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

关键词；吸收；分布；代谢；排泄；ADME；代谢物鉴定；毒代动力学；毒性机制；2，3-丁二酮；双乙酰；N，N-二甲基乙酰乙酰胺；闭塞性毛细支气管炎；细胞色素；丁香酚；黄樟素；雌酚；茴香脑；肉豆蔻素；异黄樟素；异丁香酚；甲基亮酚；1，3-二氯-2-丙醇；2-甲氧基-4-硝基苯胺；二甲基氨基硼烷；对羟基苯甲酸；对羟基苯甲酸；正丁基对羟基苯甲酸；放射性标记化合物；体内；体外；皮下注射；IV；吸入；质量平衡； 摘要：本合同的目标是为国家毒理学计划(NTP)的危险识别活动提供支持，旨在预防因环境和职业暴露于化学或物理制剂而导致的疾病或不良影响。根据合同设计的项目使用体内啮齿动物模型和体外啮齿动物和人类模型来调查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，通常使用放射性标记的化学物质以及用于NTP毒性和致癌性研究的动物物种和品系来进行。机械学研究旨在回答有关新陈代谢或毒性的具体问题。在这项工作过程中开发的数据用于NTP毒性和致癌性研究的设计和解释。在本年度，1，3-二氯-2-丙醇(DCP)、二甲胺硼烷(DMAB)、2-甲氧基-4-硝基苯胺(MNA)和对羟基苯甲酸丁酯(BPB)的研究继续进行，而2，3-丁二酮(二乙酰)(2，3-BD)、N，N-二甲基乙酰乙酰胺、丙烯和烯丙基苯的研究则继续进行。2，3-BD是从微波爆米花生产厂的空气样本中发现的主要成分，因此被认为在爆米花行业工人中观察到的闭塞性毛细支气管炎起主要作用。目前的工作重点是评估这种化学物质在气管内滴注后在啮齿动物体内的全身暴露和与血液蛋白的结合。DCP是一种半挥发性液体，在化学合成中作为中间体大量使用。在环境中暴露于DCP可能来自于摄入添加了盐酸催化的植物蛋白的食物。环氧氯丙烷(ECH)是一种2A类致癌物质，被认为是DCP的代谢物。目前的工作是为了证实在口服DCP的啮齿动物中是否形成ECH作为DCP的代谢物。DMAB在许多行业中被广泛用作还原剂，因此通过皮肤和口腔途径接触DMAB是可能的。关于这种化学物质的ADME性质的信息很少。目前开展的研究通过皮肤、口腔和静脉途径研究这种化学物质的处置和代谢。MNA用于合成颜料黄74；因此，它存在于许多消费品、黄色纹身油墨和印刷油墨中。人类可能通过皮肤和口腔途径接触到这种化学物质。目前的研究旨在通过上述途径研究该化合物的ADME性质，并研究MNA的反应性代谢产物(S)与预期靶器官中的大分子的结合。对羟基苯甲酸(丁基对羟基苯甲酸，BPB)在食品、药品和化妆品中广泛用作抗氧化剂和防腐剂。人体接触可通过吸入、摄入或皮肤接触发生。关于这种化学物质的ADME数据很少。因此，目前的研究旨在表征ADME的暴露途径，剂量对ADME特性的影响，并鉴定BPB的代谢物。在本报告所述期间，完成了对丙烯基苯和烯丙基苯(丁香酚、黄樟素、雌酚、茴香脑、肉豆蔻素、异黄樟素、异丁香酚和甲基亮丁香酚)和N，N-二甲基乙酰乙酰胺的研究，目前正在编写最后报告。

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.