[Federal Register Volume 59, Number 1 (Monday, January 3, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 93-31820]


[[Page Unknown]]

[Federal Register: January 3, 1994]


_______________________________________________________________________

Part III





Department of Labor





_______________________________________________________________________



Occupational Safety and Health Administration



_______________________________________________________________________



29 CFR Parts 1915 and 1926



Standard for Cadmium in Shipyard Employment and in Construction Work; 
Reprint With Corrections and Technical Amendments; Final Rule
DEPARTMENT OF LABOR

Occupational Safety and Health Administration

29 CFR Parts 1915 and 1926

 

Occupational Safety and Health Standards for Cadmium in Shipyard 
Employment and Construction

AGENCY: Occupational Safety and Health Administration, Department of 
Labor.

ACTION: Final rule; miscellaneous corrections, technical amendments, 
and redesignation.

-----------------------------------------------------------------------

SUMMARY: The Occupational Safety and Health Administration (OSHA) is 
correcting an error stemming from the wording of the amendatory 
language of the final rule that incorporated applicable General 
Industry standards for toxic substances into the Occupational Safety 
and Health Standards for Shipyard Employment. The final rule, which 
appeared in the Federal Register on July 1, 1993, had the effect of 
mistakenly inferring that the cadmium standard for shipyard employment 
from the Code of Federal Regulations was being deleted though the 
preamble made it clear it was retained. This correction reprints the 
full text of the cadmium standard as published on September 14, 1992, 
and incorporates changes from an April 23, 1993, document that made 
corrections and amendments to the original publication. In addition, 
several cross-references regarding employee records are being amended 
to reflect the designation of a new section in the shipyard employment 
standards, and a number of effective dates are being converted to dates 
certain.
    In addition, OSHA is redesignating the cadmium standard for 
construction employment, also published in the same September 14 
document, into a different subpart. The redesignation merges it in with 
the newly created subpart that contains specific toxic substance 
standards for construction.

EFFECTIVE DATE: July 1, 1993.

FOR FURTHER INFORMATION CONTACT: Mr. James F. Foster, OSHA Office of 
Public Affairs, Room N-3647, U.S. Department of Labor, 200 Constitution 
Avenue NW., Washington, DC 20210, telephone (202) 219-8151.

SUPPLEMENTARY INFORMATION:

Background

    The final regulations which are the subject of this action was 
published in the Federal Register on June 30 and July 1, 1993 (58 FR 
35076 and 35512, respectively). Up until then, most health standards 
applicable to shipyard employment and construction were not codified in 
the parts of title 29 of the Code of Federal Regulations that contained 
the bulk of the standards applicable to shipyards (part 1915) and 
construction (part 1926). These toxic substance standards were made 
applicable by cross-reference to subpart Z of the general industry 
standards (part 1910) and other parts and documents.
    The Shipyard Employment Standard Advisory Committee (SESAC) 
recommended that OSHA incorporate all toxic substance standards 
covering shipyards into 29 CFR part 1915. As a first step to carry out 
this recommendation, when OSHA issued the cadmium standard on September 
14, 1992 (57 FR 42102), it created a subpart Z in part 1915 to include 
health standards applicable to shipyards and included the cadmium 
standard in subpart Z as Sec. 1915.1027. On April 23, 1993 (58 FR 
21780), OSHA published a document that made corrections and amendments 
to the September 14 document. As a second step, OSHA published a 
technical amendment in the July 1, 1993, issue of the Federal Register, 
which incorporated a comprehensive subpart Z into 29 CFR part 1915. The 
July 1 document included the other toxic substance standards besides 
cadmium, and added certain related standards applicable to shipyards.
    In similar fashion to what SESAC sought, the Advisory Committee for 
Construction Safety and Health also asked that OSHA incorporate the 
general industry standards deemed applicable to construction into 
OSHA's construction standards. This incorporation of the pertinent 1910 
standards into part 1926 was accomplished on June 30, 1993 (58 FR 
35076), and in doing so, OSHA created a subpart Z in part 1926, for the 
applicable specific toxic substance standards.

Need for Correction

    As published, the July 1 final regulation contained amendatory 
language that had the effect of removing the regulatory text and 
appendixes of Sec. 1915.1027--Cadmium, by mistake. The preamble of that 
document made it clear that the Cadmium standard remained applicable to 
shipyard employment (58 FR 35513). This document reinserts the 
regulatory text and appendices of Sec. 1915.1027 into subpart Z--Toxic 
and Hazardous Substances of part 1915 along with the corrections and 
amendments made on April 23, 1993.
    In addition, in the July 1 document, the text of existing 
Sec. 1910.20, entitled ``Access to employee exposure and medical 
records,'' was reprinted as an additional standard in part 1915, to add 
it to the shipyard employment standards as new Sec. 1915.1120. OSHA is 
changing cross-references in paragraphs (m) and (n) of the cadmium 
standard to reflect the designation for the new section regarding 
employee records within part 1915. These changes are to 
Sec. 1915.1027(m)(4)(iii)(H), where the reference to ``Sec. 1910.20(g) 
(1) and (2)'' is changed to read ``Sec. 1915.1120(g) (1) and (2)''; in 
Sec. 1915.1027(n) (1)(iii), (3)(iii), and (5)(i), the reference to ``29 
CFR 1910.20'' is changed to read ``Sec. 1915.1120 of this part''; and 
in Sec. 1915.1027(n)(6), the reference to ``29 CFR 1910.20(h)'' is 
changed to read ``Sec. 1915.1120(h) of this part.''
    In this document, OSHA is also converting a number of effective 
dates that were not computed to dates certain. As published on 
September 14, 1992, the standard included over a dozen effective dates 
that were based on the effective dates of the cadmium document, such as 
for 60 and 90 days after the section or standard became effective. 
These dates, set out in paragraphs (p)(2)(i)-(viii) (57 FR 42399) are 
being computed in this document. The following list details the 
specific instances where these changes are made:
     In Sec. 1915.1027(p)(2)(i), the words ``60 days after the 
effective date of this standard'' are changed to read ``February 12, 
1993'';
     In Sec. 1915.1027(p)(2)(vi)(A), the words ``60 days after 
the effective date of this section'' are changed to read ``February 12, 
1993'';
     In Sec. 1915.1027(p)(2) (ii) and (iii), the words ``90 
days after the effective date of this section'' are changed to read 
``March 15, 1993'';
     In Sec. 1915.1027(p)(2) (vii) and (viii), the words ``90 
days after the effective date of this standard'' are changed to read 
``March 15, 1993'';
     In Sec. 1915.1027(p)(2)(i), the words ``120 days after the 
effective date of this standard'' are changed to read ``April 14, 
1993'';
     In Sec. 1915.1027(p)(2) (ii) and (iii), the words ``150 
days after the effective date of this section'' are changed to read 
``May 14, 1993'';
     In Sec. 1915.1027(p)(2) (vii) and (viii), the words ``180 
days after the effective date of this standard'' are changed to read 
``June 14, 1993'';
     In Sec. 1915.1027(p)(2) (iv) and (iv)(B), the words ``1 
year after the effective date of this section'' are changed to read 
``December 14, 1993''; and
     In Sec. 1915.1027(p)(2)(v), the words ``two (2) years 
after the effective date of this section'' are changed to read 
``December 14, 1994.''
    When it was published in the same September 14, 1992, document, at 
57 FR 42452, the cadmium standard for construction was codified as 
Sec. 1926.63 in subpart D, which covers occupational health and 
environmental controls. With the publication of the June 30, 1993, 
document that created a separate subpart Z for specific toxic 
substances within OSHA's construction standards, it follows that the 
cadmium standard belongs with the new subpart. Therefore, this document 
is redesignating Sec. 1926.63 as Sec. 1926.1127, to place it in the 
appropriate place subpart Z of the construction standards.
    In addition, in the June 30 document, the text of existing 
Sec. 1910.20, entitled ``Access to employee exposure and medical 
records,'' was reprinted as an additional standard in part 1926, to add 
it to the construction standards as new Sec. 1926.33. OSHA is amending 
cross-references in paragraphs (m) and (n) of the cadmium standard 
(redesignated as Sec. 1926.1127) to reflect the designation for the new 
section regarding employee records within part 1926. These changes are 
to paragraph (m)(4)(iii)(H), where the reference to ``Sec. 1910.20(g) 
(1) and (2)'' is changed to read ``Sec. 1926.33(g) (1) and (2)''; in 
paragraphs (n) (1)(iii), (3)(iii), and (5)(i), where the reference to 
``29 CFR 1910.20'' is changed to read ``Sec. 1926.33 of this part''; 
and in paragraph (n)(6), the reference to ``29 CFR 1910.20(h)'' is 
changed to read ``Sec. 1926.33(h) of this part.''
    The corrections and technical amendments in this document are not 
substantive regulatory actions, and therefore are not required to have 
notice, comment, or an advance effective date. They are being made 
retroactively effective, as of July 1, 1993, to make it clear that the 
cadmium standard has been in effect covering shipyard employment since 
December 14, 1992. The cadmium standard remained in effect subsequent 
to the July 1, 1993, Federal Register document, as was OSHA's clearly 
expressed intent.

List of Subjects

29 CFR Part 1915

    Air contaminants, Hazardous materials, Hazard communication, 
Laboratories, Medical records, Occupational safety and health, 
Recordkeeping, Shipyards, Shipbuilding, Ship repairing, Shipbreaking, 
Toxic chemicals.

29 CFR Part 1926

    Construction industry, Hazardous materials, Occupational safety and 
health, Protective equipment.

Authority and Signature

    This document was prepared under the direction of Joseph A. Dear, 
Assistant Secretary of Labor for Occupational Safety and Health, U.S. 
Department of Labor, 200 Constitution Avenue, NW., Washington, DC 
20210.
    Accordingly, pursuant to sections 4, 6, and 8 of the Occupational 
Safety and Health Act (29 U.S.C. 653, 655, and 657); section 107 of the 
Contract Work Hours and Safety Standards Act (Construction Safety Act) 
(40 U.S.C. 333); section 41 Longshore and Harbor Workers Compensation 
Act (33 U.S.C. 941); section 4 of the Administrative Procedure Act (5 
U.S.C. 553); and Secretary of Labor's Order No. 1-90 (55 FR 9033); OSHA 
is issuing these corrections and technical amendments.

    Signed at Washington, DC, 17th day of December, 1993.
Joseph A. Dear,
Assistant Secretary of Labor.
    Accordingly, 29 CFR part 1915, subpart Z is corrected by the 
following amendment:

PART 1915--OCCUPATIONAL SAFETY AND HEALTH STANDARDS FOR SHIPYARD 
EMPLOYMENT

    1. The authority citation for subpart Z of part 1915 continues to 
read as follows:

    Authority: Sections 4, 6, 8 Occupational Safety and Health Act, 
29 U.S.C. 653, 655, 657; Sec. 4 of the Administrative Procedure Act, 
5 U.S.C. 553; Secretary of Labor's Orders 12-71 (36 FR 8754), 8-76 
(41 FR 25059), 9-83 (48 FR 35736), or 1-90 (55 FR 9033), as 
applicable; and 29 CFR part 1911.

Subpart Z--Toxic and Hazardous Substances [Amended]

    2. Subpart Z of part 1915 is corrected by adding the text and 
appendices of Sec. 1915.1027 as follows:


Sec. 1915.1027  Cadmium.

    (a) Scope. This standard applies to all occupational exposures to 
cadmium and cadmium compounds, in all forms, and in all industries 
covered by the Occupational Safety and Health Act, except the 
construction-related industries, which are covered under 29 CFR 
1926.63.
    (b) Definitions.
    Action level (AL) is defined as an airborne concentration of 
cadmium of 2.5 micrograms per cubic meter of air (2.5 g/m\3\), 
calculated as an 8-hour time-weighted average (TWA).
    Assistant Secretary means the Assistant Secretary of Labor for 
Occupational Safety and Health, U.S. Department of Labor, or designee.
    Authorized person means any person authorized by the employer and 
required by work duties to be present in regulated areas or any person 
authorized by the OSH Act or regulations issued under it to be in 
regulated areas.
    Director means the Director of the National Institute for 
Occupational Safety and Health (NIOSH), U.S. Department of Health and 
Human Services, or designee.
    Employee exposure and similar language referring to the air cadmium 
level to which an employee is exposed means the exposure to airborne 
cadmium that would occur if the employee were not using respiratory 
protective equipment.
    Final medical determination is the written medical opinion of the 
employee's health status by the examining physician under paragraphs 
(l)(3)-(12) of this section or, if multiple physician review under 
paragraph (l)(13) of this section or the alternative physician 
determination under paragraph (l)(14) of this section is invoked, it is 
the final, written medical finding, recommendation or determination 
that emerges from that process.
    High-efficiency particulate air (HEPA) filter means a filter 
capable of trapping and retaining at least 99.97 percent of mono-
dispersed particles of 0.3 micrometers in diameter.
    Regulated area means an area demarcated by the employer where an 
employee's exposure to airborne concentrations of cadmium exceeds, or 
can reasonably be expected to exceed the permissible exposure limit 
(PEL).
    This section means this cadmium standard.
    (c) Permissible Exposure Limit (PEL). The employer shall assure 
that no employee is exposed to an airborne concentration of cadmium in 
excess of five micrograms per cubic meter of air (5 g/m\3\), 
calculated as an eight-hour time-weighted average exposure (TWA).
    (d) Exposure monitoring--(1) General. (i) Each employer who has a 
workplace or work operation covered by this section shall determine if 
any employee may be exposed to cadmium at or above the action level.
    (ii) Determinations of employee exposure shall be made from 
breathing zone air samples that reflect the monitored employee's 
regular, daily 8-hour TWA exposure to cadmium.
    (iii) Eight-hour TWA exposures shall be determined for each 
employee on the basis of one or more personal breathing zone air 
samples reflecting full shift exposure on each shift, for each job 
classification, in each work area. Where several employees perform the 
same job tasks, in the same job classification, on the same shift, in 
the same work area, and the length, duration, and level of cadmium 
exposures are similar, an employer may sample a representative fraction 
of the employees instead of all employees in order to meet this 
requirement. In representative sampling, the employer shall sample the 
employee(s) expected to have the highest cadmium exposures.
    (2) Specific. (i) Initial monitoring. Except as provided for in 
paragraphs (d)(2)(ii) and (d)(2)(iii) of this section, the employer 
shall monitor employee exposures and shall base initial determinations 
on the monitoring results.
    (ii) Where the employer has monitored after September 14, 1991, 
under conditions that in all important aspects closely resemble those 
currently prevailing and where that monitoring satisfies all other 
requirements of this section, including the accuracy and confidence 
levels of paragraph (d)(6) of this section, the employer may rely on 
such earlier monitoring results to satisfy the requirements of 
paragraph (d)(2)(i) of this section.
    (iii) Where the employer has objective data, as defined in 
paragraph (n)(2) of this section, demonstrating that employee exposure 
to cadmium will not exceed the action level under the expected 
conditions of processing, use, or handling, the employer may rely upon 
such data instead of implementing initial monitoring.
    (3) Monitoring Frequency (periodic monitoring). (i) If the initial 
monitoring or periodic monitoring reveals employee exposures to be at 
or above the action level, the employer shall monitor at a frequency 
and pattern needed to represent the levels of exposure of employees and 
where exposures are above the PEL to assure the adequacy of respiratory 
selection and the effectiveness of engineering and work practice 
controls. However, such exposure monitoring shall be performed at least 
every six months. The employer, at a minimum, shall continue these 
semi-annual measurements unless and until the conditions set out in 
paragraph (d)(3)(ii) of this section are met.
    (ii) If the initial monitoring or the periodic monitoring indicates 
that employee exposures are below the action level and that result is 
confirmed by the results of another monitoring taken at least seven 
days later, the employer may discontinue the monitoring for those 
employees whose exposures are represented by such monitoring.
    (4) Additional monitoring. The employer also shall institute the 
exposure monitoring required under paragraphs (d)(2)(i) and (d)(3) of 
this section whenever there has been a change in the raw materials, 
equipment, personnel, work practices, or finished products that may 
result in additional employees being exposed to cadmium at or above the 
action level or in employees already exposed to cadmium at or above the 
action level being exposed above the PEL, or whenever the employer has 
any reason to suspect that any other change might result in such 
further exposure.
    (5) Employee notification of monitoring results. (i) Within 15 
working days after the receipt of the results of any monitoring 
performed under this section, the employer shall notify each affected 
employee individually in writing of the results. In addition, within 
the same time period the employer shall post the results of the 
exposure monitoring in an appropriate location that is accessible to 
all affected employees.
    (ii) Wherever monitoring results indicate that employee exposure 
exceeds the PEL, the employer shall include in the written notice a 
statement that the PEL has been exceeded and a description of the 
corrective action being taken by the employer to reduce employee 
exposure to or below the PEL.
    (6) Accuracy of measurement. The employer shall use a method of 
monitoring and analysis that has an accuracy of not less than plus or 
minus 25 percent ( 25%), with a confidence level of 95 
percent, for airborne concentrations of cadmium at or above the action 
level, the permissible exposure limit (PEL), and the separate 
engineering control air limit (SECAL).
    (e) Regulated areas--(1) Establishment. The employer shall 
establish a regulated area wherever an employee's exposure to airborne 
concentrations of cadmium is, or can reasonably be expected to be in 
excess of the permissible exposure limit (PEL).
    (2) Demarcation. Regulated areas shall be demarcated from the rest 
of the workplace in any manner that adequately establishes and alerts 
employees of the boundaries of the regulated area.
    (3) Access. Access to regulated areas shall be limited to 
authorized persons.
    (4) Provision of respirators. Each person entering a regulated area 
shall be supplied with and required to use a respirator, selected in 
accordance with paragraph (g)(2) of this section.
    (5) Prohibited activities. The employer shall assure that employees 
do not eat, drink, smoke, chew tobacco or gum, or apply cosmetics in 
regulated areas, carry the products associated with these activities 
into regulated areas, or store such products in those areas.
    (f) Methods of compliance--(1) Compliance hierarchy. (i) Except as 
specified in paragraphs (f)(1) (ii), (iii) and (iv) of this section the 
employer shall implement engineering and work practice controls to 
reduce and maintain employee exposure to cadmium at or below the PEL, 
except to the extent that the employer can demonstrate that such 
controls are not feasible.
    (ii) Except as specified in paragraphs (f)(1) (iii) and (iv) of 
this section, in industries where a separate engineering control air 
limit (SECAL) has been specified for particular processes (See Table 1 
in this paragraph (f)(1)(ii)), the employer shall implement engineering 
and work practice controls to reduce and maintain employee exposure at 
or below the SECAL, except to the extent that the employer can 
demonstrate that such controls are not feasible. 

   Table 1.--Separate Engineering Control Airborne Limits (SECALs) for  
                    Processes in Selected Industries                    
------------------------------------------------------------------------
                                                                SECAL   
         Industry                      Process              (g/
                                                                 m3)    
------------------------------------------------------------------------
Nickel cadmium battery....  Plate making, plate                      50 
                             preparation.                               
                            All other processes...........           15 
Zinc/Cadmium refining*....  Cadmium refining, casting,               50 
                             melting, oxide production,                 
                             sinter plant.                              
Pigment manufacture.......  Calcine, crushing, milling,              50 
                             blending.                                  
                            All other processes...........           15 
Stabilizers*..............  Cadmium oxide charging,                  50 
                             crushing, drying, blending.                
Lead smelting*............  Sinter plant, blast furnace,             50 
                             baghouse, yard area.                       
Plating*..................  Mechanical plating............           15 
------------------------------------------------------------------------
*Processes in these industries that are not specified in this table must
  achieve the PEL using engineering controls and work practices as      
  required in f(1)(i).                                                  

    (iii) The requirement to implement engineering and work practice 
controls to achieve the PEL or, where applicable, the SECAL does not 
apply where the employer demonstrates the following:
    (A) The employee is only intermittently exposed; and
    (B) The employee is not exposed above the PEL on 30 or more days 
per year (12 consecutive months).
    (iv) Wherever engineering and work practice controls are required 
and are not sufficient to reduce employee exposure to or below the PEL 
or, where applicable, the SECAL, the employer nonetheless shall 
implement such controls to reduce exposures to the lowest levels 
achievable. The employer shall supplement such controls with 
respiratory protection that complies with the requirements of paragraph 
(g) of this section and the PEL.
    (v) The employer shall not use employee rotation as a method of 
compliance.
    (2) Compliance program. (i) Where the PEL is exceeded, the employer 
shall establish and implement a written compliance program to reduce 
employee exposure to or below the PEL by means of engineering and work 
practice controls, as required by paragraph (f)(1) of this section. To 
the extent that engineering and work practice controls cannot reduce 
exposures to or below the PEL, the employer shall include in the 
written compliance program the use of appropriate respiratory 
protection to achieve compliance with the PEL.
    (ii) Written compliance programs shall include at least the 
following:
    (A) A description of each operation in which cadmium is emitted; 
e.g., machinery used, material processed, controls in place, crew size, 
employee job responsibilities, operating procedures, and maintenance 
practices;
    (B) A description of the specific means that will be employed to 
achieve compliance, including engineering plans and studies used to 
determine methods selected for controlling exposure to cadmium, as well 
as, where necessary, the use of appropriate respiratory protection to 
achieve the PEL;
    (C) A report of the technology considered in meeting the PEL;
    (D) Air monitoring data that document the sources of cadmium 
emissions;
    (E) A detailed schedule for implementation of the program, 
including documentation such as copies of purchase orders for 
equipment, construction contracts, etc.;
    (F) A work practice program that includes items required under 
paragraphs (h), (i), and (j) of this section;
    (G) A written plan for emergency situations, as specified in 
paragraph (h) of this section; and
    (H) Other relevant information.
    (iii) The written compliance programs shall be reviewed and updated 
at least annually, or more often if necessary, to reflect significant 
changes in the employer's compliance status.
    (iv) Written compliance programs shall be provided upon request for 
examination and copying to affected employees, designated employee 
representatives as well as to the Assistant Secretary, and the 
Director.
    (3) Mechanical ventilation. (i) When ventilation is used to control 
exposure, measurements that demonstrate the effectiveness of the system 
in controlling exposure, such as capture velocity, duct velocity, or 
static pressure shall be made as necessary to maintain its 
effectiveness.
    (ii) Measurements of the system's effectiveness in controlling 
exposure shall be made as necessary within five working days of any 
change in production, process, or control that might result in a 
significant increase in employee exposure to cadmium.
    (iii) Recirculation of air. If air from exhaust ventilation is 
recirculated into the workplace, the system shall have a high 
efficiency filter and be monitored to assure effectiveness.
    (iv) Procedures shall be developed and implemented to minimize 
employee exposure to cadmium when maintenance of ventilation systems 
and changing of filters is being conducted.
    (g) Respirator protection--(1) General. Where respirators are 
required by this section, the employer shall provide them at no cost to 
the employee and shall assure that they are used in compliance with the 
requirements of this section. Respirators shall be used in the 
following circumstances:
    (i) Where exposure levels exceed the PEL, during the time period 
necessary to install or implement feasible engineering and work 
practice controls;
    (ii) In those maintenance and repair activities and during those 
brief or intermittent operations where exposures exceed the PEL and 
engineering and work practice controls are not feasible or are not 
required;
    (iii) In regulated areas, as prescribed in paragraph (e) of this 
section;
    (iv) Where the employer has implemented all feasible engineering 
and work practice controls and such controls are not sufficient to 
reduce exposures to or below the PEL;
    (v) In emergencies;
    (vi) Wherever an employee who is exposed to cadmium at or above the 
action level requests a respirator;
    (vii) Wherever an employee is exposed above the PEL in an industry 
to which a SECAL is applicable; and
    (viii) Wherever an employee is exposed to cadmium above the PEL and 
engineering controls are not required under paragraph (f)(1)(iii) of 
this section.
    (2) Respirator selection. (i) Where respirators are required under 
this section, the employer shall select and provide the appropriate 
respirator as specified in Table 2 in this paragraph (g)(2)(i). The 
employer shall select respirators from among those jointly approved as 
acceptable protection against cadmium dust, fume, and mist by the Mine 
Safety and Health Administration (MSHA) and by the National Institute 
for Occupational Safety and Health (NIOSH) under the provisions of 30 
CFR part 11. 

                                  Table 2.--Respiratory Protection for Cadmium                                  
----------------------------------------------------------------------------------------------------------------
Airborne concentration or condition of usea                       Required respirator typeb                     
----------------------------------------------------------------------------------------------------------------
10  x  or less.............................  A half mask, air-purifying respirator equipped with a HEPAc        
                                              filter.d                                                          
25  x  or less.............................  A powered air-purifying respirator (``PAPR'') with a loose-fitting 
                                              hood or helmet equipped with a HEPA filter, or a supplied-air     
                                              respirator with a loose-fitting hood or helmet facepiece operated 
                                              in the continuous flow mode.                                      
50  x  or less.............................  A full facepiece air-purifying respirator equipped with a HEPA     
                                              filter, or a powered air-purifying respirator with a tight-fitting
                                              half mask equipped with a HEPA filter, or a supplied air          
                                              respirator with a tight-fitting half mask operated in the         
                                              continuous flow mode.                                             
250  x  or less............................  A powered air-purifying respirator with a tight-fitting full       
                                              facepiece equipped with a HEPA filter, or a supplied-air          
                                              respirator with a tight-fitting full facepiece operated in the    
                                              continuous flow mode.                                             
1000  x  or less...........................  A supplied-air respirator with half mask or full facepiece operated
                                              in the pressure demand or other positive pressure mode.           
>1000  x  or unknown concentrations........  A self-contained breathing apparatus with a full facepiece operated
                                              in the pressure demand or other positive pressure mode, or a      
                                              supplied-air respirator with a full facepiece operated in the     
                                              pressure demand or other positive pressure mode and equipped with 
                                              an auxiliary escape type self-contained breathing apparatus       
                                              operated in the pressure demand mode.                             
Fire fighting..............................  A self-contained breathing apparatus with full facepiece operated  
                                              in the pressure demand or other positive pressure mode.           
----------------------------------------------------------------------------------------------------------------
aConcentrations expressed as multiple of the PEL.                                                               
bRespirators assigned for higher environmental concentrations may be used at lower exposure levels. Quantitative
  fit testing is required for all tight-fitting air purifying respirators where airborne concentration of       
  cadmium exceeds 10 times the TWA PEL (10 x 5 g/m3=50 g/m3). A full facepiece respirator is  
  required when eye irritation is experienced.                                                                  
cHEPA means High Efficiency Particulate Air.                                                                    
dFit testing, qualitative or quantitative, is required.                                                         
SOURCE: Respiratory Decision Logic, NIOSH, 1987.                                                                

