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1961 TOXIC EQUIVALENCY FACTORS ARE NOT UNIVERSAL WITHIN VERTEBRATE CLASSES: EVIDENCE, MECHANISTIC REASONS, AND REGULATORY IMPLICATIONS. E. A. Carlson 1 , C. H. Sutter 2 , T. R. Sutter 2 and J. B. Silkworth 1 . 1 General Electric, Niskayuna, NY and 2 University of Memphis, Memphis, TN. At least forty years ago, investigators realized that extreme differences in sensitivity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related dioxin-like compounds (DLCs) exist among animal species. It was also recognized that these chemicals are invariably found in complex mixtures, leading to approaches for summarizing the toxic equivalency (TEQ) of such mixtures for risk assessment purposes. The World Health Organization (WHO) toxic equivalency factor (TEF) scheme, which compares individual DLC toxicity to that of TCDD, is now used for determining mixture TEQs. Although it was probably thought initially that species differences in sensitivity to TCDD and DLCs would be effectively normalized for congener-specific TEFs by generating relative potency (REP) estimates within experiments, the WHO panel soon realized that different vertebrate classes required different sets of TEFs. Sufficient evidence now exists that even within a vertebrate class, REPs are not universal. Species-specific REPs have been identified in experiments comparing responses of human and rodent cells, among avian species, and even among rodent strains. For example, our laboratory has demonstrated a human REP of 0.002 for 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126), as determined by cytochrome P450 1A1 (CYP1A1) induction in fresh human hepatocytes and normal human epidermal keratinocytes (NHEKs), significantly lower than its assigned TEF of 0.1 (derived mainly from rodent studies). For fresh human and rat hepatocytes, this species difference extends to genes other than just CYP1A1 and is directly related to species differences in the aryl hydrocarbon receptor pathway. Furthermore, using NHEKs, we have demonstrated that such species difference extends to other congeners. Identified species- and congener-specific REPs are robust, repeatable, and significant. Such differences call into question the indiscriminant use of TEFs to predict risk in a species from which they were not derived. 1962 LOW DOSE RESPONSE RELATIONSHIPS FOR NON- CANCER ENDPOINTS: OZONE, MERCURY, AND XENOESTROGENS. L. Zeise 2 , G. Ginsberg 1 and M. S. Sandy 2 . 1 Connecticut Department of Public Health, Hartford, CT and 2 Cal EPA Office of Environmental Health Hazard Assessment, Oakland, CA. The 2009 National Academy of Sciences report “Science and Decisions: Advancing Risk Assessment” describes different approaches to modeling dose response relationships – that depend on background exposures (endogenous and exogenous) of chemicals that contribute to the disease process, ongoing disease processes, commonness of the disease, and sensitive and vulnerable populations. These factors are explored with three chemical substances: Ozone, mercury and xenoestrogens. While potential mechanisms of action may suggest low dose non-linearities at the individual level (due for example to host defense), this cannot be generalized, because of variability in exposures and ongoing health and disease processes that can translate to linear dose response at the population level. Acute, clinical ozone exposure studies in humans provide evidence of a linear dose response in FEV1 at low doses. These and other studies suggest that commonly experienced concentrations are still above the threshold for toxicity, at even the individual level for healthy adults for some endpoints. For methylmercury neurodevelopmental effects, modeling and data suggest low dose linearity at the population level. We explore the case of mercury further by considering the limited epidemiology studies for Hg° from dental amalgams, potential impacts of methylmercury on low dose observations of Hg° effects, and other factors. Integration of animal data into low dose modeling of Hg° effects is explored. For xenoestrogens, background exposures and disease processes suggest low dose linearity for a variety of effects. These case studies suggest linear dose response at the population level for environmental exposures, similar to what has been found for particulate matter and lead. 1963 ANALYZING THE SAFETY OF GULF SEAFOOD AFTER THE OIL SPILL BASED ON POPULATION SPECIFIC EXPOSURE SCENARIOS AND INCORPORATION OF DISPERSANT AND HEAVY METAL TOXICITY PARAMETERS. J. M. Gohlke. Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL. Gulf fishermen are facing a number of challenges since the British Petroleum Deepwater Horizon explosion, oil spill and cleanup. One challenge is re-instating consumer confidence in their product. Since the re-opening of closed Gulf waters 420 SOT 2011 ANNUAL MEETING to fisheries, numerous groups, including members of Congress, non-governmental organizations, scientists, local fisherman, processors, and chefs, have raised concerns over the adequacy of the National Oceanic and Atmospheric Administration (NOAA) and Food and Drug Administration (FDA) protocol for ensuring the safety of seafood caught in the Gulf. Primary concerns raised include reliance on an initial smell test and chemical testing only for a select number of polycyclic aromatic hydrocarbon (PAH) components of oil, as well as questions regarding the sampling scheme and risk assessment methodology employed. There is considerable uncertainty regarding the potential for toxicity related to the use of Corexit 9500A and Corexit 9527, the primary dispersants employed to break up the oil in the Gulf. For example, the potential for bioaccumulation of components of the dispersant in finfish, particularly those that are long-lived and at the top of the food chain is uncertain. Large amounts of heavy metals have also been released into the Gulf. Recent research suggests oil spills alter natural filtration processes of arsenic, raising the concern that increased levels of arsenic exposure via seafood consumption may be an issue. This project details assumptions in the NOAA/FDA methodology and develops region specific exposure assessments reflecting local consumption patterns, particularly in potentially vulnerable populations of subsistence fisherman, pregnant women and young children. In addition, the project focuses on risk characterization methodologies that estimate composite risk of cancer and non-cancer endpoints based on toxicity of dispersant components, heavy metal exposure, as well as relevant PAHs, resulting in novel estimates of levels of concern (LOCs). 1964 CORN OIL AS A CAUSATIVE FACTOR FOR PROLIFERATIVE LESIONS OF THE FORESTOMACH IN B6C3F1 MICE EXPOSED BY GAVAGE. L. M. Plunkett 1 , T. Starr 2 , J. A. MacGregor 3 and A. M. Jonyas 4 . 1 Integrative Biostrategies LLC, Houston, TX, 2 TBS Associates, Raleigh, NC, 3 Toxicology Consulting Services, Arnold, MD and 4 Amvac Chemical Corporation, Newport Beach, CA. A National Toxicology Program (NTP) cancer bioassay has established that the dose of corn oil that is routinely administered daily in gavage studies (5 ml/kg for F344 rats) is by itself associated with altered tumor incidence rates. Thus, corn oil is a potential confounding factor in carcinogenicity testing/ data interpretation. While mice receive twice the rat dose (10 ml/kg) in NTP corn oil gavage studies, a similar study of corn oil effects in B6C3F1 mice has not been conducted. Our previous work has implicated daily administration of corn oil by gavage as a causative factor for proliferative lesions of the forestomach in B6C3F1 mice. In the present analysis, the role of corn oil was examined by comparing tumor incidence rates in mice exposed to corn oil or water via gavage. A rigorous statistical assessment of heterogeneity was conducted using mouse forestomach hyperplasia and tumor incidence rates as reported for control groups of mice in the NTP bioassay series. Results were compared with those from our earlier analyses that assessed heterogeneity among control group incidence rates for studies using dietary and inhalation exposure routes. The combined analyses reveal significantly lower incidence rates of forestomach lesions in control groups of mice exposed via water gavage, the diet, or by inhalation, as compared to the rates of these lesions in corn oil gavage studies. The combined analyses show that daily gavage with corn oil can be a causative factor for proliferative forestomach lesions in B6C3F1 mice, and that corn oil by itself is a significant contributing factor in mouse forestomach lesion development. 