The Effects of Dose, Route, and Repeated Dosing on the Disposition and Kinetics of Tetrabromobisphenol A in Male F-344 Rats (original) (raw)
Related papers
2006
The comparative in vitro metabolism of the flame retardant tetrabromo-bisphenol A was studied in rat and human using a [ 14 C]radio-labelled molecule. Tetrabromo-bisphenol A is metabolised into the corresponding glucuronide (liver S9 fractions) and several other metabolites produced by cytochrome P450 dependent pathways (liver microsomes and liver S9 fractions). No major qualitative differences were observed between rat and human, regardless of the selected concentration, within the 20-200 lM range. Tetrabromobisphenol A undergoes an oxidative cleavage near the central carbon of the molecule, that leads to the production of hydroxylated dibromo-phenol, hydroxylated dibromo-isopropyl-phenol and glutathione conjugated dibromo-isopropyl-phenol. The main metabolites of tetrabromo-bisphenol A are two molecules of lower polarity than the parent compound, characterised as a hexa-brominated compound with three aromatic rings and a hepta-brominated dimer-like compound, respectively. Both structures, as well as the lower molecular weight metabolites resulting from the breakdown of the molecule, suggest the occurrence of chemically reactive intermediates formed following a first step oxidation of tetrabromo-bisphenol A.
Chemico-Biological Interactions, 1993
The distribution of 2,3,7,8-tetrachloro-[3H]dibenzofuran ([3H]TCDF; 40 micrograms/kg) resembled that earlier reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin, with a strong accumulation in the liver and a selective uptake in the nasal olfactory mucosa of adult and fetal mice. Pretreatments with a series of selected congeners of polychlorinated biphenyls (PCBs), i.e.. I (IUPAC)-77, I-105, I-118, I-126, I-153, I-156, I-169, and a commercial preparation, Aroclor 1254 (25-100 mg/kg body wt. i.p.), were found to modulate the hepatic uptake of [3H]TCDF (24 h post-3H-injection). At a short pretreatment time (4 h), non-ortho-chlorinated congeners decreased the uptake of [3H]TCDF equivalents in the liver (e.g., I-126 = 3,3',4,4',5-pentachlorobiphenyl: 34% of control), while several mono- and di-ortho PCB congeners and Aroclor 1254 increased the hepatic uptake of [3H]TCDF (e.g., I-156 = 2,3,3',4,4',5-hexachlorobiphenyl: 183% of control). At a longer pretreatment time (48 h), both a non-ortho (I-169 = 3,3',4,4',5,5'-hexachlorobiphenyl) and mono-ortho PCB congener(s) (e.g. I-156) markedly increased the hepatic 3H-uptake (190%), a probable effect of an induction of hepatic binding sites for TCDF. Ethoxyresorufin-O-deethylase activities, regarded to mirror the metabolic activity of cytochrome P-450 IA1 (CYP IA1), were strongly and time-dependently induced after I-169, but not after I-156, pretreatment (25 mg/kg). The initial liver concentrations of the two PCB congeners were similar and increased for I-169 but not for I-156 at later time points. In conclusion, the results show a selective uptake of [3H]TCDF in the mouse liver and nasal olfactory mucosa of both dam and fetus. The uptake of [3H]TCDF in the liver is influenced both by dose and pre-exposure with PCBs. The presence of a PCB-sensitive, but CYP IA1-independent, hepatic binding site for TCDF is suggested. Consequently, pharmacokinetic interactions with PCBs complicate the toxicity assessment of TCDF in complex mixtures.
