Swenberg J A, Koc H, Upton P B, Georguieva N, Ranasinghe A, Walker V E, Henderson R
Laboratory of Molecular Carcinogenesis and Mutagenesis, Department of Environmental Sciences and Engineering, CB# 7400, University of North Carolina, Chapel Hill, NC 27599-7400, USA.
Chem Biol Interact. 2001 Jun 1;135-136:387-403. doi: 10.1016/s0009-2797(01)00221-6.
The purpose of this paper is to review what we know about various biomarkers of butadiene in animal, human and in vitro studies, and to draw inferences from these data that impact on the accurate assessment of human risks for cancer. Studies comparing the DNA and hemoglobin adducts of butadiene with exposure, metabolism and genotoxicity have provided a great deal of insight that is applicable to biologically based risk assessment. First, the DNA and hemoglobin adduct data strongly support the conclusion that 3,4-epoxy-1,2-butanediol is the major electrophile available for binding to these macromolecules. Biomarker studies have also provided insight into the possibility of a sensitive population associated with the GSTT1 null genotype. While it is clear that lymphocytes from GSTT1 null individuals are more sensitive for the induction of sister chromatid exchanges (SCE) following in vitro exposure to 1,2,3,4-diepoxybutane, there was no such increase in SCE or other biomarkers of genotoxicity in workers exposed to 1-3 p.p.m. butadiene, regardless of GST genotype. The globin adduct data also demonstrate that there is roughly a tenfold range for interindividual differences in the metabolism of butadiene. This type of analysis represents an excellent means for providing scientific data for this critical determinant. Another useful application of hemoglobin adducts in risk assessment was demonstrated by regressing data for various endpoints for genotoxicity against that individual's biologically effective dose, thereby providing an independent mechanism for evaluation that excludes any possible confounding by inappropriate controls. Finally, biomarker studies have identified critical gaps in our knowledge that are needed for the accurate assessment of butadiene. Most notable of these is the lack of diepoxide-specific biomarkers in mice, rats and humans.
本文的目的是回顾我们在动物、人体和体外研究中对丁二烯各种生物标志物的了解，并从这些数据中得出影响人类癌症风险准确评估的推论。比较丁二烯的DNA和血红蛋白加合物与暴露、代谢和遗传毒性的研究提供了许多适用于基于生物学的风险评估的见解。首先，DNA和血红蛋白加合物数据有力地支持了以下结论：3,4-环氧-1,2-丁二醇是可与这些大分子结合的主要亲电试剂。生物标志物研究还深入探讨了与GSTT1无效基因型相关的敏感人群的可能性。虽然很明显，GSTT1无效个体的淋巴细胞在体外暴露于1,2,3,4-二环氧丁烷后对姐妹染色单体交换（SCE）的诱导更敏感，但在暴露于1-3 ppm丁二烯的工人中，无论GST基因型如何，SCE或其他遗传毒性生物标志物均未增加。珠蛋白加合物数据还表明，丁二烯代谢的个体间差异大致有10倍的范围。这种分析是为这一关键决定因素提供科学数据的极佳手段。血红蛋白加合物在风险评估中的另一个有用应用是通过将各种遗传毒性终点的数据与个体的生物学有效剂量进行回归分析来证明的，从而提供了一种独立的评估机制，排除了不适当对照可能造成的任何混淆。最后，生物标志物研究已经确定了我们在准确评估丁二烯方面所需知识中的关键差距。其中最值得注意的是小鼠、大鼠和人类中缺乏二环氧物特异性生物标志物。
