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.

许多化学物质会对人类和某些动物产生神经毒性。 毒理学研究和流行病学证据表明 同时接触有机磷杀虫剂细磷磷和 工业溶剂正己烷和甲苯导致神经病爆发 处理这些化学品的工人中。 Leptophos 属于一组 能够引起迟发性神经毒性（OPIDN）的化学物质。 成年母鸡 是研究 OPIDN 的首选动物，因为啮齿动物不那么敏感。 正己烷及其一些相关化学物质会对人体产生神经毒性 和动物身上。 甲苯可能导致神经功能缺损 在人类中。 因为人类经常同时接触来自以下物质的化学物质： 这些群体，我们一直在研究这些产生的神经毒性 单独和组合化学品。 在这些的第一阶段 我们将母鸡作为实验动物进行了研究，以调查 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） 苯基硫代膦）和正己烷、2-己酮（MnBK）、2,5-己二醇 (2,5-HDOH) 和 2,5-己二酮 (2,5-HD)。 结果表明 同时暴露于 EPN 和 MnBK 会增强神经毒性 每种化学品单独。 此外，非神经毒性的甲基异丁基酮 (MiBK) 协同弱神经毒剂正己烷的神经毒性。 这种联合神经毒性作用的机制似乎是相关的，至少 部分地诱导肝微粒体细胞色素 P-450。 我们建议 研究脂肪族六碳诱导的分子机制 这些药物的神经毒性和肝微粒体酶诱导 神经毒物。 这将包括交联的分离 来自暴露于正己烷/MiBK蒸气的母鸡的神经丝蛋白和 使用这些蛋白质作为脂肪族六碳神经毒性的标记物和 神经毒性酯酶，用于 EPN 诱导的神经毒性。 细胞色素 P-450 母鸡接触正己烷相关化学品可诱导形成的形式，以及 EPN 单独或一起在母鸡肝微粒体中测定。 在 [14C]标记的正己烷、2,5-HDOH、2,5-HD 和 EPN 的体外代谢 将测定鸡肝微粒体。 吸收和 [14C]EPN 重复给药后单次皮肤剂量的药代动力学 将研究正己烷及其代谢物的剂量。 神经毒性 甲苯蒸气的含量将在鸡吸入后测定。 这 甲苯、正己烷和/或 EPN 的联合神经毒性作用 调查了。