a Wnt/tankyrase inhibitor, induced malformations while showing no change in Axin2 or Cyclin D1 expression. XAV939, a more selective tankyrase inhibitor, induced malformations such as micropthalmia, misshapen head and heart, and tail defects but had little expression change. SB415286, a GSK3β inhibitor, increased in Axin2 and Cyclin D1 expression at 10 hpf. Wnt/PCP pathway was also evaluated by measurement of VANGL2 expression. Following IWR-1 treatment VANGL2 expression increased by 2 fold at 24 hpf and by 4 fold at 5 days. TFC4 and β-Catenin Morpholinos were injected into embryos at the 2 cell stage and evaluated for defects/mortality at 48 hpf. Both the TCF4 and β-Catenin Morpholinos had severe phenotypic effects. In summary, prototypic inhibitors of the Wnt/β-Catenin pathway have measurable effects on Wnt target gene expression and phenoptypic malformations are similar though less extreme than that of Morpholino knock down in the developing Zf embryo. 1742 ASSESSMENT OF DRUG-INDUCED, SEIZURE-LIKE MOVEMENT IN ZEBRAFISH. D. Park, J. Meidenbauer, W. L. Seng and P. McGrath. Phylonix, Cambridge, MA. Zebrafish has been shown to be a predictive animal model for assessing drug induced seizure-like activity. In a recent study, using a video camera, we recorded swim movement of 6 dpf zebrafish for 60 min after treatment with 9 compounds known to induce seizures in mammals including: aminophylline hydrate, 4aminopyridine, amoxapine, bicuculline methoiodide, enoxacin, methoxychlorate, pentylenetetrazole, picrotoxin, and strychnine hemisulphate, and a negative control, lidocaine. Using video recordings, we quantitated high speed (>20 mm/sec) movement which correlated with seizure-like activity. Distance moved (cm) at high speed in 1 min intervals was plotted against recording time. As shown by each time course curve, 7 test drugs, aminophylline hydrate, 4-aminopyridine, amoxapine, methoxychlorate, pentylenetetrazole, picrotoxin, and strychnine hemisulphate, induced peak movement. In addition, although the kinetics of induction and the duration of seizure-like activity varied by drug, a dose-dependent increase in high speed movement was observed for 7 test drugs. Cumulative distance moved (cm) at high speed after drug treatment was also plotted against time and 8 test drugs, aminophylline hydrate, 4-aminopyridine, amoxapine, bicuculline methoiodide, methoxychlorate, pentylenetetrazole, picrotoxin, and strychnine hemisulphate, showed a dose-dependent change. Drugs known to cause seizure effects in mammals showed similar effects in zebrafish. Since the assay correctly predicted results for 8 of 9 positive drugs, sensitivity was 89% (excellent). Our data support use of zebrafish model for assessing drug induced seizures. This functional motility assay can be combined with other zebrafish assays to assess drug effects on CNS. Advantages of zebrafish for safety and toxicity studies include: large number of embryos per mating, drug delivery directly in the fish water, small amount of compound required (μM vs mM) and statistically significant number of animals per experiment. 1743 VALIDATION OF AN AUTOMATED SCREENING ASSAY BASED IN A ZEBRAFISH MODEL FOR THE DETECTION OF COMPOUNDS THAT INHIBIT ANGIOGENESIS. C. Quevedo, C. Callol and A. Letamendia. Scientific, Biobide, San Sebastian, Guipuzkoa, Spain. Sponsor: S. Tripathi. Angiogenesis plays an essential role in tumor growth and metastasis, so it is a wellestablished therapeutic target. The zebrafish is the only vertebrate model compatible with the paradigms of drug discovery. The small size and transparency of zebrafish embryos make them amenable for the automation necessary in high-throughput screens. We have developed an automated, quantitative screening assay for the discovery of antiangiogenic compounds using transgenic zebrafish embryos that express Cop-GFP under the control of the endothelial specific flk-1 promoter. The assay includes automated methods for embryo dispensation, compound delivery and embryo imaging. The angiogenic vessels that perfuse the trunk of the embryo (intersegmental vessels) at ~24 hours post-fertilization constitute the readout of the assay. To validate this method, a battery of known inhibitors for different targets implicated in angiogenesis (mainly Tyrosine kinase inhibitors) has being used. We can discriminate different and specific phenotypes related with vascular disruption (endothelial proliferation and migration and neovascular stabilization). Our data shows the suitability of a vertebrate animal model for drug discovery assays with libraries of multiple compounds as well as the capacity to visualize antiangiogenic compounds with high specificity and sensibility in an in vivo model. 