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916 RESEARCH PLAN TO FILL DATA GAPS IN THE MODE OF ACTION FOR CANCER RISK ASSESSMENT OF HEXAVALENT CHROMIUM IN DRINKING WATER. L. Haws 3 , D. Proctor 1 , C. Thompson 2 and M. Harris 2 . 1 ToxStrategies, Inc., Rancho Santa Margarita, CA, 2 ToxStrategies, Inc., Houston, TX and 3 ToxStrategies, Inc., Austin, TX. Using the mode-of-action (MOA) frameworks proposed by the U.S. EPA and ILSI/IPCS, we outlined key events and their temporal sequencing in a proposed MOA for intestinal tumors in mice following ingestion of Cr(VI). Data gaps identified during this MOA analysis were used to inform the design of a 90-day drinking water study to better inform the MOA for the observed responses. Sequentially, the proposed key events are saturation of the reductive capacity of the upper gastrointestinal tract, absorption of Cr(VI) into the intestinal epithelium, oxidative stress and inflammation, cell proliferation, DNA modifications (direct and/or epigenetic), and mutagenesis. Given clear species differences in carcinogenic response, key data gaps include direct measures of species-specific pharmacokinetic determinants (e.g. reduction and uptake), direct evidence for oxidative stress and inflammation as contributors to cell proliferation, and the nature of DNA modifications. Additionally, it is not known whether DNA modification and mutation occur at lower doses and early time points during exposure to Cr(VI) in drinking water. In order to address these data gaps, rats and mice were exposed to Cr(VI) for 7 or 90 days, followed by evaluation of histopathology, toxicogenomics, oxidative and inflammatory responses, DNA damage, in vivo mutations, target tissue chromium concentrations, and rates and capacities of Cr(VI) reduction in gastric fluid. These in vivo measures were collected in target tissues of both species at doses carcinogenic to rodents, as well as at concentrations more environmentally relevant to humans. Comparisons between responsive and unresponsive species and tissues will be used to further inform the carcinogenic MOA and provide mechanistic and dosimetric information necessary for human health risk assessment. 917 TOXICOGENOMIC ANALYSIS OF CR(VI) EFFECTS ON INTESTINAL AND ORAL EPITHELIUM. T. R. Zacharewski 1 , A. K. Kopec 1 , A. L. Forgacs 1 , S. Kim 1 , S. D. Grimes 2 and C. D. Hébert 2 . 1 Biochemistry & Molecular Biology and Center for Integrative Toxicology, Michigan State University, East Lansing, MI and 2 Southern Research Institute, Birmingham, AL. Chronic administration of hexavalent chromium (CrVI)-containing sodium dichromate dihydrate (SDD) is linked to intestinal and oral cancer in rodents. In this study, the dose-dependent gene expression effects of SDD (0, 0.3, 4, 14, 60, 170 or 520 mg/L) in female B6C3F1 duodenal, jejunal and oral epithelial tissues were examined after 7 days of exposure in drinking water. 4x44 K Agilent two-color oligonucleotide arrays identified 6453, 4360 and 698 unique gene expression changes in duodenum, jejunum and oral mucosa, respectively (|fold change|>1.5, P1(t)>0.999). Robust dose-dependent differential gene expression was identified in duodenal and jejunal epithelium. Automated dose-response modeling of the microarray data identified 2491 duodenal, 965 jejunal but only 141 oral mucosa genes displaying a sigmoidal dose-response profile with ED50 values within the experimental dose range. Comparisons between duodenal and jejunal expression profiles showed significant overlap with duodenal differential gene expression responses exhibiting greater efficacy compared to jejunum. The median and interquartile ED50 range overlapped between duodenum and jejunum with greater than 70% of all sigmoidal ED50 values between 10 and 100 mg/L SDD. Complementary histopathology identified crypt hyperplasia, cytoplasmic vacuolization in the intestinal epithelium and histiocytic infiltration in the villous lamina propria, consistent with the differential expression of genes associated with cell cycle, lipid metabolism and immune response in the duodenum and jejunum. Cancer associated genes were also over-represented within intestinal differential gene expression, and to a lesser extent in the oral mucosa. Collectively, these results indicate that intestinal epithelium is highly responsive to CrVI and early gene expression signatures may mediate neoplastic changes observed with prolonged SDD exposure. 918 GENETIC TOXICITY OF HEXAVALENT CHROMIUM IN THE GASTROINTESTINAL TRACT FOLLOWING ORAL EXPOSURE. T. J. O’Brien 1 , H. Ding 1 , C. D. Hébert 2 , R. D. May 2 and S. R. Patierno 1 . 