Environ. Sci. Technol. 2000, 34, 573-577
Hospital Effluents as a Source of Gadolinium in the Aquatic Environment KLAUS KU ¨ MMERER* AND ECKARD HELMERS† Institut fu ¨ r Umweltmedizin und Krankenhaushygiene, Universita¨tsklinikum Freiburg, Hugstetterstrasse 55, D-79106 Freiburg i.Br., Germany, and Chemisches Institut im Amt fu ¨ r Umweltschutz, Stafflenbergstrasse 81, D-70184 Stuttgart, Germany
Total annual Gd emission of a hospital offering a maximum spectrum medical services using Gd complexes in magnetic resonance imaging was computed and independently measured by ICP/MS. The Gd emission was between 2.1 and 4.2 kg per year, yielding a theoretical concentration of 8.5-30.1 µg per L in the hospital’s effluent. Gd concentrations measured on different days were below detection limit (1 µg per L) and 55 µg per L, and annual average concentrations were between 10.5 and 20.5 µg per L as calculated from analytical results, water flow, and total water consumption. The concentrations in the influent of the municipal sewage treatment plant (STP) receiving the effluent were always below detection limit indicating that there was no other major discharge of Gd. Based on consumption data, total Gd input by German hospitals is estimated to be roughly 132 kg per year. An elevation of the natural concentration of Gd in German surface waters by 0.003-0.004 µg per L will result from this amount, if there is no elimination in sewage treatment plants. Using the number of MRI apparatus used in Germany the annual emission by hospitals is 484 and 1160 kg by hospitals and practices, resulting in an additional Gd concentration in German surface water of 0.011 and 0.026 µg per L, respectively. Therefore, the emission of Gd compounds used in magnetic resonance imaging have to be considered as one source among others of anthropogenic Gd anomaly in surface waters.
1. Introduction Bau and Dulski (1) reported positive Gd anomalies in river and lake waters. They hypothesized that these anomalies are of anthropogenic origin, as the anomalies were found in waters receiving sewage treatment plant (STP) discharges. Gd-containing substances are applied during magnetic resonance imaging (MRI). Gd has been used since 1988 (2) because of its high magnetic moment (3) imaging of the digestive tract or for cranial and spinal MRI. Typical compounds used for MRI are gadodiamide, gadopentetic acid ([N,N-bis[2-[(carboxmethyl)[{methylcarbamoyl)methyl]amino]ethyl]glycinato(3-)gadolinium (I)‚H2O), or Gddiethylenetriaminepentaacetate [)Gd(DTPA)] dimeglumin * Corresponding author phone: +761/270-5464; fax: +761/2705485; e-mail:
[email protected]. † Present address: University of Applied Sciences, Postfach 1380, D-55761 Birkenfeld. 10.1021/es990633h CCC: $19.00 Published on Web 01/14/2000
2000 American Chemical Society
salt (see Figure 1 for structure of the latter compound) and others. The compounds are applied orally or intravenously. This way, up to 0.3 mmol of Gd-DTPA per kg body weight may be applied without a health risk (4, 5). The contrast media are excreted nonmetabolized into hospital sewage within a few hours after application. Complexed Gd is introduced into the sewage systems via the hospital wastewaters. The behavior of the substances within the process of sewage treatment, in ambient surface waters, as well as in drinking water processing is widely unknown (1, 5). Bau and Dulski (1) stated that the ability of excess Gd to escape removal during sewage treatment and tap water purification suggests that Gd is still bound in a very stable aqueous complex. Gd-containing contrast media are not biodegradable in aqueous test systems (4). There is little knowledge of the environmental properties and amounts emitted as well as concentrations in surface