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Clinical Chemistry 44: 817-824, 1998;
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(Clinical Chemistry. 1998;44:817-824.)
© 1998 American Association for Clinical Chemistry, Inc.

Automation and Analytical Techniques

Direct determination of urinary iodine by inductively coupled plasma mass spectrometry using isotope dilution with iodine-129

Max Haldimann1,a, Bernhard Zimmerli1, Claudine Als2, and Hans Gerber3

1 Swiss Federal Office of Public Health, Division of Food Science, Section of Food Chemistry and Analysis, 3003 Bern, Switzerland.

2 University of Bern, Inselspital, Department of Pathology, 3010 Bern, Switzerland.

3 University Hospital, Inselspital, Department of Clinical Chemistry, 3010 Bern, Switzerland.
a Author for correspondence. Fax (41) 31 322 95 74; e-mail max.haldimann{at}bag.admin.ch.


   Abstract
Top
 Abstract
Introduction
 Theory
 Materials and Methods
 Results and Discussion
 References
 
An inductively coupled mass spectrometric method was developed for the direct determination of iodine in urine. The application of isotope dilution analysis with added 129I offers new possibilities for automatic and accurate determinations. The sample preparation consists of dilution with an ammonia solution containing 129I. The validation was made by comparison with the results obtained in another laboratory by a spectrophotometric method based on the Sandell–Kolthoff reaction. Different regression models, including maximum likelihood estimation, were used to compare the methods. None of the models revealed analytical bias between the two methods. The urine samples analyzed for validation were from three persons previously exposed to an iodine bath and covered a concentration range of 0.2 to 2.8 µmol/L. A detection limit of 0.02 µmol/L, a within-run CV of 2.5%, and a between-run CV of 11.9% were estimated for the proposed method.


   Introduction
Top
 Abstract
 Introduction
Theory
 Materials and Methods
 Results and Discussion
 References
 
Iodine is an essential component of the thyroid hormones that play an important role in human development, growth, and metabolism. Iodine deficiency disorders (IDDs),1 the effects of iodine deficiency, are still a major problem in public health in many parts of the world. Approximately 1.6 billion people are at risk of developing IDDs because they live in areas with natural iodine deficiencies (1)(2)(3). One of the recommended methods for assessing the iodine status within a group of individuals is to measure the iodine excretion in urine.2 According to the World Health Organization, the epidemiological criteria for IDD are as follows (median values): severe, <20 µg/L (0.16 µmol/L); moderate, 20–49 µg/L (0.16–0.38 µmol/L); mild, 50–99 µg/L (0.39–0.78 µmol/L); and no deficiency, >100 µg/L (0.79 µmol/L) (1).

Switzerland was one of the pioneering countries in the prevention of IDDs by iodizing table salt. In 1922, iodized salt became commercially available for human consumption (4)(5) in that country. One of the earliest studies on the trace analytical chemistry, occurrence, and importance of iodine in various environmental and biological samples was published by this laboratory (Federal Office) in 1923 (6). At that time, the spectrophotometric method consisted of a simple optical device in which the color was visually perceived. Today, more sophisticated analytical methods have been established. Of the different methods available, the most commonly used is the sensitive spectrophotometric procedure based on the Sandell–Kolthoff reaction, in which iodine has a catalytic effect on the reaction between cerium(IV) and arsenic(III) (7)(8)(9).

During the last 10 years, inductively coupled plasma mass spectrometry (ICP-MS) has become a popular method for the reliable determination of trace elements in samples of biological and environmental origin. Although iodine has a relatively high ionization energy (10 eV) and is, therefore, ionized in the plasma only to a limited extent (~25%), it can be readily determined by ICP-MS in a sensitive way. Several ICP-MS methods have been described for the determination of the total iodine content in biological materials (10–15). However, only a few of these applications have been described for clinical chemistry (12)(15).

