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CD8 + T cell function occurs without a detectable change in lymphoid organ cellularity or in the distribution of immune cell subpopulations, we hypothesize that inappropriate AhR activation during development alters epigenetic regulatory mechanisms such that the response of T lymphocytes is permanently altered. This represents a new paradigm in developmental immunotoxicology, suggesting that AhR influences epigenetic control of immune function. 2667 THE EFFECTS OF ORAL BISPHENOL A EXPOSURE IN THE DEVELOPING CD1 AND C57BL/6 MOUSE. E. Kendig, S. Christie, C. Cookman, C. Lo, D. Buesing, T. McCutchan, J. Cooper and S. Belcher. Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, OH. The endocrine disrupting effects of Bisphenol A (BPA) have been demonstrated in various mammalian and non-mammalian model systems. However, there is some inconsistency in the ability to replicate results. The significance of studies demonstrating harmful effects of BPA and those reporting little or no effect have been highly scrutinized and become the subject of much controversy. Here we report findings from preliminary studies designed to assess the comparative effects of preand postnatal dietary exposure of BPA and 17α-ethinyl estradiol on various developmental, reproductive and cardiovascular endpoints in developing and adult C57Bl/6 and, CD1 (swiss) mice. Preliminary results indicate clear sex- and strainspecific differences in sensitivity to treatment-related changes in measures of fertility. These data also suggest potential cardiovascular effects of treatment with BPA including altered heart rate and the promotion of arrhythmogenesis, suggestive of altered calcium dynamics in the heart. The sensitivity of the mouse strain used appears to be a significant variable in the study of developmental toxicity of endocrine disruptors, suggesting that strain selection is a significant variable for each endpoint of interest. 2668 A BBDR-HPT AXIS MODEL FOR THE LACTATING RAT AND NURSING PUP: EVALUATION OF IODIDE DEFICIENCY. S. Li 1 and J. W. Fisher 2 . 1 Biostatistics, Medical College of Georgia, Augusta, GA and 2 Food & Drug Administration, Jefferson, AR. The hypothalamic-pituitary-thyroid (HPT) axis controls many physiologic functions, including metabolism, growth, development and reproduction. However, there is no adequate risk assessment tools exist to evaluate the health outcomes of chemical/dietary induced changed changes in serum thyroxine (T4, T3) concentrations in either euthyroid or sensitive populations. Ongoing collaborative studies are underway examining the effects of iodide deficiency on CNS development in the rat pup at the USEPA (Drs Mary Gilbert and Kevin Crofton). Electrophysiological, biochemical and molecular studies of the pup brain combined with behavioral studies are used for evaluating HPT mediated developmental neurotoxicity. Our Biologically Based Dose Response (BBDR) HPT axis model for the lactating rat and nursing pups aims to better understand and predict the relationship between brain concentration of T3 and serum concentration of T4. We also investigated the effects of two negative feedback loops: the first being TSH production and brain concentration of T3, and the second being serum TSH stimulation of the thyroid sodium iodide symporter (NIS) and thyroid hormone (T3 and T4) synthesis and production under both sufficient iodine and deficiency iodine uptake conditions. The model is calibrated to predict dietary iodine deficiency-induced perturbation in serum and brain thyroid hormones (regulation of deiodinase I, II and III enzymes) during the nursing period. After successful building of the BBDR model for iodide deficiency, the model will be expanded to include thyroid active chemicals. For example, we have conducted several studies with perchlorate and PCB126, both are thyroid active chemicals, with fairly well defined modes of action on the HPT axis. These models will allow for simulation of complex dose response and exposure conditions that are likely to result in adverse developmental neurotoxicty and ultimately serve as a template for the future development of human gestation and lactation BBDR HPT axis models for use in risk assessment. 2669 VASCULAR INJURY: A FIGMENT OF YOUR INFLAMMATION? H. W. Smith 1 and M. P. Lawton 2 . 