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: 3254334
• 负责人: MARVIN S LEGATOR
• 金额: $ 21.33万
• 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 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3254334
• 关键词: DNA damage; DNA repair; chemical carcinogen; chromosome aberrations; diene; gene frequency; gene mutation; human population study; human subject; hypoxanthine phosphoribosyltransferase; industry; interview; longitudinal human study; occupational hazard; questionnaires; rubber; urinalysis

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品，已被证明是 在小鼠和大鼠体内浓度降至6.25的多效性致癌物质 Ppm。虽然职业暴露水平正在降低，以应对 对于这些发现，目前的情况还需要很多年才能充分 保护工人健康的暴露水平可以用以下方法来判断 传统的流行病学方法。有可能评估 当时接触遗传毒性化学物质的生物学意义 通过测量暴露人群中的遗传损伤水平来确定暴露的风险 和适当的对照组。我们已经进行了初步研究 评价职业性接触者的致突变性和生化效应 在生产设施中接触丁二烯。八名来自各地的工人 暴露平均为3.5ppm，来自暴露区域的五名工人 平均为0.03ppm，6名志愿者未受雇于石化公司 对工业中含有淋巴细胞的频率进行了评估 HPRT基因的突变。最高暴露组有平均突变 频率大约是低频率或非暴露频率的三倍 组(p&lt；0.05)。在一项对相同人群的合作研究中， 发现最高暴露组排出一种N-乙酰半胱氨酸基 丁二烯的共轭浓度显著高于任何一种 对照组(P&lt；0.03)。突变频率之间的相关性 代谢产物浓度高(R=0.85)。我们建议延长和 确认这些研究以确定当前的职业暴露是否 丁二烯会导致基因损伤。15人暴露在危险之中 来自丁二烯生产设施的15名接触较少的工人和15名 未受雇于石化行业的受试者将接受 使用以下终点的淋巴细胞的遗传损伤：1)HPRT 突变试验，2)结构染色体畸变分析，3) 评估DNA修复的保真度和4)测定 丁二烯特定代谢物(1，2-二羟基-4-(N- 乙酰半胱氨酸基)S丁烷。一项纵向研究设计 将在六个月内对受试者进行五次评估 间隔时间。重复抽样将被用来建立模式 暴露对这些终点的影响，以评估 暴露的变化，并增加研究的统计力量。 在最后一年的研究中，聚丁二烯中的另外两个种群， 和丁苯橡胶制造厂也将接受评估。 这项研究将确定人类对低水平的敏感性 丁二烯暴露，并提供将在 确定适当的职业接触限值。