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content cytotoxicity screening (HCS) on human HepG2 has been proposed as a valuable early screening model (applicable during the discovery phase) for the prediction of DILI in man (O’ Brien; 2004). Here we show the in house validation of a 6-endpoint HCS-approach based on 99 reference compounds (biased between hepatotoxic and non toxic compounds). We could demonstrate a sensitivity of 72% towards the prediction of strong hepatotoxic compounds and 53% when all hepatotoxicants were included. Specificity of the assay remained 100%, a crucial prerequisite for any early cytotoxicity screening assay. To further improve the prediction of DILI during the discovery phase, we propose a combined strategy including the HCS and the phenotypic zebrafish hepatotoxicity assay. The simplicity of the HCS allows higher throughput screening, while the complexity of the zebrafish enables the detection of more complex mechanisms of hepatotoxicity at a later stage of the discovery phase. Here we show our evaluation of zebrafish larvae as an additional model to predict human hepatotoxicity. Although some shortcomings of the assay were identified (subjective endpoint, uptake issues and screening of one target organ toxicity only) the obtained predictivity was promising. Significant higher sensitivity indices were achieved, indicating the whole liver system of the zebrafish is able to detect more hepatotoxicants compared to the HCS, due to its higher level of complexity. Another important aspect of improving the prediction is the characterization of the reference compounds in function of their induction mechanisms of toxicity. With a subset of 45 compounds thoroughly characterized, we do succeed in obtaining significantly higher sensitivity indices. 1896 MULTIPLEX DETECTION OF OXIDATIVE PHOSPHORYLATION AS A MECHANISTIC INDICATOR FOR DRUG-INDUCED MITOCHONDRIAL TOXICITY. W. Zheng 1 , L. Goretzki 1 , G. Korzus 1 , J. Wang 1 , J. Murray 2 and R. Capaldi 2 . 1 R&D, EMD Millipore, San Diego, CA and 2 R&D, MitoSciences, Eugene, OR. Sponsor: R. Wiese. Oxidative phosphorylation (OXPHOS) produces more than 95% of the conserved cellular energy in the form of ATP under normal conditions. This process involves 5 different protein complexes, OXPHOS Complex I-V. The overall process of oxidative phosphorylation is tightly controlled by transcriptional, post-translational and substrate feedback regulations. Due to the dual genetic origins of OXPHOS enzymes from both nuclear and mitochondrial DNA, the mitochondrial DNA and its OXPHOS protein products are specifically susceptible to toxicity induced by a variety of drugs including antiviral and antibiotic compounds. Not surprisingly, the ability to monitor the levels of the 5 OXPHOS complexes need to be a key part of drug development and drug toxicity studies. However suitable high throughput approaches do not exist. Here we describe a high throughput, multiplex approach to monitoring OXPHOS complex I, II, III, IV, V and NNT using the Luminex xMAP technology. To evaluate the utility of the assay in the early detection of drug induced mitochondrial toxicity, HepG2 cells were treated with chloramphenicol, an antibiotic compound, ddC, an antiviral compound and two anti-diabetes drugs, rosiglitazone and troglitazone, one in widespread use but with safety concerns for cardiotoxicity, the other pulled from the market because of serious hepatotoxicity. The OXPHOS multiplex panel was used to quantify the OXPHOS complexes in the treated cells in comparison to the mock treated controls. The results indicated that the OXPHOS panel can effectively detect the mitochondrial toxicity and provides mechanistic insights into the drug induced cellular and organ damages at the OXPHOS expression level. The data suggest that OXPHOS multiplex assay could be used as a novel safety screen tool to identify potential off-target effects for new antiviral, antibiotic and other drug molecule leads. 1897 IMPORTANCE OF RAT AND HUMAN SCREENS FOR ARYL HYDROCARBON RECEPTOR (AHR) ACTIVATION/CYP1A INDUCTION. H. J. Garside, S. Atwal, M. R. Brown, J. Bowes, M. Graham and J. Valentin. Global Safety Assessment, AstraZeneca, Macclesfield, United Kingdom. Persistent activation of the aryl hydrocarbon receptor (AhR) by xenobiotics can lead to a wide array of toxicological responses including tumour promotion and endocrine disruption in both pre-clinical animal models and man. However, as there can be species specific differences between compounds that activate rat and human AhR, assessment of compound action on the AhR from both species allows better prediction of toxicological risk throughout drug discovery and development. Activation of the AhR can be detected by quantifying levels of the endogenous downstream transcriptional targets, CYP1A1 and CYP1A2 in both rat and human immortalised cell lines using commercially available antibodies. In this system the standard AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produced an EC50 value of 5.4 pM in the rodent H4-II-E-C3 cell line and 167 pM in the 406 SOT 2011 ANNUAL MEETING