waters. Toxicity of the free metal ions of lanthanides is considerably reduced by complexing with ethylenediaminetetraacetate (EDTA) or DTPA. With K ) 1028, the stability of Fe3+-EDTA is much higher compared with Gd3+-EDTA (K ) 1023). Reaction of Gd(DTPA)2- with Zn2+ and Cu2+ (25% and 21% in equilibrium, respectively) is reported (6). Both ions are present in wastewater. As Fe(III)-salts are used during the flocculation within the drinking water purification process, nontoxic complexed Gd from MRI may possibly be transformed to noncomplexed and toxic Gd species (5). Tu et al. found that carp has low ability to take up Gd and other rare earth elements (7). No data on the environmental fate and effects on aquatic organisms of Gd contrast agents for MRI are reported in the literature. Short term toxicity of the Gd-containing MRI compounds to aquatic bacteria is low, e.g. effect concentration for 10% growth inhibition (EC10) in the Ps. putida growth inhibition test is 870 mg per L (4). Gd deposits were found in rat liver after administration of Gd chloride (8). Gd3+ is known to be the most paramagnetic ion but is also a very toxic cation when not complexed. GdCl3 may alter the susceptibility of hepatocytes to toxicity caused by certain chemicals (9) and induce macrophage apoptosis (10). Intravenous administration of GdCl3 to rats resulted in effects on the glandular mucosa of the stomach. Neurotoxicity of Gd contrast agents for MRI was reported for rats with disrupted blood-brain barrier (11, 12) as well as cardiovascular effects of gadopentetate dimeglumine at high doses (13, 14). A study demonstrated GdCl3 toxicity on human neutrophil viability, while gadodiamide was not harmful (15). The possible significance of this effect of clinical use of Gd-containing chelates in MRI requires further investigation (16). Bau and Dulski reported elevated Gd concentrations (“Gd anomalies”) in German surface water in areas with high population density (1) up to 0.1 µg per L. The natural background was in the range of 0.6 ng per L (1). They supposed gadodiamide to be a source of anthropogenic Gd. Therefore, our study focused on Gd concentrations in a hospital sewage and the rough quantification of gadolinium emissions by all German hospitals applying MRI. Two h mixed samples were taken over periods of 24 h from a hospital effluent, and Gd concentrations were measured. Theoretical annual average concentrations were computed for this purpose on the basis of the measured concentrations and the total annual amount of Gd-containing contrast media applied in a hospital of maximum medical service spectrum. Statistical data on use of MRI apparatus in Germany were the basis of additional calculations. VOL. 34, NO. 4, 2000 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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FIGURE 1. (DTPA)Gd-dimeglumine: diethylenetriaminepentaacetate-Gd(III)-bis(D-(-)-1-methylamino-1-desoxy-D-glucite).
TABLE 1: ICP-MS Instrumental Parameters cooling gas auxiliary gas nebulizer gas nebulizer type RF power detector mode acquisition screening mode acquisition quantitative mode sampler
13 L/min 0.75 L/min 0.98 L/min V-split (De Galan) 1350 W pulse counting scanning, 320 µs dwell, 25 channels/amu peak jumping, five runs, three points/peak 40 s uptake - 60 s acquisition 60 s rinse
TABLE 2: Gadolinium Isotopes and Related Possible Interferences during ICP-MS Detectiona Adapted from Dulski (28) mass
abundance (%)
155
15
156 157 158 160
20.5 15.7 24.8 21.9
a
isobaric
Dy (0.06%) Dy (0.1%) Dy (2%)
further interferences of GD isotope interferences BaOH (72%), LaOH (99.7%), CeOH (0.25%) CeO (88.3%) PrO (99.8%), CeOH (88.3%) CeO (11%), NdO (27%) NdO (24%), SmO (3%), NdOH (12%)
Abundances of the isotopes in percent.