    (ii) The employer shall provide a powered, air-purifying respirator 
(PAPR) in lieu of a negative pressure respirator wherever:
    (A) An employee entitled to a respirator chooses to use this type 
of respirator; and
    (B) This respirator will provide adequate protection to the 
employee.
    (3) Respirator program. (i) Where respiratory protection is 
required, the employer shall institute a respirator protection program 
in accordance with 29 CFR 1910.134.
    (ii) The employer shall permit each employee who is required to use 
an air purifying respirator to leave the regulated area to change the 
filter elements or replace the respirator whenever an increase in 
breathing resistance is detected and shall maintain an adequate supply 
of filter elements for this purpose.
    (iii) The employer shall also permit each employee who is required 
to wear a respirator to leave the regulated area to wash his or her 
face and the respirator facepiece whenever necessary to prevent skin 
irritation associated with respirator use.
    (iv) If an employee exhibits difficulty in breathing while wearing 
a respirator during a fit test or during use, the employer shall make 
available to the employee a medical examination in accordance with 
paragraph (l)(6)(ii) of this section to determine if the employee can 
wear a respirator while performing the required duties.
    (v) No employee shall be assigned a task requiring the use of a 
respirator if, based upon his or her most recent examination, an 
examining physician determines that the employee will be unable to 
continue to function normally while wearing a respirator. If the 
physician determines the employee must be limited in, or removed from 
his or her current job because of the employee's inability to wear a 
respirator, the limitation or removal shall be in accordance with 
paragraphs (l) (11) and (12) of this section.
    (4) Respirator fit testing. (i) The employer shall assure that the 
respirator issued to the employee is fitted properly and exhibits the 
least possible facepiece leakage.
    (ii) For each employee wearing a tight-fitting, air purifying 
respirator (either negative or positive pressure) who is exposed to 
airborne concentrations of cadmium that do not exceed 10 times the PEL 
(10  x  5 g/m\3\ = 50 g/m\3\), the employer shall 
perform either quantitative or qualitative fit testing at the time of 
initial fitting and at least annually thereafter. If quantitative fit 
testing is used for a negative pressure respirator, a fit factor that 
is at least 10 times the protection factor for that class of 
respirators (Table 2 in paragraph (g)(2)(i) of this section) shall be 
achieved at testing.
    (iii) For each employee wearing a tight-fitting air purifying 
respirator (either negative or positive pressure) who is exposed to 
airborne concentrations of cadmium that exceed 10 times the PEL (10  x  
5 g/m\3\ = 50 g/m\3\), the employer shall perform 
quantitative fit testing at the time of initial fitting and at least 
annually thereafter. For negative-pressure respirators, a fit factor 
that is at least 10 times the protection factor for that class of 
respirators (Table 2 in paragraph (g)(2)(i) of this section) shall be 
achieved during quantitative fit testing.
    (iv) For each employee wearing a tight-fitting, supplied-air 
respirator or self-contained breathing apparatus, the employer shall 
perform quantitative fit testing at the time of initial fitting and at 
least annually thereafter. This shall be accomplished by fit testing an 
air purifying respirator of identical type facepiece, make, model, and 
size as the supplied air respirator or self-contained breathing 
apparatus that is equipped with HEPA filters and tested as a surrogate 
(substitute) in the negative pressure mode. A fit factor that is at 
least 10 times the protection factor for that class of respirators 
(Table 2 in paragraph (g)(2)(i) of this section) shall be achieved 
during quantitative fit testing. A supplied-air respirator or self-
contained breathing apparatus with the same type facepiece, make, 
model, and size as the air purifying respirator with which the employee 
passed the quantitative fit test may then be used by that employee up 
to the protection factor listed in Table 2 for that class of 
respirators.
    (v) Fit testing shall be conducted in accordance with appendix C of 
this section.
    (h) Emergency situations. The employer shall develop and implement 
a written plan for dealing with emergency situations involving 
substantial releases of airborne cadmium. The plan shall include 
provisions for the use of appropriate respirators and personal 
protective equipment. In addition, employees not essential to 
correcting the emergency situation shall be restricted from the area 
and normal operations halted in that area until the emergency is 
abated.
    (i) Protective work clothing and equipment--(1) Provision and use. 
If an employee is exposed to airborne cadmium above the PEL or where 
skin or eye irritation is associated with cadmium exposure at any 
level, the employer shall provide at no cost to the employee, and 
assure that the employee uses, appropriate protective work clothing and 
equipment that prevents contamination of the employee and the 
employee's garments. Protective work clothing and equipment includes, 
but is not limited to:
    (i) Coveralls or similar full-body work clothing;
    (ii) Gloves, head coverings, and boots or foot coverings; and
    (iii) Face shields, vented goggles, or other appropriate protective 
equipment that complies with 29 CFR 1910.133.
    (2) Removal and storage. (i) The employer shall assure that 
employees remove all protective clothing and equipment contaminated 
with cadmium at the completion of the work shift and do so only in 
change rooms provided in accordance with paragraph (j)(1) of this 
section.
    (ii) The employer shall assure that no employee takes cadmium-
contaminated protective clothing or equipment from the workplace, 
except for employees authorized to do so for purposes of laundering, 
cleaning, maintaining, or disposing of cadmium contaminated protective 
clothing and equipment at an appropriate location or facility away from 
the workplace.
    (iii) The employer shall assure that contaminated protective 
clothing and equipment, when removed for laundering, cleaning, 
maintenance, or disposal, is placed and stored in sealed, impermeable 
bags or other closed, impermeable containers that are designed to 
prevent dispersion of cadmium dust.
    (iv) The employer shall assure that bags or containers of 
contaminated protective clothing and equipment that are to be taken out 
of the change rooms or the workplace for laundering, cleaning, 
maintenance or disposal shall bear labels in accordance with paragraph 
(m)(3) of this section.
    (3) Cleaning, replacement, and disposal. (i) The employer shall 
provide the protective clothing and equipment required by paragraph 
(i)(1) of this section in a clean and dry condition as often as 
necessary to maintain its effectiveness, but in any event at least 
weekly. The employer is responsible for cleaning and laundering the 
protective clothing and equipment required by this paragraph to 
maintain its effectiveness and is also responsible for disposing of 
such clothing and equipment.
    (ii) The employer also is responsible for repairing or replacing 
required protective clothing and equipment as needed to maintain its 
effectiveness. When rips or tears are detected while an employee is 
working they shall be immediately mended, or the worksuit shall be 
immediately replaced.
    (iii) The employer shall prohibit the removal of cadmium from 
protective clothing and equipment by blowing, shaking, or any other 
means that disperses cadmium into the air.
    (iv) The employer shall assure that any laundering of contaminated 
clothing or cleaning of contaminated equipment in the workplace is done 
in a manner that prevents the release of airborne cadmium in excess of 
the permissible exposure limit prescribed in paragraph (c) of this 
section.
    (v) The employer shall inform any person who launders or cleans 
protective clothing or equipment contaminated with cadmium of the 
potentially harmful effects of exposure to cadmium and that the 
clothing and equipment should be laundered or cleaned in a manner to 
effectively prevent the release of airborne cadmium in excess of the 
PEL.
    (j) Hygiene areas and practices--(1) General. For employees whose 
airborne exposure to cadmium is above the PEL, the employer shall 
provide clean change rooms, handwashing facilities, showers, and 
lunchroom facilities that comply with 29 CFR 1910.141.
    (2) Change rooms. The employer shall assure that change rooms are 
equipped with separate storage facilities for street clothes and for 
protective clothing and equipment, which are designed to prevent 
dispersion of cadmium and contamination of the employee's street 
clothes.
    (3) Showers and handwashing facilities. (i) The employer shall 
assure that employees who are exposed to cadmium above the PEL shower 
during the end of the work shift.
    (ii) The employer shall assure that employees whose airborne 
exposure to cadmium is above the PEL wash their hands and faces prior 
to eating, drinking, smoking, chewing tobacco or gum, or applying 
cosmetics.
    (4) Lunchroom facilities. (i) The employer shall assure that the 
lunchroom facilities are readily accessible to employees, that tables 
for eating are maintained free of cadmium, and that no employee in a 
lunchroom facility is exposed at any time to cadmium at or above a 
concentration of 2.5 g/m\3\.
    (ii) The employer shall assure that employees do not enter 
lunchroom facilities with protective work clothing or equipment unless 
surface cadmium has been removed from the clothing and equipment by 
HEPA vacuuming or some other method that removes cadmium dust without 
dispersing it.
    (k) Housekeeping. (1) All surfaces shall be maintained as free as 
practicable of accumulations of cadmium.
    (2) All spills and sudden releases of material containing cadmium 
shall be cleaned up as soon as possible.
    (3) Surfaces contaminated with cadmium shall, wherever possible, be 
cleaned by vacuuming or other methods that minimize the likelihood of 
cadmium becoming airborne.
    (4) HEPA-filtered vacuuming equipment or equally effective 
filtration methods shall be used for vacuuming. The equipment shall be 
used and emptied in a manner that minimizes the reentry of cadmium into 
the workplace.
    (5) Shoveling, dry or wet sweeping, and brushing may be used only 
where vacuuming or other methods that minimize the likelihood of 
cadmium becoming airborne have been tried and found not to be 
effective.
    (6) Compressed air shall not be used to remove cadmium from any 
surface unless the compressed air is used in conjunction with a 
ventilation system designed to capture the dust cloud created by the 
compressed air.
    (7) Waste, scrap, debris, bags, containers, personal protective 
equipment, and clothing contaminated with cadmium and consigned for 
disposal shall be collected and disposed of in sealed impermeable bags 
or other closed, impermeable containers. These bags and containers 
shall be labeled in accordance with paragraph (m)(2) of this section.
    (l) Medical surveillance--(1) General--(i) Scope. (A) Currently 
exposed--The employer shall institute a medical surveillance program 
for all employees who are or may be exposed to cadmium at or above the 
action level unless the employer demonstrates that the employee is not, 
and will not be, exposed at or above the action level on 30 or more 
days per year (twelve consecutive months); and,
    (B) Previously exposed--The employer shall also institute a medical 
surveillance program for all employees who prior to the effective date 
of this section might previously have been exposed to cadmium at or 
above the action level by the employer, unless the employer 
demonstrates that the employee did not prior to the effective date of 
this section work for the employer in jobs with exposure to cadmium for 
an aggregated total of more than 60 months.
    (ii) To determine an employee's fitness for using a respirator, the 
employer shall provide the limited medical examination specified in 
paragraph (l)(6) of this section.
    (iii) The employer shall assure that all medical examinations and 
procedures required by this standard are performed by or under the 
supervision of a licensed physician, who has read and is familiar with 
the health effects section of appendix A to this section, the 
regulatory text of this section, the protocol for sample handling and 
laboratory selection in appendix F to this section, and the 
questionnaire of appendix D to this section. These examinations and 
procedures shall be provided without cost to the employee and at a time 
and place that is reasonable and convenient to employees.
    (iv) The employer shall assure that the collecting and handling of 
biological samples of cadmium in urine (CdU), cadmium in blood (CdB), 
and beta-2 microglobulin in urine (2-M) taken from 
employees under this section is done in a manner that assures their 
reliability and that analysis of biological samples of cadmium in urine 
(CdU), cadmium in blood (CdB), and beta-2 microglobulin in urine 
(2-M) taken from employees under this section is 
performed in laboratories with demonstrated proficiency for that 
particular analyte. (See appendix F to this section.)
    (2) Initial examination. (i) The employer shall provide an initial 
(preplacement) examination to all employees covered by the medical 
surveillance program required in paragraph (l)(1)(i) of this section. 
The examination shall be provided to those employees within 30 days 
after initial assignment to a job with exposure to cadmium or no later 
than 90 days after the effective date of this section, whichever date 
is later.
    (ii) The initial (preplacement) medical examination shall include:
    (A) A detailed medical and work history, with emphasis on: Past, 
present, and anticipated future exposure to cadmium; any history of 
renal, cardiovascular, respiratory, hematopoietic, reproductive, and/or 
musculo-skeletal system dysfunction; current usage of medication with 
potential nephrotoxic side-effects; and smoking history and current 
status; and
    (B) Biological monitoring that includes the following tests:
    (1) Cadmium in urine (CdU), standardized to grams of creatinine (g/
Cr);
    (2) Beta-2 microglobulin in urine (2-M), standardized 
to grams of creatinine (g/Cr), with pH specified, as described in 
appendix F to this section; and
    (3) Cadmium in blood (CdB), standardized to liters of whole blood 
(lwb).
    (iii) Recent Examination: An initial examination is not required to 
be provided if adequate records show that the employee has been 
examined in accordance with the requirements of paragraph (l)(2)(ii) of 
this section within the past 12 months. In that case, such records 
shall be maintained as part of the employee's medical record and the 
prior exam shall be treated as if it were an initial examination for 
the purposes of paragraphs (l)(3) and (4) of this section.
    (3) Actions triggered by initial biological monitoring. (i) If the 
results of the initial biological monitoring tests show the employee's 
CdU level to be at or below 3 g/g Cr, 2-M level 
to be at or below 300 g/g Cr and CdB level to be at or below 5 
g/lwb, then:
    (A) For currently exposed employees, who are subject to medical 
surveillance under paragraph (l)(1)(i)(A) of this section, the employer 
shall provide the minimum level of periodic medical surveillance in 
accordance with the requirements in paragraph (l)(4)(i) of this 
section; and
    (B) For previously exposed employees, who are subject to medical 
surveillance under paragraph (l)(1)(i)(B) of this section, the employer 
shall provide biological monitoring for CdU, 2-M, and CdB 
one year after the initial biological monitoring and then the employer 
shall comply with the requirements of paragraph (l)(4)(v) of this 
section.
    (ii) For all employees who are subject to medical surveillance 
under paragraph (l)(1)(i) of this section, if the results of the 
initial biological monitoring tests show the level of CdU to exceed 3 
g/g Cr, the level of 2-M to exceed 300 
g/g Cr, or the level of CdB to exceed 5 g/lwb, the 
employer shall:
    (A) Within two weeks after receipt of biological monitoring 
results, reassess the employee's occupational exposure to cadmium as 
follows:
    (1) Reassess the employee's work practices and personal hygiene;
    (2) Reevaluate the employee's respirator use, if any, and the 
respirator program;
    (3) Review the hygiene facilities;
    (4) Reevaluate the maintenance and effectiveness of the relevant 
engineering controls;
    (5) Assess the employee's smoking history and status;
    (B) Within 30 days after the exposure reassessment, specified in 
paragraph (l)(3)(ii)(A) of this section, take reasonable steps to 
correct any deficiencies found in the reassessment that may be 
responsible for the employee's excess exposure to cadmium; and,
    (C) Within 90 days after receipt of biological monitoring results, 
provide a full medical examination to the employee in accordance with 
the requirements of paragraph (l)(4)(ii) of this section. After 
completing the medical examination, the examining physician shall 
determine in a written medical opinion whether to medically remove the 
employee. If the physician determines that medical removal is not 
necessary, then until the employee's CdU level falls to or below 3 
g/g Cr, 2-M level falls to or below 300 
g/g Cr and CdB level falls to or below 5 g/lwb, the 
employer shall:
    (1) Provide biological monitoring in accordance with paragraph 
(l)(2)(ii)(B) of this section on a semiannual basis; and
    (2) Provide annual medical examinations in accordance with 
paragraph (l)(4)(ii) of this section.
    (iii) For all employees who are subject to medical surveillance 
under paragraph (l)(1)(i) of this section, if the results of the 
initial biological monitoring tests show the level of CdU to be in 
excess of 15 g/g Cr, or the level of CdB to be in excess of 15 
g/lwb, or the level of 2-M to be in excess of 
1,500 g/g Cr, the employer shall comply with the requirements 
of paragraphs (l)(3)(ii)(A)-(B) of this section. Within 90 days after 
receipt of biological monitoring results, the employer shall provide a 
full medical examination to the employee in accordance with the 
requirements of paragraph (l)(4)(ii) of this section. After completing 
the medical examination, the examining physician shall determine in a 
written medical opinion whether to medically remove the employee. 
However, if the initial biological monitoring results and the 
biological monitoring results obtained during the medical examination 
both show that: CdU exceeds 15 g/g Cr; or CdB exceeds 15 
g/lwb; or 2-M exceeds 1500 g/g Cr, and 
in addition CdU exceeds 3 g/g Cr or CdB exceeds 5 g/
liter of whole blood, then the physician shall medically remove the 
employee from exposure to cadmium at or above the action level. If the 
second set of biological monitoring results obtained during the medical 
examination does not show that a mandatory removal trigger level has 
been exceeded, then the employee is not required to be removed by the 
mandatory provisions of this paragraph. If the employee is not required 
to be removed by the mandatory provisions of this paragraph or by the 
physician's determination, then until the employee's CdU level falls to 
or below 3 g/g Cr, 2-M level falls to or below 
300 g/g Cr and CdB level falls to or below 5 g/lwb, 
the employer shall:
    (A) Periodically reassess the employee's occupational exposure to 
cadmium;
    (B) Provide biological monitoring in accordance with paragraph 
(l)(2)(ii)(B) of this section on a quarterly basis; and
    (C) Provide semiannual medical examinations in accordance with 
paragraph (l)(4)(ii) of this section.
    (iv) For all employees to whom medical surveillance is provided, 
beginning on January 1, 1999, and in lieu of paragraphs (l)(3)(i)-(iii) 
of this section:
    (A) If the results of the initial biological monitoring tests show 
the employee's CdU level to be at or below 3 g/g Cr, 
2-M level to be at or below 300 g/g Cr and CdB 
level to be at or below 5 g/lwb, then for currently exposed 
employees, the employer shall comply with the requirements of paragraph 
(l)(3)(i)(A) of this section, and for previously exposed employees, the 
employer shall comply with the requirements of paragraph (l)(3)(i)(B) 
of this section;
    (B) If the results of the initial biological monitoring tests show 
the level of CdU to exceed 3 g/g Cr, the level of 
2-M to exceed 300 g/g Cr, or the level of CdB to 
exceed 5 g/lwb, the employer shall comply with the 
requirements of paragraphs (l)(3)(ii)(A)-(C) of this section; and,
    (C) If the results of the initial biological monitoring tests show 
the level of CdU to be in excess of 7 g/g Cr, or the level of 
CdB to be in excess of 10 g/lwb, or the level of 
2-M to be in excess of 750 g/g Cr, the employer 
shall: Comply with the requirements of paragraphs (l)(3)(ii)(A)-(B) of 
this section; and, within 90 days after receipt of biological 
monitoring results, provide a full medical examination to the employee 
in accordance with the requirements of paragraph (l)(4)(ii) of this 
section. After completing the medical examination, the examining 
physician shall determine in a written medical opinion whether to 
medically remove the employee. However, if the initial biological 
monitoring results and the biological monitoring results obtained 
during the medical examination both show that: CdU exceeds 7 
g/g Cr; or CdB exceeds 10 g/lwb; or 2-M 
exceeds 750 g/g Cr, and in addition CdU exceeds 3 g/g 
Cr or CdB exceeds 5 g/liter of whole blood, then the physician 
shall medically remove the employee from exposure to cadmium at or 
above the action level. If the second set of biological monitoring 
results obtained during the medical examination does not show that a 
mandatory removal trigger level has been exceeded, then the employee is 
not required to be removed by the mandatory provisions of this 
paragraph. If the employee is not required to be removed by the 
mandatory provisions of this paragraph or by the physician's 
determination, then until the employee's CdU level falls to or below 3 
g/g Cr, 2-M level falls to or below 300 
g/g Cr and CdB level falls to or below 5 g/lwb, the 
employer shall: periodically reassess the employee's occupational 
exposure to cadmium; provide biological monitoring in accordance with 
paragraph (l)(2)(ii)(B) of this section on a quarterly basis; and 
provide semiannual medical examinations in accordance with paragraph 
(l)(4)(ii) of this section.
    (4) Periodic medical surveillance. (i) For each employee who is 
covered under paragraph (l)(1)(i)(A) of this section, the employer 
shall provide at least the minimum level of periodic medical 
surveillance, which consists of periodic medical examinations and 
periodic biological monitoring. A periodic medical examination shall be 
provided within one year after the initial examination required by 
paragraph (l)(2) of this section and thereafter at least biennially. 
Biological sampling shall be provided at least annually, either as part 
of a periodic medical examination or separately as periodic biological 
monitoring.
    (ii) The periodic medical examination shall include:
    (A) A detailed medical and work history, or update thereof, with 
emphasis on: Past, present and anticipated future exposure to cadmium; 
smoking history and current status; reproductive history; current use 
of medications with potential nephrotoxic side-effects; any history of 
renal, cardiovascular, respiratory, hematopoietic, and/or musculo-
skeletal system dysfunction; and as part of the medical and work 
history, for employees who wear respirators, questions 3-11 and 25-32 
in Appendix D to this section;
    (B) A complete physical examination with emphasis on: Blood 
pressure, the respiratory system, and the urinary system;
    (C) A 14 inch by 17 inch, or a reasonably standard sized posterior-
anterior chest X-ray (after the initial X-ray, the frequency of chest 
X-rays is to be determined by the examining physician);
    (D) Pulmonary function tests, including forced vital capacity (FVC) 
and forced expiratory volume at 1 second (FEV1);
    (E) Biological monitoring, as required in paragraph (l)(2)(ii)(B) 
of this section;
    (F) Blood analysis, in addition to the analysis required under 
paragraph (l)(2)(ii)(B) of this section, including blood urea nitrogen, 
complete blood count, and serum creatinine;
    (G) Urinalysis, in addition to the analysis required under 
paragraph (l)(2)(ii)(B) of this section, including the determination of 
albumin, glucose, and total and low molecular weight proteins;
    (H) For males over 40 years old, prostate palpation, or other at 
least as effective diagnostic test(s); and
    (I) Any additional tests deemed appropriate by the examining 
physician.
    (iii) Periodic biological monitoring shall be provided in 
accordance with paragraph (l)(2)(ii)(B) of this section.
    (iv) If the results of periodic biological monitoring or the 
results of biological monitoring performed as part of the periodic 
medical examination show the level of the employee's CdU, 
2-M, or CdB to be in excess of the levels specified in 
paragraphs (l)(3) (ii) or (iii); or, beginning on January 1, 1999, in 
excess of the levels specified in paragraphs (l)(3) (ii) or (iv) of 
this section, the employer shall take the appropriate actions specified 
in paragraphs (l)(3)(ii)-(iv) of this section.
    (v) For previously exposed employees under paragraph (l)(1)(i)(B) 
of this section:
    (A) If the employee's levels of CdU did not exceed 3 g/g 
Cr, CdB did not exceed 5 g/lwb, and 2-M did not 
exceed 300 g/g Cr in the initial biological monitoring tests, 
and if the results of the followup biological monitoring required by 
paragraph (l)(3)(i)(B) of this section one year after the initial 
examination confirm the previous results, the employer may discontinue 
all periodic medical surveillance for that employee.
    (B) If the initial biological monitoring results for CdU, CdB, or 
2-M were in excess of the levels specified in paragraph 
(l)(3)(i) of this section, but subsequent biological monitoring results 
required by paragraph (l)(3)(ii)-(iv) of this section show that the 
employee's CdU levels no longer exceed 3 g/g Cr, CdB levels no 
longer exceed 5 g/lwb, and 2-M levels no longer 
exceed 300 g/g Cr, the employer shall provide biological 
monitoring for CdU, CdB, and 2-M one year after these 
most recent biological monitoring results. If the results of the 
followup biological monitoring, specified in this paragraph, confirm 
the previous results, the employer may discontinue all periodic medical 
surveillance for that employee.
    (C) However, if the results of the follow-up tests specified in 
paragraph (l)(4)(v)(A) or (B) of this section indicate that the level 
of the employee's CdU, 2-M, or CdB exceeds these same 
levels, the employer is required to provide annual medical examinations 
in accordance with the provisions of paragraph (l)(4)(ii) of this 
section until the results of biological monitoring are consistently 
below these levels or the examining physician determines in a written 
medical opinion that further medical surveillance is not required to 
protect the employee's health.
    (vi) A routine, biennial medical examination is not required to be 
provided in accordance with paragraphs (l)(3)(i) and (l)(4) of this 
section if adequate medical records show that the employee has been 
examined in accordance with the requirements of paragraph (l)(4)(ii) of 
this section within the past 12 months. In that case, such records 
shall be maintained by the employer as part of the employee's medical 
record, and the next routine, periodic medical examination shall be 
made available to the employee within two years of the previous 
examination.
    (5) Actions triggered by medical examinations. (i) If the results 
of a medical examination carried out in accordance with this section 
indicate any laboratory or clinical finding consistent with cadmium 
toxicity that does not require employer action under paragraph (l)(2), 
(3) or (4) of this section, the employer, within 30 days, shall 
reassess the employee's occupational exposure to cadmium and take the 
following corrective action until the physician determines they are no 
longer necessary:
    (A) Periodically reassess: The employee's work practices and 
personal hygiene; the employee's respirator use, if any; the employee's 
smoking history and status; the respiratory protection program; the 
hygiene facilities; and the maintenance and effectiveness of the 
relevant engineering controls;
    (B) Within 30 days after the reassessment, take all reasonable 
steps to correct the deficiencies found in the reassessment that may be 
responsible for the employee's excess exposure to cadmium;
    (C) Provide semiannual medical reexaminations to evaluate the 
abnormal clinical sign(s) of cadmium toxicity until the results are 
normal or the employee is medically removed; and
    (D) Where the results of tests for total proteins in urine are 
abnormal, provide a more detailed medical evaluation of the toxic 
effects of cadmium on the employee's renal system.
    (6) Examination for respirator use. (i) To determine an employee's 
fitness for respirator use, the employer shall provide a medical 
examination that includes the elements specified in paragraph (l)(6)(i) 
(A)-(D) of this section. This examination shall be provided prior to 
the employee's being assigned to a job that requires the use of a 
respirator or no later than 90 days after this section goes into 
effect, whichever date is later, to any employee without a medical 
examination within the preceding 12 months that satisfies the 
requirements of this paragraph.
    (A) A detailed medical and work history, or update thereof, with 
emphasis on: Past exposure to cadmium; smoking history and current 
status; any history of renal, cardiovascular, respiratory, 
hematopoietic, and/or musculoskeletal system dysfunction; a description 
of the job for which the respirator is required; and questions 3-11 and 
25-32 in appendix D to this section;
    (B) A blood pressure test;
    (C) Biological monitoring of the employee's levels of CdU, CdB and 
2-M in accordance with the requirements of paragraph 
(l)(2)(ii)(B) of this section, unless such results already have been 
obtained within the previous 12 months; and
    (D) Any other test or procedure that the examining physician deems 
appropriate.
    (ii) After reviewing all the information obtained from the medical 
examination required in paragraph (l)(6)(i) of this section, the 
physician shall determine whether the employee is fit to wear a 
respirator.
    (iii) Whenever an employee has exhibited difficulty in breathing 
during a respirator fit test or during use of a respirator, the 
employer, as soon as possible, shall provide the employee with a 
periodic medical examination in accordance with paragraph (l)(4)(ii) of 
this section to determine the employee's fitness to wear a respirator.
    (iv) Where the results of the examination required under paragraph 
(l)(6)(i), (ii), or (iii) of this section are abnormal, medical 
limitation or prohibition of respirator use shall be considered. If the 
employee is allowed to wear a respirator, the employee's ability to 
continue to do so shall be periodically evaluated by a physician.
    (7) Emergency examinations. (i) In addition to the medical 
surveillance required in paragraphs (l)(2)-(6) of this section, the 
employer shall provide a medical examination as soon as possible to any 
employee who may have been acutely exposed to cadmium because of an 
emergency.
    (ii) The examination shall include the requirements of paragraph 
(l)(4)(ii) of this section, with emphasis on the respiratory system, 
other organ systems considered appropriate by the examining physician, 
and symptoms of acute overexposure, as identified in paragraphs II 
(B)(1)-(2) and IV of appendix A to this section.
    (8) Termination of employment examination. (i) At termination of 
employment, the employer shall provide a medical examination in 
accordance with paragraph (l)(4)(ii) of this section, including a chest 
X-ray, to any employee to whom at any prior time the employer was 
required to provide medical surveillance under paragraphs (l)(1)(i) or 
(l)(7) of this section. However, if the last examination satisfied the 
requirements of paragraph (l)(4)(ii) of this section and was less than 
six months prior to the date of termination, no further examination is 
required unless otherwise specified in paragraphs (l)(3) or (l)(5) of 
this section;
    (ii) However, for employees covered by paragraph (l)(1)(i)(B) of 
this section, if the employer has discontinued all periodic medical 
surveillance under paragraph (l)(4)(v) of this section, no termination 
of employment medical examination is required.
    (9) Information provided to the physician. The employer shall 
provide the following information to the examining physician:
    (i) A copy of this standard and appendices;
    (ii) A description of the affected employee's former, current, and 
anticipated duties as they relate to the employee's occupational 
exposure to cadmium;
    (iii) The employee's former, current, and anticipated future levels 
of occupational exposure to cadmium;
    (iv) A description of any personal protective equipment, including 
respirators, used or to be used by the employee, including when and for 
how long the employee has used that equipment; and
    (v) relevant results of previous biological monitoring and medical 
examinations.
    (10) Physician's written medical opinion. (i) The employer shall 
promptly obtain a written, signed medical opinion from the examining 
physician for each medical examination performed on each employee. This 
written opinion shall contain:
    (A) The physician's diagnosis for the employee;
    (B) The physician's opinion as to whether the employee has any 
detected medical condition(s) that would place the employee at 
increased risk of material impairment to health from further exposure 
to cadmium, including any indications of potential cadmium toxicity;
    (C) The results of any biological or other testing or related 
evaluations that directly assess the employee's absorption of cadmium;
    (D) Any recommended removal from, or limitation on the activities 
or duties of the employee or on the employee's use of personal 
protective equipment, such as respirators;
    (E) A statement that the physician has clearly and carefully 
explained to the employee the results of the medical examination, 
including all biological monitoring results and any medical conditions 
related to cadmium exposure that require further evaluation or 
treatment, and any limitation on the employee's diet or use of 
medications.
    (ii) The employer promptly shall obtain a copy of the results of 
any biological monitoring provided by an employer to an employee 
independently of a medical examination under paragraphs (l)(2) and 
(l)(4) of this section, and, in lieu of a written medical opinion, an 
explanation sheet explaining those results.
    (iii) The employer shall instruct the physician not to reveal 
orally or in the written medical opinion given to the employer specific 
findings or diagnoses unrelated to occupational exposure to cadmium.
    (11) Medical Removal Protection (MRP)--(i) General. (A) The 
employer shall temporarily remove an employee from work where there is 
excess exposure to cadmium on each occasion that medical removal is 
required under paragraph (l)(3), (l)(4), or (l)(6) of this section and 
on each occasion that a physician determines in a written medical 
opinion that the employee should be removed from such exposure. The 
physician's determination may be based on biological monitoring 
results, inability to wear a respirator, evidence of illness, other 
signs or symptoms of cadmium-related dysfunction or disease, or any 
other reason deemed medically sufficient by the physician.
    (B) The employer shall medically remove an employee in accordance 
with paragraph (l)(11) of this section regardless of whether at the 
time of removal a job is available into which the removed employee may 
be transferred.
    (C) Whenever an employee is medically removed under paragraph 
(l)(11) of this section, the employer shall transfer the removed 
employee to a job where the exposure to cadmium is within the 
permissible levels specified in that paragraph as soon as one becomes 
available.
    (D) For any employee who is medically removed under the provisions 
of paragraph (l)(11)(i) of this section, the employer shall provide 
follow-up biological monitoring in accordance with (l)(2)(ii)(B) of 
this section at least every three months and follow-up medical 
examinations semi-annually at least every six months until in a written 
medical opinion the examining physician determines that either the 
employee may be returned to his/her former job status as specified 
under paragraph (l)(11)(iv)-(v) of this section or the employee must be 
permanently removed from excess cadmium exposure.
    (E) The employer may not return an employee who has been medically 
removed for any reason to his/her former job status until a physician 
determines in a written medical opinion that continued medical removal 
is no longer necessary to protect the employee's health.
    (ii) Where an employee is found unfit to wear a respirator under 
paragraph (l)(6)(ii) of this section, the employer shall remove the 
employee from work where exposure to cadmium is above the PEL.
    (iii) Where removal is based on any reason other than the 
employee's inability to wear a respirator, the employer shall remove 
the employee from work where exposure to cadmium is at or above the 
action level.
    (iv) Except as specified in paragraph (l)(11)(v) of this section, 
no employee who was removed because his/her level of CdU, CdB and/or 
2-M exceeded the medical removal trigger levels in 
paragraph (l)(3) or (l)(4) of this section may be returned to work with 
exposure to cadmium at or above the action level until the employee's 
levels of CdU fall to or below 3 g/g Cr, CdB falls to or below 
5 g/lwb, and 2-M falls to or below 300 
g/g Cr.
    (v) However, when in the examining physician's opinion continued 
exposure to cadmium will not pose an increased risk to the employee's 
health and there are special circumstances that make continued medical 
removal an inappropriate remedy, the physician shall fully discuss 
these matters with the employee, and then in a written determination 
may return a worker to his/her former job status despite what would 
otherwise be unacceptably high biological monitoring results. 
Thereafter, the returned employee shall continue to be provided with 
medical surveillance as if he/she were still on medical removal until 
the employee's levels of CdU fall to or below 3 g/g Cr, CdB 
falls to or below 5 g/lwb, and 2-M falls to or 
below 300 g/g Cr.
    (vi) Where an employer, although not required by paragraph 
(l)(11)(i)-(iii) of this section to do so, removes an employee from 
exposure to cadmium or otherwise places limitations on an employee due 
to the effects of cadmium exposure on the employee's medical condition, 
the employer shall provide the same medical removal protection benefits 
to that employee under paragraph (l)(12) of this section as would have 
been provided had the removal been required under paragraph (l)(11)(i)-
(iii) of this section.
    (12) Medical Removal Protection Benefits (MRPB). (i) The employer 
shall provide MRPB for up to a maximum of 18 months to an employee each 
time and while the employee is temporarily medically removed under 
paragraph (l)(11) of this section.
    (ii) For purposes of this section, the requirement that the 
employer provide MRPB means that the employer shall maintain the total 
normal earnings, seniority, and all other employee rights and benefits 
of the removed employee, including the employee's right to his/her 
former job status, as if the employee had not been removed from the 
employee's job or otherwise medically limited.
    (iii) Where, after 18 months on medical removal because of elevated 
biological monitoring results, the employee's monitoring results have 
not declined to a low enough level to permit the employee to be 
returned to his/her former job status:
    (A) The employer shall make available to the employee a medical 
examination pursuant to this section in order to obtain a final medical 
determination as to whether the employee may be returned to his/her 
former job status or must be permanently removed from excess cadmium 
exposure; and
    (B) The employer shall assure that the final medical determination 
indicates whether the employee may be returned to his/her former job 
status and what steps, if any, should be taken to protect the 
employee's health.
    (iv) The employer may condition the provision of MRPB upon the 
employee's participation in medical surveillance provided in accordance 
with this section.
    (13) Multiple physician review. (i) If the employer selects the 
initial physician to conduct any medical examination or consultation 
provided to an employee under this section, the employee may designate 
a second physician to:
    (A) Review any findings, determinations, or recommendations of the 
initial physician; and
    (B) Conduct such examinations, consultations, and laboratory tests 
as the second physician deems necessary to facilitate this review.
    (ii) The employer shall promptly notify an employee of the right to 
seek a second medical opinion after each occasion that an initial 
physician provided by the employer conducts a medical examination or 
consultation pursuant to this section. The employer may condition its 
participation in, and payment for, multiple physician review upon the 
employee doing the following within fifteen (15) days after receipt of 
this notice, or receipt of the initial physician's written opinion, 
whichever is later:
    (A) Informing the employer that he or she intends to seek a medical 
opinion; and
    (B) Initiating steps to make an appointment with a second 
physician.
    (iii) If the findings, determinations, or recommendations of the 
second physician differ from those of the initial physician, then the 
employer and the employee shall assure that efforts are made for the 
two physicians to resolve any disagreement.
    (iv) If the two physicians have been unable to quickly resolve 
their disagreement, then the employer and the employee, through their 
respective physicians, shall designate a third physician to:
    (A) Review any findings, determinations, or recommendations of the 
other two physicians; and
    (B) Conduct such examinations, consultations, laboratory tests, and 
discussions with the other two physicians as the third physician deems 
necessary to resolve the disagreement among them.
    (v) The employer shall act consistently with the findings, 
determinations, and recommendations of the third physician, unless the 
employer and the employee reach an agreement that is consistent with 
the recommendations of at least one of the other two physicians.
    (14) Alternate physician determination. The employer and an 
employee or designated employee representative may agree upon the use 
of any alternate form of physician determination in lieu of the 
multiple physician review provided by paragraph (l)(13) of this 
section, so long as the alternative is expeditious and at least as 
protective of the employee.
    (15) Information the employer must provide the employee. (i) The 
employer shall provide a copy of the physician's written medical 
opinion to the examined employee within two weeks after receipt 
thereof.
    (ii) The employer shall provide the employee with a copy of the 
employee's biological monitoring results and an explanation sheet 
explaining the results within two weeks after receipt thereof.
    (iii) Within 30 days after a request by an employee, the employer 
shall provide the employee with the information the employer is 
required to provide the examining physician under paragraph (l)(9) of 
this section.
    (16) Reporting. In addition to other medical events that are 
required to be reported on the OSHA Form No. 200, the employer shall 
report any abnormal condition or disorder caused by occupational 
exposure to cadmium associated with employment as specified in Chapter 
(V)(E) of the Reporting Guidelines for Occupational Injuries and 
Illnesses.
    (m) Communication of cadmium hazards to employees--(1) General. In 
communications concerning cadmium hazards, employers shall comply with 
the requirements of OSHA's Hazard Communication Standard, 29 CFR 
1910.1200, including but not limited to the requirements concerning 
warning signs and labels, material safety data sheets (MSDS), and 
employee information and training. In addition, employers shall comply 
with the following requirements:
    (2) Warning signs. (i) Warning signs shall be provided and 
displayed in regulated areas. In addition, warning signs shall be 
posted at all approaches to regulated areas so that an employee may 
read the signs and take necessary protective steps before entering the 
area.
    (ii) Warning signs required by paragraph (m)(2)(i) of this section 
shall bear the following information:

