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;1,3-dichloro-2-propanol;2-methoxy-4-nitroaniline;dimethylamineborane;p-hydroxybenzoic acid;n-butylparaben;Radiolabeled compounds;In vivo;In vitro;Dermal;Gavage;IV;Inhalation;Mass balance; Abstract;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 1,3-dichloro-2-propanol (DCP), dimethylamineborane (DMAB), 2-methoxy-4-nitroaniline (MNA), and n-butylparaben (BPB) were undertaken while continuing on 2,3-butanedione (diacetyl) (2,3-BD), N,N-dimethylacetoacetamide, and propenyl- and allyl-benzenes reported during last period. 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. Current work is focusing on estimating the systemic exposure of this chemical and binding to blood proteins in rodents after intratracheal instillation. DCP is a semi-volatile liquid that is used in high volume as an intermediate in chemical synthesis. Environmental exposure to DCP can come from ingestion of food to which hydrochloric acid catalyzed vegetable protein has been added. Epochlorohydrin (ECH), which is a Group 2A carcinogen, is proposed as a metabolite of DCP. The current work is undertaken to confirm whether ECH is formed as a metabolite of DCP in rodents administered orally with DCP. DMAB is widely used as a reducing agent in many industries and hence exposure to this via both dermal and oral routes is possible. Very little information is available on the ADME properties of this chemical. The current studies undertaken investigates the disposition and metabolism of this chemical via dermal, oral, and intravenous routes. MNA is used in the synthesis of pigment yellow 74;therefore it is present in numerous consumer products, yellow tattoo inks, and printing inks. Human exposure to this chemical is possible via both dermal and oral routes. Current studies are designed to investigate the ADME properties of this chemical via above mentioned routes as well as to investigate the binding of the reactive metabolite(s) of MNA with macromolecules in prospective target organs. P-hydroxybenzoic acid (butylparaben, BPB) is widely used as an antioxidant and preservative in foods, pharmaceuticals, and cosmetics. Human exposure can occur via inhalation, ingestion, or dermal contact. There is very little data available on ADME of this chemical. Hence, current studies are designed to characterize ADME on route of exposure, effect of dose on ADME properties, and to identify metabolites of BPB. Studies on propenyl- and allylbenzenes (eugenol, safrole, estragole, anethole, myristicin, isosafrole, isoeugenol and methyleugenol) and N. N-dimethylacetoacetamide were completed during this reporting period and final reports are being prepared.
