Derivation of biomonitoring equivalents (BE values) for bismuth.

Bismuth (Bi) is a natural element present in the environmental media. Bismuth has been used medicinally for centuries, specifically for the treatment of gastrointestinal (GI) disorders. Although bismuth toxicity is rare in humans, an outbreak of bismuth-induced neurotoxicity was reported in France and Australia in the mid-1970s. The primary source of bismuth exposure in the general population is via food. US FDA (2019) estimated recommended daily intake (RDI) for bismuth as 848 mg bismuth/day (12.1 mg Bi/kg-d assuming a body weight of 70 kg) for GI tract disorders. Exposures to bismuth can be quantified by measuring concentrations in blood and urine. Biomonitoring equivalents (BEs) were derived based on US FDA's RDI as a tool for interpretation of population-level biomonitoring data. A regression between steady state plasma concentrations and oral intakes was used to derive plasma BEs. A whole blood: plasma partitioning coefficient of 0.6 was used to convert plasma BE into whole blood BE. A mass balance equation with a urinary excretion fraction of 0.0003 was used to derive urinary BE. The BE values associated with US FDA's RDI for plasma, whole blood and urine were 8.0, 4.8 and 0.18 µg/L, respectively. These BE values together with bismuth biomonitoring data may be used in screening and prioritization of health risk assessment of bismuth in the general population.

Kinetics and tissue distribution of bismuth, tin and lead after implantation of miniature shotgun alloy pellets in rats.

INTRODUCTION: Shotgun pellets containing bismuth (Bi) as substitute for lead (Pb) are increasingly being used due to environmental concerns. Information on toxicokinetics of Bi is lacking for the assessment of humans accidentally shot by Bi-containing shotgun alloy pellets. METHODS: Male Wistar rats were exposed to miniature alloy pellets containing Bi, tin (Sn) and minor amounts of Pb by implantation in muscle tissues of the hind legs. RESULTS: The concentrations of Bi in whole blood and urine increased up to 53 weeks after implantation. The highest concentrations of Sn in whole blood were observed three weeks after implantation, then declining to background levels 53 weeks after implantation. Lead in whole blood increased up to 13 weeks of exposure, and declined for the remaining observation period. Bismuth and Sn accumulated mainly in kidney, but also in liver, testicle and brain. Analytical field emission scanning electron microscopy of post-implant pellets showed depletion of Pb towards the pellet surface. Oxygen and chlorine accumulated in Sn rich lamellas in areas next to the pellet surface. The distribution of Bi remained visually unaffected as compared to pre-implant pellets. CONCLUSION: The concentration of Bi increased during the whole observation period in blood, urine, kidney, brain, testicle and liver. The decline in the concentrations of Pb and Sn in blood and urine after reaching the peak concentration may be related to alterations in the chemical composition and element distribution of the implanted alloy pellets.

Facile Chip-Based Array Monolithic Microextraction System Online Coupled with ICPMS for Fast Analysis of Trace Heavy Metals in Biological Samples.

Trace heavy metals have great impact on biological system; therefore, it is essential to develop suitable analytical methods for the determination of trace heavy metals in biological samples to elucidate their biochemical and physiological functions in organisms. Herein, we presented a chip-based array monolithic microextraction system and combined it with inductively coupled plasma mass spectrometry (ICPMS) for online analysis of trace Hg, Pb, and Bi in real-world biological samples. Six ethylenediamine modified poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) (poly(GMA-co-EDMA-NH2)) capillary monolithic columns were embedded parallelly in microchannels of a microfluidic chip for array monolithic microextraction. Various parameters affecting the chip-based array monolithic microextraction of target metals were investigated. The sample throughput of the proposed method was 16 h-1, with the limits of detection for Hg, Pb, and Bi of 23, 12, and 13 ng L-1, respectively. The developed method was validated by the determination of trace Hg, Pb, and Bi in HepG2 cells and human urine samples, and the recoveries for the spiked samples were in the range of 90.4-102%. This chip-based array monolithic microextraction system is easy to prepare, and the proposed online analytical system provides a new platform for trace elements analysis in biological samples with the merits of high sample throughput, high sensitivity, and low sample/reagents consumption.

Solubility, absorption, and anti-Helicobacter pylori activity of bismuth subnitrate and colloidal bismuth subcitrate: In vitro data Do not predict In vivo efficacy.

