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of REPs required a complex mixed-effects Hill model that assumed DLC partial agonism. The accuracy of 50% effective concentration (EC50)-derived REPs in the presence of uncertain maximal effects of differing magnitudes is questionable. However, the responses observed at low agonist concentrations appeared to be extremely consistent across NHEK donor cultures. To capitalize on this feature, responses and concentrations were first log10-transformed, revealing a donor-invariant dose at which a minimally significant response (MSR) was first achieved. After removal of high concentration data at which the responses showed evidence of saturation, a simple linear regression model of log relative response against log concentration (a power law model) was used to directly estimate the “minimally significant” dose (MSD), using only data from the remaining doses at which statistically significant responses were observed. The resulting MSDs and the related low-dose REPs were largely invariant, regardless of whether or not the response slopes (Hill coefficients) were assumed equal across the different AHR agonists. By simultaneously modeling all three compounds, low-dose REPs were derived. Overall, this power law modeling procedure for REP derivation can likely be applied to in vitro systems where donor variability in response and/or the presence of partial agonists may pose problems for EC50 estimation. 475 NON-THRESHOLD BIOLOGICAL PROCESSES AND THE ASSUMPTION OF LOW-DOSE LINEARITY: CONSIDERATION OF RECEPTOR-MEDIATED EVENTS IN RISK ASSESSMENT. P. D. White, M. A. Spassova, R. P. Subramaniam and L. Kopylev. U.S. EPA, Washington, DC. Sponsor: S. Vulimiri. Important classes of toxic substances act through biological processes that modify the function of nuclear receptors. The shape of dose-response relationships for these processes continues to be contentious. A brief review is presented of scientific arguments for non-threshold and for low-dose linear behavior and their relevance for receptor-mediated toxicity. Dose-response inferences based upon mechanistic arguments, dose-additivity to background biological processes, and the impact of population variability are discussed. Secondly, a focused review and statistical analysis of examples of empirical data on dose-response relationships for receptor mediated biological responses is presented. Misimpressions regarding the shape of such relationships due to plotting of observed data on semi-log plots are elucidated. For example, a low-dose linear curve, such as a Michaelis-Menten relationship, will appear “sigmoidal” when plotted on a semi-log scale, yet one can easily see that a Michaelis-Menten relationship is linear at low doses when the plots are presented on linear scales. Datasets illustrating receptor mediated effects including induction of P450 enzymes, epidermal growth factor receptor regulation, and observed damage to DNA are statistically analyzed. The data analyzed are generally consistent with low-dose linearity, (e.g., are acceptably fit using Michaelis-Menten relationships) and generally do not show evidence of steep (non-proportional) decrease within the studied dose ranges. In specific cases where steeper than linear dose-response relationships are observed for apical toxicological responses at high dose, limits on the magnitude of a low-dose linear component of the risk relationship are examined. Disclaimers: The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the U.S. EPA. 476 THE HUMAN-RELEVANT-POTENCY-THRESHOLD: UNCERTAINTY ANALYSIS AND HUMAN CALIBRATION FOR CUMULATIVE RISK ASSESSMENTS. E. Sargent 2 , R. Golden 4 , D. Dietrich 3 , G. Casella 5 and C. Borgert 1 . 1 Applied Pharmacology & Toxicology, Inc., Gainesville, FL, 2 EV Sargent LLC, Clearwater, FL, 3 Faculty of Biology, University of Konstanz, Konstanz, Germany, 4 ToxLogic, Potomac, MD and 5 Department of Statistics, University of Florida, Gainesville, FL. Cumulative effect models based on concentration addition (CA), e.g., relative potency, TEF/TEQ, Hazard Index, are the defaults for toxicological health risk assessments of chemical mixtures with constituents presumed to have similar modes of action or to produce similar toxic effects. CA models predict toxic effects according to the relative potencies of mixture constituents summed by dose, extrapolating the prediction irrespective of the potency of the chemicals or the concentrations to which humans may be exposed. Methods to assess uncertainties inherent in this extrapolation are seldom employed and methods for calibrating the extrapolation to potencies and concentrations relevant for humans have yet to be devised. Using anti-androgens (phthalates, procymidone, finasteride, DES) as a test dataset, we demonstrate that uncertainties in cumulative effects data for the observable toxicity range in rodent studies may be 2-fold or more, and may be orders of magnitude greater when extrapolated to lower, human-relevant doses. We present a novel Human-Relevant-Potency-Threshold approach that can improve application of the concentration addition model and obviate a need to use default uncertainty factors in deriving human-protective point-of-departure doses (e.g., RfDs) for estimating cumulative toxicity and projecting human risk. The HRPT approach uses data for 102 SOT 2011 ANNUAL MEETING hormonally active pharmaceutical chemicals or natural receptor ligands, prioritizing human clinical data and relating the human observable effect range to those from animal toxicology studies. We discuss how an HRPT for anti-androgens might be developed and how it could be used to improve the application of CA models in cumulative risk extrapolation. 477 THRESHOLD ANALYSES FOR ACRYLONITRILE AND BRAIN TUMORS IN RATS. D. E. Strother 1 and C. R. Kirman 2 . 1 ToxSolve LLC, Manassas, VA and 2 Summit Toxicology LLP, Orange, OH. The potential risks from exposures to acrylonitrile (AN) have historically been assessed based upon its potential carcinogenicity, primarily driven by brain tumor response in rats. Analyses were performed to evaluate the presence of a threshold for brain tumor response in rats based upon pooled data, which includes twelve data sets (six oral and six inhalation), spanning 34 nonzero dose groups and 12 control groups, expressed in terms of an internal dose measure (peak 2-cyanoethylene oxide or CEO in brain). Stepwise addition of the nonzero dose groups indicates no evidence of a dose-response relationship below 0.012 mg/L (peak CEO in brain). The slope of the dose-response relationship above 0.012 mg/L is significantly different from zero, and is significantly different from the slope of the dose-response relationship predicted below 0.012 mg/L. Inclusion of a threshold term did not result in a significant improvement of the fit of a Weibull dose-response model to the pooled rat brain tumor data, demonstrating the difficulty in proving the existence of a threshold based solely upon changes in goodness of fit tests. The dose-response relationship for AN and rat brain tumors is well correlated with published measures for oxidative stress (8-oxo-dG, oxidative DNA damage), while showing a lack of correlation with direct DNA damage. Together the statistical and biological approaches provide support for adopting a nonlinear dose-response assessment (i.e., cancer reference values) when assessing risks to human populations exposed to AN. 478 EFFICIENT DESIGN OF BIOLOGICAL EXPERIMENTS FOR DOSE-RESPONSE MODELING IN TOXICOLOGY STUDIES. F. Yang 1 and D. Porter 2 . 1 West Virginia University, Morgantown, WV and 2 NIOSH, Morgantown, WV. This work is concerned with the efficient design of biological experiments to quantify the dose-response relationship of a substance, which is one of the most fundamental steps in risk assessment. To obtain such relationships, biological experiments need to be performed at different dose levels to observe the corresponding bioactivity responses of animals. Because of costs, ethics, or other limitations, sample sizes are usually restricted and efficient use of resources is critical. Thus, the design of experiments, i.e., the selection of experimental doses and the allocation of animals, plays an important role in the estimation of dose-response relationships. Efficient design for dose-response modeling is challenging due to the special features of toxicity data, i.e., the possibly nonlinear nature of dose-response curves and the typical variance heterogeneity (non-constant variance) involved. In this work, an experimental design procedure particularly suitable to toxicity data collection is developed to guide the dose selection and animal allocation in experiments. The design procedure is built in a two-stage Bayesian paradigm, which provides a statistically valid mechanism to utilize prior information for the design of future experiments. Most appropriate dose-response and variance models are identified to describe the toxicity data. Bootstrapping, a computationally intensive resampling method as opposed to conventional statistical inference methods, are used to derive important information from the preliminary data required by the subsequent experimental design. To achieve practically useful designs, multiple design criteria are considered simultaneously, and multi-objective metaheuristics are adapted to search for a set of Pareto optimum designs, which allow for the evaluation of various tradeoffs in practical experimental settings. The efficiency of the proposed design methods over conventional designs is demonstrated through extensive simulation experiments as well as the toxicology study of a series of engineering nanomaterials. 