Absorption and disposition of bromate in F344 rats
Toxicology, 2012
Bromate (BrO 3 −) is a ubiquitous by-product of using ozone to disinfect water containing bromide (Br −). The reactivity of BrO 3 − 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 BrO 3 − is systemically bioavailable via oral exposure and broadly identify its pathways of degradation. In vitro experiments of BrO 3 − degradation in rat blood indicate a rapid initial degradation immediately upon addition that is >98% complete at concentrations up to 66 M 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 BrO 3 − was due to its reduction. In vivo experiments were conducted using doses of BrO 3 − 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 BrO 3 − 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) were linearly related to IV dose up to 0.77 mg/kg; however, disproportionate increases in the AUC and C t=5 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 BrO 3 − from oral administration was 37 min, but this was influenced by background levels of BrO 3 − at lower doses. With oral doses, the AUC and C max increased linearly with dose up to 15.3 mg BrO 3 − /kg. BrO 3 − appeared to be 19-25% bioavailable without an obvious dose-dependency between 0.077 and 1.9 mg/kg. The urinary elimination of BrO 3 − and Br − was measured from female F344 rats for four days following administration of single doses of 8.1 mg KBrO 3 /kg and for 15 days after a single dose of 5.0 mg KBr/kg. BrO 3 − elimination was detected over the first 12 h, but Br − elimination from BrO 3 − over the first 48 h was 18% lower than expected based on that eliminated from an equimolar dose of Br − (15.5 ± 1.6 vs. 18.8 ± 1.2 mol/kg, respectively). The cumulative excretion of Br − from KBr vs. KBrO 3 was equivalent 72 h after administration. The recovery of unchanged administered BrO 3 − in the urine ranged between 6.0 and 11.3% (creatinine corrected) on the 27th day of treatment with concentrations of KBrO 3 of 15, 60, and 400 mg/L of drinking water. The recovery of total urinary bromine as Br − + BrO 3 − ranged between 61 and 88%. An increase in the fraction of the daily BrO 3 − 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 BrO 3 −-induced cancer remains to be established.
Environment International, 2020
The measurement of bisphenol-S (BPS) and its glucurono-conjugate (BPSG) in urine may be used for the biomonitoring of exposure in populations. However, this requires a thorough knowledge of their toxicokinetics. The time courses of BPS and BPSG were assessed in accessible biological matrices of orally and dermally exposed volunteers. Under the approval of the Research Ethics Committee of the University of Montreal, six volunteers were orally exposed to a BPS-d8 deuterated dose of 0.1 mg/kg body weight (bw). One month later, 1 mg/kg bw of BPS-d8 were applied on 40 cm 2 of the forearm and then washed 6 h after application. Blood samples were taken prior to dosing and at fixed time periods over 48 h after treatment; complete urine voids were collected pre-exposure and at pre-established intervals over 72 h postdosing. Following oral exposure, the plasma concentration-time courses of BPS-d8 and BPSG-d8 over 48 h evolved in parallel, and showed a rapid appearance and elimination. Average peak values (± SD) were reached at 0.7 ± 0.1 and 1.1 ± 0.4 h postdosing and mean (± SD) apparent elimination half-lives (t ½) of 7.9 ± 1.1 and 9.3 ± 7.0 h were calculated from the terminal phase of BPS-d8 and BPSG-d8 in plasma, respectively. The fraction of BPS-d8 reaching the systemic circulation unchanged (i.e. bioavailability) was further estimated at 62 ± 5% on average (± SD) and the systemic plasma clearance at 0.57 ± 0.07 L/kg bw/h. Plasma concentration-time courses and urinary excretion rate profiles roughly evolved in parallel for both substances, as expected. The average percent (± SD) of the administered dose recovered in urine as BPS-d8 and BPSG-d8 over the 0-72 h period postdosing was 1.72 ± 1.3 and 54 ± 10%. Following dermal application, plasma levels were under the lower limit of quantification (LLOQ) at most time points. However, peak values were reached between 5 and 8 h depending on individuals, suggesting a slower absorption rate compared to oral exposure. Similarly, limited amounts of BPS-d8 and its conjugate were recovered in urine and peak excretion rates were reached between 5 and 11 h postdosing. The average percent (± SD) of the administered dose recovered in urine as BPS-d8 and BPSG-d8 was about 0.004 ± 0.003 and 0.09 ± 0.07%, respectively. This study provided greater precision on the kinetics of this contaminant in humans and, in particular, evidenced major differences between BPA and BPS kinetics with much higher systemic levels of active BPS than BPA, an observation explained by a higher oral bioavailability of BPS than BPA. These data should also be useful in developing a toxicokinetic model for a better interpretation of biomonitoring data.