2. Methods and Materials 2.1. Sampling. The hospital under investigation was the Freiburg University Hospital which is a hospital of maximum medical service spectrum offering MRI diagnostics (three MRI systems, 15-25 patients per day). Using an automated sampler time proportional sampling was performed. Samples were taken from the main drain of the hospital every 10 min. Twelve mixed samples each covering a period of 2 h (1 L) for 24 h were taken. Sampling was undertaken in dry weather conditions in June 1996 and July 1997. Since hospital effluents may contain hazardous substances such as antineoplastic drugs and pathogenic organisms, samples should be handled with care. In the influent and effluent of the municipal sewage treatment plant (STP) 24 h sampling was performed as described above on the same days. All samples were taken in polyethylene bottles and stored at -18 °C until analysis. Prior to analysis, they were acidified with nitric acid (Suprapur, Merck, Darmstadt, FRG). Sewage sludge obtained from the municipal STP receiving the Freiburg University hospital effluent was also analyzed by ICP-MS to study possible accumulation of Gd compounds (N ) 4, sampled July 31, 1997). 2.2. Analytical Method and Quality Assurance. Gadolinium was quantified by ICP-MS employing a PQ2+ device by Fisons/VG (Mainz-Castell, FRG). The measurement conditions are displayed in Table 1. Mean Gd concentrations were calculated with results from the four isotopes 156Gd, 157Gd, 158Gd, and 160Gd. On one hand, ICP-MS detection in this range of mass is very sensitive in comparison with lower masses. On the other hand, there is the danger of oxidation and particularly isobaric interferences during lanthanide detection. Consequently, much effort was invested to ascertain the reliability of measurements with respect to possible interferences (Table 2): The only interference quantitatively relevant is barium hydroxide of mass 155. Analytical results of three of the samples exhibited a result of mass 155 which was 1-2 mg per L higher than on the other four Gd masses. Calculated barium hydroxide formation rate is approximately 0.5% in these cases. Consequently, results of mass 155 were not considered. The oxidation rate was studied during analysis of natural urine originating from a patient treated with Gd compounds 574
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in the course of a MRI. Analysis resulted in 8000 µg Gd per L of urine as well as 68 µg per L measured of the isotope 172Yb and 50 µg per L measured of the isotope 174Yb. 172Yb interfered with GdO (20%) and GdOH (15%), and also 174Yb interfered with GdO (24%) and GdOH (16%). Altogether, interference with Gd is 4.3% of mass 172 and 2.6% of mass 174. Concentrations of elements which might possibly be interfering (Table 2) in the samples were studied in detail: Dy, Pr, and La were < 0.5 µg per L, Nd and Sm < 2 µg per L, and Ce < 5 µg per L. Assuming a CeO formation rate of 5%, 5 µg of Ce per L would simulate less than 0.3 µg of Gd per L. However, Gd is measured with mass 160, with which CeO does not interfere (Table 2) and does not exhibit significantly lower results compared with results from the masses 156158. Consequently, a relevant interference of CeO can be excluded during these measurements. The deviation between the results from the four masses 156Gd, 157Gd, 158Gd, and 160Gd are lower than 2.1%. The natural
isotopes 152Gd (0.2% abundance) and 154Gd (2.2% abundance) were not considered analytically. Reliability was also checked by Gd analysis of a certified reference material (fine fly ash CTA-FFA-1, Promochem, Wesel, FRG): measured 7.6 ( 0.4 mg per kg (N ) 3), certified 10.0 ( 2.6 mg per kg, respectively. The detection limit was slightly below 1 µg Gd per L, as also reported by Falter and Wilken (5). Standard deviations of four independent ICP-MS measurements each are quoted in the subscript of Figure 2. These numbers are equivalent to 1.1-2.5% SD in the concentration range of 6-54 µg Gd per L, respectively 2.22.6% at lower concentrations (1.0-3.4 µg Gd per L). 2.3. Calculations. Concentrations in Hospital Effluent and Emitted Amounts. Annual consumption data of Gd-containing contrast media for the years 1994, 1996, and 1997 were obtained from the hospital purchasing department. Along with the annual water usage these data allowed an estimation of the theoretical annual average concentrations of Gd in the effluent of the hospital. Remainders of the contrast media are collected separately in the hospital and were neglected for the calculations. An excretion rate of 90% into the hospital sewage was used for the calculation of expected Gd concentration in the sewage.