OBJECTIVES: The aim of this study was to compare the dissolution, bioavailability, and anti-Helicobacter pylori activity of bismuth subnitrate and colloidal bismuth subcitrate. This could, first, provide insights into the mechanism of action of bismuth and, second, help to develop optimal therapeutic strategies. METHODS: Solubility and aquated size of bismuth species were determined in human gastric juice, while absorption into blood and urinary excretion of bismuth was determined in volunteers. Activity against H. pylori was determined in vitro in the presence and absence of antibiotics, while H. pylori eradication was compared in vivo. RESULTS: Bismuth from colloidal bismuth subcitrate was at least 10% soluble and ultrafilterable and was absorbed in volunteers (>0.5%), whereas that from bismuth subnitrate was insoluble and not absorbed (<0.01%). Colloidal bismuth subcitrate was active against H. pylori (mean inhibitory concentration, 400 microg/ml); neither was synergistic with antibiotics. With in vivo triple therapy, bismuth subnitrate was as effective as colloidal bismuth subcitrate in eradicating H. pylori (74% and 70% eradicated, respectively). CONCLUSIONS: Colloidal bismuth subcitrate, unlike bismuth subnitrate, is partially soluble, absorbed in humans, and directly toxic to H. pylori in vitro. Surprisingly, however, these preparations had similar efficacy in vivo against H. pylori within triple therapy, suggesting that bismuth compounds may also exhibit indirect antimicrobial effects. We propose that this is an effect on the gastric mucus layer. Nonabsorbable bismuth compounds should be preferentially considered in bismuth-based therapies against H. pylori, as they would minimize toxicity while maintaining efficacy.

Site of bismuth absorption from bismuth subsalicylate: implications for treatment of colonic conditions.

Poorly absorbed bismuth preparations may benefit a variety of chronic colonic conditions including ulcerative colitis. Bismuth-induced neurotoxicity is a potential complication of the chronic use of these preparations, and a less-absorbable form of bismuth is needed. If bismuth absorption occurs primarily in the upper gut, a delayed-release bismuth preparation could reduce absorption. We studied the site of bismuth absorption from bismuth subsalicylate (BSS) in rats. For 15 days, BSS (50 mg/day) was ingested or infused directly into the cecum via a chronically implanted cannula. Oral BSS resulted in serum and urine bismuth levels many times higher (3.5 +/- 0.3 microg/liter and 1,570 +/- 286 microg/g creatinine, respectively) than with cecal administration (undetectable (<1.5 microg/liter) and 75 +/- 25 microg/g creatinine). Thus, bismuth absorption from BSS occurred almost entirely in the upper gut. These findings provide a rationale for a similar study of delayed-release bismuth preparations in humans.

Comparison of enhanced elimination of bismuth in humans after treatment with meso-2,3-dimercaptosuccinic acid and D,L-2,3-dimercaptopropane-1-sulfonic acid.

Two groups of 12 human volunteers, who had been treated with colloidal bismuth subcitrate, because of Helicobacter pylori-associated gastritis, participated in the study. The patients received a single dose of meso-2,3-dimercaptosuccinic acid (DMSA) or D,L-2,3-dimercaptopropane-1-sulfonic acid (DMPS) at a dose of 30 mg kg-1 in a randomized single blind study. In contrast to DMPS, increasing concentrations of bismuth in blood were observed during the first 4 h after intake of DMSA. In urine, both chelators induced a 50-fold increase in urinary bismuth excretion compared with the control urines. The treatment was well tolerated. The results indicate that both DMSA and DMPS effectively increase the elimination of bismuth in human urine. Consequently, both chelators may be of benefit in the treatment of patients with bismuth intoxication.

Determination of bismuth in urine and prescription medicines using atomic absorption with an on-line hydride generation system.

The bismuth contents of various digested urine samples and prescription medicines were determined by atomic absorption spectrometry combined with hydride generation. The procedure followed was a standard addition method for urine and direct calibration for the prescription medicines. The detection limit of the method was determined to be 320 pg ml-1 Bi with an analytical frequency of 150 h-1. A relative standard deviation of 4.7% was found for Bi in urine at the level of 4.3 ng ml-1 Bi. Interference caused by NiII, CoII, CuII, AgI, SeIV, SbIII and HgII could be controlled with a masking solution of thiourea (0.2%)-KI (10%).

The determination of metals (antimony, bismuth, lead, cadmium, mercury, palladium, platinum, tellurium, thallium, tin and tungsten) in urine samples by inductively coupled plasma-mass spectrometry.

