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2539 PREDICTION OF HEPATOTOXICITY IN ZEBRAFISH. C. Callol, C. Quevedo and A. Letamendia. Biobide S.L., San Sebastian, Spain. Sponsor: S. Tripathi. Drug-induced hepatotoxicity is one of the most important causes of drug withdrawal in the process of Drug Discovery. The low correlation of the in vitro cytotoxicity studies, with human hepatotoxicity, especially in the early stages of Drug Discovery, make human hepatotoxicity difficult to predict. Therefore, the finding of new methods and models to predict hepatotoxicity is a growing area of research. The zebrafish model has been extensively studied in the last decades for its ability to regenerate. Specifically, the liver is one of the organs with the highest regenerative capacity and research over the past 10 years have characterized many of the mechanisms that occur during this process leading to an important knowledge of the signaling pathways that govern zebrafish liver function and development. Therefore, because of the functional and development similarities between the liver of zebrafish and mammals, we propose to analyze the potential of zebrafish for prediction of hepatotoxic agents. For this purpose, the following aspects have been studied: i) The stage at which adult liver markers are expressed has been identified. ii) Several techniques have been developed for assessing the hepatotoxicity of a compound in zebrafish. iii) These techniques will be validated by testing different drugs. iv) The results will be compared with those obtained in mammals. Our results indicate that zebrafish embryos could be used as an alternative model in the Drug Discovery process complementing the information of in vitro models and mammals and providing pharmaceutical industry of new assays which might decrease the current huge gap between in vitro and in vivo assays. 2540 PREDICTION OF DRUG-INDUCED LIVER INJURY WITH HIGH SENSITIVITY AND SPECIFICITY WITH HIGH-CONTENT CELL-BASED IMAGING. R. N. Ghosh, S. J. Hong, B. A. Samson, K. Corkan, M. Pietila, C. Vasudevan and J. R. Haskins. Thermo Fisher Scientific, Pittsburgh, PA. Drug-induced liver injury is a major reason for drug failure and withdrawal from the market. An assay system that enabled early and accurate prediction of drug-induced hepatotoxicity with high sensitivity and specificity would benefit drug development by improving the safety profile of newly developed drugs. Developing an in vitro assay that accurately predicts the toxicology of drug candidates remains a challenge in drug development. A critical factor contributing to the predictive nature of such assays is the ability to measure early indicators of cell stress and toxicity in liver cells. We report here a predictive, automated cell-based high-content imaging assay that simultaneously quantifies the multiplexed response from five different cellular properties in a single assay platform: cell loss, DNA content, intracellular reduced glutathione level, intracellular reactive oxygen species level and mitochondrial membrane potential changes. In this assay, liver cells (HepG2 cells, primary hepatocytes) were treated with a panel of compounds, including those known to be idiosyncratic human hepatotoxicants such as troglitazone, dantrolene, and tetracycline, as well as non-hepatotoxic compounds including rosiglitazone, aspirin, fluoxetine and melatonin. The cells were then labeled with specific fluorescent probes for the distinct cellular properties and automatically imaged and quantitatively analyzed using the Thermo Scientific ToxInsight IVT platform. By combining the individual responses from the five assay targets, we defined several multiplexed toxicity indices that accurately predicted drug-induced hepatotoxicity with greater than 80% specificity and sensitivity on the hepatic models tested. Additionally, the different multiplexed toxicity indices had better specificity and sensitivity in determining compound hepatotoxicity than measuring the individual assay target responses. We believe our approach shows an effective method of predicting hepatoxicity of compounds and thus reduce drug attrition. 2541 GENE EXPRESSION PROFILING OF AN IN VITRO HUMAN SKIN MODEL AFTER PSORALEN PLUS ULTRAVIOLET LIGHT-INDUCED PHOTOTOXICITY. L. F. Pratt 1 , G. L. DeGeorge 1 and M. Cunningham 2 . 