FIGURE 2. Gd concentrations and amounts emitted during the sampling period of July 23/24, 1996, main drain Freiburg University Hospital. Standard deviations range from 0.2 g Gd per L at a concentration of 6 µg per L to 1.0 µg per L at a concentration of 54 µg per L. At lower concentrations (1.0-3.4 µg Gd per L) SDs are < 0.1 µg Gd per L. Water clocks were used to measure the amount of freshwater used in the hospital during each of the 2 h periods. Taking as a basis the measured concentrations and the water flow during each of the 2 h sampling periods, the daily average concentration of Gd in sewage as well as the daily and annual amounts emitted were calculated. Total Emission by Hospitals. Freiburg University Hospital, the hospital investigated in this study, is quite typical for a German hospital applying MRI techniques. Some 100 000110 000 beds are in use in German hospitals for this medical service (17, 18). Accordingly, to estimate roughly the order of magnitude of total Gd emission by German hospitals, specific emission per bed and year at Freiburg University Hospital (1700 beds) was extrapolated. The German average concentration of Gd in the influent of the STPs was calculated via the calculated amounts used in Germany as predicted environmental concentration (PEC) in surface water according to the draft of the risk assessment guidelines for new pharmaceuticals in the European Union (19), as described elsewhere in detail (20)
PEC [g/L] ) A × (100 - R)/(365 × P × V × D × 100) where A [kg] is the predicted amount used per year in the EU country (see calculations), R [%] is the removal rate due to loss by adsorption, volatilization, hydrolysis, biodegradation, or other processes (0% for Gd-containing MRI), P is the number of inhabitants of the country (80 000 000 for Germany), V [m3] is the volume of wastewater per capita and day (generally 0.15-0.30 m3), and D is the factor for dilution of wastewater by surface water flow, 10, as proposed in ref 21.
3. Results and Discussion 3.1. Measured Concentrations in Hospital Effluents. During all sampling periods concentrations measured (Figure 2) were low throughout the night. The concentrations increased steeply in the morning and also exhibited several peaks in the afternoon. These findings correspond well with the consumption and excretion pattern of MRI contrast media. Although the biological residence time is only 70 min with an excretion of 95-98% within 24 h (4), Gd concentrations measured in urine samples of patients treated with these substances are between 350 mg per L 1 day after application and are still 7 µg per L as measured 39 days after application. The application of 1.1 g of Gd per adult patient (70 kg body
TABLE 3: Annual Consumption of Gd by MRI Contrast Media and Gd Concentration in the Main Drain of the University Hospital Freiburga Gd consumption in kg per year
annual av Gd concn in µg/L
year
inventory
measurement
inventory
1994 1996
2.1 3.1
3.1
8.5 20.7
4.2
1.8c
30.1
1997
measurement 17.8 20.5b 10.5b,c
a
Theoretical concentrations calculated with 220 working days. b Only during the day time (8 a.m.-10 p.m.). c Sampling during holidays.
weight (4)) shows that a concentration of 1 g of Gd per L of urine is realistic within the first day after application. Approximately 90% of the Gd is excreted during the hospital stay of persons on whom MRI has been performed. Outpatients also stay in the hospital for 1 or 2 h after MRI and will mostly excrete the Gd into the hospital effluent. During sampling periods (2 h) the water flow varied between 8.8 and 150 m3. The input of 1 g of Gd during a sampling period would result in between 6 and 133 µg per L of Gd in the hospital sewage. 3.2. Consumption Data and Measurements. Consumption of Gd-containing MRI contrast media increased at Freiburg University Hospital in proportion to gradual replacement between 1994 and 1997 of X-ray imaging techniques by MRI (Table 3). In 1996 the annual amount calculated from measurement corresponds well with the amount calculated from the hospital inventory of Gdcontaining contrast media (Table 3). In 1997 the measured values were lower than the values expected from the inventory. In 1994, an annual consumption of 2.1 kg of Gd is consistent with approximately 1900 examinations per year, i.e., 8-9 examinations per working day (basis: 220 working days per year). As one MRI examination per day corresponds to 12.5% of the calculated mean of the concentration per day, we expect considerable deviations from day to day as well as from hour to hour. Although there are differences between the inventory and measured concentrations, quite a lot of the Gd used for MRI was emitted into hospital effluent (Table 3). 3.3. Total Amounts of Gd Emitted by German Hospitals. A rough order-of-magnitude estimation of the nationwide VOL. 34, NO. 4, 2000 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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TABLE 4: Use and Emission of Gd into the Aquatic Environment by MRI Containing Gd in Germany in 1996
