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ing duration, high tissue levels (≥400 μg/g) correlated with the appearance of pancreatic lesions. A series of in vitro and in vivo studies were carried out to confirm this hypothesis and identify a path forward. Rapid uptake of SD-5749 (the active component of SD-3651) into pancreatic acinar cells occurred via the y+ transporter system, which normally targets cationic amino acids. An in vitro assay measuring uptake of radiolabeled SD-5749 into isolated dog pancreatic acinar cells was utilized to identify compounds that did not compete with SD-5749 for this cellular uptake pathway. Promising compounds were subsequently tested in a series of in vivo assays in dogs including 1) measurement of tissue accumulation following a single oral dose of 10 mg/kg, 2) an IV infusion study measuring plasma and pancreatic tissue levels after 4 and 8 hr, and 3) a definitive 7-day study at an exposure equivalent to SD-5749 that produced pancreatic toxicity. The in vitro cellular uptake assay proved predictive of in vivo tissue accumulation and toxicity. Two compounds with reduced in vitro cellular uptake were identified that resulted in greatly reduced pancreas tissue levels and lack of mitochondrial swelling or atrophy in the 7-day dog study. In contrast, a third molecule, which was similar to SD-5749 in the acinar cell uptake assay, produced a very high pancreatic tissue burden and caused mitochondrial swelling and atrophy. These results validated the “pancreatic tissue burden” hypothesis and led to the identification of compounds with reduced tendency for accumulation in pancreatic tissue. 1077 MECHANISM OF EXOCRINE PANCREATIC TOXICITY INDUCED BY AN ARGININE-BASED INOS INHIBITOR. D. C. Thompson 1 , M. A. Panyik 1 , J. Sagartz 2 , P. Manning 3 , R. Bell 1 and D. L. Morris 1 . 1 Drug Safety Research & Development, Pfizer, Chesterfield, MO, 2 Seventh Wave, Chesterfield, MO and 3 Washington University School of Medicine, St. Louis, MO. Development-limiting exocrine pancreatic toxicity (mitochondrial swelling and atrophy) was observed in pre-clinical safety studies in dogs with an arginine-based iNOS inhibitor, which prompted a series of investigative studies in an effort to uncover a potential mechanism for these effects. SD-5749 had no direct effect on mitochondrial respiration; however, concentration-dependent swelling and release of cytochrome c were observed at high concentrations in isolated dog pancreas mitochondria. Basic (lysine and arginine) but not neutral amino acids (alanine, glycine) produced similar effects. In marked contrast, none of the compounds produced swelling or cytochrome c release in liver mitochondria, suggesting that factors unique to acinar cells were initiating the mitochondrial effects in pancreas. SD- 5749 induced zymogen granule lysis and enzyme release at lower concentrations than required for mitochondrial swelling. In addition, when added to liver mitochondria, zymogen granule lysate or individual enzymes stimulated mitochondrial swelling which was not inhibited by cyclosporin A. These data correlated with in vivo findings on the accumulation of high levels of SD-5749 in pancreas tissue following oral administration, and with in vitro studies demonstrating cationic amino acid transporter-assisted uptake into acinar cells. When the pancreas tissue burden exceeded approximately 400 μg/g (equivalent to ~ 2 mM) toxicity was observed. These data suggest that the mechanism for SD-5749-mediated pancreatic toxicity involves transporter-assisted tissue accumulation, initial lysis of zymogen granules with intracellular release of degradative enzymes, followed by mitochondrial membrane damage and swelling. Subsequent release of cytochrome c and binding to the apoptosome leads to caspase activation and eventual acinar cell apoptosis. 