Studies to Evaluate the Toxicological Potential of Test Articles

这份合同的目的是进行研究，这将有助于国家毒理学计划(NTP)确定与短期接触各种化学品有关的毒理学特征。这些研究旨在确定可能的毒性靶器官、性别和动物物种之间的敏感性差异以及剂量-反应关系，以及可能的毒性机制。NTP将使用慢性前研究的数据来确定和报告所研究的化学品的毒性，并确定为随后的长期致癌性研究选定的化学品的剂量水平。对转基因小鼠模型的研究旨在验证模型作为两年小鼠生物检测的替代品的使用，并获得有关肿瘤发生机制的信息。转基因模型还被用于前瞻性地评估化学品的毒理潜力。毒理基因组学研究旨在确定使用基因组技术是否可以在较短的时间内检测到潜在的致癌物。2006财年期间已经完成或正在进行以下研究：用于毒素基因组变异性研究的RNA提取：正在从来自两个不同实验室的不同年龄的哨兵Fischer 344只大鼠中分离RNA，以确定肝脏差异基因表达(DGE)的变异性。这项研究正在进行中，分离的肝脏RNA将被送到另一个合同实验室进行基因表达谱分析。四种大鼠肝脏致癌物质和三种非致癌物质在雄性Fischer 344大鼠体内的毒理基因组学评价：这项研究的生活部分已经由实验室完成。本研究将对肝脏组织病理学、谷胱甘肽、临床病理学、肝脏RNA分离和随后的微阵列图谱、肝脏蛋白质组学和血清多重分析物图谱(MAP)进行检测。CB6F1-TG(HRAS2)转基因小鼠中多溴二苯醚同系物DE-47的围产期研究：实验室正在进行一项初步研究，预计2007财年会有结果。壳聚糖的6个月安全性研究：本研究的生活部分仍在进行中，将研究在剂量饲料中给予壳聚糖对SD-Dawley大鼠骨质减少和骨质疏松的影响，对脂肪和钙吸收的影响，以及对脂溶维生素(A，K，E和25-羟基维生素D代谢物)状态和其他毒理学效应的影响。通过植入遥测法延长Beagle犬QT间期：这项研究已授予实验室，以确定清醒犬无线电遥测模型评估六种药物(索他洛尔、特非尼定、倍普利、氯雷他定、洛伐他丁和地尔硫卓)延长QT间期的敏感性和特异性。。如果成功，将扩大确凿的研究范围，以检查该检测的敏感性和特异性。FDA-NTP插入突变研究-先导研究：实验室已经获得了为期12周的先导研究，以开发和验证用于评估逆转录病毒载体介导的插入肿瘤发生风险的临床前模型。这项研究计划于2007财年开始。番泻叶在p53(+/-)转基因小鼠中的39周研究：实验室已获奖，以确定番泻叶在杂合子p53(+/-)转基因小鼠模型中的毒性/肿瘤反应。研究工作将于2007财年开始。熟练程度评估支持暴露生物学计划的小鼠方案部分：该项目的目标是开发一组环境因素(臭氧、香烟烟雾、内毒素和过敏原)的生物反应标记物，这些环境因素已知会扰乱生物系统，导致呼吸道变化，从而导致慢性呼吸道疾病的发展。为了建立一个方案基础设施来支持这些项目，我们向实验室发出了一份工作任务，将用来确定实验室对选定的特殊技术的熟练程度。 毒理学评价；围产期研究；大鼠-F344/N；CB6F1-TG(HRAS2)转基因小鼠；转基因小鼠模型；RNA提取；毒理基因组学评价；基因芯片；差异基因表达；肝脏蛋白质组学；血清多分析物图谱；N-乙酰基-对氨基酚；亚硝基二甲胺；蒽醌；黄曲霉毒素B1；抗坏血酸；L-色氨酸；甲基丁香酚；番泻叶；多溴联苯醚同系物；PBDE-47；致癌物质和非致癌物质；RNA制备；壳聚糖；QT延长；插入突变；通气性、烯丙基苯、丙烯基苯、风味成分、甲基亮香酚、黄樟素、雌酚、异黄樟素、丁香酚、异丁香酚、肉豆蔻素和茴香脑。

The purpose of this contract is to conduct studies, which will help the National Toxicology Program (NTP) in the toxicologic characterization associated with short-term exposures to a variety of chemicals. The studies are designed to identify possible target organs of toxicity and differences in sensitivity between sexes and species of animals and dose-response relationships, and possible mechanism of toxicity. Data from prechronic studies will be used by the NTP to characterize and report the toxicity of chemicals studied and for establishment of dose levels of chemicals selected for subsequent long-term carcinogenicity studies. The studies in genetically modified mouse models are designed to validate the use of models as a replacement of the two-year mouse bioassay and to obtain information about mechanisms involved in tumorgenesis. The transgenic models are also used prospectively to evaluate chemicals for their toxicologic potential. Toxicogenomic studies are designed to determine whether the use of genomic technology can detect potential carcinogens in a shorter time frame. The following studies have been completed or are ongoing during FY 2006: RNA isolation for Toxicogenomic Variability Study: RNA is being isolated from sentinel Fischer 344 rats of varying ages from two different laboratories to determine the variability of Differential Gene Expression (DGE) in liver. This study is ongoing and the isolated hepatic RNA will be sent to another contract lab for gene expression profiling. Toxicogenomic evaluation of four rat liver carcinogens and three