human HepG2 cell line. The rodent PXR agonist/CYP3A inducer pregnenolone- 16 alpha-carbonitrile (PCN) was used as a negative control compound and, as expected, did not produce a signal above control levels in either cell line. Results from internal screening programmes show that 34% of compounds induce CYP1A levels in the rat cell line, 10% in both the rat and human cell lines and 2% in the human cell line alone. Results indicate that the rat cell line is more sensitive to AhR activators than the human counterpart and that IC50 values should be used as a factor in the risk assessment of this liability. Taken together these data can be used to predict and explain the mechanism of effects on the liver, immune and endocrine systems in preclinical safety studies in early and late development. Importantly, the identification of human specific AhR activators, whose potential toxicological effects would be missed in preclinical animal work, can be detected at an early stage of the drug discovery process. 1898 NOVEL IN VITRO APPROACH FOR ASSESSING CARDIAC CONTRACTILE LIABILITIES USING MICROPATTERNED MUSCULAR THIN FILMS. A. Grosberg 1, 2 , M. D. Brigham 1 , J. A. Goss 1 , P. W. Alford 1 and K. K. Parker 1, 2 . 1 Harvard School of Engineering and Applied Sciences, Boston, MA and 2 Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA. Sponsor: A. Bahinski. Cardiotoxicity is one of the major forms of toxicity seen in drugs and accounts for a major portion of drug recalls and delays experienced in regulatory approvals. In addition, recent regulation by the FDA has made assessment of cardiovascular safety a critical focus during the development of new antidiabetic therapies for Type 2 diabetes mellitus. It is therefore necessary to develop novel and better human-predictive screening assay systems in order to reduce attrition and increase drug discovery productivity. We have been able to microengineer functional heart tissues by culturing cardiomyocytes on one surface of elastomeric polymer thin films (muscular thin film; MTF) micropatterned with extracellular matrix proteins to promote spatially ordered, two-dimensional myogenesis. In this device, the MTFs remain secured at their base to a glass surface. During the contraction cycle the films bend up from the glass coverslips, and the degree of bending is directly correlated to the contractility of the cardiomyocytes. These heart tissue constructs are electrically functional and actively contractile, generating stresses comparable to those produced by native cardiac muscle. Cardiac muscle engineered with neonatal rat ventricular myocytes and paced at 0.5 Hz generated stresses of 9.2 ± 3.5 kPa at peak systole, similar to measurements of the contractility of papillary muscle from adult rats. These MTFs are amenable to incorporation into microfluidic channels and multiwell plates, providing a platform that uses a significantly smaller amount of cells and ability to multiplex the assay. This technology provides higher throughput analysis of anisotropic cardiac tissue contractility, which can be used to measure the cardiac contractile liability of drugs, biologics and nanotherapeutics. 1899 A NOVEL IN VITRO APPROACH TO IDENTIFY MECHANISMS OF HEPATOTOXICITY. C. Hu, D. Pietrzak, K. French and K. Frazier. Safety Assessment, GlaxoSmithKline, King of Prussia, PA. Hepatocellular toxicity is a serious issue in drug development. Defining a mechanism can be difficult because of the numerous mechanisms involved and their overlapping temporal nature. We developed a multiparameter approach in HepG2 cells using both cytometric and biochemical techniques and verified endpoint sensitivity using various toxicants with discrete and well-defined mechanisms. Nuclear density, cell viability, mitochondrial membrane potential (MMP) and oxidative stress (OS) were monitored using HO33342, TO-PRO-3, TMRM and c-H2DCFDA, respectively, and quantified using laser scanning cytometry. Cells were exposed to carbonyl cyanide 3-chlorophenyharazone (CCCP), a known mitochondrial uncoupler, and menadione (MD), an OS inducer, for 2h and 24h. CCCP markedly depolarized mitochondria and unexpectedly increased OS in a dose-dependent manner with no effect on cell viability after 2h exposure and depolarized mitochondria with no effect on OS and minor effect on viability after 24h. In MD treated cells, increased OS and cytotoxicity were observed at both time points. Intracellular ATP concentrations were measured via bioluminescence and reduced glutathione (GSH) content was measured via flow cytometry using monobromobimane (MBBr) and known GSH depleter N-ethylmaleimide. Intracellular calcium ion levels were measured via flow cytometry using Indo-1 AM and levels rapidly increased after the addition of the toxicant ionomycin. Lipid peroxidation was measured via thiobarbituric acid-reactive substance quantification, which was increased with the addition of the toxicant cumene hydroperoxide. This novel multiparameter approach successfully evaluated multiple key mechanisms of hepatotoxicity and can easily be adapted to assessment of drug candidates during development.