In many of the ionization methods used in mass spectrometry, the most accurate results can be obtained with isotope dilution analysis (IDA) (16)(17). For the determination of monoisotopic natural iodine, the long-lived radioisotope I is used for some IDA applications (17)(18)(19). I is produced either naturally by cosmic ray interaction with xenon in the atmosphere or as an artificial fission product of uranium or plutonium. Because I in environmental samples presently occurs in extremely low concentrations, its abundance in urine can be neglected (19)(20)(21). Even in urine samples from three technicians who disassembled the pressure vessel of a boiling water nuclear power reactor, I was not detected (detection limit, 0.01 µmol/L).

The I standard is radioactive; however, the analysis of ~20 000 urine samples per year does not represent a radiological hazard. Even if a person ingested the total amount of I necessary to carry out this number of measurements, it would cause only an effective dose equivalent of ~2 mSv/y, a dose that is comparable with the annual global average of human exposure to radiation from natural sources.

For the fourth time during this century, changes of dietary habits have made an increase of the iodine content in Swiss table salt mandatory (22)(23)(24). A longitudinal study to reassess the Swiss iodine status is planned. The aim of this work is to present a simple dilute-and-inject method for the determination of iodine in urine.


   Theory
Top
 Abstract
 Introduction
 Theory
Materials and Methods
 Results and Discussion
 References
 
IDA
IDA is an explicit method where only the ratio between the added isotope and a selected reference isotope is measured, unlike most analytical methods that measure relative to external standards. A known quantity of an enriched isotope with a minor natural abundance is usually added to the sample. However, because iodine is a monoisotopic element, a radioisotope (I) must be used. IDA calibration methods generally correct for analyte losses, matrix effects, and instrumental drifts (16).

After adding the enriched solution, a mixture of I and I, to the urine, the resulting I and I intensity ratio R, which is measured experimentally by ICP-MS, can be defined as:

(1)
ns and nu are the number of moles of iodine in the supplement and urine; as127, as129, au127,and au129 represent the isotopic abundance of iodine in the supplement and urine, respectively. Rearranging Eq. 1Up and assuming that au127 = 100%, the unknown number of moles iodine in urine can be calculated:

(2)
A drawback of the ICP-MS system is that the acquired isotope ratios exhibit an inherent instrumental error (mass bias) due to the different transmission efficiencies of I and I ions from the point where they enter the sampling device until their final detection. The mass bias factor f must, therefore, be measured experimentally and multiplied by the biased ratio R that is obtained from the ICP-MS measurements. In a separate experiment, f is determined using a standard of known isotopic composition:

(3)
where Rtrue is the expected ratio known from the certificate or from an alternative measurement that yields the exact abundance. Rexp is obtained from measurements under experimental conditions. Equal mass biases in standard and sample solutions are assumed in this correction. The deviation of Rtrue from Rexp is 0–6%. The final equation for the calculation of the number of moles iodine in urine is then obtained:

(4)
The measurements of the mass bias and the analysis of samples are made at different times and are thus susceptible to variation in the magnitude of bias, e.g., the stability of instrumental conditions. Regular measurements and updates of the mass bias corrections are, therefore, necessary to monitor possible long term instabilities.

The error of the measured isotope ratio contributes to the error of the final iodine concentration and is theoretically expressed by a nonlinear function of R. Optimal measurements are usually achieved for R {approx} 1. However, for monoisotopic elements such as iodine, the corresponding relation is linear (16).

validation procedure
We applied four statistical linear regression models to estimate the intercept (a) and slope (b) of the line y = a bx: linear least-squares regression, Bartlett's three-group method, orthogonal regression, and maximum likelihood regression (25)(26)(27)(28)(29)(30)(31)(32). A gaussian distribution was assumed for analytical errors, and alternatives were not considered. Additional important assumptions in the first model are that one method (x values) is without error, and the error variances of y are constant over the concentration range. The second model requires no knowledge of the error variances, and the third model assumes a constant variance ratio. Theoretically, only the maximum likelihood regression model gives correct estimates of a and b even if the data are heteroscedastic, as is typical in analytical chemistry. It applies statistical weight to each point; therefore, determining the measurement variances for each sample is necessary (28)(32).


   Materials and Methods
Top
 Abstract
 Introduction
 Theory
 Materials and Methods
Results and Discussion
 References
 
reagents
ICP-MS.
Analytical grade ammonia (25%) solution was obtained from Merck. Deionized, filtered water was taken from an Easypure(TM) cartridge system from Barnstead. Argon with a purity grade of 99.998% was supplied by Carbagas.