1078 A CELLULAR SYSTEMS BIOLOGY METHOD OF EVALUATING IN VITRO CARDIOTOXICITY. N. M. Radio, P. Hodor, L. Vernetti, A. Gough and P. Johnston. Cellular Toxicology, Cellumen, Pittsburgh, PA. A novel cellular cardiotoxicity panel has been developed by Cellumen that combines Cellular System Biology (CSB) and an advanced classifier database to generate cardiac toxicity profiles of pharmaceutical and environmental agents. This CSB panel evaluates a broad range of markers indicative of the cellular state, including oxidative stress generation, cellular apoptosis, DNA damage, mitochondrial membrane potential, fatty acid accumulation, cellular hypertrophy as well as general metrics of toxicity including nuclear size and overall cell loss. The rationale was to evaluate the specificity and sensitivity of this cardiac panel using a calibration test set consisting of 32 negative compounds considered safe to the heart and 64 positive compounds known to be deleterious to cardiac tissue in vivo. This calibration set was evaluated across all eight cardiotoxicity biomarkers over three time points and a 10-point dose response curve (0 – 100 μM). The results demonstrate that 26 of the 32 negative controls did not produce significant toxicological responses in any feature or time point evaluated (81% specificity). Conversely, 48 of 64 positive controls caused at least one significant toxicological response in at least one time point (75% sensitivity). The sensitivity of the assay can be further improved to 87% (48/55) by excluding those compounds whose Cmax value is 100X greater than the highest concentration evaluated (100 μM). Furthermore, the panel demonstrates the importance of cardiac organ specificity, as several known cardiotoxicants including the antihistamine terfenadine activated more toxicity biomarkers in this cardiac panel when compared to a hepatic model. Taken together, these results demonstrate this Cellular Systems Biology cardiotoxicity panel from Cellumen is both selective and sensitive in accurately discriminating safe and toxic compounds in cardiac tissue as well as elucidating the potential mechanisms responsible for cardiotoxicity. 1079 A CELLULAR SYSTEMS BIOLOGY APPROACH TO DISCRIMINATE HEPATIC TOXICITY WITHIN STRUCTURAL CLASSES. L. Vernetti, N. M. Radio, P. Hodor, A. Gough and P. Johnston. Cellular Toxicology, Cellumen, Pittsburgh, PA. Despite an aggressive campaign in the pharmaceutical industry to identify liver liability earlier in the development process, clinical hepatotoxicity continues to be an important cause of late stage drugs failures. The Cellular Systems Biology approach from Cellumen captures the response of 24 or more phenotypic and mechanistic biomarkers in relevant cell types at multiple doses and time points. The responses comprise a profile which can be compared to Cellumen’s drug profile database to identify correlations with known in vivo effects and to classify or rank order the risk of liver injury. This technology was applied to 5 pairs of compounds that met the following criteria: (a) silent in animal safety studies, (b) structural analogs, (c) withdrawn from market due to unacceptable hepatotoxicity, and (d) difficult to discriminate toxic from non-toxic with existing technology. The sets include the hepatotoxic compounds: Trovofloxacin, Tolcapone, Bromfenac, Ibufenac, Nefazodone matched to the clinically non- hepatotoxic or reduced hepatotoxic compounds: Lomefloxacin, Entacapone, Diclofenac, Ibuprofen and Trazodone. The matched sets were tested at 3 time points and 10 doses in a HepG2 panel of 10 assays, and in a rat primary hepatyocyte panel of 8 assays. The Cellumen HepG2 panel includes features to measure oxidative stress, stress kinase activity, DNA damage, mitochondrial function, cell cycle modulation, nuclear size and cell loss. The Cellumen rat hepatocyte panel includes markers to measure ER stress/DNA damage, apoptosis, phospholipidosis, steatosis, mitochondrial function, DNA fragmentation, nuclear size and cell loss. Three computational classifiers were used to score the compounds for hepatotoxicity based on their profiles. One classifier, which combines the profiles of both panels, out-performed a HepG2-only and a rat hepatocyte-only classifier, correctly ranking 4 out of 5 toxic compounds. These studies indicate the value of Cellumen’s Cellular Systems Biology approach to identify compounds of high risk to elicit clinical hepatotoxicity. 