DANGER
CADMIUM
CANCER HAZARD
CAN CAUSE LUNG AND KIDNEY DISEASE
AUTHORIZED PERSONNEL ONLY
RESPIRATORS REQUIRED IN THIS AREA

    (iii) The employer shall assure that signs required by this 
paragraph are illuminated, cleaned, and maintained as necessary so that 
the legend is readily visible.
    (3) Warning labels. (i) Shipping and storage containers containing 
cadmium, cadmium compounds, or cadmium contaminated clothing, 
equipment, waste, scrap, or debris shall bear appropriate warning 
labels, as specified in paragraph (m)(3)(ii) of this section.
    (ii) The warning labels shall include at least the following 
information:

DANGER
CONTAINS CADMIUM
CANCER HAZARD
AVOID CREATING DUST
CAN CAUSE LUNG AND KIDNEY DISEASE

    (iii) Where feasible, installed cadmium products shall have a 
visible label or other indication that cadmium is present.
    (4) Employee information and training. (i) The employer shall 
institute a training program for all employees who are potentially 
exposed to cadmium, assure employee participation in the program, and 
maintain a record of the contents of such program.
    (ii) Training shall be provided prior to or at the time of initial 
assignment to a job involving potential exposure to cadmium and at 
least annually thereafter.
    (iii) The employer shall make the training program understandable 
to the employee and shall assure that each employee is informed of the 
following:
    (A) The health hazards associated with cadmium exposure, with 
special attention to the information incorporated in appendix A to this 
section;
    (B) The quantity, location, manner of use, release, and storage of 
cadmium in the workplace and the specific nature of operations that 
could result in exposure to cadmium, especially exposures above the 
PEL;
    (C) The engineering controls and work practices associated with the 
employee's job assignment;
    (D) The measures employees can take to protect themselves from 
exposure to cadmium, including modification of such habits as smoking 
and personal hygiene, and specific procedures the employer has 
implemented to protect employees from exposure to cadmium such as 
appropriate work practices, emergency procedures, and the provision of 
personal protective equipment;
    (E) The purpose, proper selection, fitting, proper use, and 
limitations of respirators and protective clothing;
    (F) The purpose and a description of the medical surveillance 
program required by paragraph (l) of this section;
    (G) The contents of this section and its appendices; and
    (H) The employee's rights of access to records under Sec. 1915.1120 
(e) and (g).
    (iv) Additional access to information and training program and 
materials.
    (A) The employer shall make a copy of this section and its 
appendices readily available without cost to all affected employees and 
shall provide a copy if requested.
    (B) The employer shall provide to the Assistant Secretary or the 
Director, upon request, all materials relating to the employee 
information and the training program.
    (n) Recordkeeping--(1) Exposure monitoring. (i) The employer shall 
establish and keep an accurate record of all air monitoring for cadmium 
in the workplace.
    (ii) This record shall include at least the following information:
    (A) The monitoring date, duration, and results in terms of an 8-
hour TWA of each sample taken;
    (B) The name, social security number, and job classification of the 
employees monitored and of all other employees whose exposures the 
monitoring is intended to represent;
    (C) A description of the sampling and analytical methods used and 
evidence of their accuracy;
    (D) The type of respiratory protective device, if any, worn by the 
monitored employee;
    (E) A notation of any other conditions that might have affected the 
monitoring results.
    (iii) The employer shall maintain this record for at least thirty 
(30) years, in accordance with Sec. 1915.1120 of this part.
    (2) Objective data for exemption from requirement for initial 
monitoring. (i) For purposes of this section, objective data are 
information demonstrating that a particular product or material 
containing cadmium or a specific process, operation, or activity 
involving cadmium cannot release dust or fumes in concentrations at or 
above the action level even under the worst-case release conditions. 
Objective data can be obtained from an industry-wide study or from 
laboratory product test results from manufacturers of cadmium-
containing products or materials. The data the employer uses from an 
industry-wide survey must be obtained under workplace conditions 
closely resembling the processes, types of material, control methods, 
work practices and environmental conditions in the employer's current 
operations.
    (ii) The employer shall establish and maintain a record of the 
objective data for at least 30 years.
    (3) Medical surveillance. (i) The employer shall establish and 
maintain an accurate record for each employee covered by medical 
surveillance under paragraph (l)(1)(i) of this section.
    (ii) The record shall include at least the following information 
about the employee:
    (A) Name, social security number, and description of the duties;
    (B) A copy of the physician's written opinions and an explanation 
sheet for biological monitoring results;
    (C) A copy of the medical history, and the results of any physical 
examination and all test results that are required to be provided by 
this section, including biological tests, X-rays, pulmonary function 
tests, etc., or that have been obtained to further evaluate any 
condition that might be related to cadmium exposure;
    (D) The employee's medical symptoms that might be related to 
exposure to cadmium; and
    (E) A copy of the information provided to the physician as required 
by paragraph (l)(9)(ii)-(v) of this section.
    (iii) The employer shall assure that this record is maintained for 
the duration of employment plus thirty (30) years, in accordance with 
Sec. 1915.1120 of this part.
    (4) Training. The employer shall certify that employees have been 
trained by preparing a certification record which includes the identity 
of the person trained, the signature of the employer or the person who 
conducted the training, and the date the training was completed. The 
certification records shall be prepared at the completion of training 
and shall be maintained on file for one (1) year beyond the date of 
training of that employee.
    (5) Availability. (i) Except as otherwise provided for in this 
section, access to all records required to be maintained by paragraphs 
(n)(1)-(4) of this section shall be in accordance with the provisions 
of Sec. 1915.1120 of this part.
    (ii) Within 15 days after a request, the employer shall make an 
employee's medical records required to be kept by paragraph (n)(3) of 
this section available for examination and copying to the subject 
employee, to designated representatives, to anyone having the specific 
written consent of the subject employee, and after the employee's death 
or incapacitation, to the employee's family members.
    (6) Transfer of records. Whenever an employer ceases to do business 
and there is no successor employer to receive and retain records for 
the prescribed period or the employer intends to dispose of any records 
required to be preserved for at least 30 years, the employer shall 
comply with the requirements concerning transfer of records set forth 
in Sec. 1915.1120(h) of this part.
    (o) Observation of monitoring--(1) Employee observation. The 
employer shall provide affected employees or their designated 
representatives an opportunity to observe any monitoring of employee 
exposure to cadmium.
    (2) Observation procedures. When observation of monitoring requires 
entry into an area where the use of protective clothing or equipment is 
required, the employer shall provide the observer with that clothing 
and equipment and shall assure that the observer uses such clothing and 
equipment and complies with all other applicable safety and health 
procedures.
    (p) Dates--(1) Effective date. This section shall become effective 
December 14, 1992.
    (2) Start-up dates. All obligations of this section commence on the 
effective date except as follows:
    (i) Exposure monitoring. Except for small businesses (nineteen (19) 
or fewer employees), initial monitoring required by paragraph (d)(2) of 
this section shall be completed as soon as possible and in any event no 
later than February 12, 1993. For small businesses, initial monitoring 
required by paragraph (d)(2) of this section shall be completed as soon 
as possible and in any event no later than April 14, 1993.
    (ii) Regulated areas. Except for small business, defined under 
paragraph (p)(2)(i) of this section, regulated areas required to be 
established by paragraph (e) of this section shall be set up as soon as 
possible after the results of exposure monitoring are known and in any 
event no later than March 15, 1993. For small businesses, regulated 
areas required to be established by paragraph (e) of this section shall 
be set up as soon as possible after the results of exposure monitoring 
are known and in any event no later than May 14, 1993.
    (iii) Respiratory protection. Except for small businesses, defined 
under paragraph (p)(2)(i) of this section, respiratory protection 
required by paragraph (g) of this section shall be provided as soon as 
possible and in any event no later than 90 days after the effective 
date of this section. For small businesses, respiratory protection 
required by paragraph (g) of this section shall be provided as soon as 
possible and in any event no later than March 15, 1993.
    (iv) Compliance program. Written compliance programs required by 
paragraph (f)(2) of this section shall be completed and available for 
inspection and copying as soon as possible and in any event no later 
than December 14, 1993.
    (v) Methods of compliance. The engineering controls required by 
paragraph (f)(1) of this section shall be implemented as soon as 
possible and in any event no later than December 14, 1994. Work 
practice controls shall be implemented as soon as possible. Work 
practice controls that are directly related to engineering controls to 
be implemented in accordance with the compliance plan shall be 
implemented as soon as possible after such engineering controls are 
implemented.
    (vi) Hygiene and lunchroom facilities. (A) Handwashing facilities, 
permanent or temporary, shall be provided in accordance with 29 CFR 
1910.141 (d)(1) and (2) as soon as possible and in any event no later 
than February 12, 1993.
    (B) Change rooms, showers, and lunchroom facilities shall be 
completed as soon as possible and in any event no later than December 
14, 1993.
    (vii) Employee information and training. Except for small 
businesses, defined under paragraph (p)(2)(i) of this section, employee 
information and training required by paragraph (m)(4) of this section 
shall be provided as soon as possible and in any event no later than 
March 15, 1993. For small businesses, employee information and training 
required by paragraph (m)(4) of this standard shall be provided as soon 
as possible and in any event no later than June 14, 1993.
    (viii) Medical surveillance. Except for small businesses, defined 
under paragraph (p)(2)(i) of this section, initial medical examinations 
required by paragraph (l) of this section shall be provided as soon as 
possible and in any event no later than March 15, 1993. For small 
businesses, initial medical examinations required by paragraph (l) of 
this section shall be provided as soon as possible and in any event no 
later than June 14, 1993.
    (q) Appendices. (1) Appendix C to this section is incorporated as 
part of this section, and compliance with its contents is mandatory.
    (2) Except where portions of appendices A, B, D, E, and F to this 
section are expressly incorporated in requirements of this section, 
these appendices are purely informational and are not intended to 
create any additional obligations not otherwise imposed or to detract 
from any existing obligations.

Appendix A to Sec. 1915.1027--Substance Safety Data Sheet

Cadmium

I. Substance Identification

    A. Substance: Cadmium.
    B. 8-Hour, Time-weighted-average, Permissible Exposure Limit 
(TWA PEL):
    1. TWA PEL: Five micrograms of cadmium per cubic meter of air 5 
g/m3, time-weighted average (TWA) for an 8-hour 
workday.
    C. Appearance: Cadmium metal--soft, blue-white, malleable, 
lustrous metal or grayish-white powder. Some cadmium compounds may 
also appear as a brown, yellow, or red powdery substance.

II. Health Hazard Data

    A. Routes of Exposure. Cadmium can cause local skin or eye 
irritation. Cadmium can affect your health if you inhale it or if 
you swallow it.
    B. Effects of Overexposure.
    1. Short-term (acute) exposure: Cadmium is much more dangerous 
by inhalation than by ingestion. High exposures to cadmium that may 
be immediately dangerous to life or health occur in jobs where 
workers handle large quantities of cadmium dust or fume; heat 
cadmium-containing compounds or cadmium-coated surfaces; weld with 
cadmium solders or cut cadmium-containing materials such as bolts.
    2. Severe exposure may occur before symptoms appear. Early 
symptoms may include mild irritation of the upper respiratory tract, 
a sensation of constriction of the throat, a metallic taste and/or a 
cough. A period of 1-10 hours may precede the onset of rapidly 
progressing shortness of breath, chest pain, and flu-like symptoms 
with weakness, fever, headache, chills, sweating and muscular pain. 
Acute pulmonary edema usually develops within 24 hours and reaches a 
maximum by three days. If death from asphyxia does not occur, 
symptoms may resolve within a week.
    3. Long-term (chronic) exposure. Repeated or long-term exposure 
to cadmium, even at relatively low concentrations, may result in 
kidney damage and an increased risk of cancer of the lung and of the 
prostate.
    C. Emergency First Aid Procedures.
    1. Eye exposure: Direct contact may cause redness or pain. Wash 
eyes immediately with large amounts of water, lifting the upper and 
lower eyelids. Get medical attention immediately.
    2. Skin exposure: Direct contact may result in irritation. 
Remove contaminated clothing and shoes immediately. Wash affected 
area with soap or mild detergent and large amounts of water. Get 
medical attention immediately.
    3. Ingestion: Ingestion may result in vomiting, abdominal pain, 
nausea, diarrhea, headache and sore throat. Treatment for symptoms 
must be administered by medical personnel. Under no circumstances 
should the employer allow any person whom he retains, employs, 
supervises or controls to engage in therapeutic chelation. Such 
treatment is likely to translocate cadmium from pulmonary or other 
tissue to renal tissue. Get medical attention immediately.
    4. Inhalation: If large amounts of cadmium are inhaled, the 
exposed person must be moved to fresh air at once. If breathing has 
stopped, perform cardiopulmonary resuscitation. Administer oxygen if 
available. Keep the affected person warm and at rest. Get medical 
attention immediately.
    5. Rescue: Move the affected person from the hazardous exposure. 
If the exposed person has been overcome, attempt rescue only after 
notifying at least one other person of the emergency and putting 
into effect established emergency procedures. Do not become a 
casualty yourself. Understand your emergency rescue procedures and 
know the location of the emergency equipment before the need arises.

III. Employee Information

    A. Protective Clothing and Equipment.
    1. Respirators: You may be required to wear a respirator for 
non-routine activities; in emergencies; while your employer is in 
the process of reducing cadmium exposures through engineering 
controls; and where engineering controls are not feasible. If 
respirators are worn in the future, they must have a joint Mine 
Safety and Health Administration (MSHA) and National Institute for 
Occupational Safety and Health (NIOSH) label of approval. Cadmium 
does not have a detectable odor except at levels well above the 
permissible exposure limits. If you can smell cadmium while wearing 
a respirator, proceed immediately to fresh air. If you experience 
difficulty breathing while wearing a respirator, tell your employer.
    2. Protective Clothing: You may be required to wear impermeable 
clothing, gloves, foot gear, a face shield, or other appropriate 
protective clothing to prevent skin contact with cadmium. Where 
protective clothing is required, your employer must provide clean 
garments to you as necessary to assure that the clothing protects 
you adequately. The employer must replace or repair protective 
clothing that has become torn or otherwise damaged.
    3. Eye Protection: You may be required to wear splash-proof or 
dust resistant goggles to prevent eye contact with cadmium.
    B. Employer Requirements.
    1. Medical: If you are exposed to cadmium at or above the action 
level, your employer is required to provide a medical examination, 
laboratory tests and a medical history according to the medical 
surveillance provisions under paragraph (1) of this standard. (See 
summary chart and tables in this appendix A.) These tests shall be 
provided without cost to you. In addition, if you are accidentally 
exposed to cadmium under conditions known or suspected to constitute 
toxic exposure to cadmium, your employer is required to make special 
tests available to you.
    2. Access to Records: All medical records are kept strictly 
confidential. You or your representative are entitled to see the 
records of measurements of your exposure to cadmium. Your medical 
examination records can be furnished to your personal physician or 
designated representative upon request by you to your employer.
    3. Observation of Monitoring: Your employer is required to 
perform measurements that are representative of your exposure to 
cadmium and you or your designated representative are entitled to 
observe the monitoring procedure. You are entitled to observe the 
steps taken in the measurement procedure, and to record the results 
obtained. When the monitoring procedure is taking place in an area 
where respirators or personal protective clothing and equipment are 
required to be worn, you or your representative must also be 
provided with, and must wear the protective clothing and equipment.
    C. Employee Requirements.--You will not be able to smoke, eat, 
drink, chew gum or tobacco, or apply cosmetics while working with 
cadmium in regulated areas. You will also not be able to carry or 
store tobacco products, gum, food, drinks or cosmetics in regulated 
areas because these products easily become contaminated with cadmium 
from the workplace and can therefore create another source of 
unnecessary cadmium exposure.
    Some workers will have to change out of work clothes and shower 
at the end of the day, as part of their workday, in order to wash 
cadmium from skin and hair. Handwashing and cadmium-free eating 
facilities shall be provided by the employer and proper hygiene 
should always be performed before eating. It is also recommended 
that you do not smoke or use tobacco products, because among other 
things, they naturally contain cadmium. For further information, 
read the labeling on such products.

IV. Physician Information

    A. Introduction.--The medical surveillance provisions of 
paragraph (1) generally are aimed at accomplishing three main 
interrelated purposes: First, identifying employees at higher risk 
of adverse health effects from excess, chronic exposure to cadmium; 
second, preventing cadmium-induced disease; and third, detecting and 
minimizing existing cadmium-induced disease. The core of medical 
surveillance in this standard is the early and periodic monitoring 
of the employee's biological indicators of: (a) Recent exposure to 
cadmium; (b) cadmium body burden; and (c) potential and actual 
kidney damage associated with exposure to cadmium.
    The main adverse health effects associated with cadmium 
overexposure are lung cancer and kidney dysfunction. It is not yet 
known how to adequately biologically monitor human beings to 
specifically prevent cadmium-induced lung cancer. By contrast, the 
kidney can be monitored to provide prevention and early detection of 
cadmium-induced kidney damage. Since, for non-carcinogenic effects, 
the kidney is considered the primary target organ of chronic 
exposure to cadmium, the medical surveillance provisions of this 
standard effectively focus on cadmium-induced kidney disease. Within 
that focus, the aim, where possible, is to prevent the onset of such 
disease and, where necessary, to minimize such disease as may 
already exist. The by-products of successful prevention of kidney 
disease are anticipated to be the reduction and prevention of other 
cadmium-induced diseases.
    B. Health Effects.--The major health effects associated with 
cadmium overexposure are described below.
    1. Kidney: The most prevalent non-malignant disease observed 
among workers chronically exposed to cadmium is kidney dysfunction. 
Initially, such dysfunction is manifested as proteinuria. The 
proteinuria associated with cadmium exposure is most commonly 
characterized by excretion of low-molecular weight proteins (15,000 
to 40,000 MW) accompanied by loss of electrolytes, uric acid, 
calcium, amino acids, and phosphate. The compounds commonly excreted 
include: beta-2-microglobulin (2-M), retinol binding 
protein (RBP), immunoglobulin light chains, and lysozyme. Excretion 
of low molecular weight proteins are characteristic of damage to the 
proximal tubules of the kidney (Iwao et al., 1980).
    It has also been observed that exposure to cadmium may lead to 
urinary excretion of high-molecular weight proteins such as albumin, 
immunoglobulin G, and glycoproteins (Ex. 29). Excretion of high-
molecular weight proteins is typically indicative of damage to the 
glomeruli of the kidney. Bernard et al., (1979) suggest that damage 
to the glomeruli and damage to the proximal tubules of the kidney 
may both be linked to cadmium exposure but they may occur 
independently of each other.
    Several studies indicate that the onset of low-molecular weight 
proteinuria is a sign of irreversible kidney damage (Friberg et al., 
1974; Roels et al., 1982; Piscator 1984; Elinder et al., 1985; Smith 
et al., 1986). Above specific levels of 2-M associated 
with cadmium exposure it is unlikely that 2-M levels 
return to normal even when cadmium exposure is eliminated by removal 
of the individual from the cadmium work environment (Friberg, Ex. 
29, 1990).
    Some studies indicate that such proteinuria may be progressive; 
levels of 2-M observed in the urine increase with time 
even after cadmium exposure has ceased. See, for example, Elinder et 
al., 1985. Such observations, however, are not universal, and it has 
been suggested that studies in which proteinuria has not been 
observed to progress may not have tracked patients for a 
sufficiently long time interval (Jarup, Ex. 8-661).
    When cadmium exposure continues after the onset of proteinuria, 
chronic nephrotoxicity may occur (Friberg, Ex. 29). Uremia results 
from the inability of the glomerulus to adequately filter blood. 
This leads to severe disturbance of electrolyte concentrations and 
may lead to various clinical complications including kidney stones 
(L-140-50).
    After prolonged exposure to cadmium, glomerular proteinuria, 
glucosuria, aminoaciduria, phosphaturia, and hypercalciuria may 
develop (Exs. 8-86, 4-28, 14-18). Phosphate, calcium, glucose, and 
amino acids are essential to life, and under normal conditions, 
their excretion should be regulated by the kidney. Once low 
molecular weight proteinuria has developed, these elements dissipate 
from the human body. Loss of glomerular function may also occur, 
manifested by decreased glomerular filtration rate and increased 
serum creatinine. Severe cadmium-induced renal damage may eventually 
develop into chronic renal failure and uremia (Ex. 55).
    Studies in which animals are chronically exposed to cadmium 
confirm the renal effects observed in humans (Friberg et al., 1986). 
Animal studies also confirm problems with calcium metabolism and 
related skeletal effects which have been observed among humans 
exposed to cadmium in addition to the renal effects. Other effects 
commonly reported in chronic animal studies include anemia, changes 
in liver morphology, immunosuppression and hypertension. Some of 
these effects may be associated with co-factors. Hypertension, for 
example, appears to be associated with diet as well as cadmium 
exposure. Animals injected with cadmium have also shown testicular 
necrosis (Ex. 8-86B).

2. Biological Markers

    It is universally recognized that the best measures of cadmium 
exposures and its effects are measurements of cadmium in biological 
fluids, especially urine and blood. Of the two, CdU is 
conventionally used to determine body burden of cadmium in workers 
without kidney disease. CdB is conventionally used to monitor for 
recent exposure to cadmium. In addition, levels of CdU and CdB 
historically have been used to predict the percent of the population 
likely to develop kidney disease (Thun et al., Ex. L-140-50; WHO, 
Ex. 8-674; ACGIH, Exs. 8-667, 140-50).
    The third biological parameter upon which OSHA relies for 
medical surveillance is Beta-2-microglobulin in urine 
(2-M), a low molecular weight protein. Excess 
2-M has been widely accepted by physicians and 
scientists as a reliable indicator of functional damage to the 
proximal tubule of the kidney (Exs. 8-447, 144-3-C, 4-47, L-140-45, 
19-43-A).
    Excess 2-M is found when the proximal tubules can 
no longer reabsorb this protein in a normal manner. This failure of 
the proximal tubules is an early stage of a kind of kidney disease 
that commonly occurs among workers with excessive cadmium exposure. 
Used in conjunction with biological test results indicating abnormal 
levels of CdU and CdB, the finding of excess 2-M can 
establish for an examining physician that any existing kidney 
disease is probably cadmium-related (Trs. 6/6/90, pp. 82-86, 122, 
134). The upper limits of normal levels for cadmium in urine and 
cadmium in blood are 3 g Cd/gram creatinine in urine and 5 
gCd/liter whole blood, respectively. These levels were 
derived from broad-based population studies.
    Three issues confront the physicians in the use of 
2-M as a marker of kidney dysfunction and material 
impairment. First, there are a few other causes of elevated levels 
of 2-M not related to cadmium exposures, some of which 
may be rather common diseases and some of which are serious diseases 
(e.g., myeloma or transient flu, Exs. 29 and 8-086). These can be 
medically evaluated as alternative causes (Friberg, Ex. 29). Also, 
there are other factors that can cause 2-M to degrade 
so that low levels would result in workers with tubular dysfunction. 
For example, regarding the degradation of 2-M, workers 
with acidic urine (pH<6) might have 2-M levels that 
are within the ``normal'' range when in fact kidney dysfunction has 
occurred (Ex. L-140-1) and the low molecular weight proteins are 
degraded in acid urine. Thus, it is very important that the pH of 
urine be measured, that urine samples be buffered as necessary (See 
appendix F.), and that urine samples be handled correctly, i.e., 
measure the pH of freshly voided urine samples, then if necessary, 
buffer to pH>6 (or above for shipping purposes), measure pH again 
and then, perhaps, freeze the sample for storage and shipping. (See 
also appendix F.) Second, there is debate over the pathological 
significance of proteinuria, however, most world experts believe 
that 2-M levels greater than 300 g/g Cr are 
abnormal (Elinder, Ex. 55, Friberg, Ex. 29). Such levels signify 
kidney dysfunction that constitutes material impairment of health. 
Finally, detection of 2-M at low levels has often been 
considered difficult, however, many laboratories have the capability 
of detecting excess 2-M using simple kits, such as the 
Phadebas Delphia test, that are accurate to levels of 100 g 
2-M/g Cr U (Ex. L-140-1).
    Specific recommendations for ways to measure 2-M 
and proper handling of urine samples to prevent degradation of 
2-M have been addressed by OSHA in appendix F, in the 
section on laboratory standardization. All biological samples must 
be analyzed in a laboratory that is proficient in the analysis of 
that particular analyte, under paragraph (l)(1)(iv). (See appendix 
F). Specifically, under paragraph (l)(1)(iv), the employer is to 
assure that the collecting and handling of biological samples of 
cadmium in urine (CdU), cadmium in blood (CdB), and beta-2 
microglobulin in urine (2-M) taken from employees is 
collected in a manner that assures reliability. The employer must 
also assure that analysis of biological samples of cadmium in urine 
(CdU), cadmium in blood (CdB), and beta-2 microglobulin in urine 
(2-M) taken from employees is performed in 
laboratories with demonstrated proficiency for that particular 
analyte. (See appendix F.)

3. Lung and Prostate Cancer

    The primary sites for cadmium-associated cancer appear to be the 
lung and the prostate (L-140-50). Evidence for an association 
between cancer and cadmium exposure derives from both 
epidemiological studies and animal experiments. Mortality from 
prostate cancer associated with cadmium is slightly elevated in 
several industrial cohorts, but the number of cases is small and 
there is not clear dose-response relationship. More substantive 
evidence exists for lung cancer.
    The major epidemiological study of lung cancer was conducted by 
Thun et al., (Ex. 4-68). Adequate data on cadmium exposures were 
available to allow evaluation of dose-response relationships between 
cadmium exposure and lung cancer. A statistically significant excess 
of lung cancer attributed to cadmium exposure was observed in this 
study even when confounding variables such as co-exposure to arsenic 
and smoking habits were taken into consideration (Ex. L-140-50).
    The primary evidence for quantifying a link between lung cancer 
and cadmium exposure from animal studies derives from two rat 
bioassay studies; one by Takenaka et al., (1983), which is a study 
of cadmium chloride and a second study by Oldiges and Glaser (1990) 
of four cadmium compounds.
    Based on the above cited studies, the U.S. Environmental 
Protection Agency (EPA) classified cadmium as ``B1'', a probable 
human carcinogen, in 1985 (Ex. 4-4). The International Agency for 
Research on Cancer (IARC) in 1987 also recommended that cadmium be 
listed as ``2A'', a probable human carcinogen (Ex. 4-15). The 
American Conference of Governmental Industrial Hygienists (ACGIH) 
has recently recommended that cadmium be labeled as a carcinogen. 
Since 1984, NIOSH has concluded that cadmium is possibly a human 
carcinogen and has recommended that exposures be controlled to the 
lowest level feasible.

4. Non-carcinogenic Effects

    Acute pneumonitis occurs 10 to 24 hours after initial acute 
inhalation of high levels of cadmium fumes with symptoms such as 
fever and chest pain (Exs. 30, 8-86B). In extreme exposure cases 
pulmonary edema may develop and cause death several days after 
exposure. Little actual exposure measurement data is available on 
the level of airborne cadmium exposure that causes such immediate 
adverse lung effects, nonetheless, it is reasonable to believe a 
cadmium concentration of approximately 1 mg/m3 over an eight 
hour period is ``immediately dangerous'' (55 FR 4052, ANSI; Ex. 8-
86B).
    In addition to acute lung effects and chronic renal effects, 
long term exposure to cadmium may cause other severe effects on the 
respiratory system. Reduced pulmonary function and chronic lung 
disease indicative of emphysema have been observed in workers who 
have had prolonged exposure to cadmium dust or fumes (Exs. 4-29, 4-
22, 4-42, 4-50, 4-63). In a study of workers conducted by Kazantzis 
et al., a statistically significant excess of worker deaths due to 
chronic bronchitis was found, which in his opinion was directly 
related to high cadmium exposures of 1 mg/m3 or more (Tr. 6/8/
90, pp. 156-157).
    Cadmium need not be respirable to constitute a hazard. 
Inspirable cadmium particles that are too large to be respirable but 
small enough to enter the tracheobronchial region of the lung can 
lead to bronchoconstriction, chronic pulmonary disease, and cancer 
of that portion of the lung. All of these diseases have been 
associated with occupational exposure to cadmium (Ex. 8-86B). 
Particles that are constrained by their size to the extra-thoracic 
regions of the respiratory system such as the nose and maxillary 
sinuses can be swallowed through mucocillary clearance and be 
absorbed into the body (ACGIH, Ex. 8-692). The impaction of these 
particles in the upper airways can lead to anosmia, or loss of sense 
of smell, which is an early indication of overexposure among workers 
exposed to heavy metals. This condition is commonly reported among 
cadmium-exposed workers (Ex. 8-86-B).

C. Medical Surveillance

    In general, the main provisions of the medical surveillance 
section of the standard, under paragraphs (l)(1)-(17) of the 
regulatory text, are as follows:
    1. Workers exposed above the action level are covered;
    2. Workers with intermittent exposures are not covered;
    3. Past workers who are covered receive biological monitoring 
for at least one year;
    4. Initial examinations include a medical questionnaire and 
biological monitoring of cadmium in blood (CdB), cadmium in urine 
(CdU), and Beta-2-microglobulin in urine (2-M);
    5. Biological monitoring of these three analytes is performed at 
least annually; full medical examinations are performed biennially;
    6. Until five years from the effective date of the standard, 
medical removal is required when CdU is greater than 15 g/
gram creatinine (g Cr), or CdB is greater than 15 g/liter 
whole blood (lwb), or 2-M is greater than 1500 
g/g Cr, and CdB is greater than 5 g/lwb or CdU is 
greater than 3 g/g Cr;
    7. Beginning five years after the standard is in effect, medical 
removal triggers will be reduced;
    8. Medical removal protection benefits are to be provided for up 
to 18 months;
    9. Limited initial medical examinations are required for 
respirator usage;
    10. Major provisions are fully described under section (l) of 
the regulatory text; they are outlined here as follows:
    A. Eligibility
    B. Biological monitoring
    C. Actions triggered by levels of CdU, CdB, and 2-
M (See Summary Charts and Tables in Attachment-1.)
    D. Periodic medical surveillance
    E. Actions triggered by periodic medical surveillance (See 
appendix A Summary Chart and Tables in Attachment-1.)
    F. Respirator usage
    G. Emergency medical examinations
    H. Termination examination
    I. Information to physician
    J. Physician's medical opinion
    K. Medical removal protection
    L. Medical removal protection benefits
    M. Multiple physician review
    N. Alternate physician review
    O. Information employer gives to employee
    P. Recordkeeping
    Q. Reporting on OSHA form 200
    11. The above mentioned summary of the medical surveillance 
provisions, the summary chart, and tables for the actions triggered 
at different levels of CdU, CdB and 2-M (in appendix A 
Attachment-1) are included only for the purpose of facilitating 
understanding of the provisions of paragraphs (l)(3) of the final 
cadmium standard. The summary of the provisions, the summary chart, 
and the tables do not add to or reduce the requirements in paragraph 
(l)(3).

