1-溴丙烷神经毒性的研究进展

1-溴丙烷作为臭氧层破坏物氟氯烃类替代品之一而被广泛推广使用,然而1-溴丙烷中毒事件的报道,促使对其进行职业人群流行病学的研究,结果表明1-溴丙烷对人具有潜在的神经毒性,会引起人体外周神经传导速度降低、下肢振动觉下降、共济失调等症状体征。为尝试解释1-溴丙烷的神经毒性作用机制,同时也进行了动物实验研究。国内外学者对1-溴丙烷神经毒性方面的研究资料已进行过整理,在此基础上,就近几年1-溴丙烷神经毒性的研究进展作一简要综述。     

1-溴丙烷神经毒性作用机制及生物标志研究进展

1-溴丙烷因其特有的化学性质成为可对臭氧层造成破坏的一类清洗剂的理想替代产品,广泛应用于精密仪器清洗等生产领域。1-溴丙烷具有神经毒性、生殖毒性和肝毒性,其中以神经毒性最为显著。本文从1-溴丙烷主要代谢酶、蛋白质组学技术和神经元损伤等几方面,分析了1-溴丙烷对神经系统毒性作用的可能机制及典型的生物标志。     

1-溴丙烷职业接触限值研究进展

1-溴丙烷是消耗臭氧层的化学物—氟利昂类物质的替代物,随着近年在工业上的广泛应用,不断出现职业中毒的个案报道。本文就1-溴丙烷的毒性以及国外对其职业接触限值的研究进展作一简要综述,为今后国内制定1-溴丙烷的职业接触限值提供参考。     

2—溴丙烷的男性生殖毒性研究进展

对２－溴丙烷的生殖毒性研究,源于１９９５年韩国报道的一起２－溴丙烷职业卫生事故。２３名工人为事故受害者,其中８名男工中,２名罹患无精症,４名出现不同程度的精子减少［１－３］。这一事故报道立即引发了韩国、日本和中国职业卫生学家对２－溴丙烷男（雄）性生殖毒性的研究． ２－溴丙烷（ＣＡＳ ７５－２６３）,曾广泛用于药物、杀虫剂的中间体,长期以来在封闭系统下生产．近年来,２－溴丙烷作为氟氯化合物（如氟氯昂）的替代物,被大量运用于集成电路板的清洗剂和制冷剂,出现在开放的生产环境中,使工人接触高浓度２－溴丙烷…     

二溴氯丙烷中毒一例

二溴氯丙烷 ,化学名 1,2 二溴 3氯丙烷 ,由氯丙烯、溴素反应而成 ,对线虫有良好的防治效果。山东省从 2 0世纪 70年代中期到 80年代初开始生产和广泛使用二溴氯丙烷 ,同时也对其毒性进行了深入细致的研究[1 ] 。我们将近期收治的 1例二溴氯丙烷急性中毒病例加以总结分析 ,介绍如下。患者男 ,4 0岁 ,农民 ,因“进食二溴氯丙烷处理过的花生后感恶心、乏力、右上腹痛 3d”就诊 ,门诊以“二溴氯丙烷中毒”收入院。患者 3d前进食由农药二溴氯丙烷处理过的花生后不久即出现恶心、乏力、上腹部不适、右上腹痛 ,1d后背部出现片状红斑 ,曾到当地医院…     

溴丙烷职业危害研究进展

溴丙烷中毒已列入法定职业病和职业性化学中毒目录,该职业病防治关键技术随即成为亟待解决的关键问题。为了更好促进职业环境中溴丙烷接触人群的流行病学和健康监护的研究和应用,重点对溴丙烷的理化性质、代谢过程、毒性作用、生物标志物及接触限值的研究进展做了综述。     

1-溴丙烷对两种雄性大鼠生殖毒性的研究

目的研究1-溴丙烷对两种雄性大鼠的生殖毒性。方法将18只Fischer344大鼠和18只Wistar大鼠分别随机分为两组,一组给予新鲜空气,一组给予1000ppm1-溴丙烷,每天8h,连续暴露4周。在显微镜下对附睾的精子活动率和形态进行评价;睾丸等生殖器官进行了病理学评价。结果1-溴丙烷的暴露可引起大鼠的体重及生殖器官重量的下降;附睾的精子数减少、活动率下降、形态异常的精子增多;睾丸病理切片观察到曲精小管的精子释放延迟以及附睾的病理变化。结论1-溴丙烷暴露对两种雄性大鼠的生殖系统产生毒性影响,提示1-溴丙烷也可能对男性工人生殖系统产生不良影响。     

