1-溴丙烷健康危险度评价
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摘要
根据蒙特利尔草案,全球已经逐步停止了臭氧层消耗剂含氯氟烃(HCFCs)的生产和消耗。1-溴丙烷(1-BP)被USEPA新替代物政策项目选为HCFCs的替代物,主要用作精密仪器清洗剂、喷雾粘合剂和冷浴去脂剂,其对接触人群的潜在危害不容忽视。
本研究以我国1-BP工厂的职业流行病学调查为基础,结合动物实验,对1-BP毒性相关基因表达谱的改变、1-BP对接触工人的健康影响、人群GSTM1和GSTT1基因的多态性与1-BP神经毒性易感性关系等进行研究,计算职业接触人群中1-BP毒效应的基准剂量。并且在综合文献分析的基础上,对1-BP进行健康危险度评价,提出国内1-BP职业接触限值建议。
以往动物研究表明,1-BP对神经系统、生殖系统具有毒性。然而迄今为止,关于1-BP引发毒性基因水平的研究尚未见报道。我们运用cDNA微阵列和实时定量PCR等方法,研究1-BP引发毒性相关基因的变化,从mRNA水平上探讨1-BP毒性的可能作用机制。研究选用F344/NSIc大鼠12只,随机分为2组,分别吸入新鲜空气或1-BP 5030.00mg／m3(1000ppm)8h。染毒后16h处死大鼠取出睾丸和脑组织,测定基因表达谱的变化。结果显示,在大鼠基因芯片5,087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(Cypl9a),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。本研究提示急性高剂量染毒1-BP可引起大鼠Cypl9a、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神经和生殖毒性。
1-BP对人群健康影响的流行病学研究资料很少。本研究对国内1-BP生产厂工人进行了调查,旨在探讨1-BP对职业接触人群的健康影响,为1-BP健康危险度评价以及制订国内职业接触限值提供依据。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的监测运用直读式检气管和个体采样器测定。对工人进行问卷调查、神经行为学测试、胫神经和腓神经电生理检查、振动觉检查、血常规、血生化和激素等检查。结果显示,作业环境中1-BP的浓度范围为0-402.40 mg/m3(0-80ppm),平均值32.19 mg/m3(6.40ppm),工人接触时间加权平均浓度(TWA-8h)范围为0.35-535.19mg／m3(0.07-106.40ppm),平均值14.08 mg／m3(2.80ppm)。与对照组相比,1-BP接触工人的运动神经传导速度(MCV)(44.8±8.7m/s)和感觉神经传导速度(SCV)(45.5±4.9m/s)下降、远端潜伏期(DL)延长(7.5±2.1ms)、足趾振动觉降低(双足音叉振动延迟时间分别为6.2±4.4 s和5.7±4.4 s)、神经行为学POMS量表中愤怒情绪得分增高(21.0±5.5),紧张、疲劳、迷茫等情绪得分降低,差异具有统计学意义(p<0.05)；接触组白细胞(21.0±5.5×103／μL)、红细胞(3.9±0.4×106／μL)、血红蛋白(121.1±14.g/L)和肌酸激酶(82.0±27.5 IU／L)均显著降低,差异有统计学意义(p<0.05),血清总蛋白(8.0±0.5g/dL)、乳酸脱氢酶(335.2±356.6 IU／L)、促甲状腺激素(3.6±2.3μIU/mL)和卵泡刺激素水平(18.7±24.4mIU/mL)显著上升，,差异有统计学意义(p<0.05)。研究提示,1-BP接触可能影响工人外周神经和中枢神经系统,并引起血液及生化学指标的异常。
基因芯片研究结果表明,1-BP能引起大鼠GSTT1基因表达发生显著的变化。人群中GSTM1和GSTT1基因存在多态性现象,对这两个基因的多态性与1-BP神经毒性易感性关系的研究在1-BP职业危害的预防控制、1-BP接触人群的健康保护等方面将有重要的意义。本研究探讨了谷胱甘肽S转移酶基因多态性对1-BP接触者神经传导速度的影响。选择116名1-BP接触工人为接触组,133名无1-BP接触史的工人为对照组,用神经电生理检测技术测定工人的运动神经传导速度、感觉神经传导速度和远端潜伏期,用等位基因特异性扩增(ASA)方法检测两组GSTT1和GSTM1基因型的分布。结果表明,GSTT1基因多态性和1-BP接触对工人的SCV和DL的影响有交互作用,SNK两两比较结果显示,与对照组GSTT1基因携带者相比,接触组中GSTT1基因缺失型工人的SCV明显减慢[分别为(45.3±5.0)m／s和(40.1±5.3)m／s]、DL明显延长[分别为(6.3±1.3)ms和(8.3±2.0)ms],差别有统计学意义(P<0.05)；去除交互项后的两因素方差分析显示,GSTT1基因多态性对工人的MCV有独立的影响(P<0.05)。未发现GSTM1基因多态性对接触者外周神经传导速度有影响。研究提示,GSTT1基因多态性与接触者对1-BP外周神经毒性的易感性有关。