1 Department of Pharmacology and Physiology, The George Washington University Medical Center, Washington, DC and 2 Southern Research Institute, Birmingham, AL. Occupational exposure to hexavalent chromium [Cr(VI))]-containing compounds has been shown to cause lung cancer. Cr(VI)-induced carcinogenesis has been proposed to involve direct modification of DNA by Cr, inflammation and alteration of 196 SOT 2011 ANNUAL MEETING cell signaling pathways. Recently Cr(VI) has been shown to induce tumors of the duodenum of rodents following drinking water exposure at concentrations exceeding 60 mg/L sodium dichromate dihydrate (SDD). Because some chromium species interact with DNA, it is thought that DNA damage and mutagenecity play a role in the mode of action (MOA). To investigate the genotoxicity of Cr(VI) in the GI tract of rodents, SDD at 0, 0.3, 4, 14, 60, 170, 520 mg/L was administered ad libitum for 7 or 90 days. Samples were analyzed for 8-Oxo-2’-deoxyguanosine (8-OHdG) at 90 days (10 animals/group), and Cr-DNA binding at 7 and 90 days (5 animals/group). For Cr-DNA binding, DNA was isolated from scrapings of the oral, duodenal and jejunal epithelium and analyzed by ICP/MS. 8-OHdG analysis was performed on whole tissue from the duodenum and oral cavity using an ELISA. 8-OHdG levels were 2-3 times higher in the duodenal epithelium versus oral mucosa; however, a concentration-dependent increase in oxidized DNA bases was not observed. Concentration-dependent increases in Cr-DNA binding were observed in oral, jejunal and duodenal epithelium at 7 and 90 days, with evidence of the accumulation of Cr-binding observed overtime in all tissues. Slightly higher, but not statistically significant, levels of Cr-DNA binding were observed in the jejunum, as compared to the duodenum. In addition, an apparent threshold seems to exist for Cr-DNA binding in all tissues examined. Because we also observed villous cytotoxicity histopathologically, these results suggest that cytotoxicity in the duodenum villi may contribute to Cr(VI) carcinogenicity through a wound-rehealing mechanism involving the crypt cells. 919 A FRAMEWORK FOR EVALUATING DATA IN SUPPORT OF A MUTAGENIC MOA. R. Schoeny. Office of Water, U.S. EPA, Washington, DC. Sponsor: D. Proctor. To support its 2005 Guidelines for Cancer Risk Assessment the U.S. EPA Risk Assessment Forum convened a technical panel to develop guidance in evaluating data for determination that a chemical carcinogen acts through a mutagenic mode of action (MOA). The panel proposed definitions for mutagenicity and genotoxicity. Mutagenicity is the induction of permanent, transmissible changes in the amount, chemical properties, or structure of the genetic material. Genotoxicity is a broader term encompassing any alterations to genetic material including those that are transient. The technical panel noted that there is no “default MOA” for carcinogenicity but that all such judgements are data intensive exercises. A framework for data evaluation was proposed. While acknowledging the iterative nature of risk assessment, the framework considers 4 steps: 1. assemble all relevant data; 2. evaluate the data against current acceptance and quality criteria; 3. judge weight of evidence that the chemical has mutagenic activity, and if so, what type(s) of mutational activity; 4. by applying the Cancer Guidelines MOA framework, assess the evidence as to whether mutation is an early key event in the induction of tumors. The technical panel further proposed a hierarchy of data preference in making the weight of evidence decisions. The ideal data are cancer-relevant oncogene or tumor suppressor gene mutations detected in the tumor target tissue following chemical exposure. However, these results are rarely available, and the risk assessor must rely on more standard test batteries such as those from OCSPP guideline studies (i.e., gene mutations, cytogenetic damage, DNA adducts and/or primary DNA damage). Several case studies have been published that use principles of the proposed framework. Chloroform has sufficient evidence that the MOA does not include mutagenicity; whereas cyclophosphamide has sufficient evidence of a mutagenic MOA (McCarroll et al. 2008); and CrVI has adequate, but not overwhelming evidence of a mutagenic MOA (McCarrroll et al. 2010). [The opinions in this abstract are those of the author and do not necessarily reflect policies of the U.S. EPA.] 920 PHARMACOKINETICS OF INGESTED CR(VI) IN RODENTS: EXTRAPOLATIONS TO TARGET TISSUE DOSE IN HUMANS. S. Hays 1 , L. Aylward 2 and C. Kirman 3 . 1 Summit Toxicology, Inc., Lyons, Co., 2 Summit Toxicology, Inc., Falls Church, VA and 3 Summit Toxicology, Inc., Orange Village, OH. The target tissues for carcinogenic effects following chronic oral exposure to Cr(VI) in drinking water are the oral cavity in rats, and the small intestines (duodenum and jejunum) in mice, for which a response gradient is readily apparent (duodenum>jejunum>ileum) suggesting that neoplastic and non-neoplastic effects are due to direct contact of Cr(VI) in the lumen of the small intestine rather than systemic absorption. The ability of gastric and other body fluids to reduce Cr(VI) to Cr(III) before absorption occurs is recognized as a detoxification process providing protection against Cr(VI) toxicity following ingestion. However, saturation of reductive capacity occurs at some level of exposure, and serves as a potential source of nonlinear toxicokinetics for Cr(VI) . A series of studies were conducted to develop PBPK models to estimate species-specific target tissue dose following Cr(VI) ingestion. These included an ex vivo study of Cr(VI) reduction kinetics (rate and capacity) using real rat, mouse and human gastric fluid, and measures of Cr and Fe tissue
