ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION (ADME) IN MAMMALS

点击翻译按钮获取中文摘要

The goal of this contract is to provide support of National Toxicology Program (NTP) hazard identification activities targeted toward the prevention of diseases or adverse effects caused by environmental and occupational exposure to chemical or physical agents. Projects designed under the contract investigate the fate and the mechanism of toxicity of chemicals commonly found in the environmental and occupational settings using rodent models in vivo and rodent and human models in vitro. Fate of a chemical agent is studied by its absorption, distribution, metabolism and excretion (ADME) properties and in general are conducted using radiolabeled chemical and the species and strains of animals used in NTP toxicity and carcinogenicity studies. Mechanistic studies are designed to answer specific questions about mechanism of metabolism or toxicity. Data developed in the course of this work are used in the design and interpretation of NTP toxicity and carcinogenicity studies. During the current year, studies involving in vitro and in vivo fate (in vitro and/or in vivo) of 2',2'''-dithiobisbenzanilide (DTBBA), 2-hydroxy-4-methoxybenzophenone (HMB), and β-N-methylamino-L-alanine (BMAA), and 2,2'-dimorpholinodiethyl ether (DMDEE) have been conducted under this contract. Final study reports on fullerene and dimethylethanolamine are being reviewed by the COTR for inclusion into the NTP database. DTBBA is a plasticizer for natural and synthetic rubber and is high production chemical with potential for occupational and consumer exposure. Very little information is available on the ADME properties of this chemical. Therefore, the current work is focused on the metabolism and disposition of this chemical in rodents. HMB is used as a UV filter in cosmetic and sunscreen products. The exposure to HMB is possible via both dermal and oral routes. The available ADME data in the literature shows species and sex dependent metabolism and disposition of HMB. NTP is investigating toxicity and carcinogenicity of this chemical in Harlan Sprague Dawley rats and B6C3F1 mice. Therefore, the focus of the work conducted under the contract is to investigate the metabolism and disposition of HMB in these strains following dermal and oral administration. BMAA is a chemical produced by some members of blue-green algae. Potential human exposure to this is possible via consumption of blue-green algae dietary supplements and other food supplies. Exposure of BMAA in rats exhibited neurotoxicity. A proposed mechanism of chronic neuropathy in humans is based on the hypothesis that BMAA accumulate in neuroproteins. There is no ADME data in the literature for this chemical. Therefore, ADME is being investigated following oral exposure in rats and mice. Exposure to DMDEE is expected in the work place during the production of flexible foam. NTP is investigating the toxicity of this chemical. There is no ADME data in the literature for DMDEE. Therefore, the ADME of this is investigated in the current contract in rodents with special attention to the formation of carcinogenic metabolite N-nitrosomorpholine.