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4.10. Conclusions
The experiments performed in this evaluation show the two atomic absorption analytical techniques included in this method to be precise and accurate and have sufficient sensitivity to measure airborne cadmium over a broad range of exposure levels and sampling periods.
5. References:
5.1. Slavin, W. Graphite Furnace AAS - A Source Book; Perkin-Elmer Corp., Spectroscopy Div.: Ridgefield, CT , 1984; p. 18 and pp. 83-90.
5.2. Grosser, Z., Ed.; Techniques in Graphite Furnace Atomic Absorption Spectrophotometry; Perkin-Elmer Corp., Spectroscopy Div.: Ridgefield, CT, 1985.
5.3. Occupational Safety and Health Administration Salt Lake Technical Center: Metal and Metalloid Particulate in Workplace Atmospheres (Atomic Absorption) (USDOL/OSHA Method No. ID-121). In OSHA Analytical Methods Manual 2nd ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1991.
5.4. Occupational Safety and Health Administration Salt Lake Technical Center: Metal and Metalloid Particulate in Workplace Atmospheres (ICP) (USDOL/OSHA Method No. ID-125G). In OSHA Analytical Methods Manual 2nd ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1991.
5.5. Windholz, M., Ed.; The Merck Index, 10th ed.; Merck & Co.: Rahway, NJ, 1983.
5.6. Analytical Methods for Atomic Absorption Spectrophotometry, The Perkin-Elmer Corporation: Norwalk, CT, 1982.
5.7. Slavin, W., D.C. Manning, G. Carnrick, and E. Pruszkowska: Properties of the Cadmium Determination with the Platform Furnace and Zeeman Background Correction. Spectrochim. Acta 38B:1157-1170 (1983).
5.8. Occupational Safety and Health Administration Salt Lake Technical Center: Standard Operating Procedure for Atomic Absorption. Salt Lake City, UT: USDOL/OSHA-SLTC, In progress.
5.9. Occupational Safety and Health Administration Salt Lake Technical Center: AAS-HGA Standard Operating Procedure. Salt Lake City, UT: USDOL/OSHA-SLTC, In progress.
5.10. Mandel, J.: Accuracy and Precision, Evaluation and Interpretation of Analytical Results, The Treatment of Outliers. In Treatise On Analytical Chemistry, 2nd ed., Vol.1, edited by I. M. Kolthoff and P. J. Elving. New York: John Wiley and Sons, 1978. pp. 282-285.
5.11. National Institute for Occupational Safety and Health: Documentation of the NIOSH Validation Tests by D. Taylor, R. Kupel, and J. Bryant (DHEW/NIOSH Pub. No. 77-185). Cincinnati, OH: National Institute for Occupational Safety and Health, 1977.
5.12. Occupational Safety and Health Administration Analytical Laboratory: Precision and Accuracy Data Protocol for Laboratory Validations. In OSHA Analytical Methods Manual 1st ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists (Pub. No. ISBN: 0-936712-66-X), 1985.
5.13. Long, G.L. and J.D. Winefordner: Limit of Detection -A Closer Look at the IUPAC Definition. Anal.Chem. 55:712A-724A (1983).
5.14. American Conference of Governmental Industrial Hygienists: Documentation of Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.
Table I Cd Detection Limit Study (Flame AAS Analysis)
_________________________________________________________
STD Absorbance Reading Statistical
(<>g/mL) at 228.8 nm Analysis
_________________________________________________________
Reagent Blank 5 2 n = 6
4 3 mean = 3.50
4 3 std dev = 1.05
CV = 0.30
0.001 6 6 n = 6
2 4 mean = 5.00
6 6 std dev = 1.67
CV = 0.335
0.002 5 7 n = 6
7 3 mean = 5.50
7 4 std dev = 1.76
CV = 0.320
0.005 7 7 n = 6
8 8 mean = 7.33
8 6 std dev = 0.817
CV = 0.111
0.010 10 9 n = 6
10 13 mean = 10.3
10 10 std dev = 1.37
CV = 0.133
0.020 20 23 n = 6
