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1736 CARDIOVASCULAR EFFECTS OF ACUTE ISOTONIC VOLUME OVERLOAD IN TELEMETERED CYNOMOLGUS MONKEYS: MAJOR ROLE FOR ANP. E. Bou-Abboud 1 , N. Crosby 1 , F. Sannajust 1 , B. Lee 1 , R. Harris 1 , Y. Mori 1 , J. Tilton 1 , J. Ogle 1 , P. Franklin 1 , R. Eyre 1 , J. Klaassen 1 , S. Meyer 1 and R. Nagata 2 . 1 SNBL USA Ltd., Everett, WA and 2 Shin Nippon Biomedical Laboratories, Ltd., Tokyo, Japan. In order to meet the scientific requirements for preclinical safety assessment studies, some NCEs or Biologics require IV infusion of large volumes or for long period of time. The objective of this study was to examine the potential cardiovascular effects of two Acute Volume Overload (AVO) challenges resulting from a 30-min. IV infusion of 15 mL/kg (Day 1) and 30 mL/kg (Day 3) sterile, isotonic saline in (n=4) telemetered (DSI/D70-PCT) adult male (4.9-6.9 kg) cynomolgus monkeys, previously implanted with a chronic femoral vein catheter. Arterial BP (SBP, DBP), heart rate (HR), ECG parameters, derived respiratory frequency, body temperature, hematology and serum chemistry parameters as well as, Atrial (ANP) and Brain (BNP) Natriuretic Peptides were assessed on Day-1 (Baseline levels), and during AVO challenges on Days 1 & 3. Either AVO did not induce any changes in hematology and serum chemistry parameters (Day 1 & Day 3 vs Day-1). Analysis (rANOVA/ Dunnett’s test vs Day-1) performed over 0-6h (post-start of infusion) showed that, both AVO challenges caused significant (p
1740 PROFILING COMPOUNDS WITH CARDIOTOXIC POTENTIAL USING HIGH CONTENT IMAGING IN RAT H9C2 CELLS AND HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES. A. Hoffman 3 , S. Hamilton 3 , K. Zipf 3 , S. Kameoka 1 , N. Tandon 1 , B. Swanson 2 , W. Wang 2 , B. Anson 2 and K. L. Kolaja 1 . 1 Nonclinical Safety, Hoffmann-LaRoche, Nutley, NJ, 2 Cellular Dynamics International, Madison, WI and 3 Discovery Technology, Hoffmann-LaRoche, Nutley, NJ. A high content imaging strategy was implemented to compare the toxicological properties of a set of compounds across two distinct cell systems, the rat H9C2 cell line and human induced pluripotent stem (hiPS) cell-derived cardiomyocytes. The use of a multiplexed approach includes parameters suitable for detecting DNA damage, nuclear morphology, mitochondrial membrane potential, oxidative stress, effects on lysosomal integrity, glutathione redox status, and apoptotic events. A test panel of compounds with known in vivo cardiotoxicological attributes including doxorubicin and many well characterized kinase inhibitors were used as reference set to assist in interpretation of the high content imaging assay results. The toxicity profile investigations revealed that cardiotoxicants are more readily identified using hiPS cell-derived cardiomyocytes compared to H9C2 cells. In particular doxirubicin and other overt cardiotoxicants induced a dose responsive change in cellular ATP, caspase 3/7 activity, and mitochondrial membrane potential in hiPS derived cardiomyocytes. This study supports the continued use of high content imaging and stem-cell derived models as a part of a safety evaluation strategy implemented during the early phase of drug discovery. As the availability of additional differentiated hIPs cell types are developed, high content imaging techniques can then be rapidly deployed to provide more complete insight into the early safety profile of a molecule. 1741 THE TECHNICAL MERITS REQUIRED TO DEVELOP HIGH CONTENT IMAGING APPLICATIONS FOR CARDIOMYOCYTES DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS. S. Hamilton 3 , A. Hoffman 3 , W. Wang 2 , J. Ma 2 , N. Tandon 1 , S. Kameoka 1 , B. Swanson 3 , B. Anson 2 , K. Zipf 3 and K. L. Kolaja 1 . 1 Nonclinical Safety, Hoffmann- LaRoche, Nutley, NJ, 2 Cellular Dynamics International, Madison, WI and 3 Discovery Technology, Hoffmann-LaRoche, Nutley, NJ. The potential of utilizing human primary cardiomyoctes in early safety programs for compound assessment has been historically limited by cell availability and technical challenges. However, recently, human induced pluripotent stem (hIPS) cellderived cardiomyocytes have been established in suitable scale sufficient for the conduct of characterization experiments. During bulk production of hIPS cell-derived cardiomyocytes, particular emphasis was placed upon defining appropriate quality controls for consistent manufacturing including cardiomyocyte purity and post-cryopreservation viability. From a functional utility purpose, initial sets of validation experiments assessed the hiPS cell derived cardiomyocytes for their suitability to profiling molecules for their safety pharmacological and toxicological properties. In doing so, a set of specific cytotoxic endpoints were identified. This presentation will highlight the method development for cell handling and provide select examples of the high-content screening (HCS) assays and feature measurements that have been adapted for such studies. Illustrated features include, but are not limited to, cell viability, cell purity, nuclear morphology, DNA damage, mitochondrial membrane potential, oxidative stress, reactive oxygen species, lysosomal integrity, and apoptotic events. 