1080 OPTIMISING CELL MODELS FOR DETECTING DRUG- INDUCED MITOCHONDRIAL DYSFUNCTION. K. Howe, L. Bazley, S. Song and J. Dykens. Drug Safety R&D, Pfizer, Sandwich, United Kingdom. Drug-induced mitochondrial dysfunction is increasingly implicated in the etiology of organ toxicities, underscoring the need for predictive preclinical models. Cell lines, such as HepG2, are typically grown at high concentrations of glucose where they generate ATP via glycolysis. Such cells tolerate mitochondrial toxins and so fail to detect drugs with mitochondrial liabilities. When glucose is replaced by galactose, HepG2 cells shift their bioenergetic poise towards oxidative phosphorylation and so become susceptible to mitochondrial toxins1. To determine how such cells compare to primary hepatocytes, we monitored oxygen consumption and found that while HepG2’s grown in galactose have higher respiration than cells grown in glucose, the oxygen consumption of primary hepatocytes was ~6-fold higher. Flow cytometry was also used to compare the mitochondrial membrane potential(ΔΨ), biomass and the proportion of dead cells in each population. In accord with the respiration data, HepG2 cells grown in galactose have more intense NAO staining indicative of increased cardiolipin and they maintain higher ΔΨ than cells grown in glucose, but primary hepatocytes had more mitochondria with a higher ΔΨ than either population of HepG2’s. Treatment with oligomycin yielded a dose dependent loss of mitochondrial membrane potential and cytotoxicity in the HepG2 cells grown in galactose, which was not observed in cells grown in glucose. Similar differences were seen with single doses of antimycin and rotenone; however no difference was observed when cells were treated with FCCP or KCN. In all instances, primary hepatocytes were more susceptible to these toxins than either population of HepG2 cells. The data indicate that growing HepG2 cells in galactose did increase respiration and their susceptibility to three out of five of the mitochondrial toxins evaluated here. However, primary hepatocytes are more aerobically poised and 230 SOT 2010 ANNUAL MEETING
hence more physiologically relevant predictors of in vivo toxicity, which recommends them as the in vitro model of choice for pre-clinical toxicity testing. Reference 1. Marroquin et al., 2007 Tox Sci 97 1081 IMPACT AND FREQUENCY OF DIFFERENT TOXICITIES THROUGHOUT THE PHARMACEUTICAL LIFE CYCLE. W. S. Redfern 1 , L. Ewart 1 , T. G. Hammond 1 , R. Bialecki 2 , L. Kinter 2 , S. Lindgren 3 , C. E. Pollard 1 , R. Roberts 1 , M. G. Rolf 1 and J. P. Valentin 1 . 1 Global Safety Assessment, AstraZeneca, Macclesfield, Cheshire, United Kingdom, 2 Global Safety Assessment, AstraZeneca, Wilmington, DE and 3 Global Safety Assessment, AstraZeneca, Sodertalje, Sweden. Prioritisation of safety assessment resources according to impact and prevalence of toxicities is often based on opinion, anecdotal examples, recent issues with specific projects, and regulatory focus. Evidence-based decision-making requires reliable data on drug-induced toxicities across a range of organs/categories. We have collated information from published reviews across the following categories of toxicity: cardiovascular (CV), nervous system (N), respiratory (RES), gastrointestinal (GI), renal (REN), hepatotox (HEP), musculoskeletal (MSK), haematology/bone marrow (HBM), immunotox/photosensitivity (IMT/PTS), reprotox (RTX), genetic tox (GTX), and carcinogenicity (CNG). Some datasets relate to frequency of candidate/marketed drugs associated with the toxicity; others contain data on prevalence of the toxicity in subjects/patients, as follows. 1. Nonclinical attrition (based on 88 CDs stopped): CV (27%) > N (14%); RTX (13% > HBM; IMT/PTS (7%) > GTX (5%) > MSK (4%) > GI; CNG (3%) > REN;RESP (2% each). 2. Phase I serious ADRs (based on 43 events in 1,015 subjects): N (28%) > GI (23%) > IMT/PTS (16%) > CV (9%) > HEP (7%) > HBM (2%). 3. Clinical development – causes of attrition (based on 82 CDs stopped): N; CV; HEP (21%) > IMT/PTS (11%) > REN (9%) > GI (5%) > HBM (4%). 4. Marketed drugs - serious ADRs (based on 21,298 patients): N (39%) > IMT/PTS (34%) > CV (15%) > GI (14%) > HBM (10%) > RESP (8%) > MSK (3%) > REN (2%). 