基于职业人群资料,我们计算了1-BP毒性基准剂量。使用美国环保局提供的BMD软件对1-BP毒效应的基准剂量进行评估,选择10%为基准反应值,95%可信限,选择拟合度最佳的模型来计算BMD和BMDL。以远端潜伏期为1-BP诱导的神经毒效应的敏感终点,计算出1-BP接触工人TWA-8h的BMD和BMDL分别为36.77 mg/m3(7.31 ppm)和21.73 mg/m3(4.32 ppm)；以血清肌酸激酶作为血液生化效应终点计算的BMD和BMDL分别为88.28 mg／m3(17.55 ppm)和44.82 mg／m3(8.91 ppm)；以血清促甲状腺激素作为血液效应终点计算的BMD和BMDL分别为47.23 mg／m3(9.39 ppm)和31.54 mg／m3(6.27ppm),均高于以DL为终点计算得出的基准剂量,提示DL延长是1-BP毒性的最为敏感的指标。
在以上研究及相关文献综合分析的基础上,对1-BP的健康危害进行了危险度评价。根据1-BP的暴露资料确定,1-BP人体主要的暴露途径为职业接触。对1-BP的危害认定主要来源于动物实验资料,以及少量的人群研究资料。动物实验可以证实1-BP导致大鼠的发育毒性、生殖毒性和神经毒性的结论,且毒性呈剂量-效应关系；尚无明确证据表明1-BP具有血液毒性、遗传毒性和致癌性。根据大鼠吸入染毒发育毒性实验计算出的BMDL为1534.15 mg／m3(305ppm)；根据吸入染毒两代生殖毒性实验得出雌性生殖毒性的LOAEC为1534.15 mg／m3(305ppm)、NOAEC为503.00 mg/m3(100ppm)；另两项生殖毒性实验得出1-BP生殖毒性的LOAEC为1006.00 mg／m3(200ppm)、NOAEC为503.00 mg／m3(100ppm)。目前没有关于人体接触1-BP的发育毒性资料。1-BP中毒个案报道以及职业流行病学调查结果均证实了1-BP的神经毒性。
我国目前尚未制订1-BP职业接触限值的标准。基于职业人群资料的剂量-效应关系和BMD值,以及参照国外EPA和ACGIH提出的1-BP接触限值,我们建议国内1-BP职业接触限值TWA-8h为25.15 mg／m3(5 ppm),对1-BP接触工人应定期检测神经功能及血生化,及早发现职业健康危害,保护工人健康。
综上所述,本研究进行了1-BP职业流行病学调查,首次报道1-BP接触工人出现运动神经远端潜伏期延长、振动觉减弱等神经异常,以及血清肌酸激酶降低和促甲状腺激素水平升高的血液生化学改变。基于人群资料研究计算出1-BP神经毒性的BMD和BMDL分别为36.77 mg／m3(7.31 ppm)和21.73 mg／m3(4.32 ppm)；1-BP血液影响的BMD和BMDL分别为47.23 mg/m3(9.39 ppm)和31.54 mg／m3(6.27 ppm)。本研究建议国内1-BP职业接触限值TWA-8h为25.15 mg/m3(5 ppm)。此外,研究还提示GSTT1基因缺失型人群可能为1-BP诱发毒性的易感人群。
1-Bromopropane (1-BP) is currently under review per the US EPA Significant New Alternatives Policy program in identification of substitutes for ozone-depleting substances. 1-BP is being considered as a possible replacement for chlorofluorocarbons (HCFC), 1,1,1-trichloroethane and methyl chloroform for nonaerosol solvent cleaning of metals and electronics and for adhesives, coatings, aerosol propellant, and solvent applications. Since late '90s, the production and use of 1-BP are increasing rapidly.