溴丙烷两种同分异构体对雄性大鼠生殖系统的影响

目的了解溴丙烷两种同分异构体对雄性大鼠的生殖毒性和初步的毒性机制。方法将18只SPF级SD大鼠随机分为对照组、1-溴丙烷组(1g/kg)和2-溴丙烷组(1g/kg),连续腹腔注射1周。对附睾的精子数量和形态进行评价;HE和PAS染色评价睾丸的病理变化;运用TUNEL染色法和caspase-3活性的免疫组化法评价睾丸的细胞凋亡损伤;利用化学比色法对谷胱甘肽(GSH)、丙二醛(MDA)和超氧化物歧化酶(SOD)等氧化应激指标进行测量。结果溴丙烷导致睾丸重量下降、精子数量减少和精子形态异常比例增加。与对照组比较,1-溴丙烷显著增加大鼠睾丸谷胱甘肽还原酶(GR)活性(7.42±2.98vs.4.25±1.18)、附睾的MDA含量(0.49±0.20vs.0.39±0.08)和SOD活性(91.87±3.93vs.80.59±9.92)(均P0.05);2-溴丙烷显著升高睾丸和附睾的MDA含量(0.42±0.07vs.0.24±0.11;0.48±0.08vs.0.39±0.08),降低GSH含量(6.35±1.86vs.10.89±3.69),以及附睾谷胱甘肽转移酶(GST)(53.21±9.60vs.61.98±10.41)及GR活性(2.48±1.21vs.7.75±8.56)(均P0.05)。1-溴丙烷的病理切片除观察到睾丸生精小管的精子释放延迟外,未见其他病理变化,而2-溴丙烷的暴露使生精小管出现萎缩和空泡,生殖细胞发生减少、坏死。伴随着2-溴丙烷引起的睾丸病理变化,TUNEL标记结果显示每小管睾丸凋亡细胞数、凋亡百分比和凋亡指数明显高于对照组(17.72±4.59vs.5.92±1.05,P0.05;0.34±0.14vs.0.10±0.02,P0.05;6.64±3.40vs.0.59±0.20,P0.01),与1-溴丙烷组相比,凋亡百分比(0.34±0.14vs.0.12±0.03)和凋亡指数(6.64±3.40vs.0.76±0.21)明显升高(P0.05)。2-溴丙烷暴露使caspase-3活性增强,与对照组和1-溴丙烷组相比,平均每生精小管的阳性细胞数和caspase-3阳性百分比有明显的升高(均P0.01)。结论溴丙烷的两种同分异构体对雄性大鼠有一定的毒性,两种同分异构体可能具有不同的毒性机制,2-溴丙烷的毒性可能高于1-溴丙烷。     

1-溴丙烷吸入暴露对雄性大鼠生殖系统的影响

目的研究1-溴丙烷亚急性暴露对雄性大鼠的生殖毒性.方法将48只雄性大鼠分为对照组、1-溴丙烷1 000、2000、4000 mg/m3暴露组.暴露组给予7 d,每天8 h的吸入暴露.结果1-溴丙烷高浓度暴露组大鼠的体重、前列腺和精囊质量显著下降,附睾精子运动率降低,形态异常精子增多.血浆肌酸激酶活力和肌型肌酸激酶含量降低.睾丸病理切片观察到曲细精管的精子释放延迟.结论1-溴丙烷亚急性暴露对雄性大鼠的生殖系统产生毒性影响,附睾精子运动率的下降是本次实验的最敏感指标.     

4例疑似1-溴丙烷中毒病例临床分析

收集4例疑似1-溴丙烷中毒患者资料,对1-溴丙烷接触情况、发病过程、临床表现和神经-肌电图变化以及治疗经过进行分析。本组资料中3例以感觉性共济失调表现起病,神经-肌电图均显示不同程度和范围的运动和/或感觉神经的轴突变性和/或脱髓鞘变性。提示1-溴丙烷中毒可能侵犯脊髓中枢神经及远端末梢神经,表现为以感觉性共济失调为主的多发性周围神经病或脊髓病变。     

Investigation of toxicity through human cases and animal experiments--study of bromopropanes