Toxicological Sciences, 2002
This study was done to generate kinetic data on individual congeners of chlorinated biphenyls in the low dose range, which could be of value in the risk assessment procedure. Male Sprague-Dawley rats were given a single oral dose of a mixture of polychlorinated biphenyls (CBs) containing either CBs 105, 118, 138, 153, 156, 157, 170, and 180 (A-mix) or CBs 28, 52, 77, 87, and 101 (B-mix). Liver, serum, and adipose tissue were collected after 6 h up to 135 days, from rats given the A-mix, and after 6 h up to 4 days from rats given the B-mix. CB concentrations were measured in liver, serum, and adipose tissue. In addition, this study provides kinetic data of one of the major CB metabolites, 4-hydroxy-2,3,3,4,5-pentachlorobiphenyl (4-OH-CB107). The low doses used resulted in serum CB concentrations similar to human background serum concentrations. In the A-mix experiment all CBs show high initial liver and serum concentrations followed by redistribution into adipose tissue. Differences between congeners were correlated to molecular weight. High molecular weight correlated to lower uptake and slower redistribution. During dynamic steady-state the tissue concentrations decreased with a calculated first order rate between 54-129 days for halving the concentrations (halflife). Most of the decrease in concentration was explained by the growth-related increase of tissue masses in general and adipose tissue in particular. In the B-mix experiment, the concentrations of CBs in adipose tissue decreased with between 25 and 59% from day 1 to day 4. These results show that the B-mix congeners, given at low dose, have longer half-lives than previously reported in high dose studies. Partition coefficients between body compartments are reported and for the first time a high and congener specific liver-to-serum ratio of CB 77 is observed.
Distribution and Elimination of 14C-Hexachlorobenzene after Single Oral Exposure in the Male Rat
Acta Pharmacologica Et Toxicologica, 2009
The distribution and excretion of 14C-hexachlorobenzene (I4C-HCB) after administration to rats of a single oral dose of 50 pCi I4C-HCB per kg body weight was studied by whole-body autoradiography and liquid scintillation counting. Radiolabelled HCB was distributed throughout the body in 2 hours. Peak levels were found at 4 hours in the liver and the brown fat and at 24 hours in the abdominal and subcutaneous fat. The highest concentrations were found in the adipose tissues, the bone marrow, the skin, the Harderian gland, the nasal mucosa, the praeputial gland, and the intestinal tract. After 90 days, substantial amounts were present only in the adipose tissue, the skin, the nasal mucosa, and the praeputial gland. Part of the radioactivity in the brown fat, the bone marrow, the praeputial gland, the adrenal gland, the liver, the blood, the kidney, the spleen, the lungs, the heart and the gastrointestinal contents was found not to be evaporable on sections heated to 50" for 24 hrs and was considered to represent metabolites of HCB. Some radioactivity remained in the liver, the kidney, the heart and the intestinal contents after evaporation and extraction of the sections with polar and nonpolar solvents and was supposed to reflect metabolites of HCB associated to tissue macromolecules. Besides urine and faeces, the results indicated the following excretory pathways: Intestinal rnucosa, sebacous glands, nasal mucosa and the praeputial and Harderian gland.