1900 GENERATION OF PRECISION CUT LIVER SLICES FROM PINCH BIOPSY SECTIONS. K. Kowalkowski, A. Lisowski, W. R. Buck, E. Blomme and Y. Yang. Abbott Laboratories, Abbott Park, IL. Precision-cut tissue slices retain the multicellular, structural and functional features of tissues and offers a more relevant approach to interrogate toxicity compared to cell-based in vitro techniques. This study examined the feasibility of generating viable tissue slices from biopsy-derived liver. In separate experiments, liver sections were removed from dogs and monkeys. One set of sections was removed using a traditional 8-mm coring tool, and the other set was removed using a pinch biopsy forceps, to replicate in vivo collection. For the traditional cores, slicing proceeded using standard methods. To facilitate slicing, the much smaller biopsy sections were first embedded in 2% agar to create 8-mm diameter plugs. Slices were cultured for 48 hours with 100 μM Rotenone as positive control for liver toxicant, with samples taken at 24 hours as intermediate time point. Supernatants and tissue homogenates (n=3) were analyzed for liver enzymes (ALT, AST and LDH) as endpoints for toxic effects. Slices were processed for histological evaluation. All vehicle-treated slices showed similar viability and low release for all three liver enzymes. In rotenonetreated slices there were differences between species and time points. In dog liver, histological examination showed rotenone-induced time-dependent hepatocellular necrosis correlating with significant release of enzymes. The severity was comparable in the biopsy and whole slices. In the monkey, there were no significant increases of enzymes at the 24 hour time point, but after 48 hours significant levels of all three enzymes were released from the traditional slices. For the biopsy slices, the only significant change was in the LDH levels. These data demonstrate the feasibility of using biopsy sections as a source of liver slices, which would enable toxicological evaluation without sacrificing animals, and justify further exploration and refinement of this technique. 1901 A HUMAN BREATHING LUNG-ON-A-CHIP FOR DRUG SCREENING AND NANOTOXICOLOGY APPLICATIONS. D. Huh 1, 2 , B. D. Matthews 2 , A. Mammoto 2 , M. Montoya 1 , H. Hsin 2 and D. E. Ingber 1, 2, 3 . 1 Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, 2 Children’s Hospital Boston and Harvard Medical School, Boston, MA and 3 School of Engineering and Applied Sciences, Harvard University, Cambridge, MA. Sponsor: A. Bahinski. A major problem slowing the development and regulatory approval of new and safer medical products is the lack of experimental in vitro model systems that can replace costly and time-consuming animal studies by predicting drug efficacy and toxicity in man. Here we describe a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of the human lung and exposes it to cyclic mechanical strain and fluid dynamic forces that mimic breathing and blood flow. This microdevice reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into the alveolar space by inducing expression of intercellular adhesion molecule-1 (ICAM-1) on the microvascular endothelium surface, adhesion of circulating blood-borne neutrophils, their transmigration across the capillary-alveolar interface, and phagocytosis of the infectious pathogens, which can be visualized using real-time, high-resolution microscopy. Using this approach, we developed novel nanotoxicology models and revealed that physiological cyclic mechanical strain greatly accentuates toxic and inflammatory responses of the lung to silica nanoparticles by promoting rapid release of reactive oxygen species by alveolar epithelial cells and upregulating endothelial ICAM-1 expression. Mechanical strain also enhances nanoparticle uptake by the epithelial cells and stimulates their transport into the underlying microvasculature. Importantly, similar effects of physiological breathing on nanoparticle absorption were observed in whole lung using a mouse lung ventilation-perfusion model. This mechanically active biomimetic microsystem represents valuable new model systems for in vitro analysis of various physiological functions and disease processes, in addition to providing low-cost alternatives to animal and clinical studies for drug screening and toxicology applications. 1902 IN VITRO PREDICTION OF INJECTION SITE REACTIONS USING L6 RAT SKELETAL MUSCLE CELLS. J. A. Willy 1 , N. Schulte 2 , E. Kreklau 1 , J. Walgren 1 , A. Stauber 1 , J. L. Stevens 1 and T. K. Baker 1 . 