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, studies on sulfolane was undertaken while continuing studies on hydroquinone (HQ), N-butylbenzene sulfonamide (NBBS) , 2-ethylhexyl-p-methoxycinnamate (EHMC), Tris(4-chlorophenyl)methane (TCPME), Tris(4-chlorophenylmethanol) (TCPMOH), and Bisphenol AF (BPAF). EHMC is a common active ingredient in sunscreens and hence the human exposure is widespread and the exposure can occur over a large portion of an individuals lifespan. FDA regulates this chemical at a maximum level of 7.5% in sunscreens. There is no relevant ADME data for EHMC in rodents. Current studies are evaluating the ADME of this chemical in rats and mice. In addition the research will also focus on evaluating whether EHMC is metabolized to the developmental toxicant, 2-ethylhexanol. NBBS is widely used as a plasticizer. It also possesses antifungal properties. There is high potential for human exposure to NBBS due to its likely occurrence in drinking water and leaching from NBBS-containing products such as cooking utensils. Currently, ADME studies of this chemical in rodents and humans are lacking. Therefore, studies are undertaken to investigate the disposition and metabolism of this chemical via oral and intravenous routes in both rats and mice. Both TCPME and TCPMOH are used in the production of synthetic high polymers, lightfast dyes for acrylic fibers, and agrochemicals, indicating potential for occupational exposure. TCPME is a byproduct during dichlorodiphenyltrichloroethane production. TCPMOH is a presumed metabolite of TCPME. Both TCPME and TCPMOH have been found in tissues of a variety of animals, such as fish, birds, and marine mammals indicating widespread exposure. However, there is no information on the ADME and toxicokinetic (TK) properties of these chemicals. Therefore, ADME and TK studies of TCPME and TCPMOH are investigated in rats and mice following gavage and intravenous administration. Special attention is made to the possible formation of TCPMOH from the metabolism of TCPME. HQ is present in some foods and beverages, is used as a reducing agent, an antioxidant, a polymerization inhibitor, a stabilizer in various products, as a medicine to treat abnormal skin pigmentation, and is present in many over-the-counter (OTC) products used to lighten skin. HQ can be neurotoxic at high doses. HQ has been shown to form DNA adducts and cause chromosomal aberrations, abnormal mitoses, formation of micronuclei, and sister chromatid exchange in in vitro assays. It is known that HQ is well absorbed following oral administration and poorly absorbed following dermal application in F344 rats but there is limited data in mice. In addition, ADME and TK data are needed in appropriate rodent models to provide interpretive data for future NTP oral reproductive toxicity studies and dermal chronic toxicity studies. Therefore, the work under this contract is evaluating ADME and TK properties of HQ in NTP rodent models following oral and dermal administration. BPAF is used as a cross linking agent for certain fluoroelastomers and as a monomer for polyimides, polyamides, polyesters, polycarbonate copolymers, and other specialty polymers. It has structural similarity to the well-researched bisphenol A (BPA), but there is a lack of adequate toxicity data for BPAF. There are no metabolism and disposition studies of BPAF in the literature. Therefore, ADME studies of BPAF are investigated in this contract in rats and mice following gavage exposure. Sulfolane is a solvent primarily used in the refining of natural gas and petroleum. Sulfolane was nominated for toxicity testing by various entities in Alaska and ATSDR due to exposure from contaminated well water in Alaska. There is no ADME/TK data for sulfolane. Research on sulfolane under this contract will provide data to understand the disposition of this chemical in rodents.