1965 ASSESSING RISKS FOR SEC- AND TERT- BUTYLBENZENE: A SURROGATE METHOD. N. Y. Wang 1 and C. J. Moudgal 2 . 1 National Center for Environmental Assessment, U.S. EPA, Cincinnati, OH and 2 Environmental Risk & Toxicology, ICF International, Dublin, CA. As part of the U.S. Environmental Protection Agency’s (U.S. EPA) mission to protect the environment, chemicals-of-concern (CoCs) at Superfund or other hazardous waste sites are cleaned up based on their potential toxicity to humans and the surrounding ecosystem. However, often CoCs have limited or no toxicity data to assess their impacts on human health or the ecosystem. In these instances the application of alternative approaches, such as Structure-Activity Relationship (SAR) can be considered in conjunction with supporting data such as toxicokinetic and chemical class-specific toxicity data to identify suitable surrogates for CoCs. secand tert-Butylbenzenes are two CoCs from the alkylbenzenes class of chemicals that have very little relevant toxicity data for risk assessment purposes. We propose a SAR-based surrogate application for sec- and tert-butylbenzenes by using a combination of toxicokinetic and class-specific toxicity data. Three potential structural and metabolic surrogates for sec- and tert-butylbenzene were identified: ethylbenzene, n-butylbenzene, and isopropylbenzene. While these potential surrogates exhibited some similarity in toxicokinetic characteristics and toxicity manifestation, the branched alkylbenzenes, which include isopropylbenzene and sec- and tert-
utylbenzenes, exhibited most similar patterns in absorption, distribution and excretion as well as metabolic activity. Additionally, the acute toxicities of branched alkylbenzenes were reported to be higher in various tissues compared to their linear counterparts such as ethylbenzene and n-butylbenzene. A similarity search using U.S. EPA’s DSSTox database and National Library of Medicine (NLM) ChemIDPlus also support isopropylbenzene as an appropriate surrogate for secand tert-butylbenzene. Based on this weight-of-evidence analysis, toxicity data on isopropylbenzene may serve as a surrogate for both sec- and tert-butylbenzenes. 1966 EVALUATING IN SILICO AND IN VITRO TECHNOLOGIES FOR PREDICTING HEPATOTOXICITY. W. J. Bailey 3 , A. Bahl 1 , E. Keough 2 , K. R. Leander 2 , C. Gretzula 4 , I. Pak 1 , M. C. Kuhls 3 , C. Kreatsoulas 5 , R. P. Sheridan 5 , A. G. Aslamkhan 3 , L. Kiss 4 , A. Bagchi 1 and B. J. Howell 2 . 1 Informatics IT, Merck & Co., Inc., West Point, PA, 2 RNA Therapeutics, Merck & Co., Inc., West Point, PA, 3 Analytical & Systems Toxicology, Merck & Co., Inc., West Point, PA, 4 in vitro Pharmacology, Merck & Co., Inc., West Point, PA and 5 Chemistry Modeling & Informatics, Merck & Co., Inc., West Point, PA. In vitro predictive toxicology strategies deployed in the hit-to-lead space can serve to enrich the candidate pool for less toxic compounds, thus driving down the cost and uncertainty of drug development. As hepatotoxicity is a major source of attrition during preclinical and clinical development, we focused on developing and evaluating different technologies (in silico and in vitro) for building classifiers that predict dose-dependent liver injury. The in silico approach utilizes predicted physical properties (PPP) derived from chemical structures alone (e.g. lipophilicity), thereby providing an assay-free means to guide compound choices very early in the drug discovery pipeline. Among the two in vitro technologies that we studied, highthroughput screens (HTS) interrogate select toxicological biomarkers in a liver cell line upon chemical perturbation using simple assays amenable to automation (e.g. cell viability), allowing deployment in pipeline phases expecting a routinely high flux of compounds to be tested. The second in vitro technology examined, highcontent screening (HCS), is an image-based methodology for profiling cellular effects across a spectrum of chosen hepatotoxicity endpoints simultaneously in individual cultured liver cells upon compound treatment, providing richer information than HTS assays that is useful for mechanistic dissection, but which comes with an associated increase in assay complexity that limits throughput. In this study, we present the cost, complexity, throughput, and performance profiles of PPP-, HTS-, and HCS-based predictive toxicology approaches benchmarked on an internal Merck compound set where in vivo liver histopathology endpoints are known. 