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  • Title: 1,3-butadiene: cancer, mutations, and adducts. Part V: Hemoglobin adducts as biomarkers of 1,3-butadiene exposure and metabolism.
    Author: Swenberg JA, Christova-Gueorguieva NI, Upton PB, Ranasinghe A, Scheller N, Wu KY, Yen TY, Hayes R.
    Journal: Res Rep Health Eff Inst; 2000 Mar; (92):191-210; discussion 211-9. PubMed ID: 10925842.
    Abstract:
    1,3-Butadiene (BD) is an important chemical used largely in the manufacture of synthetic rubber and thermoplastic resins. In addition, it has been identified in cigarette smoke, automobile exhaust, and gasoline vapor. The objective of this research was to develop highly sensitive and specific assays for the detection and quantitation of hemoglobin adducts of three BD metabolites: 1,2-epoxy-3-butene (BDO), 1,2,3,4-diepoxybutane (BDO2), and 1,2-dihydroxy-3,4-epoxybutane (BDO-diol). We have successfully developed an assay for both N-(2-hydroxy-3-butenyl)valine (HBVal) and N-(2,3,4-trihydroxybutyl)valine (THBVal) in hemoglobin. The six adducts measured were the two diastereomers (isomers I and II) of HBVal and the four diastereomers of THBVal (isomers I through IV, which were eluted as three peaks, 1, 2, and 3). HBVal and THBVal were measured in control and exposed B6C3F1 mice and Sprague-Dawley rats (1,000 ppm BD for 13 weeks at 6 hours/day, 5 days/week). In a second set of animal exposures, total THBVal was determined in B6C3F1 female mice (n = 5) exposed to 1,250 ppm BD for 1, 5, or 10 days (6 hours/day, 5 days/week). THBVal adducts were also monitored in occupationally exposed Chinese workers and nonoccupationally exposed U.S. laboratory workers. This study utilized the modified Edman degradation method of Törnqvist and colleagues (1986). Briefly, the samples were subjected to Edman degradation, Centricon-30 ultrafiltration, washing on C18 columns, and acetylation for isomers of THBVal only, followed by gas chromatography-mass spectrometry (GC-MS) quantitation. For the HBVal assay, an authentic internal standard globin alkylated with [2H6]BDO was used; for the THBVal assay, a synthesized external standard, THB[13C5]Val, was used after Edman degradation. The mean +/- SD amounts of total HBVal measured in exposed mice (in pmol/g globin) were 16,560 +/- 3,910 for female mice (n = 4) and 12,400 +/- 2,030 for male mice (n = 5). The corresponding values for rats were 8,690 +/- 930 for female rats (n = 5) and 5,480 +/- 2,880 for male rats (n = 3). The total amount of THBVal (eluted peaks 1, 2, and 3) in male mice (n = 5) was 78,900 +/- 13,700; and in females (n = 2) was 56,100 +/- 100. In male rats (n = 3), the detected value was 9,650 +/- 1,620 and in females (n = 3) the value was 21,600 +/- 6,780. In control male mice (n = 4), the total level of THBVal isomers was approximately 27 pmol/g globin. In a control male rat, total THBVal was approximately 15 pmol/g globin. In the time course study, the amount of THBVal adducts increased linearly with exposure, resulting in values of 4,200 +/- 830, 19,760 +/- 1,780, and 35,940 +/- 3,460 pmol/g globin following 1, 5, or 10 days of exposure to 1,250 ppm BD, respectively. Detection of HBVal in human samples was difficult due to low concentrations of adducts and a high background in the chromatograms. In a pooled sample from 4 individuals, we performed multiple separations with high-pressure liquid chromatography (HPLC) of the derivatized adducts and detected 4.6 pmol/g globin (that is, 2.7 and 1.9 pmol/g globin for isomers I and II, respectively). We measured the amounts of THBVal in both nonoccupationally exposed U.S. laboratory workers and occupationally exposed workers from a polybutadiene plant in China. The mean total amount of THBVal among the U.S. laboratory workers was 36 +/- 23 pmol/g globin for nonsmokers (n = 7) and 40 +/- 9 for smokers (n = 4), compared with a mean total amount of 39 +/- 13 pmol/g globin in a control set of Chinese workers (n = 25). These control values are overestimations of the true values because the amounts of THBVal in globin samples from other unexposed individuals (15 of 51) were below our limit of detection. BD-exposed Chinese workers had a total amount of 88 +/- 59 pmol/g globin THBVal. The difference between smokers and nonsmokers was not significant, whereas the difference between control and exposed Chinese workers was highly significant (p < 0.001).
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