20 22 mean = 20.8
20 20 std dev = 1.33
CV = 0.064
0.050 42 42 n = 6
42 42 mean = 42.5
42 45 std dev = 1.22
CV = 0.029
0.10 84 n = 3
80 mean = 82.3
83 std dev = 2.08
CV = 0.025
Table II Cd Standard Working Range Study (Flame AAS Analysis)
_________________________________________________________________________
STD Absorbance Reading Statistical
(<>g/mL) at 228.8 nm Analysis
_________________________________________________________________________
Reagent Blank 5 2 n = 6
4 3 mean = 3.50
4 3 std dev = 1.05
CV = 0.30
0.020 20 23 n = 6
20 22 mean = 20.8
20 20 std dev = 1.33
CV = 0.064
0.050 42 42 n = 6
42 42 mean = 42.5
42 45 std dev = 1.22
CV = 0.029
0.10 84 n = 3
80 mean = 82.3
83 std dev = 2.08
CV = 0.025
0.20 161 n = 3
161 mean = 160.0
158 std dev = 1.73
CV = 0.011
0.50 391 n = 3
389 mean = 391.0
393 std dev = 2.00
CV = 0.005
1.00 760 n = 3
748 mean = 753.3
752 std dev = 6.11
CV = 0.008
2.00 1416 n = 3
1426 mean = 1414.3
1401 std dev = 12.6
CV = 0.009
Table III Cd Detection Limit Study (AAS-HGA Analysis)
____________________________________________________________
STD Peak Area Readings Statistical
(ng/mL) x 10 [FN3] at 228.8
nm Analysis
____________________________________________________________
Reagent Blank 0 0 n = 6
0 1 mean = 0.167
0 0 std dev = 0.41
CV = 2.45
0.1 8 6 n = 6
5 7 mean = 7.7
13 7 std dev = 2.8
CV = 0.366
0.2 11 13 n = 6
11 12 mean = 11.8
12 12 std dev = 0.75
CV = 0.064
0.5 28 33 n = 6
26 28 mean = 28.8
28 30 std dev = 2.4
CV = 0.083
1.0 52 55 n = 6
56 58 mean = 54.8
54 54 std dev = 2.0
CV = 0.037
2.0 101 112 n = 6
110 110 mean = 108.8
110 110 std dev = 3.9
CV = 0.036
Table IV Cd Standard Working Range Study (AAS-HGA Analysis)
__________________________________________________
STD Peak Area Readings Statistical
(ng/mL) x 10 [FN3] at 228.8
nm Analysis
__________________________________________________
0.2 11 13 n = 6
11 12 mean = 11.8
12 12 std dev = 0.75
CV = 0.064
0.5 28 33 n = 6
26 28 mean = 28.8
28 30 std dev = 2.4
CV = 0.083
1.0 52 55 n = 6
56 58 mean = 54.8
54 54 std dev = 2.0
CV = 0.037
2.0 101 112 n = 6
110 110 mean = 108.8
110 110 std dev = 3.9
CV = 0.036
5.0 247 265 n = 6
268 275 mean = 265.5
259 279 std dev = 11.5
CV = 0.044
10.0 495 520 n = 6
523 513 mean = 516.7
516 533 std dev = 12.7
CV = 0.025
20.0 950 953 n = 6
951 958 mean = 941.8
949 890 std dev = 25.6
CV = 0.027
30.0 1269 1291 n = 6
1303 1307 mean = 1293
1295 1290 std dev = 13.3
CV = 0.010
40.0 1505 1567 n = 6
1535 1567 mean = 1552
1566 1572 std dev = 26.6
CV = 0.017
Table V Analytical Method Recovery (Flame AA Analysis)
Test
Level 0.5x 1.0x 2.0x
<>g <>g % <>g <>g % <>g <>g %
Taken Found Rec. Taken Found Rec. Taken Found Rec.
1.00 1.0715 107.2 2.00 2.0688 103.4 4.00 4.1504 103.8
1.00 1.0842 108.4 2.00 2.0174 100.9 4.00 4.1108 102.8
1.00 1.0842 108.4 2.00 2.0431 102.2 4.00 4.0581 101.5
1.00 1.0081 100.8 2.00 2.0431 102.2 4.00 4.0844 102.1
[FNa1] [FNa-
1]
1.00 1.0715 107.2 2.00 2.0174 100.9 4.00 4.1504 103.8
1.00 1.0842 108.4 2.00 2.0045 100.2 4.00 4.1899 104.7
n = 5 6 6
mean = 107.9 101.6 103.1
std dev = 0.657 1.174 1.199
CV1 = 0.006 0.011 0.012
CV1 (pooled) = 0.010
[FNa1] -Rejected as an outlier - this value did not pass the outlier T-test at
the 99% confidence level.
Test
Level 0.1x
m g m g %
Taken Found Rec.
0.200 0.2509 125.5
0.200 0.2509 125.5
0.200 0.2761 138.1
0.200 0.2258 112.9
0.200 0.2258 112.9
0.200 0.1881 94.1
n = 6
mean = 118.2
std dev = 15.1
CV 1 = 0.128
Table VI Analytical Method Recovery (AAS-HGA Analysis)
Test
Level 0.5x 1.0x 2.0x
ng ng % ng ng % ng ng %
Taken Found Rec. Taken Found Rec. Taken Found Rec.