374 SOT 2011 ANNUAL MEETING 1744 THE EFFECTS OF CHEMICALS IN THE U.S. EPA’S TOXCAST LIBRARY ON CAENORHABDITIS ELEGANS AND ZEBRAFISH DEVELOPMENT. W. A. Boyd 1 , M. V. Smith 2 and J. H. Freedman 1 . 1 NIEHS, Durham, NC and 2 SRA International, Durham, NC. The need to characterize the potential toxicity of thousands of chemicals has led government organizations to explore the use of high-throughput in vitro screens and alternative model systems. These approaches are part of an effort to develop a tiered toxicity testing scheme. As part of this effort, the EPA developed a standardized collection of chemicals: the ToxCast Phase I library. This library is composed of 309 unique compounds, including pesticide active ingredients that have well-characterized mammalian toxicities. The nematode Caenorhabditis elegans and zebrafish Danio rerio are two popular model organisms used to study developmental biology that are also used as alternative toxicological models. The effects of the chemicals in the ToxCast library on zebrafish embryonic development and C. elegans larval growth were compared. The C. elegans growth assay monitors changes in nematode size following exposure to chemicals from the first through the last larval stage, while the zebrafish assay monitors malformations in larvae following exposure from 6h to 6d post-fertilization. The ToxCast library was screened for effects on C. elegans growth at seven concentrations (0.5 - 200 μM) and zebrafish development at eleven concentrations (0.001 – 80 μM). A high percentage of compounds caused developmental defects in zebrafish and decreased growth in C. elegans. A high concordance was observed between the nematode and zebrafish results. Over 40% of the compounds were toxic to both organisms and 30% were not toxic to either at the maximum concentrations tested. The class of pesticides with the highest number of toxic compounds included conazoles, pyrethroids, and organophosphates. The compounds’ activities in both organisms were highly correlated with log octanol-water partition coefficients and molecular weights. These results can be compared with those obtained from rodent assays and high-throughput screens to assess their utility in tiered toxicity testing. 1745 A PROTEOMIC ANALYSIS OF ARSENIC EXPOSED ZEBRAFISH (DANIO RERIO) SUGGESTS ALTERED LIPID METABOLISM. P. Carlson 1 and R. J. Van Beneden 1, 2 . 1 Graduate School of Biomedical Sciences, University of Maine, Orono, ME and 2 School of Marine Sciences, University of Maine, Orono, ME. Sponsor: G. Mayer. The zebrafish (Danio rerio), a well-established model of liver development and disease, was used to investigate differential protein expression following arsenic exposure. Several disorders have been linked to arsenic exposure including cancer, diabetes and lipid metabolism dysregulation, although the mechanisms of arsenic toxicity are still poorly understood. In vitro, arsenic has been shown to induce free radical formation as well as to interfere with the phosphorylation of a number of key regulatory proteins, including p53 and the epidermal growth factor receptor. Other studies have described altered gene expression and mitogenic signaling, but the effects on protein expression following arsenic exposure over a prolonged period have yet to be described. A bottom-up proteomics approach was employed to investigate arsenic induced alteration in the zebrafish liver proteome. Over 740 proteins were identified, with fewer than 2% showing differential expression. The data suggest that arsenic exposure altered the expression of proteins involved in lipid metabolism. Two key pathways have been identified, involving peroxisome proliferator-activated receptor gamma (PPARγ) and