5. Marketed drugs - withdrawals (based on 47 drugs withdrawn 1975-07): CV (45%) > HEP (32%) > HBM (9%) > N;GI;REN;RES (2%). These data require cautious interpretation, but are a first step to assessing frequency and impact of different drug-induced adverse effects throughout drug discovery, development and marketing. Sources: 1. ADD (2006) 1;53-65; 2. EJCP (1998) 54;13-20; 3. RegTP (2000) 32;56-67; 4. JAMA (2006) 296;1858-66; 5. DDT (2009) 14;162-67. 1082 THE USE OF IMPLANTATION OF TRANSPONDERS IN TG.RASH2 MODELS FOR CARCINOGENICITY ASSESSMENT: THE USE OF SUBCUTANEOUS IMPLANTATION OF TRANSPONDERS IN TG.RASH2 MODELS FOR CARCINOGENICITY ASSESSMENT. M. Paranjpe, M. Wenk and E. A. Zahalka. Toxicology, BioReliance Corp, Rockville, MD. Subcutaneous implantation of transponders is a commonly used method for animal identification in preclinical studies. Sufficient toxicity data is available to support the use of these implants in various conventionally used rodent strains that are commonly used in toxicology studies. However, robust data is not available to support the use subcutaneous transponders in the emerging transgenic models,such as the Tg.rasH2 mice. This mouse model is commonly used in 26-week carcinogenicity studies, and the objective of this study is to determine if implantation of transponders increases the incidence of tumors in this model over a 26-week period. Forty Tg.rasH2 mice per sex (8±2 weeks) were implanted with microchip transponder subcutaneously, and an additional 20 males and 25 females were used as a trocar control group (not implanted with the transponder, but subjected to subcutaneous injection procedure). Mice were necropsied 26 weeks post-implantation of the transponder. The primary endpoints of the study were macroscopic and microscopic analyses of implantation (injection) sites. No gross lesions were noted at the skin site of injection (SOI) in transponder-implanted or trocar control mice at necropsy. The skin SOI of trocar control mice was considered to be within normal limits for all mice. Histopathological evaluation revealed that the transponder-implanted skin SOI was within normal limits for 14/40 males and 12/40 females. In the transponder-implanted animals, skin cavity formation was noted in the dermis of 25/40 male and 27/40 female mice, and connective tissue surrounding these cavities was compressed in 24/40 males and 26/40 females. Fibrosis, of minimal to mild intensity, was noted in the dermis directly surrounding the cavities in some of these mice. No tumors were observed at the SOI in any of the mice at all groups. It is therefore, concluded that the use of transponders in the Tg.rasH2 mice would not negatively impact the outcome of a 26-week carcinogenicity study. 1083 METHODS FOR SUCCESSFUL CONDUCT OF CHRONIC TOXICOLOGY INTRAVENOUS TAIL VEIN INJECTION STUDIES IN RATS. R. Gendron, C. Parente, S. Y. Smith and C. Copeman. Toxicology, Charles River Laboratories, Preclinical Services (PCS-MTL), Senneville, QC, Canada. Sponsor: M. Vézina. Performing rodent chronic toxicology studies via daily intravenous injection can be challenging. Appropriate experimental procedures as well as consideration for the dose volume and properties of the formulation to be administered are required. Studies were conducted at PCS-MTL using phosphate buffered saline or 0.9% saline administered by daily slow bolus intravenous injection (tail vein) for up to 182 consecutive days. The rats were between Day 21 post partum and 7 weeks old at the start of dosing. Animals were restrained using the Horizontal Cylinder (claw type) device as per PCS-MTL standard operating procedures. Rats were placed in the restrainer and adjustments made as necessary so as not to restrict chest expansion for breathing. To facilitate injection, a heating device, the Hot Pad, was used to dilate the caudal vein. If the injection site was compromised, dosing was suspended for up to 6 consecutive days to allow sufficient recovery. To minimize the severity of any skin lesion along the tail and/or to aid recovery at the injection site, calamine lotion was occasionally used as an antipruritic agent. Dosing holidays were required for 12% of the animals (26 rats from a total of 210 animals) with a maximum of 19 non-consecutive days (10% of the total number of doses) without dose administration for any given animal over the 182 days of dosing. Damage to an injection site such that dosing was no longer possible requiring that the animal was removed from the study occurred in 3% of animals. Two animals necessitated surgical intervention for amputation of a portion of the tail; however, dosing was still successfully maintained. In conclusion, it was demonstrated that with appropriate care of the injection site, rats starting as young as Day 21 post partum can successfully be dosed by daily intravenous injection via the tail vein for up to 26 consecutive weeks. 