Disinfection byproducts and halogen-specific total organic halogen speciation in chlorinated source waters - The impact of iopamidol and bromide.

This study investigated the speciation of halogen-specific total organic halogen and disinfection byproducts (DBPs) upon chlorination of natural organic matter (NOM) in the presence of iopamidol and bromide (Br-). Experiments were conducted with low bromide source waters with different NOM characteristics from Northeast Ohio, USA and varied spiked levels of bromide (2-30 µmol/L) and iopamidol (1-5 µmol/L). Iopamidol was found to be a direct precursor to trihalomethane (THM) and haloacetic acid formation, and in the presence of Br- favored brominated analogs. The concentration and speciation of DBPs formed were impacted by iopamidol and bromide concentrations, as well as the presence of NOM. As iopamidol increased the concentration of iodinated DBPs (iodo-DBPs) and THMs increased. However, as Br- concentrations increased, the concentrations of non-brominated iodo- and chloro-DBPs decreased while brominated-DBPs increased. Regardless of the concentration of either iopamidol or bromide, bromochloroiodomethane (CHBrClI) was the most predominant iodo-DBP formed except at the lowest bromide concentration studied. At relevant concentrations of iopamidol (1 µmol/L) and bromide (2 µmol/L), significant quantities of highly toxic iodinated and brominated DBPs were formed. However, the rapid oxidation and incorporation of bromide appear to inhibit iodo-DBP formation under conditions relevant to drinking water treatment.

Co-metabolic degradation of iomeprol by a Pseudomonas sp. and its application in biological aerated filter systems.

The non-ionic water-soluble X-ray contrast agent iomeprol (IOM) enters the water supply through sewage treatment plants, which can cause considerable environmental harm. In this study, Pseudomonas sp. I-24 (I-24) was tested for its ability to remove IOM from water via co-metabolic pathways. The optimum removal rate of IOM by I-24 was 38.43% ± 3.70% when starch served as the source of external carbon, and its co-metabolism of IOM conformed to the first-order kinetics. The highest activity of intracellular enzyme (degrading enzyme) extracted from I-24 was 0.143 ± 0.005 mU in starch condition. The Michaelis constant of the degrading enzyme was found to be 91.08 µmol L-1. However, glucose and maltose showed the best promotive effects on the growth and electron transport activity of I-24, indicating that overgrowth may result in competitive inhibition and a reduced degradation rate of IOM. Adding I-24 and degrading enzymes to biological aerated filters increased IOM removal rates without affecting CODMn removal.

The impact of iodinated X-ray contrast agents on formation and toxicity of disinfection by-products in drinking water.

The presence of iodinated X-ray contrast media (ICM) in source waters is of high concern to public health because of their potential to generate highly toxic disinfection by-products (DBPs). The objective of this study was to determine the impact of ICM in source waters and the type of disinfectant on the overall toxicity of DBP mixtures and to determine which ICM and reaction conditions give rise to toxic by-products. Source waters collected from Akron, OH were treated with five different ICMs, including iopamidol, iopromide, iohexol, diatrizoate and iomeprol, with or without chlorine or chloramine disinfection. The reaction product mixtures were concentrated with XAD resins and the mammalian cell cytotoxicity and genotoxicity of the reaction mixture concentrates was measured. Water containing iopamidol generated an enhanced level of mammalian cell cytotoxicity and genotoxicity after disinfection. While chlorine disinfection with iopamidol resulted in the highest cytotoxicity overall, the relative iopamidol-mediated increase in toxicity was greater when chloramine was used as the disinfectant compared with chlorine. Four other ICMs (iopromide, iohexol, diatrizoate, and iomeprol) expressed some cytotoxicity over the control without any disinfection, and induced higher cytotoxicity when chlorinated. Only iohexol enhanced genotoxicity compared to the chlorinated source water.

Application of metabolite profiling tools and time-of-flight mass spectrometry in the identification of transformation products of iopromide and iopamidol during advanced oxidation.