75 71.23 95.0 150 138.00 92.0 300 258.43 86.1
75 71.47 95.3 150 138.29 92.2 300 258.46 86.2
75 70.02 93.4 150 136.30 90.9 300 280.55 93.5
75 77.34 103.1 150 146.62 97.7 300 288.34 96.1
75 78.32 104.4 150 145.17 96.8 300 261.74 87.2
75 71.96 95.9 150 144.88 96.6 300 277.22 92.4
n = 6 6 6
mean = 97.9 94.4 90.3
std dev= 4.66 2.98 4.30
CV 1 = 0.048 0.032 0.048
CV 1 (pooled) = 0.043
Appendix E -Attachment A
Instrumental Parameters for Flame AAS Analysis
Atomic Absorption Spectophotometer (Perkin-Elmer Model 603)
Flame: Air/Acetylene lean, blue
Oxidant Flow: 55
Fuel Flow: 32
Wavelength: 228.8 nm
Slit: 4 (0.7 nm)
Range: UV
Signal: Concentration (4 exp)
Integration Time: 3 sec
Appendix E -Attachment B
Instrumental Parameters for HGA Analysis
Atomic Absorption Spectrophotometer (Perkin-Elmer Model 5100)
Signal Type: Zeeman AA
Slitwidth: 0.7 nm
Wavelength: 228.8 nm
Measurement: Peak Area
Integration Time: 6.0 sec
BOC Time: 5 sec
BOC = Background Offset Correction
Zeeman Graphite Furnace (Perkin-Elmer Model HGA-600)
Step Ramp Hold Temp. Argon Read
Time Time Flow
(sec) (sec) (° C) (mL/min) (sec)
1)Predry 5 10 90 300 -
2)Dry 30 10 140 300 -
3)Char 10 20 900 300 -
4)Cool Down 1 8 30 300 -
5)Atomize 0 5 1600 0 -1
6)Burnout 1 8 2500 300 -
Appendix F: Nonmandatory Protocol for Biological Monitoring
1.0 INTRODUCTION
Under the final OSHA cadmium rule, monitoring of biological specimens and several periodic medical examinations are required for eligible employees. These medical examinations are to be conducted regularly, and medical monitoring is to include the periodic analysis of cadmium in blood (CDB), cadmium in urine (CDU) and beta-2-microglobulin in urine (B2MU). As CDU and B2MU are to be normalized to the concentration of creatinine in urine (CRTU), then CRTU must be analyzed in conjunction with CDU and B2MU analyses.
The purpose of this protocol is to provide procedures for establishing and maintaining the quality of the results obtained from the analyses of CDB, CDU and B2MU by commercial laboratories. Laboratories conforming to the provisions of this nonmandatory protocol shall be known as "participating laboratories." The biological monitoring data from these laboratories will be evaluated by physicians responsible for biological monitoring to determine the conditions under which employees may continue to work in locations exhibiting airborne-cadmium concentrations at or above defined actions levels (see paragraphs (1)(3) and (1)(4) of the final rule). These results also may be used to support a decision to remove workers from such locations.
Under the medical monitoring program for cadmium, blood and urine samples must be collected at defined intervals from workers by physicians responsible for medical monitoring; these samples are sent to commerical laboratories that perform the required analyses and report results of these analyses to the responsible physicians. To ensure the accuracy and reliability of these laboratory analyses, the laboratories to which samples are submitted should participate in an ongoing and efficacious proficiency testing program. Availability of proficiency testing programs may vary with the analyses performed.
To test proficiency in the analysis of CDB, CDU and B2MU, a laboratory should participate either in the interlaboratory comparison program operated by the Centre de Toxicologie du Quebec (CTQ) or an equivalent program. (Currently, no laboratory in the U.S. performs proficiency testing on CDB, CDU or B2MU.) Under this program, CTQ sends participating laboratories 18 samples of each analyte (CDB, CDU and/or B2MU) annually for analysis. Participating laboratories must return the results of these analyses to CTQ within four to five weeks after receiving the samples.
The CTQ program pools analytical results from many participating laboratories to derive consensus mean values for each of the samples distributed. Results reported by each laboratory then are compared against these consensus means for the analyzed samples to determine the relative performance of each laboratory. The proficiency of a participating laboratory is a function of the extent of agreement between results submitted by the participating laboratory and the consensus values for the set of samples analyzed.
Proficiency testing for CRTU analysis (which should be performed with CDU and B2MU analyses to evaluate the results properly) also is recommended. In the U.S., only the College of American Patholgists (CAP) currently conducts CRTU proficiency testing; participating laboratories should be accredited for CRTU analysis by the CAP.
Results of the proficiency evaluations will be forwarded to the participating laboratory by the proficiency-testing laboratory, as well as to physicians designated by the participating laboratory to receive this information. In addition, the participating laboratory should, on request, submit the results of their internal Quality Assurance/Quality Control (QA/QC) program for each analytic procedure (i.e., CDB, CDU and/or B2MU) to physicians designated to receive the proficiency results. For participating laboratories offering CDU and/or B2MU analyses, QA/QC documentation also should be provided for CRTU analysis. (Laboratories should provide QA/QC information regarding CRTU analysis directly to the requesting physician if they perform the analysis in-house; if CRTU analysis is performed by another laboratory under contract, this information should be provided to the physician by the contract laboratory.)
