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2690 APPLICATION-SPECIFIC CONSIDERATIONS IN EVALUATION OF PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODELS. L. M. Sweeney. TERA, Cincinnati, OH. “One size fits all” statements regarding model confidence (i.e., the model is simply “acceptable” or “unacceptable”) fail to capture the subtleties inherent in the many ways physiologically based pharmacokinetic (PBPK) models can be used in risk assessment. For example, a model that is acceptable in one context, such as route-toroute extrapolation, many not be adequate for other purposes, such as interspecies extrapolation. Predictions of a given dose metric that may be bounded (e.g., by physiological considerations) could be considered to be reliably estimated by a model for which other dose metrics are not characterized with sufficient confidence. Application-specific considerations should be incorporated in PBPK model evaluation to ensure that these useful tools are appropriately applied in risk assessment. 2691 CHARACTERIZATION OF POPULATION DISTRIBUTIONS IN PBPK MODEL PARAMETERS. H. J. Clewell. The Hamner Institutes for Health Sciences, Research Triangle Park, NC. Population analysis is being applied in PBPK modeling, through rigorous Bayesian statistical analysis and simulation of population variability by Monte-Carlo sampling of parameters. Bayesian analysis in particular provides estimates of population variability and uncertainty in various parameters, but the outcome depends to some extent on the assumed initial (prior) distributions, and can only represent what is known from the study population analyzed, rather than the population as a whole. This talk discusses appropriate choices of parameter distributions such that the full population variability and uncertainty can be captured as well as considerations on how probabilistic modeling results can be integrated into current risk assessment practice. 2692 ALTERNATE APPROACHES AND ISSUES IN INTEGRATING PHARMACOKINETIC WITH BENCHMARK-DOSE (BMD) MODELING. P. M. Schlosser. NCEA, U.S. EPA, Washington, DC. Physiologically-based and traditional pharmacokinetic (PK) models may be integrated with benchmark-dose (BMD) dose-response modeling by using PK-modelpredicted internal doses as inputs to BMD analysis, which estimates a point-of-departure (POD) dose equivalent to a no-observed adverse effect level. A human PBPK model would then used to estimate the human-equivalent exposure. However, each time the PK model is revised, which may happen several times during an extensive regulatory review process, the BMD analysis must be revised accordingly; if the analysis is for multiple animal species/genders/target tissues/endpoints, the effort involved can become substantial vs. simply conducting the BMD analysis once using applied exposure levels. Also, if tumors arise in multiple tissues, a single dose metric must be used to correctly estimate total tumor risk with current standard statistical methods. These and other issues to be discussed make the approach for integration of PK and BMD modeling less than straightforward. Different approaches are therefore likely to be preferred for different assessments, depending on the details and level of complexity of the analysis. (Disclaimer: The views expressed in this abstract are those of the author and do not represent the policy of the U.S. Environmental Protection Agency.) 2693 EXPLICIT PHARMACOKINETIC MODELING: TOOLS FOR DOCUMENTATION, VERIFICATION, AND PORTABILITY. J. F. Wambaugh 1 , R. Tornero-Velez 2 , E. McLanahan 3 , Y. Tan 2 , W. Setzer 1 and I. Shah 1 . 1 National Center for Computational Toxicology, U.S. EPA, Research Triangle Park, NC, 2 National Exposure Research Laboratory, U.S. EPA, Research Triangle Park, NC and 3 National Center for Environmental Assessment, U.S. EPA, Research Triangle Park, NC . Quantitative estimates of tissue dosimetry of environmental chemicals due to multiple exposure pathways require the use of complex mathematical models, such as physiologically-based pharmacokinetic (PBPK) models. The process of translating the abstract mathematics of a PBPK model description into a computational implementation is typically a tedious process fraught with the potential for error. Sometimes key information, such as parameters or even whole equations, is unintentionally omitted from published results. Furthermore, complex models are often 576 SOT 2011 ANNUAL MEETING interpreted by a wide community of scientists and policy makers; it is important that the language used to communicate the model be explicit and coherent. Fields allied with toxicology, such as systems biology, have created markup languages (i.e. Systems Biology Markup Language) to standardize the syntax of mathematics and documentation, allowing models to be disseminated as supplemental material in articles or through on-line databases. We propose a formal declarative description of