~
Standard Reference MateriaIs for Clinical Measurements W. WAYNE MEINKE Analytical Chemistry Division National Bureau of Standards Washington, D. C. 20234
Sational Bureau of issued its first biomedical standard produced specifically for use in clinical laboratories. This standard, cholesterol ( S R l I 911) , has been widely accepted as a primary standard by the clinical laboratories, and was followed in 1968 by urea (SRM 912), uric acid (SRJI 913), and ‘creatinine (SRY 914), and in 1969 by calcium carbonate (SRM 915). S B S traditionally has been oriented toward basic physical and chemical standards for science, industry, and technology, but entered the biomedical standards field a t the urging of the College of American Pathologists and the American ,4ssociation of Clinical Chemists. One may ask, ‘ W h a t is the function of the Xational Bureau of Standards in the area of clinical chemistry?” While we certainly are not clinical chemists, we are experts in measurement and have a very broad set of competences represented throughout the Analytical Chemistry Division. Furthermore, we have found that many of the problems of accurate measurement encountered by clinical chemists are amenable to the same competences we have applied in other areas such as metals analysis, oceanography, lunar samples, or air pollution. Thus, in addition to the five above-mentioned standard reference materials (SRhfs) , a glucose (SRM 917) and a potassium chloride ISRN 918) have been made avail-
ix 1967
THE
I Standards
28 A
* ANALYTICAL CHEMISTRY, VOL.
able. Recently the Bureau completed a detailed study of bilirubin and made samples of this material available as SRM 916. At the same time, an extensive study of spectrophotometry measurements has led to the issuance of a set of neutral density filters for the calibration of spectrophotometers. KBS also has available many other SRMs which, though not aimed specifically for use in the clinical laboratory, are prerequisites for accurate quality control in any laboratory performing chemical analyses. Basic standardization of titrimetric procedures should be established via S B S primary standards. p H meters should be calibrated against XBS p H standards. Of the more than 700 SRMs available from NBS, many have particular applicability in establishing and maintaining the highest quality control in clinical or biomedical research laboratories. NBS Standard Reference llaterials provide unequivocal “thirdparty” certification of composition. purity, or some physical property. -4 number of other government agencies tie their regulations to KBS-SRRfs. Sixty-five years of experience have built a tradition of “accuracy awareness’’ into the S R N program which is unique throughout the world. Experience has shown that this vector to\yard accurate measurement can be applied with important consequences to many fields. History
The Analytical Chemistry Division of the Bureau first became interested in the problems of measurement in clinical chemistry about five vears ago when Bradley E. Copeland, M.D., Chairman of the 43, NO. 6, MAY 1971
Standards Committee of the College of American Pathologists, pointed out the major discrepancies found in cholesterol measurements performed in different laboratories throughout the country. Our attention was also called to the difficulties various clinical laboratories were having in standardizing spectrophotometers. Indeed, it was through Dr. Copeland’s energetic persuasions that me became conyinced that we could make an important contribution by providing an SRM of cholesterol. Results of the cholesterol study, as we learned from Dr. Copeland, were indeed startling. I n 1962 the Standards Committee of the College of American Pathologists surveyed a large number of clinical laboratories in this country with regard to the measurement of cholesterol. Over 6000 clinical laboratories n’ere invited to participate in an intercomparison, and 1088 useful replies were received. Two 5ml serum samples with different concentrations of cholesterol were distributed for measurement, one containing 152 mg/100 ml, and the other 269 mg/100 ml. The laboratories were requested to measure each sample routinely and to return the results to the College of hmerican Pathologists. The results of the 1088 laboratories are plotted in Figure 1, in which the reported value on Sample A is plotted against that for Sample B. Wide scattering around the “true value” is apparent. Indeed, some results were as much as 35-50% in error in the in tercomparison. Dr. Copeland also emphasized the results of another intercomparison made h.; his Standards Committee in which samples o[ potassium nitrate and pyrene were sent