The efficiency of wastewater treatment systems in removing pharmaceuticals is often assessed on the basis of the decrease in the concentration of the parent compound. However, what is perceived as "removal" during treatment may not necessarily mean mineralization of the pharmaceutical compound but simply conversion into different transformation products (TPs). Using liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer (LC-QToF-MS), we demonstrated conversion of iopromide in wastewater to at least 14 TPs after an advanced oxidation process (AOP) using UV (fluence = 1500 mJ/cm(2)) and H2O2 (10 mg/L). Due to the complexity of the wastewater matrix, the initial experiments were performed using a high concentration (10 mg/L) of iopromide in order to facilitate the identification of TPs. Despite the high concentration of iopromide used, cursory inspection of UV and mass spectra only revealed four TPs in the chromatograms of the post-AOP samples. However, the use of METLIN database and statistics-based profiling tools commonly used in metabolomics proved effective in discriminating between background signals and TPs derived from iopromide. High-resolution mass data allowed one to predict molecular formulas of putative TPs with errors below 5 ppm relative to the observed m/z. Tandem mass spectrometry (MS/MS) data and isotope pattern comparisons provided necessary information that allowed one to elucidate the structure of iopromide TPs. The presence of the proposed iopromide TPs was determined in unspiked wastewater from a municipal wastewater treatment plant, but no iopromide and TPs were detected. Using analogous structural modifications and oxidation that results from the AOP treatment of iopromide, the potential TPs of iopamidol (a structurally similar compound to iopromide) were predicted. The same mass fragmentation pattern observed in iopromide TPs was applied to the predicted iopamidol TPs. LC-QToF-MS revealed the presence of two iopamidol TPs in unspiked AOP-treated wastewater.

LC-HRMS suspect screening for detection-based prioritization of iodinated contrast media photodegradates in surface waters.

The objective of the study was to demonstrate the applicability of suspect screening for the detection of six iodinated contrast media (ICM) and their phototransformation products (TPs) in surface waters. First, a photodegradation study of ICM in surface water using a sunlight lab-scale simulator was performed. By means of a guided differential sample analysis, the exact masses of the molecular ions and the retention times of TPs were identified. Positive findings were filtered manually generating a suspect list of 108 photoproducts. Following a generic solid-phase extraction of surface water samples, LC-HRMS was used to screen for the presence of the compounds previously detected in the photodegradation samples. On the basis of detection frequencies (>50% of the samples), 11 TPs were prioritized and their structures elucidated by HRMS and NMR. In the real surface water samples, median concentration of parent compounds was 110 ng/L reaching up to 6 µg/L for iomeprol, while TPs were found at median concentration of 8 ng/L, reaching up to 0.4 µg/L for iomeprol TP651-B. In summary, the proposed screening approach facilitates the evaluation of the degradation of polar compounds at a real scale with a fast detection of TPs without prior availability of the standards.

Reactive transport of iomeprol during stream-groundwater interactions.

The transport and biochemical transformations of the iodinated X-ray contrast medium (ICM) iomeprol were studied at the stream/groundwater interface. During a one-month field experiment piezometric pressure heads, temperatures, and concentrations of redox-sensitive species, iomeprol and 15 of its transformation products (TPs) were collected in stream- and groundwater. The data set was analyzed and transformation processes and rates identified by comparing conservative and reactive transport simulations. ICM and TP transformations were simulated as a cometabolic process during organic carbon degradation. Using iomeprol/TPs ratios as calibration constrain mitigated the uncertainties associated with the high variability of the ICM wastewater discharge into the investigated stream. The study provides evidence that biodegradation of ICM occurs at the field-scale also for predominantly denitrifying conditions. Under these anaerobically dominated field conditions shortest simulated half-life (21 days) was in the same range as previously reported laboratory-determined half-lives for aerobic conditions.

Pilot study of Iopamidol-based quantitative pH imaging on a clinical 3T MR scanner.