1 Eli Lilly and Company, Indianapolis, IN and 2 Pfizer, Groton, CT. Because drug-induced vascular injury (DIVI) is a process rather than a single disease entity, diagnosing and predicting it is like chasing an apparition—there are many sightings but the descriptions are often different. The preclinical finding of 572 SOT 2011 ANNUAL MEETING vascular injury was initially described in rats and dogs, but has also been observed in mice and non-human primates in recent years. While vasculitis in humans appears to be immune-related, the triggers that induce blood vessels to become damaged and inflamed in animals have not been determined. In addition, it is difficult to distinguish the primary event from secondary inflammation that accompanies the induced damage. In animals, the injury can be observed within hours of drug exposure, whereas in humans it may not appear for weeks or months. With the disparity of observations between preclinical species and humans, it is unclear whether drugs that cause vascular injury or immune-mediated vasculitis in animals do so in humans, and whether a finding of preclinical DIVI predicts the risk of vascular injury in humans. As pharmaceutical companies expand their drug discovery efforts into new chemical spaces, higher incidences of preclinical DIVI are being observed in a broader variety of organs, which continue to impede drug development. If DIVI in animals represents a real hazard to humans, it is paramount for the pharmaceutical industry to develop means for early detection and monitoring of vascular injury. An overview of the current understanding of the pathobiology of vascular injury will be provided and the challenges in diagnosing and predicting DIVI with new advances in biomarker strategies will be discussed. In an exploration of the impact of DIVI on drug development, investigative models and case studies will be shared using examples of small and large molecule-induced vascular injury in animals. 2670 THE PATHOBIOLOGY OF VASCULAR INJURY. J. R. Turk. Amgen, Thousand Oaks, CA. Sponsor: M. Lawton. Drugs and xenobiotics may modulate the function of myriad enzymes that impact vasomotor tone, hemostasis, vascular permeability, inflammation, angiogenesis, tissue oxygenation, and metabolic stress. The microscopic anatomy of the vasculature is relatively simple, consisting of three tunicae: (1) intima, composed of endothelial cells; (2) media, composed of smooth muscle cells and bounded by porous internal and external elastic laminae; and (3) adventitia, composed primarily of fibroblasts, that in epicardial conduit and other larger vessels, are surrounded by and interdigitate with vasa vasorum, and adipose tissue that contains not only adipocytes, but also capillaries, lymphocytes, macrophages, mast cell/basophils, neutrophils, and nerves. Each of these cell types may express potential biomarkers of injury associated with characteristic histopathologic lesions. Biomarkers are sought for those that may precede and predict characteristic changes on histopathology. A review of extant knowledge of drug induced vascular injury will be presented. 2671 THE IMPACT OF VASCULAR INJURY ON DRUG DEVELOPMENT. W. Kerns. Accellient Partners LLC, Harvard, MA. Over the past 30 years, countless compounds in development have been labeled as causing vascular injury in healthy animals during the routine conduct of safety studies. Although some of these compounds have been approved as products, a majority have been shelved while industry and academic scientists attempt to define methods to prove that these hazards are not relevant to humans. In humans, there is a background of vascular pathology in most western cultures, making this even more challenging. Proving a negative is a daunting task. The intent of this presentation is to review this drug development problem across the industry and to assess its impact from a cost and lost opportunity perspective. 2672 PROGRESS IN IDENTIFYING BIOMARKERS OF VASCULAR INJURY. B. E. Enerson. Drug Safety Research and Development, Pfizer, Groton, CT. Sponsor: M. Lawton. There is a need for sensitive and specific biomarkers of vascular injury that can be qualified for use in preclinical and clinical settings. In addition, the use of biomarkers of vascular injury in early toxicity studies during drug development has the potential to reduce compound attrition from this difficult to manage finding. Although it is likely there are common pathological processes that contribute to drug-induced vascular injury, this toxicity is complex, with different primary mechanisms of injury that depends on the pharmacological class, off-target profile and/or physical structure of the drug. Therefore selection of biomarkers should be based on identifying a limited but still broad selection of potential markers that cover different mechanisms of injury in different species that are specific, sensitive, and prognostic for vascular injury. This presentation will review recent advances in vascular injury biomarker research and will highlight collaborative efforts towards regulatory acceptance.