OBJECTIVE: An analytical method has been established to determine the concentration of antimony (Sb), bismuth (Bi), lead (Pb), cadmium (Cd), mercury (Hg), Palladium (Pd), platinum (Pt), tellurium (Te), tin (Sn), thallium (Tl) and tungsten (W) in urine. The aim was to develop a method which is equally suitable for the determination of environmentally as well as occupationally caused metal excretion. METHODS: Inductively coupled plasma-mass spectroscopy (ICP-MS) was used for the determination of metals. Calibration was done using aqueous solutions and standard addition respectively. RESULTS: Urine samples of 14 persons occupationally non-exposed to metals were analysed. With the exception of Pt and Bi all the metals were found in these urine samples. The detection limits for these metals lie between 5 and 50 ng/l. CONCLUSIONS: For some metals, which are important from an occupational as well as an environmental viewpoint, ICP-MS is more sensitive than atomic absorption spectrometry (AAS). ICP-MS, moreover, is welcome as a reference method for AAS with the additional advantage of multi-element measurement.

Mass balance of 14C-bismuth sucrose octasulfate in Sprague-Dawley rats: evidence for dissociation of bismuth from sucrose octasulfate.

The mass balance of 14C bismuth sucrose octasulfate (BISOS) was investigated in eight male Sprague-Dawley rats after single oral doses of 1.0 g kg-1. Bismuth and radioactivity were monitored in blood, urine, and feces for up to 144 h post-dose, while kidneys, brain, liver, and lungs were assayed for bismuth at 144 h post-dose. In a separate experiment, bismuth was monitored in bile of bile-duct-cannulated animals for 48 h post-dose. Fecal excretion of bismuth averaged 95.8 +/- 5.30% bismuth dose, while 99.2 +/- 3.63% of the radiolabel was excreted in feces. Urinary excretion of bismuth averaged 0.051 +/- 0.028% bismuth dose, and 1.83 +/- 1.08% radioactive dose. Biliary excretion of bismuth averaged 0.0003 +/- 0.0006% bismuth dose, and 0.026 +/- 0.030% radiolabeled dose. An average 0.005 +/- 0.002% of the bismuth dose was present in kidney, liver, and lung. Bismuth levels in brain were below quantifiable limits. Though BISOS contains 57.3% by weight of bismuth, peak blood concentrations of bismuth were three orders of magnitude lower than for BISOS equivalents (Cmax for BISOS averaged 110 +/- 55.4 micrograms eq mL-1, while for bismuth it was 26.1 +/- 10.3 ng mL-1). This data indicates that bismuth dissociates from sucrose octasulfate, probably during the absorption phase, and exhibits differential pharmacokinetic characteristics from sucrose octasulfate. The low biliary and urinary excretion of both bismuth and BISOS equivalents is indicative of low systemic absorption. Greater than 96% recovery in feces, bile, and urine indicates that mass balance was achieved following oral administration.

Plasma and tissue distribution of bismuth in normal and cirrhotic rats.

The effect of liver disease on total body handling of bismuth was studied in normal and cirrhotic rats to test the hypothesis that hepatic function can be a significant determinant of heavy metal handling. Excretion and tissue distribution of bismuth were investigated in animals administered bismuth subcitrate by the intramuscular route for 70 d. Plasma bismuth in control rats reached an apparent steady state of 31.89 +/- 4.15 micrograms l-1 (mean +/- standard error of mean, n = 12) by day 28-35. The plasma profile in cirrhotic rats resembled that of controls until day 42 after which bismuth concentrations became significantly elevated. At day 70 of dosing the mean plasma bismuth concentration was 63.68 +/- 9.68 micrograms l-1 (n = 11) in cirrhotic rats compared with 32.68 +/- 4.24 micrograms l-1 (n = 12) in control rats (p < 0.05). Total urinary excretion of cirrhotic animals closely paralleled that of controls; however, urinary bismuth clearance was significantly reduced beyond 42 d, as was faecal excretion. Bismuth tissue distribution was analysed in a randomly selected sub-set of control and cirrhotic animals. There was a significantly higher concentration of bismuth in the liver, bone, spleen, lungs and heart of the cirrhotic rats, with no change in the kidney. There was minimal accumulation of bismuth in the central nervous system of either normal or cirrhotic animals. Bismuth accumulation in cirrhotic rats suggests that patients with cirrhosis could be at risk from similar accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Bismuth concentration in blood and urine of children treated with ventrisol (polfa) preliminary study.

