Neurotoxicity of 2-bromopropane and 1-bromopropane, alternative solvents for chlorofluorocarbons

To clarify the neurotoxicity of 2-bromopropane (2-BP) in comparison with 1-bromopropane (1-BP), 36 Wistar strain male rats were divided into 4 groups of 9 and exposed daily to 100-ppm 2-BP, 1000-ppm 2-BP, 1000-ppm 1-BP, or fresh air for 8 h a day. Exposure to 1000 ppm of 1-BP was discontinued after 5 or 7 weeks' exposure because of the unexpected appearance of incomplete hindlimb paralysis followed by serious emaciation. The other groups were sacrificed at the end of 12 weeks' exposure. Exposure to 1000 ppm of 2-BP resulted in significant decreases in body weight and motor nerve conduction velocity (MCV) and elongation in distal latency (DL). A ball-like enlargement of myelin sheaths was observed. Significant reductions in the number of erythrocytes, platelets, and leukocytes, testicular germ cell loss, and seminiferous atrophy were also observed in this group, but not in 100-ppm 2-BP group. Exposure to 1000 ppm of 1-BP for 5 or 7 weeks caused a significant decrease in body weight and MCV and elongation in DL. Linearly arranged ovoid- or bubble-like debris of the axons and myelin sheaths in the teased tibial nerves and axonal swelling in gracilis nucleus were found in this group. No significant changes in hematological indices or histopathological findings of the testis were found in this group. In conclusion, 2-BP is neurotoxic to the peripheral nerves in addition to its toxic effects on the reproductive and hematopoietic systems at 1000 ppm. No noticeable changes were found in the rats exposed to 100 ppm of 2-BP. 1-BP is a potent neurotoxicant at 1000 ppm for 5 or 7 weeks, while testicular and hematopoietic toxicity was not found.     

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.     

1-溴丙烷暴露对大鼠认知功能的影响

目的 观察1-溴丙烷(1-bromopropane,1-BP)对大鼠学习记忆功能及对胆碱能神经系统的影响.方法 雄性Wistar大鼠40只,随机分为4组:1-BP低剂量组(200mg/kg1-BP)、中剂量组(400mg/kg1-BP)、高剂量组(800mg/kg 1-BP)和对照组,每组10只.各组动物分别经灌胃给予相应受试物7 d后,采用Morris水迷宫定位航行试验和空间探索试验检测大鼠学习和记忆功能.水迷宫试验结束后次日断头处死大鼠,迅速剥离大鼠大脑和海马,冰浴中制备匀浆,取上清液,测定乙酰胆碱酯酶(AChE)、乙酰胆碱转移酶(ChAT)的活力.结果 定位航行试验中,1-BP染毒后,与对照组相比,中、高剂基组的逃避潜伏期、游泳路程明显延长,搜索效能降低,差异均有统计学意义(P＜0.05,P＜0.01).空间探索试验中,低、中、高剂量组穿越平台次数(分别为4.30±2.6、3.78±2.0、2.50±2.1)呈降低趋势,与对照组(7.20±2.8)比较,差异均有统计学意义(P＜0.05,P＜0.01),高剂量组的平台周边时间/总时间比值(0.55±0.14)明显低于对照组(0.76±0.15)和低剂量组(0.69±0.18),差异有统计学意义(P＜0.01).中、高剂量组大鼠大脑皮层AChE活力[分别为(1.246±0.423)、(1.397±0.503)U/mgpro]明显升高,与对照组[(0.918±0.276)U/mg pro]的差异有统计学意义(P＜0.05,P＜0.01),高剂量组海马组织中AChE活力[(0.583±0.118)U/mgpro]也明显高于对照组[(0.491±0.075)U/mgpro],差异有统计学意义(P＜0.05).1-BP染毒后,大脑皮层ChAT活力有降低趋势,但与对照组相比,差异无统计学意义(P＞0.05).结论 1-BP暴露能明显损伤大鼠学习记忆能力,可能与AChE活力升高相关.     