hepatocyte nuclear factor 4 alpha (HNF4α). PPARγ acts as a key regulator of adipocyte differentiation and blood glucose homeostasis; HNF4α is a transcription factor for several lipid metabolism enzymes and insulin. Altered expression of proteins in the PPARγ pathway include fatty acid binding protein (FABP), collagen 1A1 (COL1A1); enzymes altered in the HNF4α pathway include hydroxysteroid dehydrogenase like 2 (HSDL2) and Nacetylgalactosaminidase α (NAGA). These results are being confirmed by ongoing studies of the regulation of PPARγ and HNF4α. 1746 LOCALIZATION OF MEGALIN ALONG ZEBRAFISH LATERAL LINE. C. Doshna 1 , C. Nykyforchyn 2 , P. Burch 1 and M. D. Aleo 1 . 1 DSRD, Pfizer, Groton, CT and 2 University of CT, Storrs, CT. Megalin is most abundantly located in renal proximal tubule & inner ear epithelial cells in mammals, acting as an endocytic receptor for aminoglycosides (AG) & other polybasic drugs that cause nephrotoxic & ototoxic effects in mammals. The presence of megalin has been shown in zebrafish (Zfish) embryos however, its potential role in the ototoxic response to AG & polymyxins has only recently been suggested through work by this lab. The fact that Zfish hair cells are both physio-
logically & morphologically similar to that of human hair cells, along with our studies, indicate that megalin is likely located in/near hair cells of the Zfish lateral line. Zfish exposure to AG & cisplatin resulted in a loss of fluorescently-labeled hair cells, corresponding to cell death. Furthermore, concomitant application of known megalin binding agents led to partial protection of drug-induced Zfish hair cell death. The purpose of this study is to determine whether megalin is located in/near Zfish hair cells as well as further investigate effectiveness of protective agents in preventing hair cell death & loss of fluorescence. Zfish at 5 days post fertilization (dpf) labeled with anti-megalin antibody showed patterns closely resembling neuromast structures seen with fluorescent labeling. These results show megalin is located in hair cell neuromast structures along the lateral line of Zfish. Zfish at 4 dpf were treated with polymyxin B, polymyxin B nonapeptide or gentamicin +/- poly-L-asparagine, labeled with the fluorescent dye YoPro1 & imaged using fluorescence microscopy to look for a loss of hair cell fluorescence vs. controls. Only partial protection was seen with pretreatment of megalin binding agent. Nephrotoxic cephalosporins that do not go through megalin were also tested & no loss of fluorescence was seen up to 100 μM, further supporting the conclusion that megalin plays a key role in the mechanism through which nephrotoxic drugs illicit an ototoxic effect in Zfish. Drugs that bind to megalin could conceivably be screened in Zfish using hair cell toxicity as a potential predictor for nephro- and ototoxicity in mammals. 1747 PERSISTENT LIFE HISTORY EFFECTS OF ATRAZINE EXPOSURE IN ZEBRAFISH: A MULTI-GENERATIONAL STUDY ENCOMPASSING GENE EXPRESSION, FITNESS, AND EPIGENETIC EFFECTS. S. Lewis1 , G. J. Weber2 , S. M. Peterson2 , J. L. Freeman2 and M. S. Sepulveda1 . 1Forestry and Natural Resources, Purdue University, West Lafayette, IN and 2School of Health Sciences, Purdue University, West Lafayette, IN. Atrazine is one of the most widely used herbicides in the United States because it is highly effective against a wide spectrum of broadleaf and grass weeds and because it is relatively inexpensive. At present, the maximum contaminant level goals (MCLG) for atrazine, set by the U.S. EPA, is 3 ppb (parts per billion) for drinking water. The safety of atrazine exposure is currently being re-evaluated by the EPA due to recent studies linking exposure with cancer and endocrine disruption. Therefore, we are studying the lasting effects of a one-time developmental atrazine exposure in later life stages of the exposed individuals and in their offspring by evaluating differential gene expression, fitness, survival of offspring and hatching success. In a previous study using microarray technology, an exposure of embryonic zebrafish through 72 hours post fertilization (hpf) to 0.3 ppb, 3 ppb, or 30 ppb atrazine resulted in differentially expressed gene lists enriched