In 1995, workers in a Korean electronic factory exhibited oligospermia or amenorrhea. We investigated the toxicity of 2-bromopropane used as an alternative to chlorofluorocarbons in the factory in animal experiments, and clarified that exposure to 2-bromopropane depletes spermatogenic cells in male rats and oocytes in female rats. Subsequently, we investigated the neurotoxicity of 2-bromopropane on the basis of the reported neuropathy in the Korean workers exposed to 2-bromopropane. For comparison, we employed 1-bromopropane, which is now used as a new alternative to chlorofluorocarbons. The results showed that 1-bromopropane is more neurotoxic than 2-bromopropane, causing harm to reproductive organs by inhibiting spermiation in the testis and impairing follicular development in the ovary. Shortly after the initial investigation of 1-bromopropane in animals, human cases were reported in the United States. Neurologic abnormalities in Chinese workers exposed to 1-bromopropane were also reported, such as the elongation of distal latency and lowered sense of vibration in the lower limbs. Thus, these serial studies revealed that 1-bromopropane is neurotoxic, but its dose-response relationship in humans remains unknown. In the investigation of 2-bromopropane toxicity, initial animal studies were designed on the basis of human studies, while in research on 1-bromopropane, animal studies preceded human studies and contributed to the prediction of toxicity in humans. However, the use of animal model is limited in its ability to predict the toxicity of chemicals introduced depending on species differences. Further studies should focus more on the differences and commonality between animals and humans in response to toxic agents.     

1—溴丙烷工厂工人健康状况调查及接触生物标记物的研究

目的 分析1-溴丙烷毒性并评价其危险度，探讨适宜的接触生物标记物，方法 对37名工人进行问卷调查。血液学指标和血生化指标的测定。包括垂体激素和性激素测定。以该工厂工人为接触组，食品厂工人为对照组，比较两组间的血浆，脶酸激酶（CK）活性和血浆肌酸激酶M亚基（CK-M）。尿中1-溴丙烷用气相色谱仪检测，个体暴露蓄积水平用个体采样器估测。结果 接触组工人出现眼，鼻，口腔，喉的粘膜刺激症状。部分工人出现眩晕，可能是神经系统的反应。结论 接触1-溴丙烷引起的主诉症状提示它能刺激上呼吸道粘膜，在约100mg/m^3浓度水平可影响中枢神经系统，尿1-溴丙烷浓度有望成为接触的生物标记物。     

Neuro-reproductive toxicities of 1-bromopropane and 2-bromopropane

2-Bromopropane was used as an alternative to chlorofluorocarbons in a Korean electronics factory and caused reproductive and hematopoietic disorders in male and female workers. This causality was revealed by animal studies, and target cells were identified in subsequent studies. After identification of 2-bromopropane toxicity, 1-bromopropane was introduced to the workplace as a new alternative to ozone-depleting solvents. 1-Bromopropane was considered less mutagenic than 2-bromopropane, but, in contrast, animal experiments revealed that 1-bromopropane is a potent neurotoxic compound compared with 2-bromopropane. It was also revealed that 1-bromopropane has reproductive toxicity, but the target cells are different from those of 2-bromopropane. Exposure to 1-bromopropane inhibits spermiation in male rats and disrupts the development of follicles in female rats, in contrast to 2-bromopropane, which targets spermatogonia and oocytes in primordial follicles. After the first animal study describing the neurotoxicity of 1-bromopropane, human cases were reported. Those cases showed decreased sensation of vibration and perception, paresthesia in the lower extremities, decreased sensation in the ventral aspects of the thighs and gluteal regions, stumbling and headache, as well as mucosal irritation, as the initial symptoms. The dose–response of bromopropanes in humans and mechanism(s) underlying the differences in the toxic effects of the two bromopropanes remain to be determined.     

A survey on exposure level, health status, and biomarkers in workers exposed to 1-bromopropane

BACKGROUND: The aim of this study was to evaluate the health effects of exposure mainly to 1-bromopropane, which is an alternative to ozone-depleting solvents, and to establish biomarkers for assessing 1-bromopropane exposure. METHODS: Twenty-four female and 13 male workers of a 1-bromopropane-factory were interviewed, and their urine and blood samples were collected. Measured parameters included 1-bromopropane levels in the factory, as well as individual exposure levels, urinary 1-bromopropane levels, enzymatic activity and M subunit's concentration of serum creatine kinase (CK). RESULTS: Frequent symptoms reported by workers exposed to 1-bromopropane were nose, throat, and eyes irritation or malaise and/or headache. Urinary 1-bromopropane levels correlated significantly with individual exposure levels, but enzymatic activity or CK-M subunit did not. CONCLUSIONS: The symptoms suggested irritation of the mucous membrane and possible adverse effects on the central nervous system. There were no severe chronic symptoms suggestive of neurological damage in workers exposed to less than 170 ppm. Urinary 1-bromopropane level may be a good indicator of exposure. Am. J. Ind. Med. 45:63-75, 2004.     

