Absorption and disposition of bromate in F344 rats

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• 作者：Richard J. Bull ; Narendrababu Kolisetty ; Xiaoling Zhang ; Srinivasa Muralidhara ; Oscar Qui?ones ; Kok Yong Lim ; Zhongxian Guo ; Joseph A. Cotruvo ; Jeffrey W. Fisher ; Xiaoxia Yang ; Don Delker ; Shane A. Snyder ; Brian S. Cummings
• 关键词：Bromate ; Absorption ; Disposition ; Reaction products ; Rat
• 刊名：Toxicology
• 出版年：2012
• 出版时间：9 October, 2012
• 年：2012
• 卷：300
• 期：1-2
• 页码：83-91
• 全文大小：952 K

文摘

Bromate (BrO₃^?) is a ubiquitous by-product of using ozone to disinfect water containing bromide (Br^?). The reactivity of BrO₃^? with biological reductants suggests that its systemic absorption and distribution to target tissues may display non-linear behavior as doses increase. The intent of this study is to determine the extent to which BrO₃^? is systemically bioavailable via oral exposure and broadly identify its pathways of degradation. In vitro experiments of BrO₃^? degradation in rat blood indicate a rapid initial degradation immediately upon addition that is >98 % complete at concentrations up to 66 ¦ÌM in blood. As initial concentrations are increased, progressively lower fractions are lost prior to the first measurement. Secondary to this initial loss, a slower and predictable first order degradation rate was observed (10 % /min). Losses during both phases were accompanied by increases in Br^? concentrations indicating that the loss of BrO₃^? was due to its reduction. In vivo experiments were conducted using doses of BrO₃^? ranging from 0.077 to 15.3 mg/kg, administered intravenously (IV) or orally (gavage) to female F344 rats. The variable nature and uncertain source of background concentrations of BrO₃^? limited derivation of terminal half-lives, but the initial half-life was approximately 10 min for all dose groups. The area under the curve (AUC) and peak concentrations (C_t=5¡ä) were linearly related to IV dose up to 0.77 mg/kg; however, disproportionate increases in the AUC and C_t=5¡ä and a large decrease in the volume of distribution was observed when IV doses of 1.9 and 3.8 mg/kg were administered. The average terminal half-life of BrO₃^? from oral administration was 37 min, but this was influenced by background levels of BrO₃^? at lower doses. With oral doses, the AUC and C_max increased linearly with dose up to 15.3 mg BrO₃^?/kg. BrO₃^? appeared to be 19-25 % bioavailable without an obvious dose-dependency between 0.077 and 1.9 mg/kg. The urinary elimination of BrO₃^? and Br^? was measured from female F344 rats for four days following administration of single doses of 8.1 mg KBrO₃/kg and for 15 days after a single dose of 5.0 mg KBr/kg. BrO₃^? elimination was detected over the first 12 h, but Br^? elimination from BrO₃^? over the first 48 h was 18 % lower than expected based on that eliminated from an equimolar dose of Br^? (15.5 ¡À 1.6 vs. 18.8 ¡À 1.2 ¦Ìmol/kg, respectively). The cumulative excretion of Br^? from KBr vs. KBrO₃ was equivalent 72 h after administration. The recovery of unchanged administered BrO₃^? in the urine ranged between 6.0 and 11.3 % (creatinine corrected) on the 27th day of treatment with concentrations of KBrO₃ of 15, 60, and 400 mg/L of drinking water. The recovery of total urinary bromine as Br^? + BrO₃^? ranged between 61 and 88 % . An increase in the fraction of the daily BrO₃^? dose recovered in the urine was observed at the high dose to both sexes. The deficit in total bromine recovery raises the possibility that some brominated biochemicals may be produced in vivo and more slowly metabolized and eliminated. This was supported by measurements of dose-dependent increases of total organic bromine (TOBr) that was eliminated in the urine. The role these organic by-products play in BrO₃^?-induced cancer remains to be established.