Studies to Evaluate the Toxicological Potential of Test Articles

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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.