Absorption, distribution, metabolism, excretion (ADME) of chemicals in mammals

该合同的目标是为国家毒理学计划（NTP）的危害识别活动提供支持，目标是预防因环境和职业暴露于化学或物理剂而引起的疾病或不利影响。根据合同设计的项目利用体内啮齿动物模型和体外啮齿动物和人体模型，调查在环境和职业环境中常见的化学品的命运和毒性机制。化学制剂的命运是通过其吸收、分布、代谢和排泄（ADME）特性来研究的，通常是在NTP毒性和致癌性研究中使用的动物物种和品系中使用放射性标记的化学物质进行的。机制研究旨在回答有关代谢或毒性机制的具体问题。在这项工作过程中开发的数据用于设计和解释NTP毒性和致癌性研究。本年度，在对对苯二酚（HQ）、正丁基苯磺酰胺（NBBS）、2-乙基己基对甲氧基肉桂酸（EHMC）、三（4-氯苯基）甲烷（TCPME）、三（4-氯苯基甲醇）（TCPMOH）和双酚AF （BPAF）进行研究的同时，开展了对亚砜的研究。EHMC是防晒霜中常见的一种活性成分，因此人类接触到EHMC的情况很普遍，而且可能会在个人生命的很大一部分时间里接触到EHMC。FDA规定这种化学物质在防晒霜中的最高含量为7.5%。啮齿动物EHMC无相关ADME数据。目前的研究正在评估这种化学物质在大鼠和小鼠中的ADME。此外，研究还将重点评估EHMC是否代谢为发育毒性物质2-乙基己醇。NBBS被广泛用作增塑剂。它还具有抗真菌的特性。人类接触NBBS的可能性很大，因为它很可能出现在饮用水中，并从含有NBBS的产品（如炊具）中浸出。目前，缺乏对这种化学物质在啮齿动物和人类中的ADME研究。因此，在大鼠和小鼠中进行了研究，通过口服和静脉注射途径来调查这种化学物质的处置和代谢。TCPME和TCPMOH都用于生产合成高聚物，丙烯酸纤维的耐光染料和农用化学品，这表明职业接触的可能性。TCPME是二氯二苯三氯乙烷生产过程中的副产品。TCPMOH被认为是TCPME的代谢产物。TCPME和TCPMOH均存在于多种动物的组织中，如鱼类、鸟类和海洋哺乳动物，表明其广泛暴露。然而，没有关于这些化学品的ADME和毒性动力学（TK）特性的信息。因此，在大鼠和小鼠灌胃和静脉给药后，研究了TCPME和TCPMOH的ADME和TK研究。特别注意的是TCPME的代谢可能形成TCPMOH。HQ存在于一些食品和饮料中，被用作还原剂、抗氧化剂、聚合抑制剂、各种产品的稳定剂，作为治疗异常皮肤色素沉着的药物，也存在于许多用于提亮皮肤的非处方（OTC）产品中。高剂量的HQ对神经有毒性。在体外实验中，HQ已被证明可以形成DNA加合物并引起染色体畸变、有丝分裂异常、微核形成和姐妹染色单体交换。已知HQ在F344大鼠中口服后吸收良好，皮敷后吸收不良，但在小鼠中的数据有限。此外，还需要适当啮齿类动物模型的ADME和TK数据，以便为未来的NTP口服生殖毒性研究和皮肤慢性毒性研究提供解释性数据。因此，该合同下的工作是在口服和皮肤给药后评估NTP啮齿动物模型中HQ的ADME和TK特性。BPAF用作某些含氟弹性体的交联剂，也用作聚酰亚胺、聚酰胺、聚酯、聚碳酸酯共聚物和其他特种聚合物的单体。它在结构上与研究充分的双酚A （BPA）相似，但缺乏足够的双酚A毒性数据。文献中没有关于BPAF的代谢和处置的研究。因此，本研究在大鼠和小鼠灌胃暴露后对BPAF进行ADME研究。环己烷是一种溶剂，主要用于天然气和石油的精炼。由于阿拉斯加受污染的井水暴露，阿拉斯加和ATSDR的各个实体提名对硫代烷进行毒性测试。没有亚砜的ADME/TK数据。根据该合同，对亚砜的研究将为了解这种化学品在啮齿动物体内的处置提供数据。

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 individual’s 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.