1084 ATRIOVENTRICULAR (AV) VALVULAR INJURY CAUSED BY A VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR (VEGFR) INHIBITOR IN RATS APPEARS TO BE RODENT SPECIFIC. S. Ottinger 1 , T. Salcedo 1 , W. Freebern 1 , R. Westhouse 2 , S. Martin 1 , J. Li 2 , D. Li 2 , A. Fletcher 1 , H. Fang 1 , W. Foster 2 , R. Zidell 1 , S. Chen 2 , P. Levesque 2 , B. Car 2 , G. Schulze 1 and T. Reilly 1 . 1 Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, NY and 2 Discovery Toxicology, Bristol-Myers Squibb, Lawrenceville, NJ. VEGFR inhibition is a useful therapeutic strategy for treatment of a variety of cancer types, but has also been associated with a battery of unintended effects. In a rat 6 month oral toxicity study with a VEGFR inhibitor, dose-dependent increases in incidence and/or severity of AV valve thickening and hypercellularity were noted beginning at 3 months at doses of 20, 110, 200/160 mg/kg/day, which progressed to a valvulopathy characterized by endothelial loss and fibrin deposition (with or without proliferation of mesenchymal cells) in some males at 110 and 200/160 mg/day. Conversely, through 1 year of daily dosing with exposures overlapping those noted in rats, monkeys showed no evidence of valvular injury, including no effects on echocardiograms, clinical biomarkers of cardiac injury or histopathologic effects on the AV valves. In separate telemetry studies, rats had a robust increase (up to 22 mmHg) in blood pressure (BP) following treatment with the VEGFR inhibitor while there was only a minimal increase in BP in monkeys, generally within normal fluctuation of controls. Detailed transcriptional examination of right and left AV valves in the rat heart, upstream of lesion development (ie, after 3 days and 1 month of dosing), failed to demonstrate a direct mechanistic based effect, but did suggest effects on inflammatory and extracellular matrix related transcripts. It has been reported that rodents have a spontaneous age-related endocardial myxomatous change in heart valves that is similar to some cases of drug induced valvulopathy. Based on these data, the valvulopathy induced by this VEGFR inhibitor appears to be secondary to sustained increases in BP and a drug-related reduced ability for valvular repair that exacerbated a rodent-specific predisposition to valvular injury with little relevance to higher-order species, including humans. 1085 COMBINATIONAL TREATMENT OF GAP JUNCTIONAL ACTIVATOR AND TAMOXIFEN IN BREAST CANCER CELLS. T. A. Nguyen, G. Gakhar and D. H. Hua. Diagnostic Medicine, Kansas State University, Manhattan, KS. Tamoxifen is a drug of choice for endocrine-responsive breast tumor patients. However, tamoxifen resistance has become a major concern for the treatment of breast cancer. Combinational therapies of tamoxifen and different drugs are being SOT 2010 ANNUAL MEETING 231
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The Toxicologist Supplement to Toxi
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The Toxicologist Supplement to Toxi
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1 BIOLOGICAL PATHWAY ANALYSIS: AN I
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11 ICH INITIATIVES FOR CONDUCTING P
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models. Experimental approaches and
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30 SILICA AND ASBESTOS IMMUNOTOXICI
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40 NONCANCER TOXICITY POTENTIAL AT
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ased products for patient administr
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nase regulates Hsp27-induced reorga
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exposure resulted in splenomegaly.