D. Recommendations to Physicians

    1. It is strongly recommended that patients with tubular 
proteinuria are counseled on: The hazards of smoking; avoidance of 
nephrotoxins and certain prescriptions and over-the-counter 
medications that may exacerbate kidney symptoms; how to control 
diabetes and/or blood pressure; proper hydration, diet, and exercise 
(Ex. 19-2). A list of prominent or common nephrotoxins is attached. 
(See appendix A Attachment-2.)
    2. DO NOT CHELATE; KNOW WHICH DRUGS ARE NEPHROTOXINS OR ARE 
ASSOCIATED WITH NEPHRITIS.
    3. The gravity of cadmium-induced renal damage is compounded by 
the fact there is no medical treatment to prevent or reduce the 
accumulation of cadmium in the kidney (Ex. 8-619). Dr. Friberg, a 
leading world expert on cadmium toxicity, indicated in 1992, that 
there is no form of chelating agent that could be used without 
substantial risk. He stated that tubular proteinuria has to be 
treated in the same way as other kidney disorders (Ex. 29).
    4. After the results of a workers' biological monitoring or 
medical examination are received the employer is required to provide 
an information sheet to the patient, briefly explaining the 
significance of the results. (See Attachment 3 of this appendix A.)
    5. For additional information the physician is referred to the 
following additional resources:
    a. The physician can always obtain a copy of the preamble, with 
its full discussion of the health effects, from OSHA's Computerized 
Information System (OCIS).
    b. The Docket Officer maintains a record of the rulemaking. The 
Cadmium Docket (H-057A), is located at 200 Constitution Ave. NW., 
room N-2625, Washington, DC 20210; telephone: 202-219-7894.
    c. The following articles and exhibits in particular from that 
docket (H-057A):

------------------------------------------------------------------------
 Exhibit No.                    Author and paper title                  
------------------------------------------------------------------------
8-447.......  Lauwerys et. al., Guide for physicians, ``Health          
               Maintenance of Workers Exposed to Cadmium,'' published by
               the Cadmium Council.                                     
4-67........  Takenaka, S., H. Oldiges, H. Konig, D. Hochrainer, G.     
               Oberdorster. ``Carcinogenicity of Cadmium Chloride       
               Aerosols in Wistar Rats''. JNCI 70:367-373, 1983. (32)   
4-68........  Thun, M.J., T.M. Schnoor, A.B. Smith, W.E. Halperin, R.A. 
               Lemen. ``Mortality Among a Cohort of U.S. Cadmium        
               Production Workers--An Update.'' JNCI 74(2):325-33, 1985.
               (8)                                                      
4-25........  Elinder, C.G., Kjellstrom, T., Hogstedt, C., et al.,      
               ``Cancer Mortality of Cadmium Workers.'' Brit. J. Ind.   
               Med. 42:651-655, 1985. (14)                              
4-26........  Ellis, K.J. et al., ``Critical Concentrations of Cadmium  
               in Human Renal Cortex: Dose Effect Studies to Cadmium    
               Smelter Workers.'' J. Toxicol. Environ. Health 7:691-703,
               1981. (76)                                               
4-27........  Ellis, K.J., S.H. Cohn and T.J. Smith. ``Cadmium          
               Inhalation Exposure Estimates: Their Significance with   
               Respect to Kidney and Liver Cadmium Burden.'' J. Toxicol.
               Environ. Health 15:173-187, 1985.                        
4-28........  Falck, F.Y., Jr., Fine, L.J., Smith, R.G., McClatchey,    
               K.D., Annesley, T., England, B., and Schork, A.M.        
               ``Occupational Cadmium Exposure and Renal Status.'' Am.  
               J. Ind. Med. 4:541, 1983. (64)                           
8-86A.......  Friberg, L., C.G. Elinder, et al., ``Cadmium and Health a 
               Toxicological and Epidemiological Appraisal, Volume I,   
               Exposure, Dose, and Metabolism.'' CRC Press, Inc., Boca  
               Raton, FL, 1986. (Available from the OSHA Technical Data 
               Center)                                                  
8-86B.......  Friberg, L., C.G. Elinder, et al., ``Cadmium and Health: A
               Toxicological and Epidemiological Appraisal, Volume II,  
               Effects and Response.'' CRC Press, Inc., Boca Raton, FL, 
               1986. (Available from the OSHA Technical Data Center)    
L-140-45....  Elinder, C.G., ``Cancer Mortality of Cadmium Workers'',   
               Brit. J. Ind. Med., 42, 651-655, 1985.                   
L-140-50....  Thun, M., Elinder, C.G., Friberg, L, ``Scientific Basis   
               for an Occupational Standard for Cadmium, Am. J. Ind.    
               Med., 20; 629-642, 1991.                                 
------------------------------------------------------------------------

V. Information Sheet

    The information sheet (appendix A Attachment-3.) or an equally 
explanatory one should be provided to you after any biological 
monitoring results are reviewed by the physician, or where 
applicable, after any medical examination.

Appendix A

Attachment 1--Appendix A Summary Chart and Tables A and B of Actions 
Triggered by Biological Monitoring

Appendix A Summary Chart: Section (1)(3) Medical Surveillance

Categorizing Biological Monitoring Results

    (A) Biological monitoring results categories are set forth in 
Appendix A Table A for the periods ending December 31, 1998 and for 
the period beginning January 1, 1999.
    (B) The results of the biological monitoring for the initial 
medical exam and the subsequent exams shall determine an employee's 
biological monitoring result category.

Actions Triggered by Biological Monitoring

    (A)
    (i) The actions triggered by biological monitoring for an 
employee are set forth in Appendix A Table B.
    (ii) The biological monitoring results for each employee under 
section (1)(3) shall determine the actions required for that 
employee. That is, for any employee in biological monitoring 
category C, the employer will perform all of the actions for which 
there is an X in column C of Appendix A Table B.
    (iii) An employee is assigned the alphabetical category (``A'' 
being the lowest) depending upon the test results of the three 
biological markers.
    (iv) An employee is assigned category A if monitoring results 
for all three biological markers fall at or below the levels 
indicated in the table listed for category A.
    (v) An employee is assigned category B if any monitoring result 
for any of the three biological markers fall within the range of 
levels indicated in the table listed for category B, providing no 
result exceeds the levels listed for category B.
    (vi) An employee is assigned category C if any monitoring result 
for any of the three biological markers are above the levels listed 
for category C.
    (B) The user of Appendix A Tables A and B should know that these 
tables are provided only to facilitate understanding of the relevant 
provisions of paragraph (l)(3) of this section. Appendix A Tables A 
and B are not meant to add to or subtract from the requirements of 
those provisions.

Appendix A Table A

Categorization of Biological Monitoring Results 

                                          Applicable Through 1998 Only                                          
----------------------------------------------------------------------------------------------------------------
                                                                            Monitoring result categories        
                        Biological marker                         ----------------------------------------------
                                                                       A                B                  C    
----------------------------------------------------------------------------------------------------------------
Cadmium in urine (CdU) (g/g creatinine).................  3 and 15        >15 
2-microglobulin (2-M) (g/g creatinine)  300 and 1500      >1500*
Cadmium in blood (CdB) (g/liter whole blood)............  5 and 15        >15 
----------------------------------------------------------------------------------------------------------------
* If an employee's 2-M levels are above 1,500 g/g creatinine, in order for mandatory medical  
  removal to be required (See Appendix A Table B.), either the employee's CdU level must also be >3 g/g
  creatinine or CdB level must also be >5 g/liter whole blood.                                         


                                      Applicable Beginning January 1, 1999                                      
----------------------------------------------------------------------------------------------------------------
                                                                            Monitoring result categories        
                        Biological marker                         ----------------------------------------------
                                                                       A                B                  C    
----------------------------------------------------------------------------------------------------------------
Cadmium in urine (CdU) (g/g creatinine).................  3 and 7         >7 
2-microglobulin (2-M) (g/g creatinine)  300 and 750       >750*
Cadmium in blood (CdB) (g/liter whole blood)............  5 and 10        >10 
----------------------------------------------------------------------------------------------------------------
* If an employee's 2-M levels are above 750 g/g creatinine, in order for mandatory medical    
  removal to be required (See Appendix A Table B.), either the employee's CdU level must also be >3 g/g
  creatinine or CdB level must also be >5 g/liter whole blood.                                         

Appendix A Table B--Actions Determined by Biological Monitoring

    This table presents the actions required based on the monitoring 
result in Appendix A Table A. Each item is a separate requirement in 
citing non-compliance. For example, a medical examination within 90 
days for an employee in category B is separate from the requirement to 
administer a periodic medical examination for category B employees on 
an annual basis. 

------------------------------------------------------------------------
                                          Monitoring result category    
          Required actions           -----------------------------------
                                         A\1\        B\1\        C\1\   
------------------------------------------------------------------------
(1) Biological monitoring:                                              
    (a) Annual......................  X           ..........  ..........
    (b) Semiannual..................  ..........  X           ..........
    (c) Quarterly...................  ..........  ..........  X         
(2) Medical examination:                                                
    (a) Biennial....................  X           ..........  ..........
    (b) Annual......................  ..........  X           ..........
    (c) Semiannual..................  ..........  ..........  X         
    (d) Within 90 days..............  ..........  X           X         
(3) Assess within two weeks:                                            
    (a) Excess cadmium exposure.....  ..........  X           X         
    (b) Work practices..............  ..........  X           X         
    (c) Personal hygiene............  ..........  X           X         
    (d) Respirator usage............  ..........  X           X         
    (e) Smoking history.............  ..........  X           X         
    (f) Hygiene facilities..........  ..........  X           X         
    (g) Engineering controls........  ..........  X           X         
    (h) Correct within 30 days......  ..........  X           X         
    (i) Periodically assess           ..........  ..........  X         
     exposures.                                                         
(4) Discretionary medical removal...  ..........  X           X         
(5) Mandatory medical removal.......  ..........  ..........  X\2\      
------------------------------------------------------------------------
\1\For all employees covered by medical surveillance exclusively because
  of exposures prior to the effective date of this standard, if they are
  in Category A, the employer shall follow the requirements of          
  paragraphs (l)(3)(i)(B) and (l)(4)(v)(A). If they are in Category B or
  C, the employer shall follow the requirements of paragraphs           
  (l)(4)(v)(B)-(C).                                                     
\2\See footnote Appendix A Table A.                                     

Appendix A--Attachment-2: List of Medications

    A list of the more common medications that a physician, and the 
employee, may wish to review is likely to include some of the 
following: (1) Anticonvulsants: Paramethadione, phenytoin, 
trimethadone; (2) antihypertensive drugs: Captopril, methyldopa; (3) 
antimicrobials: Aminoglycosides, amphotericin B, cephalosporins, 
ethambutol; (4) antineoplastic agents: Cisplatin, methotrexate, 
mitomycin-C, nitrosoureas, radiation; (4) sulfonamide diuretics: 
Acetazolamide, chlorthalidone, furosemide, thiazides; (5) 
halogenated alkanes, hydrocarbons, and solvents that may occur in 
some settings: Carbon tetrachloride, ethylene glycol, toluene; 
iodinated radiographic contrast media; nonsteroidal anti-
inflammatory drugs; and, (7) other miscellaneous compounds: 
Acetominophen, allopurinol, amphetamines, azathioprine, cimetidine, 
cyclosporine, lithium, methoxyflurane, methysergide, D-
penicillamine, phenacetin, phenendione. A list of drugs associated 
with acute interstitial nephritis includes: (1) Antimicrobial drugs: 
Cephalosporins, chloramphenicol, colistin, erythromycin, ethambutol, 
isoniazid, para-aminosalicylic acid, penicillins, polymyxin B, 
rifampin, sulfonamides, tetracyclines, and vancomycin; (2) other 
miscellaneous drugs: Allopurinol, antipyrene, azathioprine, 
captopril, cimetidine, clofibrate, methyldopa, phenindione, 
phenylpropanolamine, phenytoin, probenecid, sulfinpyrazone, 
sulfonamid diuretics, triamterene; and, (3) metals: Bismuth, gold.
    This list have been derived from commonly available medical 
textbooks (e.g., Ex. 14-18). The list has been included merely to 
facilitate the physician's, employer's, and employee's 
understanding. The list does not represent an official OSHA opinion 
or policy regarding the use of these medications for particular 
employees. The use of such medications should be under physician 
discretion.

Attachment 3--Biological Monitoring and Medical Examination Results

Employee---------------------------------------------------------------
Testing Date-----------------------------------------------------------
    Cadmium in Urine ______ g/g Cr--Normal Levels: 
3 g/g Cr.
    Cadmium in Blood ______ g/lwb--Normal Levels: 
5 g/lwb.
    Beta-2-microglobulin in Urine ______ g/g Cr--Normal 
Levels: 300 g/g Cr.
    Physical Examination Results: N/A ______ Satisfactory ______ 
Unsatisfactory ______ (see physician again).
    Physician's Review of Pulmonary Function Test: N/A ______ Normal 
______ Abnormal ______.
Next biological monitoring or medical examination scheduled for--------

    The biological monitoring program has been designed for three 
main purposes: 1) to identify employees at risk of adverse health 
effects from excess, chronic exposure to cadmium; 2) to prevent 
cadmium-induced disease(s); and 3) to detect and minimize existing 
cadmium-induced disease(s).
    The levels of cadmium in the urine and blood provide an estimate 
of the total amount of cadmium in the body. The amount of a specific 
protein in the urine (beta-2-microglobulin) indicates changes in 
kidney function. All three tests must be evaluated together. A 
single mildly elevated result may not be important if testing at a 
later time indicates that the results are normal and the workplace 
has been evaluated to decrease possible sources of cadmium exposure. 
The levels of cadmium or beta-2-microglobulin may change over a 
period of days to months and the time needed for those changes to 
occur is different for each worker.
    If the results for biological monitoring are above specific 
``high levels'' [cadmium urine greater than 10 micrograms per gram 
of creatinine (g/g Cr), cadmium blood greater than 10 
micrograms per liter of whole blood (g/lwb), or beta-2-
microglobulin greater than 1000 micrograms per gram of creatinine 
(g/g Cr)], the worker has a much greater chance of 
developing other kidney diseases.
    One way to measure for kidney function is by measuring beta-2-
microglobulin in the urine. Beta-2-microglobulin is a protein which 
is normally found in the blood as it is being filtered in the 
kidney, and the kidney reabsorbs or returns almost all of the beta-
2-microglobulin to the blood. A very small amount (less than 300 
g/g Cr in the urine) of beta-2-microglobulin is not 
reabsorbed into the blood, but is released in the urine. If cadmium 
damages the kidney, the amount of beta-2-microglobulin in the urine 
increases because the kidney cells are unable to reabsorb the beta-
2-microglobulin normally. An increase in the amount of beta-2-
microglobulin in the urine is a very early sign of kidney 
dysfunction. A small increase in beta-2-microglobulin in the urine 
will serve as an early warning sign that the worker may be absorbing 
cadmium from the air, cigarettes contaminated in the workplace, or 
eating in areas that are cadmium contaminated.
    Even if cadmium causes permanent changes in the kidney's ability 
to reabsorb beta-2-microglobulin, and the beta-2-microglobulin is 
above the ``high levels'', the loss of kidney function may not lead 
to any serious health problems. Also, renal function naturally 
declines as people age. The risk for changes in kidney function for 
workers who have biological monitoring results between the ``normal 
values'' and the ``high levels'' is not well known. Some people are 
more cadmium-tolerant, while others are more cadmium-susceptible.
    For anyone with even a slight increase of beta-2-microglobulin, 
cadmium in the urine, or cadmium in the blood, it is very important 
to protect the kidney from further damage. Kidney damage can come 
from other sources than excess cadmium-exposure so it is also 
recommended that if a worker's levels are ``high'' he/she should 
receive counseling about drinking more water; avoiding cadmium-
tainted tobacco and certain medications (nephrotoxins, 
acetaminophen); controlling diet, vitamin intake, blood pressure and 
diabetes; etc.

Appendix B to Sec. 1915.1027--Substance Technical Guidelines for 
Cadmium

I. Cadmium Metal.
    A. Physical and Chemical Data.
    1. Substance Identification.
    Chemical name: Cadmium.
    Formula: Cd.
    Molecular Weight: 112.4.
    Chemical Abstracts Service (CAS) Registry No.: 7740-43-9.
    Other Identifiers: RETCS EU9800000; EPA D006; DOT 2570 53.
    Synonyms: Colloidal Cadmium: Kadmium (German): CI 77180.
    2. Physical data.
    Boiling point: (760 mm Hg): 765 degrees C.
    Melting point: 321 degrees C.
    Specific Gravity: (H[email protected] 20  deg.C): 8.64.
    Solubility: Insoluble in water; soluble in dilute nitric acid 
and in sulfuric acid.
    Appearance: Soft, blue-white, malleable, lustrous metal or 
grayish-white powder.
    B. Fire, Explosion and Reactivity Data.
    1. Fire.
    Fire and Explosion Hazards: The finely divided metal is 
pyrophoric, that is the dust is a severe fire hazard and moderate 
explosion hazard when exposed to heat or flame. Burning material 
reacts violently with extinguishing agents such as water, foam, 
carbon dioxide, and halons.
    Flash point: Flammable (dust).
    Extinguishing media: Dry sand, dry dolomite, dry graphite, or 
sodimum chloride.
    2. Reactivity.
    Conditions contributing to instability: Stable when kept in 
sealed containers under normal temperatures and pressure, but dust 
may ignite upon contact with air. Metal tarnishes in moist air.
    Incompatibilities: Ammonium nitrate, fused: Reacts violently or 
explosively with cadmium dust below 20  deg.C. Hydrozoic acid: 
Violent explosion occurs after 30 minutes. Acids: Reacts violently, 
forms hydrogen gas. Oxidizing agents or metals: Strong reaction with 
cadmium dust. Nitryl fluoride at slightly elevated temperature: 
Glowing or white incandescence occurs. Selenium: Reacts 
exothermically. Ammonia: Corrosive reaction. Sulfur dioxide: 
Corrosive reaction. Fire extinguishing agents (water, foam, carbon 
dioxide, and halons): Reacts violently. Tellurium: Incandescent 
reaction in hydrogen atmosphere.
    Hazardous decomposition products: The heated metal rapidly forms 
highly toxic, brownish fumes of oxides of cadmium.
    C. Spill, Leak and Disposal Procedures.
    1. Steps to be taken if the materials is released or spilled. Do 
not touch spilled material. Stop leak if you can do it without risk. 
Do not get water inside container. For large spills, dike spill for 
later disposal. Keep unnecessary people away. Isolate hazard area 
and deny entry. The Superfund Amendments and Reauthorization Act of 
1986 Section 304 requires that a release equal to or greater than 
the reportable quantity for this substance (1 pound) must be 
immediately reported to the local emergency planning committee, the 
state emergency response commission, and the National Response 
Center (800) 424-8802; in Washington, DC metropolitan area (202) 
426-2675.
II. Cadmium Oxide.
    A. Physical and Chemical Date.
    1. Substance identification.
    Chemical name: Cadmium Oxide.
    Formula: CdO.
    Molecular Weight: 128.4.
    CAS No.: 1306-19-0.
    Other Identifiers: RTECS EV1929500.
    Synonyms: Kadmu tlenek (Polish).
    2. Physical data.
    Boiling point (760 mm Hg): 950 degrees C decomposes.
    Melting point: 1500  deg.C.
    Specific Gravity: (H[email protected]  deg.C): 7.0.
    Solubility: Insoluble in water; soluble in acids and alkalines.
    Appearance: Red or brown crystals.
    B. Fire, Explosion and Reactivity Data.
    1. Fire.
    Fire and Explosion Hazards: Negligible fire hazard when exposed 
to heat or flame.
    Flash point: Nonflammable.
    Extinguishing media: Dry chemical, carbon dioxide, water spray 
or foam.
    2. Reactivity.
    Conditions contributing to instability: Stable under normal 
temperatures and pressures.
    Incompatibilities: Magnesium may reduce CdO2 explosively on 
heating.
    Hazardous decomposition products: Toxic fumes of cadmium.
    C. Spill Leak and Disposal Procedures.
    1. Steps to be taken if the material is released or spilled. Do 
not touch spilled material. Stop leak if you can do it without risk. 
For small spills, take up with sand or other absorbent material and 
place into containers for later disposal. For small dry spills, use 
a clean shovel to place material into clean, dry container and then 
cover. Move containers from spill area. For larger spills, dike far 
ahead of spill for later disposal. Keep unnecessary people away. 
Isolate hazard area and deny entry. The Superfund Amendments and 
Reauthorization Act of 1986 Section 304 requires that a release 
equal to or greater than the reportable quantity for this substance 
(1 pound) must be immediately reported to the local emergency 
planning committee, the state emergency response commission, and the 
National Response Center (800) 424-8802; in Washington, DC 
metropolitan area (202) 426-2675.
III. Cadmium Sulfide.
    A. Physical and Chemical Data.
    1. Substance Identification.
    Chemical name: Cadmium sulfide.
    Formula: CdS.
    Molecular weight: 144.5.
    CAS No. 1306-23-6.
    Other Identifiers: RTECS EV3150000.
    Synonyms: Aurora yellow; Cadmium Golden 366; Cadmium Lemon 
Yellow 527; Cadmium Orange; Cadmium Primrose 819; Cadmium Sulphide; 
Cadmium Yellow; Cadmium Yellow 000; Cadmium Yellow Conc. Deep; 
Cadmium Yellow Conc. Golden; Cadmium Yellow Conc. Lemon; Cadmium 
Yellow Conc. Primrose; Cadmium Yellow Oz. Dark; Cadmium Yellow 
Primrose 47-1400; Cadmium Yellow 10G Conc.; Cadmium Yellow 892; 
Cadmopur Golden Yellow N; Cadmopur Yellow: Capsebon; C.I. 77199; 
C.I. Pigment Orange 20; CI Pigment Yellow 37; Ferro Lemon Yellow; 
Ferro Orange Yellow; Ferro Yellow; Greenockite; NCI-C02711.
    2. Physical data.
    Boiling point (760 mm. Hg): sublines in N2 at 980  deg.C.
    Melting point: 1750 degrees C (100 atm).
    Specific Gravity: (H[email protected] 20  deg.C): 4.82.
    Solubility: Slightly soluble in water; soluble in acid.
    Appearance: Light yellow or yellow-orange crystals.
    B. Fire, Explosion and Reactivity Data.
    1. Fire.
    Fire and Explosion Hazards: Neglible fire hazard when exposed to 
heat or flame.
    Flash point: Nonflammable.
    Extinguishing media: Dry chemical, carbon dioxide, water spray 
or foam.
    2. Reactivity.
    Conditions contributing to instability: Generally non-reactive 
under normal conditions. Reacts with acids to form toxic hydrogen 
sulfide gas.
    Incompatibilities: Reacts vigorously with iodinemonochloride.
    Hazardous decomposition products: Toxic fumes of cadmium and 
sulfur oxides.
    C. Spill Leak and Disposal Procedures.
    1. Steps to be taken if the material is released or spilled. Do 
not touch spilled material. Stop leak if you can do it without risk. 
For small, dry spills, with a clean shovel place material into 
clean, dry container and cover. Move containers from spill area. For 
larger spills, dike far ahead of spill for later disposal. Keep 
unnecessary people away. Isolate hazard and deny entry.
IV. Cadmium Chloride.
    A. Physical and Chemical Data.
    1. Substance Identification.
    Chemical name: Cadmium chloride.
    Formula: CdCl2.
    Molecular weight: 183.3.
    CAS No. 10108-64-2.
    Other Identifiers: RTECS EY0175000.
    Synonyms: Caddy; Cadmium dichloride; NA 2570 (DOT); UI-CAD; 
dichlorocadmium.
    2. Physical data.
    Boiling point (760 mm Hg): 960 degrees C.
    Melting point: 568 degrees C.
    Specific Gravity: (H2O=1 @ 20  deg.C): 4.05.
    Solubility: Soluble in water (140 g/100 cc); soluble in acetone.
    Appearance: Small, white crystals.
    B. Fire, Explosion and Reactivity Data.
    1. Fire.
    Fire and Explosion Hazards: Negligible fire and negligible 
explosion hazard in dust form when exposed to heat or flame.
    Flash point: Nonflamable.
    Extinguishing media: Dry chemical, carbon dioxide, water spray 
or foam.
    2. Reactivity.
    Conditions contributing to instability: Generally stable under 
normal temperatures and pressures.
    Incompatibilities: Bromine triflouride rapidly attacks cadmium 
chloride. A mixture of potassium and cadmium chloride may produce a 
strong explosion on impact.
    Hazardous decomposition products: Thermal ecompostion may 
release toxic fumes of hydrogen chloride, chloride, chlorine or 
oxides of cadmium.
    C. Spill Leak and Disposal Procedures.
    1. Steps to be taken if the materials is released or spilled. Do 
not touch spilled material. Stop leak if you can do it without risk. 
For small, dry spills, with a clean shovel place material into 
clean, dry container and cover. Move containers from spill area. For 
larger spills, dike far ahead of spill for later disposal. Keep 
unnecessary people away. Isolate hazard and deny entry. The 
Superfund Amendments and Reauthorization Act of 1986 Section 304 
requires that a release equal to or greater than the reportable 
quantity for this substance (100 pounds) must be immediately 
reported to the local emergency planning committee, the state 
emergency response commission, and the National Response Center 
(800) 424-8802; in Washington, DC Metropolitan area (202) 426-2675.

Appendix C to Sec. 1915.1027--Qualitative and Quantitative Fit 
Testing Procedures

I. Fit Test Protocols

    A. General: The employer shall include the following provisions 
in the fit test procedures. These provisions apply to both 
qualitative fit testing (QLFT) and quantitative fit testing (QNFT). 
All testing is to be conducted annually.
    1. The test subject shall be allowed to pick the most 
comfortable respirator from a selection including respirators of 
various sizes from different manufacturers. The selection shall 
include at least three sizes of elastomeric facepieces of the type 
of respirator that is to be tested, i.e., three sizes of half mask; 
or three sizes of full facepiece. Respirators of each size must be 
provided from at least two manufacturers.
    2. Prior to the selection process, the test subject shall be 
shown how to put on a respirator, how it should be positioned on the 
face, how to set strap tension and how to determine a comfortable 
fit. A mirror shall be available to assist the subject in evaluating 
the fit and positioning the respirator. This instruction may not 
constitute the subject's formal training on respirator use; it is 
only a review.
    3. The test subject shall be informed that he/she is being asked 
to select the respirator which provides the most comfortable fit. 
Each respirator represents a different size and shape, and if 
fitted, maintained and used properly, will provide substantial 
protection.
    4. The test subject shall be instructed to hold each facepiece 
up to the face and eliminate those which obviously do not give a 
comfortable fit.
    5. The more comfortable facepieces are noted; the most 
comfortable mask is donned and worn at least five minutes to assess 
comfort. Assistance in assessing comfort can be given by discussing 
the points in item 6 below. If the test subject is not familiar with 
using a particular respirator, the test subject shall be directed to 
don the mask several times and to adjust the straps each time to 
become adept at setting proper tension on the straps.
    6. Assessment of comfort shall include reviewing the following 
points with the test subject and allowing the test subject adequate 
time to determine the comfort of the respirator:
    (a) Position of the mask on the nose;
    (b) Room for eye protection;
    (c) Room to talk; and
    (d) Position of mask on face and cheeks.
    7. The following criteria shall be used to help determine the 
adequacy of the respirator fit:
    (a) Chin properly placed;
    (b) Adequate strap tension, not overly tightened;
    (c) Fit across nose bridge;
    (d) Respirator of proper size to span distance from nose to 
chin;
    (e) Tendency of respirator to slip; and
    (f) Self-observation in mirror to evaluate fit and respirator 
position.
    8. The test subject shall conduct the negative and positive 
pressure fit checks as described below or in ANSI Z88.2-1980. Before 
conducting the negative or positive pressure test, the subject shall 
be told to seat the mask on the face by moving the head from side-
to-side and up and down slowly while taking in a few slow deep 
breaths. Another facepiece shall be selected and retested if the 
test subject fails the fit check tests.
    (a). Positive pressure test. Close off the exhalation valve and 
exhale gently onto the facepiece. The face fit is considered 
satisfactory if a slight positive pressure can be built up inside 
the facepiece without any evidence of outward leakage of air at the 
seal. For most respirators this method of leak testing requires the 
wearer to first remove the exhalation valve cover before closing off 
the exhalation valve and then carefully replacing it after the test.
    (b). Negative pressure test. Close off the inlet opening of the 
canister or cartridge(s) by covering with the palm of the hand(s) or 
by replacing the filter seal(s). Inhale gently so that the facepiece 
collapses slightly, and hold the breath for ten seconds. If the 
facepiece remains in its slightly collapsed condition and no inward 
leakage of air is detected, the tightness of the respirator is 
considered satisfactory.
    9. The test shall not be conducted if there is any hair growth 
between the skin and the facepiece sealing surface, such as stubble 
beard growth, beard, or long sideburns which cross the respirator 
sealing surface. Any type of apparel which interferes with a 
satisfactory fit shall be altered or removed.
    10. If a test subject exhibits difficulty in breathing during 
the tests, she or he shall be referred to a physician trained in 
respiratory disease or pulmonary medicine to determine, in 
accordance with paragraph (l)(2) and (3) of this standard, whether 
the test subject can wear a respirator while performing her or his 
duties.
    11. The test subject shall be given the opportunity to wear the 
successfully fitted respirator for a period of two weeks. If at any 
time during this period the respirator becomes uncomfortable, the 
test subject shall be given the opportunity to select a different 
facepiece and to be retested.
    12. The employer shall maintain a record of the fit test 
administered to an employee. The record shall contain at least the 
following information:
    (a) Name of employee;
    (b) Type of respirator;
    (c) Brand, size of respirator;
    (d) Date of test; and
    (e) Where QNFT is used, the fit factor and strip chart recording 
or other recording of the results of the test. The record shall be 
maintained until the next fit test is administered.
    13. Exercise regimen. Prior to the commencement of the fit test, 
the test subject shall be given a description of the fit test and 
the test subject's responsibilities during the test procedure. The 
description of the process shall include a description of the test 
exercises that the subject will be performing. The respirator to be 
tested shall be worn for at least 5 minutes before the start of the 
fit test.
    14. Test Exercises. The test subject shall perform exercises, in 
the test environment, in the manner described below:
    (a) Normal breathing. In a normal standing position, without 
talking, the subject shall breathe normally.
    (b) Deep breathing. In a normal standing position, without 
talking, the subject shall breathe slowly and deeply, taking care so 
as to not hyperventilate.
    (c) Turning head side to side. Standing in place, the subject 
shall slowly turn his/her head from side to side between the extreme 
positions on each side. The head shall be held at each extreme 
momentarily so the subject can inhale at each side.
    (d) Moving head up and down. Standing in place, the subject 
shall slowly move his/her head up and down. The subject shall be 
instructed to inhale in the up position (i.e., when looking toward 
the ceiling).
    (e) Talking. The subject shall talk out loud slowly and loud 
enough so as to be heard clearly by the test conductor. The subject 
can read from a prepared text such as the Rainbow Passage, count 
backward from 100, or recite a memorized poem or song.
    (f) Grimace. The test subject shall grimace by smiling or 
frowning.
    (g) Bending over. The test subject shall bend at the waist as if 
he/she were to touch his/her toes. Jogging in place shall be 
substituted for this exercise in those test environments such as 
shroud type QNFT units which prohibit bending at the waist.
    (h) Normal breathing. Same as exercise 1. Each test exercise 
shall be performed for one minute except for the grimace exercise 
which shall be performed for 15 seconds. The test subject shall be 
questioned by the test conductor regarding the comfort of the 
respirator upon completion of the protocol. If it has become 
uncomfortable, another model of respirator shall be tried.