Comparison method.
Analytical grade perchloric acid (70%), nitric acid (65%), arsenic trioxide (As2O3), ceric ammonium sulfate [(NH4)4Ce(SO4)4]·2H2O, and potassium iodate (KIO3) were obtained from Merck.

standards
I solution SRM 4949C was obtained from the NIST (Gaithersburg, MD). The activity of the solution per unit mass was certified at 3451 ± 22 Bq/g. A concentration of 4.09 ± 0.03 mmol/L (528 mg/L) I was calculated based on a half-life of 1.57 x 10 years for I. The concomitant quantity of natural I was not certified; it was determined by ICP-MS using the standard addition method, which is free from mass bias: 10 additions, in increasing increments of 8 nmol I, to solutions containing 8 nmol I in 5 mL. An I concentration of 0.69 ± 0.03 mmol/L (ns) was obtained. This corresponds to an unbiased I and I ratio for the NIST standard of 5.9 ± 0.2 (Rtrue).

Seronorm(TM) urine trace element control material (lot 403125) was obtained from Nycomed. No certified iodine concentration was given. The lyophilized urine was reconstituted with 5.0 mL water.

samples
The urine samples came from three healthy persons (1 male, 2 females; aged 6, 37, and 38 years) and were taken before and after their exposure to a therapeutic saline bath containing an iodine concentration of ~70 µmol/L, after which they inhaled an iodine-rich vapor. A total of 60 collections were measured in the Department of Clinical Chemistry of the University Hospital by the comparison method. The samples were then stored in polystyrene tubes at -20 °C. To have a broad range of concentrations, we selected 47 samples for triple determinations by ICP-MS according to their expected iodine concentrations; however, we performed the analyses under blind conditions. The samples were reconditioned at 35 °C for 1 h; however, some of the precipitates did not dissolve completely. The analysis of samples stored for several weeks at -20 °C did not show any variation in iodine concentration with respect to those analyzed earlier.

I solution and sample preparation and measurement
NIST SRM 4949C control material (18.6 mg) was diluted to 150 mL with 0.29 mol/L ammonia solution. This solution was freshly prepared for each series of urine samples, consisting of 47 samples, that were measured 3 times on different days.

The sample solutions consisted of 1.75 mL of the supplement solution and 0.75 mL of urine that were pipetted and dispensed using the automatic dilution device, Duo, from TAM. The settings for the volumes of sample and I solutions had been controlled previously using a PR/SR balance from Mettler. The resulting sample solution, containing 1.03 nmol (total of both isotopes) of the supplemented iodine, was shaken vigorously to mix the iodine isotopes completely. Fine precipitates, which sedimented to the bottom of the test tubes, were observed occasionally, but filtration was not necessary.

A reagent blank and an I solution were measured at intervals of every 10th sample to detect any variation during the measurement period. This control is of particular importance because the mass bias correction factor f was determined based on this ratio (Eq. 3Up ). Quantitative determinations of iodine (I) were carried out by IDA according to the principles outlined above (Eq. 4Up ).

instruments
A Perkin-Elmer Sciex Elan 5000 ICP-MS equipped with the Perkin-Elmer AS90 autosampler and a parallel path high solids nebulizer obtained from Technical Solutions were used. Because the efficiency of a pneumatic nebulizer is <10%, the major portion of the iodine was collected and pumped into a waste container. To avoid clogging the nebulizer orifice, which may lead to an erratic loss of signal intensity, the height of the autosampler capillary was adjusted to pump the clear sample solution above the precipitates at the bottom of the test tubes. Additional details of the instrument and operating conditions are summarized in Table 1 .