1-Bromopropane is a neuro and reproductive toxicant in animals and humans, however, the toxic mechenism at gene level remains unknown. The present study explored the change of gene expression profile in male F344/N rats after exposure to 1-BP to clarify its possible toxic mechenism at mRNA level. Twelve F344/NSIc male rats were randomly divided into two groups of 6 each. Rats were exposed to either fresh air or 5030 mg/m3 1-BP through inhalation for 8 h. Rats were sacrificed and testes and brains were removed at 16 h after exposure. Global changes in gene expression were determined by microarray analysis using rat chip followed by Real-time PCR validation. Results showed that among the 5082 genes and ESTs in the genital chip,62 genes were down-regulated and 3 genes were up-regulated by 1-BP, which include synthetic sex hormone-related genes cytochrome P450 aromatase (Cypl9a), glutathione S-transferase (GSTT1), creatine kinase (Ckb), myelin and lymphocyte protein (Mal) and S100 calcium-binding protein (S100a4). Classification analysis revealed that the majority of gene changes was invoved protein/lipid metabolism, followed by the stress-associated defense response. Real-time PCR confirmed the down-regulation of Cyp19a, GSTT1, Mal and S100a4 genes. The study demonstrate that acute high-dose exposure to 1-BP causes the down-regulation of Cypl9a, S100a4, GSTT1 and Mal mRNA in rats. This altered gene profiles might reflect the toxic mechanism which suggested that 1-BP disrupt the biological metabolism and endocrine balance.
So far, very limited human data regarding 1-BP exposure could be found. This study investigated the health effects of 1-BP on exposed workers in four 1-BP manufacturing plants. Workers were interviewed with questionnaire and examined with neurobehavioral core test battery, nerve conduction velocity tests of nervus tibialis and nervus suralis, vibration sensation test, hematological and biochemical tests. Ambient 1-BP concentration was measured with detection tube, and time-weighed average levels of individual workers were estimated with passive samplers. Results showed that 1-BP concentration in the plants ranged 0-402.40 mg/m3 (0-80ppm),Geomean 32.19mg/m3(6.40ppm). Time-weighted average exposure levels (TWA-8h) ranged 0.35-535.19 mg/m3 (0.07-106.40ppm),Geomean 14.08mg/m3 (2.80ppm). Compared with the control group,1-BP exposed workers showed reduced motor nerve conduction velocity (44.8±8.7m/s) and sensory nerve conduction velocity(45.5±4.9m/s), prolonged distal latency(7.5±2.1ms), reduced toe vibration perception, and altered neurobehavior parameters (POMS Vigor, Tension, Anxiety, Confusion) significantly (p<0.05). As to hematological and biochemical indicators, the exposed workers showed decreased white blood cell count (21.0±5.5×103/μL), red blood cell count (3.9±0.4×106/μL), hemoglobin (121.1±14.5 g/L) and creatine kinase (82.0±27.5 IU/L) (p <0.05), and increased serum total protein (8.0±0.5 g/dL), lactate dehydrogenase (335.2±356.6 IU/L), thyroid-stimulating hormone (3.6±2.3μIU/mL) and follicle-stimulating hormone levels (18.7±24.4mIU/mL) (p<0.05). The study indicate that 1-BP exposure may affect peripheral nerves and central nervous system, and lead to abnormal hematological and biomedical indicators.
Our microarray study showed that 1-BP exposure could induce the GSTT1 gene expression significantly. GSTM1 and GSTT1 polymorphism phenomena exist commonly in population. Study on the relationship between these two polymorphism and the workers' susceptibility to 1-BP neurotoxicity will play an important role in the prevention and control of occupational hazards as well as the protection of susceptible workers.