2673 IMMUNE-MEDIATED VASCULAR INJURY IN NON- HUMAN PRIMATES. J. L. Bussiere 1 and C. Johnson 2 . 1 Toxicology, Amgen, Inc., Thousand Oaks, CA and 2 Pathology, Amgen, Inc., Thousand Oaks, CA. Anti-drug antibody (ADA) responses can potentially affect the outcome and interpretation of a toxicology study and assessing the relevance of toxicity that may be ADA-mediated in nonhuman primates to clinical populations can be difficult. During the development of a monoclonal antibody (MAb) drug which targets the immune system, a vascular lesion was noted that was not immediately explainable as drug or ADA-related. In a 6-week cynomolgus monkey study with weekly dosing of 10, 75 or 300 mpk IV or 300 mpk SC, chronic periarteritis involving multiple organs was observed in 2/6 animals given 300 mpk IV, and in 1 tissue in 1/6 animals given 300 mpk IV, 1/6 animals given 75 mpk IV and in 1/6 animals given 300 mpk SC. The etiology of the vascular lesion was uncertain based on routine histopathology evaluation. A vascular target was not anticipated based on literature describing target-deficient humans or KO mice and was thus thought not to be related to the mechanism of action of the MAb. Evidence of an immune response to the MAb associated with enhanced clearance was noted in 3/5 animals with the lesion, and these animals tended to develop ADA quicker than non-affected animals that eventually became antibody positive. The safety margin at the NOAEL of 10 mpk was ~5x/20x based on AUC/Cmax, and FIH trials were initiated. In a follow up 3-month study with weekly SC dosing of 5, 25, or 90 mpk, periarteritis was noted in only 1 tissue of 1 animal at the mid dose. Immunohistochemical (IHC) staining for antihuman IgG and antimonkey IgG and IgM revealed granular staining in blood vessels with the vascular lesions of animals from both studies. This staining pattern suggested that ADA/drug complex deposits might have a role in the pathogenesis of the lesion. No periarteritis was seen in a 6 month study at similar doses. These data supported the conclusion that ADA contributed to the toxicity seen with this MAb and was not likely to be relevant to humans. Close monitoring of ADA in the clinical trials, along with other endpoints allowed for progression of single and multiple dosing. 2674 IMAGING AS A TRANSLATIONAL TOOL FOR ASSESSING CLINICAL RELEVANCE OF DRUG- INDUCED VASCULAR INJURY. A. Lerman. Mayo Clinic, Rochester, MN. Sponsor: H. Smith. There is a growing need to identify the potential cardiovascular effect of new therapeutic options prior to launching large randomized clinical trials, and particularly introducing the new therapy to clinical practice. The endothelium is strategically located between the circulation and the vascular wall and regulates vascular tone, growth and thrombosis. The vascular wall continues to undergo continuous vascular injury and repair, and the role of the endothelium is to mediate this repair process. An abnormality that impairs this process results in endothelial dysfunction and progresses to more severe vascular injury that can mediate a cardiovascular event and mortality. There are several methodologies to assess the effect of a specific drug on the endothelial function. In vitro methods such as organ baths, to assess the effect of a drug on the vascular function and specifically on the endothelium. Further studies can be done in small and large animals to assess the effect of acutely or chronically administered drug on the vascular endothelial function,. When the studies with the new drug continue into a human investigation, there are several methodologies that enable us to assess the specific effects of this new therapeutic modality on endothelial function in humans. These methods include noninvasive and methods to assess the specific effect on the coronary endothelial function. Additionally, there are novel imaging modality to assess not only the effect on the function, on the structure of the vascular wall. This imaging modality, particularly of interest in the coronary circulation, can have a more accurate imaging of the effect of the drug on the vascular wall. Thus, the application of these in vitro, nonclinical, and clinical methodologies to the assessment of new therapeutic drugs on vascular function and specifically on endothelial function may increase the safety of the drug and prevent the clinical incidence of drug-induced cardiovascular morbidity and mortality. 2675 ARE WE THERE YET? – ATTRITION IN THE PHARMACEUTICAL INDUSTRY AND IMPACTFUL STRATEGIES FOR REDUCING FAILURE. J. Stevens 6 , C. Afshari 5 , B. Car 1 , I. Cotgreave 2 , K. Kolaja 3 and B. Pennie 4 . 1 Bristol-Myers Squibb, Lawrenceville, NJ, 2 Astra-Zeneca, Uppsala, Sweden, 3 Roche, Nutley, NJ, 4 Pfizer, Groton, CT, 5 Amgen Inc., Thousand Oaks, CA and 6 Lilly, Indianapolis, IN. There have been many reports over the years that indicate a significant amount of attrition of candidate molecules in the pharmaceutical industry is due to safety related failures. In the recent years new approaches have been deployed to shift safety related attrition earlier in the pipeline. The impact of these new strategies will not be fully realized until they are in place for a number of years. In the meantime, there is no way to objectively assess to what extent and in what manner we are improving as an industry and what further changes and areas of research are needed. Therefore it is important to begin dialogue that aims to provide a forum to discuss contemporary views of the rate and causes of current safety related pharmaceutical attrition. An analysis of the strategies that appear to be most useful (or least useful) to drive this attrition earlier, i.e. fail fast will be included. Varying perspectives will be provided on the primary reasons for safety related attrition within companies and the current strategies deployed to address the problem. Special focus will be given to the early stage portfolio work through the first in human trials. The strategies that will be discussed will include the integration of in vitro and in vivo models with technologies such as imaging platforms, genomics, and protein/biochemical analyses. Gaps or areas for future research support will be highlighted as appropriate. 