REPORT FOR ANALYTICAL CHEMISTS Pressures on the modern clinical laboratory to provide rapid and accurate analyses have produced a great demand for standard reference materials N e w S R M s being developed a t the National Bureau of Standards will have particular applicability in establishing and maintaining the highest quality control in clinical or biomedical research laboratories
to 94 different laboratories for measurement on recording spectrophotometers. Figure 2 shows the results of this intercomparison in a plot of potassium nitrate us. pyrene measurements. The 94 results fall onto 11 points on the plot, each point corresponding to a particular make of recording spectrophotometer. I n other words, comparisons on this simple measurement system were ea& intercomparable between different laboratories, when made ivith the same make and model of instrument, but comparisons between different types of instruments introduced significant errors. Soon after our initial contacts with Dr. Copeland, we also began a series of very fruitful discussions with George N. Bowers, Jr., M.D., Chairman of the Standards Committee of the American A4ssociation of Clinical Chemists. This active group heartily endorsed the urgency of efforts on cholesterol and spectrophotometry standards. They went further and provided a priority list of many other clinical measurements which they felt could be markedly improved by SRlIs. The list included clinical standards which they felt mere needed prior to 1970, another list needed prior to 1975, and a third list which they felt would be important to have prior to 1980. This long-range advice and perspective in clinical chemistry have been particularly helpful to us. I n clinical measurement there is an increased use of automation and computer control without commensurate attention t o meaningful standardization. With the number of clinical analyses being performed in this country each year approaching one billion, it is obvious that in-
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V A L U E FOUND Figure 1. National Cholesterol Survey-1962, of American Pathologists
PATHOLOGISTS
180 210 240 270 300 STD. A by Standaids Committee of College
-
Courtesy, Dr. 6 . E. Copeland
A B S 0 RBANCE
"."." 94 RECORDING S P E C T R O P H O T O M E T E R S
0.860
BY M A N U F A C T U R E R
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0.850
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302 nm
PYRENE
2 7 2 nm
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creased automation and computerization is essential. However, it is also essential t h a t automated instruments be subjected t o accurate standardization, or the increasing flow of data may be meaningless. Indeed, in a field such as clinical chemistry erroneous data may be more than meaningless; it may be actually harmful t o a patient. Within the last decade NBS has become increasingly aware of its responsibilities and opportunities for assistance in improving measurement capabilities in national problem areas such as biomaterials, air and water pollution, and safety. [Indeed i t is this awareness that has led to our cosponsorship this summer of the Analytical Summer Symposium with the topic, “Analytical Chemistry-Key to Progress in National Problem Areas” ( 1 ).] Thus as an outgrowth of this trend within S B S the Analytical
Chemistry Division in 1966 made the decision to enter the field of clinical standardization with high purity SRMs. I n 1969 the National Institute for General Medical Sciences of N I H initiated a substantial cooperative program with the Bureau to provide increased impetus in this S R l I area. Organic SRMs for Clinical Chemistry
Robert Schaffer, Chief of the Organic Chemistry Section, has provided the dedicated leadership for the certification of organic SRMs for clinical chemistry. Thomas W. llears, Organic Standards Coordinator of the KBS Office of Standard Reference Materials, has worked with suppliers to provide large quantities of high-quality material. Dr. Schaffer and associates in organic chemistry have then made appropriate measurements to guaran-
tee homogeneity throughout the supply and then, along with Division experts in a number of other competences, have exhaustively studied the material for purity (and impurities). It is this Divison and S B S capability to make measurements on a material by many different independent competences which is unique and which permits us to pursue the concepts of accuracy in depth. hpplication of our broad Division experience in accurate measurement to clinical SRMs has proved very fruitful. Cholesterol. The determination of cholesterol in blood is very important in the clinical laboratory. Often cholesterol determinations are made in routine screening of adult populations. Above-normal cholesterol levels in blood may be symptomatic of atherosclerosis or other clinical conditions; belownormal values may occur with he-