The present study explored the association between GSTTl and GSTM1 Gene polymorphism and nerve conduction velocity in workers exposed to 1-BP. Neuroelectrophysiological studies were carried out on 116 1-BP exposed and 133 non-exposed workers. The polymorphism of GSTT1,and GSTM1 were analyzed by allele specific amplification(ASA) method. Result showed that GSTT1 gene polymorphism and exposure had an interact effect on sensory nerve conduction velocity(SCV) and distal latency(DL). Workers with GSTT1 gene null type in exposed group had a slower SCV (40.1±5.3m/s) and longer DL (8.3±2.0ms) compared with those with GSTT1 gene normal type in non-exposed group [SCV(45.3±5.0)m/s, DL(6.3±1.3)ms](P<0.05). There is no evidence that GSTM1 gene polymorphism had effect on nerve conduction velocity of these workers. The study suggest that GSTT1 gene polymorphism might be associated with the susceptibility to neurotoxicity of 1-BP.
Based on the data of workers, the study calculated the 1-BP toxicity benchmark dose. USEPA BMDS 1.4.1c software was applied to calculate 1-BP benchmark dose (BMD) and its 95% lower limit (BMDL). BMD calculation based on DL as 1-BP neurotoxic effect endpoint showed that TWA-8h of the BMD value and BMDL value were 36.77 mg/m (7.31 ppm)and 21.73 mg/m3(4.32 ppm). BMD calculation based on serum CK as 1-BP biochemical toxic effect endpoint showed the BMD value and BMDL value were 88.28 mg/m3 (17.55 ppm) and 44.82 mg/m3 (8.91 ppm). BMD calculation based on serum TSH as 1-BP biochemical toxic effect endpoint showed the BMD value and BMDL value were 47.23 mg/m3 (9.39 ppm)和31.54 mg/m3 (6.27 ppm).
Health-based risk assessment of 1-BP was conducted on the basis of the comprehensive analysis of above animal/human studies and literatures. It is assumed that 1-BP is not a chemical widespread in the environment and occupational exposure is considered the main route of its exposure to humans. The risk identification of 1-BP was mainly dependent on animal data as very few evidence in humans are available. There is sufficient evidence in rats that 1-BP causes dose-dependent neurotoxicity, developmental and reproductive toxicity. There is insufficient evidence in animals that 1-BP causes hemotoxicity, genetic toxicity and carcinogenicity. A benchmark concentration 95th percentile lower confidence limit of 1,534.00 mg/m3(305 ppm) was identified from a rat inhalation developmental toxicity.. A LOAEC of 1,257.00 mg/m3(250 ppm) for female reproduction (NOAEC= 503.00 mg/m3[100 ppm] was identified from an inhalation, two-generation reproductive toxicity study.. A LOAEC of 1,006.00 mg/m3(200 ppm) for male reproduction (NOAEC-503.00 mg/m3[100 ppm] was identified from other two reproductive toxicity studies. Available human data are insufficient to draw conclusions on the reproductive or developmental toxicity of 1-BP. Case reports of 1-BP intoxication and the occupational epidemiology studies confirmed the neurotoxicity of 1-BP in humans.
So far there is no occupational exposure limit of 1-BP in China. Based on the above BMD calculations in workers and with reference to the limits set by EPA and ACGIH, the present study is recmmending an TWA-8h exposure limit of 25.15 mg/m3 (5 ppm). It is recommended that 1-BP exposed workers undergo health examination on neurological functions and blood tests regularly, for an early detection of occupational health hazards.
In summary, the present study conducted 1-BP occupational epidemiology investigation in China, and reported that workers exposed to 1-BP showed neurological abnormalities manifested as enlongated distal motor latency (DL) and reduced vibration sense, and serum biochemical changes manifested as elevated CK elevated and decreased TSH levels. The BMD calculated with DL as toxic endpoint and this provided a central estimate for the BMD of 36.77 mg/m3 (7.31 ppm) and BMDL of 21.73 mg/m3 (4.32 ppm). The BMD calculated with serum CK level as toxic endpoint and this provided a central estimate for the BMD of 47.23 mg/m3 (9.39 ppm) and BMDL of 31.54 mg/m3 (6.27 ppm). The present study is recmmending an TWA-8h exposure limit of 25.15 mg/m3 (5 ppm) as the 1-BP occupational exposure limit in China. The study suggest that GSTT1 gene polymorphism might be associated with the susceptibility to neurotoxicity of 1-BP. The study also suggest that the toxic mechanism of 1-BP involve the disruption to the biological metabolism and endocrine balance.