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  		Table 1. ICP-MS operating conditions.

principles of the comparison method
The comparison method was based on the Sandell–Kolthoff reaction, as described by Wawschinek et al. (33); the method has been adapted to modern laboratory equipment by G. Bechtner (manuscript in preparation) and modified in our laboratory by Wüthrich (34). In contrast to the autoanalyzer methods, oxidation of the iodine calibrators and urine samples for the comparison method was performed manually in single glass tubes in a block heater. Urine samples (0.4 mL) and KIO3 calibrators (0.4 mL) ranging from 0 to 3.0 µmol/L were added to 0.25 mL of a mixture (1:4 by volume) of HNO3 (65%) and HClO4 (70%) and digested in the block heater at a nominal 225 °C for 25 min. After the solution cooled, 2 mL of water was added, and the solution was shaked; 100 µL of this solution was then pipetted directly into 96-well microwell plates. One hundred microliters of As2O3 solution (final As concentration, 40 mmol/L) and 50 µL of (NH4)4Ce(SO4)3 solution (final Ce concentration, 6.4 mmol/L) were added to each well. The iodine calibrators were measured with each microplate. The absorption was measured after a reaction time of 30 min by an automatic microwell-plate reader (SLT-Labinstruments spectrophotometer) at 405 nm. Three replicates of each sample were analyzed consecutively.

The modified method was validated by use of primary reference standards (34) that were prepared, as were the calibrators, by directly weighing KIO3 to produce solutions whose concentrations are exactly known. In addition, the method was compared with the classical Technicon AutoAnalyzer method (35), which had been used for decades in our institute (23)(24)(36)(37). This comparison showed an excellent agreement between the two methods (34).

calculations
Calculations of the results of the ICP-MS ratio measurements according to Eq. 4Up were made with spreadsheet software (Excel, Ver. 5.0; Microsoft). The calibration curve for the spectrophotometric comparison method was fitted using a cubic equation (spline), and the results were computed using the Elias program (Elias Medizinaltechnik).

In the method validation procedure, the parameters a and b estimated by the maximum likelihood regression were computed using the Systat 6.0 program (SPSS); all other regression models were computed using spreadsheet software.


   Results and Discussion
Top
 Abstract
 Introduction
 Theory
 Materials and Methods
 Results and Discussion
References
 
ICP-MS MEASUREMENTS
Memory effects.
In general, a serious problem with iodine analysis arises from memory effects. Our initial experiments were carried out to study how the solvent influences the wash-out time and the results. There were no noticeable differences between the profiles of signals, e.g., plateau and tailing, in urine samples (n = 8; diluted 1:1 by volume) measured in alkaline (0.67 mol/L NH3) or acidic (0.13 mol/L HNO3) solutions. The acidic solutions showed signal intensities approximately twice as high for both iodine isotopes, but no effects on the isotope ratios and the final results were observed. However, at acidic pH the blank showed a steady increase of the blank signal intensity after measurements of only a few samples, which is in accordance with the observations of Vanhoe et al. (11). Such memory effects probably originate from the spray chamber in which the aerosol produced by the nebulizer is separated into two fractions. The fine droplets are carried with the nebulizer gas into the plasma, whereas the larger droplets are deposited on the inner walls of the spray chamber. Because some species of iodine, e.g., hydrogen iodide, are volatile at ambient temperatures under acidic conditions, their gradual release from the spray chamber leads to memory effects. Therefore, measurements were finally carried out at alkaline pH. A rinsing time of 150 s was subsequently sufficient to reduce the memory effects to negligible concentrations. To measure iodine in urine under acidic conditions, a special spray chamber with a cooling system was an improvement; however, a long rinsing time of 500 s was still necessary (15).

The analysis of various sample series has never shown any cross-contamination. Urinary alkalinity promotes the precipitation of Mg3(PO4)2 and ammonium urate. Because the analytical results of measurements in both acidic and alkaline solutions were equal, it can be concluded that iodine did not coprecipitate with these fine residues.

Background.
Xenon occurs as an impurity in the argon plasma gas. Therefore, its natural isotope, Xe, interferes with the measurement of I, which can only be determined after correction of the total ion intensity at m/z=129. This was achieved either by measuring Xe and correcting the Xe contribution proportional to its natural abundance or by simply subtracting a reagent blank (0.2 mol/L ammonia solution without I). Because there was no notable difference between the two procedures, the latter was followed throughout this work. However, the Xe signal was still monitored as an additional check of possible instrumental instability. No noticeable interference was found for iodine at the mass/charge ratio m/z=127. The use of more expensive high purity argon (99.9999%) lowered the Xe contribution to some extent; however, a purity grade of 99.998% was sufficient for the determination of urinary iodine. Under experimental conditions, the maximum nonspecific signal contribution from Xe amounted to 0.5% of the total signal at m/z = 129.