PBPK models, PhLexicOn, to assure published models are thoroughly documented and can be readily translated into popular simulation software. Completeness of a model is not sufficient, it must make sense in terms of the relationships among tissue volumes, blood flows and other fundamental biology. Plausibility is assessed though an ontology that defines the appropriate constituents of physiologicallybased systems. Tools are in development to: efficiently verify semantic validity based on the ontology, and automate translation into executable simulations to evaluate consistency with published results. PhLexicOn is a framework for documenting, verifying, and translating legacy and state-of-the-art models for re-usability and efficient dosimetry estimation of chemicals for use in human health risk assessments. This abstract does not necessarily reflect U.S. EPA policy. 2694 ROLE OF BIOMARKERS IN ASSESSING TOBACCO HARM REDUCTION: A TOXICOLOGICAL PERSPECTIVE. C. Timchalk and R. Corley. Pacific Northwest National Laboratory, Richland, WA. In 2009, the Family Smoking Prevention and Tobacco Act was passed by Congress, signed into law, and the U.S. FDA was tasked with regulating tobacco. The U.S. FDA’s stated goals are to use the best available science to guide the development and implementation of effective public health strategies to reduce the burden of illness and death caused by tobacco products. A potential component of this effort is the implementation of a risk/harm reduction strategy, in which the removal or reduction of harmful ingredients within tobacco products is one possible approach. In this regard, a joint World Health Organization (WHO) and International Agency for Cancer Research (IARC) working group proposed a strategy for lowering toxicant yields in tobacco products based on animal and human toxicity data for individual constituents. This risk based approach requires the prioritization of main stream smoke (MSS) constituents according to their individual risk of developing cancer. In this context, we will explore current and new strategies that have the potential to identify priority constituents for reduction. This will include strategies that utilized conventional approaches to MSS risk assessment which calculate risks according to exposure and hazard. A potential alternative approach for evaluation of MSS constituents exploits a strategy developed by the International Program on Chemical Safety (IPCS) to improve individual chemical risk assessment utilizes a weight-of-evidence approach within a mode-of-action (MOA) framework. Finally, a Quantitative Risk Assessment (QRA) strategy will be considered which combines advanced computational and experimental lung dosimetry, smoking patterns and behavior data, human variability, and available toxicity/cancer potency factors to develop compound-specific comparative estimates of risk for MSS constituents. The primary focus will be placed on both the strengths and weaknesses of the various approaches in the context of a MSS harm reduction strategy. 2695 LEGISLATIVE AND REGULATORY OVERVIEW. M. Zeller. Pinney Associates, Bethesda, MD. Sponsor: C. Timchalk. Tobacco harm reduction policy is a complex and emotionally charged issue. For many decades, the public health community found it difficult to independently evaluate express and implied risk and harm reduction marketing tactics of the tobacco industry. The challenge was exacerbated by the absence of tobacco product regulation. The classic example of the impact of no regulation was the marketing of “light” and “low tar” cigarettes that implied lower risk to smokers. As a consequence, we have witnessed generations of smokers who otherwise may have been motivated to quit that instead compensated for the lower tar and nicotine by increasing consumption, thereby negating any real or perceived reductions in risk. Recent passage of the Family Smoking Prevention and Tobacco Control Act (FSPTCA) changes everything. Under the new law, the U.S. Food and Drug Administration now has a set of regulatory tools to control toxicant delivery, exposure and risk reduction claims, and many other aspects of tobacco product manufacturing and marketing. Similar opportunities for effective, science-based tobacco product regulation are possible under the Framework Convention for Tobacco Control. This presentation will provide an overview of the history of how the tobacco industry made health-related claims in the unregulated marketplace. Key provisions of the FSPTCA will be described, including those which empower FDA