Standard Reference Materials for Clinical Measurements. SRM No. 40h
83c 84h 136c 186Ic 186IIc 350 911 912 913 914 915 916 917 918 922
Name Sodium oxalate Arsenic trioxide Acid potassium phthalate Potassium dichromate Potassium d ihydroge n phosphate Disodium hydrogen phosphate Benzoic acid Cholesterol Urea Uric acid Creatinine Calcium carbonate Bilirubin D-Glucose Potassium chloride tris(Hydroxymethy1)aminomethane
Purity,
%
99.95 99.99 99* 993 99.98 99.9 99.9 99.98 99.4 99.7 99.7 99.8 99.9 99 99.9 99.9 99.9
Property certified Reductometric standard
Date issued April 24, 1969
PH
60 75 60 60 30 30 30 0.5 25 10 10 20 0.1 25 20 25
PH
35
May 1, 1971
Absorbance
3 filters
Feb. 24, 1971
Major and trace constituents
75 120
Jan. 28, 1971
160
May 1, 1971
Reductometric standard Acidimetric standard Oxidation standard PH PH Acidimetric standard Identity and purity Identity and purity Identity and purity Identity and purity Identity and purity Identity and purity Identity and purity Identity and purity
923
tris(Hyd roxymet hyl)aminomethane hydrochloride
930
Glass filters for spectrophotometry
1571 2201
Orchard leaves NaCl
99.9
PNa PCI
2202
KCI
99.9
PK PCI
99.7
Amount, g
Feb. 6, 1962 July 9, 1969 March 24, 1970 July 29, 1966 Sept. 1, 1970 April 15, 1958 Oct. 20, 1967 Sept. 24, 1968 Sept. 24, 1968 Sept. 24, 1968 March 4, 1969 March 10, 1971 Nov. 18, 1970 Jan. 22, 1971 May 1, 1971
April 15, 1971
Orders and requests for information about these SRM’s should be directed to t h e Office of Standard Reference Materials, National Bureau of Standards, Washington, D. C. 20234.
ANALYTICAL CHEMISTRY, VOL. 43, NO. 6, MAY 1971
31A
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Report for Analytical Chemists
patic disease and hyperthyroidism. Cholesterol is estimated by a number of procedures. Cholesterol and esters of cholesterol are extracted from the serum, and then either separated from each other and estimated independently or the combined total is estimated together by the color produced on reaction with acetic anhydride and sulfuric acid (Liebermann-Burchard reaction) or by the color produced on reaction with FeC13, acetic acid, and sulfuric acid. Although the sensitivity is greater with the latter reagent mixture, the method of Abell e t al. ( 2 ) ,which employs the Liebermann-Burchard reagent, is usually recognized as the preferred method. Because their modification is not easily adapted to use with large numbers of determinations, quicker methods are utilized for routine analyses. The survey carried out in 1962 by the College of American Pathologists on the proficiency of laboratories testing for cholesterol led to the conclusion that an essential step needed for improving cholesterol determinations would be the provision of a cholesterol preparation of assured high purity to be used as a standard. The cholesterol of high purity which XBS has certified provides a uniform base line to which clinical laboratories can standardize their procedures. The purity of the cholesterol was originally certified as 99.4 k 0.3% , but is now known to be 99.7 0.2% (95% confidence level). The cholesterol had been purified according to the method of L. F. Fieser (S)-Le., preparing cholesterol dibromide, regenerating the cholesterol by reacting the dibromide with zinc dust, and crystallizing. Reliance on the use of this procedure was incorporated into a set of criteria ( 4 ) proposed for obtaining and characterizing a highly pure, crystalline preparation of cholesterol to be used in standardizing the clinical measurement. The SRlI cholesterol was analyzed for conformance to the expected elemental composition and tested for melting behavior and optical rotation. It was also examined by spectrophotometry (ultraviolet and infrared), by spectrometry (mass and nmr), and by
*
gas-liquid and thin-layer chromatography (GLC and T L C ) . For revealing impurities in the very pure cholesterol, ultraviolet spectra and T L C proved most useful, but it required use of differential scanning calorimetry and phase solubility analysis to secure estimates of the purity. These techniques showed 99.8 mol % and 99.8 w t % purities, respectively. We regard these methods to be accurate to within t0.270 for the cholesterol. The standard material shows a 0.013 i 0.005% bromine content, a trace indication of the purification procedure employed. The cholesterol (SRM 911) is packaged in an amber bottle under nitrogen. It had been suggested that the material should not be issued after one-year storage. We have now followed the shelf life of the SRM cholesterol for over three years