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see whether both were needed or if one assay was sufficient in detecting mitochondrial impairment. The first assay uses isolated rat liver mitochondria and measures a compound’s effect on oxygen consumption. The second assay uses HepG2 cells grown in either glucose or galactose containing media. Cells grown in galactose are susceptible to mitochondrial insult, whereas cells grown in glucose are resistant. We tested three sets of compounds that were associated with different organ-specific toxicity. We tested 197 cardiac, 254 hepatic, and 83 nephritic compounds, which included both, Pfizer internal and commercially available compounds. Of the 534 compounds, 2.5 % flagged positive in isolated mitochondria as well as in galactose grown HepG2 cells, 3.5% flagged in isolated mitochondria and glucose and galactose cells, indicative of additional toxicity mechanisms. To our surprise 5% of the compounds (27 total) only showed toxicity in the isolated rat liver mitochondria assay but not in HepG2 cells. We further analyzed these compounds using the Seahorse platform which measures oxygen consumption rate and extracellular acidification rate of intact cells simultaneously in real time. The mitochondrial impairment was confirmed in the Seahorse experiments when compounds were analyzed in real time. However, time course experiments revealed that cells could recover from the insult and therefore exhibited no frank cell toxicity. In summary, the current results indicate that including both assays in assessing mitochondrial toxicity is important for identifying the greatest number of compounds showing mitochondrial impairment. The mechanism behind the compensatory response warrants additional future mechanistic work. 2530 JC-1 MITOCHONDRIAL MEMBRANE POTENTIAL MEASUREMENTS OF H9C2 CELLS GROWN IN GLUCOSE AND GALACTOSE CONTAINING MEDIA DOES NOT PROVIDE ADDITIONAL PREDICTIVITY TOWARDS MITOCHONDRIAL TOXICITY ASSESSMENT. P. Rana, Y. Will and S. Nadanaciva. Compound Safety Prediction, Pfizer Global Research & Development, Groton, CT. Drug-induced mitochondrial toxicity has been recognized to be a contributing factor to a variety of organ toxicities. The fact that some, but not all members of a particular drug class can induce mitochondrial dysfunction has necessitated the need to deploy predictive screens within the drug development process. One of these screens is a cell viability assay done in two types of media, one supplemented with glucose and the other with galactose. Since galactose-grown cells are more susceptible to mitochondrial toxicants than glucose-grown cells, this assay distinguishes compounds that cause toxicity primarily through mitochondrial targets from those that cause multifactorial toxicity. However, the assay cannot distinguish compounds that cause toxicity through secondary effects on mitochondria from those that cause toxicity through non-mitochondrial targets. Mitochondrial membrane potential measurements are thought to be indicative of mitochondrial impairment and can be measured in the absence of frank cytotoxicity. Here we investigated if multiplexing mitochondrial membrane potential measurements with the fluorescent dye, JC-1; together with cell viability measurements in glucose and galactosegrown H9C2 cells could provide additional value for compounds that have a multifactorial toxicity. We tested 29 drugs with well characterized mechanistic toxicity profiles. These compounds set included compounds with different therapeutic uses i.e. antidepressants, anti-diabetic agents, anti cancers, etc. The multiplexed assay was able to detect mitochondrial toxicants correctly but did not reveal additional information regarding compounds that exhibited multifactorial toxicity; hence, JC- 1 measurements did not provide additional information beyond what was detected using the cell viability assay. Thus, we conclude that even though this multiplexed assay is useful for HTS applications, it provides no additional value over the glucose-galactose cell viability assay. 2531 TREATMENT OF FATTY ACIDS INCREASES THE SUSCEPTIBILITY OF CELLS TO TOXIC COMPOUND INDUCED INJURY. Y. Luo, P. Rana and Y. Will. Compound Safety Prediction, Pfizer Global Research & Development, Groton, CT. Fatty acids are important source of energy and cells are exposed to various fatty acids under physiological conditions. Excessive energy intake results in elevated levels of fatty acids or triglycerides and cause metabolic disorders such as dyslipidemia, obesity, insulin resistance and diabetes. Several lines of evidence suggest that metabolic diseases increase the susceptibility to drug induced liver injury, cardiotoxicity and renal toxicity. Regular cell culture conditions contain very low levels of fatty acids, much less that than physiological concentrations. It has never been reported whether fatty acids influence the sensitivity of cells to drug induced toxicity. The aim of this study is to investigate the effects of fatty acids on drug induced toxicity. 