basis of calculation
total use in Germany (kg per year)
emissions by hospitals (kg per year)
predicted environmental concn (µg per L)
predicted environmental concn attributable to hospitals (µg per L)
local data Freiburg local data Berlin Federal Statistical Agency
1355 1160
120-132 741 484
0.031 0.026
0.003-0.004 0.017 0.011
consumption of Gd in MRI contrast media is based on Gd consumption at Freiburg University Hospital. In 1997, approximately 1700 beds were in use, corresponding to an average annual emission of 1.2 g of Gd per bed per year (out-patients included). The total number of hospital beds in Germany with a comparable medical service spectrum is some 100 000-110 000 (17, 18). These numbers imply a total annual emission of Gd into hospital effluents of some 120132 kg in Germany. 3.4. Gd in Sewage Sludge and Treatment Plant Input and Output. A Gd concentration of 1.3 ( 0.05 mg per kg was measured in the sludge samples. This is close to the geogenic background of 4 mg of Gd per kg (21). Falter and Wilken (5) measured between 0.3 and 1.9 mg per kg in sludges from drinking water treatment facilities, while Vivian (22) found up to 0.3 mg per kg in sludges dumped at sea. Moreover, Vivian (22) reported 0.36-2 mg of Gd per kg for municipal sewage sludge, the higher concentrations related to emissions from glass making industry. As all these data are relatively congruent, enrichment of Gd within the sewage sludge can be excluded. This is in agreement with the properties of the compounds which lead to rapid excretion. However, local geological background data were not available for this study. Gd concentrations were below 1 µg per L in all influent and effluent samples of the STP. Natural Gd concentrations in river waters are of the order of 0.0006 µg of Gd per L (1). Moreover, investigations revealed a peak concentration of 1.1 µg of Gd per L in the effluent of a STP located in Berlin (1). Due to anthropogenic input of Gd, e.g. as a consequence of its application in MRI, increased Gd concentrations were found in nearly all river waters located in densely populated regions (1). Gd concentrations below 0.2 µg of Gd per L for rivers receiving STP effluents were also reported by Bau and Dulski (1). If the MRI contrast media are not eliminated in STPs, input by hospitals results in an additional Gd concentration of 0.003-0.011 µg per L in German surface water as calculated according to (19). A Gd concentration of 0.026 µg/L stems from the application of Gd complexes as MRI contrast medium in hospitals and practices (Table 4). 3.5. Emission Balance. As reported by Bau and Dulski (1), in the Berlin area with its population of more than 4 000 000 people, Gd consumption and disposal by medical diagnosis is estimated to be of the order of 100 kg of Gd per year. The total population in Germany is some 80 million, which according to the data supplied by Bau and Dulski (1) would correspond to a total annual nationwide Gd emission of approximately 2000 kg. These numbers are by far higher than the ones calculated in our study and probably resulted from a very rough extrapolation of the local Berlin situation. Furthermore, MRI apparatus are also used outside hospitals in areas with high population densities where they cause higher emissions per capita and higher concentrations in surface waters compared to areas with low population density. Our study used average nationwide concentrations for Germany including areas of lower population density and consumption of Gd. Furthermore, Bau and Dulski (1) obtained their samples during the summer when STP effluents comprise more than 50% of the water in Berlin rivers and lakes. Therefore, on this basis concentrations of 576
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anthropogenic Gd in surface water of between 0.1 and 0.3 µg per L and total amounts of 100-350 kg per year released by MRI from hospitals seems to be quite reasonable for Germany. The total Gd consumption by hospitals calculated for Germany on the basis of the local data from the Freiburg University hospital may underestimate the used amounts as not only hospitals with maximum medical service spectrum use MRI apparatus. In 1996, 224 MRI apparatus were in use in German hospitals and 241 outside hospitals (data from the German Federal Statistical Agency). Taking as a basis 10 examinations per day per MR tomograph an annual consumption of 2.4 kg per apparatus results (220 work days). Going by this amount, in 1996, total Gd consumption in German hospitals