QA/QC information, along with the actual biological specimen measurements, should be provided to the responsible physician using standard formats. These physicians then may collate the QA/QC information with proficiency test results to compare the relative performance of laboratories, as well as to facilitate evaluation of the worker monitoring data. This information supports discretionary decisions made by the physician with regard to the biological monitoring program, and for mandating medical removal.
This protocol describes procedures that may be used by the responsible physicians to identify laboratories most likely to be proficient in the analysis of samples used in the biological monitoring of cadmium; also provided are procedures for record keeping and reporting by laboratories participating in proficiency testing programs, and recommendations to assist these physicians in interpreting analytical results determined by participating laboratories. As the collection and handling of samples affects the quality of the data, recommendations are made for these tasks. Specifications for analytical methods to be used in the medical monitoring program are included in this protocol as well.
In conclusion, this document is intended as a supplement to characterize and maintain the quality of medical monitoring data collected under the final cadmium rule promulgated by OSHA. OSHA has been granted authority under the Occupational Safety and Health Act of 1970 to protect workers from the effects of exposure to hazardous substances in the work place and to mandate adequate monitoring of workers to determine when adverse health effects may be occurring. This nonmandatory protocol is intended to provide guidelines and recommendations to improve the accuracy and reliability of the procedures used to analyze the biological samples collected as part of the medical monitoring program for cadmium.
2.0 DEFINITIONS
When the terms below appear in this protocol, use the following definitions.
Accuracy:
A measure of the bias of a data set. Bias is a systematic error that is either inherent in a method or caused by some artifact or idiosyncracy of the measurement system. Bias is characterized by a consistent deviation (positive or negative) in the results from an accepted reference value.
Arithmetic Mean:
The sum of measurements in a set divided by the number of measurements in a set.
Blind Samples:
A quality control procedure in which the concentration of analyte in the samples should be unknown to the analyst at the time that the analysis is performed.
Coefficient of Variation:
The ratio of the standard deviation of a set of measurements to the mean (arithmetic or geometric) of the measurements.
Compliance Samples:
Samples from exposed workers sent to a participating laboratory for analysis.
Control Charts:
Graphic representations of the results for quality control samples being analyzed by a participating laboratory.
Control Limits:
Statistical limits which define when an analytic procedure exceeds acceptable parameters; control limits provide a method of assessing the accuracy of analysts, laboratories, and discrete analytic runs.
Control Samples:
Quality control samples.
F/T:
The measured amount of an analyte divided by the theoretical value (defined below) for that analyte in the sample analyzed; this ratio is a measure of the recovery for a quality control sample.
Geometric Mean:
The natural antilog of the mean of a set of natural log- transformed data.
Geometric Standard Deviation:
The antilog of the standard deviation of a set of natural log-transformed data.
Limit of Detection:
Using a predifined level of confidence, this is the lowest measured value at which some of the measured material is likely to have come from the sample.
Mean:
A central tendency of a set of data; in this protocol, this mean is defined as the arithmetic mean (see definition of arithmetic mean above) unless stated otherwise.
Performance:
A measure of the overall quality of data reported by a laboratory.
Pools:
Groups of quality-control samples to be established for each target value (defined below) of an analyte. For the protocol provided in attachment 3, for example, the theoretical value of the quality control samples of the pool must be within a range defined as plus or minus ( +) 50% of the target value. Within each analyte pool, there must be quality control samples of at least 4 theoretical values.
Precision:
The extent of agreement between repeated, independent measurements of the same quantity of an analyte.
Proficiency:
The ability to satisfy a specified level of analyte performance.
Proficiency Samples:
Specimens, the values of which are unknown to anyone at a participating laboratory, and which are submitted by a participating laboratory for proficiency testing.
Quality or Data Quality:
A measure of the confidence in the measurement value.
Quality Control (QC) Samples:
Specimens, the value of which is unknown to the analyst, but is known to the appropriate QA/QC personnel of a participating laboratory; when used as part of a laboratory QA/QC program, the theoretical values of these samples should not be known to the analyst until the analyses are complete. QC samples are to be run in sets consisting of one QC sample from each pool (see definition of "pools" above).
Sensitivity:
For the purposes of this protocol, the limit of detection.
Standard Deviation:
A measure of the distribution or spread of a data set about the mean; the standard deviation is equal to the positive square root of the variance, and is expressed in the same units as the original measurements in the data set.
Standards:
Samples with values known by the analyst and used to calibrate equipment and to check calibration throughout an analytic run. In a laboratory QA/QC program, the values of the standards must exceed the values obtained for compliance samples such that the lowest standard value is near the limit of detection and the highest standard is higher than the highest compliance sample or QC sample. Standards of at least three different values are to be used for calibration, and should be constructed from at least 2 different sources.
Target Value:
Those values of CDB, CDU or B2MU which trigger some action as prescribed in the medical surveillance section of the regulatory text of the final cadmium rule. For CDB, the target values are 5, 7, 10 and 15 m g/l. For CDU, the target values are 3, 5, 10 and 15 m g/g CRTU. For B2MU, the target value are 300, 500, 1000 and 1500 m g/g CRTU. (Note that target values may vary as a function of time.)
