Keywords: Metabolite identification; NMR; HPLC; Mass spectrometry; Absorption; Distribution; Metabolism, Excretion; Kinetics; LSC; In vivo; In vitro; Radiolabeled compounds; Dermal; Gavage; IV; Inhalation; Mass balance; Chromium; Fullerene; Cumene; 5-Amino-o-cresol, Choline, Dimethylethanolamine, Tungsten. The goal of this contract is to provide support of National Toxicology Program (NTP) hazard assessment activities targeted toward the prevention of diseases or adverse effects caused by environmental exposure to chemical or physical agents. Projects conducted under this contract are designed to investigate the fate (absorption, distribution, metabolism, and excretion, or ADME) and mechanisms of toxicity of chemicals commonly found in the environment, workplace, or in consumer products. These studies usually involve the use of radiolabeled chemicals, as well as species and strains of animals used in NTP studies of toxicology and carcinogenicity. Data developed by this work are used in the design and interpretation of the NTP studies. In the past fiscal year (2008), studies involving chromium, cumene, dimethylethanolamine (DMAE), fullerenes, and tungsten (sodium tungstate) have been conducted under this contract. Additionally, the 5-amino-o-cresol project report was finalized, accepted by the project officer and submitted for inclusion into the NTP electronic database system. Projects involving the potential water contaminants, chromium, and tungsten were completed and the final project reports for the two chemicals are currently being revised and reviewed prior to acceptance by the project officer. During the reporting period, studies describing the work for 5-amino-o-cresol and tungsten were published in the literature. Major progress was made on characterizing cumene metabolism in rodents. A primary metabolic pathway involved hydroxylation of the side chain of cumene and excretion as glucuronide conjugates in urine. Formation of potential reactive metabolites was indicated by the detection of specific metabolites in excreta. An assessment and comparison of different routes of administration (intratracheal, insufflation, and jugular vein cannulation) for determining ADME of fullerenes in rodents was in progress. The DMAE project was a new start in this fiscal year. DMAE is a high production chemical used in industry, present in some dietary supplements, and similar in structure to choline. The current studies are designed to investigate the ADME of DMAE and the effect of DMAE exposure on the uptake of choline in rats and mice. Initial experiments, have included administration of 14C choline to male rats and female mice and to male rats receiving pretreatment of DMAE. Metabolite identification is underway for a group of female mice dosed with 14C DMAE.