本研究以我国1-BP工厂的职业流行病学调查为基础,结合动物实验,对1-BP毒性相关基因表达谱的改变、1-BP对接触工人的健康影响、人群GSTM1和GSTT1基因的多态性与1-BP神经毒性易感性关系等进行研究,计算职业接触人群中1-BP毒效应的基准剂量。并且在综合文献分析的基础上,对1-BP进行健康危险度评价,提出国内1-BP职业接触限值建议。
以往动物研究表明,1-BP对神经系统、生殖系统具有毒性。然而迄今为止,关于1-BP引发毒性基因水平的研究尚未见报道。我们运用cDNA微阵列和实时定量PCR等方法,研究1-BP引发毒性相关基因的变化,从mRNA水平上探讨1-BP毒性的可能作用机制。研究选用F344/NSIc大鼠12只,随机分为2组,分别吸入新鲜空气或1-BP 5030.00mg／m3(1000ppm)8h。染毒后16h处死大鼠取出睾丸和脑组织,测定基因表达谱的变化。结果显示,在大鼠基因芯片5,087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(Cypl9a),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。本研究提示急性高剂量染毒1-BP可引起大鼠Cypl9a、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神经和生殖毒性。
1-BP对人群健康影响的流行病学研究资料很少。本研究对国内1-BP生产厂工人进行了调查,旨在探讨1-BP对职业接触人群的健康影响,为1-BP健康危险度评价以及制订国内职业接触限值提供依据。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的监测运用直读式检气管和个体采样器测定。对工人进行问卷调查、神经行为学测试、胫神经和腓神经电生理检查、振动觉检查、血常规、血生化和激素等检查。结果显示,作业环境中1-BP的浓度范围为0-402.40 mg/m3(0-80ppm),平均值32.19 mg/m3(6.40ppm),工人接触时间加权平均浓度(TWA-8h)范围为0.35-535.19mg／m3(0.07-106.40ppm),平均值14.08 mg／m3(2.80ppm)。与对照组相比,1-BP接触工人的运动神经传导速度(MCV)(44.8±8.7m/s)和感觉神经传导速度(SCV)(45.5±4.9m/s)下降、远端潜伏期(DL)延长(7.5±2.1ms)、足趾振动觉降低(双足音叉振动延迟时间分别为6.2±4.4 s和5.7±4.4 s)、神经行为学POMS量表中愤怒情绪得分增高(21.0±5.5),紧张、疲劳、迷茫等情绪得分降低,差异具有统计学意义(p<0.05)；接触组白细胞(21.0±5.5×103／μL)、红细胞(3.9±0.4×106／μL)、血红蛋白(121.1±14.g/L)和肌酸激酶(82.0±27.5 IU／L)均显著降低,差异有统计学意义(p<0.05),血清总蛋白(8.0±0.5g/dL)、乳酸脱氢酶(335.2±356.6 IU／L)、促甲状腺激素(3.6±2.3μIU/mL)和卵泡刺激素水平(18.7±24.4mIU/mL)显著上升，,差异有统计学意义(p<0.05)。研究提示,1-BP接触可能影响工人外周神经和中枢神经系统,并引起血液及生化学指标的异常。
基因芯片研究结果表明,1-BP能引起大鼠GSTT1基因表达发生显著的变化。人群中GSTM1和GSTT1基因存在多态性现象,对这两个基因的多态性与1-BP神经毒性易感性关系的研究在1-BP职业危害的预防控制、1-BP接触人群的健康保护等方面将有重要的意义。本研究探讨了谷胱甘肽S转移酶基因多态性对1-BP接触者神经传导速度的影响。选择116名1-BP接触工人为接触组,133名无1-BP接触史的工人为对照组,用神经电生理检测技术测定工人的运动神经传导速度、感觉神经传导速度和远端潜伏期,用等位基因特异性扩增(ASA)方法检测两组GSTT1和GSTM1基因型的分布。结果表明,GSTT1基因多态性和1-BP接触对工人的SCV和DL的影响有交互作用,SNK两两比较结果显示,与对照组GSTT1基因携带者相比,接触组中GSTT1基因缺失型工人的SCV明显减慢[分别为(45.3±5.0)m／s和(40.1±5.3)m／s]、DL明显延长[分别为(6.3±1.3)ms和(8.3±2.0)ms],差别有统计学意义(P<0.05)；去除交互项后的两因素方差分析显示,GSTT1基因多态性对工人的MCV有独立的影响(P<0.05)。未发现GSTM1基因多态性对接触者外周神经传导速度有影响。研究提示,GSTT1基因多态性与接触者对1-BP外周神经毒性的易感性有关。
