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

哺乳动物对化学物质的吸收、分布、代谢、排泄 (ADME)

• 批准号: 8428911
• 金额: $ 91.08万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8428911
• 关键词: ADME Study; Adverse effects; Agrochemicals; Animals; Antioxidants; Binding; Birds; Breathing; Carcinogens; Chemical Agents; Chemicals; Conflict (Psychology); Contracts; Cosmetics; Data; Databases; Dermal; Dose; Dyes; Environmental Exposure; Environmental and Occupational Exposure; Epichlorohydrin; Excretory function; Exposure to; Fiber; Fishes; Food; Goals; Hazard Identification; Health; Human; Hydrochloric Acid; Industry; Ingestion; Ink; Intravenous; Isopropanol; Knowledge; Laboratories; Liquid substance; Literature; Mammals; Marines; Metabolism; Methane; Mus; National Toxicology Program; Nylons; Occupational; Occupational Exposure; Oral; Organ; Pharmacologic Substance; Pigments; Plasticizers; Polymers; Printing; Production; Property; Radiolabeled; Rattus; Reducing Agents; Reporting; Research Design; Risk; Rodent; Rodent Model; Route; Structure-Activity Relationship; Sunscreening Agents; Tattooing; Thyroid Hormones; Tissues; Toxic effect; Toxicology; Vegetable Proteins; Weight; Work; absorption; bisphenol A; carcinogenicity; chemical property; chemical synthesis; consumer product; crosslink; design; disorder prevention; exposed human population; in vitro Model; in vivo; macromolecule; polycarbonate; polysulphone; prospective; radiotracer; reproductive; xenoestrogen

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.

关键词；吸收；分配;代谢;排泄;阿德梅；代谢物鉴定；毒代动力学；毒性机制； 2,3-丁二酮；二乙酰； N,N-二甲基乙酰乙酰胺；闭塞性细支气管炎; CYP；丁子香酚；黄樟素；草蒿脑；茴香脑；肉豆蔻甙；异黄樟素；异丁子香酚；甲基丁子香酚；1,3-二氯-2-丙醇； 2-甲氧基-4-硝基苯胺；二甲胺硼烷；对羟基苯甲酸；对羟基苯甲酸正丁酯；放射性标记化合物；体内；体外;真皮；灌胃；四、吸入；质量平衡； 抽象的;该合同的目标是为国家毒理学计划 (NTP) 危害识别活动提供支持，旨在预防因环境和职业接触化学或物理制剂而引起的疾病或不利影响。根据合同设计的项目使用啮齿动物体内模型以及啮齿动物和人类体外模型来研究环境和职业环境中常见化学品的归宿和毒性机制。化学剂的归宿是通过其吸收、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品以及 NTP 毒性和致癌性研究中使用的动物物种和品系进行。机制研究旨在回答有关代谢或毒性机制的具体问题。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。今年，在继续进行 2、上一时期报告了 3-丁二酮（二乙酰）(2,3-BD)、N,N-二甲基乙酰乙酰胺以及丙烯基苯和烯丙基苯。 2,3-BD 是微波爆米花生产厂空气样本中的主要成分，因此被认为在爆米花行业工人观察到的闭塞性细支气管炎中发挥着重要作用。目前的工作重点是估计这种化学物质的全身暴露以及气管内滴注后与啮齿动物血液蛋白的结合。 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。 DCP 的环境暴露可能来自于摄入添加了盐酸催化植物蛋白的食物。环氧氯丙烷 (ECH) 是 2A 类致癌物，被提议作为 DCP 的代谢物。目前的工作是确认在口服 DCP 的啮齿动物中 ECH 是否是作为 DCP 的代谢物形成的。 DMAB 在许多行业中广泛用作还原剂，因此可以通过皮肤和口服途径接触它。有关该化学品 ADME 特性的信息非常少。目前进行的研究调查了这种化学物质通过皮肤、口服和静脉途径的处置和代谢。 MNA用于颜料黄74的合成；因此，它存在于许多消费品、黄色纹身油墨和印刷油墨中。人类可以通过皮肤和口腔途径接触这种化学物质。目前的研究旨在通过上述途径研究该化学品的 ADME 特性，以及研究 MNA 的反应性代谢物与预期靶器官中大分子的结合。对羟基苯甲酸（对羟基苯甲酸丁酯，BPB）广泛用作食品、药品和化妆品中的抗氧化剂和防腐剂。人类可通过吸入、摄入或皮肤接触发生接触。有关该化学品 ADME 的可用数据非常少。因此，当前的研究旨在表征 ADME 的暴露途径、剂量对 ADME 特性的影响，并鉴定 BPB 的代谢物。对丙烯基苯和烯丙基苯（丁子香酚、黄樟脑、草蒿脑、茴香脑、肉豆蔻素、异黄樟素、异丁子香酚和甲基丁子香酚）以及N.N-二甲基乙酰乙酰胺的研究已在本报告期内完成，最终报告正在编写中。