B. Qualitative Fit Test (QLFT) Protocols

1. General

    (a) The employer shall assign specific individuals who shall 
assume full responsibility for implementing the respirator 
qualitative fit test program.
    (b) The employer shall assure that persons administering QLFTs 
are able to prepare test solutions, calibrate equipment and perform 
tests properly, recognize invalid tests, and assure that test 
equipment is in proper working order.
    (c) The employer shall assure that QLFT equipment is kept clean 
and well maintained so as to operate within the parameters for which 
it was designed.

2. Isoamyl Acetate Protocol

    (a) Odor threshold screening. The odor threshold screening test, 
performed without wearing a respirator, is intended to determine if 
the individual tested can detect the odor of isoamyl acetate.
    (1) Three 1-liter glass jars with metal lids are required.
    (2) Odor free water (e.g. distilled or spring water) at 
approximately 25 degrees C shall be used for the solutions.
    (3) The isoamyl acetate (IAA) (also known as isopentyl acetate) 
stock solution is prepared by adding 1 cc of pure IAA to 800 cc of 
odor free water in a 1 liter jar and shaking for 30 seconds. A new 
solution shall be prepared at least weekly.
    (4) The screening test shall be conducted in a room separate 
from the room used for actual fit testing. The two rooms shall be 
well ventilated and shall not be connected to the same recirculating 
ventilation system.
    (5) The odor test solution is prepared in a second jar by 
placing 0.4 cc of the stock solution into 500 cc of odor free water 
using a clean dropper or pipette. The solution shall be shaken for 
30 seconds and allowed to stand for two to three minutes so that the 
IAA concentration above the liquid may reach equilibrium. This 
solution shall be used for only one day.
    (6) A test blank shall be prepared in a third jar by adding 500 
cc of odor free water.
    (7) The odor test and test blank jars shall be labeled 1 and 2 
for jar identification. Labels shall be placed on the lids so they 
can be periodically peeled, dried off and switched to maintain the 
integrity of the test.
    (8) The following instruction shall be typed on a card and 
placed on the table in front of the two test jars (i.e., 1 and 2): 
``The purpose of this test is to determine if you can smell banana 
oil at a low concentration. The two bottles in front of you contain 
water. One of these bottles also contains a small amount of banana 
oil. Be sure the covers are on tight, then shake each bottle for two 
seconds. Unscrew the lid of each bottle, one at a time, and sniff at 
the mouth of the bottle. Indicate to the test conductor which bottle 
contains banana oil.''
    (9) The mixtures used in the IAA odor detection test shall be 
prepared in an area separate from where the test is performed, in 
order to prevent olfactory fatigue in the subject.
    (10) If the test subject is unable to correctly identify the jar 
containing the odor test solution, the IAA qualitative fit test 
shall not be performed.
    (11) If the test subject correctly identifies the jar containing 
the odor test solution, the test subject may proceed to respirator 
selection and fit testing.
    (b) Isoamyl acetate fit test--
    (1) The fit test chamber shall be similar to a clear 55-gallon 
drum liner suspended inverted over a 2-foot diameter frame so that 
the top of the chamber is about 6 inches above the test subject's 
head. The inside top center of the chamber shall have a small hook 
attached.
    (2) Each respirator used for the fitting and fit testing shall 
be equipped with organic vapor cartridges or offer protection 
against organic vapors. The cartridges or masks shall be changed at 
least weekly.
    (3) After selecting, donning, and properly adjusting a 
respirator, the test subject shall wear it to the fit testing room. 
This room shall be separate from the room used for odor threshold 
screening and respirator selection, and shall be well ventilated, as 
by an exhaust fan or lab hood, to prevent general room 
contamination.
    (4) A copy of the test exercises and any prepared text from 
which the subject is to read shall be taped to the inside of the 
test chamber.
    (5) Upon entering the test chamber, the test subject shall be 
given a 6-inch by 5-inch piece of paper towel, or other porous, 
absorbent, single-ply material, folded in half and wetted with 0.75 
cc of pure IAA. The test subject shall hang the wet towel on the 
hook at the top of the chamber.
    (6) Allow two minutes for the IAA test concentration to 
stabilize before starting the fit test exercises. This would be an 
appropriate time to talk with the test subject; to explain the fit 
test, the importance of his/her cooperation, and the purpose for the 
head exercises; and to demonstrate some of the exercises.
    (7) If at any time during the test, the subject detects the 
banana like odor of IAA, the respirator fit is inadequate. The 
subject shall quickly exit from the test chamber and leave the test 
area to avoid olfactory fatigue.
    (8) If the respirator fit was inadequate, the subject shall 
return to the selection room and remove the respirator, repeat the 
odor sensitivity test, select and put on another respirator, return 
to the test chamber and again begin the procedure described in 
paragraph (I)(B)(2)(b) (1) through (7) of this appendix. The process 
continues until a respirator that fits well has been found. Should 
the odor sensitivity test be failed, the subject shall wait about 5 
minutes before retesting. Odor sensitivity will usually have 
returned by this time.
    (9) When a respirator is found that passes the test, its 
efficiency shall be demonstrated for the subject by having the 
subject break the face seal and take a breath before exiting the 
chamber.
    (10) When the test subject leaves the chamber, the subject shall 
remove the saturated towel and return it to the person conducting 
the test. To keep the test area from becoming contaminated, the used 
towels shall be kept in a self sealing bag so there is no 
significant IAA concentration build-up in the test chamber during 
subsequent tests.

3. Irritant Fume Protocol

    (a) The respirator to be tested shall be equipped with high-
efficiency particulate air (HEPA) filters.
    (b) The test subject shall be allowed to smell a weak 
concentration of the irritant smoke before the respirator is donned 
to become familiar with its characteristic odor.
    (c) Break both ends of a ventilation smoke tube containing 
stannic oxychloride, such as the MSA part No. 5645, or equivalent. 
Attach one end of the smoke tube to a low flow air pump set to 
deliver 200 milliliters per minute.
    (d) Advise the test subject that the smoke can be irritating to 
the eyes and instruct the subject to keep his/her eyes closed while 
the test is performed.
    (e) The test conductor shall direct the stream of irritant smoke 
from the smoke tube towards the face seal area of the test subject. 
He/she shall begin at least 12 inches from the facepiece and 
gradually move to within one inch, moving around the whole perimeter 
of the mask.
    (f) The exercises identified in section I. A. 14 above shall be 
performed by the test subject while the respirator seal is being 
challenged by the smoke.
    (g) Each test subject passing the smoke test without evidence of 
a response shall be given a sensitivity check of the smoke from the 
same tube once the respirator has been removed to determine whether 
he/she reacts to the smoke. Failure to evoke a response shall void 
the fit test.
    (h) The fit test shall be performed in a location with exhaust 
ventilation sufficient to prevent general contamination of the 
testing area by the test agent.

4. Saccharin Solution Aerosol Protocol

    The entire screening and testing procedure shall be explained to 
the test subject prior to the conduct of the screening test.
    (a) Taste threshold screening. The saccharin taste threshold 
screening, performed without wearing a respirator, is intended to 
determine whether the individual being tested can detect the taste 
of saccharin.
    (1) Threshold screening as well as fit testing subjects shall 
wear an enclosure about the head and shoulders that is approximately 
12 inches in diameter by 14 inches tall with at least the front 
portion clear and that allows free movements of the head when a 
respirator is worn. An enclosure substantially similar to the 3M 
hood assembly, parts # FT 14 and # FT 15 combined, is adequate.
    (2) The test enclosure shall have a \3/4\ inch hole in front of 
the test subject's nose and mouth area to accommodate the nebulizer 
nozzle.
    (3) The test subject shall don the test enclosure. Throughout 
the threshold screening test, the test subject shall breathe through 
his/her wide open mouth with tongue extended.
    (4) Using a DeVilbiss Model 40 Inhalation Medication Nebulizer 
the test conductor shall spray the threshold check solution into the 
enclosure. This nebulizer shall be clearly marked to distinguish it 
from the fit test solution nebulizer.
    (5) The threshold check solution consists of 0.83 grams of 
sodium saccharin USP in 1 cc of warm water. It can be prepared by 
putting 1 cc of the fit test solution (see (b)(5) below) in 100 cc 
of distilled water.
    (6) To produce the aerosol, the nebulizer bulb is firmly 
squeezed so that it collapses completely, then released and allowed 
to fully expand.
    (7) Ten squeezes are repeated rapidly and then the test subject 
is asked whether the saccharin can be tasted.
    (8) If the first response is negative, ten more squeezes are 
repeated rapidly and the test subject is again asked whether the 
saccharin is tasted.
    (9) If the second response is negative, ten more squeezes are 
repeated rapidly and the test subject is again asked whether the 
saccharin is tasted.
    (10) The test conductor will take note of the number of squeezes 
required to solicit a taste response.
    (11) If the saccharin is not tasted after 30 squeezes (step 10), 
the test subject may not perform the saccharin fit test.
    (12) If a taste response is elicited, the test subject shall be 
asked to take note of the taste for reference in the fit test.
    (13) Correct use of the nebulizer means that approximately 1 cc 
of liquid is used at a time in the nebulizer body.
    (14) The nebulizer shall be thoroughly rinsed in water, shaken 
dry, and refilled at least each morning and afternoon or at least 
every four hours.
    (b) Saccharin solution aerosol fit test procedure
    (1) The test subject may not eat, drink (except plain water), or 
chew gum for 15 minutes before the test.
    (2) The fit test uses the same enclosure described in (a) above.
    (3) The test subject shall don the enclosure while wearing the 
respirator selected in section (a) above. The respirator shall be 
properly adjusted and equipped with a particulate filter(s).
    (4) A second DeVilbiss Model 40 Inhalation Medication Nebulizer 
is used to spray the fit test solution into the enclosure. This 
nebulizer shall be clearly marked to distinguish it from the 
screening test solution nebulizer.
    (5) The fit test solution is prepared by adding 83 grams of 
sodium saccharin to 100 cc of warm water.
    (6) As before, the test subject shall breathe through the open 
mouth with tongue extended.
    (7) The nebulizer is inserted into the hole in the front of the 
enclosure and the fit test solution is sprayed into the enclosure 
using the same number of squeezes required to elicit a taste 
response in the screening test.
    (8) After generating the aerosol the test subject shall be 
instructed to perform the exercises in section I.A. 14 above.
    (9) Every 30 seconds the aerosol concentration shall be 
replenished using one half the number of squeezes as initially.
    (10) The test subject shall indicate to the test conductor if at 
any time during the fit test the taste of saccharin is detected.
    (11) If the taste of saccharin is detected, the fit is deemed 
unsatisfactory and a different respirator shall be tried''.

C. Quantitative Fit Test (QNFT) Protocol

1. General

    (a) The employer shall assign specific individuals who shall 
assume full responsibility for implementing the respirator 
quantitative fit test program.
    (b) The employer shall ensure that persons administering QNFT 
are able to calibrate equipment and perform tests properly, 
recognize invalid tests, calculate fit factors properly and assure 
that test equipment is in proper working order.
    (c) The employer shall assure that QNFT equipment is kept clean 
and well maintained so as to operate at the parameters for which it 
was designed.

2. Definitions

    (a) Quantitative fit test. The test is performed in a test 
chamber. The normal air-purifying element of the respirator is 
replaced by a high-efficiency particulate air (HEPA) filter in the 
case of particulate QNFT aerosols or a sorbent offering contaminant 
penetration protection equivalent to high-efficiency filters where 
the QNFT test agent is a gas or vapor.
    (b) Challenge agent means the aerosol, gas or vapor introduced 
into a test chamber so that its concentration inside and outside the 
respirator may be measured.
    (c) Test subject means the person wearing the respirator for 
quantitative fit testing.
    (d) Normal standing position means standing erect and straight 
with arms down along the sides and looking straight ahead.
    (e) Maximum peak penetration method means the method of 
determining test agent penetration in the respirator as determined 
by strip chart recordings of the test. The highest peak penetration 
for a given exercise is taken to be representative of average 
penetration into the respirator for that exercise.
    (f) Average peak penetration method means the method of 
determining test agent penetration into the respirator utilizing a 
strip chart recorder, integrator, or computer. The agent penetration 
is determined by an average of the peak heights on the graph or by 
computer integration, for each exercise except the grimace exercise. 
Integrators or computers which calculate the actual test agent 
penetration into the respirator for each exercise will also be 
considered to meet the requirements of the average peak penetration 
method.
    (g) ``Fit Factor'' means the ration of challenge agent 
concentration outside with respect to the inside of a respirator 
inlet covering (facepiece or enclosure).

3. Apparatus

    (a) Instrumentation. Aerosol generation, dilution, and 
measurement systems using corn oil or sodium chloride as test 
aerosols shall be used for quantitative fit testing.
    (b) Test chamber. The test chamber shall be large enough to 
permit all test subjects to perform freely all required exercises 
without disturbing the challenge agent concentration or the 
measurement apparatus. The test chamber shall be equipped and 
constructed so that the challenge agent is effectively isolated from 
the ambient air, yet uniform in concentration throughout the 
chamber.
    (c) When testing air-purifying respirators, the normal filter or 
cartridge element shall be replaced with a high-efficiency 
particulate filter supplied by the same manufacturer.
    (d) The sampling instrument shall be selected so that a strip 
chart record may be made of the test showing the rise and fall of 
the challenge agent concentration with each inspiration and 
expiration at fit factors of at least 2,000. Integrators or 
computers which integrate the amount of test agent penetration 
leakage into the respirator for each exercise may be used provided a 
record of the readings is made.
    (e) The combination of substitute air-purifying elements, 
challenge agent and challenge agent concentration in the test 
chamber shall be such that the test subject is not exposed in excess 
of an established exposure limit for the challenge agent at any time 
during the testing process.
    (f) The sampling port on the test specimen respirator shall be 
placed and constructed so that no leakage occurs around the port 
(e.g. where the respirator is probed), a free air flow is allowed 
into the sampling line at all times and so that there is no 
interference with the fit or performance of the respirator.
    (g) The test chamber and test set up shall permit the person 
administering the test to observe the test subject inside the 
chamber during the test.
    (h) The equipment generating the challenge atmosphere shall 
maintain the concentration of challenge agent inside the test 
chamber constant to within a 10-percent variation for the duration 
of the test.
    (i) The time lag (interval between an event and the recording of 
the event on the strip chart or computer or integrator) shall be 
kept to a minimum. There shall be a clear association between the 
occurrence of an event inside the test chamber and its being 
recorded.
    (j) The sampling line tubing for the test chamber atmosphere and 
for the respirator sampling port shall be of equal diameter and of 
the same material. The length of the two lines shall be equal.
    (k) The exhaust flow from the test chamber shall pass through a 
high-efficiency filter before release.
    (l) When sodium chloride aerosol is used, the relative humidity 
inside the test chamber shall not exceed 50 percent.
    (m) The limitations of instrument detection shall be taken into 
account when determining the fit factor.
    (n) Test respirators shall be maintained in proper working order 
and inspected for deficiencies such as cracks, missing valves and 
gaskets, etc.

4. Procedural Requirements

    (a) When performing the initial positive or negative pressure 
test the sampling line shall be crimped closed in order to avoid air 
pressure leakage during either of these tests.
    (b) An abbreviated screening isoamyl acetate test or irritant 
fume test may be utilized in order to quickly identify poor fitting 
respirators which passed the positive and/or negative pressure test 
and thus reduce the amount of QNFT time. When performing a screening 
isoamyl acetate test, combination high-efficiency organic vapor 
cartridges/canisters shall be used.
    (c) A reasonably stable challenge agent concentration shall be 
measured in the test chamber prior to testing. For canopy or shower 
curtain type of test units the determination of the challenge agent 
stability may be established after the test subject has entered the 
test environment.
    (d) Immediately after the subject enters the test chamber, the 
challenge agent concentration inside the respirator shall be 
measured to ensure that the peak penetration does not exceed 5 
percent for a half mask or 1 percent for a full facepiece 
respirator.
    (e) A stable challenge concentration shall be obtained prior to 
the actual start of testing.
    (f) Respirator restraining straps shall not be overtightened for 
testing. The straps shall be adjusted by the wearer without 
assistance from other persons to give a reasonable comfortable fit 
typical of normal use.
    (g) The test shall be terminated whenever any single peak 
penetration exceeds 5 percent for half masks and 1 percent for full 
facepiece respirators. The test subject shall be refitted and 
retested. If two of the three required tests are terminated, the fit 
shall be deemed inadequate.
    (h) In order to successfully complete a QNFT, three successful 
fit tests are required. The results of each of the three independent 
fit tests must exceed the minimum fit factor needed for the class of 
respirator (e.g. half mask respirator, full facepiece respirator).
    (i) Calculation of fit factors.
    (1) The fit factor shall be determined for the quantitative fit 
test by taking the ratio of the average chamber concentration to the 
concentration inside the respirator.
    (2) The average test chamber concentration is the arithmetic 
average of the test chamber concentration at the beginning and at 
the end of the test.
    (3) The concentration of the challenge agent inside the 
respirator shall be determined by one of the following methods:
    (i) Average peak concentration;
    (ii) Maximum peak concentration;
    (iii) Integration by calculation of the area under the 
individual peak for each exercise. This includes computerized 
integration.
    (j) Interpretation of test results. The fit factor established 
by the quantitative fit testing shall be the lowest of the three fit 
factor values calculated from the three required fit tests.
    (k) The test subject shall not be permitted to wear a half mask, 
or full facepiece respirator unless a minimum fit factor equivalent 
to at least 10 times the hazardous exposure level is obtained.
    (l) Filters used for quantitative fit testing shall be replaced 
at least weekly, or whenever increased breathing resistance is 
encountered, or when the test agent has altered the integrity of the 
filter media. Organic vapor cartridges/canisters shall be replaced 
daily (when used) or sooner if there is any indication of 
breakthrough by a test agent.

Appendix D to Sec. 1915.1027--Occupational Health History Interview 
With Reference to Cadmium Exposure

Directions

(To be read by employee and signed prior to the interview)

    Please answer the questions you will be asked as completely and 
carefully as you can. These questions are asked of everyone who works 
with cadmium. You will also be asked to give blood and urine samples. 
The doctor will give your employer a written opinion on whether you are 
physically capable of working with cadmium. Legally, the doctor cannot 
share personal information you may tell him/her with your employer. The 
following information is considered strictly confidential. The results 
of the tests will go to you, your doctor and your employer. You will 
also receive an information sheet explaining the results of any 
biological monitoring or physical examinations performed.
    If you are just being hired, the results of this interview and 
examination will be used to:
    (1) Establish your health status and see if working with cadmium 
might be expected to cause unusual problems,
    (2) Determine your health status today and see if there are changes 
over time,
    (3) See if you can wear a respirator safely.
    If you are not a new hire:
    OSHA says that everyone who works with cadmium can have periodic 
medical examinations performed by a doctor. The reasons for this are:
    (a) If there are changes in your health, either because of cadmium 
or some other reason, to find them early,
    (b) to prevent kidney damage.

Please sign below.

    I have read these directions and understand them:

----------------------------------------------------------------------
Employee signature

----------------------------------------------------------------------
Date

    Thank you for answering these questions. (Suggested Format)
Name-------------------------------------------------------------------
Age--------------------------------------------------------------------
Social Security #------------------------------------------------------
Company----------------------------------------------------------------
Job--------------------------------------------------------------------
    Type of Preplacement Exam:
    [  ] Periodic
    [  ] Termination
    [  ] Initial
    [  ] Other
Blood Pressure---------------------------------------------------------
Pulse Rate-------------------------------------------------------------
1. How long have you worked at the job listed above?
    [  ] Not yet hired
    [  ] Number of months
    [  ] Number of years
2. Job Duties etc.

----------------------------------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
3. Have you ever been told by a doctor that you had bronchitis?
    [  ] Yes
    [  ] No
    If yes, how long ago?
    [  ] Number of months
    [  ] Number of years
4. Have you ever been told by a doctor that you had emphysema?
    [  ] Yes
    [  ] No
    If yes, how long ago?
    [  ] Number of years
    [  ] Number of months
5. Have you ever been told by a doctor that you had other lung 
problems?
    [  ] Yes
    [  ] No
    If yes, please describe type of lung problems and when you had 
these problems
----------------------------------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
6. In the past year, have you had a cough?
    [  ] Yes
    [  ] No
    If yes, did you cough up sputum?
    [  ] Yes
    [  ] No
    If yes, how long did the cough with sputum production last?
    [  ] Less than 3 months
    [   ] 3 months or longer
    If yes, for how many years have you had episodes of cough with 
sputum production lasting this long?
    [  ] Less than one
    [  ] 1
    [  ] 2
    [  ] Longer than 2
7. Have you ever smoked cigarettes?
    [  ] Yes
    [  ] No
8. Do you now smoke cigarettes?
    [  ] Yes
    [  ] No
9. If you smoke or have smoked cigarettes, for how many years have 
you smoked, or did you smoke?
    [  ] Less than 1 year
    [  ] Number of years
    What is or was the greatest number of packs per day that you 
have smoked?
    [  ] Number of packs
    If you quit smoking cigarettes, how many years ago did you quit?
    [  ] Less than 1 year
    [  ] Number of years
    How many packs a day do you now smoke?
    [  ] Number of packs per day
10. Have you ever been told by a doctor that you had a kidney or 
urinary tract disease or disorder?
    [  ] Yes
    [  ] No
11. Have you ever had any of these disorders? 

                                                                        
                                                                        
                                                                        
Kidney stones...................................  [] Yes      [] No     
Protein in urine................................  [] Yes      [] No     
Blood in urine..................................  [] Yes      [] No     
Difficulty urinating............................  [] Yes      [] No     
Other kidney/Urinary disorders..................  [] Yes      [] No     
                                                                        

    Please describe problems, age, treatment, and follow up for any 
kidney or urinary problems you have had:
----------------------------------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
12. Have you ever been told by a doctor or other health care 
provider who took your blood pressure that your blood pressure was 
high?
    [  ] Yes
    [  ] No
13. Have you ever been advised to take any blood pressure 
medication?
    [  ] Yes
    [  ] No
14. Are you presently taking any blood pressure medication?
    [  ] Yes
    [  ] No
15. Are you presently taking any other medication?
    [  ] Yes
    [  ] No
16. Please list any blood pressure or other medications and describe 
how long you have been taking each one:

Medicine:
----------------------------------------------------------------------
----------------------------------------------------------------------
-----------------------------------------------------------------------

How Long Taken
----------------------------------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
17. Have you ever been told by a doctor that you have diabetes? 
(sugar in your blood or urine)
    [  ] Yes
    [  ] No
    If yes, do you presently see a doctor about your diabetes?
    [  ] Yes
    [  ] No
    If yes, how do you control your blood sugar?
    [  ] Diet alone
    [  ] Diet plus oral medicine
    [  ] Diet plus insulin (injection)
18. Have you ever been told by a doctor that you had: 

                                                                        
                                                                        
                                                                        
Anemia..........................................  [] Yes      [] No     
A low blood count?..............................  [] Yes      [] No     
                                                                        

19. Do you presently feel that you tire or run out of energy sooner 
than normal or sooner than other people your age?
    [  ] Yes
    [  ] No
    If yes, for how long have you felt that you tire easily?
    [  ] Less than 1 year
    [  ] Number of years
20. Have you given blood within the last year?
    [  ] Yes
    [  ] No
    If yes, how many times?
    [  ] Number of times
    How long ago was the last time you gave blood?
    [  ] Less than 1 month
    [  ] Number of months
21. Within the last year have you had any injuries with heavy 
bleeding?
    [  ] Yes
    [  ] No
    If yes, how long ago?
    [  ] Less than 1 month
    [  ] Number of months
Describe:--------------------------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
22. Have you recently had any surgery?
    [  ] Yes
    [  ] No
If yes, please describe:-----------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
23. Have you seen any blood lately in your stool or after a bowel 
movement?
    [  ] Yes
    [  ] No
24. Have you ever had a test for blood in your stool?
    [  ] Yes
    [  ] No
    If yes, did the test show any blood in the stool?
    [  ] Yes
    [  ] No
What further evaluation and treatment were done?-----------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
    The following questions pertain to the ability to wear a 
respirator. Additional information for the physician can be found in 
The Respiratory Protective Devices Manual.
25. Have you ever been told by a doctor that you have asthma?
    [  ] Yes
    [  ] No
    If yes, are you presently taking any medication for asthma? Mark 
all that apply.
    [  ] Shots
    [  ] Pills
    [  ] Inhaler
26. Have you ever had a heart attack?
    [  ] Yes
    [  ] No
    If yes, how long ago?
    [  ] Number of years
    [  ] Number of months
27. Have you ever had pains in your chest?
    [  ] Yes
    [  ] No
    If yes, when did it usually happen?
    [  ] While resting
    [  ] While working
    [  ] While exercising
    [  ] Activity didn't matter
28. Have you ever had a thyroid problem?
    [  ] Yes
    [  ] No
29. Have you ever had a seizure or fits?
    [  ] Yes
    [  ] No
30. Have you ever had a stroke (cerebrovascular accident)?
    [  ] Yes
    [  ] No
31. Have you ever had a ruptured eardrum or a serious hearing 
problem?
    [  ] Yes
    [  ] No
32. Do you now have a claustrophobia, meaning fear of crowded or 
closed in spaces or any psychological problems that would make it 
hard for you to wear a respirator?
    [  ] Yes
    [  ] No
    The following questions pertain to reproductive history.
33. Have you or your partner had a problem conceiving a child?
    [  ] Yes
    [  ] No
    If yes, specify:
    [  ] Self
    [  ] Present mate
    [  ] Previous mate
34. Have you or your partner consulted a physician for a fertility 
or other reproductive problem?
    [  ] Yes
    [  ] No
    If yes, specify who consulted the physician:
    [  ] Self
    [  ] Spouse/partner
    [  ] Self and partner
If yes, specify diagnosis made:----------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
35. Have you or your partner ever conceived a child resulting in a 
miscarriage, still birth or deformed offspring?
    [  ] Yes
    [  ] No
    If yes, specify:
    [  ] Miscarriage
    [  ] Still birth
    [  ] Deformed offspring
If outcome was a deformed offspring, please specify type:--------------
----------------------------------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
36. Was this outcome a result of a pregnancy of:
    [  ] Yours with present partner
    [  ] Yours with a previous partner
37. Did the timing of any abnormal pregnancy outcome coincide with 
present employment?
    [  ] Yes
    [  ] No
List dates of occurrences:---------------------------------------------
----------------------------------------------------------------------
38. What is the occupation of your spouse or partner?
----------------------------------------------------------------------
----------------------------------------------------------------------

For Women Only

39. Do you have menstrual periods?
    [  ] Yes
    [  ] No
    Have you had menstrual irregularities?
    [  ] Yes
    [  ] No
If yes, specify type:--------------------------------------------------
----------------------------------------------------------------------
----------------------------------------------------------------------
If yes, what was the approximate date this problem began?--------------
----------------------------------------------------------------------
Approximate date problem stopped?--------------------------------------
----------------------------------------------------------------------

For Men Only

40. Have you ever been diagnosed by a physician as having prostate 
gland problem(s)?
    [  ] Yes
    [  ] No
If yes, please describe type of problem(s) and what was done to 
evaluate and treat the problem(s):-------------------------------------
----------------------------------------------------------------------

Appendix E to Sec. 1915.1027--Cadmium in Workplace Atmospheres

Method Number: ID-189
Matrix: Air
OSHA Permissible Exposure Limits: 5 g/m\3\ (TWA), 2.5 
g/m\3\ (Action Level TWA)
Collection Procedure: A known volume of air is drawn through a 37-mm 
diameter filter cassette containing a 0.8-m mixed cellulose 
ester membrane filter (MCEF).
Recommended Air Volume: 960 L
Recommended Sampling Rate: 2.0 L/min
Analytical Procedure: Air filter samples are digested with nitric 
acid. After digestion, a small amount of hydrochloric acid is added. 
The samples are then diluted to volume with deionized water and 
analyzed by either flame atomic absorption spectroscopy (AAS) or 
flameless atomic absorption spectroscopy using a heated graphite 
furnace atomizer (AAS-HGA).
Detection Limits:
Qualitative: 0.2 g/m\3\ for a 200 L sample by Flame AAS, 
0.007 g/m\3\ for a 60 L sample by AAS-HGA
Quantitative: 0.70 g/m\3\ for a 200 L sample by Flame AAS, 
0.025 g/m\3\ for a 60 L sample by AAS-HGA
Precision and Accuracy: (Flame AAS Analysis and AAS-HGA Analysis):
    Validation Level: 2.5 to 10 g/m\3\ for a 400 L air vol, 
1.25 to 5.0 g/m\3\ for a 60 L air vol
    CV1 (pooled): 0.010, 0.043
Analytical Bias: +4.0%, -5.8%
Overall Analytical Error: 6.0%, 14.2%
Method Classification: Validated
Date: June, 1992

    Inorganic Service Branch II, OSHA Salt Lake Technical Center, 
Salt Lake City, Utah
    Commercial manufacturers and products mentioned in this method 
are for descriptive use only and do not constitute endorsements by 
USDOL-OSHA. Similar products from other sources can be substituted.

1. Introduction

1.1. Scope

    This method describes the collection of airborne elemental 
cadmium and cadmium compounds on 0.8-m mixed cellulose 
ester membrane filters and their subsequent analysis by either flame 
atomic absorption spectroscopy (AAS) or flameless atomic absorption 
spectroscopy using a heated graphite furnace atomizer (AAS-HGA). It 
is applicable for both TWA and Action Level TWA Permissible Exposure 
Level (PEL) measurements. The two atomic absorption analytical 
techniques included in the method do not differentiate between 
cadmium fume and cadmium dust samples. They also do not 
differentiate between elemental cadmium and its compounds.

1.2. Principle

    Airborne elemental cadmium and cadmium compounds are collected 
on a 0.8-m mixed cellulose ester membrane filter (MCEF). 
The air filter samples are digested with concentrated nitric acid to 
destroy the organic matrix and dissolve the cadmium analytes. After 
digestion, a small amount of concentrated hydrochloric acid is added 
to help dissolve other metals which may be present. The samples are 
diluted to volume with deionized water and then aspirated into the 
oxidizing air/acetylene flame of an atomic absorption 
spectrophotometer for analysis of elemental cadmium.
    If the concentration of cadmium in a sample solution is too low 
for quantitation by this flame AAS analytical technique, and the 
sample is to be averaged with other samples for TWA calculations, 
aliquots of the sample and a matrix modifier are later injected onto 
a L'vov platform in a pyrolytically-coated graphite tube of a Zeeman 
atomic absorption spectrophotometer/graphite furnace assembly for 
analysis of elemental cadmium. The matrix modifier is added to 
stabilize the cadmium metal and minimize sodium chloride as an 
interference during the high temperature charring step of the 
analysis (5.1., 5.2.).

