Academic journal article Environmental Health Perspectives

Albumin Adducts of Electrophilic Benzene Metabolites in Benzene-Exposed and Control Workers

Academic journal article Environmental Health Perspectives

Albumin Adducts of Electrophilic Benzene Metabolites in Benzene-Exposed and Control Workers

Article excerpt

BACKGROUND: 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.

OBJECTIVES: 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.

METHODS: 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 [greater than or equal to] 1 ppm. Mixed-effects models were used to estimate within-person and between-person variance components of adduct levels.

RESULTS: 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 [greater than or equal to] 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.

CONCLUSIONS: Although albumin adducts of BO and the benzoquinones reflect exposures to benzene [greater than or equal to] 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.

KEY WORDS: albumin adduct, benzene oxide, benzoquinone, nonlinear, variation. Environ Health Perspect 115:28-34 (2007). doi:10.1289/ehp.8948 available via [Online 25 September 2006]


Benzene is a ubiquitous environmental contaminant generated from petroleum products and from combustion of organic matter, including cigarette smoking. Air concentrations of benzene are typically < 0.01 ppm in ambient environments but can exceed 10 ppm in industrial settings where benzene-containing products are used [International Agency for Research on Cancer (IARC) 1989; Wallace 1996]. Workers exposed to benzene have consistently experienced increased risks of hematopoietic disorders and leukemias (Hayes et al. 2000; Lan et al. 2004; Savitz and Andrews 1997). These toxic effects are thought to result from metabolism of benzene to reactive products (Snyder 2002).

As shown in Figure 1, benzene metabolites include several reactive electrophiles, namely, benzene oxide (BO), 1,2- and 1,4-benzoquinone (1,2-BQ and 1,4-BQ, respectively), the muconaldehydes, and benzene diolepoxide [reviewed by (Snyder 2000a, 2000b, 2002)]. Because these electrophilic species are short lived in vivo, they have been investigated in animals and humans by measuring their adducts with hemoglobin, serum albumin, and bonemarrow proteins (Bechtold et al. …

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