2676 THE INTEGRATION OF MULTI-DISCIPLINARY APPROACHES WITH DISCOVERY TOXICOLOGY IN OPTIMIZING DRUG CANDIDATES. B. D. Car. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princton, NJ. Discovery Toxicology has been integral to the drug discovery and development process at BMS and legacy companies for over 13 years. This department approaches target and candidate selection with a multi-disciplinary team including pathologists, cardiologists/safety pharmacologists, toxicologists, molecular and cell biologists. DT has leveraged the integration of classic approaches such as in vivo toxicology and pathology with new technologies including genomics and metabonomics approaches and close partnerships with Discovery Metabolism and Pharmacokinetics, Biotransformation, Bioanalytical and Pharmaceutics groups. Focusing initially on in silico and in vitro technologies, the group moved to a more integrated in vitro/vivo approach to addressing failures due to preventable developability issues and avoidable target-associated safety issues. Collectively, this improved target success and resulted in a lower compound attrition rate. Recognizing that such an approach can create a checkbox mentality and reduce hypothesis testing, the focus has shifted to more a risk-adjusted and therefore fiscally responsible direction, which was achieved without compromising attrition. Key to the success has been high level integration across associated disciplines and within the context of expert chemistry and pharmacology groups, leveraging their expertise whenever possible. 2677 POTENTIAL USES OF STEM CELL TECHNOLOGY IN EARLY PIPELINE SAFETY SCREENING. I. Cotgreave. Global Safety Assessment, Molecular Toxicology, AstraZeneca, Södertälje, Sweden. Sponsor: C. Afshari. Strategies to reduce late- stage attrition are associated with a need to develop and explore novel systems for lead selection. One area that is under exploration is the optimal use for stem cell models. Current attrition reasons and strategies to reduce at Astra-Zeneca will be discussed. Strategies to produce safety screening techniques based on human embryonic stem cells and induced pluripotency will be discussed, focusing primarily on the need to predict human cadio- and hepatotoxicity. Several collaborative initiatives will be high-lighted, including the Stem Cells for Safety of Medicine (SC4SM) program, a UK-based public-private consortium. Results of initial validation exercises will discussed and the expectations for the near future debated. 2678 EFFECTIVE AND EMERGING PLATFORMS FOR PREDICTIVE TOXICOLOGY. K. L. Kolaja. Nonclinical Safety, F. Hoffmann-LaRoche, Nutley, NJ. Attrition of drug candidates within the pharmaceutical industry occurs throughout the entire development process. Ideal screening strategies identify liabilities early and accurately to enable project teams to make lead optimization decisions that will match the clinical goals for a given program. A combination of effective assays that survey genetic toxicology, teratogenicity, cardioavascular toxicity, and target organ SOT 2011 ANNUAL MEETING 573
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The Toxicologist Supplement to Toxi
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The Toxicologist Supplement to Toxi
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1 BIODEGRADABLE MATERIALS FOR TISSU
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that genetic toxicology data are ge
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well-orchestrated lung inflammation
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scribed in the literature. We have
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years ago). We will illustrate how
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involved in the biodegradation proc
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stem cells but rather a treatment i
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additional compound showed agreemen
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82 COMPARISON OF 3H-THYMIDINE INCOR
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irritants. While in practice these
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alleles are especially vulnerable t
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109 CD4+ T CELL INTRINSIC TNF RECEP
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118 TO STUDY THE SIGNAL TRANSDUCTIO
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PAHs, such as dioxins, are prevalen
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containing substituents and/or hydr
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146 COMPUTATIONAL MODELING FOR QT P
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suggest that the combination of too
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164 TRANSLOCATOR PROTEIN (18 KDA) (
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function as a metal binding protein
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laboratory has demonstrated that NR
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known. The aim of this study was to
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from 5 to 28 days in duration) in e
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positive cells, caspase-3 activatio
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creased level in the 46 kDa preproe
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invasiveness at concentrations repr
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thracene (DMBA,50 μg in acetone, a
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247 CO-CARCINOGENESIS OF N, N- DIET
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sponds to the endosomal dsRNA that
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ODD in both WT (maximum 177% of con