non-carcinogens in male Fischer 344 rats: The in-life portion of this study has been completed by the lab. Liver histopathology, glutathione, clinical pathology, hepatic RNA isolation and subsequent microarray profiling, liver proteomics and serum multiple analyte profiles (MAPs) will be determined in this study. Perinatal study of polybrominated diphenyl ether congener DE-47 in CB6F1-Tg(HRAS2) transgenic mice: A pilot study is being performed at the lab and the results are expected in FY 2007. Six Month Safety Study of Chitosan: The in-life portion of this study is ongoing and will investigate the effect of chitosan administered in dosed feed on bone osteopenia and osteoporosis, on fat and calcium absorption, and on the status of fat soluble vitamins (A, K, E, and 25-hydroxy vitamin D metabolites) and other toxicological effects in Sprague-Dawley rats. QT Prolongation in Beagle Dog via Implantable Telemetry: This study has been awarded to the lab to determine the sensitivity and specificity of the conscious canine radio telemetry model for the evaluation of QT interval prolongation using six drugs (Sotalol, Terfenedine, Bepridil, Loratadine, Lovastatin, and Diltiazem). . If successful, definitive studies will be extended to examine the sensitivity and specificity of the assay. FDA-NTP Studies of Insertional Mutagenesis - Pilot Study: 12-week pilot study has been awarded to the lab to develop and validate preclinical model for assessing risk of retroviral vector-mediated insertional tumorgenesis. The study is proposed to start in FY 2007. 39-week study of Senna in p53 (+/-) transgenic mice: Study has been awarded to the lab to determine the toxic/neoplastic responses of Senna in heterozygous p53 (+/-) transgenic mouse model. Studies will start in FY-2007. Proficiency Evaluation in Support of the Murine Protocol Section of the Exposure Biology Program: The goal of this project is to develop a panel of biologic response markers for environmental agents (ozone, cigarette smoke, endotoxin, and allergen) that are known to perturb biologic systems resulting in changes in the airway that lead to the development of chronic airway disease. In order to establish a programmatic infrastructure to support these projects we have issued a work assignment to the lab that will be used to establish laboratory proficiency in selected special techniques. Keywords Toxicologic evaluation; Perinatal study; Rats- F344/N; CB6F1-Tg(HRAS2)transgenic mice; Genetically Modified Mouse Models; RNA isolation; Toxicogenomic evaluation; Microarray; Differential Gene Expression (DGE);liver proteomics; serum multiple analyte profiles (MAPs); N-acetyl-p-Aminophenol(APAP); Nitrosodimethylamine; Anthraquinone; Aflatoxin B1; Ascorbic acid; l-tryptophan; Methlyeugenol; Senna; PolyBrominated diphenyl ether congeners; PBDE-47; Carcinogen and Non-carcinogen; RNA Preparation, Chitosan; QT Prolongation; Insertional Mutagenesis; Airway Proficiency, Allylbenzene, Propenylbenzene, Flavor constituents, Methyleugenol, Safrole, Estragole, Isosafrole, Eugenol, Isoeugenol, Myristicin, and Anethole.