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-丁二醇是一种主要的工业化学品， 在小鼠和大鼠中的多能致癌物，浓度低至6.25 ppm. 虽然职业接触水平正在降低， 根据这些发现，目前的充足性还需要很多年的时间。 保护工人健康的暴露水平可以通过以下方式判断： 传统的流行病学方法。 可以评估 当时暴露于遗传毒性化学品的生物学意义 通过测量暴露人群的遗传损伤水平来评估暴露程度 适当的控制组。 我们进行了初步研究， 评价职业性食品的诱变和生化效应， 在生产设施中暴露于丁二烯。 八名工人来自 平均暴露量为3.5 ppm， 平均为0.03 ppm，6名志愿者未受雇于石化行业， 工业界评估了淋巴细胞的频率，其中 hprt基因突变。 最高暴露组平均突变率为 频率约为低或未暴露的三倍 两组间差异有显著性（P<0.05）。 在一项针对同一人群的合作研究中， 最高暴露组被发现排泄N-乙酰半胱氨酸 丁二烯的共轭物浓度显着高于任何一种 对照组的差异有统计学意义（p<0.03）。 突变频率与 代谢物浓度高（R=0.85）。 我们建议延长和 确认这些研究，以确定目前的职业暴露是否 会导致遗传损伤。 15名受感染者， 15名来自丁二烯生产设施的接触较少的工人和15名 将对未在石化行业就业的受试者进行评估， 淋巴细胞中的遗传损伤使用以下终点：1）HPRT 突变试验，2）结构染色体畸变分析，3） 评价DNA修复的保真度和4）确定 丁二烯特异性代谢物（1，2-二羟基-4-（N- 乙酰半胱氨酰-）S-丁烷）。 纵向研究设计 将在6个月时对受试者进行5次评价 的间隔 将使用重复采样来建立以下模式： 暴露对这些终点的影响，以评价 暴露量的变化，并增加研究的统计功效。 在研究的最后一年，聚丁二烯中的另外两个种群， 和丁苯橡胶制造厂也将受到评价。 这项研究将确定人类对低水平 丁二烯接触，并提供信息，这将是重要的， 确定适当的职业接触限值。