基于职业人群资料,我们计算了1-BP毒性基准剂量。使用美国环保局提供的BMD软件对1-BP毒效应的基准剂量进行评估,选择10%为基准反应值,95%可信限,选择拟合度最佳的模型来计算BMD和BMDL。以远端潜伏期为1-BP诱导的神经毒效应的敏感终点,计算出1-BP接触工人TWA-8h的BMD和BMDL分别为36.77 mg/m3(7.31 ppm)和21.73 mg/m3(4.32 ppm)；以血清肌酸激酶作为血液生化效应终点计算的BMD和BMDL分别为88.28 mg／m3(17.55 ppm)和44.82 mg／m3(8.91 ppm)；以血清促甲状腺激素作为血液效应终点计算的BMD和BMDL分别为47.23 mg／m3(9.39 ppm)和31.54 mg／m3(6.27ppm),均高于以DL为终点计算得出的基准剂量,提示DL延长是1-BP毒性的最为敏感的指标。
在以上研究及相关文献综合分析的基础上,对1-BP的健康危害进行了危险度评价。根据1-BP的暴露资料确定,1-BP人体主要的暴露途径为职业接触。对1-BP的危害认定主要来源于动物实验资料,以及少量的人群研究资料。动物实验可以证实1-BP导致大鼠的发育毒性、生殖毒性和神经毒性的结论,且毒性呈剂量-效应关系；尚无明确证据表明1-BP具有血液毒性、遗传毒性和致癌性。根据大鼠吸入染毒发育毒性实验计算出的BMDL为1534.15 mg／m3(305ppm)；根据吸入染毒两代生殖毒性实验得出雌性生殖毒性的LOAEC为1534.15 mg／m3(305ppm)、NOAEC为503.00 mg/m3(100ppm)；另两项生殖毒性实验得出1-BP生殖毒性的LOAEC为1006.00 mg／m3(200ppm)、NOAEC为503.00 mg／m3(100ppm)。目前没有关于人体接触1-BP的发育毒性资料。1-BP中毒个案报道以及职业流行病学调查结果均证实了1-BP的神经毒性。
我国目前尚未制订1-BP职业接触限值的标准。基于职业人群资料的剂量-效应关系和BMD值,以及参照国外EPA和ACGIH提出的1-BP接触限值,我们建议国内1-BP职业接触限值TWA-8h为25.15 mg／m3(5 ppm),对1-BP接触工人应定期检测神经功能及血生化,及早发现职业健康危害,保护工人健康。
综上所述,本研究进行了1-BP职业流行病学调查,首次报道1-BP接触工人出现运动神经远端潜伏期延长、振动觉减弱等神经异常,以及血清肌酸激酶降低和促甲状腺激素水平升高的血液生化学改变。基于人群资料研究计算出1-BP神经毒性的BMD和BMDL分别为36.77 mg／m3(7.31 ppm)和21.73 mg／m3(4.32 ppm)；1-BP血液影响的BMD和BMDL分别为47.23 mg/m3(9.39 ppm)和31.54 mg／m3(6.27 ppm)。本研究建议国内1-BP职业接触限值TWA-8h为25.15 mg/m3(5 ppm)。此外,研究还提示GSTT1基因缺失型人群可能为1-BP诱发毒性的易感人群。
1-Bromopropane (1-BP) is currently under review per the US EPA Significant New Alternatives Policy program in identification of substitutes for ozone-depleting substances. 1-BP is being considered as a possible replacement for chlorofluorocarbons (HCFC), 1,1,1-trichloroethane and methyl chloroform for nonaerosol solvent cleaning of metals and electronics and for adhesives, coatings, aerosol propellant, and solvent applications. Since late '90s, the production and use of 1-BP are increasing rapidly.