1-溴丙烷吸入对大鼠坐骨神经影响

目的 研究1-溴丙烷(1-BP)对大鼠坐骨神经功能和组织形态学的影响.方法 无特定病原体级雄性Wistar大鼠48只按体质量随机分为低、中、高剂量组和对照组4组,每组12只.大鼠均置于动式吸入染毒柜内,低、中、高剂量组分别给予质量浓度为1 250、2 500和5 000 mg/m3 1-BP暴露染毒,对照组给予新鲜空气,每天染毒8h,每周染毒5d,连续4周.染毒结束,采用肌电图仪对所有大鼠进行双侧坐骨神经电生理检测.每组各取3只大鼠灌流固定,取坐骨神经,行苏木精-伊红染色和砂罗铬花青法染色,观察其组织形态学的改变.结果 1-BP各染毒组大鼠双侧坐骨神经运动神经传导速度均低于对照组(P＜0.01),运动末端潜伏期均较对照组延长(P ＜0.05或P＜0.01);1-BP高剂量组大鼠双侧坐骨神经感觉神经传导速度低于对照组(P＜0.05或P＜0.01),潜伏期较对照组延长(P＜0.05或P＜0.01).病理学观察显示1-BP高剂量组大鼠坐骨神经髓鞘疏松变性、排列杂乱,部分呈现空泡样变,轴索偏移.结论 运动神经传导速度是反映1-BP周围神经损伤的检测指标之一.     

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.     

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。     

Influence of 2-bromopropane on reproductive system--short-term administration of 2-bromopropane inhibits ovulation in F344 rats.

The present study was performed to investigate the toxic effects of 2-bromopropane (2BP) on the female reproductive system. Female F344 rats were administered 2BP (500 or 1000 mg/kg, i.p.) at intervals of 2 or 3 days for 15-17 days. The body weights were measured and estrous stages were observed throughout the experimental period. Ovulation, organ weights, ovarian histology, and blood biochemistry were investigated on the terminal day of the experiment. Uterine weights in rats treated with 2BP were significantly lower than those in control animals. Body, liver, kidney, and adrenal weights in 2BP-treated rats showed no significant differences from control values. 2BP treatment prolonged estrous cycles and decreased the number of ovulated ova in spontaneous ovulation. In addition, histological examinations showed that the preovulatory follicles in the ovary were altered markedly in 2BP groups. These results show that even in short-term treatment, 2BP injured the ovary, particularly the preovulatory follicles. It appears that these damages of the preovulatory follicles induced by 2BP reduced the numbers of spontaneously ovulated ova in female F344 rats.     

二十二碳六烯酸对1-溴丙烷致大鼠学习能力损伤的拮抗作用

目的 观察二十二碳六烯酸(DHA)对1-溴丙烷(1-BP)致大鼠学习能力损伤的拮抗作用.方法 将48只健康成年SPF级雄性Wistar大鼠随机分为4组,即对照(玉米油)组、1-BP染毒组和低、高剂量DHA干预组,每组12只.1-BP染毒组和低、高剂量DHA干预组每天灌胃染毒800 mg/kg的1-BP;4 h后,低、高剂量DHA干预组分别灌胃染毒250、500mg/kg的DHA,每日1次,连续11d.染毒第8～11天采用Morris水迷宫试验中的定位导航试验检测大鼠的学习能力.染毒结束后,检测大脑皮层匀浆中还原型谷胱甘肽(GSH)、丙二醛(MDA)含量及谷胱甘肽还原酶(GR)活力.采用Westernblotting方法检测大脑皮层脑红蛋白(neuroglobin,Ngb)的表达.结果 与对照组比较,1-BP染毒组大鼠游泳总路程和逃避潜伏期延长(P＜0.05);与1-BP染毒组相比,各剂量DHA干预组大鼠的游泳路程和逃避潜伏期缩短(P＜0.05).与对照组比较,1-BP染毒组大鼠大脑皮层匀浆中GSH含量及GR活力均下降,而1-BP染毒组MDA含量及高剂量DHA干预组GSH含量均升高(P＜0.05);与1-BP染毒组比较,各剂量DHA干预组大鼠大脑皮层匀浆中GSH含量及GR活力均升高,MDA含量均下降(P＜0.05).与对照组比较,1-BP染毒组和低剂量DHA干预组大鼠大脑皮层匀浆中Ngb蛋白的表达水平均下降,而高剂量DHA干预组Ngb蛋白的表达水平升高(P＜0.05);与1-BP染毒组比较,各剂量DHA干预组大鼠大脑皮层匀浆中Ngb蛋白的表达水平均升高(P＜0.05).结论 DHA能够减轻1-BP导致的大鼠中枢神经系统氧化应激反应及由此引起的学习能力损伤,激活GR活力、增强Ngb表达可能是DHA的保护机制之一.     