479 PHARMACOKINETIC AND TOXICOLOGICAL PROFILING OF NATURAL PRODUCTS AND DRUGS. C. Hasselgren 1 , H. Chen 2 , Y. Yang 2 , S. Boyer 1 , T. I. Oprea 3 and S. Muresan 2 . 1 Global Safety Assessment, AstraZeneca, Mölndal, Sweden, 2 DECS, AstraZeneca, Mölndal, Sweden and 3 Division of Biocomputing, University of New Mexico, Albuquerque, NM. Natural products are often considered relevant starting points in drug discovery projects due to their diversity, novelty and intrinsic biological activity. In addition to being complex structures and difficult to synthesize, a major challenge when working with libraries based on scaffolds derived from natural products is their
pharmacokinetic and toxicological profile optimization. During the development of a new lead compound, several in silico tools and models are normally used. These are however built using compounds that may look quite different from conventional drug compounds and/or natural products and have a different distribution in their physicochemical properties. To understand how chemistry and pharmacokinetic and toxicological profiles compare between natural products and synthetic molecules and to determine the reliability of our current tools, we have analyzed and compared a number of data sets from different sources. These were the Clinical candidate database (9 800 compounds) and the Natural Product database (121 600 compounds) from GVKBio, a set of 2 000 oral drugs and the KEGG set of 11 700 compounds. For all datasets, we computed physicochemical properties as well as standard DMPK and safety models such as Caco-2, Ames and hERG. We reviewed the structural space overlap between the different sets using Principal Component Analysis (PCA) and established usability of our current models for the natural drug compounds. Physicochemical property models can be validated against experimental data but safety models can mainly be assessed by space coverage and model domain applicability as experimental data is not generally available for natural products. When possible, validation against experimental data was done. The results show that there are some significant differences between the distributions of simple molecular properties and that the classes (synthetic drug/natural drug) can be partially separated using PCA. The reliability of our current models is also discussed in relation to these differences. 480 A FLEXIBLE METHOD FOR BUILDING AND USING PREDICTIVE MODELS APPLIED TO SAFETY ENDPOINTS. O. Spjuth2 , L. Carlsson1 , M. Eklund2 , E. Ahlberg Helgee1 and S. Boyer1 . 1Computational Toxicology, AstraZeneca, Mölndal, Sweden and 2Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. We present a general method for building and using predictive in silico models. The method can take any collection of compounds with activities as input, and automatically produces several different predictive models; (1) Similarity searches using InChI, signatures and fingerprints (exact matches and nearest neighbours) (2) A classification or regression QSAR model using a support vector machine (SVM) and interpretable signature descriptors (3) Discriminative signatures (structural alerts or toxicophores). All models can be run simultaneously for novel chemical structures and produce interpretable results with important substructures highlighted in a chemical editor or spreadsheet, with the possibility to generate hypothesis on how to avoid safety hazards by making changes to the chemical structure and watch how this change affects the predictions. The method is available from the Bioclipse workbench, can be run on desktop computers and does not necessarily require a network connection. We demonstrate our method on publicly available data for three endpoints: mutagenicity, carcinogenicity, and AhR inhibition. The results indicate that combining local data with established and well tested models together with interpretable results can aid scientists in making better informed decisions in safety assessment. 481 ASSESSING DOSE-RESPONSE OF ENVIRONMENTAL CHEMICALS INTERACTION WITH DNA USING A SYSTEM BIOLOGY MODELING APPROACH. J. M. Gavina, Y. Feng and A. Nong. Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada. Genotoxicity of environmental pollutants is investigated at the molecular level for DNA damage or instability, disruption of cellular metabolic processes, carcinogenicity, or mutagenic modifications. Chemical interaction with cellular DNA can be screened using genetic or proteomic assays, sensitive chromatography, or mass spectrometry techniques. The difficulty with the in-vitro chemical screens at the target receptor lies in the interpretation of these results for in-vivo or even human internal dose levels. System biology modeling approaches integrate genomic and proteomic data with biological mechanism of response. These models provide understanding of the process as well for correlation in doses ranges of concern. In this pilot study, a biological model or system motif was developed to described the kinetic reaction of DNA adduct formation following exposure to different chemicals (tetrachlorohydroquinone, styrene-7,8-oxide, methyl methane sulfonate, PGE, and BPDE). A HPLC screening method was used to detect and quantify DNA products. A simple experiment was designed to expose double stranded DNA oligonucleotides under controlled conditions over time and various doses. DNA adducts were then separated and measured respectively by chromatography and spectrometry. The motif model parameters were then calibrated with the time series and validated with the dose-response relationship data. The estimated rate constants of these reactions are chemical dependent. The dose-response behaviour is linear, where a Hill coefficient of 1 was estimated, for all chemicals except for tetrachlorohydroquinone. This in-vitro system motif provides as basis for more complex biological toxic response such as cellular DNA damage. Combined with internal dosimetry models (e.g. PBPK), system biology models can serve as a useful tools to predict the dose-response at the target receptor for environmental exposure risk assessment of contaminants. 482 USING A MULTIPLE STAGE DECISION TREE TO MAKE ACTIVITY CALLS IN QUANTITATIVE HIGH- THROUGHPUT SCREENING (QHTS) DATA. K. R. Shockley 1 , G. E. Kissling 1 , R. Huang 2 , M. Xia 2 , C.P.Austin 2 and R. R. Tice 1 . 1 National Toxicology Program/National Inistitute of Environmental Health Sciences, Research Triangle Park, NC and 2 NIH Chemical Genomic Center, Bethesda, MD. The goals of the Tox21 collaboration are to identify mechanisms of toxicity, prioritize chemicals for in vivo testing and predict adverse responses to environmental chemicals in humans. Quantitative high throughput screening (qHTS) assays provide an opportunity to meet these goals, holding the potential for wide chemical coverage, reduced cost of testing on a per-substance basis and minimal use of animals. Moreover, the ability of a substance to induce a toxicological response is better understood by analyzing the response profile over a broad dose range than by evaluating effects at one or a few doses. Pharmaceutical applications of qHTS generally seek to minimize false positives in activity assessment and often rely on heuristic algorithms to make activity calls. In contrast, multiple questions must be asked to determine the toxicological relevance of a chemical and statistical testing should be used to minimize false negatives. Here, we developed a multiple-stage decision tree statistical model and applied it to qHTS data from nine cell-based nuclear receptor agonist assays (AR, ER, FXR, GR, PPARα, PPARλ, RXR,TRβ, VDR). Data were fit to a four-parameter Hill equation and an overall F-test comparing the best fit to the Hill equation and a horizontal line (no response) was calculated for each chemical. Substances with a robust dose-response were identified in the first stage. In the second stage, compounds not detected as active in the first stage were evaluated for a maximal response at the lowest dose by comparing the distribution of measured responses to a control value. Chemicals with a weak dose-response were identified in the third stage, and the final stage separated substances exhibiting a cytotoxic response at the lowest dose from inactive compounds. Our model identified more active compounds than a previously utilized heuristic approach. 483 TESTING MULTIPLE AVAILABLE QSARS FOR REPRODUCTIVE TOXICITY AND CARCINOGENICITY TO DRINKING WATER CONTAMINANTS. M. Heringa 1 , A. Roncaglioni 2 , R. Benigni 3 and A. Worth 4 . 