Matrix effects.
In addition to the background effects outlined in the previous section, the sample matrix may also introduce changes in the analyte signal intensity. Urine is a relatively complex matrix and contains a wide variety of organic and inorganic substances at variable concentrations. The signal responses of the I isotope, which is present in equal concentrations in the urine sample solutions, is shown in Fig. 1 . The two measurements, performed on different days, show similar signal patterns with a day-to-day shift in intensities. In some of the sample solutions, high concentrations of concomitant ions, e.g., sodium chloride, severely suppressed the I signal. IDA compensates for but does not eliminate such matrix effects. The degree of suppression is the same for I and I ions; thus the isotope ratio is not affected (Eq. 1Up ).



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  		Figure 1. Comparison of the periodic monitoring of the 129I signal intensity.

129I was added as a supplement in equal concentrations (0.4 µmol/L) to 47 diluted urine samples. The signal patterns demonstrate the strong matrix dependence of the iodine signal. The sample sets were measured on different days (two of three sets are shown).

Detection limit.
The detection limit in IDA is related to the quantity of added I (16). The isotope enrichment of commercially available standards is rarely 100%; hence the isotope that has to be determined is added in combination with the enriched isotope. The addition of smaller supplemental quantities may lower the detection limit to some extent. However, in this study, equal amounts of I solution were added to each sample. Therefore, the detection limit was estimated on the basis of the isotope ratio measurements (Rexp) in solutions with added I (16):

(5)
I and I are the measured intensities of the iodine isotopes, and s is the SD of the isotope ratio measurements in the I solution. The mean ratios and SDs, as measured in each of the series under experimental conditions, are given in Table 2 . A detection limit of 0.02 µmol/L (2.5 µg/L) for iodine in urine was estimated by replacing the ratio R in Eq. 2Up with the value Rexp calculated in Eq. 5Up . Day-to-day variations of the mean ratios made it mandatory to measure the I isotope reference standard along with samples.


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  		Table 2. 129I/127I ratios of the 129I solution under experimental conditions measured on different days and estimates of the detection limits.

Repeatability.
The repeatability, here defined as the ability of a method to give the same answer when repeated several times in a single day by a single analyst, was estimated and is summarized in Table 3 . Pooled coefficients of variation (CVp) for the ICP-MS method and comparison method of 2.5% (n = 20) and 4.2% (n = 25), respectively, were calculated (38).


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  		Table 3. Repeatability measurement.

A scatter plot of ICP-MS vs spectrophotometric measurements is shown in Fig. 2 ; each of the crosses on the graph represents the mean values and the SD of three replicates of a sample. Although not in a linear manner, the SDs of both methods apparently increased with higher concentrations (heteroscedastic), whereas the CVs did not.



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  		Figure 2. Scatter plot of mean values (n = 3) of urinary iodine concentrations determined by ICP-MS and spectrophotometry.

The bars indicate the SDs of both procedures.

For the comparison method, no proper between-run data were available because the replicates were measured consecutively. A CVp of 7.5% was obtained for the entire sample set (n = 47).

As a measure of the between-run precision of the ICP-MS method, a pooled CVp of 11.9% was obtained (n = 47). Previously, direct measurement of samples that had not been mineralized generally resulted in poorer precision (39). In addition, the instability of plasma, the mass spectrometer, and the ion optics impose limitations on the precision of the measured isotope ratios. However, the exact cause of variation was not identified or controlled and was, therefore, accepted as part of the variability of the method. The precision value, however, conformed to between-run CVs of 7.9% to 10.2% obtained by a method similar to the comparison method used in this study (40).