concentrations in six tissues and blood following 90 days of drinking water exposure at six doses from 0.1 to 180 mg Cr(VI)/L to refine existing PBPK models with rates of extracellular reduction, absorption, distribution and excretion in rats and mice. Because Cr competes with Fe and causes microcytic anemia, clinical measures of iron status were also collected to evaluate the affects on Cr kinetics. Using these species-specific PBPK models, we (1) estimated target tissue dose, characterizing tissue concentration gradients in the small intestine; (2) extrapolated between species; and (3) extrapolated from the high doses of Cr(VI) that causes cancer in rodents to the low doses to which humans are typically exposed. 921 USEOFMODEOFACTIONAND PHARMACOKINETICS TO INFORM THE CANCER RISK ASSESSMENT OF INGESTED CR(VI): A CASE STUDY. D. Proctor 1 , L. Haws 2 , C. Thompson 3 and M. Harris 3 . 1 ToxStrategies, Inc., Rancho Santa Margarita, CA, 2 ToxStrategies, Inc., Austin, TX and 3 ToxStrategies, Inc., Houston, TX. We conducted a Mode of Action (MOA) analysis for intestinal tumors observed in mice following chronic exposure to Cr(VI) in drinking water. Data gaps in the MOA were used to design a 90-day drinking water study including the collection of histopathological, biochemical, toxicogenomic, and pharmacokinetic data, as well as measures of DNA modification in rats and mice at concentrations of sodium dichromate dihydrate (SDD) from 0 to 520 mg/L. These data were used to evaluate whether the MOA for intestinal tumors is initiated through mutagenic or nonmutagenic mechanisms, interspecies differences, and dose-response at environmentally-relevant exposures. After 90 days of exposure in mice, crypt hyperplasia and villous atrophy were observed in the duodenum at exposures ≥ 170 mg/L SDD. Cytoplasmic signs of toxicity and stress were observed at ≥ 60 mg/L SDD. Clear signs of cellular oxidative stress (8-isoprostane) were apparent at ≥ 60 mg/L SDD, whereas changes in redox (GSH/GSSG) were apparent starting at 4 mg/L SDD. Together, these data suggest graded, dose-dependent changes in cell physiology beginning with mild oxidation, followed by oxidative stress, cytoplasmic toxicity, villous blunting and regenerative cell proliferation. These findings indicate a point-ofcontact response for Cr(VI) in the lumen with the epithelium of the small intestine, and target tissue response in the mouse at concentrations ≥ 4 mg/L SDD. Oxidative DNA damage was not significantly elevated in the duodenum, but preliminary data on chromium content in genomic DNA of intestinal epithelium suggests a similar dose-dependent increase in the duodenum and jejunum of mice. These data, along with an evaluation of in vivo mutations and gene expression in the duodenum and oral mucosa of mice, and corresponding information in the rat, were used to inform the MOA for rodent tumors. Toxicokinetic models were used to relate tissue responses to relevant internal dose metrics, model dose-response, and for interspecies extrapolation. 922 LOOKING BACK 50 YEARS OF TOXICOLOGY TO LOOK FORWARD. S. G. Gilbert 1 and J. G. Pounds 2 . 1 INND, Seattle, WA and 2 Cell Biology & Biochemistry, Pacific Northwest National Laboratory, Richland, WA. Toxicology has contributed enormously to environmental and human health. During the past 50 years significant rules and regulations were enacted to protect and enhance human and ecological health, often following a serious toxicological event. Most notably, toxicological sciences have shaped drug development through the U.S. FDA and chemical use through the U.S. EPA. Workplace exposure and health issues are addressed by OSHA and NIOSH. There is increasing concern about low-dose effects on the developing organisms of not only humans but also animals. Our panel of experts will review how advances in toxicological sciences over the past 50 years have driven the regulatory, societal, and medical view of key toxicants. After examination of some key contributions to the field, we will reflect on how advances in the science of toxicology will shape the future environment regarding drug and chemical development and use. 923 METALS 50 YEARS OF EXPLORATION. B. Weiss. Department of Environmental Medicine, University of Rochester, Rochester, NY. Metals are enormously useful and essential in our society but are not without hazards to health. Although we knew long ago of the potential health hazards of lead and mercury, only in the last 50 years have we begun to appreciate the subtle kinds of damage they might exert, particularly