1-Bromopropane is a neuro and reproductive toxicant in animals and humans, however, the toxic mechenism at gene level remains unknown. The present study explored the change of gene expression profile in male F344/N rats after exposure to 1-BP to clarify its possible toxic mechenism at mRNA level. Twelve F344/NSIc male rats were randomly divided into two groups of 6 each. Rats were exposed to either fresh air or 5030 mg/m3 1-BP through inhalation for 8 h. Rats were sacrificed and testes and brains were removed at 16 h after exposure. Global changes in gene expression were determined by microarray analysis using rat chip followed by Real-time PCR validation. Results showed that among the 5082 genes and ESTs in the genital chip,62 genes were down-regulated and 3 genes were up-regulated by 1-BP, which include synthetic sex hormone-related genes cytochrome P450 aromatase (Cypl9a), glutathione S-transferase (GSTT1), creatine kinase (Ckb), myelin and lymphocyte protein (Mal) and S100 calcium-binding protein (S100a4). Classification analysis revealed that the majority of gene changes was invoved protein/lipid metabolism, followed by the stress-associated defense response. Real-time PCR confirmed the down-regulation of Cyp19a, GSTT1, Mal and S100a4 genes. The study demonstrate that acute high-dose exposure to 1-BP causes the down-regulation of Cypl9a, S100a4, GSTT1 and Mal mRNA in rats. This altered gene profiles might reflect the toxic mechanism which suggested that 1-BP disrupt the biological metabolism and endocrine balance.
So far, very limited human data regarding 1-BP exposure could be found. This study investigated the health effects of 1-BP on exposed workers in four 1-BP manufacturing plants. Workers were interviewed with questionnaire and examined with neurobehavioral core test battery, nerve conduction velocity tests of nervus tibialis and nervus suralis, vibration sensation test, hematological and biochemical tests. Ambient 1-BP concentration was measured with detection tube, and time-weighed average levels of individual workers were estimated with passive samplers. Results showed that 1-BP concentration in the plants ranged 0-402.40 mg/m3 (0-80ppm),Geomean 32.19mg/m3(6.40ppm). Time-weighted average exposure levels (TWA-8h) ranged 0.35-535.19 mg/m3 (0.07-106.40ppm),Geomean 14.08mg/m3 (2.80ppm). Compared with the control group,1-BP exposed workers showed reduced motor nerve conduction velocity (44.8±8.7m/s) and sensory nerve conduction velocity(45.5±4.9m/s), prolonged distal latency(7.5±2.1ms), reduced toe vibration perception, and altered neurobehavior parameters (POMS Vigor, Tension, Anxiety, Confusion) significantly (p<0.05). As to hematological and biochemical indicators, the exposed workers showed decreased white blood cell count (21.0±5.5×103/μL), red blood cell count (3.9±0.4×106/μL), hemoglobin (121.1±14.5 g/L) and creatine kinase (82.0±27.5 IU/L) (p <0.05), and increased serum total protein (8.0±0.5 g/dL), lactate dehydrogenase (335.2±356.6 IU/L), thyroid-stimulating hormone (3.6±2.3μIU/mL) and follicle-stimulating hormone levels (18.7±24.4mIU/mL) (p<0.05). The study indicate that 1-BP exposure may affect peripheral nerves and central nervous system, and lead to abnormal hematological and biomedical indicators.
Our microarray study showed that 1-BP exposure could induce the GSTT1 gene expression significantly. GSTM1 and GSTT1 polymorphism phenomena exist commonly in population. Study on the relationship between these two polymorphism and the workers' susceptibility to 1-BP neurotoxicity will play an important role in the prevention and control of occupational hazards as well as the protection of susceptible workers.