1 KWR Watercycle Research Institute, Nieuwegein, Netherlands, 2 Istituto di Ricerche Farmacologiche “Mario Negri”(IRFMN), Milan, Italy, 3 Istituto Superiore di Sanita (ISS), Rome, Italy and 4 European Commission - Joint Research Centre (JRC), Ispra, Italy. Within the REACH legislation in Europe, Quantitative or Qualitative Structure Activity Relationship- (QSAR-) toxicity predictions are an important alternative to animal testing. Also in the hazard identification of detected drinking water contaminants for which no experimental toxicity data can be found, QSARs are helpful. However, proper use of QSARs is not always straightforward, as there are many models available, each with its own specifications. To illustrate what a risk-assessor runs into when using QSARs, toxicity predictions were sought for 10 selected case compounds for the endpoints mutagenicity, carcinogenicity, and reproductive toxicity (here: developmental toxicity and estrogenicity). The models applied were: CASETOX, TOPKAT, Derek for Windows, PharmaAlgorithms, the OSIRIS IRFMN RBA model, HazardExpert, Toxtree, and lazar. Only two of these models could be judged as “scientifically valid”, a requirement posed by REACH, which is based on the five OECD principles. The other models were used as supportive information. For mutagenicity, for eight of the ten compounds all models (seven) agreed in their predictions, for carcinogenicity this was the case for one compound only, for developmental toxicity for three compounds and for estrogenicity for nine compounds. The application of multiple QSAR models has made apparent that it is unclear how conflicting predictions of multiple models should be evaluated. This indicates a strategy on the use of multiple QSAR models is necessary, for which some ideas are discussed. 484 CONSENSUS MULTIPLE-POTENCY QSAR MODELING FOR PREDICTION OF RODENT CARCINOGENICITY. E. J. Matthews 2 and K. P. Cross 1 . 1 Leadscope, Inc., Columbus, OH and 2 U.S. FDA/CFSAN/OFAS, College Park, MD. Sponsor: R. Tice. The performance of quantitative structure-activity relationship (QSAR) models depends extensively upon the quality of the data used to construct the models, and the methods employed to optimize model predictive performance. For rodent carcinogenicity models, the nature, location, prevalence, and extensiveness of tumors SOT 2011 ANNUAL MEETING 103
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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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Page 57 and 58: 247 CO-CARCINOGENESIS OF N, N- DIET
Page 59 and 60: sponds to the endosomal dsRNA that
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Page 63 and 64: Lastly, using p53siRNA cells, p53 w
Page 65 and 66: its receptor Mpl to exert its funct
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Page 69 and 70: lunar surface presented potential h
Page 71 and 72: lar about cellular export mechanism
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Page 81 and 82: 358 CHARACTERIZATION OF GENOME-WIDE
Page 83 and 84: RNAi were also performed to identif
Page 85 and 86: 376 A FUNCTIONAL CROSSTALK BETWEEN
Page 87 and 88: UGT1A gene induction, while this re
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Page 93 and 94: histone deacetylase that is necessa
Page 95 and 96: ment. Paradoxically, buthionine sul
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Page 99 and 100: 442 GENE EXPRESSION AND MORPHOLOGIC
Page 101 and 102: 451 INHIBITION OF THE MITOCHONDRIAL
Page 103 and 104: 460 SULFORAPHANE PREVENTS ACETAMINO
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Page 109 and 110: 489 USE OF ‘OMICS DATA TO IMPROVE
Page 111 and 112: 498 APPLICATION OF AGE-SPECIFIC ADJ
Page 113 and 114: 507 A DOSE VOLUME TOLERABILITY STUD
Page 115 and 116: involved the use of an acute inflam
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Page 119 and 120: (ABC) transporters actively transpo
Page 121 and 122: 545 BEHAVIORAL EFFECTS OF REPIN IN
Page 123 and 124: a blood pressure phenotype that res
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Page 127 and 128: and lethality associated with these
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Page 131 and 132: therefore more accurate and reprodu
Page 133 and 134: commercial chrysotile product that
Page 135 and 136: elative to their controls. ST-depre
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Page 139 and 140: in the China Jintan Child Cohort St
Page 141 and 142: corneum thickness, cellular epiderm
Page 143 and 144: 645 EVALUATION OF THE IN VITRO EPIS
Page 145 and 146: 654 TCDD ADSORBED ONTO NATURAL AND
Page 147 and 148: tion revealed no test article-relat
Page 149 and 150: 671 INFLAMMATION AND TISSUE DAMAGE
Page 151 and 152: model, ethanol was found to inhibit
Page 153 and 154: 689 ENHANCED SUPPRESSIVE FUNCTION O
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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
Page 421 and 422:
NPC and sinonasal cancer in neighbo
Page 423 and 424:
showed incidences of lung and nasal
Page 425 and 426:
utylbenzenes, exhibited most simila
Page 427 and 428:
1975 DIFFERENTIAL MODULATION OF CYP
Page 429 and 430:
organic As to MMA(V) and a lower ca
Page 431 and 432:
ole in invasion and metastasis of c
Page 433 and 434:
3T3-L1 cells to low-levels of arsen
Page 435 and 436:
2011 IDENTIFICATION OF A NOVEL VX M
Page 437 and 438:
This work was supported by Cooperat
Page 439 and 440:
2029 EFFICACY OF ENDOTRACHEAL ADMIN
Page 441 and 442:
Diazepam injections and its combina
Page 443 and 444:
2047 ESTERASE ACTIVITIES AND HEMOST
Page 445 and 446:
nanoparticle-induced toxicity progr
Page 447 and 448:
house, were iv infused into rats ov
Page 449 and 450:
een explored. This study investigat
Page 451 and 452:
croscopic analysis revealed that on
Page 453 and 454:
egg yolk collected from turtles inh
Page 455 and 456:
consistency of results in both expe
Page 457 and 458:
2111 CYTOCHROME P450 3A5 GENOTYPE I
Page 459 and 460:
esidues of organophosphates or thei
Page 461 and 462:
manganism. Recent work from our lab
Page 463 and 464:
Aβ1-40 in CSF and hippocampus in P
Page 465 and 466:
2147 CATALASE MANIPULATIONS MODIFY
Page 467 and 468:
ation based on real-world exposure
Page 469 and 470:
NPs. Aggregation of citrate-stabili
Page 471 and 472:
2175 THE ROLE OF SURFACE CHEMISTRY
Page 473 and 474:
seen rapid uptake in biological ima
Page 475 and 476:
effect on uterine weight or vaginal
Page 477 and 478:
dicating widespread exposure. While
Page 479 and 480:
components into the liver parenchym
Page 481 and 482:
2223 ISOLATION AND DETECTION OF RIC
Page 483 and 484:
stored (-20 celsius degree). The co
Page 485 and 486:
2241 DDA, A BIOMARKER FOR ENVIRONME
Page 487 and 488:
2249 INTERACTION BETWEEN DIETARY SE
Page 489 and 490:
2258 PHARMACOKINETICS, EXCRETION BA
Page 491 and 492:
2267 SENSITIVE AND SPECIFIC FLUORES
Page 493 and 494:
2276 METABOLISM AND DISPOSITION OF
Page 495 and 496:
ment of hypertension in companion a
Page 497 and 498:
for the propyl series can be used f
Page 499 and 500:
2304 IN VITRO EXPOSURE AND EVALUATI
Page 501 and 502:
2313 THE SYNERGISTIC EFFECT OF SODI
Page 503 and 504:
genes that play a crucial role in M
Page 505 and 506:
2330 THE ROLE OF TRANSFORMING GROWT
Page 507 and 508:
ined following up to 96 h continuou
Page 509 and 510:
effect doses obtained with the rat
Page 511 and 512:
diated transcriptional response of
Page 513 and 514:
docrine disruptor activities of EDC
Page 515 and 516:
individuals. Week 6 results were qu
Page 517 and 518:
functionality of photosystem II and
Page 519 and 520:
wild mice (Mus musculus) from areas
Page 521 and 522:
2406 TOXICITY AND BIOACCUMULATION O
Page 523 and 524:
Isocitric acid is the acid in the h
Page 525 and 526:
2425 EFFECTS OF FUMONISINS IN ETHAN
Page 527 and 528:
centration(μg/g) were: 5.1-95.3; 2
Page 529 and 530:
2445 AUTOPHAGY IN DEVELOPMENT: A LI
Page 531 and 532:
sures to inhaled Mn in dust. Nevert
Page 533 and 534:
2466 CRITICAL EVALUATION OF ANIMAL
Page 535 and 536:
elationships predict that resting r
Page 537 and 538:
2489 COMPARATIVE TOXICITY OF BIODIE
Page 539 and 540:
2497 TRANSCRIPTIONAL REGULATION OF
Page 541 and 542:
2506 TOXICOLOGICAL CONSIDERATIONS O
Page 543 and 544:
launched with the aim of developing
Page 545 and 546:
forms mRNA expression levels were a
Page 547 and 548:
2534 CUTANEOUS WOUND HEALING IN THE
Page 549 and 550:
wells (0, 1, 5, 10, 25, 50, 100, an
Page 551 and 552:
2553 AN ORGANOTYPIC MICROLIVER PLAT
Page 553 and 554:
serum-free media. At 24 hrs, the gr
Page 555 and 556:
2572 INCREASED ARSENIC BIOACCESSIBI
Page 557 and 558:
nology to develop improved methods.
Page 559 and 560:
tuna, swordfish, or mako shark (3.5
Page 561 and 562:
nificantly reduce circulating thyro
Page 563 and 564:
grouped into 9 observation periods
Page 565 and 566:
histopathological or biochemical ev
Page 567 and 568:
exhibited a hyperactive phenotype,
Page 569 and 570:
the search of effective drugs for e
Page 571 and 572:
2644 COVALENT BINDING OF 14 C 2-MET
Page 573 and 574:
aries targeting all transcription f
Page 575 and 576:
(p 9 weeks) and CSC phenotype acqui
Page 577 and 578:
2673 IMMUNE-MEDIATED VASCULAR INJUR
Page 579 and 580:
for risk identification and charact
Page 581 and 582:
to control toxicant delivery in tob
Page 583 and 584:
Author Index (Continued) The numera
Page 585 and 586:
Page 587 and 588:
Page 589 and 590:
Page 591 and 592:
Page 593 and 594:
Page 595 and 596:
Page 597 and 598:
Page 599 and 600:
Page 601 and 602:
Page 603 and 604:
Page 605 and 606:
Page 607 and 608:
Page 609 and 610:
Page 611 and 612:
Keyword Index (Continued) Arsenite
Page 613 and 614:
Keyword Index (Continued) Covalent
Page 615 and 616:
Keyword Index (Continued) flow cyto
Page 617 and 618:
Keyword Index (Continued) innate im
Page 619 and 620:
Keyword Index (Continued) nanoparti
Page 621 and 622:
Keyword Index (Continued) preservat
Page 623 and 624:
Keyword Index (Continued) Thrombocy
Page 625 and 626:
Toxicological Sciences The Official
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