1742 REPRODUCIBILITY OF AORTIC PLAQUE DEVELOPMENT IN APOE-/- MICE FOLLOWING CIGARETTE SMOKE INHALATION EXPOSURE. J. E. Swauger and G. M. Curtin. Regulatory Oversight, RAI Services Company, Winston Salem, NC. Initial studies revealed that ApoE-/- mice fed a pro-atherogenic diet exhibit increased atherosclerotic progression within select aortic regions in response to cigarette smoke inhalation exposure. Specifically, time- and dose-dependent increases for free cholesterol and cholesteryl ester accumulation were observed for the thoracic and abdominal aorta. In an effort to reproduce and extend these novel findings, stereological methodologies were applied to directly assess atherosclerotic plaque incidence, grade, and volume for ApoE-/- mice fed either a pro-atherogenic (high-fat) or normal chow diet and exposed to cigarette smoke; assessments were conducted for the root sinus, arch, thoracic, and abdominal aortic regions. Experimental findings from these studies reveal markedly different atherogenic responses for cigarette smoke-exposed mice based on diet type. Mice fed a high-fat diet and exposed to cigarette smoke exhibited dose-dependent increases (with maximal responses) for atherosclerotic plaque incidence, high-grade plaque development, and (plaque) lesion volume within the thoracic aorta. In terms of demonstrating a range of responses suitable for comparative toxicological testing, lesion volumes for sham- and cigarette smoke-exposed (0.16, 0.32 and 0.48 mg WTPM/L) mice were determined to be 9.37+/-3.02, 71.14+/-17.99, 156.33+/- 14.95 and 156.83+/-30.55 (x 10-3 mm3, mean+/-SEM), respectively. Additional cigarette smoke-mediated effects included increased high-grade plaque development and lesion volume for the aortic arch and abdominal aorta. No meaningful increases for atherosclerotic plaque incidence, grade, or volume were observed for cigarette smoke-exposed mice fed a normal chow diet. Collectively, these data demonstrate the reproducibility of dose-dependent increases for cigarette smokemediated atherosclerotic progression within a preclinical rodent inhalation model. 1743 COMPROMISE IN MITOCHONDRIAL OXIDATIVE CAPACITY INDUCED BY CHRONIC EXPOSURE OF CARDIOMYOCYTES TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS). Y. Liu, T. Baris and M. C. Poirier. National Cancer Institute, Bethesda, MD. NRTIs comprise the cornerstones of antiretroviral drug combinations used for HIV-1 therapy, turning HIV-1 infection into a manageable clinical entity. Despite the highly-effective initial impact of NRTI use, therapeutic experience has revealed side effects of chronic use that particularly affect the heart and manifest as mitochondrial dysfunction. To determine mechanisms of NRTI toxicity, and possibly design therapeutic interventions, we established cardiomyocyte cultures of rat H9c2 cells and mouse HL-1 cells, and exposed them to the NRTIs Zidovudine (AZT) and Didanosine (ddI). Short-term growth inhibition assays indicated that the H9c2 cells would grow well in 50μM AZT and the combination 50μM AZT/50μM ddI, and the HL-1 cells would grow in 10μM AZT and 10μM AZT/10μM ddI. Subsequently, mitochondrial function, in the form of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), was measured by Seahorse XF24 analyzer. In H9c2 cells exposed for 11 passages(P) and uncoupled to maximal mitochondrial respiration with carbonyl-cyanide-4-(trifluoromethoxy)phenlyhydrazone (FCCP), OCR was decreased by 30% with 50μM AZT and 56% with 50μM AZT/50μM ddI, compared to unexposed controls. Cell growth in NRTI-exposed H9c2 cells was 85-90% of that seen in the controls. In FCCP-uncoupled HL-1 cells exposed for 10P, OCR capacity was decreased by 68% with 10μM AZT and 59% with 10μM AZT/10μM ddI, compared to unexposed controls. Cell growth in NRTI-exposed HL-1 cells was 70-80% of that observed in the controls. Also, compared to unexposed controls, ECAR, a measure of lactic acid production, was elevated in NRTI-exposed H9c2 cells by 25-37% and in HL-1 cells by 28-86%. Therefore, long-term NRTI exposures in cultured rodent cardiomyocytes impair maximal mitochondrial capacity and induce glycolytic compensation at doses that support cell viability. We plan to use this system to evaluate a series of potentially protective intervention strategies. 1744 EFFECTS OF MODULATING IN VIVO NITRIC OXIDE PRODUCTION ON THE INCIDENCE AND SEVERITY OF PHOSHODIESTERASE 4 (PDE4) INHIBITOR CI- 1044 INDUCED VASCULAR INJURY. C. M. Sheth 1 , B. E. Enerson 2 , D. Peters 1 , S. Stewart 1 , M. Lawton 2 and J. L. Weaver 1 . 1 DAPR, CDER FDA, Silver Spring, MD and 2 Safety Sciences, Pfizer Groton Laboratories, Groton, CT. Drug Induced Vascular Injury (DIVI), is an adverse finding during preclinical safety studies of many classes of drugs including PDE4 inhibitors. The mechanism(s) of injury are poorly understood. Nitric oxide (NO) produces vasodilatation and is a mediator of inflammatory signal transmission. To determine if NO has a direct role in DIVI, rats were treated with CI-1044 alone or in combination with nitric oxide synthase inhibitors L-NAME or L-NIL or nitric oxide donors SIN-1 or NOC-18. Mesenteries were collected and processed for microscopic evaluation; blood was also collected and analyzed for serum nitrite (SN), an indirect quantitative measure of in vivo NO production. Compared to the vehicle control, CI-1044 resulted in a 1.4 fold increase in SN, which was reversible by co-treatment with L- NIL. SN values for animals receiving L-NAME were reduced 1.8 fold from the vehicle control, while SN for animals receiving SIN-1 were increased 1.8 fold from control values. Co-administration of CI-1044 and L-NAME resulted in a 2.8 fold reduction in SN compared to CI-1044 alone. Co-administration of CI-1044 and SOT 2010 ANNUAL MEETING 371