was 538 and 622 kg outside hospitals (Table 4). Applying an excretion rate of 90% into hospital sewage, total Gd emission from hospitals is 484 kg per year. The amount of the MRI contrast media which is not applied is unclear but can be estimated as 10-20%. The remains may end up in waste or in wastewater, depending on local procedures and staff training. Using the data supplied by Bau and Dulski (1) and the number of MR tomographs carried out in the city of Berlin would result in a local Gd use of 67.7 kg. Extrapolation of the Berlin data to Germany as a whole results in a consumption of 1355 kg. Eight hundred twentythree kilograms of this amount must be attributed to hospitals, resulting in an emitted amount of 741 kg (Table 4). Therefore, one can conclude that the data presented on the basis of local measurements and local as well as nationwide balances agree quite well and give the range of Gd use by hospitals and private practices and their Gd input into the aquatic environment. The data show that local differences may be important, as concentrations measured at Freiburg were lower than the German-wide average and Berlin as a region of high population density showed concentrations which were higher than the German-wide average. In the literature available during this study, there were no data reported on sources of Gd emission other than magnetic resonance imaging. Additional sources are industries or cars equipped with catalytic converters. Investigations by Bau and Dulski (1) in the city of Remscheid (Germany) revealed that sewage from households, metal working companies, and a hospital yielded excess gadolinium, but surface runoff sampled from a collecting basin did not. Lanthanides such as Ce, La, and Nd in polluted grass sampled near a highway were analyzed in order to quantify emission from automobile catalysts (23). These elements belong to the matrix constituents of automobile catalysts (23). Ceriumoxide, generally added to three-way catalysts as a promoter of the watergas shift reaction (24), should also be accompanied by a minor fraction of Gd. Relation of Ce: Gd in the earth crust is between 4:1 (25) and 15:1 (21). Gd concentrations which decrease in proportion to increasing distance from the road imply that Gd was emitted by automobile catalysts. In comparison to the emission balance published for platinum (26), which is also emitted by automobile catalysts as their catalytically active component (27), Gd emission by this source may be roughly quantified
as implicated by these data (Ce:Gd measured 8:1 (24)). Up to 3400 kg of Gd may be emitted per year by this source in Germany. A portion of the Gd emitted by cars is then introduced together with the street runoff into the sewerage system possibly causing an increase of Gd in sewage sludges. However, this source must be quantified in a separate study. We can suggest only the order of magnitude to which Gd is emitted from automobile catalysts. It should be mentioned that Gd from this source is probably mainly received by the soils nearby the roads. Furthermore, the Gd emitted by cars will almost certainly possess different toxicity and display different behavior during the wastewater cleaning and treatment process, because different species of Gd have to be considered. The manufacturing of phosphors and of garnets for microwave application (2) as main uses of Gd may also contribute to Gd input into the environment. One would thus expect residues from these processes to be contained in industrial landfills and not emitted in municipal sewage and STP effluents. Leaking from landfill sites is probably insignificant but may compete with modest fluxes from hospitals presented here. Data are not available. As the emissions are not quantifiable, this must be undertaken in a separate study. In summary it may be said that there are not sufficient data to assess different Gd fluxes of anthropogenic origin and the extent to which they contribute to Gd in sewage and surface water. However, among the other sources MRI compounds containing Gd may add significantly to the positive Gd anomaly found in surface water.
Acknowledgments We are grateful to N. Mergel, who carefully performed ICPMS analysis. A. Schuster provided the data on MRI contrast media usage, A. Haiss, A. Henninger, and I. Bulowski took the samples, and Mr. Dries from the Abwasserzweckverband Breisgauer Bucht allowed the use of an automatic sampling device. C. Ehritt-Braun from the Radiology Department of the Freiburg University Hospital kindly provided information about MRI contrast media use. With P. Dulski from the GeoForschungsZentrum Potsdam we shared fruitful discussions and information about MRI contrast media use in Berlin. The helpful comments of the anonymous reviewers are acknowledged.
