2,3-Butanedione (BD) is a reactive diketone in artificial butter flavors that is thought to cause
bronchiolitis obliterans in workers in microwave popcorn manufacturing.
Bronchiolitis obliterans is generally not diagnosed until irreversible damage has occurred; therefore a
biomarker of early exposure is needed. The potential systemic uptake of BD from inhalation exposure has not been evaluated. The objective here was to evaluate the systemic exposure of BD and binding to
hemoglobin and
albumin. [(14)C]BD was administered to male Harlan Sprague Dawley rats (100 mg/kg, intratracheal instillation) and B6C3F1/N mice (157 mg/kg, oropharyngeal aspiration). Blood and plasma was collected 24 h after administration and analyzed for (14)C content. At 24h, 0.88±0.07% of the administered dose was in rat blood, 0.66±0.06% in rat plasma, 0.38±0.13% in mouse blood and 0.17±0.05% in mouse plasma.
Albumin binding in rats was 269±24.2 ng equiv./mg, which accounts for 38% of the radioactivity in plasma. In mice, binding was 85.0±22.3 ng equiv./mg
albumin, which accounts for 51% of the radioactivity in plasma. The binding to
hemoglobin in rats was 38.2±17.6 ng equiv./mg, and to
globin was 29.1±3.96 ng equiv./mg. In mice, the binding to
hemoglobin was 16.2±9.0 ng equiv./mg. The site(s) of adduction on
hemoglobin and
albumin was investigated by mass spectrometry. In rat
globin,
arginine adducts were detected at R-30 and R-104 of the beta chain in vitro and in vivo. In rat
albumin, adducts were detected in vitro on R-219/221, R-360, and R-368, and in vivo on a variety of
arginine residues. This study demonstrated that BD enters the systemic circulation and reacts with
arginine on
hemoglobin and
albumin. These results indicate that
hemoglobin and
albumin adducts may be useful as
biomarkers of BD exposure in humans.