Theoretical Value (or Theoretical Amount):
The reported concentration of a quality-control sample (or calibration standard) derived from prior characterizations of the sample.
Value or Measurement Value:
The numerical result of a measurement.
Variance:
A measure of the distribution or spread of a data set about the mean; the variance is the sum of the squares of the differences between the mean and each discrete measurement divided by one less than the number of measurements in the data set.
3.0 PROTOCOL
This protocol provides procedures for characterizing and maintaining the quality of analytic results derived for the medical monitoring program mandated for workers under the final cadmium rule.
3.1 Overview
The goal of this protocol is to assure that medical monitoring data are of sufficient quality to facilitate proper interpretation. The data quality objectives (DQOs) defined for the medical monitoring program are summarized in Table 1. Based on available information, the DQOs presented in Table 1 should be achievable by the majority of laboratories offering the required analyses commercially; OSHA recommends that only laboratories meeting these DQOs be used for the analysis of biological samples collected for monitoring cadmium exposure.
TABLE 1
RECOMMENDED DATA QUALITY OBJECTIVES (DQOs) FOR THE CADMIUM MEDICAL MONITORING
PROGRAM
Analyte/Concentration Pool Limit of Precision Accuracy
Detection ion (CV)
Cadmium in Blood 0.5<>g/l 40 % + 1<>g/l or 15
%
<=2<>g/l 20 % of the mean
>2<>g/1
-------------------------------------------------------------------------------
Cadmium in Urine 0.5<>g/g 40 % + 1<>g/l or 15
%
<=2<>g/l creatinine 20 % of the mean
creatinine
>2<>g/l
creatinine
-------------------------------------------------------------------------------
b-2-Microglobulin in Urine 100<>g/g 5 % + 15 % of the mean
100<>g/g creatinine
creatinine
-------------------------------------------------------------------------------
To satisfy the DQOs presented in Table 1, OSHA provides the following guidelines:
1. Procedures for the collection and handling of blood and urine are specified (Section 3.4.1 of this protocol);
2. preferred analytic methods for the analysis of CDB, CDU and B2MU are defined (and a method for the determination of CRTU also is specified since CDU and B2MU results are to be normalized to the level of CRTU).
3. procedures are described for identifying laboratories likely to provide the required analyses in an accurate and reliable manner;
4. these guidelines (Sections 3.2.1 to 3.2.3, and Section 3.3) include recommendations regarding internal QA/QC programs for participating laboratories, as well as levels of proficiency through participation in an interlaboratory proficiency program;
5. procedures for QA/QC record keeping (Section 3.3.2), and for reporting QC/QA results are described (Section 3.3.3); and,
6. procedures for interpreting medical monitoring results are specified (Section 3.4.3).
Methods recommended for the biological monitoring of eligible workers are:
1. The method of Stoeppler and Brandt (1980) for CDB determinations (limit of detection: 0.5 m g/l);
2. the method of Pruszkowska et al. (1983) for CDU determinations (limit of detection: 0.5 m g/l of urine); and,
3. the Pharmacia Delphia test kit (Pharmacia 1990) for the determination of B2MU (limit of detection: 100 m g/l urine).
Because both CDU and B2MU should be reported in mg/g CRTU, an independent determination of CRTU is recommended. Thus, both the OSHA Salt Lake City Technical Center (OSLTC) method (OSHA, no date) and the Jaffe method (Du Pont, no date) for the determination of CRTU are specified under this protocol (i.e., either of these 2 methods may be used). Note that although detection limits are not reported for either of these CRTU methods, the range of measurements expected for CRTU (0.9-1.7 m g/l) are well above the likely limit of detection for either of these methods (Harrison, 1987).
Laboratories using alternate methods should submit sufficient data to the responsible physicians demonstrating that the alternate method is capable of satisfying the defined data quality objectives of the program. Such laboratories also should submit a QA/QC plan that documents the performance of the alternate method in a manner entirely equivalent to the QA/QC plans proposed in Section 3.3.1.
3.2 Duties of the Responsible Physician
The responsible physician will evaluate biological monitoring results provided by participating laboratories to determine whether such laboratories are proficient and have satisfied the QA/QC recommendations. A requirement of the medical monitoring program mandated under the cadmium rule is that responsible physicians have the duty to employ laboratories to perform the required CDB, CDU and B2MU analyses of biological samples collected from eligible workers (paragraph (l)(1)(iv) of the final rule). In determining which laboratories to employ for this purpose, these physicians should review proficiency and QA/QC data submitted to them by the participating laboratories.
Participating laboratories should demonstrate proficiency for each analyte (CDU, CDB and B2MU) sampled under the biological monitoring program. Participating laboratories involved in analyzing CDU and B2MU also should demonstrate proficiency for CRTU analysis, or provide evidence of a contract with a laboratory proficient in CRTU analysis.