with genes associated with neuroendocrine development, cell proliferation, and cancer development. From these gene set lists, a subset of candidate genes were chosen as genetic biomarkers for neuroendocrine functions and gene expression alterations confirmed with quantitative real-time PCR (qPCR) in the 72 hpf larvae. Lasting effects on gene expression of these same genes were also measured by qPCR in 33-day old juveniles and in sexually mature adults. Additionally, the effect of atrazine on sex ratio in the exposed generation (F0) and on the number of offspring and hatching success of the F1 was also measured. No alteration in sex ratio was observed, but the lowest atrazine treatment of 0.3 ppb resulted in decreased survivorship in the F1 generation. No effects on survivorship or hatching rate were observed in the offspring of the fish exposed to 3 ppb and 30 ppb atrazine. 1748 MOLECULAR EVALUATION OF RABBIT CORNEAL OCULAR SULFUR MUSTARD INJURY: TOWARDS MECHANISMS OF PERSISTENT INJURY. D. Milhorn 2 , P. McNutt 1 , T. Hamilton 1 and R. Lawrence 1 . 1 USAMRICD, Aberdeen Proving Ground- Edgewood Area, MD and 2 Medical Research and Materiel Command, Fort Detrick, MD. Sponsor: G. Rockwood. Sulfur mustard (SM, bis-(2-chloroethyl) sulfide) is a highly reactive, bifunctional alkylating agent that covalently modifies DNA, proteins, and other macromolecules. Ocular SM exposure results in a severe acute injury involving inflammation and corneal erosions that rapidly resolve. Many victims subsequently undergo a delayed injury that severely compromises eyesight, characterized by corneal erosions, persistent edema and neovascularization. The etiology of these recurrent keratopathies is unknown. Diverse therapeutic approaches have failed to mitigate the delayed injury, suggesting that researchers need an improved understanding of the mechanisms underlying injury progression. We have developed a novel rabbit corneal vapor exposure model that exhibits acute and long-term sequelae commensurate with human clinical reports and characterized consistent and reproducible metrics of injury progression. Exposure to SM results in sloughing of corneal epithelium and stromal cell necrosis within 24 hr. The corneal lesion is re-epithelialized within 96 hr, and there is minimal evidence of injury by 1-2 wk. However, 75% of animals undergo a recurrent injury between 3-5 wk that is progressive and more severe than the acute injury, characterized by neovascularization, persistent immune cell infiltration, significant corneal edema and recurrent corneal erosions. For the first time we present correlations between ultrastructural and clinical aspects of the acute and recurrent injuries from 0-5 wk, correlating architectural changes in the corneal epithelium, basement membrane and stroma with the onset of recurrent sequelae. We evaluate these results in terms of injury mechanism(s) and novel, evidence-based therapeutic approaches as well as propose future research directions to identify the contribution of specific corneal tissues to SM injury. 1749 INDUCTION OF AUTOPHAGY IN A MOUSE KERATINOCYTE CONSTRUCT MODEL BY THE VESICANT 2-CHLOROETHYL ETHYL SULFIDE; REGULATION BY MAP KINASES AND CAVEOLAE. A. T. Black 1 , R. P. Casillas 2 , D. E. Heck 3 , D. R. Gerecke 1 , D. L. Laskin 1 and J. D. Laskin 4 . 1 Rutgers University, Piscataway, NJ, 2 Battelle Biomedical Research Center, Columbus, OH, 3 New York Medical College, Valhalla, NY and 4 UMDNJ- RWJ Medical School, Piscataway, NJ. Sulfur mustard is a potent vesicant that causes inflammation, edema and blistering in the skin. These effects are associated with basal keratinocyte damage and cytotoxicity. Autophagy is a membrane-trafficking mechanism for protein and cytoplasmic organelle degradation and is enhanced in stressed cells. In the present studies, we analyzed the effects of the half mustard 2-chloroethyl ethyl sulfide (CEES) on the autophagic process in keratinocytes using a skin construct model in which cells are grown at an air-surface interface. CEES (100-1000 μM) caused a concentration-dependent increase in autophagy in keratinocytes as detected by flow cytometry in conjunction with acridine orange staining. CEES treatment also upregulated