1967 CANCER HAZARD IDENTIFICATION UTILIZING STRUCTURE-ACTIVITY CONSIDERATIONS FOR 1, 3- DICHLOROPROPANOL AND 3- MONOCHLOROPROPANE-1, 2-DIOL. D. W. Morry, R. S. Tomar, F. C. Tsai, M. S. Sandy and L. Zeise. Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA. 1,3-Dichloropropanol (1,3-DCP), a high production volume chemical, and 3monochloropropane-1,2-diol (3-MCPD), a rodenticide, are chlorinated three-carbon alcohols that are also found in certain processed foods. These two compounds were recently added to the Proposition 65 list of chemicals known to the State of California to cause cancer. Here we focus on the structure-activity information that contributed to the evidence used to identify these compounds as carcinogens. We compare 1,3-DCP and 3-MCPD with seven related three-carbon compounds and two phosphate triesters that are metabolized to three-carbon halogenated alcohols. The three-carbon compounds are: 2,3-dibromo-1-propanol, epichlorohydrin, glycidol, 1,3-dichloroacetone, 1,2,3-trichloropropane, 1,3-dichloropropene (Telone II), and 1,2-dibromo-3-chloropropane. The phosphate triesters are: tris(1,3dichloro-2-propyl)phosphate (TDCPP) and tris(2,3-dibromopropyl)phosphate (TDPP). All of these compounds have positive evidence of genotoxicity, and all but two (1,3-dichloroacetone, TDCPP) have been identified as carcinogens by IARC or Proposition 65. The rodent carcinogenicity data on these chemicals indicate that they are capable of inducing tumors at multiple sites. Many of these chemicals induce tumors at one or more of the same sites as 1,3-DCP and 3-MCPD. Several mechanisms have been proposed to explain how these eleven compounds induce tumors, including genotoxicity, possibly via formation of glutathione metabolites capable of forming DNA adducts. We conclude that structure-activity considerations can provide valuable information for the assessment of cancer hazard. 1968 ARSENIC INDUCES METABOLIC REGULATORS AND DIFFERENTIATION IN ADIPOSE TISSUE. L. R. Klei, Y. Garciafigueroa, R. T. Cattley and A. Barchowsky. Environmental and Occupational Health, Universtity of Pittsburgh, Pittsburgh, PA. Consumption of low to moderate levels of arsenic promotes a number of diseases that stem from altered metabolism, such as cardiovascular disease and diabetes. The patterns of diseases suggest enhanced metabolic syndrome, but underlying mechanisms are less clear. To investigate potential mechanisms, we explored the hypothesis that arsenic exposure promotes pathogenic phenotypic or functional change in mouse adipose tissues. C57Bl/6 mice were assessed for circulating lipid levels and adipose tissue expression of regulators of lipid and energy metabolism. Decreased serum triglyceride was the only observable circulating lipid change. Analysis of RNA and protein extracts isolated from interscapular brown adipose tissue (BAT) demonstrated up regulation of transcriptional programs for thermogenesis with increased expression of PGC-1α, PnPla2, UCP1, PPARγ, and PPARδ. Interestingly, transcript levels for a number of inflammatory mediators (CRP, Ccl3, IL6, and vaspin) decreased in BAT. Epididymal white adipose tissue (WAT) demonstrated similar patterns of change, especially with increases in PGC-1α and UCP1 at both the transcript and protein levels. These regulators of BAT thermogenesis are normally very lowly expressed in WAT and the expression indicates WAT acquiring BAT character. This phenotypic change would be supported by the increased markers of adipose stem cell differentiation, such as PPARγ. Increased PECAM1, IGF1, and VEGF indicated enhanced WAT vascularization. Interestingly, many adipose genes, such as visfatin, leptin, lipoprotein lipase, and adipophilin were unchanged. However, PEPCK, the rate limiting step in gluconeogenesis, levels were increased. Together, the pattern of arsenic-related change in adipose tissues explain the decrease in serum triglycerides, but disrupted metabolism with enhanced potential for released glucose. Further investigation is warranted to determine the full impact of these metabolic changes to etiology of arsenic related metabolic diseases. Supported by NIEHS grant R01ES013781. 