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(3) Hammond, C. R.; Gadolinium. In CRC Handbook of Chemistry and Physics, 78th ed.; Lide, D. R., Ed.; CRC Press Inc.: Boca Raton, FL, 1995. (4) Nycomed. Data sheet for Omniscan; Munich, 1995. (5) Falter, R.; Wilken, R.-D. Vom Wasser 1998, 90, 57. (6) Tweedle, M. F.; Kumar, K. Magnetic resonance imgaging (MRI) contrast agents. In Metallopharmaceuticals II. Diagnosis and Therapie; Clarke, M. J., Sadler, P. J., Eds.; Springer: Berlin, Heidelberg, New York, 1999; p 23. (7) Tu, Q.; Wang, X. R.; Tian, L. Q.; Dai, L. M. Environ. Pollut. 1994, 85, 345. (8) Spencer, A. J.; Wilson, S. A.; Batchelor, J.; Reid, A.; Rees, J.; Harpur, E. Toxicol. Pathol. 1997, 25, 245. (9) Badger, D. A.; Kuester, R. K.; Sauer, J. M.; Sipes, I. G. Toxicology 1997, 121, 143. (10) Mizgerd, J. P.; Molina, R. M.; Stearns, R. C.; Brain, J. D.; Warner, A. E. J. Leucocyte Biol. 1996, 59, 189. (11) Rees, J.; Spencer, A.; Wilson, S.; Reid, A.; Harpur, E. Toxicol. Pathol. 1997, 25, 582. (12) Takahashi, M.; Tsutsui, H.; Murayama, C.; Miyazawa, T.; FritzZieroth, B. Magn. Reson. Imaging 1996, 14, 619. (13) Ray, D. E.; Cavanagh, J. B.; Nolan, C. C.; Williams, S. C. Am. J. Neuroradiol. 1996, 17, 365. (14) Bokenes, J.; Hustvedt, S. O.; Refsum, H. Acad. Radiol. 1997, 4, 204. (15) Akre, B. T.; Dunkel, J. A.; Hustvedt, S. O.; Refsum, H. Acad. Radiol. 1997, 4, 283. (16) Behra-Miellet, J.; Gressier, B.; Brunet, C.; Dine, T.; Luyckx, M.; Cazin, M.; Cazin, J. C. Methodol. Find. Exp. Clin. 1996, 18, 437. (17) Schwabe, U.; Paffrath, D. Arzneiverordnungsreport 1996; Gustav Fischer Verlag: Stuttgart Jena, 1996. (18) Statistische A¨ mter des Bundes und der La¨nder. Federal German Statistical Agency: 1996. (19) European Union, Direction General III. Assessment of potential risks to the environment posed by medical products for human use (excluding products containing live genetically modified organisms); No. 5504/94 Draft 6, version 4; Brussels, January 5, 1995. (20) Ku ¨mmerer, K.; Steger-Hartmann, T.; Meyer, M. Water Res. 1997, 31, 2705. (21) Wedepohl, K. H. Geochim. Cosmochim. Acta 1995, 59, 1217. (22) Vivian, C. M. G. Environ. Technol. Lett. 1986, 7, 593. (23) Helmers, E. Chemosphere 1996, 33, 405. (24) Taylor, K. C. Automobile catalytic converters; Springer: Berlin, 1984; p 54. (25) Hollemann and Wiberg. Lehrbuch der anorganischen Chemie; Walter de Gruyter Verlag: Berlin, New York, 1976. (26) Ku ¨ mmerer, K.; Helmers, E.; Hubner, P.; Mascart, G.; Milandri, M.; Reinthaler, F.; Zwakenberg, M. Sci. Tot. Environ. 1999, 225, 155. (27) Helmers, E. . ESPR-Environ. Sci. Pollut. Res. 1997, 4, 100. (28) Dulski, P. Fres. J. Anal. Chem. 1994, 350, 194.
Received for review June 2, 1999. Revised manuscript received November 8, 1999. Accepted November 15, 1999. ES990633H
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