ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION (ADME) IN MAMMALS

该合同的目的是为国家毒理学计划（NTP）的危害识别活动提供支持，这些活动旨在预防因环境和职业暴露于化学或物理制剂而引起的疾病或不良影响。根据合同设计的项目利用啮齿动物体内模型和啮齿动物和人类体外模型，调查环境和职业环境中常见的化学品的归宿和毒性机制。通过其吸收、分布、代谢和排泄（ADME）特性研究化学试剂的转归，通常使用放射性标记化学品以及NTP毒性和致癌性研究中使用的动物种属和品系进行研究。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，根据该合同进行了涉及2 '，2''-二硫代双苯甲酰苯胺（DTBBA）、2-羟基-4-甲氧基二苯甲酮（HMB）和-N-甲氨基-L-丙氨酸（BMAA）以及2，2'-二吗啉代二乙基醚（DMDEE）的体外和体内转归（体外和/或体内）的研究。关于富勒烯和二甲基乙醇胺的最后研究报告正在由COTR审查，以便纳入NTP数据库。 DTBBA是一种天然和合成橡胶的增塑剂，是一种高产量化学品，有可能造成职业和消费者接触。关于这种化学品的ADME特性的信息很少。因此，目前的工作重点是这种化学品在啮齿动物中的代谢和处置。HMB在化妆品和防晒产品中用作紫外线过滤剂。可能通过皮肤和口服途径暴露于HMB。文献中可用的ADME数据显示HMB的代谢和处置具有种属和性别依赖性。NTP正在哈兰Sprague道利大鼠和B6 C3 F1小鼠中研究该化学品的毒性和致癌性。因此，根据合同开展的工作重点是研究经皮和经口给药后HMB在这些菌株中的代谢和处置。BMAA是由蓝绿藻的一些成员产生的化学物质。人类可能通过食用蓝绿藻膳食补充剂和其他食品供应而接触到这种物质。大鼠接触BMAA表现出神经毒性。提出的人类慢性神经病的机制是基于BMAA在神经蛋白中积累的假设。文献中没有该化学品的ADME数据。因此，正在研究大鼠和小鼠经口暴露后的ADME。在生产软质泡沫塑料的工作场所，预计会接触到二甲基二甲醚。NTP正在研究这种化学物质的毒性。文献中没有DMDEE的ADME数据。因此，在啮齿类动物中研究了其ADME，特别关注致癌代谢物N-亚硝基吗啉的形成。

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 involving in vitro and in vivo fate (in vitro and/or in vivo) of 2',2'''-dithiobisbenzanilide (DTBBA), 2-hydroxy-4-methoxybenzophenone (HMB), and β-N-methylamino-L-alanine (BMAA), and 2,2'-dimorpholinodiethyl ether (DMDEE) have been conducted under this contract. Final study reports on fullerene and dimethylethanolamine are being reviewed by the COTR for inclusion into the NTP database. DTBBA is a plasticizer for natural and synthetic rubber and is high production chemical with potential for occupational and consumer exposure. Very little information is available on the ADME properties of this chemical. Therefore, the current work is focused on the metabolism and disposition of this chemical in rodents. HMB is used as a UV filter in cosmetic and sunscreen products. The exposure to HMB is possible via both dermal and oral routes. The available ADME data in the literature shows species and sex dependent metabolism and disposition of HMB. NTP is investigating toxicity and carcinogenicity of this chemical in Harlan Sprague Dawley rats and B6C3F1 mice. Therefore, the focus of the work conducted under the contract is to investigate the metabolism and disposition of HMB in these strains following dermal and oral administration. BMAA is a chemical produced by some members of blue-green algae. Potential human exposure to this is possible via consumption of blue-green algae dietary supplements and other food supplies. Exposure of BMAA in rats exhibited neurotoxicity. A proposed mechanism of chronic neuropathy in humans is based on the hypothesis that BMAA accumulate in neuroproteins. There is no ADME data in the literature for this chemical. Therefore, ADME is being investigated following oral exposure in rats and mice. Exposure to DMDEE is expected in the work place during the production of flexible foam. NTP is investigating the toxicity of this chemical. There is no ADME data in the literature for DMDEE. Therefore, the ADME of this is investigated in the current contract in rodents with special attention to the formation of carcinogenic metabolite N-nitrosomorpholine.