to the developing nervous system. More recently, we have also become aware of their contribution to the disorders of aging, such as Alzheimer’s disease. Moreover, metals we had conceived of primarily as essential components of the diet, such as manganese, are now viewed as potential threats to health as well, underscoring the importance of exposure context. Because we can now build bridges between health indices and cellular and molecular mechanisms, we are in a better position to apply scientific understanding to how we gauge health risks and their translation into policy and regulation. Tracing the history of metal toxicology provides a compelling lesson in how toxicology intersects with our lives as well as an example of how scientific progress tends to proceed in unpredictable directions. 924 HALOGENATED AROMATIC HYDROCARBONS (PCBS, PBB, DDT, DIOXIN). D. L. Eaton. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA. Recognition that some chemicals are highly persistent in the environment was dramatically articulated to the public with the publication of “Silent Spring” by Rachel Carson in 1962 - one year after the founding of SOT. Subsequent incidences such as the inadvertent introduction of a polybrominated biphenyl flame retardant into animal feed with resulting widespread human exposures, and an industrial accident in Seveso, Italy that resulted in relatively large release of TCDD into the environment, contributed to widespread public recognition of the potential hazards of halogenated aromatic hydrocarbons to public health. Indeed, PCBs and DDT are still routinely found in wildlife and human breast milk, a legacy of decades of previous use. Toxicologists were central to discovering the molecular mechanisms by which such persistent environmental pollutants elicited toxicological effects such as hormone receptor-dependent changes in gene expression. Understanding the mechanisms, as well as environmental fate and transport of these compounds, has facilitated development of less hazardous compounds, and improved the ability of regulatory agencies to protect public health through science-based regulatory actions. 925 RISK ASSESSMENT AND BEYOND. E. M. Faustman. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA. Risk assessment in its purist form brings together information on exposure and hazard to make an informed judgment on potential for harm. But it was soon discovered that that it is difficult to separate from risk management, risk communication and ultimately policy decisions. New perspectives such as the precautionary principle have also begun to shape risk assessment and policy decisions. In 1976 TSCA was passed and is now being considered for major revision. How is, or has, toxicology shaped chemical policy reform and what will regulatory policy look over the next 50 years? Toxicology and Toxicologists have and will continue to play an essential role in risk assessment however as we move towards a reductionist approach for identification and characterization of hazards, their expertise in systems based approaches for looking at the potential for chemicals to cause adverse endpoints across doses and conditions will be in even greater demand. Toxicologist will need to use their multidisciplinary training to predict impacts within a living system, across species and across life stages and levels of biological observation for informing risk assessments in the 21st Century and this will require our expertise to be in more demand and emphasize our use and understanding of kinetics and dynamics of response. It will also require us to re-think and energize our sometimes strained relationships with epidemiologists and clinicians to inform public decisions. Evolution of risk assessment will provide us with even greater opportunities to work with our colleagues in public health and exposure sciences. 926 CHEMICAL CARCINOGENESIS 50 YEARS TO WHERE. C. C. Harris. National Cancer Institute, National Institute of Health, Bethesda, MD. Sponsor: S. Gilbert. The Delaney Clause, a 1958 amendment to the Food, Drugs, and Cosmetic Act stated in part that “the Secretary of the Food and Drug Administration shall not approve for use in food any chemical additive found to induce cancer in man, or, after tests, found to induce cancer in animals.” The past 50 years have seen an unprecedented effort by toxicologist and the medical profession to understand the causes of environmentally-induced cancer. Toxicology has defined the role of metabolism, DNA damage and repair, inflammation, mutagenesis, and molecular/cell biology in individuals and populations at risk for cancer. SOT 2011 ANNUAL MEETING 197
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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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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
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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