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Lastly, using p53siRNA cells, p53 w
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its receptor Mpl to exert its funct
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294 LOW LEVEL OF LEAD CAN INDUCE PH
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lunar surface presented potential h
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lar about cellular export mechanism
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DNA in the kidney medulla, grandula
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5.00 and 7.50 mg/kg/day by oral gav
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events and carcinogenesis. Here we
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tinization of cells of the hair fol
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358 CHARACTERIZATION OF GENOME-WIDE
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RNAi were also performed to identif
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376 A FUNCTIONAL CROSSTALK BETWEEN
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UGT1A gene induction, while this re
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tivity, specifically peroxisome pro
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and cytotoxic effects; however, its
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histone deacetylase that is necessa
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ment. Paradoxically, buthionine sul
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drug leflunomide and its major (A77
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442 GENE EXPRESSION AND MORPHOLOGIC
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451 INHIBITION OF THE MITOCHONDRIAL
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460 SULFORAPHANE PREVENTS ACETAMINO
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drophilic/lipophilic balance. Other
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pharmacokinetic and toxicological p
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489 USE OF ‘OMICS DATA TO IMPROVE
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498 APPLICATION OF AGE-SPECIFIC ADJ
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507 A DOSE VOLUME TOLERABILITY STUD
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involved the use of an acute inflam
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sorption in the gastrointestinal (G
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(ABC) transporters actively transpo
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545 BEHAVIORAL EFFECTS OF REPIN IN
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a blood pressure phenotype that res
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and inhalation exposure system that
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and lethality associated with these
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position, on vascular reactivity an
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therefore more accurate and reprodu
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commercial chrysotile product that
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elative to their controls. ST-depre
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ats. The majority of the studies fo
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in the China Jintan Child Cohort St
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corneum thickness, cellular epiderm
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645 EVALUATION OF THE IN VITRO EPIS
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654 TCDD ADSORBED ONTO NATURAL AND
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tion revealed no test article-relat
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671 INFLAMMATION AND TISSUE DAMAGE
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model, ethanol was found to inhibit
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689 ENHANCED SUPPRESSIVE FUNCTION O
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NAC + LPS yielded different levels
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707 LIFE-STAGE PBPK MODELS FOR MULT
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downstream of the apical endpoint o
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726 UPDATED ALUMINUM PHARMACOKINETI
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global parameter sensitivity analys
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and renal inflammation induced by 2
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754 PLASMA, URINE, AND TISSUE CONCE
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cently characterized transporter OA
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exposure system was developed from
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lood cell mass and decrease in urin
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practical alternatives to MC in non
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imals dosed with 167 mg/kg THU alon
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and organ weights, clinical signs a
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yet is induced in most bladder and
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830 RISK ASSESSMENT OF THE SPILL: C
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knowledgebase creation. Results are
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852 UNDERSTANDING STRUCTURAL AND PH
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for integrating epidemiology and an
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motor activity, including age of th
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y partial purification of urine (fr
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pacity for self-renewal and may dif
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sue. The depth of our analysis led
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910 IMPLEMENTING CALIFORNIA’S GRE