1 MB Research Laboratories, Spinnerstown, PA and 2 Nanomics Biosciences, Inc., Cary, NC. To reduce the number of animals for safety screening of potential irritating chemicals and phototoxins, efforts have been made to develop more predictive in vitro assays. One model in more common use is reconstituted human epidermis (MatTek Epiderm) resembling in vivo human skin. In this investigation, these human skin models were exposed to a known skin irritant, 8-methoxypsoralen (8MOP), at a dose comparable to the EC10. The samples were also either kept in the dark or exposed to solar simulated light (SSL). Gene activity was analyzed with mRNA mi- 544 SOT 2011 ANNUAL MEETING croarrays at 1, 6, and 20 hr to determine potential cellular and molecular mechanisms of action. Two levels of biological control samples were used: a) samples not treated with 8MOP and kept in the dark or exposed to UV light and b) samples treated with sodium dodecyl sulfate (SDS) [positive control]. Purified, labeled, and fractionated cRNA isolated from each of the biological samples were hybridized onto whole human genome mRNA expression microarrays, each containing 41,000 unique probes. Data analysis was done by a tiered approach. Coefficients of variation (CV) from all the probes passing quality measures or a total of 11,335 probes for each biological sample within the treatment groups ranged from 18.5- 33.1%. The least variability was observed with the principal components analysis (PCA) for the negative control samples (those not exposed to 8MOP) and the samples exposed to 8MOP under dark conditions. The most activity was seen with 8MOP and SSL exposures at 6 and 20 hr as well as exposures to SDS, the positive control. Several genes in common between treatments with SDS and 8MOP were CXCL14, fibrillin2, tropomyosin alpha 1, CYP26B1, HSP70B AND VEGF-A. Funding was provided by NIEHS Grant No. 5-R44-ES-11927-02. 2542 OXIDATIVE STRESS AND HYPOXIA AS FACTORS IN PHOTOTOXIC DAMAGE TO A RECONSTITUTED HUMAN SKIN MODEL: GENE EXPRESSION PROFILING EVIDENCE. M. Cunningham 2 , L. F. Pratt 1 and G. L. DeGeorge 1 . 1 MB Research Laboratories, Spinnerstown, PA and 2 Nanomics Biosciences, Inc., Cary, NC. Currently there is worldwide emphasis on more predictive in vitro assays for phototoxicity, especially in screening dermatological and pharmaceutical products. Reconstituted human skin tissues modeling human skin in vivo were exposed to a known phototoxin, chlorpromazine (CPZ) with and without ultraviolet light, at a dose correlating with the EC10. The goal was to understand what cellular and genetic mechanism(s) contribute to the phototoxic response. The skin models were treated with CPZ in the dark as well as exposed to solar simulated light (SSL) and gene activity was measured with mRNA expression microarrays at 1, 6, and 20 hr post-exposure. For comparison, biological control tissues were concurrently treated with vehicle alone or left untreated CPZ, and kept either in the dark or exposed to UV light. Purified, labeled, and fractionated cRNA isolated from each of the tissue samples were hybridized onto whole human genome mRNA expression microarrays. The microarrays contained 41,000 unique probes corresponding to the full complement of sequenced human genes. The data was analyzed using a tiered approach. Coefficients of variation (CV) from all the probes passing quality measures or a total of 10,299 probes for each tissue sample within the treatment groups ranged from 5.3 to 19.2%. The least variability was observed with the principal components analysis (PCA) for the skin model samples not treated to CPZ under either dark or light conditions. The profiles for each treatment group were more similar by time point rather than by light/dark exposure. The numbers of downregulated genes ranged from 10 to 52 and the numbers of up-regulated genes ranged from 96 to 236. Noteworthy genes which were down-regulated included genes involved in differentiation and normally expressed in epithelial tissue, such as CXCL14 and DAPL1. Several genes (e.g. HSPA6, ERO1L and ANGPTL4) related to oxidative stress and hypoxia were up-regulated. Funding was provided by NIEHS Grant No. 5-R44-ES-11927-02. 2543 A NEW IN VITRO MODEL FOR IDENTIFYING LIVER SPECIFIC TOXICITY (LST). J. M. McKim, B. Wallace, P. C. Wilga, C. Toole, H. Wagner, A. Swanson and K. Rutherford. CeeTox, Inc., Kalamazoo, MI. In early drug discovery, the ability to rapidly identify compound liabilities while optimizing for desired drug qualities is critical for success in preclinical and clinical safety studies. Cell lines can provide information on general toxicity, but cannot identify organ specific toxicity. The aim of this study was to develop and optimize an in vitro system that could identify liver specific toxicity of highly toxic compounds and of compounds with low toxicity, often categorized as idiosyncratic. To accomplish this, a two cell model was used in this study, a rat hepatoma (H4IIE) cell line and rat primary hepatocytes grown in sandwich culture. Test compounds with known mechanisms of toxicity (rotenone, camptothecin, ANIT) were tested along with three groups of approved drugs, where one member of each group had shown after-market liver toxicity or a drug-drug interaction. The three groups evaluated included the antifungals (ketoconazole, itraconazole, fluconazole), the antidepressants (nefazodone, trazodone, buspirone), and the antidiabetics (troglitazone, pioglitazone, and rosiglitazone). The test compounds were applied to the culture