The present study explored the association between GSTTl and GSTM1 Gene polymorphism and nerve conduction velocity in workers exposed to 1-BP. Neuroelectrophysiological studies were carried out on 116 1-BP exposed and 133 non-exposed workers. The polymorphism of GSTT1,and GSTM1 were analyzed by allele specific amplification(ASA) method. Result showed that GSTT1 gene polymorphism and exposure had an interact effect on sensory nerve conduction velocity(SCV) and distal latency(DL). Workers with GSTT1 gene null type in exposed group had a slower SCV (40.1±5.3m/s) and longer DL (8.3±2.0ms) compared with those with GSTT1 gene normal type in non-exposed group [SCV(45.3±5.0)m/s, DL(6.3±1.3)ms](P<0.05). There is no evidence that GSTM1 gene polymorphism had effect on nerve conduction velocity of these workers. The study suggest that GSTT1 gene polymorphism might be associated with the susceptibility to neurotoxicity of 1-BP.
Based on the data of workers, the study calculated the 1-BP toxicity benchmark dose. USEPA BMDS 1.4.1c software was applied to calculate 1-BP benchmark dose (BMD) and its 95% lower limit (BMDL). BMD calculation based on DL as 1-BP neurotoxic effect endpoint showed that TWA-8h of the BMD value and BMDL value were 36.77 mg/m (7.31 ppm)and 21.73 mg/m3(4.32 ppm). BMD calculation based on serum CK as 1-BP biochemical toxic effect endpoint showed the BMD value and BMDL value were 88.28 mg/m3 (17.55 ppm) and 44.82 mg/m3 (8.91 ppm). BMD calculation based on serum TSH as 1-BP biochemical toxic effect endpoint showed the BMD value and BMDL value were 47.23 mg/m3 (9.39 ppm)和31.54 mg/m3 (6.27 ppm).
Health-based risk assessment of 1-BP was conducted on the basis of the comprehensive analysis of above animal/human studies and literatures. It is assumed that 1-BP is not a chemical widespread in the environment and occupational exposure is considered the main route of its exposure to humans. The risk identification of 1-BP was mainly dependent on animal data as very few evidence in humans are available. There is sufficient evidence in rats that 1-BP causes dose-dependent neurotoxicity, developmental and reproductive toxicity. There is insufficient evidence in animals that 1-BP causes hemotoxicity, genetic toxicity and carcinogenicity. A benchmark concentration 95th percentile lower confidence limit of 1,534.00 mg/m3(305 ppm) was identified from a rat inhalation developmental toxicity.. A LOAEC of 1,257.00 mg/m3(250 ppm) for female reproduction (NOAEC= 503.00 mg/m3[100 ppm] was identified from an inhalation, two-generation reproductive toxicity study.. A LOAEC of 1,006.00 mg/m3(200 ppm) for male reproduction (NOAEC-503.00 mg/m3[100 ppm] was identified from other two reproductive toxicity studies. Available human data are insufficient to draw conclusions on the reproductive or developmental toxicity of 1-BP. Case reports of 1-BP intoxication and the occupational epidemiology studies confirmed the neurotoxicity of 1-BP in humans.
So far there is no occupational exposure limit of 1-BP in China. Based on the above BMD calculations in workers and with reference to the limits set by EPA and ACGIH, the present study is recmmending an TWA-8h exposure limit of 25.15 mg/m3 (5 ppm). It is recommended that 1-BP exposed workers undergo health examination on neurological functions and blood tests regularly, for an early detection of occupational health hazards.
In summary, the present study conducted 1-BP occupational epidemiology investigation in China, and reported that workers exposed to 1-BP showed neurological abnormalities manifested as enlongated distal motor latency (DL) and reduced vibration sense, and serum biochemical changes manifested as elevated CK elevated and decreased TSH levels. The BMD calculated with DL as toxic endpoint and this provided a central estimate for the BMD of 36.77 mg/m3 (7.31 ppm) and BMDL of 21.73 mg/m3 (4.32 ppm). The BMD calculated with serum CK level as toxic endpoint and this provided a central estimate for the BMD of 47.23 mg/m3 (9.39 ppm) and BMDL of 31.54 mg/m3 (6.27 ppm). The present study is recmmending an TWA-8h exposure limit of 25.15 mg/m3 (5 ppm) as the 1-BP occupational exposure limit in China. The study suggest that GSTT1 gene polymorphism might be associated with the susceptibility to neurotoxicity of 1-BP. The study also suggest that the toxic mechanism of 1-BP involve the disruption to the biological metabolism and endocrine balance.
引文
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