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concentrations in six tissues and b
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934 THE FDA’S LIVER TOXICITY KNOW
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943 GENOME-WIDE DNA METHYLATION DIF
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membrane localization and subsequen
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trols, respectively. Subtoxic and t
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survival using both smoking regimes
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as non-, weak, moderate, or strong
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988 NNK-INDUCED CYTOKINE ALTERATION
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group (one-way ANOVA, p90 % viabili
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ered as an organ involved in xenobi
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Transport of CPZ across the Caco-2
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estrous cycle and sexual behavior d
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mRNA expression levels. Collectivel
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1043 THE EFFECTS OF ENDOCRINE DISRU
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1052 MONO-2-ETHYLHEXYL PHTHALATE IN
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Results: MC was variable within and
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UtSMCs. Phosphorylation of FoxO1 wa
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nonpregnant and pregnant diabetic m
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1089 PFOA-INDUCED LIVER EFFECTS IN
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events in the liver. AZD9056 was ev
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The peppermint oil caused a concent
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OA did not affect food consumption.
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1126 PERSISTENT DEVELOPMENTAL ARYLH
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1135 BACH2 BINDING TO Prdm1 AS A ME
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The purpose of this project was to
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one marrow. Since Chk1 is an attrac
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1163 THE MRNA AND MIRNA PROFILE OF
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have now compared the IC50 values b
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1181 ELUCIDATION OF FACTORS DETERMI
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enced by pre-exposure to cigarette
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if abnormal PF was associated with
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weight (P=0.016) and small for gest
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portant cause of death, compared to
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posure groups. However, the differe
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Naphthalene is routinely analyzed i
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1245 SEASONAL CHARACTERIZATION OF H
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1255 URINARY T, T MUCONIC ACID LEVE
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modating a reliable data evaluation
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enzoquinone generate ROS and arylat
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teins (e.g. C3, 4, and 5, APOB, VDB
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1293 TRANSFORMING GROWTH FACTOR BET
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mation was decreased to the same le
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1312 EVALUATION OF THE SENSITIVITY
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luted OFR and CRL. Culture media ex
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urinary TCPy levels, blood and brai
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activity. The dose-response curves
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mice, each with 4 dose groups. One
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exposure to both ATR and DACT has a
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third tetratricopeptide repeats (TP
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7d. 28d after TMT injury there was
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subunits. Each cell type was treate
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1394 COMPARATIVE EFFECTS OF METHYLM
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1403 GENOTOXICITY AND PRE-NEOPLASTI
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vated only in high-dose-treated ani
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1421 DOSE-RESPONSE OF NAPHTHALENE-I
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cisplatin; 1.2-, 1.9- and 2.9-fold
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Day 11 and started to recover on Da
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1448 DEVELOPMENT OF A METHOD FOR QU
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1457 GLOBAL GENE PROFILING REVEALS
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cluding mouse and human macrophage,
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model of lung inflammation and host
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1484 NANOTOXICOLOGY AND NANOHEALTH
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throughput in vitro approach was us
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1502 IMMUNOLOGICAL ASPECTS OF AN AN
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(CIA) and the Streptococcal cell wa
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sitizers were 100% concordant among
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1530 MINIMAL RISK LEVELS FOR STYREN
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ical groups in the field of regulat