542 SOT 2011 ANNUAL MEETING In this study, we tested the effects of palmitate and oleic acid on the viability of HepG2 cells. High concentrations of fatty acid treatment induced cell apoptosis and reduced cell viability. Subsequntly, sub-toxic and toxic concentrations of fatty acid were chosen to investigate whether fatty acids could potentiate drug induced toxicity. We incubated the cells with various concentrations of fatty acids (palmitate and oleic acid) and compounds followed by analyzing cell viability. Here we report the results for statins (simvastatin, cerivastatin, lovastatin, atrovstatin, pravastatin) and glitazones (ciglitazone, troglitazone, rosiglitazone, and pioglitazone). Furthermore, increased population with metabolic diseases pose higher risk for drug induced toxicity, and this assay may identify compounds that have higher risks in this population, individually or in combination therapy. 2532 ER-STRESS AS A CONTRIBUTOR TO HEPATOTOXICITY: DEVELOPMENT OF A SCREENING PARADIGM. T. Schroeter, L. Qui, M. Pletcher and Y. Will. Compound Safety Prediction, Pfizer Global Research & Development, Groton, CT. The greatest challenge facing the pharmaceutical industry today is developing more effective decision making tools and strategies to reduce the attrition rate of novel compounds during candidate selection and clinical development. Currently, approximately 24 out of 25 compounds fail in clinical trials, a situation that is unsustainable for the industry. One of the major attrition reasons is hepatotoxicity. Gene expression profiles associated with known idiosyncratic hepatotoxicity, revealed ER stress as an important contributor to drug-induced liver toxicity. We developed two assays to investigate whether induction of the endoplasmic reticulum stress response (ERSR) is a predictive reporter of liver toxicity. The first assay detects nuclear translocation of spliced XPB-1 by enzyme fragment complementation (DiscoveRx) and the second assay is a luciferase CHOP reporter assay. We screened 180 Pfizer internal and commercial available hepatotoxicants and 42 drugs not known to cause organ toxicity in both assays. Compounds were screened in both assays at a final concentration of 150 uM. The XBP-1 screen identified 16 hits. Full dose response curves were generated for all hits and we were able to confirm 13 out of 16 XBP-1 hits. To our surprise, 4 (Ergocalciferol, Dipyridamole, Orphenadrine and Propanolol) of the 13 confirmed XBP-1 hits were drugs with no known organ toxicities. Of the 9 liver toxicants, 7 showed signs of cytotoxicity but so did two of the 4 drugs not known to be organ toxic. The CHOP screen identified 3 hits which could all be validated. All of them are known liver toxicants (Riluzole, Colchicine and Oxybendazole) with Riluzole showing signs of cytotoxicity. Current work centers around confirmation of pathway activity of all active compounds in HepG2 cells to assist in vitro to in vivo correlation. 2533 HIGH-CONTENT IMAGING ASSAY FOR DETECTING ACCUMULATION OF COMPOUNDS IN LYSOSOMES. S. Nadanaciva 1 , S. Lu 2 and Y. Will 1 . 1 Compound Safety Prediction, Pfizer Global Research & Development, Groton, CT and 2 DSRD, Pfizer Global Research & Development, La Jolla, CA. Known as the cell’s recycling center, lysosomes are essential for the degradation of old organelles, endotoxins and engulfed microbes. Many enzymes which function in the acidic milieu of the lysosome are involved in degradative processes. Compounds which are lipophilic weak bases or lipophilic neutral amines can readily cross the lysosomal membrane from the cytoplasm. Once inside lysosomes, however, these compounds become protonated and are unable to cross the lysosomal membrane to re-enter the cytoplasm. The trapping of compounds within lysosomes can cause alkalinization of these organelles, resulting in lysosomal dysfunction. Hence, high-throughput screens to detect lysosomotropism, the accumulation of compounds in lysosomes, are desirable. In light of this, we developed a 96-well format multiplexed high content screening (HCS) assay that measures both lysosomotropism and cytotoxicity. The effect of a selection of compounds on these two endpoints was measured in H9c2 cells by using the fluorescent dyes, LysoTracker® Red and Hoechst. Quantitative image analysis showed that lysosomotropic compounds included the antimalarial, chloroquine, antidepressants (sertraline, paroxetine, fluoxetine, imipramine, nortriptyline), antipsychotics (chlorpromazine, thioridazine), antiarrhythmics (amiodarone, propranolol), and some anticancer agents (tamoxifen, imatinib, dasatinib, gefitinib, lapatinib). Although structurally and pharmacologically diverse, compounds which caused lysosomotropism had a CLogP value > 2 and a basic pKa value between 6.5 to 11. In contrast, compounds which did not have this combination of physicochemical properties were not lysosomotropic. The HCS assay that we developed is a robust and rapid method for investigating lysosomotropism and can be implemented within a screening paradigm for identifying drug-induced lysosomal dysfunction.