wells (0, 1, 5, 10, 25, 50, 100, and 300 μM) of either 96- or 24-well plates in replicates of 3 and allowed to incubate at 37 o C with 5% CO 2 for 24 hr. Cell health was determined by membrane leakage, mitochondrial function, cell proliferation, GSH depletion, and caspase 3 activation. Liver specific markers for canalicular damage included GGT and AP. Inhibition of UGT1A1 and BSEP were determined in a cell-free system. Analysis of the data obtained yielded a toxicity profile that accurately identified ketoconazole, nefazodone, and troglitazone as the high risk compounds. In conclusion, the LST panel described provides an excellent method for assessing risk for liver specific toxicity. 2544 DEVELOPING AN IN VITRO MODEL TO DETERMINE KIDNEY SPECIFIC TOXICITY (KST). J. F. Pregenzer 1 , K. Leach 2 , B. Feng 3 , B. Wallace 1 , D. Keller 1 , J. Willoughby 1 and J. M. McKim 1 . 1 CeeTox, Inc., Kalamazoo, MI, 2 Compound Safety Prediction, Pfizer Global Research and Development, Groton, CT and 3 Pharmacokinetics and Drug Metabolism, Pfizer Global Research and Development, Groton, CT. Kidney toxicity is induced by a wide spectrum of marketed drugs, and renal toxicity is one of the major reasons for drug failure in early preclinical safety studies. Cellular models that can be used to predict compounds that may cause renal toxicity would be of great value. Most observed toxicity in the kidney occurs in the proximal tubule. Therefore, a human derived in vitro model that accurately reflects the in vivo orientation and function of the kidney would provide data specific to the function of kidney. Cryopreserved human renal proximal tubule cells (hRPTC) were obtained commercially and seeded onto 12-well transwell plates coated with collagen at a density of 100,000, 200,000 or 500,000 cells per well. The cells were allowed to grow for 7-10 days to establish tight junctions and proper polarity. Incubation with Lucifer Yellow demonstrated an adequate barrier between the apical and basolateral compartments. The presence of major renal drug transporters including OAT1, OAT3, and megalin was confirmed by either qRT-PCR or immunohistochemical staining. To further characterize transporter function, 5 μM of 14 C-PAH or 50 μM 14 C-TEA was added to the basolateral side of the cells. Transport of the radiolabeled compounds to the apical side suggested that these cells display functional OAT and OCT transport activity. OAT activity was further validated by probenecid inhibition. Incubation of these cells with the nephrotoxic compound cisplatin (1 to 500 μM) for 24 hr resulted in reduced cell viability, as measured by LDH release and propidium iodide staining. In contrast, cisplatin did not inhibit the growth of the kidney cell lines NRK-52E or LLC-PK1 at concentrations up to 500 μM. In conclusion, hRPTCs display kidney-specific functional activity and thus may be a sensitive model for predicting nephrotoxicity. 2545 IN VITRO ASSESSMENT OF EYE TOLERANCE USING THE SKINETHIC HCE TEST METHOD APPLIED TO INGREDIENTS USED IN COSMETICS. M. H. Grandidier, N. Alépée, S. Blond, J. Eilstein, D. Duché, J. Cotovio and J. R. Meunier. L’Oréal, Aulnay sous Bois, France. Sponsor: H. Toutain. To comply with the EU Cosmetic Directive, accurate sensitive and predictive alternative methods are required in order to evaluate eye damage potential of chemicals. Linked to the complexity of both the eye irritation mechanism and the diversity of the intrinsic molecular behavior of chemicals, assessment of the potential eye irritation of ingredients is a complicated issue. The role of corneal epithelium is crucial because it represents the first line of defense against many types of injury. Thus we have used the standardized SkinEthic reconstructed human corneal epithelial (HCE) model to evaluate in vitro eye irritancy (Cotovio et al, 2010). We have determined the chemical reactivity parameter by measuring the depletion of synthetic peptide containing Cysteine or Lysine residues in contact with chemicals. The reactivity peptide binding assay (RPBA-HCE) defining the reactivity status of chemicals was optimized from the DPRA assay (skin sensitization evaluation) for assessing the eye irritancy using the SkinEthic HCE test method. The Prediction Model (PM), applied for a set of more than 180 chemicals, is based on a 5.95 % depletion cut off, with 2 categorizations (reactive and non reactive). In parallel, SkinEthic HCE protocol (10 min and 1 hr + 16 hrs post-exposure incubation) used with the same set of chemicals confirmed that the PM based on a 50 % viability cut-off allowed the drawing up of irritants and non irritants classes. Results (~1/3 reactive versus ~2/3 non reactive chemicals) showed that the measure of molecular reactivity of these chemicals used to orientate the tested chemicals towards the suitable time exposure allowed to discriminate irritants from non irritants. Consequently, the resulting performances of the testing battery combining SkinEthic HCE assays and chemical reactivity measurement greatly enhanced the applicability domain of the SkinEthic HCE assay. 2546 USING FUNDULUS HETEROCLITUS TO STUDY BENZO(A)PYRENE EFFECTS ON THE HYPOTHALAMUS-PITUITARY-GONAD (HPG) AXIS. F. T. Booc 1 , C. Thornton 1 , D. MacLatchy 2 , A. Lister 2 and K. L. Willett 1 . 