1969 TRANSCRIPTIONAL REPRESSOR INVOLVED IN GLUCOSE METABOLISM PLAYS A KEY ROLE IN PROTECTION AGAINST ARSENITE TOXICITY. T. Takahashi, N. Miyanaga, T. Yano and A. Naganuma. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan. Arsenic is known to be an environmental toxic metalloid that causes various cancers and skin disorders, but its mechanism of toxicity are not yet clearly understood. To elucidate more detail mechanism of arsenic toxicity, we have previously searched for factors that determine sensitivity of cells to arsenite using budding yeast as a model eukaryote and found that disruption of Reg1, a regulatory subunit of protein phosphatase 1 (PP1), increased sensitivity of yeast cells to arsenite. In this study, we found that the deletion of Reg1 increased sensitivity of yeast cells to arsenite through activation of Snf1 kinase. Therefore, we investigated the relationship between downstream factors of Snf1 and arsenic toxicity and found that deletion of Mig1, a transcriptional repressor involved in glucose metabolism, conferred hypersensitivity to arsenite. Mig1 is known to be down-regulated by Snf1 via phosphorylation. Simultaneous deletion of Reg1 and Mig1 showed no additive or synergistic effects on sensitization to arsenite, suggesting that sensitization of yeast cells to arsenite by deletion of Reg1 might be involved in depression of Mig1 by Snf1. On the other hand, arsenite enhanced phosphorylation of Mig1 and decreased the transcriptional repressor activity of Mig1. These results suggest that inactivation of Mig1 via phosphorilation might be involved in development of arsenic toxicity. 1970 CHRONIC EXPOSURE TO MODERATE DOSES OF ARSENIC INCREASES ATHEROSCLEROSIS FORMATION OF UNSTABLE PLAQUES. M. Lemaire 1 , C. A. Lemarié 2 , M. Flores-Molina 1 , E. L. Schiffrin 2 , S. Lehoux 2 and K. K. Mann 1 . 1 Oncology, McGill University, Montreal, QC, Canada and 2 Medicine, McGill University, Montreal, QC, Canada. Arsenic is a widespread environmental contaminant to which millions of people are exposed worldwide. The current maximum acceptable level of arsenic in municipal water is set at 10 ppb, but well water in many North American counties averages 10-fold higher than this limit. Arsenic exposure has been linked to atherosclerosis, however molecular mechanisms involved or minimal required doses are unknown. Therefore, we assessed the effects of a chronic exposure to moderate concentrations of arsenic on plaque formation and plaque composition in the ApoE-/- murine atherosclerosis model. We exposed ApoE-/- mice to two doses of arsenic (200 ppb or SOT 2011 ANNUAL MEETING 421
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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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Page 391 and 392: toxicity of nanomaterials relates s
Page 393 and 394: 1815 MEASURING COMPOUND SELECTIVITY
Page 395 and 396: 1825 EFFECTS OF METABOLISM BY INTES
Page 397 and 398: cyanoacetic acid increased 2-3 fold
Page 399 and 400: 1845 IS THE PROMISCUITY OF THE ARYL
Page 401 and 402: crorarray analysis. RT-PCR results
Page 403 and 404: are a family of phase-II biotransfo
Page 405 and 406: ous labs. As a result of positive s
Page 407 and 408: down the doses may produce more tox
Page 409 and 410: spectively. Below 100 mg/l of gemfi
Page 411 and 412: 1900 GENERATION OF PRECISION CUT LI
Page 413 and 414: iomarkers or observation of lesions
Page 415 and 416: creased reticulocytes and lymphocyt
Page 417 and 418: statistically significant interacti
Page 419 and 420: monize sample preparation and analy
Page 421 and 422: NPC and sinonasal cancer in neighbo
Page 423: showed incidences of lung and nasal
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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The Toxicologist - Society of Toxicology

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