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

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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 in 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, study reports for 2,2-Dithiobisbenzanilide (DTBBA), 2-Hydroxy-4-methoxybenzophenone (HMB), β -N-methylamino-L-alanine (BMAA) and 2’,2”-Dimorpholinodiethyl ether (DMDEE) were completed and studies on ethyleneglycol-2-ethyl-hexylether (EGEHE) was initiated. DTBBA is a high-production-volume chemical used as a peptizing agent for rubber. DTBBA is mostly consumed by the tire industry, but is also present in other products such as belts, cables, hoses, rubber gloves, latex gloves, printing screen rollers, and athletic shoes. Occupational exposure to DTBBA in the rubber industry may occur through inhalation and dermal contact, but the extent of dermal absorption is not known. Under this contract, the ADME of DTBBA in rats and mice are investigated following dermal and oral exposure. HMB which is also known as benzophenone-3, is used as an ultraviolet (UV) filter in cosmetic and sunscreen products and hence there is widespread human exposure. Current studies are undertaken to investigate the ADME and toxicokinetics (TK) of HMB in rat and mouse strains used in NTP toxicity and carcinogenicity studies following oral and dermal exposure. BMAA is produced by all known groups of cyanobacteria (blue-green algae), including symbiotic and free-living cyanobacteria present in terrestrial, freshwater, brackish, and marine environments. Humans may be exposed to BMAA from consuming blue-green algae dietary supplements and foods and/or water containing the chemical. However, ADME data for this chemical is limited in the literature. In this contract, ADME properties of BMAA are investigated in rats and mice following oral administration to mimic relevant human exposure. DMDEE is a specialty amine catalyst used in the production of flexible foam, high-resilient molded foam, and in coatings and adhesives. DMDEE is also used as a catalyst in polyurethane insulating foams released under pressure or from pressurized cans, in hot melt urethane adhesives, in the formation of flexible orthopedic casts and in warm melt adhesives used in book-binding applications. Occupational exposure to DMDEE is likely via oral and dermal. Hence, the ADME is investigated in rats and mice following these routes. In addition, experiments were conducted to investigate the formation of nitrosomorpholine as a metabolite of DMDEE in rodents. EGEHE is a solvent used in a variety of products including coatings, paints, sealants and cleaners. The other members of the glycol ether class, ethylene glycol methyl ether (EGME), ethylene glycol ethyl ether (EGEE) and ethylene glycol butyl ether (EGBE), have shown to exhibit reproductive, developmental and hematological toxicities and hence there is a concern that EGEHE may exhibit similar toxicities. Work performed under this contract is evaluating the disposition and metabolism of EGEHE to aid in the interpretation of toxicity data.