1-溴丙烷对两种雄性大鼠肝脏毒性的研究

目的研究1-溴丙烷对两种雄性大鼠的肝脏毒性及谷胱甘肽S-转移酶(GST)在肝脏解毒代谢中的作用。方法将18只Fischer344大鼠和18只Wistar大鼠分别随机分为两组,一组给予新鲜空气,一组给予1000ppm1-溴丙烷,每天8h,连续暴露4周。通过血浆的生化指标和病理切片对肝脏的功能和形态进行了评价。利用化学比色法和实时定量PCR法对肝脏中的GST的活力和基因表达水平进行测量。结果1-溴丙烷暴露可引起两种大鼠体重的下降及肝脏重量的上升;病理发现肝脏中央静脉周围的肝细胞出现空泡样改变,血浆中CK、ALT和TBIL和DBIL等指标上升明显;两种大鼠肝脏细胞胞浆的GST活力增强,Fischer344大鼠微粒体GST的活力也增强;肝脏组织的GSTmRNA表达水平升高。结论1-溴丙烷暴露对两种雄性大鼠具有肝脏毒性,GST在1-溴丙烷的肝脏解毒代谢中可能起到较重要作用。     

1-溴丙烷暴露生物标志研究进展

1-溴丙烷作为氟氯烃类化合物的替代物,其使用和生产量都在逐年增加。近几年,学者开展了多项职业流行病学研究,探讨1-溴丙烷暴露的有效生物标志。拟通过文献综述,对1-溴丙烷可能的暴露标志进行比较分析。     

Diffusive Sampling and Biological Monitoring of 2-Bromopropane

The possibilities to apply personal ambient air monitoring by diffusive sampling and biological exposure monitoring by urinalysis for 2-bromopropane or its metabolites were explored. The abilities of carbon cloth to adsorb 2-bromopropane was examined by experimental vapor exposure followed by solvent extraction and FID-GC. Urine from factory workers and rats exposed to 2-bromopropane were analyzed for 2-bromopropane, acetone and isopropyl alcohol by FID-GC, and for bromide ion by ECD-GC after chemical methylation. Carbon cloth adsorbed 2-bromopropane in a manner linearly related to exposures up to 1500 mg/m³ and to 8 h. The adsorption could quantitatively detect a 15 min peak exposure at 3,000 mg/m³. In rat experiments, analyses of urine samples collected over a 4-h period after termination of a 4-h exposure to 2-bromopropane at 500, 1,000 or 1,500 mg/m³ showed that acetone and bromide ion were excreted dose-dependently. Essentially, no 2-bromopropane or isopropyl alcohol was detected. When the analytical methods were applied to urine samples from 5 male workers exposed to 2-bromopropane at a low level (3 mg/m³ as a geometric mean), acetone and bromide ion levels were within respective normal ranges in four cases, but were higher than the upper limits of the normal ranges in the fifth case of a foreman who probably had the highest exposure. Thus, diffusive sampling is applicable to monitor exposure to 2-bromopropane. Urinalysis for acetone and bromide ion in combination appears to be a promising selective tool for biological monitoring of occupational exposure to 2-bromopropane. Received: 26 February 1996/Revised: 29 May 1996     

Occupational health survey on workers exposed to 2-bromopropane at low concentrations

BACKGROUND: Recent case studies in Korea and animal studies revealed the reproductive and hematopoietic toxicity of 2-bromopropane introduced into workplaces as an alternative to ozone-layer depleting chlorofluorocarbons. We aimed to clarify the dose-effect relationship of 2-bromopropane in workers. METHOD: The exposure concentration of 2-bromopropane and hematological indices, hormonal levels, menstruation status, and sperm indices were examined in 25 workers (11 males, 14 females) at a 2-bromopropane factory. Regression analyses of the examined indices against time-weighted average (TWA) of exposure concentration were conducted. RESULTS: Amenorrhea or polymenorrhea was observed only in older females. Hematological indices had a significant relation with TWA of exposure concentration in females with normal menstruation. However, no other indices showed any significant relation with TWA of 2-bromopropane. CONCLUSIONS: No severe cases of reproductive or hematopoietic disorders were found at less than 10 ppm (TWA), but a possible adverse effect of 2-bromopropane on hematopoiesis could not be disproved.