2534 CUTANEOUS WOUND HEALING IN THE EPIDERM-FT FULL-THICKNESS IN VITRO HUMAN SKIN MODEL. P. J. Hayden, A. Armento, C. Cooney, G. Stolper, M. Li, H. Kandarova and M. Klausner. MatTek Corporation, Ashland, MA. Cutaneous wound healing involves interactions between dermal fibroblasts (FB) and epidermal keratinocytes (KC) as well as cell-extracellular matrix interactions. The current study describes wound healing experiments conducted in a full thickness in vitro human skin model (EpiDerm-FT). The model exhibits stratified epidermal components, a well developed basement membrane and in vivo-like barrier function. Small epidermal-only wounds (3mm biopsy punch) or full-thickness wounds (cauterizer burns) were induced in the model and cultures were processed for histological evaluation at various time points to observe the healing process. H&E stained sections of burn wounds showed necrotic epithelium and denatured collagen matrix immediately following burning. Beginning at day 1, matrix degradation and KC migration into the wounded area was observed. Over the course of 7 days, migrating KC covered the wounded area and FB were observed repairing the dermal matrix. Biopsy wound experiments were conducted in growth factor free medium or medium supplemented with 2% human serum (HS). Wounded tissues cultured without growth factors had a reduced healing rate where KC did not cover the entire wound within 6 days. Wounded tissues cultured in 2% HS had a significant increased healing rate with complete wound coverage by day 6. Increased FB proliferation in dermal areas directly adjacent to epidermal wounds was observed in cultures supplemented with 2% HS. Gene expression profiling of the wounded area showed temporally regulated changes in mRNA expression of basement membrane components, collagens and genes involved in extracellular matrix remodeling. FB proliferation and epidermal healing in tissues cultured in 2% HS was severely impaired in the presence of an EGFR tyrosine kinase inhibitor or a TGFα neutralizing antibody. These results demonstrate that EpiDerm−FT is a useful in vitro skin model for investigating dermal−epidermal interactions during wound healing and evaluation of the role of growth factors or new therapeutics in the cutaneous wound healing process. 2535 EVALUATION OF EPISKIN AND EPIDERM SKIN IRRITATION METHODS FOR TESTING SILICON- BASED MATERIALS. M. L. Jovanovic, J. Arthurton and P. Jean. Dow Corning, Auburn, MI. In vitro skin irritation test methods have been formally validated and adopted within the European Union as an OECD Test guideline. Since silicone-based materials were not included in the validation effort, it is necessary to assess the methods and outcome as it relates to silicon-based materials with properties that may prove difficult to use in the existing protocols. The assay is based on the reduction of cell viability in treated tissues, measured by enzymatic conversion of the vital dye MTT into a blue formazon salt, and expressed as a percentage of the negative control. The cut-off value of percentage cell viability distinguishing irritant from non-irritant is 50%. In vitro data are compared to the in vivo irritation score obtained in rabbits (Draize test). Fifteen silicone materials (12 non- irritants and 3 irritants by Globally Harmonized System classification) from seven different chemical classes (siloxane, polysiloxane, polysiloxane/copolymer, organosilane, silicone resin, silazane and microemulsion) were selected to evaluate the ability of the test method employing reconstituted human epidermis (RhE) models, EpiSkin and EpiDerm, to reliably discriminate skin irritants from non-irritants. However, the lack of silicon-based materials with known irritation potential resulted in an unbalanced distribution of irritation categories. We found that the EpiSkin model under-predicted irritants (33% sensitivity), while the EpiDerm model showed a lower accuracy when identifying non-irritants (58% specificity). The overall accuracy obtained with EpiSkin and EpiDerm was 87% and 67%, respectively. The work presented here provides a platform for further mechanistic and validation efforts and emphasizes the need to test additional silicon-based material irritants to afford a balanced determination of the predictive capacity of these in vitro test methods. 2536 COMPARISON OF FCM AND ELISA IN THE EVALUATION OF THE OF SKIN SENSITIZATION BY NON-RADIOACTIVE MURINE LOCAL LYMPH NODE ASSAY USING BROMODEOXYURIDINE. Y. Yum 1 , Y. Lee1 , K. Jung2 , K. Lim2 , J. Park1 , H. Park1 , J. Kim1 , J. Yang1 , S. Sohn1 , J. Chung3 and S. Han1 . 