gene and protein expression of LC3B, beclin-1, and p62, proteins known to participate in autophagy, as well as caveolin-1, the primary structural protein of caveolae. Isolation of cytosolic and caveolar fractions from keratinocytes showed that LC3B and p62 were specifically localized within caveolae, while beclin-1 was found primarily in the cytosol of control cells, and in both cytosolic and caveolar fractions of CEES-treated cells. Disruption of caveolae using filipin (20 μM) or methyl-β-cyclodextrin (5 mM) markedly suppressed expression of LC3B, beclin-1 and p62 in CEES-treated keratinocytes. CEES also activated the JNK and p38 MAP kinase signaling pathways in keratinocytes. Treatment of the cells with inhibitors of JNK (SP600125, 20 μM) or p38 (SB203580, 10 μM) markedly suppressed expression of LC3B, beclin-1 and p62, as well as caveolin-1. Taken together, these data indicate that caveolae play a key role in CEES-induced autophagy in keratinocytes and that this process is regulated JNK and p38 MAP kinases. Supported by CA093798, ES004738, ES005022, GM034310 and AR055073. 1750 ROLE OF CAVEOLAE IN REGULATING EXPRESSION OF HSP27 AND HSP70 FOLLOWING EXPOSURE OF HUMAN AND MOUSE SKIN MODELS TO THE VESICANT 2-CHLOROETHYL ETHYL SULFIDE. J. D. Laskin 1 , A. T. Black 2 , P. J. Hayden 3 , R. P. Casillas 4 , D. E. Heck 5 , D. R. Gerecke 2 and D. L. Laskin 2 . 1 UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, 2 Rutgers University, Piscataway, NJ, 3 MatTek Corporation, Ashland, MA, 4 Batelle Memorial Institute, Columbus, OH and 5 New York Medical College, Valhalla, NY. Dermal exposure to the vesicant sulfur mustard causes marked inflammation and tissue damage. Although sulfur mustard is a non-specific alkylating agent, basal keratinocytes appear to be a major target. In the present studies, mechanisms mediating sulfur mustard-induced skin toxicity were examined using a full-thickness human skin equivalent (EpiDerm-FT TM ) and a mouse keratinocyte skin construct model. In both models, treatment of keratinocytes at the air surface with 2chloroethyl ethyl sulfide (CEES, 100-1000 μM) induced gene and protein expression of caveolin-1, a major component of caveolae which are membrane structural elements important in regulating intracellular signaling. CEES treatment also increased gene and protein expression for heat shock proteins 27 and 70 (Hsp27 and Hsp70). In the full-thickness human skin equivalent, immunohistochemistry revealed that Hsp27, Hsp70 and caveolin-1 were localized in basal and suprabasal layers of the epidermis. Caveolin-1 was also detected in fibroblasts in the dermal component. Isolation of caveolar fractions from control and CEES-treated mouse keratinocytes from the skin constructs using sucrose density gradient ultracentrifugation showed that Hsp27 and Hsp70 were localized in caveolae. Treatment of keratinocytes with filipin (20 μM) or methyl-β-cyclodextrin (5 mM), two agents which disrupt caveolar structure, markedly suppressed CEES-induced Hsp27 and Hsp70 gene and protein expression. These data indicate that caveolae-mediated regulation of heat shock protein expression is likely to play an important role in the pathophysiology of vesicant-induced skin toxicity. Supported by CA093798, CA132624, ES004738, ES005022, GM034310 and AR055073. SOT 2011 ANNUAL MEETING 375
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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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Page 357 and 358: egulated targets were selected for
Page 359 and 360: U/L after tetracycline. Minocycline
Page 361 and 362: peri-pubertal FasL-/- mice show a d
Page 363 and 364: showed similar levels of apoptosis
Page 365 and 366: 1676 TWO BIOMARKERS FOR EVALUATION
Page 367 and 368: motifs selected. This system was ap
Page 369 and 370: 1693 VOC SERUM LEVELS IN THE GENERA
Page 371 and 372: 1702 DOES THE CLOCK MAKE THE POISON
Page 373 and 374: those with high nickel content are
Page 375 and 376: isk assessment. However, unique cha
Page 377: model of APAP metabolism and glutat
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 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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