HUMAN SENSITIVITY TO GENOTOXIC EFFECTS OF BUTADIENE

人类对丁二烯基因毒性作用的敏感性

• 批准号: 2154844
• 负责人: MARVIN S LEGATOR
• 金额: $ 22.13万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2154844
• 关键词: HUMAN; SENSITIVITY; GENOTOXIC; EFFECTS; BUTADIENE

1,3-Butadiene is a major industrial chemical which has been shown to be a multipotent carcinogen in mice and rats at concentrations down to 6.25 ppm. While occupational exposure levels are being reduced in response to these findings, it will be many years before the adequacy of current exposure levels for protecting worker health can be judged using traditional epidemiological methods. It is possible to evaluate the biological significance of exposure to genotoxic chemicals at the time of exposure by measuring levels of genetic damage in exposed populations and appropriate control groups. We have conducted a preliminary study to evaluate the mutagenic and biochemical effects of occupational exposure to butadiene in a production facility. eight workers from areas where exposures average 3.5 ppm, five workers from areas where exposures averaged 0.03 ppm and six volunteers not employed in the petrochemical industry were evaluated for the frequency of lymphocytes containing mutations at the hprt gene. The highest exposed group had average mutant frequencies about three-fold greater than either the low, or non-exposed groups (p<0.05). In a collaborative study of the same population, the highest exposed group was found to excrete an n-acetyl cysteinyl conjugate of butadiene at significantly higher concentrations than either of the control groups (p<0.03). The correlation between mutant frequency and metabolite concentration was high (R=0.85). We propose to extend and confirm these studies to determine whether current occupational exposures to butadiene result in genetic damage. A population of 15 exposed and 15 less-exposed workers from a butadiene production facility and 15 subjects not employed in the petrochemical industry will be evaluated for genetic damage in lymphocytes using the following endpoints: 1) hprt mutation assay, 2) structural chromosome aberration analysis, 3) evaluation of fidelity of DNA repair and 4) determination of the concentration of a butadiene specific metabolite (1,2-dihydroxy-4-(N- acetylcysteinyl-)S-butane) in the urine. A longitudinal study design will be used in which subjects will be evaluated five times at six month intervals. Repeated sampling will be used to establish the patterns of effects of exposure on these endpoints, to evaluate the effects of changes in exposure, and to increase the statistical power of the study. In the last year of study, two additional populations in polybutadiene, and butadiene-styrene rubber manufacturing plants will also be evaluated. This study will determine the sensitivity of humans to low level butadiene exposure and provide information which will be significant in determining appropriate occupational exposure limits.

1,3-丁二烯是一种主要的工业化学化学化学物质 小鼠和大鼠的多态致癌，浓度低于6.25 ppm。 而职业暴露水平正在降低 对于这些发现，将需要多年 可以使用保护工人健康的暴露水平 传统流行病学方法。 可以评估 当时暴露于遗传毒性化学物质的生物学意义 通过测量暴露人群的遗传损害水平来暴露 和适当的对照组。 我们已经进行了初步研究 评估职业的诱变和生化作用 在生产设施中接触丁二烯。 来自地区的八名工人 在平均暴露3.5 ppm的地方，五名工人来自暴露的地区 平均为0.03 ppm和六名在石化中不使用的志愿者 评估了含有淋巴细胞的频率 HPRT基因的突变。 最高的裸露组具有平均突变体 频率大于低或不暴露的频率 组（p <0.05）。 在对同一人群的合作研究中 发现最高暴露组以排泄N-乙酰基半胱氨酸 丁二烯的共轭浓度明显高于 对照组（p <0.03）。 突变频率之间的相关性 代谢物浓度高（r = 0.85）。 我们建议扩展和 确认这些研究以确定当前的职业暴露是否发生 丁二烯会导致遗传损害。 15人的人口暴露 来自丁二烯生产设施的15名暴露较低的工人和15名 将评估未在石化行业中使用的受试者 使用以下终点在淋巴细胞中的遗传损伤：1）HPRT 突变测定，2）结构性染色体畸变分析，3） 评估DNA修复的保真度和4）确定 丁二烯特异性代谢产物的浓度（1,2-二羟基-4-（n-） 尿液中的乙酰囊这基 - ）二丁烷。 纵向研究设计 将使用在六个月时对受试者进行五次评估的主题 间隔。 重复采样将用于建立模式 暴露对这些终点的影响，以评估 暴露的变化，并增加研究的统计能力。 在研究的最后一年，多丁二烯的另外两个人群， 还将评估丁二烯 - 苯乙烯橡胶制造厂。 这项研究将确定人类的敏感性 丁二烯暴露并提供信息 确定适当的职业暴露限制。