3.2.1 Recommendations for Selecting Among Existing Laboratories
OSHA recommends that existing laboratories providing commercial analyses for CDB, CDU and/or B2MU for the medical monitoring program satisfy the following criteria:
1. Should have performed commercial analyses for the appropriate analyte (CDB, CDU and/or B2MU) on a regular basis over the last 2 years;
2. should provide the responsible physician with an internal QA/QC plan;
3. if performing CDU or B2MU analyses, the participating laboratory should be accredited by the CAP for CRTU analysis, and should be enrolled in the corresponding CAP survey (note that alternate credentials may be acceptable, but acceptability is to be determined by the responsible physician); and,
4. should have enrolled in the CTQ interlaboratory comparison program for the appropriate analyte (CDB, CDU and/or B2MU).
Participating laboratories should submit appropriate documentation demonstrating compliance with the above criteria to the responsible physician. To demonstrate compliance with the first of the above criteria, participating laboratories should submit the following documentation for each analyte they plan to analyze (note that each document should cover a period of at least 8 consecutive quarters, and that the period designated by the term "regular analyses" is at least once a quarter):
1. Copies of laboratory reports providing results from regular analyses of the appropriate analyte (CDB, CDU and/or B2MU);
2. copies of 1 or more signed and executed contracts for the provision of regular analyses of the appropriate analyte (CDB, CDU and/or B2MU); or,
3. copies of invoices sent to 1 or more clients requesting payment for the provision of regular analyses of the appropriate analyte (CDB, CDU and/or B2MU).
Whatever the form of documentation submitted, the specific analytic procedures conducted should be identified directly. The forms that are copied for submission to the responsible physician also should identify the laboratory which provided these analyses.
To demonstrate compliance with the second of the above criteria, a laboratory should submit to the responsible physician an internal QA/QC plan detailing the standard operating procedures to be adopted for satisfying the recommended QA/QC procedures for the analysis of each specific analyte (CDB, CDU and/or B2MU). Procedures for internal QA/QC programs are detailed in Section 3.3.1 below.
To satisfy the third of the above criteria, laboratories analyzing for CDU or B2MU also should submit a QA/QC plan for creatinine analysis (CRTU); the QA/QC plan and characterization analyses for CRTU must come from the laboratory performing the CRTU analysis, even if the CRTU analysis is being performed by a contract laboratory.
Laboratories enrolling in the CTQ program (to satisfy the last of the above criteria) must remit, with the enrollment application, an initial fee of approximately $100 per analyte. (Note that this fee is only an estimate, and is subject to revision without notice.) Laboratories should indicate on the application that they agree to have proficiency test results sent by the CTQ directly to the physicians designated by participating laboratories.
Once a laboratory's application is processed by the CTQ, the laboratory will be assigned a code number which will be provided to the laboratory on the initial confirmation form, along with identification of the specific analytes for which the laboratory is participating. Confirmation of participation will be sent by the CTQ to physicians designated by the applicant laboratory.
3.2.2 Recommended Review of Laboratories Selected to Perform Analyses
Six months after being selected initially to perform analyte determinations, the status of participating laboratories should be reviewed by the responsible physicians. Such reviews should then be repeated every 6 months or whenever additional proficiency or QA/QC documentation is received (whichever occurs first).
As soon as the responsible physician has received the CTQ results from the first 3 rounds of proficiency testing (i.e., 3 sets of 3 samples each for CDB, CDU and/or B2MU) for a participating laboratory, the status of the laboratory's continued participation should be reviewed. Over the same initial 6-month period, participating laboratories also should provide responsible physicians the results of their internal QA/QC monitoring program used to assess performance for each analyte (CDB, CDU and/or B2MU) for which the laboratory performs determinations. This information should be submitted using appropriate forms and documentation.
The status of each participating laboratory should be determined for each analyte (i.e., whether the laboratory satisfies minimum proficiency guidelines based on the proficiency samples sent by the CTQ and the results of the laboratory's internal QA/QC program). To maintain competency for analysis of CDB, CDU and/or B2MU during the first review, the laboratory should satisfy performance requirements for at least 2 of the 3 proficiency samples provided in each of the 3 rounds completed over the 6-month period. Proficiency should be maintained for the analyte(s) for which the laboratory conducts determinations.
To continue participation for CDU and/or B2MU analyse, laboratories also should either maintain accreditation for CRTU analysis in the CAP program and participate in the CAP surveys, or they should contract the CDU and B2MU analyses to a laboratory which satisfies these requirements (or which can provide documentation of accreditation/participation in an equivalent program).
The performance requirement for CDB analysis is defined as an analytical result within + m g/l blood or 15% of the consensus mean (whichever is greater). For samples exhibiting a consensus mean less than 1 m g/l, the performance requirement is defined as a concentration between the detection limit of the analysis and a maximum of 2 m g/l. The purpose for redefining the acceptable interval for low CDB values is to encourage proper reporting of the actual values obtained during measurement; laboratories, therefore, will not be penalized (in terms of a narrow range of acceptability) for reporting measured concentrations smaller than 1 m g/l.