1 Pharmacology, University of Mississippi, University, MS and 2 Biology, Wilfrid Laurier University, Waterloo, ON, Canada. Polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BaP) alter aromatase (CYP19) expression. Because aromatase is responsible for converting androgens to estrogens, hormone concentrations in exposed individuals could also be affected. Altered steroid homeostasis may, in turn, negatively affect reproductive physiology and other downstream physiological processes. In order to further study possible physiological effects, a short-term reproductive bioassay was done using Fundulus heteroclitus adults exposed to waterborne concentrations of BaP (0, 1 or 10 μg/L) for 28 days. Males and females were kept separate days 0-14. The sexes were combined for days 14-28 so that spawning and reproductive success could be measured. BaP exposure did not alter male or female gonad somatic index (GSI) or liver somatic index (LSI) significantly. Similarly, sperm counts, egg production and fertilization success (n = 6 tanks per treatment; 3 fish of each sex per tank) were not altered by exposure. In conclusion, BaP-mediated changes in aromatase expression have the potential to cause changes in the HPG axis, but more endpoints will need to be analyzed (e.g. plasma steroid concentrations, LH and FSH expression, vitellogenin) before definitive statements can be made about its potential to negatively impact reproductive and developmental success at these concentrations. (Supported by NIEHS R03 ES018962) 2547 PORCINE ADRENAL CORTEX MICROSOMES AS IN VITRO ALTERNATIVE ASSAY FOR SCREENING ON SEX STEROIDOGENESIS TOXICITY. M. Roelofs 1, 2 , M. van den Berg 1 , A. H. Piersma 2, 1 and M. B. van Duursen 1 . 1 Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands and 2 National Institute for Public Health and the Environment, Bilthoven, Netherlands. The majority of experimental animal use in chemical risk assessment occurs in reproductive toxicity testing. Therefore, there is a high need for in vitro alternative assays. In this study we investigated the potential use of porcine adrenal cortex microsomes (PACMans) for screening of compounds for their potential interaction with the steroidogenic pathway. Porcine adrenals were obtained from the slaughterhouse and microsomal fractions were prepared through ultracentrifugation. PACMans were incubated with pregnenolone and NADPH whereupon production of dehydroepiandrosterone (DHEA), testosterone (T), and estradiol (E2) was determined using commercially available radioimmunoassays (RIAs). Our data show that PACMans contain all key enzymes of the steroidogenic pathway since DHEA, T, and E2 could all be determined. However, T and E2 production was very low at 8.53 and 2.3*10 -3 pg/mg protein/min, respectively. These findings are supported by the low activity of aromatase (CYP19) in the PACMans (0.56 ± 0.06 pmol/hr/mg protein). In contrast, DHEA production could very well be determined (0.60 ng/mg protein/min) indicating a high cytochrome P450 17 (CYP17) activity. Adding CYP17 inhibitor SU10603 significantly reduced DHEA levels to background. Furthermore, concentration-dependent inhibition of DHEA production by ketoconazole (IC 50 = 1 μM) and prochloraz (IC 50 = 0.4 μM) but not bisphenol A was observed. This corroborates with findings in the H295R (human adrenocorticocarinoma cell line) assay. Although T and E2 production are too low for sensitive screening, PACMans could prove useful in testing for interactions with CYP17 activity. CYP17 is one of the key enzymes in sex steroidogenesis for which currently no specific rapid bioassay is available. Studies are ongoing to determine the predictivity and applicability of this assay, and will include screening of several potential endocrine disruptors. 2548 EARLY DISRUPTION OF ANGIOGENESIS-RELATED GENES BY METHYL TERT-BUTYL ETHER (MTBE) LEADS TO VASCULAR SPECIFIC LESIONS IN THE ZEBRAFISH (DANIO RERIO). J. A. Bonventre, L. A. White and K. R. Cooper. Joint Graduate Program in Toxicology, Rutgers University/UMDNJ, Piscataway, NJ. MTBE disrupts normal vascular development in embryos. Exposure to 0.625 to 10mM MTBE resulted in a dose dependent increase in pooled blood in common cardinal vein, cranial hemorrhages and abnormal intersegmental vessels. Stage specific exposures were carried out to determine the developmental period most sensitive to MTBE vascular disruption. Embryos were treated with 10mM MTBE from SOT 2011 ANNUAL MEETING 545
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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
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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
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: 2534 CUTANEOUS WOUND HEALING IN THE
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 599 and 600:
Author Index (Continued) The numera
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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