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We investigated the effect of imati
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well plate prevented free cell move
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98 DERIVING SIGNATURES OF IN VIVO T
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sulfate, cinnamic aldehyde, 2,4-din
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The final product will be a system
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mercially available STP brands by m
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for six weeks, with 10 mg/kg azoxym
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eceived RES post-TCDD exposure when
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morigenesis. Knocking down of JARID
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163 MICROPET IMAGING OF [18F]-DFNSH
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These results are comparable to tha
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activity as assessed by lever press
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for measured physico-chemical param
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199 DEVELOPMENT OF A MULTIPARAMETER
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To cause PLD, a drug needs to enter
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In contrast to the parent PBDEs and
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transiently transfected HEK 293 cel
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TCDD exposure, 24 h prior to a 20 %
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244 NON-ADDITIVE EFFECTS OF PCB153
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253 COMPARISON OF MIXTURE TOXICITY
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two cerium oxide nanoparticles of v
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271 SIZE-DEPENDENT EFFECTS OF TUNGS
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adigms such as Tox 21 and Toxcast,
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QDs with emission maximum at 800nm
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Cleveland, while others were found
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without the need of animal testing.
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Conclusions: These results are cons
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ing oxime reactivation and organoph
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335 A NON-OXIME IMPROVES SURVIVAL I
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alties suffer from permanent lung i
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ies have established inflammatory b
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363 GENETIC VARIATION IN ISOGENIC M
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372 EVALUATING THE BIOLOGICAL INTER
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dose of 1/20 LD50 (400 mg/kg.bwt) f
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median CR-adjusted isoflavone conce
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data indicate that AhR deletion pro
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February 2006). The rabbit is one o
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tal neurotoxicity (DNT) test (OECD
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of selected microorganisms that are
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BVI. Histopathological analysis was
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446 MOLECULAR CLONING AND CHARACTER
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portant in predicting risk. CYPs 1A
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ats, which involves metabolic activ
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473 BOVINE CORNEAL OPACITY AND PERM
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482 TYPE III DEIODINASE (D3) IS PRO
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tancy evaluation and ranking of bat
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501 CHARACTERIZATION OF ESTERASE, G
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510 REDOX CYCLING BY ENDOGENOUS 2-
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prostate cancer cells. All 8 BEL de
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metallic nickel nanoparticles. Acti
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variety of more or less reactive ch
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550 QUALIFICATION STRATEGIES-GENOTO
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ferentiation, and 3) how mixtures o
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572 LOW-CHRONIC ARSENIC EXPOSURE: E
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582 IDENTIFICATION OF SENSITIVE URI
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duced by the genetic outcross of fe
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fects of new compounds are equally
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acterize the current state of the s
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620 CHARACTERIZATION OF POTENTIAL I
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ways. Moreover, both MAP kinase and
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641 POPS IN THE U.S. POPULATION AND
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studies such as the NCS, consider h
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the beginning of the academic caree
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trophil infiltration, a significant
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tactic response and optokinetic res
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usually high spontaneous PIG-A MFs.
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699 PROMUTAGEN ACTIVATION AND P450
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oxodG in bone marrow, spleen, kidne
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718 GENOTOXICITY OF ORGANIC EXTRACT
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ment were 18.0 and 4.5 nM for BEAS-
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strongest activation of nuclear fac
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746 MACROPHAGE INHIBITORY CYTOKINE-
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screening of cell migration. High-c
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dase inhibition). In contrast, inhi
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mice; the decrease was more pronoun
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Markers of oxidative damage reached
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793 PULMONARY RESPONSE, OXIDATIVE S
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cilitate clinical and industrial ap
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sion of p-p38, p-p53, p21 and cycli
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821 KIDNEY INJURY MOLECULE-2 GENE D
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commercial applications, and have b
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Page 201 and 202: 922 A STUDY OF PHOTOTOXICITY FOLLOW
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1315 EVALUATION OF 3- AND 1-METHYLH
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prior to kainic acid-induced seizur
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1334 AFFECT OF GENETIC VARIATION ON
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1346 THE OTHER WORLD OF THE TRANSCR
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strate, leading to excess microvesi
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1368 OVERVIEW OF THERAPEUTIC VACCIN
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to a bovine adrenal cortical epithe
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DOTC had no effects. These results
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1398 PULMONARY TOXICITY OF CERIUM D