to control toxicant delivery in tobacco products. Critical policy issues will be identified. Research gaps and priorities will also be highlighted. The presentation will also emphasize the relevance of consumer perception and behavior. 2696 ASSOCIATION BETWEEN THE DESIGN, CONTENTS, EMISSIONS, USE, AND BIOMARKERS OF EXPOSURE FROM TOBACCO PRODUCTS. D. L. Ashley. Center for Tobacco Products, U.S. FDA, Rockville, MD. Sponsor: C. Timchalk. Cigarette smoke is a complex mixture of chemical compounds bound to aerosol particles and free in the gas phase. Chemical compounds can be distilled directly from tobacco into smoke or react to form other materials, which are then delivered in the smoke. Published literature reports that many of these chemicals in tobacco smoke are mutagenic, carcinogenic, and addictive. The International Agency for Research on Cancer (IARC) list of carcinogens includes the tobacco-specific nitrosamines, polynuclear aromatic hydrocarbons, volatiles, and heavy metals. Studies have shown that the levels of exposure to these chemicals in smoke can be altered by cigarette design, other chemical additives to the tobacco product and the way people consume the cigarette. In addition, changes to the pH of smokeless tobacco result in higher or lower levels of free nicotine, the form more biologically available. Studies in the laboratory and with smokers indicate that the addition of filter ventilation to cigarettes reduces the levels of smoke delivered using the standard smoking regimen, but this does not adequately reflect the exposure that smokers receive, since they can block the holes, take larger puffs, or take more frequent puffs. Thus, smokers of the same cigarette can inhale a wide variation in the amount of smoke. By examining a wide variety of tobacco products, researchers have determined that the use of specific types of tobacco can alter the relative levels of the chemical constituents in smoke. This can impact the levels of biomarkers in users of these products. By comparing the levels found in the smoke, the characteristics of the tobacco products and how people smoke, we can better understand how these influence the delivery of addictive and toxic chemicals to people. There are critical design and content considerations that can substantially influence the levels of toxic, carcinogenic, and addictive components of tobacco product emissions. 2697 TOBACCO CARCINOGEN AND TOXICANT BIOMARKERS: POTENTIAL APPLICATIONS IN TOBACCO HARM REDUCTION AND REGULATION. S. S. Hecht, J. Yuan and D. K. Hatsukami. Masonic Cancer Center, University of Minnesota, Minneapolis, MN. Sponsor: C. Timchalk. Tobacco products contain complex mixtures of carcinogens and toxicants that are responsible for the deadly effects of these products. Cigarette smoke has over 70 established carcinogens and numerous toxicants. The 20th century method for assessing levels of these substances was machine smoking, but this has severe limitations which are well documented. The 21st century method should integrate tobacco carcinogen and toxicant biomarkers into the assessment of tobacco product carcinogenicity and toxicity. Tobacco carcinogen and toxicant biomarkers are metabolites or protein or DNA adducts of specific carcinogens or toxicants in tobacco products. Highly reliable analytical methods based mainly on mass spectrometry are now available and have been applied in large studies of many of these biomarkers. A panel of tobacco carcinogen and toxicant biomarkers that could be used in studies on tobacco harm reduction and in regulation of tobacco products includes, among others, urinary nicotine and tobacco-specific nitrosamine metabolites, 1-hydroxypyrene, and mercapturic acids of volatile organics. The critical question is: what are the mean biomarker values below which one would see a decrease in tobacco-induced cancer? The answer to this question potentially can be derived from molecular epidemiology studies in which biomarker levels are related to cancer risk. Examples include the relationship of tobacco-specific nitrosamine metabolites to cancer. 2698 MODE OF ACTION: ASSESSMENT OF CANCER RISK AND IDENTIFICATION OF KEY DATA NEEDS. A. R. Boobis. Centre for Pharmacology & Therapeutics, Imperial College London, London, United Kingdom. Cigarette smoking has been causally related to cancer at over a dozen sites in humans, the most commonly affected being the lung. It has proven very difficult to produce an animal model for the lung cancer effects of smoking. Tobacco smoke is a complex mixture of chemicals, both organic and inorganic, many of which have been shown to be mutagenic or carcinogenic in experimental systems. However, inhalation of tobacco smoke also involves exposure to heat and particulates. There is evidence for a number of effects that could be involved in the mode of action for lung cancer. These include mutagenesis by compounds such as nitrosamines and polycyclic aromatic hydrocarbons, cytotoxicity by aldehydes and inflammatory mediators induced by particulates, and the formation of reactive oxygen species. Many biomarkers have been used to study tobacco-related cancer and it important to distinguish exposure from effect. For example, it is still not clear what role is played by some DNA adducts in the etiology of tobacco-related cancer. In