and have found no decomposition (less than 0.2% when stored below O O C ) . Indeed, a t this high purity, cholesterol is reasonably stable. Apparently, impurities in cholesterol catalyze its decomposition. Since November 1967, we have distributed about 600 samples of cholesterol to over 300 different clinical laboratories within the United States. Within the next six months we expect to issue a renewal of the cholesterol SRhl packaged in individual-use vials. A detailed paper, “Cholesterol: Standard Reference Material 911” by R. Schaffer et al. has been submitted to the American Journal of Clinical Pathology ( 5 ) . Urea. The clinical test for urea is one of the most frequently performed in the clinical laboratory. Urea is formed in the liver from the amino groups of amino acids as the end product of nitrogen metabolism and is subsequently excreted by the kidney. Impaired kidney function leads to high urea in the serum. I n clinical procedures urea is determined either by reaction with diacetyl monoxime followed by measurement of the color, or by use of the enzyme urease and measurement of the liberated ammonia by the Berthelot reaction or by Nesslerization. The urea SRM was certified to be
99.7 t 0.1% pure. A satisfactory method for drying the urea was not found. Either incomplete drying, or excessive (and progressive) weight loss occurred, depending on the degree and intensity of heating and evacuation. However, there was little tendency to gain or lose weight (t0.00370) when the SRM was exposed to laboratory air for a tmo-week period. Hence, analyses should be performed on the SRM urea without attempting to lower its moisture content. The reported moisture content of 0.18% was determined by the Karl Fischer titration method. The apparent purity of the urea was determined by t\vo methods. Differential scanning calorimetry indicated an apparent purity of 99.82 mol %. Phase solubility analysis of the urea in isopropyl alcohol indicated an apparent purity of 99.82 wt 7.. These values are designated as “apparent purity” because neither method accounted for the moisture content of the urea. Biuret in the urea was estimated spectrophotometrically to be 0.07%. Neither paper chromatography nor TLC indicated any evidence of biuret or cyanuric acid. Neither infrared (ir) absorption nor nmr spectroscopy revealed any unexpected peaks, and hence, they gave no evidence of impurity. For trace metallic constituents, analysis by emission spectrometry and activation analysis showed the following t o be present: aluminum, silicon, iron, sodium, nickel, calcium, chlorine, magnesium, manganese, copper, and zinc. Uric Acid. Measurements of uric acid in serum are made only 10-207. as often as measurements of urea. This can still amount to several thousand tests a year in a large hospital. Cric acid is the metabolic end product of purines and is found in the blood in increased concentration in patients with gout, or undergoing rapid release of nucleic acids owning to drug treatmen6i.e.. for leukemia -and in cases of renal failure. The clinical procedure using the enzyme uricase follows the decrease in absorbance a t about 290 nm due to uric acid as it is converted into other substances. Alternatively, its reaction with alkaline phospho-
ANALYTICAL CHEMISTRY, VOL. 43, NO. 6, MAY 1971
33 A
Report for Analytical Chemists
tungstate produces tungsten blue, which is measured. The uric acid SRN was certified 0.1% pure. The uric acid 99.7 used in this standard reference material was found to be homogeneous by paper chromatography and T L C with several solvent systems. This homogeneity was further verified by GLC of the trimethylsilylated material. The 0.14% volatile material was determined by heating the sample overnight a t 110°C. The ash, 0.0577. of the total weight, was composed principally of sodium and potassium salts. Aluminum, calcium, iron, phosphorus, and silicon comprise a few percent of the ash; cobalt, copper, manganese, nickel, and zinc are present as traces. A 100-gram sample of uric acid was extracted successively with 500 ml each of water, absolute ethanol, benzene, and water. The ultraviolet absorption spectrum of each of these extracts showed no absorption bands other than those of uric acid. Only uric acid Tyas detected by T L C of these same extracts. Creatinine, Between 6000 and 10,000 creatinine measurements may be made each year by a large hospital. Creatinine is studied to aid in the diagnosis of kidney disfunction and uremia. I n the clinical procedures, the creatinine is treated with alkaline picrate (the J o f f k reaction) and forms a measurable red pigment. Many modifications are used. The purity of the creatinine S R N was certified a t 99.8 i 0.1%. The homogeneity of the creatinine was determined by paper chromatography, TIX, and GLC. Volatile matter 10.0370) was determined by measurement of loss of Jyeight of the creatinine after heating for 24 hr a t 110°C. Phase solubility analysis of an oven-dried sample with absolute methanol as the solvent indicated the purity to be 99.82 ut 7..Phase solubility analysis of the undried creatinine with 95% methanol and 955% ethanol indicated purities of 99.81 and 99.76 wt 7.,respectively. Potentiometric titration required 99.82% of the theoretical amount of hydrochloric acid. The certified value for chloride 10.07%) was obtained by titration
