OCCUPATIONAL NEUROPATHIES DUE TO INDUSTRIAL CHEMICALS

工业化学品引起的职业性神经病

• 批准号: 3420063
• 负责人: MOHAMED B ABOU DONIA
• 金额: $ 15.77万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 1989-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3420063
• 关键词: cytochrome P450; cytoskeleton; electron microscopy; engine exhaust; environmental contamination; environmental toxicology; gel electrophoresis; industry; inhalation drug administration; ketones; liver cells; liver metabolism; microsomes; nervous system disorder; neurochemistry; neurotoxins; occupational disease /disorder; organophosphorus insecticide; physical chemical interaction; radioimmunoassay; radiotracer; solvents; thiones; toluene

Many chemicals produce neurotoxicity in humans and some animal species. Toxicological studies and epidemiological evidence implicated that simultaneous exposure to the organophosphorus insecticide leptophos and the industrial solvents, n-hexane and toluene, caused an outbreak of neuropathy among workers handling these chemicals. Leptophos belongs to a group of chemicals capable of causing delayed neurotoxicity (OPIDN). The adult hen is the animal of choice to study OPIDN since rodents are not as sensitive. n-Hexane and some of its related chemicals produce neurotoxicity in humans and in animals. Toluene has been implicated in causing neurologic deficits in humans. Because humans are often exposed concurrently to chemicals from these groups, we have been studying the neurotoxicity produced by these chemicals alone and in combination. During the first phase of these studies we have tested the hen as a laboratory animal to investigate the neurotoxicity produced by simultaneous administration of the organophosphorus insecticide EPN (O-ethyl 0-4-nitrophenyl phenylphosphonothioate) and n-hexane, 2-hexanone (MnBK), 2,5-hexanediol (2,5-HDOH), and 2,5-hexanedione (2,5-HD). The results showed that simultaneous exposure to EPN and MnBK potentiated neurotoxicity produced by each chemical alone. Also, the non-neurotoxic methyl iso-butyl ketone (MiBK) synergized the neurotoxicity of the weak neurotoxicant n-hexane. The mechanism of this joint neurotoxic action seems to be related, at least in part, to the induction of liver microsomal cytochrome P-450. We propose to investigate the molecular mechanism(s) for aliphatic hexacarbon-induced neurotoxicity and liver microsomal enzyme induction by these neurotoxicants. This will include the isolation of the cross-linked neurofilament proteins from hens exposed to vapors of n-hexane/MiBK and the use of these proteins as markers for aliphatic hexacarbon neurotoxicity and neurotoxic esterase for EPN-induced neurotoxicity. The cytochrome P-450 form(s) that is inducible by hen exposure to n-hexane related chemicals and EPN alone and together will be determined in hen liver microsomes. The in vitro metabolism of [14C]labeled n-hexane, 2,5-HDOH, 2,5-HD, and EPN by chicken hepatic microsomes will be determined. Absorption and pharmacokinetics of a single dermal dose of [14C]EPN following repeated doses of n-hexane and its metabolites will be studied. The neurotoxicity of toluene vapor will be determined following inhalation by chickens. The joint neurotoxic action of toluene, n-hexane, and/or EPN will be investigated.

许多化学物质在人类和某些动物物种中产生神经毒性。 毒理学研究和流行病学证据暗示 同时暴露于有机磷杀虫剂瘦磷和 N-己烷和甲苯的工业溶剂导致神经病爆发 在处理这些化学物质的工人中。 Leptophos属于一组 能够引起延迟神经毒性的化学物质（OPIDN）。 成人母鸡 由于啮齿动物不那么敏感，因此是研究OPIDN的动物。 N-己烷及其一些相关化学物质在人类中产生神经毒性 和动物。 甲苯与引起神经系统缺陷有关 在人类中。 因为人类通常会同时暴露于 这些组，我们一直在研究这些群体产生的神经毒性 单独和组合化学物质。 在第一阶段 研究我们已经测试了母鸡作为实验室动物的研究 同时给药产生的神经毒性 有机磷杀虫剂EPN（O-乙基0-4-硝基苯基 苯基磷刺）和N-己烷，2-己酮（MNBK），2,5-己二醇 （2,5-HDOH）和2,5-HEXANEDIONE（2,5-HD）。 结果表明 同时暴露于EPN和MNBK增强的神经毒性。 每种化学物质。 另外，非神经毒性甲基异丁基酮 （MIBK）协同弱神经毒性N-己烷的神经毒性。 这种联合神经毒性作用的机制似乎至少是相关的 部分是诱导肝微粒体细胞色素P-450。 我们建议 研究脂肪族己酮诱导的分子机制 这些神经毒性和肝微粒体酶诱导这些酶 神经毒性。 这将包括隔离交联 来自暴露于N-己烷/Mibk蒸气的母鸡的神经丝蛋白 这些蛋白质用作脂肪族六碳神经毒性的标记和 神经毒性酯酶用于EPN诱导的神经毒性。 细胞色素P-450 通过母鸡暴露于N-己烷相关的化学物质和 单独使用EPN并将共同确定在Hen肝微粒体中。 in [14C]标记N-己烷，2,5-HDOH，2,5-HD和EPN的体外代谢 将确定鸡肝微粒体。 吸收和 重复后，单皮剂量的[14C] EPN的药代动力学 将研究N-己烷及其代谢物的剂量。 神经毒性 鸡吸入后，将确定甲苯蒸气的含量。 这 甲苯，N-己烷和/或EPN的联合神经毒性作用将是 调查。