Lin Yu-Sheng, Vermeulen Roel, Tsai Chin H, Waidyanatha Suramya, Lan Qing, Rothman Nathaniel, Smith Martyn T, Zhang Luoping, Shen Min, Li Guilan, Yin Songnian, Kim Sungkyoon, Rappaport Stephen M
Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina, Chapel Hill, North Carolina 27599-7431, USA.
Environ Health Perspect. 2007 Jan;115(1):28-34. doi: 10.1289/ehp.8948.
Metabolism of benzene produces reactive electrophiles, including benzene oxide (BO), 1,4-benzoquinone (1,4-BQ), and 1,2-benzoquinone (1,2-BQ), that are capable of reacting with blood proteins to produce adducts.
The main purpose of this study was to characterize relationships between levels of albumin adducts of these electrophiles in blood and the corresponding benzene exposures in benzene-exposed and control workers, after adjusting for important covariates. Because second blood samples were obtained from a subset of exposed workers, we also desired to estimate within-person and between-person variance components for the three adducts.
We measured albumin adducts and benzene exposures in 250 benzene-exposed workers (exposure range, 0.26-54.5 ppm) and 140 control workers (exposure range < 0.01-0.53 ppm) from Tianjin, China. Separate multiple linear regression models were fitted to the logged adduct levels for workers exposed to benzene < 1 ppm and > or =1 ppm. Mixed-effects models were used to estimate within-person and between-person variance components of adduct levels.
We observed nonlinear (hockey-stick shaped) exposure-adduct relationships in log-scale, with inflection points between about 0.5 and 5 ppm. These inflection points represent air concentrations at which benzene contributed marginally to background adducts derived from smoking and from dietary and endogenous sources. Adduct levels were significantly affected by the blood-collection medium (serum or plasma containing either heparin or EDTA), smoking, age, and body mass index. When model predictions of adduct levels were plotted versus benzene exposure > or =1 ppm, we observed marked downward concavity, particularly for adducts of the benzoquinones. The between-person variance component of adduct levels increased in the order 1,2-BQ < 1,4-BQ < BO, whereas the within-person variance components of the three adducts followed the reverse order.
Although albumin adducts of BO and the benzoquinones reflect exposures to benzene > or = 1 ppm, they would not be useful biomarkers of exposure at ambient levels of benzene, which tend to be < 0.01 ppm, or in those working populations where exposures are consistently < 1 ppm. The concavity of exposure-adduct relationships is consistent with saturable metabolism of benzene at air concentrations > 1 ppm. The surprisingly large effect of the blood-collection medium on adduct levels, particularly those of the benzoquinones, should be further investigated.
苯的代谢会产生具有反应活性的亲电试剂，包括苯氧化物（BO）、1,4 - 苯醌（1,4 - BQ）和1,2 - 苯醌（1,2 - BQ），这些亲电试剂能够与血液蛋白质发生反应生成加合物。
本研究的主要目的是在调整重要协变量后，描述苯暴露工人和对照工人血液中这些亲电试剂的白蛋白加合物水平与相应苯暴露之间的关系。由于从一部分暴露工人中获取了第二份血样，我们还希望估计这三种加合物在个体内和个体间的方差分量。
我们测量了来自中国天津的250名苯暴露工人（暴露范围为0.26 - 54.5 ppm）和140名对照工人（暴露范围<0.01 - 0.53 ppm）的白蛋白加合物和苯暴露水平。分别对苯暴露水平<1 ppm和≥1 ppm的工人的加合物水平对数拟合多元线性回归模型。使用混合效应模型估计加合物水平在个体内和个体间的方差分量。
我们在对数尺度上观察到非线性（曲棍球棒形状）的暴露 - 加合物关系，拐点在约0.5至5 ppm之间。这些拐点代表的空气浓度下，苯对源自吸烟、饮食和内源性来源的背景加合物的贡献微乎其微。加合物水平受到采血介质（含有肝素或乙二胺四乙酸的血清或血浆）、吸烟、年龄和体重指数的显著影响。当绘制加合物水平的模型预测值与苯暴露水平≥1 ppm的关系图时，我们观察到明显的向下凹度，特别是对于苯醌的加合物。加合物水平的个体间方差分量按1,2 - BQ < 1,4 - BQ < BO的顺序增加，而三种加合物的个体内方差分量则相反。
尽管BO和苯醌的白蛋白加合物反映了苯暴露水平≥1 ppm，但它们对于环境苯水平（往往<0.01 ppm）或暴露水平持续<1 ppm的工作人群来说，并不是有用的暴露生物标志物。暴露 - 加合物关系的凹度与空气浓度>1 ppm时苯的饱和代谢一致。采血介质对加合物水平，特别是苯醌加合物水平的惊人巨大影响，应进一步研究。
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