The bismuth concentration was measured in the blood and urine of 21 children from 8 to 17 years old (13.12 +/- 2.67) treated with Ventrisol (Polfa)-tripotassium dicitrato bismuthate (TDB). One tablet of TDB-equivalent to 120 mg Bi2O3. One tablet was given orally to the patients four times a day. Blood and urine was taken for measurement of bismuth concentration in the morning, on fasting, before the administration of Ventrisol on the 6-8 days, the 27-28 days of the therapy and in the 4-5, 8-9 weeks after TDB therapy. The reason for TDB treatment was chronic gastritis and/or duodenal ulcers, which were diagnosed by endoscopic examination. No bismuth in the blood and a very low concentration in the urine were determined in 19 children before TDB treatment. After 6-8 days of TDB treatment the bismuth concentration in the blood was 40.85 +/- 31.05 micrograms/L and 75.11 +/- 82.07 micrograms/L in the urine. In the 27-28 days of the treatment the bismuth concentration in the blood was 37.67 +/- 25.06 micrograms/L, and 163.56 +/- 181.86 micrograms/L in the urine. In the 4-5 weeks after the TDB treatment the bismuth concentration in the blood was 7.77 +/- 10.56 micrograms/L, and 15.72 +/- 9.87 micrograms/L in the urine. The bismuth concentration level in the urine rose together with the rise of the bismuth concentration level in the blood, the correlation factor was r = 0.68. No symptoms of side effects caused by the TDB treatment were observed. Before the treatment a high bismuth concentration was found in the blood of two patients. These cases are discussed later.

Lack of evidence of neurotoxicity following 8 weeks of treatment with tripotassium dicitrato bismuthate.

OBJECTIVE: To search for evidence of subclinical neurotoxicity in patients treated with tripotassium dicitrato bismuthate. DESIGN: Prospective, controlled, triplicate study using urinary bismuth concentration, magnetic resonance imaging (MRI), nerve conduction studies, visual evoked response and a battery of 10 neuropsychological screening tests. SETTING: Out-patient clinics, Walsgrave Hospital, Coventry, UK. SUBJECTS: Fourteen dyspeptic patients; 8 (treatment group) treated with tripotassium dicitrato bismuthate one tablet q.d.s and 6 (control group) treated with ranitidine 150 mg b.d. for 8 weeks. MAIN OUTCOME MEASURES: Changes in urinary bismuth, MRI, nerve conduction studies, visual evoked response, and neuropsychological tests performed before, immediately after and 8 weeks after the cessation of treatment. RESULTS: In the treatment group the median (range) urinary bismuth concentration was 1 (1-12) ng/ml before treatment, increased to 560 (140-1300) immediately after treatment (P < 0.01, Wilcoxon Rank Sum test) and was still significantly elevated (23 (7-53) ng/ml) 8 weeks after the cessation of treatment. In the patient who recorded the highest urinary bismuth, a high intensity signal appeared in the globus pallidus immediately after treatment and was still present (though diminished in intensity) 8 weeks after the cessation of treatment. This isolated MRI finding was not associated with evidence of subclinical neurotoxicity. No changes in the MRI, nerve conduction studies, visual evoked response and neuropsychological tests were observed among the other patients studied. CONCLUSIONS: Bismuth accumulation occurs in patients receiving a conventional course of treatment with tripotassium dicitrato bismuthate but this is not associated with significant changes in the nervous system.

205Bi/206Bi cyclotron production from Pb-isotopes for absorption studies in humans.

Pb(p, xn) thick target excitation functions were measured in the energy range 10-38 MeV in order to optimize the production of isotopically pure radiobismuth from natPb, 206Pb, and 207Pb. Additionally, the decay of Po-isotopes from deuteron irradiation of natural bismuth (209Bi) was exploited for radiobismuth production. 205Bi was produced from 206Pb at 20 MeV with only 2% of 206Bi at 4 weeks post irradiation. Bismuth compounds as used in the treatment of peptic ulcer were labeled with 205Bi for absorption studies in animals and subjects.

Pulse polarographic trace determination of bismuth in natural waters and biological materials.

A convenient and accurate analytical procedure has been developed for the trace determination of bismuth(III) in natural waters and biological fluids. Bismuth gives a well-defined, diffusion-controlled cathodic wave in 1 M HCl with a half wave potential of -0.21 V with reference to a saturated calomel electrode. Trace amounts of Bi(III) have been determined by normal pulse and differential pulse polarographic techniques in a 1 M HCl supporting electrolyte with linear calibration plots. The determination of Bi(III) has been achieved in the presence of metals with which it is commonly associated. This is illustrated with bismuth measurements in the presence of copper and zinc. Suitable methods of preparing the samples for analysis have also been suggested. The method may also be used for the determination of Bi(III) in different natural water samples and biological materials such as blood and urine samples with lowest detection limit of 0.02 microgram/L.