OBJECTIVE: The objective of this study was to show the feasibility to perform Iopamidol-based pH imaging via clinical 3T magnetic resonance imaging (MRI) using chemical exchange saturation transfer (CEST) imaging with pulse train presaturation. MATERIALS AND METHODS: The pulse train presaturation scheme of a CEST sequence was investigated for Iopamidol-based pH measurements using a 3T magnetic resonance (MR) scanner. The CEST sequence was applied to eight tubes filled with 100-mM Iopamidol solutions with pH values ranging from 5.6 to 7.0. Calibration curves for pH quantification were determined. The dependence of pH values on the concentration of Iopamidol was investigated. An in vivo measurement was performed in one patient who had undergone a previous contrast-enhanced computed tomography (CT) scan with Iopamidol. The pH values of urine measured with CEST MRI and with a pH meter were compared. RESULTS: In the measured pH range, pH imaging using CEST imaging with pulse train presaturation was possible. Dependence between the pH value and the concentration of Iopamidol was not observed. In the in vivo investigation, the pH values in the human bladder measured by the Iopamidol CEST sequence and in urine were consistent. CONCLUSION: Our study shows the feasibility of using CEST imaging with Iopamidol for quantitative pH mapping in vitro and in vivo on a 3T MR scanner.

Assessing the skin irritation and sensitizing potential of concentrates of water chlorinated in the presence of iodinated X-ray contrast media.

Chemical disinfection of water provides significant public health benefits. However, disinfectants like chlorine can react with naturally occurring materials in the water to form disinfection byproducts (DBPs). Natural levels of iodine have been reported to be too low in some source waters to account for the levels of iodinated DBPs detected. Iodinated X-ray contrast media (ICM) have been identified as a potential source of iodine. The toxicological impact of ICM present in source water at the time of disinfection has not been fully investigated. Iopamidol, iohexol, iopromide, and diatrizoate are among the ICM most frequently detected in water. In this study, source water containing one of these four ICM was chlorinated; non-chlorinated ICM-containing water samples served as controls. Reactions were conducted at an ICM concentration of 5 µM and a chlorine dose of 100 µM over 72 hr. Water concentrates (20,000-fold) were prepared by XAD-resin/ethyl acetate extraction and DMSO solvent exchange. We used the MatTek® reconstituted human epithelial skin irritation model to evaluate the water concentrates and also assessed the dermal irritation and sensitization potential of these concentrates using the LLNA:BrdU ELISA in BALB/c mice. None of the water concentrates tested (2500X) resulted in a skin irritant response in the MatTek® skin irritation model. Likewise, none of the concentrates (2500X, 1250X, 625X, 312.5X, 156.25X) produced a skin irritation response in mice: erythema was minimal; the maximum increase in ear thickness was less than 25%. Importantly, none of the concentrates produced a positive threshold response for allergic skin sensitization at any concentration tested in the LLNA:BrdU ELISA. We conclude that concentrates of water disinfected in the presence of four different ICM did not cause significant skin irritation or effects consistent with skin sensitization at the concentrations tested.

Occurrence of iodinated X-ray contrast media and their biotransformation products in the urban water cycle.

A LC tandem MS method was developed for the simultaneous determination of four iodinated X-ray contrast media (ICM) and 46 ICM biotransformation products (TPs) in raw and treated wastewater, surface water, groundwater, and drinking water. Recoveries ranged from 70% to 130%, and limits of quantification (LOQ) varied between 1 ng/L and 3 ng/L for surface water, groundwater and drinking water, and between 10 ng/L and 30 ng/L for wastewater. In a conventional wastewater treatment plant, iohexol, iomeprol, and iopromide were transformed to >80%, while iopamidol was transformed to 35%. In total, 26 TPs were detected above their LOQ in WWTP effluents. A significant change in the pattern of ICM TPs was observed after bank filtration and groundwater infiltration under aerobic conditions. Predominately, these TPs are formed at the end of the microbial transformation pathways in batch experiments with soil and sediment. These polar ICM TPs, such as iohexol TP599, iomeprol TP643, iopromide TP701A, and iopromide TP643, were not or only partially removed during drinking water treatment. As a consequence, several ICM TPs were detected in drinking water, at concentration levels exceeding 100 ng/L, with a maximum of 500 ng/L for iomeprol TP687.

Rapid analysis of iodinated X-ray contrast media in secondary and tertiary treated wastewater by direct injection liquid chromatography-tandem mass spectrometry.