1Toxioclogical Evaluation and Research Department, National Institute of Drug and Food Safety Evaluation, Seoul, Republic of Korea, 2Amorepacific Corporation R&D Center, Yougin-si, Republic of Korea and 3College of Pharmacy, Seoul National University, Seoul, Republic of Korea. The murine local lymph node assay (LLNA) using H3-thymidine has been developed to detect chemical allergens, replacing the traditional guinea pig maximization test. Recently, non-radioactive local lymph node assay employing bromodeoxyuridine(BrdU) incorporation, LLNA: BrdU-FC method has been developed to extend its utility further. The FCM analysis of BrdU incorporation according to modified MB research’s protocol has good sensitivity, based on measuring of individual cellular level. In 2010, non-radioisotopic LLNA using ELISA method was adopted by OECD Test Guideline(OECD TG 442B). In this study, we tried to perform two nonradioactive LLNA tests of reference substances including 3 sensitizer and 1 non-sensitizer, using Balb/c strain mice. We assessed the chemicals in accordance with the decision criteria for positive sensitizer which are stimulation index(SI) ≥1.6, in LLNA:BrdU-ELISA and stimulation index(SI) ≥3, in LLNA:BrdU-FCM. 2537 ADAPTATION OF THE RAT HEPATOCYTES LONG- TERM CULTURE FOR HIGH-CONTENT IMAGING TO PREDICT CHRONIC LIVER TOXICITY IN VITRO. G. Davide, C. Zehnacker, P. Couttet, S. Chibout, O. Grenet, M. Uteng, F. Pognan, M. Dong and A. Wolf. Translational Sciences/Investigative Toxicology, Novartis Institute for Biomedical Research (NIBR), Basel, Switzerland. The conventional Collagen-sandwich culture with the soft/wet gel proved not to applicable to the high-content cellular imaging method due to interferences of the collagen with fluorescence dyes. In addition the CellomicsArrayscan® technological platform requires cells to be evenly distributed and orientated on the same plane, since it does not work in confocal mode. To overcome these hurdles MatrigelTM was used instead of Collagen as the top layer. Multiple MatrigelTM administrations were found to be essential to maintain the hepatocyte integrity for 14 days in culture. The optimal conditions achieved were three times application of MatrigelTM on day 1, 6 and 9 to cells seeded on Collagen I-coated plates. Markers of cellular integrity investigated were morphology, cellular ATP content, LDH release and the mRNA expression of several canalicular/basolateral transporters, cytochrome enzymes and nuclear receptors. The secretion of the fluorescent bile acid Choly-lysyl-fluorescein (CLF) by canalicular bile salt excretion pump (BSEP) was used as functional marker. CLF secretion rates were stable and similar during 14 days. Inhibition experiments with the BSEP inhibitor Cyclosporine A (CsA) at day 5, 9 or 14 of the culture indicated no quantitative differences in terms of the inhibitory CsA concentrations. These results demonstrated that the BSEP kept its function for 14 days under the current culture conditions. In conclusion, the further development of the rat hepatocyte long term culture allows the application of high content microscopy imaging, which may serve as powerful tool to investigate chronic liver toxic drugs under in vitro long-term incubation conditions. 2538 AN IN SILICO APPROACH FOR COMPUTING OCCUPATIONAL EXPOSURE LIMITS OF ORGANIC SOLVENTS. M. Debia and K. Krishnan. Département de Santé Environnementale et Santé au Travail, Université de Montréal, Montréal, QC, Canada. Health-based occupational exposure limits (OELs) are derived either on the basis of human observations or from animal point of departures. In the absence of relevant human or animal data for identifying the point of departure, it is a real challenge to derive or propose an OEL. The objective of this study was to develop an in silico approach for computing OELs in data-poor situations. Quantitative Property- Property Relationship (QPPR) approaches were developed using a database of 88 solvents which have health-based Time-Weighted Average (TWA) OELs published by the American Conference of Governmental Industrial Hygienists (ACGIH). Three surrogates of biotic lipid:air partition coefficients [n-octanol:air (Koa), olive oil:air (Koila) and fat:air (Kfa)] were selected for evaluating the descriptive/predictive relationship with OELs for solvents with local modes of action. Koa is the most accurate predictor of OELs [OEL (ppm) =10xEXP((-0.45*logKoa)+3.65); n=21; r^2=0.71; PRESS/SSY=0.36; F=45.5 with p
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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
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1825 EFFECTS OF METABOLISM BY INTES
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cyanoacetic acid increased 2-3 fold
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1845 IS THE PROMISCUITY OF THE ARYL
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crorarray analysis. RT-PCR results
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are a family of phase-II biotransfo
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ous labs. As a result of positive s
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down the doses may produce more tox
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spectively. Below 100 mg/l of gemfi
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1900 GENERATION OF PRECISION CUT LI
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iomarkers or observation of lesions
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creased reticulocytes and lymphocyt
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statistically significant interacti
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monize sample preparation and analy
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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: forms mRNA expression levels were a
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 597 and 598:
Author Index (Continued) The numera
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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The Toxicologist - Society of Toxicology

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