The performance requirement for CDU analysis is defined as an analytical result within + 1 m g/l urine or 15% of the consensus mean (whichever is greater). For samples exhibiting a consensus mean less than 1aeg/l urine, the performance requirement is defined as a concentration between the detection limit of the analysis and a maximum of 2 m g/l urine. Laboratories also should demonstrate proficiency in creatinine analysis as defined by the CAP. Note that reporting CDU results, other than for the CTQ proficiency samples (i.e., compliance samples), should be accompanied with results of analyses for CRTU, and these 2 sets of results should be combined to provide a measure of CDU in units of m g/g CRTU.
The performance requirement for B2MU is defined as analytical results within + 15% of the consensus mean. Note that reporting B2MU results, other than for CTQ proficiency samples (i.e., compliance samples), should be accompanied with results of analyses for CRTU, and these 2 sets of results should be combined to provide a measure of B2MU in units of m g/g CRTU.
There are no recommended performance checks for CRTU analyses. As stated previously, laboratories performing CRTU analysis in support of CDU or B2MU analyses should be accredited by the CAP, and participating in the CAP's survey for CRTU.
Following the first review, the status of each participating laboratory should be reevaluated at regular intervals (i.e., corresponding to receipt of results from each succeeding round of proficiency testing and submission of reports from a participating laboratory's internal QA/QC program).
After a year of collecting proficiency test results, the following proficiency criterion should be added to the set of criteria used to determine the participating laboratory's status (for analyzing CDB, CDU and/or B2MU): A participating laboratory should not fail performance requirements for more than 4 samples from the 6 most recent consecutive rounds used to assess proficiency for CDB, CDU and/or B2MU separately (i.e., a total of 18 discrete proficiency samples for each analyte). Note that this requirement does not replace, but supplements, the recommendation that a laboratory should satisfy the performance criteria for at least 2 of the 3 samples tested for each round of the program.
3.2.3 Recommendations for Selecting Among Newly-Formed Laboratories (or Laboratories that Previously Failed to Meet the Protocol Guidelines)
OSHA recommends that laboratories that have not previously provided commercial analyses of CDB, CDU and/or B2MU (or have done so for a period less than 2 years), or which have provided these analyses for 2 or more years but have not conformed previously with these protocol guidelines, should satisfy the following provisions for each analyte for which determinations are to be made prior to being selected to analyze biological samples under the medical monitoring program:
1. Submit to the responsible physician an internal QA/QC plan detailing the standard operating procedures to be adopted for satisfying the QA/QC guidelines (guidelines for internal QA/QC programs are detailed in Section 3.3.1;
2. submit to the responsible physician the results of the initial characterization analyses for each analyte for which determinations are to be made;
3. submit to the responsible physician the results, for the initial 6-month period, of the internal QA/QC program for each analyte for which determinations are to be made (if no commercial analyses have been conducted previously, a minimum of 2 mock standardization trials for each analyte should be completed per month for a 6-month period;
4. enroll in the CTQ program for the appropriate analyte for which determinations are to be made, and arrange to have the CTQ program submit the initial confirmation of participation and proficiency test results directly to the designated physicians. Note that the designated physician should receive results from 3 completed rounds from the CTQ program before approving a laboratory for participation in the biological monitoring program;
5. laboratories seeking participation for CDU and/or B2MU analyses should submit to the responsible physician documentation of accreditation by the CAP for CRTU analyses performed in conjunction with CDU and/or B2MU determinations (if CRTU analyses are conducted by a contract laboratory, this laboratory should submit proof of CAP accreditation to the responsible physician); and,
6. documentation should be submitted on an appropriate form.
To participate in CDB, CDU and/or B2MU analyses, the laboratory should satisfy the above criteria for a minimum of 2 of the 3 proficiency samples provided in each of the 3 rounds of the CTQ program over a 6-month period; this procedure should be completed for each appropriate analyte. Proficiency should be maintained for each analyte to continue participation. Note that laboratories seeking participation for CDU or B2MU also should address the performance requirements for CRTU, which involves providing evidence of accreditation by the CAP and participation in the CAP surveys (or an equivalent program).
The performance requirement for CDB analysis is defined as an analytical result within + 1 m g/l or 15% of the consensus mean (whichever is greater). For samples exhibiting a consensus mean less than 1 m g/l, the performance requirement is defined as a concentration between the detection limit of the analysis and a maximum of 2 m g/l. The purpose of redefining the acceptable interval for low CDB values is to encourage proper reporting of the actual values obtained during measurement; laboratories, therefore, will not be penalized (in terms of a narrow range of acceptability) for reporting measured concentrations less than 1 m g/l.