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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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developmental effects. The residual
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strand breaks in an in vitro model
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etate (immunotoxicity). 2,4-D was t
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867 MELATONIN AMELIORATES CYCLOPHOS
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pharmacokinetic (PBPK) models. Ten
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of radiolabeled Mn (carrier-free 54
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893 UNVEILING ASSOCIATIONS BETWEEN
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using area under the concentration
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912 COMMERCIAL FISH DIETS INDUCE VI
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922 A STUDY OF PHOTOTOXICITY FOLLOW
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from 0.1 to 2.9 g/L (saturated vapo
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vasive method for assessing several
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950 ARSENITE DOWN-REGULATES THE CAR
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inflammatory signaling is altered b
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treated wood. Seventy-five of 132 w
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ergy homeostasis and raising levels
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treated with mercury and then with
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997 IN VIVO CORRELATES OF THE MANGA
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of the panel. The panel was compris
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sponse, location, and severity scor
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tant source of n-3 fatty acids such
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old for serious, irreversible or es
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1045 SUBCHRONIC TOXICITY EVALUATION
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sites collected 3 days after inject
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1063 MOLECULAR MECHANISM OF OLANZAP
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esponses, and can be available for
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hence more physiologically relevant
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thesized apoproteins, so we tested
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vate CYP3A5 but could be released b
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1108 STYRENE-INDUCED TOXIC EFFECTS
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1118 THE PRESENCE OF DIETHYL FUMARA
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zebrafish cells were first exposed
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utene-1,4-dial, which has been show
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groups, largely due to lower non-HD
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Exposure to gluten in individuals w
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contrast to VGSC activators such as
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1175 70% HYDROFLUORIC ACID (HF) CUT
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axis. An increase in hyaline drople
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1194 esiRNA AND siRNA HIGH-THROUGHP
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1203 ARYL HYDROCARBON RECEPTOR-DNA
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permeability (calcein), mitochondri
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olytic caspase activation, caspase-
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teristics of a human T-type voltage
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80% of the activity from the yellow
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1251 DEVELOPMENTAL EXPOSURE TO DELT
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1260 MANEB ENHANCES MPP + -INDUCED
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demonstrated by knockdown of beclin
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1278 PINK1 AND MITOCHONDRIAL DYNAMI
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treatment for number of live worms.
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1297 INVESTIGATION OF THE NEUROTOXI
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1306 DEVELOPMENT OF AN IN VITRO ASS
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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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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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