Accuracy.
Preliminary validations were made by measuring various iodide solutions of known concentrations. The recoveries ranged from 90% to 100%. So far, no urine control material that is certified for iodine has been available commercially (41). The Seronorm urine standard that adequately represents the matrix being studied was measured by ICP-MS and the comparison method; values of 0.74 ± 0.01 µmol/L (n = 5) and 0.66 ± 0.03 µmol/L (n = 10), respectively, were obtained. Because iodine was not certified in this standard, the accuracy of the ICP-MS method was validated by comparison of the mean iodine concentrations with the results obtained from split samples analyzed by the comparison method. Testing the accuracy of a method over the range of possible assay values is a generally accepted practice. Intercepts (a) and slopes (b) of the regression lines obtained by four different statistical techniques are summarized in Table 4 .


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  		Table 4. Straight line fitting techniques for the comparison of ICP-MS and photometry results of urinary iodine.a

The individual intervals for a and b at the 95% confidence level include 0 and 1, respectively, and thus indicate an absence of bias. The results in Table 4Up show that there was no systematic difference between the results of analytical methods within the tested range of 0.2 to 2.8 µmol/L.

Thompson has shown that the consequences of the restrictions of the conventional linear regression model are not serious, provided that at least 10 samples cover the range of interest uniformly, and the method with the smaller random errors is represented by the x-axis (28). Thompson's assumptions were met in our data set, in which the iodine concentrations covered the range from 0.2 to 2.8 µmol/L uniformly; moreover, no erratic points (outliers) were observed. Therefore, the simple linear regression model gave valid test results as well (Fig. 3 ), which was confirmed by the other estimates.



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  		Figure 3. ICP-MS vs spectrophotometry.

The position of the linear regression line (least squares regression) indicates the absence of any analytical bias (Pearson coefficient of correlation, 0.985).

Considering that the determinations were carried out in different laboratories that used methods based on completely different physical or chemical principles, the results of both methods are in excellent agreement. The close correlation between two such fundamentally different methods excludes any effects of possible interfering substances in the method, i.e., the comparison method, that theoretically bears a higher risk of interference artifacts. Both methods were comparable in performance capability, allowed precise adjustment and control of all the measurement parameters, and were, therefore, less susceptible to systematic errors. For example, in previous work, selenium was measured in human serum by graphite furnace atomic absorption spectrometry, and the uncontrollable deposition of carbonaceous residues in the graphite tube was a source of error (42). The agreement with the comparison method, ICP-MS (42), therefore, was not as good as in the comparison of interest in this work.

In conclusion, the results of this study show that the proposed ICP-MS method provides a direct and accurate determination of iodine in human urine with sufficient precision over a wide range of concentrations. The steady throughput of >=12 samples per hour may amount to >250 analyses per day, because the measurements can continue unattended overnight. ICP-MS is a reasonable alternative to the classical semiautomatic methods, which only allow 100–200 tests per day (9). In comparison with the established procedure based on the Sandell–Kolthoff reaction, a complete mineralization of the samples is not necessary with the ICP-MS procedure; thus the operator is not exposed to toxic agents. Moreover, ICP-MS might be used for the monitoring of occupational exposure to I.

Although the instrumentation is expensive, the application of ICP-MS may become more popular in clinical chemistry in the near future because a potentially attractive feature of the technique is the ability to measure several trace elements simultaneously. However, for public health purposes, the method may be unrealistic for widespread use because of its high costs and degree of sophistication. A simple manual method for estimating the prevalence of IDD has been proposed recently (15).

A more detailed presentation and discussion on the absorption and excretion of iodine by humans as a result of exposure to iodine will be published elsewhere (manuscript in preparation).


   Acknowledgments
 
We thank Karen Dufossé and Annabelle Mompart for carrying out the ICP-MS experiments and to Murielle Groux for the iodine determinations with the spectrophotometric method. We also thank Hans Schwab, head of the Division of Food Science, for supporting this study.


   Footnotes
 
1 Nonstandard abbreviations: IDD, iodine deficiency disorder; ICP-MS, inductively coupled plasma mass spectrometry; and IDA, isotope dilution analysis.

2 5 Although the iodine in urine is mainly present as iodide, the term iodine is used throughout this study.


   References
Top
 Abstract
 Introduction
 Theory
 Materials and Methods
 Results and Discussion
 References
 

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