The performance requirement for CDU analysis is defined as an analytical result within + 1 m g/l urine or 15% of the consensus mean (whichever is greater). For samples exhibiting a consensus mean less than 1 m g/l urine, the performance requirement is defined as a concentration that falls between the detection limit of the analysis and a maximum of 2 m g/l urine. Performance requirements for the companion CRTU analysis (defined by the CAP) also should be met. Note that reporting CDU results, other than for CTQ proficiency testing (i.e., compliance samples), should be accompanied with results of CRTU analyses, and these 2 sets of results should be combined to provide a measure of CDU in units of m g/g CRTU.
The performance requirement for B2MU is defined as an analytical result within + 15% of the consensus mean. Note that reporting B2MU results, other than for CTQ proficiency testing (i.e., compliance samples), should be accompanied with results of CRTU analysis, these 2 sets of results should be combined to provide a measure of B2MU in units of m g/g CRTU.
Once a new laboratory has been approved by the responsible physician for conducting analyte determinations, the status of this approval should be reviewed periodically by the responsible physician as per the criteria presented under Section 3.2.2.
Laboratories which have failed previously to gain approval of the responsible physician for conducting determinations of 1 or more analytes due to lack of compliance with the criteria defined above for existing laboratories (Section 3.2.1), may obtain approval by satisfying the criteria for newly-formed laboratories defined under this section; for these laboratories, the second of the above criteria may be satisfied by submitting a new set of characterization analyses for each analyte for which determinations are to be made.
Reevaluation of these laboratories is discretionary on the part of the responsible physician.
Reevaluation, which normally takes about 6 months, may be expedited if the laboratory can achieve 100% compliance with the proficiency test criteria using the 6 samples of each analyte submitted to the CTQ program during the first 2 rounds of proficiency testing.
For laboratories seeking reevaluation for CDU or B2MU analysis, the guidelines for CRTU analyses also should be satisfied, including accreditation for CRTU analysis by the CAP, and participation in the CAP survey program (or accreditation/participation in an equivalent program).
3.2.4 Future Modifications to the Protocol Guidelines
As participating laboratories gain experience with analyses for CDB, CDU and B2MU, it is anticipated that the performance achievable by the majority of laboratories should improve until it approaches that reported by the research groups which developed each method. OSHA, therefore, may choose to recommend stricter performance guidelines in the future as the overall performance of participating laboratories improves.
3.3 Guidelines for Record Keeping and Reporting
To comply with these guidelines, participating laboratories should satisfy the above-stated performance and proficiency recommendations, as well as the following internal QA/QC, record keeping, and reporting provisions.
If a participating laboratory fails to meet the provisions of these guidelines, it is recommended that the responsible physician disapprove further analyses of biological samples by that laboratory until it demonstrates compliance with these guidelines. On disapproval, biological samples should be sent to a laboratory that can demonstrate compliance with these guidelines, at least until the former laboratory is reevaluated by the responsible physician and found to be in compliance.
The following record keeping and reporting procedures should be practiced by participating laboratories.
3.3.1 Internal Quality Assurance/Quality Control Procedures
Laboratories participating in the cadmium monitoring program should develop and maintain an internal quality assurance/quality control (QA/QC) program that incorporates procedures for establishing and maintaining control for each of the analytic procedures (determinations of CDB, CDU and/or B2MU) for which the laboratory is seeking participation. For laboratories analyzing CDU and/or B2MU, a QA/QC program for CRTU also should be established.
Written documentation of QA/QC procedures should be described in a formal QA/QC plan; this plan should contain the following information: Sample acceptance and handling procedures (i.e., chain-of-custody); sample preparation procedures; instrument parameters; calibration procedures; and, calculations.
Documentation of QA/QC procedures should be sufficient to identify analytical problems, define criteria under which analysis of compliance samples will be suspended, and describe procedures for corrective actions.
3.3.1.1 QA/QC procedures for establishing control of CDB and CDU analyses
The QA/QC program for CDB and CDU should address, at a minimum, procedures involved in calibration, establishment of control limits, internal QC analyses and maintaining control, and corrective-action protocols. Participating laboratory should develop and maintain procedures to assure that analyses of compliance samples are within control limits, and that these procedures are documented thoroughly in a QA/QC plan.
A nonmandatory QA/QC protocol is presented in Attachment 1. This attachment is illustrative of the procedures that should be addressed in a proper QA/QC program.
Calibration. Before any analytic runs are conducted, the analytic instrument should be calibrated. Calibration should be performed at the beginning of each day on which QC and/or compliance samples are run. Once calibration is established, QC or compliance samples may be run. Regardless of the type of samples run, about every fifth sample should serve as a standard to assure that calibration is being maintained.
Calibration is being maintained if the standard is within + 15% of its theoretical value. If a standard is more than + 15% of its theoretical value, the run has exceeded control limits due to calibration error; the entire set of samples then should be reanalyzed after recalibrating or the results should be recalculated based on a statistical curve derived from that set of standards.
It is essential that the value of the highest standard analyzed be higher than the highest sample analyzed; it may be necessary, therefore, to run a high standard at the end of the run, which has been selected based on results obtained over the course of the run (i.e., higher than any standard analyzed to that point). (continued)