The iodinated X-ray contrast media are the most widely administered intravascular pharmaceuticals and are known to persist in the aquatic environment. A rapid method using direct injection liquid chromatography-tandem mass spectrometry (DI-LC-MS/MS) has been developed to measure eight ICM. These include iopamidol, iothalamic acid, diatrizoic acid, iohexol, iomeprol, iopromide, plus both ioxaglic acid and iodipamide, which have not previously reported in the literature. The LC-MS/MS fragmentation patterns obtained for each of the compounds are discussed and the fragments lost for each transition are identified. Matrix effects in post-RO water, MQ water, tap water and secondary effluent have also been investigated. The DI-LC-MS/MS method was validated on both secondary and tertiary treated wastewater, and applied to samples from an advanced activated sludge wastewater treatment plant (WWTP) and a water recycling facility using microfiltration (MF) and reverse osmosis (RO) in Perth, Western Australia. As well as providing information of the efficacy for RO to remove specific ICM, these results also represent the first values of ICM published in the literature for Australia.

Monitoring of iodinated X-ray contrast media in surface water.

A monitoring programme was carried out in order to determine iodinated X-ray contrast media (ICM) in the River Danube and to investigate the raw water quality for drinking water production at Langenau waterworks. The study revealed that the maximum concentrations of ICM (over 500 ng l(-1) for diatrizoic acid and iopamidol) were found in 2h-composite samples taken from the downstream of the Ulm/Neu-Ulm metropolitan area. By means of a concentration profile over one month the highest ICM concentrations were observed on weekdays. The extended data evaluation with principal component analysis shows that the upstream and downstream samples had different pattern of variations in ICM concentration and also demonstrates a clear change in ICM composition by the discharge of municipal wastewater. In addition to load profiles of ICM, time-dependent plots of principal component 1 exhibited peaks, indicating a short-term discharge of ICM between the two sampling sites. In conclusion, a point source for ICM contamination between the sampling sites in Ulm upstream and Leipheim downstream seems to be the reasonable explanation for peak ICM concentrations. Due to the observed high variations of ICM concentrations in river, the evaluation of natural waters by means of a single analysis is not representative.

Iodinated X-ray contrast agents: Photoinduced transformation and monitoring in surface water.

Conventional wastewater treatment methods have shown to be unsuitable for a complete elimination of iodinated X-ray contrast agents (ICMs), which have thus been found in wastewater treatment plant (WWTP) effluent and in surface water. Once in the surface water, they could be transformed through different processes and form several transformation products that may need to be monitored as well. To this end, we studied the abatement and transformation of ICMs by combining laboratory experiments with in field analyses. We irradiated different aqueous solutions of the selected pollutants in the presence of TiO2 as photocatalyst, aimed to promote ICMs degradation and to generate photoinduced transformation products (TPs) similar to those occurring in the environment and effluent wastewater. This experimental strategy has been applied to the study of three ICMs, namely iopromide, iopamidol and diatrizoate. A total of twenty-four, ten, and ten TPs were detected from iopamidol, diatrizoate and iopromide, respectively. The analyses were performed using a liquid chromatography-LTQ-FT-Orbitrap mass spectrometer. The mineralization process and acute toxicity evolution were assessed as well over time and revealed a lack of mineralization for all ICMs and the formation of harmful byproducts. After characterizing these transformation products, WWTP effluent and surface water taken from several branches of the Chicago River were analyzed for ICMs and their TPs. HRMS with MS/MS fragmentation was used as a confirmatory step for proper identification of compounds in water and wastewater samples. All three of ICM were detected in the effluent and surface water samples, while no significant amount of TPs were detected.

Analysis of iodinated X-ray contrast agents in water samples by ion chromatography and inductively-coupled plasma mass spectrometry.

In this paper, an analytical method for the determination of six iodinated X-ray contrast agents (amidotrizoic acid, iohexol, iomeprol, iopamidol, iopromide, and ioxitalamic acid), iodide, and iodate in water samples is presented. The method is based on a separation of the analytes by ion chromatography (IC) and a subsequent detection by inductively-coupled plasma mass spectrometry (ICP-MS). The method was optimised with respect to separation conditions (column type and eluent composition) and extensively validated. Without pre-concentration of the samples, limits of detection below 0.2 microg/l could be achieved whereby reproducibility was below 6% for all compounds under investigation.

