Absorption and disposition of bromate in F344 rats

Abstract

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 66μM 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 15.3mg/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 10min for all dose groups. The area under the curve (AUC) and peak concentrations (Ct=5′) were linearly related to IV dose up to 0.77mg/kg; however, disproportionate increases in the AUC and Ct=5′ and a large decrease in the volume of distribution was observed when IV doses of 1.9 and 3.8mg/kg were administered. The average terminal half-life of BrO3− from oral administration was 37min, but this was influenced by background levels of BrO3− at lower doses. With oral doses, the AUC and Cmax increased linearly with dose up to 15.3mgBrO3−/kg. BrO3− appeared to be 19–25% bioavailable without an obvious dose-dependency between 0.077 and 1.9mg/kg. The urinary elimination of BrO3− and Br− was measured from female F344 rats for four days following administration of single doses of 8.1mgKBrO3/kg and for 15 days after a single dose of 5.0mgKBr/kg. BrO3− elimination was detected over the first 12h, but Br− elimination from BrO3− over the first 48h was 18% lower than expected based on that eliminated from an equimolar dose of Br− (15.5±1.6 vs. 18.8±1.2μmol/kg, respectively). The cumulative excretion of Br− from KBr vs. KBrO3 was equivalent 72h 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 400mg/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.