Keywords; Absorption; Distribution; Metabolism; Excretion; ADME; Metabolite identification;toxicokinetics;Mechanisms of toxicity; 2,3-butanedione; diacetyl; N,N-dimethylacetoacetamide; obliterative bronchiolitis; CYP; eugenol; safrole; estragole; anethole; myristicin; isosafrole; isoeugenol; methyleugenol;Radiolabeled compounds;In vivo; In vitro; Dermal; Gavage; IV; Inhalation; Mass balance; 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 on 2,3-butanedione (diacetyl) (2,3-BD) and N,N-dimethylacetoacetamide (DMAA) were undertaken. 2,3-BD is a major component found in air samples from microwave popcorn production plants and hence is thought to play a major role in obliterative bronchiolitis observed in workers in popcorn industry. It has been shown to bind specifically with arginine residues in proteins suggesting an immunological response to modified proteins in the respiratory tract may be a contributing factor in the development of this obstructive airway disease. Current work is focusing on developing an arginine adduct of 2,3-BD against which antibodies can be raised to study the binding of 2,3-BD in respiratory tract. Future work would be to investigate the potential of this adduct in hemoglobin as a biomarker of exposure to this chemical in popcorn industry. Work on DMAA (a co-promotor used in the production of unsaturated polyester resins and an intermediate in insecticide synthesis) showed that it is well absorbed in rodents from the gastrointestinal tract, metabolized and excreted in urine. Identification of major urinary metabolites of this chemical is underway. An in vitro investigation, in human hepatic microsomes, of a series of propenyl- and allylbenzenes (eugenol, safrole, estragole, anethole, myristicin, isosafrole, isoeugenol and methyleugenol) on potential for modulation of CYP enzymes shows that the most potent effects are exerted on CYP1A family. Repeated administration of estragole, isoeugenol, and methyleugenol in rodents in vivo showed a marked increase in CYP2B1 activity.