*
34A
with mercuric nitrate of a solution of the products resulting from an oxygen-flask combustion. The ultraviolet absorption spectrum of a solution of the SRbI in water showed a molar absorptivity (cnlah) of 7140 I 30 a t 234 nm. Infrared absorption and nmr spectra provided no evidence of impurities . Analysis for trace metallic constituents by emission spectroscopy and activation analysis showed the following to be present: silicon, chlorine, aluminum, sodium, titanium, copper, iron, manganese, and magnesium. D-Glucose. I n most general hospitals, the glucose measurement is the single most prevalent clinical determination made. Approximately 50,000 measurements may be made in one year in a 1000-bed h ospi t a1. For about 60 years, the National Bureau of Standards has made available a standard reference material dextrose for the purpose of standardization of chemical methods of analysis, primarily for the sugar industry. I n recent years, developments in the standardization of clinical analysis techniques have resulted in a national requirement for a more highly characterized D-glucose, suitable for use in both chemical and biochemical methods of analysis, and particularly in those in which enzymes are employed. Thus, clinical chemists require a D-gluCOSe standard reference in connection with analyses of blood and urine in the detection and treatinent of diabetes mellitus. The clinical test for glucose is performed by using it as a reducing agent with iron or copper containing oxidants or by using the enzyme glucose oxidase for its conversion to gluconic acid. Each method is subject to interferences. The D-glucose SRM is certified at 99.9 i- 0 1% purity. The only impurities detected in the glucose were moisture and traces of inorganic compounds. Paper, thin-layer, and high-pressure ion-exchange chromatographic techniques revealed no organic impurities. T o establish its purity, it was necessary to know the proportion of the a-D-anomer in the glucose. This was estimated
ANALYTICAL CHEMISTRY, VOL. 43, NO. 6, MAY 1971
by three methods. The ratio of the p-anomer to the a-anomer was found t o be 0.5:lOO by GLC after per (trimethylsilyl)ation of the solid standard material a t 0°C using S-(trimethylsilyl)imidazole in anhydrous pyridine to minimize possible mutarotation. Use of this GLC technique on partly melted standard material showed that the proportion of the p-anomer increases markedly during melting. Differential scanning calorimetry of the standard material shon.ed the CY-D-glLlCOse content to be 99.4%. This value represents only the proportion of anhydrous CY-D-gluCOpyranose present, since the method treats p-D-glucose, or hydrates of a-D-glucose that are stable up to the melting point, as impurities. However, proton magnetic resonance spectroscopy a t 90 RIHz indicated the ratio of p-anomer to CYanomer to be 0.9:lOO: This determination was performed 10 rnin after dissolution of 100 mg of D-glucose in 0.5 ml of methyl sulfoxide-d6, by integration of the doublets due to the anomeric hydroxyl groups. The moisture content (0.06%) was determined by the Karl Fischer and near-infrared methods. As only 0.01-0.027. in weight was lost on drying a t 70°C for 100 hr, the analyses reported herein were performed on the undried standard reference material. The ash content was determined by ignition of 20-gram samples a t 750°C. Turbidimetric assays of solutions of the standard shoTyed the presence of chloride at 2 ppm and sulfate a t 3 ppm. Neutron activation indicated chloride a t 4 ppm. Emission spectrometric analysis of the ash showed calcium to be less than 5 ppni; magnesium and silicon each less than 0.1 ppm; aluminum, boron, and iron each less than 0.05 ppm; and copper, less than 0.01 ppm. Atomic absorption spectrometry indicated that the S R I I contains less than 0.5 ppm of magnesium. Flame emission spectrometry indicated the content of calcium to be about l ppm, and sodium to be about 2.9 ppm. h detailed paper. “Characterization and Quantitative iinalysis of D-Glucose for t-se in Clinical Analy-
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