1 Toxicology, Eli Lilly and Co., Indianapolis, IN and 2 Preformulation, Eli Lilly and Co., Indianapolis, IN. Injection site reactions (ISRs) are commonly encountered in the development of parenteral drugs. Severe ISRs can lead to preclinical and clinical dose limiting toxicities. We developed an in vitro ISR screen to rank compounds for irritation risk, as a surrogate for ISRs, during early preclinical development. Reference compounds that were either known to induce ISRs or were non-irritating in vivo were used to validate this method. L6 rat myoblasts were allowed to form a confluent monolayer in 96 well plates followed by compound treatment for one hour at eight concentrations. Change in membrane integrity was measured using calcein-AM. Cells treated with non-irritants or non-irritating concentrations of compounds take up calcein- AM and convert it to fluorescent calcein which is detected using laser scanning cytometry. When membrane damage occurs, the fluorescent signal decreases in a concentration-dependent manner and comparison of concentration response curves allows for ranking of compounds. Using this assay, reference compounds were ranked in the following order (from highest to lowest irritation potential): diethylstilbestrol > mitoxantrone > mitomycin > doxorubicin > dacarbazine > vinblastine > cis-platinum > cyclophosphamide > sumatriptan succinate > metoprolol ≥ atenolol ≥ vasopressin ≥ ranitidine HCl. This rank order correlates with in vivo ISR potential for these reference compounds and, thus, demonstrates the usefulness of this assay in identifying potential irritants. While compound mediated ISR is a critical screening output for this model, it also has utility in understanding the role of dosing formulations in ISRs and the impact of formulation additives on shifting the ISR potential. 1903 HEPARG CELL MODEL IN HIGH-CONTENT SCREENING ASSAYS GIVES MECHANISTIC INSIGHT INTO METABOLISM-MEDIATED HEPATOTOXICITY. J. Mein 1, 3 , P. Walker 3 , M. Jacewicz 1, 3 , R. Annand 1, 3 , D. Steen 2 , C. Chesne 2 , H. Gill 2 and K. Tsaioun 1, 3 . 1 Apredica, Watertown, MA, 2 Biopredic, Rennes, France and 3 Cyprotex, Macclesfield, United Kingdom. Drug-induced liver injury (DILI) is the most frequent reason for the withdrawal of an approved drug from the market, and it also accounts for up to 50% of cases of acute liver failure. Assays detecting mechanisms of potential adverse drug reactions (ADRs) allow early de-risking of drug discovery programs. High Content Screening (HCS) allows multiple mechanistic observations to be made simultaneously in a single cell; here we measure mitochondrial membrane potential, cytochrome C release, membrane permeability and cell loss. This multi-parameter assay gives mechanistic insight into the toxic insult on a cell. By conducting this assay in two human hepatocyte-derived cell lines, a further insight into the mechanism of DILI is provided, by identifying if the parent compound or reactive metabolites of the parent compound are potential hepatotoxicants. HepG2 cells are used as a surrogate model for liver toxicity (parent compound), whereas HepaRG cells are used to determine whether metabolites may be responsible for cell toxicity. Differentiated HepaRG is a metabolically competent cell line that displays many hepatocyte-like functions, including human CYP expression. HepaRG cells are preferred to primary human hepatocytes, which are hampered by the irregular availability, donor variability and scarcity of donors. Both HepG2 and HepaRG cells were treated with test compounds and indicators of cell health were measured with HCS instrument. Diclofenac, cyclophosphamide, and acetaminophen were chosen as compounds known to form reactive metabolites. HepaRG cells are found to be more sensitive at detecting the toxicity to the compounds with reported metabolism-based mechanisms of toxicities. This assay will allow the identification of compounds with potential ADRs and DILI, and identify compounds with metabolism-mediated toxicity risk 1904 A NOVEL RESAZURIN/RESORUFIN CELLULAR ASSAY TO DETECT AND CHARACTERIZE REACTIVE ACYL GLUCURONIDES. M. McMillian, J. Sasaki, M. Singer, F. Xu and H. Lim. Johnson & Johnson, Raritan, NJ. Glucuronidation generally inactivates metabolites, making them more soluble and easy to eliminate. However, acyl glucuronides (AG) of some drugs are highly reactive, and may contribute to idiosyncratic reactions; NSAIDs provide many examples. Increased reduction of the redox dye resazurin to the more fluorescent resorufin was found to reflect reactive AG formation from many added parent compounds in hepatocyte and HepG2 cultures. The rank order of responses of compounds tested in this cellular assay at equimolar concentrations was somewhat different than previously reported following AG migration on glucuronidated compounds in KRH buffer. Responses ranged from very robust, such as diflunisal, flufenamic acid, and ethacrynic acid, to moderately robust, such as diclofenac, mycophenolic acid and flurbiprofen, to moderate, such as zomepirac and tolmetin, to mild or inactive, such as furosemide, fenofibrate, and valproic acid. Quantification of diflunisal and zomepirac AGs showed that more zomepirac AG was formed than SOT 2011 ANNUAL MEETING 407
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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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Page 373 and 374: those with high nickel content are
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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: spectively. Below 100 mg/l of gemfi
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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