1-溴丙烷引发雄性大鼠性腺基因表达谱的变化

目的研究1-溴丙烷(1-BP)诱发大鼠性腺基因表达谱的变化,探索1-BP雄性生殖毒性相关的mRNA改变。方法雄性F344/NSIc大鼠12只,随机分为2组,分别吸入新鲜空气或5030mg/m31-BP8h。染毒后16h处死大鼠取出睾丸,运用大鼠性腺cDNA微阵列和real-timePCR方法测定1-BP染毒后性腺相关基因表达谱的变化。结果在大鼠性腺芯片5087个cDNA微点阵中,有62个基因被1-BP显著下调,3个基因显著上调。其中包括性激素合成相关基因细胞色素P450芳香化酶(CYP19a),谷胱苷肽S-转移酶(GSTT1),肌酸激酶(Ckb),髓鞘和淋巴细胞蛋白(Mal)和S100的钙结合蛋白(S100a4)。归类分析结果显示绝大多数变化的基因与蛋白质/脂类代谢相关,其次与应激防御反应相关。实时定量PCR证实了1-BP可引起CYP19a、S100a4、GSTT1和Mal的下调。结论急性高剂量染毒1-BP可引起睾丸组织CYP19a、S100a4、GSTT1、Mal等基因的下调,提示其可能通过内分泌干扰和氧化应激效应而导致雄性生殖毒性。     

1-溴丙烷毒性研究进展

1-溴丙烷(1-bromopropane,1-BP),也称溴代正丙烷(n-propyl bromide,nPB).由于1-BP具有低毒高效、不破坏臭氧层等特点,20世纪90年代后期以来成为消耗臭氧层物质(o-zone depleting substances,ODS)清洗剂的理想替代品.     

Neurologic abnormalities in workers of a 1-bromopropane factory

We reported recently that 1-bromopropane (1-BP; n-propylbromide, CAS Registry no. 106-94-5), an alternative to ozone-depleting solvents, is neurotoxic and exhibits reproductive toxicity in rats. The four most recent case reports suggested possible neurotoxicity of 1-BP in workers. The aim of the present study was to establish the neurologic effects of 1-BP in workers and examine the relationship with exposure levels. We surveyed 27 female workers in a 1-BP production factory and compared 23 of them with 23 age-matched workers in a beer factory as controls. The workers were interviewed and examined by neurologic, electrophysiologic, hematologic, biochemical, neurobehavioral, and postural sway tests. 1-BP exposure levels were estimated with passive samplers. Tests with a tuning fork showed diminished vibration sensation of the foot in 15 workers exposed to 1-BP but in none of the controls. 1-BP factory workers showed significantly longer distal latency in the tibial nerve than did the controls but no significant changes in motor nerve conduction velocity. Workers also displayed lower values in sensory nerve conduction velocity in the sural nerve, backward recalled digits, Benton visual memory test scores, pursuit aiming test scores, and five items of the Profile of Mood States (POMS) test (tension, depression, anxiety, fatigue, and confusion) compared with controls matched for age and education. Workers hired after May 1999, who were exposed to 1-BP only (workers hired before 1999 could have also been exposed to 2-BP), showed similar changes in vibration sense, distal latency, Benton test scores, and depression and fatigue in the POMS test. Time-weighted average exposure levels in the workers were 0.34-49.19 ppm. Exposure to 1-BP could adversely affect peripheral nerves or/and the central nervous system.     

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。     

1-溴丙烷亚急性吸入染毒对大鼠大脑NR2B和GluR2影响

目的 探讨1-溴丙烷(1-BP)对大鼠大脑离子型谷氨酸受体NR2B亚基和GluR2亚基的影响.方法 无特定病原体级成年雄性Wistar大鼠36只,随机分为对照组、低剂量组、中剂量组和高剂量组4组,于动式吸入染毒柜内分别暴露于质量浓度为0、1 250、2 500和5 000 mg/m3的1-BP气体,8 h/d,每周染毒5d,连续4周.实验结束后处死大鼠,分离脑组织,应用蛋白质印迹法和实时荧光定量聚合酶链式反应法测定NR2B和GluR2的蛋白和基因表达水平.结果 中、高剂量组大鼠大脑NR2B和GluR2的蛋白表达水平均高于对照组和低剂量组(P＜0.05或P＜0.01).与对照组相比,高剂量组大鼠大脑NR2B mRNA表达水平增加(P＜0.05),各剂量组大鼠大脑GluR2 mRNA表达水平均增加(P ＜0.05或P＜0.01).结论 一定水平的1-BP亚急性吸入染毒能增加大鼠大脑NR2B和GluR2的蛋白表达.     