Elimination of matrix effects in electrothermal atomic absorption spectrophotometric determinations of bismuth in serum and urine.

A sensitive and precise electrothermal atomic absorption spectrophotometric method for determining bismuth concentration is described. Protein precipitation and the use of a palladium modifier reduce the problems of foaming and permit the use of a higher ashing temperature. The detection limit of the assay is 0.9 nmol/L. Total CVs (intra- and interassay) for serum ranged from 3.5% to 15.1% and for urine from 4.8% to 14.5% at concentrations of 60.0 and 6.0 nmol/L, respectively. Analytical recoveries of bismuth added to serum and urine were 102% and 103% over the same range. The method is robust and reproducible and can be accurately calibrated with aqueous standards.

The effect of GR122311X, a bismuth compound with H2-antagonist activity, on 24-hour intragastric acidity.

GR122311X (ranitidine bismuth citrate Glaxo Group Research Ltd) is a bismuth compound with histamine H2-receptor antagonist activity. The gastric acid antisecretory activity of three oral dosage regimens of GR122311X was compared with placebo and 150 mg ranitidine b.d. The median 24-h integrated intragastric acidity was 38, 26 and 18% of the median placebo value during dosing with GR122311X 196, 391 and 782 mg b.d., respectively. The 24-h acid suppression with GR122311X 391 mg b.d. was not significantly different to that produced by 150 mg ranitidine b.d. (24% of placebo acidity). The median 24-h urinary bismuth excretion increased with rising dosage of GR122311X from 19.2 micrograms with 196 mg b.d., to 36.4 micrograms with 391 mg b.d., to 68.7 micrograms with 782 mg b.d. In conclusion, GR122311X is an effective antisecretory agent with modest systemic bismuth absorption.

Tripotassium dicitrato bismuthate: absorption and urinary excretion of bismuth in patients with normal and impaired renal function.

We have investigated the absorption and urinary excretion of tripotassium dicitrato bismuthate during a treatment course of 4 weeks in 7 patients with normal renal function (creatinine clearance 115 +/- 29 ml/min; mean +/- S.D.), in 7 patients with impaired renal function (creatinine clearance = 34 +/- 19 ml/min) and in 4 dialysed patients. Following the first dose of tripotassium dicitrato bismuthate (216 mg bismuth b.d.), and after 2 and 4 weeks of treatment (dialysed patients received only 108 mg/b.d.), plasma and urine concentrations of bismuth were monitored for 2 and 24 h, respectively. After stopping therapy plasma and urine concentrations of bismuth were followed for 4 and 6 weeks, respectively. In all three groups of patients small amounts of bismuth (mean values 0.26 to 0.28% of dose) were rapidly (transient mean peak concentrations between 40 and 134 micrograms/L) reached within about 30 to 40 min, absorbed and plasma levels demonstrated a wide intra- and inter-individual variability. Absorption profiles were not altered during the treatment course; however, the trough plasma concentration of bismuth demonstrated an about 3- to 5-fold accumulation (correlated to creatinine clearance) from about 5 micrograms/L to 15 micrograms/L (normal renal function) or to 20-25 micrograms/L (impaired renal function). Pre-study bismuth levels could be detected within 2 to 4 weeks after stopping therapy in all subjects whereas urinary concentrations were still elevated 6 weeks after the course of treatment. Our results indicate that tripotassium dicitrato bismuthate is absorbed in very low amounts during standard therapy. However, dependent on renal function, accumulation to non-toxic levels does occur during a course of treatment. It appears prudent to halve tripotassium dicitrato bismuthate dosage in patients with severe renal insufficiency (creatinine clearance less than or equal to 20 ml/min) to avoid any possible toxic risks. In such patients monitoring of the plasma bismuth concentration might be helpful, especially if longer or repeated treatment is anticipated.

A study relating to bioavailability and renal elimination of bismuth after oral administration of basic bismuth nitrate.

The extent to which bismuth is absorbed following single and multiple oral administration of basic bismuth nitrate was investigated in healthy male subjects. The blood concentration of bismuth and the amounts excreted in urine and feces were determined. The results show that only a small fraction of the administered bismuth dose given in this form is absorbed. Existing differences in the absorption kinetics between this relatively insoluble bismuth salt and colloidal bismuth citrate are discussed.