1.3. History

    Previously, two OSHA sampling and analytical methods for cadmium 
were used concurrently (5.3., 5.4.). Both of these methods also 
required 0.8-m mixed cellulose ester membrane filters for 
the collection of air samples. These cadmium air filter samples were 
analyzed by either flame atomic absorption spectroscopy (5.3.) or 
inductively coupled plasma/atomic emission spectroscopy (ICP-AES) 
(5.4.). Neither of these two analytical methods have adequate 
sensitivity for measuring workplace exposure to airborne cadmium at 
the new lower TWA and Action Level TWA PEL levels when consecutive 
samples are taken on one employee and the sample results need to be 
averaged with other samples to determine a single TWA.
    The inclusion of two atomic absorption analytical techniques in 
the new sampling and analysis method for airborne cadmium permits 
quantitation of sample results over a broad range of exposure levels 
and sampling periods. The flame AAS analytical technique included in 
this method is similar to the previous procedure given in the 
General Metals Method ID-121 (5.3.) with some modifications. The 
sensitivity of the AAS-HGA analytical technique included in this 
method is adequate to measure exposure levels at 1/10 the Action 
Level TWA, or lower, when less than full-shift samples need to be 
averaged together.

1.4. Properties (5.5.)

    Elemental cadmium is a silver-white, blue-tinged, lustrous metal 
which is easily cut with a knife. It is slowly oxidized by moist air 
to form cadmium oxide. It is insoluble in water, but reacts readily 
with dilute nitric acid. Some of the physical properties and other 
descriptive information of elemental cadmium are given below:

CAS No.
7440-43-9
Atomic Number
48
Atomic Symbol
Cd
Atomic Weight
112.41
Melting Point
321  deg.C
Boiling Point
765  deg.C
Density
8.65 g/mL (25  deg.C)

    The properties of specific cadmium compounds are described in 
reference 5.5.

1.5. Method Performance

    A synopsis of method performance is presented below. Further 
information can be found in Section 4.
    1.5.1. The qualitative and quantitative detection limits for the 
flame AAS analytical technique are 0.04 g (0.004 
g/mL) and 0.14 g (0.014 g/mL) cadmium, 
respectively, for a 10 mL solution volume. These correspond, 
respectively, to 0.2 g/m\3\ and 0.70 g/m\3\ for a 
200 L air volume.
    1.5.2. The qualitative and quantitative detection limits for the 
AAS-HGA analytical technique are 0.44 ng (0.044 ng/mL) and 1.5 ng 
(0.15 ng/mL) cadmium, respectively, for a 10 mL solution volume. 
These correspond, respectively, to 0.007 g/m\3\ and 0.025 
g/m\3\ for a 60 L air volume.
    1.5.3. The average recovery by the flame AAS analytical 
technique of 17 spiked MCEF samples containing cadmium in the range 
of 0.5 to 2.0 times the TWA target concentration of 5 g/
m\3\ (assuming a 400 L air volume) was 104.0% with a pooled 
coefficient of variation (CV1) of 0.010. The flame analytical 
technique exhibited a positive bias of +4.0% for the validated 
concentration range. The overall analytical error (OAE) for the 
flame AAS analytical technique was 6.0%.
    1.5.4. The average recovery by the AAS-HGA analytical technique 
of 18 spiked MCEF samples containing cadmium in the range of 0.5 to 
2.0 times the Action Level TWA target concentration of 2.5 
g/m\3\ (assuming a 60 L air volume) was 94.2% with a pooled 
coefficient of variation (CV1) of 0.043. The AAS-HGA analytical 
technique exhibited a negative bias of -5.8% for the validated 
concentration range. The overall analytical error (OAE) for the AAS-
HGA analytical technique was 14.2%.
    1.5.5. Sensitivity in flame atomic absorption is defined as the 
characteristic concentration of an element required to produce a 
signal of 1% absorbance (0.0044 absorbance units). Sensitivity 
values are listed for each element by the atomic absorption 
spectrophotometer manufacturer and have proved to be a very valuable 
diagnostic tool to determine if instrumental parameters are 
optimized and if the instrument is performing up to specification. 
The sensitivity of the spectrophotometer used in the validation of 
the flame AAS analytical technique agreed with the manufacturer 
specifications (5.6.); the 2 g/mL cadmium standard gave an 
absorbance reading of 0.350 abs. units.
    1.5.6. Sensitivity in graphite furnace atomic absorption is 
defined in terms of the characteristic mass, the number of picograms 
required to give an integrated absorbance value of 0.0044 
absorbance-second (5.7.). Data suggests that under Stabilized 
Temperature Platform Furnace (STPF) conditions (see Section 1.6.2.), 
characteristic mass values are transferable between properly 
functioning instruments to an accuracy of about 20% (5.2.). The 
characteristic mass for STPF analysis of cadmium with Zeeman 
background correction listed by the manufacturer of the instrument 
used in the validation of the AAS-HGA analytical technique was 0.35 
pg. The experimental characteristic mass value observed during the 
determination of the working range and detection limits of the AAS-
HGA analytical technique was 0.41 pg.

1.6. Interferences

    1.6.1. High concentrations of silicate interfere in determining 
cadmium by flame AAS (5.6.). However, silicates are not 
significantly soluble in the acid matrix used to prepare the 
samples.
    1.6.2. Interferences, such as background absorption, are reduced 
to a minimum in the AAS-HGA analytical technique by taking full 
advantage of the Stabilized Temperature Platform Furnace (STPF) 
concept. STPF includes all of the following parameters (5.2.):

a. Integrated Absorbance,
b. Fast Instrument Electronics and Sampling Frequency,
c. Background Correction,
d. Maximum Power Heating,
e. Atomization off the L'vov platform in a pyrolytically coated 
graphite tube,
f. Gas Stop during Atomization,
g. Use of Matrix Modifiers.

1.7. Toxicology (5.14.)

    Information listed within this section is synopsis of current 
knowledge of the physiological effects of cadmium and is not 
intended to be used as the basis for OSHA policy. IARC classifies 
cadmium and certain of its compounds as Group 2A carcinogens 
(probably carcinogenic to humans). Cadmium fume is intensely 
irritating to the respiratory tract. Workplace exposure to cadmium 
can cause both chronic and acute effects. Acute effects include 
tracheobronchitis, pneumonitis, and pulmonary edema. Chronic effects 
include anemia, rhinitis/anosmia, pulmonary emphysema, proteinuria 
and lung cancer. The primary target organs for chronic disease are 
the kidneys (non-carcinogenic) and the lungs (carcinogenic).

2. Sampling

2.1. Apparatus

    2.1.1. Filter cassette unit for air sampling: A 37-mm diameter 
mixed cellulose ester membrane filter with a pore size of 0.8-
m contained in a 37-mm polystyrene two- or three-piece 
cassette filter holder (part no. MAWP 037 A0, Millipore Corp., 
Bedford, MA). The filter is supported with a cellulose backup pad. 
The cassette is sealed prior to use with a shrinkable gel band.
    2.1.2. A calibrated personal sampling pump whose flow is 
determined to an accuracy of 5% at the recommended flow 
rate with the filter cassette unit in line.

2.2. Procedure

    2.2.1. Attach the prepared cassette to the calibrated sampling 
pump (the backup pad should face the pump) using flexible tubing. 
Place the sampling device on the employee such that air is sampled 
from the breathing zone.
    2.2.2. Collect air samples at a flow rate of 2.0 L/min. If the 
filter does not become overloaded, a full-shift (at least seven 
hours) sample is strongly recommended for TWA and Action Level TWA 
measurements with a maximum air volume of 960 L. If overloading 
occurs, collect consecutive air samples for shorter sampling periods 
to cover the full workshift.
    2.2.3. Replace the end plugs into the filter cassettes 
immediately after sampling. Record the sampling conditions.
    2.2.4. Securely wrap each sample filter cassette end-to-end with 
an OSHA Form 21 sample seal.
    2.2.5. Submit at least one blank sample with each set of air 
samples. The blank sample should be handled the same as the other 
samples except that no air is drawn through it.
    2.2.6. Ship the samples to the laboratory for analysis as soon 
as possible in a suitable container designed to prevent damage in 
transit.

3. Analysis

3.1. Safety Precautions

    3.1.1. Wear safety glasses, protective clothing and gloves at 
all times.
    3.1.2. Handle acid solutions with care. Handle all cadmium 
samples and solutions with extra care (see Sect. 1.7.). Avoid their 
direct contact with work area surfaces, eyes, skin and clothes. 
Flush acid solutions which contact the skin or eyes with copious 
amounts of water.
    3.1.3. Perform all acid digestions and acid dilutions in an 
exhaust hood while wearing a face shield. To avoid exposure to acid 
vapors, do not remove beakers containing concentrated acid solutions 
from the exhaust hood until they have returned to room temperature 
and have been diluted or emptied.
    3.1.4. Exercise care when using laboratory glassware. Do not use 
chipped pipets, volumetric flasks, beakers or any glassware with 
sharp edges exposed in order to avoid the possibility of cuts or 
abrasions.
    3.1.5. Never pipet by mouth.
    3.1.6. Refer to the instrument instruction manuals and SOPs 
(5.8., 5.9.) for proper and safe operation of the atomic absorption 
spectrophotometer, graphite furnace atomizer and associated 
equipment.
    3.1.7. Because metallic elements and other toxic substances are 
vaporized during AAS flame or graphite furnace atomizer operation, 
it is imperative that an exhaust vent be used. Always ensure that 
the exhaust system is operating properly during instrument use.

3.2. Apparatus for Sample and Standard Preparation

    3.2.1. Hot plate, capable of reaching 150  deg.C, installed in 
an exhaust hood.
    3.2.2. Phillips beakers, 125 mL.
    3.2.3. Bottles, narrow-mouth, polyethylene or glass with 
leakproof caps: used for storage of standards and matrix modifier.
    3.2.4. Volumetric flasks, volumetric pipets, beakers and other 
associated general laboratory glassware.
    3.2.5. Forceps and other associated general laboratory 
equipment.

3.3. Apparatus for Flame AAS Analysis

    3.3.1. Atomic absorption spectrophotometer consisting of a(an):

Nebulizer and burner head
Pressure regulating devices capable of maintaining constant oxidant 
and fuel pressures
Optical system capable of isolating the desired wavelength of 
radiation (228.8 nm)
Adjustable slit
Light measuring and amplifying device
Display, strip chart, or computer interface for indicating the 
amount of absorbed radiation
Cadmium hollow cathode lamp or electrodeless discharge lamp (EDL) 
and power supply

    3.3.2. Oxidant: compressed air, filtered to remove water, oil 
and other foreign substances.
    3.3.3. Fuel: standard commercially available tanks of acetylene 
dissolved in acetone; tanks should be equipped with flash arresters.

    Caution: Do not use grades of acetylene containing solvents 
other than acetone because they may damage the PVC tubing used in 
some instruments.

    3.3.4. Pressure-reducing valves: two gauge, two-stage pressure 
regulators to maintain fuel and oxidant pressures somewhat higher 
than the controlled operating pressures of the instrument.
    3.3.5. Exhaust vent installed directly above the 
spectrophotometer burner head.

3.4. Apparatus for AAS-HGA Analysis

    3.4.1. Atomic absorption spectrophotometer consisting of a(an):

Heated graphite furnace atomizer (HGA) with argon purge system
Pressure-regulating devices capable of maintaining constant argon 
purge pressure
Optical system capable of isolating the desired wavelength of 
radiation (228.8 nm)
Adjustable slit
Light measuring and amplifying device
Display, strip chart, or computer interface for indicating the 
amount of absorbed radiation (as integrated absorbance, peak area)
Background corrector: Zeeman or deuterium arc. The Zeeman background 
corrector is recommended
Cadmium hollow cathode lamp or electrodeless discharge lamp (EDL) 
and power supply
Autosampler capable of accurately injecting 5 to 20 L 
sample aliquots onto the L'vov Platform in a graphite tube

    3.4.2. Pyrolytically coated graphite tubes containing solid, 
pyrolytic L'vov platforms.
    3.4.3. Polyethylene sample cups, 2.0 to 2.5 mL, for use with the 
autosampler.
    3.4.4. Inert purge gas for graphite furnace atomizer: compressed 
gas cylinder of purified argon.
    3.4.5. Two gauge, two-stage pressure regulator for the argon gas 
cylinder.
    3.4.6. Cooling water supply for graphite furnace atomizer.
    3.4.7. Exhaust vent installed directly above the graphite 
furnace atomizer.

3.5. Reagents

    All reagents should be ACS analytical reagent grade or better.
    3.5.1. Deionized water with a specific conductance of less than 
10 S.
    3.5.2. Concentrated nitric acid, HNO3.
    3.5.3. Concentrated hydrochloric acid, HCl.
    3.5.4. Ammonium phosphate, monobasic, NH4H2PO4.
    3.5.5. Magnesium nitrate, Mg(NO3)2  6H2O.
    3.5.6. Diluting solution (4% HNO3, 0.4% HCl): Add 40 mL 
HNO3 and 4 mL HCl carefully to approximately 500 mL deionized 
water and dilute to 1 L with deionized water.
    3.5.7. Cadmium standard stock solution, 1,000 g/mL: Use 
a commercially available certified 1,000 g/mL cadmium 
standard or, alternatively, dissolve 1.0000 g of cadmium metal in a 
minimum volume of 1:1 HCl and dilute to 1 L with 4% HNO3. 
Observe expiration dates of commercial standards. Properly dispose 
of commercial standards with no expiration dates or prepared 
standards one year after their receipt or preparation date.
    3.5.8. Matrix modifier for AAS-HGA analysis: Dissolve 1.0 g 
NH4H2PO4 and 0.15 g Mg(NO3)2 
6H2O in approximately 200 mL deionized water. Add 1 mL 
HNO3 and dilute to 500 mL with deionized water.
    3.5.9  Nitric Acid, 1:1 HNO3/DI H2O mixture: Carefully 
add a measured volume of concentrated HNO3 to an equal volume 
of DI H2O.
    3.5.10. Nitric acid, 10% v/v: Carefully add 100 mL of 
concentrated HNO3 to 500 mL of DI H2O and dilute to 1 L.

3.6. Glassware Preparation

    3.6.1. Clean Phillips beakers by refluxing with 1:1 nitric acid 
on a hot plate in a fume hood. Thoroughly rinse with deionized water 
and invert the beakers to allow them to drain dry.
    3.6.2. Rinse volumetric flasks and all other glassware with 10% 
nitric acid and deionized water prior to use.

3.7. Standard Preparation for Flame AAS Analysis

    3.7.1. Dilute stock solutions: Prepare 1, 5, 10 and 100 
g/mL cadmium standard stock solutions by making appropriate 
serial dilutions of 1,000 g/mL cadmium standard stock 
solution with the diluting solution described in Section 3.5.6.
    3.7.2. Working standards: Prepare cadmium working standards in 
the range of 0.02 to 2.0 g/mL by making appropriate serial 
dilutions of the dilute stock solutions with the same diluting 
solution. A suggested method of preparation of the working standards 
is given below.

------------------------------------------------------------------------
                                           Standard                     
                                           solution     Aliquot   Final 
    Working standard (g/mL)     (g/    (mL)      vol. 
                                              mL)                  (mL) 
------------------------------------------------------------------------
0.02...................................            1         10      500
0.05...................................            5          5      500
0.1....................................           10          5      500
0.2....................................           10         10      500
0.5....................................           10         25      500
1......................................          100          5      500
2......................................          100         10     500 
------------------------------------------------------------------------

    Store the working standards in 500-mL, narrow-mouth polyethylene 
or glass bottles with leak proof caps. Prepare every twelve months.

3.8. Standard Preparation for AAS-HGA Analysis

    3.8.1. Dilute stock solutions: Prepare 10, 100 and 1,000 ng/mL 
cadmium standard stock solutions by making appropriate ten-fold 
serial dilutions of the 1,000 g/mL cadmium standard stock 
solution with the diluting solution described in Section 3.5.6.
    3.8.2. Working standards: Prepare cadmium working standards in 
the range of 0.2 to 20 ng/mL by making appropriate serial dilutions 
of the dilute stock solutions with the same diluting solution. A 
suggested method of preparation of the working standards is given 
below.

------------------------------------------------------------------------
                                             Standard             Final 
         Working standard (ng/mL)            solution   Aliquot    vol. 
                                             (ng/mL)     (mL)      (mL) 
------------------------------------------------------------------------
0.2.......................................         10         2      100
0.5.......................................         10         5      100
1.........................................         10        10      100
2.........................................        100         2      100
5.........................................        100         5      100
10........................................        100        10      100
20........................................      1,000         2     100 
------------------------------------------------------------------------

    Store the working standards in narrow-mouth polyethylene or 
glass bottles with leakproof caps. Prepare monthly.

3.9. Sample Preparation

    3.9.1. Carefully transfer each sample filter with forceps from 
its filter cassette unit to a clean, separate 125-mL Phillips beaker 
along with any loose dust found in the cassette. Label each Phillips 
beaker with the appropriate sample number.
    3.9.2. Digest the sample by adding 5 mL of concentrated nitric 
acid (HNO3) to each Phillips beaker containing an air filter 
sample. Place the Phillips beakers on a hot plate in an exhaust hood 
and heat the samples until approximately 0.5 mL remains. The sample 
solution in each Phillips beaker should become clear. If it is not 
clear, digest the sample with another portion of concentrated nitric 
acid.
    3.9.3. After completing the HNO3 digestion and cooling the 
samples, add 40 L (2 drops) of concentrated HCl to each air 
sample solution and then swirl the contents. Carefully add about 5 
mL of deionized water by pouring it down the inside of each beaker.
    3.9.4. Quantitatively transfer each cooled air sample solution 
from each Phillips beaker to a clean 10-mL volumetric flask. Dilute 
each flask to volume with deionized water and mix well.

3.10. Flame AAS Analysis

    Analyze all of the air samples for their cadmium content by 
flame atomic absorption spectroscopy (AAS) according to the 
instructions given below.
    3.10.1. Set up the atomic absorption spectrophotometer for the 
air/acetylene flame analysis of cadmium according to the SOP (5.8.) 
or the manufacturer's operational instructions. For the source lamp, 
use the cadmium hollow cathode or electrodeless discharge lamp 
operated at the manufacturer's recommended rating for continuous 
operation. Allow the lamp to warm up 10 to 20 min or until the 
energy output stabilizes. Optimize conditions such as lamp position, 
burner head alignment, fuel and oxidant flow rates, etc. See the SOP 
or specific instrument manuals for details. Instrumental parameters 
for the Perkin-Elmer Model 603 used in the validation of this method 
are given in Attachment 1.
    3.10.2. Aspirate and measure the absorbance of a standard 
solution of cadmium. The standard concentration should be within the 
linear range. For the instrumentation used in the validation of this 
method a 2 g/mL cadmium standard gives a net absorbance 
reading of about 0.350 abs. units (see Section 1.5.5.) when the 
instrument and the source lamp are performing to manufacturer 
specifications.
    3.10.3. To increase instrument response, scale expand the 
absorbance reading of the aspirated 2 g/mL working standard 
approximately four times. Increase the integration time to at least 
3 seconds to reduce signal noise.
    3.10.4. Autozero the instrument while aspirating a deionized 
water blank. Monitor the variation in the baseline absorbance 
reading (baseline noise) for a few minutes to insure that the 
instrument, source lamp and associated equipment are in good 
operating condition.
    3.10.5. Aspirate the working standards and samples directly into 
the flame and record their absorbance readings. Aspirate the 
deionized water blank immediately after every standard or sample to 
correct for and monitor any baseline drift and noise. Record the 
baseline absorbance reading of each deionized water blank. Label 
each standard and sample reading and its accompanying baseline 
reading.
    3.10.6. It is recommended that the entire series of working 
standards be analyzed at the beginning and end of the analysis of a 
set of samples to establish a concentration-response curve, ensure 
that the standard readings agree with each other and are 
reproducible. Also, analyze a working standard after every five or 
six samples to monitor the performance of the spectrophotometer. 
Standard readings should agree within 10 to 15% of the 
readings obtained at the beginning of the analysis.
    3.10.7. Bracket the sample readings with standards during the 
analysis. If the absorbance reading of a sample is above the 
absorbance reading of the highest working standard, dilute the 
sample with diluting solution and reanalyze. Use the appropriate 
dilution factor in the calculations.
    3.10.8. Repeat the analysis of approximately 10% of the samples 
for a check of precision.
    3.10.9. If possible, analyze quality control samples from an 
independent source as a check on analytical recovery and precision.
    3.10.10. Record the final instrument settings at the end of the 
analysis. Date and label the output.

3.11. AAS-HGA Analysis

    Initially analyze all of the air samples for their cadmium 
content by flame atomic absorption spectroscopy (AAS) according to 
the instructions given in Section 3.10. If the concentration of 
cadmium in a sample solution is less than three times the 
quantitative detection limit [0.04 g/mL (40 ng/mL) for the 
instrumentation used in the validation] and the sample results are 
to be averaged with other samples for TWA calculations, proceed with 
the AAS-HGA analysis of the sample as described below.
    3.11.1. Set up the atomic absorption spectrophotometer and HGA 
for flameless atomic absorption analysis of cadmium according to the 
SOP (5.9.) or the manufacturer's operational instructions and allow 
the instrument to stabilize. The graphite furnace atomizer is 
equipped with a pyrolytically coated graphite tube containing a 
pyrolytic platform. For the source lamp, use a cadmium hollow 
cathode or electrodeless discharge lamp operated at the 
manufacturer's recommended setting for graphite furnace operation. 
The Zeeman background corrector and EDL are recommended for use with 
the L'vov platform. Instrumental parameters for the Perkin-Elmer 
Model 5100 spectrophotometer and Zeeman HGA-600 graphite furnace 
used in the validation of this method are given in Attachment 2.
    3.11.2. Optimize the energy reading of the spectrophotometer at 
228.8 nm by adjusting the lamp position and the wavelength according 
to the manufacturer's instructions.
    3.11.3. Set up the autosampler to inject a 5-L aliquot 
of the working standard, sample or reagent blank solution onto the 
L'vov platform along with a 10-L overlay of the matrix 
modifier.
    3.11.4. Analyze the reagent blank (diluting solution, Section 
3.5.6.) and then autozero the instrument before starting the 
analysis of a set of samples. It is recommended that the reagent 
blank be analyzed several times during the analysis to assure the 
integrated absorbance (peak area) reading remains at or near zero.
    3.11.5. Analyze a working standard approximately midway in the 
linear portion of the working standard range two or three times to 
check for reproducibility and sensitivity (see sections 1.5.5. and 
1.5.6.) before starting the analysis of samples. Calculate the 
experimental characteristic mass value from the average integrated 
absorbance reading and injection volume of the analyzed working 
standard. Compare this value to the manufacturer's suggested value 
as a check of proper instrument operation.
    3.11.6. Analyze the reagent blank, working standard, and sample 
solutions. Record and label the peak area (abs-sec) readings and the 
peak and background peak profiles on the printer/plotter.
    3.11.7. It is recommended the entire series of working standards 
be analyzed at the beginning and end of the analysis of a set of 
samples. Establish a concentration-response curve and ensure 
standard readings agree with each other and are reproducible. Also, 
analyze a working standard after every five or six samples to 
monitor the performance of the system. Standard readings should 
agree within 15% of the readings obtained at the 
beginning of the analysis.
    3.11.8. Bracket the sample readings with standards during the 
analysis. If the peak area reading of a sample is above the peak 
area reading of the highest working standard, dilute the sample with 
the diluting solution and reanalyze. Use the appropriate dilution 
factor in the calculations.
    3.11.9. Repeat the analysis of approximately 10% of the samples 
for a check of precision.
    3.11.10. If possible, analyze quality control samples from an 
independent source as a check of analytical recovery and precision.
    3.11.11. Record the final instrument settings at the end of the 
analysis. Date and label the output.

3.12. Calculations

    Note: Standards used for HGA analysis are in ng/mL. Total 
amounts of cadmium from calculations will be in ng (not g) 
unless a prior conversion is made.
    3.12.1. Correct for baseline drift and noise in flame AAS 
analysis by subtracting each baseline absorbance reading from its 
corresponding working standard or sample absorbance reading to 
obtain the net absorbance reading for each standard and sample.
    3.12.2. Use a least squares regression program to plot a 
concentration-response curve of net absorbance reading (or peak area 
for HGA analysis) versus concentration (g/mL or ng/mL) of 
cadmium in each working standard.
    3.12.3. Determine the concentration (g/mL or ng/mL) of 
cadmium in each sample from the resulting concentration-response 
curve. If the concentration of cadmium in a sample solution is less 
than three times the quantitative detection limit [0.04 g/
mL (40 ng/mL) for the instrumentation used in the validation of the 
method] and if consecutive samples were taken on one employee and 
the sample results are to be averaged with other samples to 
determine a single TWA, reanalyze the sample by AAS-HGA as described 
in Section 3.11. and report the AAS-HGA analytical results.
    3.12.4. Calculate the total amount (g or ng) of cadmium 
in each sample from the sample solution volume (mL) :

W=(C)(sample vol, mL)(DF)

Where:
    W=Total cadmium in sample
    C=Calculated concentration of cadmium
    DF=Dilution Factor (if applicable)

    3.12.5. Make a blank correction for each air sample by 
subtracting the total amount of cadmium in the corresponding blank 
sample from the total amount of cadmium in the sample.
    3.12.6. Calculate the concentration of cadmium in an air sample 
(mg/m\3\ or g/m\3\) by using one of the following 
equations:

mg/m\3\=Wbc/(Air vol sampled, L)

or

g/m\3\=(Wbc)(1,000 ng/g)/(Air vol sampled, L)
Where:
    Wbc=blank corrected total g cadmium in the sample. 
(1g=1,000 ng)

4. Backup Data

4.1. Introduction

    4.1.1. The purpose of this evaluation is to determine the 
analytical method recovery, working standard range, and qualitative 
and quantitative detection limits of the two atomic absorption 
analytical techniques included in this method. The evaluation 
consisted of the following experiments:
    1. An analysis of 24 samples (six samples each at 0.1, 0.5, 1 
and 2 times the TWA-PEL) for the analytical method recovery study of 
the flame AAS analytical technique.
    2. An analysis of 18 samples (six samples each at 0.5, 1 and 2 
times the Action Level TWA-PEL) for the analytical method recovery 
study of the AAS-HGA analytical technique.
    3. Multiple analyses of the reagent blank and a series of 
standard solutions to determine the working standard range and the 
qualitative and quantitative detection limits for both atomic 
absorption analytical techniques.
    4.1.2. The analytical method recovery results at all test levels 
were calculated from concentration-response curves and statistically 
examined for outliers at the 99% confidence level. Possible outliers 
were determined using the Treatment of Outliers test (5.10.). In 
addition, the sample results of the two analytical techniques, at 
0.5, 1.0 and 2.0 times their target concentrations, were tested for 
homogeneity of variances also at the 99% confidence level. 
Homogeneity of the coefficients of variation was determined using 
the Bartlett's test (5.11.). The overall analytical error (OAE) at 
the 95% confidence level was calculated using the equation (5.12.):

OAE=[|Bias|+(1.96)(CV1(pooled))(100%)]

    4.1.3. A derivation of the International Union of Pure and 
Applied Chemistry (IUPAC) detection limit equation (5.13.) was used 
to determine the qualitative and quantitative detection limits for 
both atomic absorption analytical techniques:

Cld=k(sd)/m        (Equation 1)

Where:
    Cld=the smallest reliable detectable concentration an 
analytical instrument can determine at a given confidence level.
    k=3 for the Qualitative Detection Limit at the 99.86% Confidence 
Level
    =10 for the Quantitative Detection Limit at the 99.99% 
Confidence Level.
    sd=standard deviation of the reagent blank (Rbl) readings.
    m=analytical sensitivity or slope as calculated by linear 
regression.

    4.1.4. Collection efficiencies of metallic fume and dust 
atmospheres on 0.8-m mixed cellulose ester membrane filters 
are well documented and have been shown to be excellent (5.11.). 
Since elemental cadmium and the cadmium component of cadmium 
compounds are nonvolatile, stability studies of cadmium spiked MCEF 
samples were not performed.

4.2. Equipment

    4.2.1. A Perkin-Elmer (PE) Model 603 spectrophotometer equipped 
with a manual gas control system, a stainless steel nebulizer, a 
burner mixing chamber, a flow spoiler and a 10 cm. (one-slot) burner 
head was used in the experimental validation of the flame AAS 
analytical technique. A PE cadmium hollow cathode lamp, operated at 
the manufacturer's recommended current setting for continuous 
operation (4 mA), was used as the source lamp. Instrument parameters 
are listed in Attachment 1.
    4.2.2. A PE Model 5100 spectrophotometer, Zeeman HGA-600 
graphite furnace atomizer and AS-60 HGA autosampler were used in the 
experimental validation of the AAS-HGA analytical technique. The 
spectrophotometer was equipped with a PE Series 7700 professional 
computer and Model PR-310 printer. A PE System 2 cadmium 
electrodeless discharge lamp, operated at the manufacturer's 
recommended current setting for modulated operation (170 mA), was 
used as the source lamp. Instrument parameters are listed in 
Attachment 2.

4.3. Reagents

    4.3.1. J.T. Baker Chem. Co. (Analyzed grade) concentrated nitric 
acid, 69.0-71.0%, and concentrated hydrochloric acid, 36.5-38.0%, 
were used to prepare the samples and standards.
    4.3.2. Ammonium phosphate, monobasic, NH4H2PO4 
and magnesium nitrate, Mg(NO3)2 6H2O, both 
manufactured by the Mallinckrodt Chem. Co., were used to prepare the 
matrix modifier for AAS-HGA analysis.

4.4. Standard Preparation for Flame AAS Analysis

    4.4.1. Dilute stock solutions: Prepared 0.01, 0.1, 1, 10 and 100 
g/mL cadmium standard stock solutions by making appropriate 
serial dilutions of a commercially available 1,000 g/mL 
cadmium standard stock solution (RICCA Chemical Co., Lot# A102) with 
the diluting solution (4% HNO3, 0.4% HCl).
    4.4.2. Analyzed Standards: Prepared cadmium standards in the 
range of 0.001 to 2.0 g/mL by pipetting 2 to 10 mL of the 
appropriate dilute cadmium stock solution into a 100-mL volumetric 
flask and diluting to volume with the diluting solution. (See 
Section 3.7.2.)

4.5. Standard Preparation for AAS-HGA Analysis

    4.5.1. Dilute stock solutions: Prepared 1, 10, 100 and 1,000 ng/
mL cadmium standard stock solutions by making appropriate serial 
dilutions of a commercially available 1,000 g/mL cadmium 
standard stock solution (J.T. Baker Chemical Co., Instra-analyzed, 
Lot# D22642) with the diluting solution (4% HNO3, 0.4% HCl).
    4.5.2. Analyzed Standards: Prepared cadmium standards in the 
range of 0.1 to 40 ng/mL by pipetting 2 to 10 mL of the appropriate 
dilute cadmium stock solution into a 100-mL volumetric flask and 
diluting to volume with the diluting solution. (See Section 3.8.2.)