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vitro with this potentially insect-
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their performance on toxicological
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need for a better understanding of
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1577 AN IN VITRO MODEL SYSTEM FOR A
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gene expression post-transcriptiona
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1595 GENE EXPRESSION PROFILE OF RAT
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to confirm a hepatotoxic property o
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1613 AN INVESTIGATION OF THE CLEARA
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its nuclear translocation was reduc
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were collected from TK animals at d
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egulated targets were selected for
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U/L after tetracycline. Minocycline
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peri-pubertal FasL-/- mice show a d
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showed similar levels of apoptosis
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1676 TWO BIOMARKERS FOR EVALUATION
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motifs selected. This system was ap
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1693 VOC SERUM LEVELS IN THE GENERA
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1702 DOES THE CLOCK MAKE THE POISON
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those with high nickel content are
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isk assessment. However, unique cha
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model of APAP metabolism and glutat
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logically & morphologically similar
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posure, blood chemistry was analyze
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elated to oxidative stress by measu
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ostasis), but work is needed to tra
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tokine products during carcinogenes
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ways as chemical stressors and, the
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toxicity of nanomaterials relates s
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1815 MEASURING COMPOUND SELECTIVITY
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1825 EFFECTS OF METABOLISM BY INTES
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cyanoacetic acid increased 2-3 fold
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1845 IS THE PROMISCUITY OF THE ARYL
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crorarray analysis. RT-PCR results
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are a family of phase-II biotransfo
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ous labs. As a result of positive s
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down the doses may produce more tox
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spectively. Below 100 mg/l of gemfi
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1900 GENERATION OF PRECISION CUT LI
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iomarkers or observation of lesions
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creased reticulocytes and lymphocyt
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statistically significant interacti
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monize sample preparation and analy
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NPC and sinonasal cancer in neighbo
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showed incidences of lung and nasal
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utylbenzenes, exhibited most simila
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1975 DIFFERENTIAL MODULATION OF CYP
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organic As to MMA(V) and a lower ca
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ole in invasion and metastasis of c
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3T3-L1 cells to low-levels of arsen
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2011 IDENTIFICATION OF A NOVEL VX M
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This work was supported by Cooperat
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2029 EFFICACY OF ENDOTRACHEAL ADMIN
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Diazepam injections and its combina
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2047 ESTERASE ACTIVITIES AND HEMOST
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nanoparticle-induced toxicity progr
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house, were iv infused into rats ov
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een explored. This study investigat
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croscopic analysis revealed that on
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egg yolk collected from turtles inh
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consistency of results in both expe
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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: (p 9 weeks) and CSC phenotype acqui
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 611 and 612: Keyword Index (Continued) Arsenite
Page 613 and 614: Keyword Index (Continued) Covalent
Page 615 and 616: Keyword Index (Continued) flow cyto
Page 617 and 618: Keyword Index (Continued) innate im
Page 619 and 620: Keyword Index (Continued) nanoparti
Page 621 and 622: Keyword Index (Continued) preservat
Page 623 and 624: Keyword Index (Continued) Thrombocy
Page 625 and 626: Toxicological Sciences The Official
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The Toxicologist - Society of Toxicology

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