The primary emphasis of the Superfund Hazardous Substances Basic Research Program, as described in the RFA, is the use of advanced basic research to improve the sensitivity and specificity of techniques for detecting adverse effects in humans or in ecological systems. Consistent with this emphasis, the theme for this project is sensitive toxic endpoints/sensitive populations for toxicity from chlorinated organic compounds. Chlorinated organic chemicals were selected as a subject of this theme in view of their importance as contaminants at Superfund and other hazardous waste sites, and because there is reason to suspect that adverse human and environmental impacts may be particularly a problem with low-level exposure to this class of contaminants. The program project consists of seven individual projects whose focus on improving sensitivity for detecting adverse effects of chlorinated compounds involves either: 1) study of mechanisms and dose-response relationships for health effects most likely to occur with environmentally-relevant exposures, viz. immune effects, reproductive/developmental effects, and cancer; 2) study of factors which lead to increased sensitivity (vulnerability) toxicity; 3) sensitive methods for detecting toxicity; or 4) sensitive methods for detecting/measuring contaminants in biological systems. The four individual projects are: Endocrine- Disrupting Effects of Chlorinated Hydrocarbons on Wildlife; Placental- Uterine Effects of Chlorinated Hydrocarbons; Dichloroacetate Kinetics, Metabolism and Human Toxicology; and Bioavailability of Superfund Chemicals. These projects will be supported by core facilities: Analytical Chemistry Core; Histology Core; Epidemiology/Biometrics Core; and Training and Outreach Core, as well as by administrative support made available by the program project. Three of the research projects are primarily or entirely biomedical in orientation, while one is primarily or entirely non-biomedical. Proposed research involves studies of toxicity in species ranging from fish and alligators to rats and mice to humans. These projects offer an integrated approach to advancing knowledge regarding the human and environmental impact of chlorinated organic contaminants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES007375-04
Application #
2684436
Study Section
Special Emphasis Panel (SRC (G1))
Project Start
1995-05-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Mangal, Naveen; James, Margaret O; Stacpoole, Peter W et al. (2018) Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children. J Clin Pharmacol 58:212-220
Jiang, Yu; Milavetz, Gary; James, Margaret O et al. (2017) A Mechanism-Based Pharmacokinetic Enzyme Turnover Model for Dichloroacetic Acid Autoinhibition in Rats. J Pharm Sci 106:1396-1404
Shroads, Albert L; Coats, Bonnie S; Langaee, Taimour et al. (2015) Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans. Drug Metab Pers Ther 30:49-55
Shroads, A L; Coats, B S; McDonough, C W et al. (2015) Haplotype variations in glutathione transferase zeta 1 influence the kinetics and dynamics of chronic dichloroacetate in children. J Clin Pharmacol 55:50-5
James, Margaret O; Kleinow, Kevin M (2014) Seasonal influences on PCB retention and biotransformation in fish. Environ Sci Pollut Res Int 21:6324-33
Garcia-Reyero, Natàlia; Martyniuk, Christopher J; Kroll, Kevin J et al. (2013) Transcriptional signature of progesterone in the fathead minnow ovary (Pimephales promelas). Gen Comp Endocrinol 192:159-69
Kocerha, Jannet; Prucha, Melinda S; Kroll, Kevin J et al. (2010) Regulation of steroidogenic acute regulatory protein transcription in largemouth bass by orphan nuclear receptor signaling pathways. Endocrinology 151:341-9
Tan, Xiaobing; Yim, Sun-Young; Uppu, Prasanna et al. (2010) Enhanced bioaccumulation of dietary contaminants in catfish with exposure to the waterborne surfactant linear alkylbenzene sulfonate. Aquat Toxicol 99:300-8
Nyagode, Beatrice A; James, Margaret O; Kleinow, Kevin M (2009) Influence of dietary Coexposure to benzo(a)pyrene on the biotransformation and distribution of 14C-methoxychlor in the channel catfish (Ictalurus punctatus). Toxicol Sci 108:320-9
Rauschenberger, R Heath; Sepulveda, Maria S; Wiebe, Jon J et al. (2009) Nutrient and organochlorine pesticide concentrations in American alligator eggs and their associations with clutch viability. J Aquat Anim Health 21:249-61

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