Dose-dependent pharmacokinetics and hepatobiliary transport of bromophenol blue in the beagle
Journal of Pharmaceutical Sciences, 1984
The pharmacokinetic profile of bromophenol blue (I) in the plasma, urine, and bile of beagle dogs was determined after intravenous administration of 5-, 20-, and 30-mg/kg doses. In addition, two competitors, probenecid and phenylbutazone, were interacted with I in uiuo and with I and rat liver cytoplasmic protein fractions Y and 2 in uitro as a means of elucidating the mechanism of intrahepatic transport of I. Compound I was determined spectrophotometrically at 587 nm. In plasma, I displayed apparent first-order dose-dependent kinetics. The percentage of I bound to plasma proteins was -92.5% over the dose range studied. Consecutive injections of equal dosesof I produced statistically different terminal half-lives (p < 0.05),
Pharmacokinetics of Dibutyl Phthalate (DBP) in the Rat Determined by UPLC-MS/MS
International Journal of Molecular Sciences, 2013
Dibutyl phthalate (DBP) is commonly used to increase the flexibility of plastics in industrial products. However, several plasticizers have been illegally used as clouding agents to increase dispersion of aqueous matrix in beverages. This study thus develops a rapid and validated analytical method by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) for the evaluation of pharmacokinetics of DBP in free moving rats. The UPLC-MS/MS system equipped with positive electrospray ionization (ESI) source in multiple reaction monitoring (MRM) mode was used to monitor m/z 279.25→148.93 transitions for DBP. The limit of quantification for DBP in rat plasma and feces was 0.05 µg/mL and 0.125 µg/g, respectively. The pharmacokinetic results demonstrate that DBP appeared to have a two-compartment model in the rats; the area under concentration versus time (AUC) was 57.8 ± 5.93 min μg/mL and the distribution and elimination half-life (t 1/2,α and t 1/2,β ) were 5.77 ± 1.14 and 217 ± 131 min, respectively, after DBP administration (30 mg/kg, i.v.). About 0.18% of the administered dose was recovered from the feces within 48 h. The pharmacokinetic behavior demonstrated that DBP was quickly degraded within 2 h, suggesting a rapid metabolism low fecal cumulative excretion in the rat.
Environmental Science & Technology
The technical mixture of 1,2-Dibromo-4-(1,2-dibromethyl)cyclohexane (TBECH or DBE-DBCH) and the pure β-TBECH isomer were subjected to in vitro biotransformation by human liver microsomes (HLM) for the first time. After 60 mins of incubation, 5 potential metabolites of TBECH were identified in microsomal assays of both the TBECH mixture and β-TBECH using UPLC-Q-Exactive Orbitrap™ mass spectrometry. These include mono-and di-hydroxylated TBECH, mono-and di-hydroxylated TriBECH as well as an α-oxidation metabolite bromo-(1,2dibromocyclohexyl)-acetic acid. Our results indicate potential hepatic biotransformation of TBECH via Cyctochrome P450-catalyzed hydroxylation, debromination and α-oxidation. Kinetic studies revealed the formation of monohydroxy-TBECH, dihydroxy-TBECH and monohydroxy-TriBECH were best fitted to a Michaelis-Menten enzyme kinetic model. Respective estimated V max values (maximum metabolic rate) for these metabolites were: (11.8 ± 4), (0.6 ± 0.1) and (10.1 ± 0.8) pmol/min/mg protein in TBECH mixture and (4992 ± 1340), (14.1 ± 4.9) and (66.1 ± 7.3) pmol/min/mg protein in β-TBECH. This indicates monohydroxy-TBECH as the major metabolite of TBECH by human liver. The estimated intrinsic clearance (Cl int) of TBECH mixture was slower (P<0.05) than that of pure β-TBECH. While the formation of monohydroxy-TBECH may reduce the bioaccumulation potential and provide a useful biomarker for monitoring TBECH exposure, further studies are required to fully understand the levels and toxicological implications of the identified metabolites.
Chemical Research in Toxicology, 2015
The purpose of this study is to characterize the tissue distribution, excretion and pharmacokinetics profiles of R-hap in healthy Wistar rats. R-hap was radiolabeled by the IODO-GEN method. Tissue distribution and urinary, fecal and biliary excretion patterns of 125 I-R-hap were investigated following a single i.v. bolus injection. Pharmacokinetics properties of 125 I-R-hap were also examined after a single i.v. bolus injection. The trichloroacetic acid (TCA) precipitated radioactivity was widely distributed and rapidly diminished in most tissues. Kidney contained the highest radioactivity among all organs and the distribution of 125 I-R-hap to fat was minimal. The cumulative excretion of 125 I-R-hap reached 71.81% ± 2.15% of the administered radioactivity at 48 h and 94.71% ± 1.50% at 120 h. Urinary excretion was the dominant route of elimination following i.v. administration, as 80.64% ± 1.47% and 14.07% ± 0.95% of administered radioactivity were recovered in urine and feces, respectively, in intact rats over 120 h. The mean areas under the plasma concentration-time curve was (8818.4 ± 576.1) Bq/h/mL. The results of tissue distribution, excretion and pharmacokinetics of R-hap in rats provided biopharmaceutical basis for the design of future clinical trials.