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PPARα, LXR, ER, AR and AhR activit
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1417 MECHANISM OF GENDER-DIVERGENT
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els, they disrupt homeostatic contr
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were to characterize exposure of th
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1448 ADVERSE OUTCOME PATHWAYS AND E
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the level in urine was 25% of the m
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1;akt-2 double mutant and pdk-1 mut
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jury effects when compared to contr
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tude than equivalent oral doses. Af
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cells; and increased iNOS and MCP-1
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B6.Cg-Kit W-sh mice. These findings
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1511 STATIN-TREATMENT EFFECTIVELY R
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1520 EFFECT OF INHALATION EXPOSURE
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numbers of IFN-γ producing cells w
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These data indicate that TCDD treat
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esponse to allogenic cells, where P
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larly suppressed LPS-induced TNF-α
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1565 INFLUENCE OF EXPOSURE ROUTE AN
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veloping animals to adverse effects
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the observed CL values were 0.07 L/
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which is most relevant for potentia
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tive impairment, suggesting that ox
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1611 AN IN VITRO METABOLOMICS APPRO
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Expression of the β6 integrin (Itg
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ats (10 μg/kg TCDD). Here we repor
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at liver slices and how the metabon
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with gender differences in AUC and
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oxetine (30 mg/kg reduced to 15 mg/
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eleased from necrotic cells where i
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plants, they are present in surface
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ferentiation (quantitative in-cell
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control for macrophage activation).
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to 0.5μg/ml. Minimal inhibitory co
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lines tested. Given that dex and AT
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tion in the absence of an immune re
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treated rats had lower calcium load
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1740 PROFILING COMPOUNDS WITH CARDI
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dothelial cells confirmed caveolin-
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1758 GINKGO BILOBA EXTRACT INDUCES
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arin-induced suppression of MDR1 ex
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1780 ANTIANDROGENIC AND ANTIPROLIFE
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included in the evaluation, most of
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1799 GUIDANCE ON THE APPLICATION OF
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However, substances with EC3 values
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1816 CD-INDUCED EGFR TRANSACTIVATIO
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1826 KERATIN 7 EXPRESSION IN INDEPE
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centa were collected at the time of
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1845 SYSTEMATIC SCREENING OF YEAST
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underlying the development of co-mo
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eing measured in experimental roden
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ufactured in the US for more than 3
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nine (N7-THB-Gua) and N7-hydroxyphe
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1892 EFFECT OF LAMBDA-CYHALOTHRIN O
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22 in Phase I. Antimicrobial pestic
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kinetic and dynamic differences, an
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iphenyl, saccharin and melamine was
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1930 DEVELOPMENT OF A RELATIVE SOUR
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1939 MODE OF ACTION FOR THE CANCER
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human was about 1.5-fold lower (60
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Disruption of BDEC integrity in alp
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1968 A HUMAN HEPG2 LUCIFERASE ASSAY
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in the offspring during tumor devel
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een developed to investigate perfus
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to 131.73 μg/mL for KLH-specific I
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cell lines (ATCC) were cultured in
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flammation and xenobiotic metabolis
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vide many contributions: with its g
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to-metal joint replacement. For exa
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to be addressed or negotiated. Deci
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especially with anti-TNF therapies.
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genic line Tg(are:eGFP) was created
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2074 COMPUTATIONAL ASSESSMENT OF TH
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2084 INHIBITION OF 11β-HSD1 DECREA
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(T) and express several enzymes inv
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2101 GENISTEIN MODULATION OF BLOOD
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males per group were dosed orally o
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ate the feasibility of assessing re
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changed. Hepatic protein carbonyl l
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sought to examine alterations in he
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2147 A SINGLE AMINO ACID CONTROLS T
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Gstm7) was independent of both CAR
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ility of tungsten trioxide (WO3), t
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ured by real-time PCR array and rel
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glucose, and creatinine levels, and
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Several studies have reported suppr
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exposure between TCDD-exposed labor
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Furthermore, with increasing number
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Society of Toxicology 2010 Author I
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Society of Toxicology 2010 Abstract
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49 th Annual Meeting and ToxExpo A
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The Official Journal of the Society
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