Effects of diatrizoate and iopamidol on spermatogenesis.

RATIONALE AND OBJECTIVES: The biological effects of iodinated contrast media were examined by using spermatogenesis in mouse testis as the experimental model. METHODS: Spermhead survival and abnormality assays were used as the biological end points. Diatrizoate meglumine/diatrizoate sodium and iopamidol were administered intravenously at equal rates and concentrations. Testicular uptake and clearance of these contrast agents were examined by high-performance liquid chromatography techniques. Appropriate mannitol solutions were employed as osmolality controls. RESULTS: Intravenous administration of the contrast agent or its respective mannitol control resulted in approximately a 30% decrease in spermhead count. A dose-related experiment with mannitol demonstrated that the spermhead count decreased rapidly until 600 mOsm/kg was reached, beyond which this decrease was minimal. Clearance of both contrast media was complete in approximately 4 hours. No significant increase in the induction of spermhead abnormalities was observed. CONCLUSION: Osmotic substances, such as iodinated contrast agents, affect the process of spermatogenesis.

An absorptiometry method for the determination of arterial blood concentration of injected iodinated contrast agent.

A single photon absorptiometry method to measure the arterial concentration of injected iodinated contrast agent was developed. A prototype absorptiometry unit was built which consists of either a square or circular cross section acrylic (polymethylmethacrylate) cuvette connected to an arterial catheter at one end and a paristaltic pump at the other via PE60 surgical tubing. At opposing ends of the length of the cuvette were a 0.4 GBq 125I source and a scintillation crystal/photomultiplier tube assembly. This assembly was connected to a single-channel analyser (SCA)/scaler unit to count the transmitted photons through the cuvette. The scaler was interfaced to an IBM PC and counts accumulated in preset time intervals were transmitted to the computer via a serial interface. Experiments were performed to calibrate the unit for measurement of blood concentration of contrast agent (Isovue 300) and to determine the dispersion characteristics of the unit. Deconvolution was used to correct the measured concentration waveform for the dispersion introduced by passage through the lead-in tubing and the cuvette. The precision of concentration measurements was determined to be between 5 and 10% using computer simulations and theoretical calculations. The method was used successfully in a number of patient and animal studies to measure the contrast concentration in blood following intravenous injection of contrast agent.

Optimum iodine concentration of contrast material through microcatheters: hydrodynamic analysis of experimental results.

It is important to increase the iodine delivery rate (I), that is the iodine concentration of the contrast material (C) x the flow rate of the contrast material (Q), through a catheter to obtain high quality arteriograms. The iodine delivery rate varies depending on the iodine concentration of the contrast material. The purpose of this study is to estimate the optimum iodine concentration (Copt) of contrast material (i.e. the iodine concentration at which I becomes maximum) through a microcatheter of a given length (L), inner diameter (D) and injection pressure (P). Iohexol, ioversol and iopamidol of 11-12 iodine concentrations (140-350, 160-350 or 160-370 mg cm(-3)) at 37 degrees C are used. I and Reynolds number (Re) of the flow of each contrast material through four microcatheters (0.49-0.68 mm in inner diameter, 1000-1500 mm in length) at injection pressures of 1.38, 2.76, 4.14 and 5.52 x 10(6) Pa (200, 400, 600 and 800 pounds per square inch) are obtained experimentally. The relationships between I and C and between I and Re are examined for each catheter and injection pressure. Copt is 160-280 mg cm(-3) for iohexol, 180-280 mg cm(-3) for ioversol and 200-300 mg cm(-3) for iopamidol. I becomes maximum when Re approximates the critical Reynolds number (Re approximately 2300). Utilizing this principle, we can estimate Copt and its flow rate through a microcatheter of a given L, D and P.

Pharmacokinetics and tissue distribution of iomeprol in animals.