order to identify key data gaps, and to identify the most informative biomarkers of effect, the IPCS cancer mode of action framework was used to assess the relationship between smoking and lung cancer. This framework provides a transparent and consistent approach to assessing the mode of action of a chemical carcinogen, the key events involved and their dose-response relationships. A key event is a necessary intermediate process or interaction, though often not sufficient, in cancer causation. The involvement of key events is assessed using criteria based on those described by Bradford Hill, including dose and time dependency, biological plausibility, experimental evidence, consistency and coherence. Through the application of the framework it is possible to identify those areas in which research should be focused to resolve uncertainties. 2699 QUANTITATIVE RISK ASSESSMENT: A COMPUTATIONAL DOSIMETRY FRAMEWORK FOR TOBACCO HARM REDUCTION. C. Timchalk, J. G. Teeguarden and R. A. Corley. Battelle Pacific Northwest Division, Richland, WA. Conventional approaches to evaluate relative risk of mainstream smoke (MSS) constituents have focused on the assessment of exposure and hazard, the latter defined by Reference Concentrations or Cancer Potency Factors. Margin of exposure (MOE)-directed target tissue dosimetry offers an alternative strategy for MSS relative risk prioritization. This strategy exploits advanced computational dosimetry modeling to incorporate smoking patterns and behavior, human variability, and available toxicity/cancer potency. To illustrate the utility of this framework several MSS constituents were evaluated on the basis of their known mode of action (MOA) and key events linking MSS exposure with target tissue dose and response. For example, acetaldehyde is a contact site irritant that causes tumors in the upper respiratory tract of rodents. The MOA involves direct contact irritation and inflammation leading to cytotoxicity as a key initiating event. To enable direct comparison of rat inhalation bioassays with human exposures to MSS, a computational fluid dynamic/physiologically based pharmacokinetic model was developed to compare site-specific doses in each region of the respiratory system. MOEs were calculated by comparing rat nasal tissue and human respiratory tract tissue acetaldehyde concentrations adjusted for exposure duration (Lifetime Average Daily Doses (LADD)). For the rat, steady-state nose-only breathing simulations were conducted at 50 ppm the NOAEL for nasal olfactory degeneration. In humans, oral breathing simulation of a single puff was conducted based on cigarette acetaldehyde yield data. The LADD’s in any region of the human respiratory tract ranged from 13- to 50-fold lower than those associated with subchronic acetaldehyde no effect levels in the rat nasal region. This modeling approach can be exploited to compare interspecies regional dosimetry for other important MSS toxicants providing a more quantitative biologically informed approach for prioritizing and targeting MSS constituents and evaluating claims of reduced risk in a tobacco harm reduction strategy. SOT 2011 ANNUAL MEETING 577
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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
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esidues of organophosphates or thei
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manganism. Recent work from our lab
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Aβ1-40 in CSF and hippocampus in P
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2147 CATALASE MANIPULATIONS MODIFY
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ation based on real-world exposure
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NPs. Aggregation of citrate-stabili
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2175 THE ROLE OF SURFACE CHEMISTRY
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seen rapid uptake in biological ima
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effect on uterine weight or vaginal
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dicating widespread exposure. While
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components into the liver parenchym
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2223 ISOLATION AND DETECTION OF RIC
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stored (-20 celsius degree). The co
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2241 DDA, A BIOMARKER FOR ENVIRONME
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2249 INTERACTION BETWEEN DIETARY SE
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2258 PHARMACOKINETICS, EXCRETION BA
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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: for risk identification and charact
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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