4.6. Detection Limits and Standard Working Range for Flame AAS Analysis

    4.6.1. Analyzed the reagent blank solution and the entire series 
of cadmium standards in the range of 0.001 to 2.0 g/mL 
three to six times according to the instructions given in Section 
3.10. The diluting solution (4% HNO3, 0.4% HCl) was used as the 
reagent blank. The integration time on the PE 603 spectrophotometer 
was set to 3.0 seconds and a four-fold expansion of the absorbance 
reading of the 2.0 g/mL cadmium standard was made prior to 
analysis. The 2.0 g/mL standard gave a net absorbance 
reading of 0.350 abs. units prior to expansion in agreement with the 
manufacturer's specifications (5.6.).
    4.6.2. The net absorbance readings of the reagent blank and the 
low concentration Cd standards from 0.001 to 0.1 g/mL and 
the statistical analysis of the results are shown in Table I. The 
standard deviation, sd, of the six net absorbance readings of the 
reagent blank is 1.05 abs. units. The slope, m, as calculated by a 
linear regression plot of the net absorbance readings (shown in 
Table II) of the 0.02 to 1.0 g/mL cadmium standards versus 
their concentration is 772.7 abs. units/(g/mL).
    4.6.3. If these values for sd and the slope, m, are used in Eqn. 
1 (Sect. 4.1.3.), the qualitative and quantitative detection limits 
as determined by the IUPAC Method are:

Cld=(3)(1.05 abs. units)/(772.7 abs. units/(g/mL))
    = 0.0041 g/mL for the qualitative detection limit.
Cld=(10)(1.05 abs. units)/(772.7 abs. units/g/mL))
    =0.014 g/mL for the quantitative detection limit.

The qualitative and quantitative detection limits for the flame AAS 
analytical technique are 0.041 g and 0.14 g 
cadmium, respectively, for a 10 mL solution volume. These 
correspond, respectively, to 0.2 g/m3 and 0.70 
g/m3 for a 200 L air volume.
    4.6.4. The recommended Cd standard working range for flame AAS 
analysis is 0.02 to 2.0 g/mL. The net absorbance readings 
of the reagent blank and the recommended working range standards and 
the statistical analysis of the results are shown in Table II. The 
standard of lowest concentration in the working range, 0.02 
g/mL, is slightly greater than the calculated quantitative 
detection limit, 0.014 g/mL. The standard of highest 
concentration in the working range, 2.0 g/mL, is at the 
upper end of the linear working range suggested by the manufacturer 
(5.6.). Although the standard net absorbance readings are not 
strictly linear at concentrations above 0.5 g/mL, the 
deviation from linearity is only about 10% at the upper end of the 
recommended standard working range. The deviation from linearity is 
probably caused by the four-fold expansion of the signal suggested 
in the method. As shown in Table II, the precision of the standard 
net absorbance readings are excellent throughout the recommended 
working range; the relative standard deviations of the readings 
range from 0.009 to 0.064.

4.7.  Detection Limits and Standard Working Range for AAS-HGA Analysis

    4.7.1. Analyzed the reagent blank solution and the entire series 
of cadmium standards in the range of 0.1 to 40 ng/mL according to 
the instructions given in Section 3.11. The diluting solution (4% 
HNO3, 0.4% HCl) was used as the reagent blank. A fresh aliquot 
of the reagent blank and of each standard was used for every 
analysis. The experimental characteristic mass value was 0.41 pg, 
calculated from the average peak area (abs-sec) reading of the 5 ng/
mL standard which is approximately midway in the linear portion of 
the working standard range. This agreed within 20% with the 
characteristic mass value, 0.35 pg, listed by the manufacturer of 
the instrument (5.2.).
    4.7.2. The peak area (abs-sec) readings of the reagent blank and 
the low concentration Cd standards from 0.1 to 2.0 ng/mL and 
statistical analysis of the results are shown in Table III. Five of 
the reagent blank peak area readings were zero and the sixth reading 
was 1 and was an outlier. The near lack of a blank signal does not 
satisfy a strict interpretation of the IUPAC method for determining 
the detection limits. Therefore, the standard deviation of the six 
peak area readings of the 0.2 ng/mL cadmium standard, 0.75 abs-sec, 
was used to calculate the detection limits by the IUPAC method. The 
slope, m, as calculated by a linear regression plot of the peak area 
(abs-sec) readings (shown in Table IV) of the 0.2 to 10 ng/mL 
cadmium standards versus their concentration is 51.5 abs-sec/(ng/
mL).
    4.7.3. If 0.75 abs-sec (sd) and 51.5 abs-sec/(ng/mL) (m) are 
used in Eqn. 1 (Sect. 4.1.3.), the qualitative and quantitative 
detection limits as determined by the IUPAC method are:

Cld= (3)(0.75 abs-sec)/(51.5 abs-sec/(ng/mL)
    = 0.044 ng/mL for the qualitative detection limit.

Cld= (10)(0.75 abs-sec)/(51.5 abs-sec/(ng/mL) = 0.15 ng/mL for 
the quantitative detection limit.
The qualitative and quantitative detection limits for the AAS-HGA 
analytical technique are 0.44 ng and 1.5 ng cadmium, respectively, 
for a 10 mL solution volume. These correspond, respectively, to 
0.007 g/m3 and 0.025 g/m3 for a 60 L air 
volume.
    4.7.4. The peak area (abs-sec) readings of the Cd standards from 
0.2 to 40 ng/mL and the statistical analysis of the results are 
given in Table IV. The recommended standard working range for AAS-
HGA analysis is 0.2 to 20 ng/mL. The standard of lowest 
concentration in the recommended working range is slightly greater 
than the calculated quantitative detection limit, 0.15 ng/mL. The 
deviation from linearity of the peak area readings of the 20 ng/mL 
standard, the highest concentration standard in the recommended 
working range, is approximately 10%. The deviations from linearity 
of the peak area readings of the 30 and 40 ng/mL standards are 
significantly greater than 10%. As shown in Table IV, the precision 
of the peak area readings are satisfactory throughout the 
recommended working range; the relative standard deviations of the 
readings range from 0.025 to 0.083.

4.8. Analytical Method Recovery for Flame AAS Analysis

    4.8.1. Four sets of spiked MCEF samples were prepared by 
injecting 20 L of 10, 50, 100 and 200 g/mL dilute 
cadmium stock solutions on 37 mm diameter filters (part no. AAWP 037 
00, Millipore Corp., Bedford, MA) with a calibrated micropipet. The 
dilute stock solutions were prepared by making appropriate serial 
dilutions of a commercially available 1,000 g/mL cadmium 
standard stock solution (RICCA Chemical Co., Lot# A102) with the 
diluting solution (4% HNO3, 0.4% HCl). Each set contained six 
samples and a sample blank. The amount of cadmium in the prepared 
sets were equivalent to 0.1, 0.5, 1.0 and 2.0 times the TWA PEL 
target concentration of 5 g/m3 for a 400 L air volume.
    4.8.2. The air-dried spiked filters were digested and analyzed 
for their cadmium content by flame atomic absorption spectroscopy 
(AAS) following the procedure described in Section 3. The 0.02 to 
2.0 g/mL cadmium standards (the suggested working range) 
were used in the analysis of the spiked filters.
    4.8.3. The results of the analysis are given in Table V. One 
result at 0.5 times the TWA PEL target concentration was an outlier 
and was excluded from statistical analysis. Experimental 
justification for rejecting it is that the outlier value was 
probably due to a spiking error. The coefficients of variation for 
the three test levels at 0.5 to 2.0 times the TWA PEL target 
concentration passed the Bartlett's test and were pooled.
    4.8.4. The average recovery of the six spiked filter samples at 
0.1 times the TWA PEL target concentration was 118.2% with a 
coefficient of variation (CV1) of 0.128. The average recovery 
of the spiked filter samples in the range of 0.5 to 2.0 times the 
TWA target concentration was 104.0% with a pooled coefficient of 
variation (CV1) of 0.010. Consequently, the analytical bias 
found in these spiked sample results over the tested concentration 
range was +4.0% and the OAE was 6.0%.

4.9. Analytical Method Recovery for AAS-HGA Analysis

    4.9.1. Three sets of spiked MCEF samples were prepared by 
injecting 15 L of 5, 10 and 20 g/mL dilute cadmium 
stock solutions on 37 mm diameter filters (part no. AAWP 037 00, 
Millipore Corp., Bedford, MA) with a calibrated micropipet. The 
dilute stock solutions were prepared by making appropriate serial 
dilutions of a commercially available certified 1,000 g/mL 
cadmium standard stock solution (Fisher Chemical Co., Lot# 913438-
24) with the diluting solution (4% HNO3, 0.4% HCl). Each set 
contained six samples and a sample blank. The amount of cadmium in 
the prepared sets were equivalent to 0.5, 1 and 2 times the Action 
Level TWA target concentration of 2.5 g/m3 for a 60 L 
air volume.
    4.9.2. The air-dried spiked filters were digested and analyzed 
for their cadmium content by flameless atomic absorption 
spectroscopy using a heated graphite furnace atomizer following the 
procedure described in Section 3. A five-fold dilution of the spiked 
filter samples at 2 times the Action Level TWA was made prior to 
their analysis. The 0.05 to 20 ng/mL cadmium standards were used in 
the analysis of the spiked filters.
    4.9.3. The results of the analysis are given in Table VI. There 
were no outliers. The coefficients of variation for the three test 
levels at 0.5 to 2.0 times the Action Level TWA PEL passed the 
Bartlett's test and were pooled. The average recovery of the spiked 
filter samples was 94.2% with a pooled coefficient of variation 
(CV1) of 0.043. Consequently, the analytical bias was -5.8% and 
the OAE was 14.2%.

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]                          
------------------------------------------------------------------------
                                Absorbance                              
    STD (g/mL)      reading at 228.8    Statistical analysis   
                                    nm                                  
------------------------------------------------------------------------
Reagent blank.............                 52  n=6.                     
                                           43  mean=3.50.               
                                           43  std dev=1.05.            
                                               CV=0.30.                 
0.001.....................                 66  n=6.                     
                                           24  mean=5.00.               
                                           66  std dev=1.67.            
                                               CV=0.335.                
0.002.....................                 57  n=6.                     
                                           73  mean=5.50.               
                                           74  std dev=1.76.            
                                               CV=0.320.                
0.005.....................                 77  n=6.                     
                                           88  mean=7.33.               
                                           86  std dev=0.817.           
                                               CV=0.111.                
0.010.....................                109  n=6.                     
                                         1013  mean=10.3.               
                                         1010  std dev=1.37.            
                                               CV=0.133.                
0.020.....................               2023  n=6.                     
                                         2022  mean=20.8.               
                                         2020  std dev=1.33.            
                                               CV=0.064.                
0.050.....................               4242  n=6.                     
                                         4242  mean=42.5.               
                                         4245  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]                          
------------------------------------------------------------------------
                                Absorbance                              
   STD (g/mL)       reading at 228.8    Statistical analysis   
                                   nm                                   
------------------------------------------------------------------------
Reagent blank.............                 52  n=6.                     
                                           43  mean=3.50.               
                                           43  std dev=1.05.            
                                               CV=0.30.                 
0.020.....................               2023  n=6.                     
                                         2022  mean=20.8.               
                                         2020  std dev=1.33.            
                                               CV=0.064.                
0.050.....................               4242  n=6.                     
                                         4242  mean=42.5.               
                                         4245  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]                           
------------------------------------------------------------------------
                                Peak area                               
                               readings  x                              
        STD (ng/mL)           103 at 228.8      Statistical analysis    
                                   nm                                   
------------------------------------------------------------------------
Reagent blank..............              00  n=6.                       
                                         01  mean=0.167.                
                                         00  std dev=0.41.              
                                             CV=2.45.                   
0.1........................              86  n=6.                       
                                         57  mean=7.7.                  
                                        137  std dev=2.8.               
                                             CV=0.366.                  
0.2........................            1113  n=6.                       
                                       1112  mean=11.8.                 
                                       1212  std dev=0.75.              
                                             CV=0.064.                  
0.5........................            2833  n=6.                       
                                       2628  mean=28.8.                 
                                       2830  std dev=2.4.               
                                             CV=0.083.                  
1.0........................            5255  n=6.                       
                                       5658  mean=54.8.                 
                                       5454  std dev=2.0.               
                                             CV=0.037.                  
2.0........................          101112  n=6.                       
                                     110110  mean=108.8.                
                                     110110  std dev=3.9.               
                                             CV=0.036.                  
------------------------------------------------------------------------


               Table IV.--Cd Standard Working Range Study               
                           [AAS-HGA Analysis]                           
------------------------------------------------------------------------
                                Peak area                               
                               readings  x                              
        STD (ng/mL)           103 at 228.8      Statistical analysis    
                                   nm                                   
------------------------------------------------------------------------
0.2........................            1113  n=6.                       
                                       1112  mean=11.8.                 
                                       1212  std dev=0.75.              
                                             CV=0.064.                  
0.5........................            2833  n=6.                       
                                       2628  mean=28.8.                 
                                       2830  std dev=2.4.               
                                             CV=0.083.                  
1.0........................            5255  n=6.                       
                                       5658  mean=54.8.                 
                                       5454  std dev=2.0.               
                                             CV=0.037.                  
2.0........................          101112  n=6.                       
                                     110110  mean=108.8.                
                                     110110  std dev=3.9.               
                                             CV=0.036.                  
5.0........................          247265  n=6.                       
                                     268275  mean=265.5.                
                                     259279  std dev=11.5.              
                                             CV=0.044.                  
10.0.......................          495520  n=6.                       
                                     523513  mean=516.7.                
                                     516533  std dev=12.7.              
                                             CV=0.025.                  
20.0.......................          950953  n=6.                       
                                     951958  mean=941.8.                
                                     949890  std dev=25.6.              
                                             CV=0.027.                  
30.0.......................        12691291  n=6.                       
                                   13031307  mean=1293.                 
                                   12951290  std dev=13.3.              
                                             CV=0.010.                  
40.0.......................        15051567  n=6.                       
                                   15351567  mean=1552.                 
                                   15661572  std dev=26.6.              
                                             CV=0.017.                  
------------------------------------------------------------------------


                                      Table V.--Analytical Method Recovery                                      
                                              [Flame AAS Analysis]                                              
----------------------------------------------------------------------------------------------------------------
    Test level         0.5 x                              1.0 x                              2.0 x              
--------------------------------  Percent   g ------------  Percent   g ------------  Percent 
                     g    rec.       taken     g    rec.       taken     g     rec.  
 g taken      found                              found                              found              
----------------------------------------------------------------------------------------------------------------
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
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                                               
*Rejected as an outlier--this value did not pass the outlier T-test at the 99% confidence level.                


------------------------------------------------------------------------
             Test level                     0.1 x                       
--------------------------------------------------------   Percent rec. 
          g taken            g found                  
------------------------------------------------------------------------
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  
CV1=................................                               0.128 


                                      Table VI.--Analytical Method Recovery                                     
                                               [AAS-HGA analysis]                                               
----------------------------------------------------------------------------------------------------------------
       Test level           0.5 x                            1.0 x                            2.0 x             
------------------------------------  Percent    ng taken -----------  Percent    ng taken -----------  Percent 
        ng taken           ng found     rec.                ng found     rec.                ng 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 
CV1=                                           0.048                         0.032                         0.048
                                                CV1(pooled)=0.043                                               

Attachment 1

Instrumental Parameters for Flame AAS Analysis

Atomic Absorption Spectrophotometer (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

Attachment 2

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)                              
----------------------------------------------------------------------------------------------------------------
                                                       Ramp time   Hold time    Temp. (   Argon flow            
                        Step                             (sec)       (sec)      deg.C)     (mL/min)   Read (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 to Sec. 1915.1027--Nonmandatory Protocol for Biological 
Monitoring

1.00  Introduction

    Under the final OSHA cadmium rule (29 CFR part 1910), 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 (l)(3) and (l)(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 Pathologists 
(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 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 (29 CFR 
part 1910). 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 predefined 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, 10, and 15 g/l. For CDU, the target values 
are 3, 7, and 15 g/g CRTU. For 
2MU, the target values are 300, 750, and 
1500 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        
----------------------------------------------------------------------------------------------------------------
                                                               Precision                                        
  Analyte/concentration pool         Limit of detection         (CV) (%)                  Accuracy              
----------------------------------------------------------------------------------------------------------------
Cadmium in blood.............  0.5 g/l.............  ...........  1 g/l or 15% of 
                                                                            the mean.                           
    2 g/l  .............................           40                                       
    >2 g/l..........  .............................           20                                       
Cadmium in urine.............  0.5 g/g creatinine..  ...........  1 g/l or 15% of 
                                                                            the mean.                           
    2 g/l  .............................           40                                       
     creatinine.                                                                                                
    >2 g/l            .............................           20                                       
     creatinine.                                                                                                
-2-microglobulin in   100 g/g creatinine..            5  15% of the mean.         
 urine: 100 g/g                                                                                        
 creatine.                                                                                                      
----------------------------------------------------------------------------------------------------------------

    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 g/l);
    2. The method of Pruszkowska et al. (1983) for CDU 
determinations (limit of detection: 0.5 g/l of urine); and,
    3. The Pharmacia Delphia test kit (Pharmacia 1990) for the 
determination of B2MU (limit of detection: 100 g/l urine).
    Because both CDU and B2MU should be reported in g/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 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. 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 1 g/l blood or 15% of 
the consensus mean (whichever is greater). For samples exhibiting a 
consensus mean less than 1 g/l, the performance requirement 
is defined as a concentration between the detection limit of the 
analysis and a maximum of 2 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 g/l.
    The performance requirement for CDU analysis is defined as an 
analytical result within 1 g/l urine or 15% of 
the consensus mean (whichever is greater). For samples exhibiting a 
consensus mean less than 1 g/l urine, the performance 
requirement is defined as a concentration between the detection 
limit of the analysis and a maximum of 2 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 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 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;n
    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 g/l or 15% of the 
consensus mean (whichever is greater). For samples exhibiting a 
consensus mean less than 1 g/l, the performance requirement 
is defined as a concentration between the detection limit of the 
analysis and a maximum of 2 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 g/l.
    The performance requirement for CDU analysis is defined as an 
analytical result within 1 g/l urine or 15% of 
the consensus mean (whichever is greater). For samples exhibiting a 
consensus mean less than 1 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 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 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 
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 
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 
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).
    Standards should be kept fresh; as samples age, they should be 
compared with new standards and replaced if necessary.
    Internal Quality Control Analyses. Internal QC samples should be 
determined interspersed with analyses of compliance samples. At a 
minimum, these samples should be run at a rate of 5% of the 
compliance samples or at least one set of QC samples per analysis of 
compliance samples, whichever is greater. If only 2 samples are run, 
they should contain different levels of cadmium.
    Internal QC samples may be obtained as commercially-available 
reference materials and/or they may be internally prepared. 
Internally-prepared samples should be well characterized and traced, 
or compared to a reference material for which a consensus value is 
available.
    Levels of cadmium contained in QC samples should not be known to 
the analyst prior to reporting the results of the analysis.
    Internal QC results should be plotted or charted in a manner 
which describes sample recovery and laboratory control limits.
    Internal Control Limits. The laboratory protocol for evaluating 
internal QC analyses per control limits should be clearly defined. 
Limits may be based on statistical methods (e.g., as 2s from the 
laboratory mean recovery), or on proficiency testing limits (e.g., 
1 g or 15% of the mean, whichever is greater). 
Statistical limits that exceed 40% should be reevaluated 
to determine the source error in the analysis.
    When laboratory limits are exceeded, analytic work should 
terminate until the source of error is determined and corrected; 
compliance samples affected by the error should be reanalyzed. In 
addition, the laboratory protocol should address any unusual trends 
that develop which may be biasing the results. Numerous, consecutive 
results above or below laboratory mean recoveries, or outside 
laboratory statistical limits, indicate that problems may have 
developed.
    Corrective Actions. The QA/QC plan should document in detail 
specific actions taken if control limits are exceeded or unusual 
trends develop. Corrective actions should be noted on an appropriate 
form, accompanied by supporting documentation.
    In addition to these actions, laboratories should include 
whatever additional actions are necessary to assure that accurate 
data are reported to the responsible physicians.
    Reference Materials. The following reference materials may be 
available:

Cadmium in Blood (CDB)

    1. Centre de Toxicologie du Quebec, Le Centre Hospitalier de 
l'Universite Laval, 2705 boul. Laurier, Quebec, Que., Canada G1V 
4G2. (Prepared 6 times per year at 1-15 g Cd/l.)
    2. H. Marchandise, Community Bureau of Reference-BCR, 
Directorate General XII, Commission of the European Communities, 
200, rue de la Loi, B-1049, Brussels, Belgium. (Prepared as Bl CBM-1 
at 5.37 g Cd/l, and Bl CBM-2 at 12.38 g Cd/l.)
    3. Kaulson Laboratories Inc., 691 Bloomfield Ave., Caldwell, NJ 
07006; tel: (201) 226-9494, FAX (201) 226-3244. (Prepared as #0141 
[As, Cd, Hg, Pb] at 2 levels.)

Cadmium in Urine (CDU)

    1. Centre de Toxicologie du Quebec, Le Centre Hospitalier de 
l'Universite Laval, 2705 boul. Laurier, Quebec, Que., Canada G1V 
4G2. (Prepared 6 times per year.)
    2. National Institute of Standards and Technology (NIST), Dept. 
of Commerce, Gaithersburg, MD; tel: (301) 975-6776. (Prepared as SRM 
2670 freeze-dried urine [metals]; set includes normal and elevated 
levels of metals; cadmium is certified for elevated level of 88.0 
g/l in reconstituted urine.)
    3. Kaulson Laboratories Inc., 691 Bloomfield Ave., Caldwell, NJ 
07006; tel: (201) 226-9494, FAX (201) 226-3244. (Prepared as #0140 
[As, Cd, Hg, Pb] at 2 levels.)

3.3.1.2  QA/QC procedures for establishing control of B2MU

    A written, detailed QA/QC plan for B2MU analysis should be 
developed. The QA/QC plan should contain a protocol similar to those 
protocols developed for the CDB/CDU analyses. Differences in 
analyses may warrant some differences in the QA/QC protocol, but 
procedures to ensure analytical integrity should be developed and 
followed.
    Examples of performance summaries that can be provided include 
measurements of accuracy (i.e., the means of measured values versus 
target values for the control samples) and precision (i.e., based on 
duplicate analyses). It is recommended that the accuracy and 
precision measurements be compared to those reported as achievable 
by the Pharmacia Delphia kit (Pharmacia 1990) to determine if and 
when unsatisfactory analyses have arisen. If the measurement error 
of 1 or more of the control samples is more than 15%, the run 
exceeds control limits. Similarly, this decision is warranted when 
the average CV for duplicate samples is greater than 5%.

3.3.2  Procedures for Record Keeping

    To satisfy reporting requirements for commercial analyses of 
CDB, CDU and/or B2MU performed for the medical monitoring program 
mandated under the cadmium rule, participating laboratories should 
maintain the following documentation for each analyte:
    1. For each analytic instrument on which analyte determinations 
are made, records relating to the most recent calibration and QC 
sample analyses;
    2. For these instruments, a tabulated record for each analyte of 
those determinations found to be within and outside of control 
limits over the past 2 years;
    3. Results for the previous 2 years of the QC sample analyses 
conducted under the internal QA/QC program (this information should 
be: Provided for each analyte for which determinations are made and 
for each analytic instrument used for this purpose, sufficient to 
demonstrate that internal QA/QC programs are being executed 
properly, and consistent with data sent to responsible physicians.
    4. Duplicate copies of monitoring results for each analyte sent 
to clients during the previous 5 years, as well as associated 
information; supporting material such as chain-of-custody forms also 
should be retained; and,
    5. Proficiency test results and related materials received while 
participating in the CTQ interlaboratory program over the past 2 
years; results also should be tabulated to provide a serial record 
of relative error (derived per Section 3.3.3 below).

3.3.3  Reporting Procedures

    Participating laboratories should maintain these documents: QA/
QC program plans; QA/QC status reports; CTQ proficiency program 
reports; and, analytical data reports. The information that should 
be included in these reports is summarized in Table 2; a copy of 
each report should be sent to the responsible physician.
      

  Table 2.--Reporting Procedures for Laboratories Participating in the  
                   Cadmium Medical Monitoring Program                   
------------------------------------------------------------------------
                          Frequency (time                               
        Report                 frame)                  Contents         
------------------------------------------------------------------------
1 QA/QC Program Plan.  Once (initially).....  A detailed description of 
                                               the QA/QC protocol to be 
                                               established by the       
                                               laboratory to maintain   
                                               control of analyte       
                                               determinations.          
2 QA/QC Status Report  Every 2 months.......  Results of the QC samples 
                                               incorporated into regular
                                               runs for each instrument 
                                               (over the period since   
                                               the last report).        
3 Proficiency Report.  Attached to every      Results from the last full
                        data report.           year of proficiency      
                                               samples submitted to the 
                                               CTQ program and Results  
                                               of the 100 most recent QC
                                               samples incorporated into
                                               regular runs for each    
                                               instrument.              
4 Analytical Data      For all reports of     Date the sample was       
 Report.                data results.          received; Date the sample
                                               was analyzed; Appropriate
                                               chain-of-custody         
                                               information; Types of    
                                               analyses performed;      
                                               Results of the requested 
                                               analyses and Copy of the 
                                               most current proficiency 
                                               report.                  
------------------------------------------------------------------------

    As noted in Section 3.3.1, a QA/QC program plan should be 
developed that documents internal QA/QC procedures (defined under 
Section 3.3.1) to be implemented by the participating laboratory for 
each analyte; this plan should provide a list identifying each 
instrument used in making analyte determinations.
    A QA/QC status report should be written bimonthly for each 
analyte. In this report, the results of the QC program during the 
reporting period should be reported for each analyte in the 
following manner: The number (N) of QC samples analyzed during the 
period; a table of the target levels defined for each sample and the 
corresponding measured values; the mean of F/T value (as defined 
below) for the set of QC samples run during the period; and, use of 
X2s (as defined below) for the set of QC samples run 
during the period as a measure of precision.
    As noted in Section 2, an F/T value for a QC sample is the ratio 
of the measured concentration of analyte to the established (i.e., 
reference) concentration of analyte for that QC sample. The equation 
below describes the derivation of the mean for F/T values, X (with N 
being analyzed the total number of samples analyzed):

TR03JA94.000

The standard deviation, s, for these measurements is derived using 
the following equation (note that 2s is twice this value):

TR03JA94.001

    The nonmandatory QA/QC protocol (see Attachment 1) indicates 
that QC samples should be divided into several discrete pools, and a 
separate estimate of precision for each pools then should be 
derived. Several precision estimates should be provided for 
concentrations which differ in average value. These precision 
measures may be used to document improvements in performance with 
regard to the combined pool.
    Participating laboratories should use the CTQ proficiency 
program for each analyte. Results of the this program will be sent 
by CTQ directly to physicians designated by the participating 
laboratories. Proficiency results from the CTQ program are used to 
establish the accuracy of results from each participating 
laboratory, and should be provided to responsible physicians for use 
in trend analysis. A proficiency report consisting of these 
proficiency results should accompany data reports as an attachment.
    For each analyte, the proficiency report should include the 
results from the 6 previous proficiency rounds in the following 
format:
    1. Number (N) of samples analyzed;
    2. Mean of the target levels, (1/N)i, 
with Ti being a consensus mean for the sample;
    3. Mean of the measurements, (1/N)i, with 
Mi being a sample measurement;
    4. A measure of error defined by:

(1/N)(Ti-Mi)\2\

    Analytical data reports should be submitted to responsible 
physicians directly. For each sample, report the following 
information: The date the sample was received; the date the sample 
was analyzed; appropriate chain-of-custody information; the type(s) 
of analyses performed; and, the results of the analyses. This 
information should be reported on a form similar to the form 
provided an appropriate form. The most recent proficiency program 
report should accompany the analytical data reports (as an 
attachment).
    Confidence intervals for the analytical results should be 
reported as X2s, with X being the measured value and 2s 
the standard deviation calculated as described above.
    For CDU or B2MU results, which are combined with CRTU 
measurements for proper reporting, the 95% confidence limits are 
derived from the limits for CDU or B2MU, (p), and the limits for 
CRTU, (q), as follows:

TR03JA94.002

For these calculations, Xp is the measurement and 
confidence limits for CDU or B2MU, and Yq is the 
measurement and confidence limit for CRTU.
    Participating laboratories should notify responsible physicians 
as soon as they receive information indicating a change in their 
accreditation status with the CTQ or the CAP. These physicians 
should not be expected to wait until formal notice of a status 
change has been received from the CTQ or the CAP.

3.4  Instructions to Physicians

    Physicians responsible for the medical monitoring of cadmium-
exposed workers must collect the biological samples from workers; 
they then should select laboratories to perform the required 
analyses, and should interpret the analytic results.

3.4.1  Sample Collection and Holding Procedures

    Blood Samples. The following procedures are recommended for the 
collection, shipment and storage of blood samples for CDB analysis 
to reduce analytical variablility; these recommendations were 
obtained primarily through personal communications with J.P. Weber 
of the CTQ (1991), and from reports by the Centers for Disease 
Control (CDC, 1986) and Stoeppler and Brandt (1980).
    To the extent possible, blood samples should be collected from 
workers at the same time of day. Workers should shower or thoroughly 
wash their hands and arms before blood samples are drawn. The 
following materials are needed for blood sample collection: Alcohol 
wipes; sterile gauze sponges; band-aids; 20-gauge, 1.5-in. stainless 
steel needles (sterile); preprinted labels; tourniquets; vacutainer 
holders; 3-ml ``metal free'' vacutainer tubes (i.e., dark-blue 
caps), with EDTA as an anti-coagulant; and, styrofoam vacutainer 
shipping containers.
    Whole blood samples are taken by venipuncture. Each blue-capped 
tube should be labeled or coded for the worker and company before 
the sample is drawn. (Blue-capped tubes are recommended instead of 
red-capped tubes because the latter may consist of red coloring 
pigment containing cadmium, which could contaminate the samples.) 
Immediately after sampling, the vacutainer tubes must be thoroughly 
mixed by inverting the tubes at least 10 times manually or 
mechanically using a Vortex device (for 15 sec). Samples should be 
refrigerated immediately or stored on ice until they can be packed 
for shipment to the participating laboratory for analysis.
    The CDC recommends that blood samples be shipped with a ``cool 
pak'' to keep the samples cold during shipment. However, the CTQ 
routinely ships and receives blood samples for cadmium analysis that 
have not been kept cool during shipment. The CTQ has found no 
deterioration of cadmium in biological fluids that were shipped via 
parcel post without a cooling agent, even though these deliveries 
often take 2 weeks to reach their destination.
    Urine Samples. The following are recommended procedures for the 
collection, shipment and storage of urine for CDU and B2MU analyses, 
and were obtained primarily through personal communications with 
J.P. Weber of the CTQ (1991), and from reports by the CDC (1986) and 
Stoeppler and Brandt (1980).
    Single ``spot'' samples are recommended. As B2M can degrade in 
the bladder, workers should first empty their bladder and then drink 
a large glass of water at the start of the visit. Urine samples then 
should be collected within 1 hour. Separate samples should be 
collected for CDU and B2MU using the following materials: Sterile 
urine collection cups (250 ml); small sealable plastic bags; 
preprinted labels; 15-ml polypropylene or polyethylene screw-cap 
tubes; lab gloves (``metal free''); and, preservatives (as 
indicated).
    The sealed collection cup should be kept in the plastic bag 
until collection time. The workers should wash their hands with soap 
and water before receiving the collection cup. The collection cup 
should not be opened until just before voiding and the cup should be 
sealed immediately after filling. It is important that the inside of 
the container and cap are not touched by, or come into contact with, 
the body, clothing or other surfaces.
    For CDU analyzes, the cup is swirled gently to resuspend any 
solids, and the 15-ml tube is filled with 10-12 ml urine. The CDC 
recommends the addition of 100 l concentrated HNO3 as 
a preservative before sealing the tube and then freezing the sample. 
The CTQ recommends minimal handling and does not acidify their 
interlaboratory urine reference materials prior to shipment, nor do 
they freeze the sample for shipment. At the CTQ, if the urine sample 
has much sediment, the sample is acidified in the lab to free any 
cadmium in the precipitate.
    For B2M, the urine sample should be collected directly into a 
polyethylene bottle previously washed with dilute nitric acid. The 
pH of the urine should be measured and adjusted to 8.0 with 0.1 N 
NaOH immediately following collection. Samples should be frozen and 
stored at -20 deg.C until testing is performed. The B2M in the 
samples should be stable for 2 days when stored at 2-8 deg.C, and 
for at least 2 months at -20 deg.C. Repeated freezing and thawing 
should be avoided to prevent denaturing the B2M (Pharmacia 1990).

