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Systemic uptake of 14C 2,3-butanedione administered by intratracheal instillation in male Sprague-Dawley rats and oropharyngeal aspiration in male B6C3F1 mice
Fennell, T. R., Morgan, D., Watson, S. L., & Waidyanatha, S. (2011). Systemic uptake of 14C 2,3-butanedione administered by intratracheal instillation in male Sprague-Dawley rats and oropharyngeal aspiration in male B6C3F1 mice. The Toxicologist, Supplement to Toxicological Sciences, 120, 2320.
2,3-Butanedione (BD) is a reactive diketone that is found in butter and has been used in artificial butter flavor, and is thought to cause bronchiolitis obliterans in popcorn workers. The extent of uptake of BD from inhalation exposure is a concern. The objective of this study was to evaluate the ability of BD to be taken up in the lung, enter the systemic circulation, and bind to hemoglobin and albumin. [1-14C] BD was administered to male Sprague Dawley rats (100 mg/kg) by intratracheal instillation (ITI), and to male B6C3F1 mice (200 mg/kg) by oropharyngeal aspiration (OPA). After 24 h, animals were euthanized and blood collected. Blood and plasma were analyzed for 14C to estimate the systemic dose at 24h. Binding to plasma albumin was assessed following isolation by trichloroacetic acid precipitation, and ultrafiltration, or by ammonium sulfate precipitation. Binding to hemoglobin was assessed by dialysis of hemolysate followed by size exclusion HPLC, or by precipitation of globin from hemolysate with acidic acetone. At 24 h, 1.2 ± 0.1 % of the dose was found in rat blood, 0.66 ± 0.06 % in rat plasma, 0.35 ± 0.12% in mouse blood and 0.17 ± 0.05 % in mouse plasma. Albumin binding in rats was 3.12 ± 0.28 nmol equiv/mg albumin, with 38% of the radioactivity in plasma bound to albumin. In mice, binding was 0.99 ± 0.26 nmol equiv./mg albumin, with 45% of the radioactivity in mouse plasma bound to albumin. The extent of binding to hemoglobin in the rat was 0.44 ± 0.20 nmol equiv/mg hemoglobin, and 0.31 ± 0.05 nmol/mg globin. In mice, the extent of binding to hemoglobin was 0.19 ± 0.10 nmol/mg. This study demonstrated that BD, following administration by ITI in rats or by OPA in mice, can enter the systemic circulation and react with hemoglobin and albumin. This shows the promise for evaluating hemoglobin and albumin adducts as biomarkers of exposure in humans