The pharmacokinetics of iomeprol, a new triiodinated nonionic radiographic contrast agent, has been studied in rats, rabbits and dogs. Following intravenous administration, iomeprol did not bind measurably to plasma proteins and was rapidly excreted in unchanged form, mostly through the kidneys. The compound was rapidly distributed to the plasma and thence to the extracellular spaces. Iomeprol did not accumulate in specific organs or tissues except for those involved in its elimination, i.e. the kidneys and the liver. However, 24 h after administration, less than 1% of the injected dose remained in the tissues. The overall profile was very similar to the published profiles of other radiographic contrast agents used in uroangiography.

Elimination of iomeprol in patients undergoing continuous ambulatory peritoneal dialysis.

OBJECTIVE: To examine the elimination of iomeprol, its safety in clinical use, and its peritoneal permeability in continuous ambulatory peritoneal dialysis (CAPD) patients with variable degrees of residual renal function (RRF). DESIGN: A nonrandomized comparison study. SETTING: Hospitalized patients in CAPD unit of Chikuho and University Hospitals. PARTICIPANTS: Fourteen patients treated by CAPD and 6 by hemodialysis (HD). INTERVENTIONS: Total dialysate, blood, and 24-hour urine collections were obtained for 4 consecutive days after the administration of iomeprol. A peritoneal equilibration test was performed just before and after the administration of iomeprol. MEASUREMENTS: Iomeprol (iodine) concentration was measured. Residual renal function was estimated as the mean of renal creatinine and urea clearances. Dialysate-to-plasma ratios (D/P) of creatinine and iomeprol were also determined. RESULTS: In all CAPD patients, plasma iomeprol clearance was markedly slow, with a biological half-life (T1/2) of over 32 hours. However, no patients suffered from any adverse effects, and over 80% of plasma iomeprol was eliminated during the 4-hour HD. The plasma iomeprol elimination rate was significantly higher from 4 hours after the iomeprol administration in CAPD patients with RRF [mean estimated creatinine clearance (CCr) 3.8 mL/min, n = 7] compared to the remaining patients (mean estimated CCr 0.6 mL/min, n = 7); however, T1/2 in patients with RRF was over 24 hours. D/P creatinine was significantly correlated with D/P iomeprol, and peritoneal iomeprol permeability may depend on an individual's peritoneal solute transport properties. CONCLUSIONS: A prolonged elimination rate of iomeprol was documented in our CAPD patients both with and without RRF. A HD procedure or intensive peritoneal dialysis just after the use of iomeprol may be advisable to promptly remove circulating iomeprol.

A simple method for the identification and assay of iopamidol and iothalamate meglumine in pharmaceutical samples based on proton nuclear magnetic resonance spectroscopy.

A proton nuclear magnetic resonance (PMR) spectroscopic method is described for the direct assay and identification of the triiodinated radiographic contrast agents iopamidol (nonionic type) and iothalamate meglumine (ionic type) in commercial solutions and as a bulk material. Samples were prepared by simply diluting an injectable solution with or dissolving a powdered sample in D2O. Sodium acetate was added to serve as an internal standard. Quantitations were based on the resonance signals for the protons of the CH3-CO-group at 1.58 ppm (iopamidol) or 2.25 ppm (iothalamate), CH3-N-group at 2.38 ppm (meglumine) and CH3-CO-group at 1.92 ppm (acetate). The mean +/- SD (n = sets of 10 samples each) recovery of iopamidol, iothalamic acid and meglumine from synthetic mixtures with the internal standard were 99.6 +/- 0.63, 99.7 +/- 0.66 and 99.9 +/- 1.18%, respectively; with the values ranging from 98.7-100.9% for iopamidol and iothalamate, and from 98.3-100.8% for meglumine.

Serum concentration of iopamidol after retrograde urethrography in male patients with outlet obstructive symptoms.

Serum concentration of iopamidol was measured in 29 male patients with outlet obstructive symptoms after retrograde urethrography. Although no patient showed extravasation, serum iopamidol level was detectable in 4 (14%) patients. Since severe adverse effects are considerably reduced with iopamidol, we prefer to use this contrast medium for retrograde urethrography in male patients with outlet obstructive symptoms.