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。     

Cerebral excitability in pup rats prenatally exposed to 1-bromopropane is suppressed by bromide accumulated in the brain

Previously, we reported that prenatal exposure to 1-bromopropane (1-BP) causes the accumulation of bromide (Br^-) in the brain of rat pups. Here, we aimed to investigate the effects of Br^- accumulation in rat pups prenatally exposed to 1-BP vapor. Dam rats were exposed to 1-BP (400 or 700 ppm; 1-BP group) by inhalation, or to NaBr (20 mM; Br^- group) in drinking water during gestation days 1–20. We also analyzed pentylenetetrazole (PTZ, 60 mg/kg, ip)-induced behavioral changes in pups prenatally exposed to 1-BP or Br^- on postnatal day (PND) 14. PTZ-induced epileptic convulsions were inhibited in both 1-BP (700 ppm) and Br^- groups. The inhibition of neuronal excitability induced by Br^- was evaluated electrophysiologically using the hippocampal slices obtained from PND14–16 pups. PTZ (2 mM) failed to induce epileptiform discharge in the presence of 1.2 mM Br^- in the slices obtained from the control group. However, it induced epileptiform discharge following the removal of Br^-, by perfusing artificial cerebrospinal fluid into the slices obtained from the Br^- group. Our results indicate that Br^- accumulates in the brain of neonatal rat pups prenatally exposed to 1-BP vapor suppressed neuronal excitability.     

1-溴丙烷对接触工人神经毒性的剂量-效应关系

目的 探索1-溴丙烷(1-BP)对接触工人神经毒性的剂量-效应关系.方法 对国内1-BP生产工厂进行职业卫生现场调查.按1:1比例选取年龄配对的接触组和对照组女工各71人.作业环境中1-BP的浓度用直读式检气管测定,工人的8 h时间加权平均(TWA)浓度用个体采样器测定.对工人进行问卷调查、神经内科检查、神经传导速度检查、振动觉检查、血常规和血液生化检查.根据TWA值和TWA×工龄值将接触工人分为3个剂量组,进行剂量-效应关系分析.使用USEPA BMDS 2.1软件计算1-BP毒作用基准剂量(BMD)和基准剂量下限值(BMDL).结果 TWA-8 h浓度范围为0.35～535.19 mg/m3,(均值14.08 mg/m3).剂量-效应关系分析表明,1-BP接触工人在运动神经远端潜伏期(DL,线性回归系数为0.0666)、双足振动觉(线性回归系数分别为0.157 2和0.193 9)、肌酸激酶水平(线性回归系数为-1.0464)和促甲状腺激素水平(线性回归系数为0.102 4)等指标与1-BP有剂量依赖关系(P<0.05).依据DL资料计算TWA-8 h的BMD值和BMDL值分别为55.55和30.78 mg/m3.结论 1-BP对接触工人具有神经毒性,可引起胫神经DL延长、振动觉下降的剂量依赖性改变.     

1-溴丙烷经口染毒致大鼠周围神经病模型的建立

目的 观察1-溴丙烷(1-bromopropane,1-BP)的周围神经毒性,建立1-BP经口染毒致周围神经病的动物模型.方法 40只雄性Wistar大鼠,随机分为低、中、高剂量组和对照组,每组10只;将1-BP溶于玉米油中,分别经口给予200、400、800 mg/kg的1-BP,对照组给予等体积玉米油,灌胃体积均为0.2 ml/100 g,每日1次,每周5d,连续16周.定期观察各组大鼠步态,测定后肢抓力和后肢撑力,染毒8周和16周时检测血液学和生化指标.结果 高剂量组染毒8～16周、中剂量组染毒14～16周和低剂量组染毒15、16周大鼠的步态评分均明显高于对照组,差异有统计学意义(P＜0.05,P＜0.01).与对照组比较,高剂量组染毒9、12、14周大鼠后肢抓力明显下降,差异有统计学意义(P＜0.05,P＜0.01);染毒16周时,动物后肢瘫痪.染毒16周时,中、低剂量组大鼠后肢抓力分别为对照组的72.6％和91.2％,差异有统计学意义(P＜0.01,P＜0.05).染毒12、14、16周时,高剂量组大鼠后肢撑力指数明显高于对照组;染毒14、16周时,中剂量组大鼠后肢撑力指数明显高于对照组,差异均有统计学意义(P＜0.05,P＜0.01).染毒8周高、中剂量组和染毒16周高、中、低剂量组血清中丙氨酸转氨酶(ALT)活力均明显低于对照组,差异均有统计学意义(P＜0.01).结论 神经系统是1-BP毒作用的敏感靶器官,1-BP暴露可导致大鼠周围神经病.     

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。