3.4.2  Recommendations for Evaluating Laboratories

    Using standard error data and the results of proficiency testing 
obtained from CTQ, responsible physicians can make an informed 
choice of which laboratory to select to analyze biological samples. 
In general, laboratories with small standard errors and little 
disparity between target and measured values tend to make precise 
and accurate sample determinations. Estimates of precision provided 
to the physicians with each set of monitoring results can be 
compared to previously-reported proficiency and precision estimates. 
The latest precision estimates should be at least as small as the 
standard error reported previously by the laboratory. Moreover, 
there should be no indication that precision is deteriorating (i.e., 
increasing values for the precision estimates). If precision is 
deteriorating, physicians may decide to use another laboratory for 
these analyses. QA/QC information provided by the participating 
laboratories to physicians can, therefore, assist physicians in 
evaluating laboratory performance.

3.4.3  Use and Interpretation of Results

    When the responsible physician has received the CDB, CDU and/or 
B2MU results, these results must be compared to the action levels 
discussed in the final rule for cadmium. The comparison of the 
sample results to action levels is straightforward. The measured 
value reported from the laboratory can be compared directly to the 
action levels; if the reported value exceeds an action level, the 
required actions must be initiated.

4.0  Background

    Cadmium is a naturally-occurring environmental contaminant to 
which humans are continually exposed in food, water, and air. The 
average daily intake of cadmium by the U.S. population is estimated 
to be 10-20 g/day. Most of this intake is via ingestion, 
for which absorption is estimated at 4-7% (Kowal et al. 1979). An 
additional nonoccupational source of cadmium is smoking tobacco; 
smoking a pack of cigarettes a day adds an additional 2-4 g 
cadmium to the daily intake, assuming absorption via inhalation of 
25-35% (Nordberg and Nordberg 1988; Friberg and Elinder 1988; Travis 
and Haddock 1980).
    Exposure to cadmium fumes and dusts in an occupational setting 
where air concentrations are 20-50 g/m\3\ results in an 
additional daily intake of several hundred micrograms (Friberg and 
Elinder 1988, p. 563). In such a setting, occupational exposure to 
cadmium occurs primarily via inhalation, although additional 
exposure may occur through the ingestion of material via 
contaminated hands if workers eat or smoke without first washing. 
Some of the particles that are inhaled initially may be ingested 
when the material is deposited in the upper respiratory tract, where 
it may be cleared by mucociliary transport and subsequently 
swallowed.
    Cadmium introduced into the body through inhalation or ingestion 
is transported by the albumin fraction of the blood plasma to the 
liver, where it accumulates and is stored principally as a bound 
form complexed with the protein metallothionein. Metallothionein-
bound cadmium is the main form of cadmium subsequently transported 
to the kidney; it is these 2 organs, the liver and kidney, in which 
the majority of the cadmium body burden accumulates. As much as one 
half of the total body burden of cadmium may be found in the kidneys 
(Nordberg and Nordberg 1988).
    Once cadmium has entered the body, elimination is slow; about 
0.02% of the body burden is excreted per day via urinary/fecal 
elimination. The whole-body half-life of cadmium is 10-35 years, 
decreasing slightly with increasing age (Travis and Haddock 1980).
    The continual accumulation of cadmium is the basis for its 
chronic noncarcinogenic toxicity. This accumulation makes the kidney 
the target organ in which cadmium toxicity usually is first observed 
(Piscator 1964). Renal damage may occur when cadmium levels in the 
kidney cortex approach 200 g/g wet tissue-weight (Travis 
and Haddock 1980).
    The kinetics and internal distribution of cadmium in the body 
are complex, and depend on whether occupational exposure to cadmium 
is ongoing or has terminated. In general, cadmium in blood is 
related principally to recent cadmium exposure, while cadmium in 
urine reflects cumulative exposure (i.e., total body burden) 
(Lauwerys et al. 1976; Friberg and Elinder 1988).

4.1  Health Effects

    Studies of workers in a variety of industries indicate that 
chronic exposure to cadmium may be linked to several adverse health 
effects including kidney dysfunction, reduced pulmonary function, 
chronic lung disease and cancer (Federal Register 1990). The primary 
sites for cadmium-associated cancer appear to be the lung and the 
prostate.
    Cancer. Evidence for an association between cancer and cadmium 
exposure comes from both epidemiological studies and animal 
experiments. Pott (1965) found a statistically significant elevation 
in the incidence of prostate cancer among a cohort of cadmium 
workers. Other epidemiology studies also report an elevated 
incidence of prostate cancer; however, the increases observed in 
these other studies were not statistically significant (Meridian 
Research, Inc. 1989).
    One study (Thun et al. 1985) contains sufficiently quantitative 
estimates of cadmium exposure to allow evaluation of dose-response 
relationships between cadmium exposure and lung cancer. A 
statistically significant excess of lung cancer attributed to 
cadmium exposure was found in this study, even after accounting for 
confounding variables such as coexposure to arsenic and smoking 
habits (Meridian Research, Inc. 1989).
    Evidence for quantifying a link between lung cancer and cadmium 
exposure comes from a single study (Takenaka et al. 1983). In this 
study, dose-response relationships developed from animal data were 
extrapolated to humans using a variety of models. OSHA chose the 
multistage risk model for estimating the risk of cancer for humans 
using these animal data. Animal injection studies also suggest an 
association between cadmium exposure and cancer, particularly 
observations of an increased incidence of tumors at sites remote 
from the point of injection. The International Agency for Research 
on Cancer (IARC) (Supplement 7, 1987) indicates that this, and 
related, evidence is sufficient to classify cadmium as an animal 
carcinogen. However, the results of these injection studies cannot 
be used to quantify risks attendant to human occupational exposures 
due to differences in routes of exposure (Meridian Research, Inc. 
1989).
    Based on the above-cited studies, the U.S. Environmental 
Protection Agency (EPA) classifies cadmium as ``B1,'' a probable 
human carcinogen (USEPA 1985). IARC in 1987 recommended that cadmium 
be listed as a probable human carcinogen.
    Kidney Dysfunction. The most prevalent nonmalignant effect 
observed among workers chronically exposed to cadmium is kidney 
dysfunction. Initially, such dysfunction is manifested by 
proteinuria (Meridian Research, Inc. 1989; Roth Associates, Inc. 
1989). Proteinuria associated with cadmium exposure is most commonly 
characterized by excretion of low-molecular weight proteins (15,000-
40,000 MW), accompanied by loss of electrolytes, uric acid, calcium, 
amino acids, and phosphate. Proteins commonly excreted include 
-2-microglobulin (B2M), retinol-binding protein (RBP), 
immunoglobulin light chains, and lysozyme. Excretion of low 
molecular weight proteins is characteristic of damage to the 
proximal tubules of the kidney (Iwao et al. 1980).
    Exposure to cadmium also may lead to urinary excretion of high-
molecular weight proteins such as albumin, immunoglobulin G, and 
glycoproteins (Meridian Research, Inc. 1989; Roth Associates, Inc. 
1989). Excretion of high-molecular weight proteins is indicative of 
damage to the glomeruli of the kidney. Bernard et al. (1979) suggest 
that cadmium-associated damage to the glomeruli and damage to the 
proximal tubules of the kidney develop independently of each other, 
but may occur in the same individual.
    Several studies indicate that the onset of low-molecular weight 
proteinuria is a sign of irreversible kidney damage (Friberg et al. 
1974; Roels et al. 1982; Piscator 1984; Elinder et al. 1985; Smith 
et al. 1986). For many workers, once sufficiently elevated levels of 
B2M are observed in association with cadmium exposure, such levels 
do not appear to return to normal even when cadmium exposure is 
eliminated by removal of the worker from the cadmium-contaminated 
work environment (Friberg, exhibit 29, 1990).
    Some studies indicate that cadmium-induced proteinuria may be 
progressive; levels of B2MU increase even after cadmium exposure has 
ceased (Elinder et al. 1985). Other researchers have reached similar 
conclusions (Frieburg testimony, OSHA docket exhibit 29, Elinder 
testimony, OSHA docket exhibit 55, and OSHA docket exhibits 8-86B). 
Such observations are not universal, however (Smith et al. 1986; 
Tsuchiya 1976). Studies in which proteinuria has not been observed, 
however, may have initiated the reassessment too early (Meridian 
Research, Inc.1989; Roth Associates, Inc. 1989; Roels 1989).
    A quantitative assessment of the risks of developing kidney 
dysfunction as a result of cadmium exposure was performed using the 
data from Ellis et al. (1984) and Falck et al. (1983). Meridian 
Research, Inc. (1989) and Roth Associates, Inc. (1989) employed 
several mathematical models to evaluate the data from the 2 studies, 
and the results indicate that cumulative cadmium exposure levels 
between 5 and 100 g-years/m\3\ correspond with a one-in-a-
thousand probability of developing kidney dysfunction.
    When cadmium exposure continues past the onset of early kidney 
damage (manifested as proteinuria), chronic nephrotoxicity may occur 
(Meridian Research, Inc. 1989; Roth Associates, Inc. 1989). Uremia, 
which is the loss of the glomerulus' ability to adequately filter 
blood, may result. This condition leads to severe disturbance of 
electrolyte concentrations, which may result in various clinical 
complications including atherosclerosis, hypertension, pericarditis, 
anemia, hemorrhagic tendencies, deficient cellular immunity, bone 
changes, and other problems. Progression of the disease may require 
dialysis or a kidney transplant.
    Studies in which animals are chronically exposed to cadmium 
confirm the renal effects observed in humans (Friberg et al. 1986). 
Animal studies also confirm cadmium-related problems with calcium 
metabolism and associated skeletal effects, which also have been 
observed among humans. Other effects commonly reported in chronic 
animal studies include anemia, changes in liver morphology, 
immunosuppression and hypertension. Some of these effects may be 
associated with cofactors; hypertension, for example, appears to be 
associated with diet, as well as with cadmium exposure. Animals 
injected with cadmium also have shown testicular necrosis.

4.2  Objectives for Medical Monitoring

    In keeping with the observation that renal disease tends to be 
the earliest clinical manifestation of cadmium toxicity, the final 
cadmium standard mandates that eligible workers must be medically 
monitored to prevent this condition (as well as cadmimum-induced 
cancer). The objectives of medical-monitoring, therefore, are to: 
Identify workers at significant risk of adverse health effects from 
excess, chronic exposure to cadmium; prevent future cases of 
cadmium-induced disease; detect and minimize existing cadmium-
induced disease; and, identify workers most in need of medical 
intervention.
    The overall goal of the medical monitoring program is to protect 
workers who may be exposed continuously to cadmium over a 45-year 
occupational lifespan. Consistent with this goal, the medical 
monitoring program should assure that:
    1. Current exposure levels remain sufficiently low to prevent 
the accumulation of cadmium body burdens sufficient to cause disease 
in the future by monitoring CDB as an indicator of recent cadmium 
exposure;
    2. Cumulative body burdens, especially among workers with 
undefined historical exposures, remain below levels potentially 
capable of leading to damage and disease by assessing CDU as an 
indicator of cumulative exposure to cadmium; and,
    3. Health effects are not occurring among exposed workers by 
determining B2MU as an early indicator of the onset of cadmium-
induced kidney disease.

4.3  Indicators of Cadmium Exposure and Disease

    Cadmium is present in whole blood bound to albumin, in 
erythrocytes, and as a metallothionein-cadmium complex. The 
metallothionein-cadmium complex that represents the primary 
transport mechanism for cadmium delivery to the kidney. CDB 
concentrations in the general, nonexposed population average 1 
g Cd/l whole blood, with smokers exhibiting higher levels 
(see Section 5.1.6). Data presented in Section 5.1.6 shows that 95% 
of the general population not occupationally exposed to cadmium have 
CDB levels less than 5 g Cd/l.
    If total body burdens of cadmium remain low, CDB concentrations 
indicate recent exposure (i.e., daily intake). This conclusion is 
based on data showing that cigarette smokers exhibit CDB 
concentrations of 2-7 g/l depending on the number of 
cigarettes smoked per day (Nordberg and Nordberg 1988), while CDB 
levels for those who quit smoking return to general population 
values (approximately 1 g/l) within several weeks (Lauwerys 
et al. 1976). Based on these observations, Lauwerys et al. (1976) 
concluded that CDB has a biological half-life of a few weeks to less 
than 3 months. As indicated in Section 3.1.6, the upper 95th 
percentile for CDB levels observed among those who are not 
occupationally exposed to cadmium is 5 g/l, which suggests 
that the absolute upper limit to the range reported for smokers by 
Nordberg and Nordberg may have been affected by an extreme value 
(i.e., beyond 2 above the mean).
    Among occupationally-exposed workers, the occupational history 
of exposure to cadmium must be evaluated to interpret CDB levels. 
New workers, or workers with low exposures to cadmium, exhibit CDB 
levels that are representative of recent exposures, similar to the 
general population. However, for workers with a history of chronic 
exposure to cadmium, who have accumulated significant stores of 
cadmium in the kidneys/liver, part of the CDB concentrations appear 
to indicate body burden. If such workers are removed from cadmium 
exposure, their CDB levels remain elevated, possibly for years, 
reflecting prior long-term accumulation of cadmium in body tissues. 
This condition tends to occur, however, only beyond some threshold 
exposure value, and possibly indicates the capacity of body tissues 
to accumulate cadmium which cannot be excreted readily (Friberg and 
Elinder 1988; Nordberg and Nordberg 1988).
    CDU is widely used as an indicator of cadmium body burdens 
(Nordberg and Nordberg 1988). CDU is the major route of elimination 
and, when CDU is measured, it is commonly expressed either as 
g Cd/l urine (unadjusted), g Cd/l urine (adjusted 
for specific gravity), or g Cd/g CRTU (see Section 5.2.1). 
The metabolic model for CDU is less complicated than CDB, since CDU 
is dependentin large part on the body (i.e., kidney) burden of 
cadmium. However, a small proportion of CDU still be attributed to 
recent cadmium exposure, particularly if exposure to high airborne 
concentrations of cadmium occurred. Note that CDU is subject to 
larger interindividual and day-to-day variations than CDB, so 
repeated measurements are recommended for CDU evaluations.
    CDU is bound principally to metallothionein, regardless of 
whether the cadmium originates from metallothionein in plasma or 
from the cadmium pool accumulated in the renal tubules. Therefore, 
measurement of metallothionein in urine may provide information 
similar to CDU, while avoiding the contamination problems that may 
occur during collection and handling urine for cadmium analysis 
(Nordberg and Nordberg 1988). However, a commercial method for the 
determination of metallothionein at the sensitivity levels required 
under the final cadmium rule is not currently available; therefore, 
analysis of CDU is recommended.
    Among the general population not occupationally exposed to 
cadmium, CDU levels average less than 1 g/l (see Section 
5.2.7). Normalized for creatinine (CRTU), the average CDU 
concentration of the general population is less than 1 g/g 
CRTU. As cadmium accumulates over the lifespan, CDU increases with 
age. Also, cigarette smokers may eventually accumulate twice the 
cadmium body burden of nonsmokers, CDU is slightly higher in smokers 
than in nonsmokers, even several years after smoking cessation 
(Nordberg and Nordberg 1988). Despite variations due to age and 
smoking habits, 95% of those not occupationally exposed to cadmium 
exhibit levels of CDU less than 3 g/g CRTU (based on the 
data presented in Section 5.2.7).
    About 0.02% of the cadmium body burden is excreted daily in 
urine. When the critical cadmium concentration (about 200 ppm) in 
the kidney is reached, or if there is sufficient cadmium-induced 
kidney dysfunction, dramatic increases in CDU are observed (Nordberg 
and Nordberg 1988). Above 200 ppm, therefore, CDU concentrations 
cease to be an indicator of cadmium body burden, and are instead an 
index of kidney failure.
    Proteinuria is an index of kidney dysfunction, and is defined by 
OSHA to be a material impairment. Several small proteins may be 
monitored as markers for proteinuria. Below levels indicative of 
proteinuria, these small proteins may be early indicators of 
increased risk of cadmium-induced renal tubular disease. Analytes 
useful for monitoring cadmium-induced renal tubular damage include:
    1. -2-Microglobulin (B2M), currently the most widely 
used assay for detecting kidney dysfunction, is the best 
characterized analyte available (Iwao et al. 1980; Chia et al. 
1989);
    2. Retinol Binding Protein (RBP) is more stable than B2M in 
acidic urine (i.e., B2M breakdown occurs if urinary pH is less than 
5.5; such breakdown may result in false [i.e., low] B2M values 
[Bernard and Lauwerys, 1990]);
    3. N-Acetyl-B-Glucosaminidase (NAG) is the analyte of an assay 
that is simple, inexpensive, reliable, and correlates with cadmium 
levels under 10 g/g CRTU, but the assay is less sensitive 
than RBP or B2M (Kawada et al. 1989);
    4. Metallothionein (MT) correlates with cadmium and B2M levels, 
and may be a better predictor of cadmium exposure than CDU and B2M 
(Kawada et al. 1989);
    5. Tamm-Horsfall Glycoprotein (THG) increases slightly with 
elevated cadmium levels, but this elevation is small compared to 
increases in urinary albumin, RBP, or B2M (Bernard and Lauwerys 
1990);
    6. Albumin (ALB), determined by the biuret method, is not 
sufficiently sensitive to serve as an early indicator of the onset 
of renal disease (Piscator 1962);
    7. Albumin (ALB), determined by the Amido Black method, is 
sensitive and reproducible, but involves a time-consuming procedure 
(Piscator 1962);
    8. Glycosaminoglycan (GAG) increases among cadmium workers, but 
the significance of this effect is unknown because no relationship 
has been found between elevated GAG and other indices of tubular 
damage (Bernard and Lauwerys 1990);
    9. Trehalase seems to increase earlier than B2M during cadmium 
exposure, but the procedure for analysis is complicated and 
unreliable (Iwata et al. 1988); and,
    10. Kallikrein is observed at lower concentrations among 
cadmium-exposed workers than among normal controls (Roels et al. 
1990).
    Of the above analytes, B2M appears to be the most widely used 
and best characterized analyte to evaluate the presence/absence, as 
well as the extent of, cadmium-induced renal tubular damage (Kawada, 
Koyama, and Suzuki 1989; Shaikh and Smith 1984; Nogawa 1984). 
However, it is important that samples be collected and handled so as 
to minimize B2M degradation under acidic urine conditions.
    The threshold value of B2MU commonly used to indicate the 
presence of kidney damage 300 g/g CRTU (Kjellstrom et al. 
1977a; Buchet et al. 1980; and Kowal and Zirkes 1983). This value 
represents the upper 95th or 97.5th percentile level of urinary 
excretion observed among those without tubular dysfunction (Elinder, 
exbt L-140-45, OSHA docket H057A). In agreement with these 
conclusions, the data presented in Section 5.3.7 of this protocol 
generally indicate that the level of 300 g/g CRTU appears 
to define the boundary for kidney dysfunction. It is not clear, 
however, that this level represents the upper 95th percentile of 
values observed among those who fail to demonstrate proteinuria 
effects.
    Although elevated B2MU levels appear to be a fairly specific 
indicator of disease associated with cadmium exposure, other 
conditions that may lead to elevated B2MU levels include high fevers 
from influenza, extensive physical exercise, renal disease unrelated 
to cadmium exposure, lymphomas, and AIDS (Iwao et al. 1980; Schardun 
and van Epps 1987). Elevated B2M levels observed in association with 
high fevers from influenza or from extensive physical exercise are 
transient, and will return to normal levels once the fever has 
abated or metabolic rates return to baseline values following 
exercise. The other conditions linked to elevated B2M levels can be 
diagnosed as part of a properly-designed medical examination. 
Consequently, monitoring B2M, when accompanied by regular medical 
examinations and CDB and CDU determinations (as indicators of 
present and past cadmium exposure), may serve as a specific, early 
indicator of cadmium-induced kidney damage.

4.4  Criteria for Medical Monitoring of Cadmium Workers

    Medical monitoring mandated by the final cadmium rule includes a 
combination of regular medical examinations and periodic monitoring 
of 3 analytes: CDB, CDU and B2MU. As indicated above, CDB is 
monitored as an indicator of current cadmium exposure, while CDU 
serves as an indicator of the cadmium body burden; B2MU is assessed 
as an early marker of irreversible kidney damage and disease.
    The final cadmium rule defines a series of action levels that 
have been developed for each of the 3 analytes to be monitored. 
These action levels serve to guide the responsible physician through 
a decision-making process. For each action level that is exceeded, a 
specific response is mandated. The sequence of action levels, and 
the attendant actions, are described in detail in the final cadmium 
rule.
    Other criteria used in the medical decision-making process 
relate to tests performed during the medical examination (including 
a determination of the ability of a worker to wear a respirator). 
These criteria, however, are not affected by the results of the 
analyte determinations addressed in the above paragraphs and, 
consequently, will not be considered further in these guidelines.

4.5  Defining to Quality and Proficiency of the Analyte Determinations

    As noted above in Sections 2 and 3, the quality of a measurement 
should be defined along with its value to properly interpret the 
results. Generally, it is necessary to know the accuracy and the 
precision of a measurement before it can be properly evaluated. The 
precision of the data from a specific laboratory indicates the 
extent to which the repeated measurements of the same sample vary 
within that laboratory. The accuracy of the data provides an 
indication of the extent to which these results deviate from average 
results determined from many laboratories performing the same 
measurement (i.e., in the absence of an independent determination of 
the true value of a measurement). Note that terms are defined 
operationally relative to the manner in which they will be used in 
this protocol. Formal definitions for the terms in italics used in 
this section can be found in the list of definitions (Section 2).
    Another data quality criterion required to properly evaluate 
measurement results is the limit of detection of that measurement. 
For measurements to be useful, the range of the measurement which is 
of interest for biological monitoring purposes must lie entirely 
above the limit of detection defined for that measurement.
    The overall quality of a laboratory's results is termed the 
performance of that laboratory. The degree to which a laboratory 
satisfies a minimum performance level is referred to as the 
proficiency of the laboratory. A successful medical monitoring 
program, therefore, should include procedures developed for 
monitoring and recording laboratory performance; these procedures 
can be used to identify the most proficient laboratories.

5.0  Overview of Medical Monitoring Tests for CDB, CDU, B2MU and CRTU

    To evaluate whether available methods for assessing CDB, CDU, 
B2MU and CRTU are adequate for determining the parameters defined by 
the proposed action levels, it is necessary to review procedures 
available for sample collection, preparation and analysis. A variety 
of techniques for these purposes have been used historically for the 
determination of cadmium in biological matrices (including CDB and 
CDU), and for the determination of specific proteins in biological 
matrices (including B2MU). However, only the most recent techniques 
are capable of satisfying the required accuracy, precision and 
sensitivity (i.e., limit of detection) for monitoring at the levels 
mandated in the final cadmium rule, while still facilitating 
automated analysis and rapid processing.

5.1  Measuring Cadmium in Blood (CDB)

    Analysis of biological samples for cadmium requires strict 
analytical discipline regarding collection and handling of samples. 
In addition to occupational settings, where cadmium contamination 
would be apparent, cadmium is a ubiquitous environmental 
contaminant, and much care should be exercised to ensure that 
samples are not contaminated during collection, preparation or 
analysis. Many common chemical reagents are contaminated with 
cadmium at concentrations that will interfere with cadmium analysis; 
because of the widespread use of cadmium compounds as colored 
pigments in plastics and coatings, the analyst should continually 
monitor each manufacturer's chemical reagents and collection 
containers to prevent contamination of samples.
    Guarding against cadmium contamination of biological samples is 
particularly important when analyzing blood samples because cadmium 
concentrations in blood samples from nonexposed populations are 
generally less than 2 g/l (2 ng/ml), while occupationally-
exposed workers can be at medical risk to cadmium toxicity if blood 
concentrations exceed 5 g/l (ACGIH 1991 and 1992). This 
narrow margin between exposed and unexposed samples requires that 
exceptional care be used in performing analytic determinations for 
biological monitoring for occupational cadmium exposure.
    Methods for quantifying cadmium in blood have improved over the 
last 40 years primarily because of improvements in analytical 
instrumentation. Also, due to improvements in analytical techniques, 
there is less need to perform extensive multi-step sample 
preparations prior to analysis. Complex sample preparation was 
previously required to enhance method sensitivity (for cadmium), and 
to reduce interference by other metals or components of the sample.

5.1.1  Analytical Techniques Used to Monitor Cadmium in Biological 
Matrices

      

Table 3.--Comparison of Analytical Procedures/Instrumentation for Determination of Cadmium in Biological Samples
----------------------------------------------------------------------------------------------------------------
                            Limit of                                                                            
  Analytical procedure   detection [ng/    Specified biological          Reference               Comments       
                           (g or ml)]             matrix                                                        
----------------------------------------------------------------------------------------------------------------
Flame Atomic Absorption  1.0  Any matrix.............  Perkin-Elmer (1982)...  Not sensitive enough  
 Spectroscopy (FAAS).                                                                      for biomonitoring    
                                                                                           without extensive    
                                                                                           sample digestion,    
                                                                                           metal chelation and  
                                                                                           organic solvent      
                                                                                           extraction.          
Graphite Furnace Atomic            0.04  Urine..................  Pruszkowska et al.      Methods of choice for 
 Absorption                                                        (1983).                 routine cadmium      
 Spectroscopy (GFAAS).                                                                     analysis.            
                         0.2  Blood..................  Stoeppler and Brandt                          
                                   0                               (1980).                                      
Inductively-Coupled                2.0   Any matrix.............  NIOSH (1984A).........  Requires extensive    
 Argon-Plasma Atomic                                                                       sample preparation   
 Emission Spectroscopy                                                                     and concentration of 
 (ICAP AES).                                                                               metal with chelating 
                                                                                           resin. Advantage is  
                                                                                           simultaneous analyses
                                                                                           for as many as 10    
                                                                                           metals from 1 sample.
Neutron Activation                 1.5   In vivo (liver)........  Ellis et al. (1983)...  Only available in vivo
 Gamma Spectroscopy                                                                        method for direct    
 (NA).                                                                                     determination of     
                                                                                           cadmium body tissue  
                                                                                           burdens; expensive;  
                                                                                           absolute             
                                                                                           determination of     
                                                                                           cadmium in reference 
                                                                                           materials.           
Isotope Dilution Mass             <1.0   Any matrix.............  Michiels and DeBievre   Suitable for absolute 
 Spectroscopy (IDMS).                                              (1986).                 determination of     
                                                                                           cadmium in reference 
                                                                                           materials; expensive.
Differential Pulse                <1.0   Any matrix.............  Stoeppler and Brandt    Suitable for absolute 
 Anodic Stripping                                                  (1980).                 determination of     
 Voltammetry (DPASV).                                                                      cadmium in reference 
                                                                                           materials; efficient 
                                                                                           method to check      
                                                                                           accuracy of          
                                                                                           analytical method.   
----------------------------------------------------------------------------------------------------------------

    A number of analytical techniques have been used for determining 
cadmium concentrations in biological materials. A summary of the 
characteristics of the most widely employed techniques is presented 
in Table 3. The technique most suitable for medical monitoring for 
cadmium is atomic absorption spectroscopy (AAS).
    To obtain a measurement using AAS, a light source (i.e., hollow 
cathode or lectrode-free discharge lamp) containing the element of 
interest as the cathode, is energized and the lamp emits a spectrum 
that is unique for that element. This light source is focused 
through a sample cell, and a selected wavelength is monitored by a 
monochrometer and photodetector cell. Any ground state atoms in the 
sample that match those of the lamp element and are in the path of 
the emitted light may absorb some of the light and decrease the 
amount of light that reaches the photodetector cell. The amount of 
light absorbed at each characteristic wavelength is proportional to 
the number of ground state atoms of the corresponding element that 
are in the pathway of the light between the source and detector.
    To determine the amount of a specific metallic element in a 
sample using AAS, the sample is dissolved in a solvent and aspirated 
into a high-temperature flame as an aerosol. At high temperatures, 
the solvent is rapidly evaporated or decomposed and the solute is 
initially solidified; the majority of the sample elements then are 
transformed into an atomic vapor. Next, a light beam is focused 
above the flame and the amount of metal in the sample can be 
determined by measuring the degree of absorbance of the atoms of the 
target element released by the flame at a characteristic wavelength.
    A more refined atomic absorption technique, flameless AAS, 
substitutes an electrothermal, graphite furnace for the flame. An 
aliquot (10-100 l) of the sample is pipetted into the cold 
furnace, which is then heated rapidly to generate an atomic vapor of 
the element.
    AAS is a sensitive and specific method for the elemental 
analysis of metals; its main drawback is nonspecific background 
absorbtion and scattering of the light beam by particles of the 
sample as it decomposes at high temperatures; nonspecific absorbance 
reduces the sensitivity of the analytical method. The problem of 
nonspecific absorbance and scattering can be reduced by extensive 
sample pretreatment, such as ashing and/or acid digestion of the 
sample to reduce its organic content.
    Current AAS instruments employ background correction devices to 
adjust electronically for background absorbtion and scattering. A 
common method to correct for background effects is to use a 
deuterium arc lamp as a second light source. A continuum light 
source, such as the deuterium lamp, emits a broad spectrum of 
wavelengths instead of specific wavelengths characteristic of a 
particular element, as with the hollow cathode tube. With this 
system, light from the primary source and the continuum source are 
passed alternately through the sample cell. The target element 
effectively absorbs light only from the primary source (which is 
much brighter than the continuum source at the characteristic 
wavelengths), while the background matrix absorbs and scatters light 
from both sources equally. Therefore, when the ratio of the two 
beams is measured electronically, the effect of nonspecific 
background absorption and scattering is eliminated. A less common, 
but more sophisticated, backgrond correction system is based on the 
Zeeman effect, which uses a magnetically-activated light polarizer 
to compensate electronically for nonspecific absorbtion and 
scattering.
    Atomic emission spectroscopy with inductively-coupled argon 
plasma (AES-ICAP) is widely used to analyze for metals. With this 
instrument, the sample is aspirated into an extremely hot argon 
plasma flame, which excites the metal atoms; emission spectra 
specific for the sample element then are generated. The quanta of 
emitted light passing through a monochrometer are amplified by 
photomultiplier tubes and measured by a photodetector to determine 
the amount of metal in the sample. An advantage of AES-ICAP over AAS 
is that multi-elemental analyses of a sample can be performed by 
simultaneously measuring specific elemental emission energies. 
However, AES-ICAP lacks the sensitivity of AAS, exhibiting a limit 
of detection which is higher than the limit of detection for 
graphite-furnace AAS (Table 3).
    Neutron activation (NA) analysis and isotope dilution mass 
spectrometry (IDMS) are 2 additional, but highly specialized, 
methods that have been used for cadmium determinations. These 
methods are expensive because they require elaborate and 
sophisticated instrumentation.
    NA analysis has the distinct advantage over other analytical 
methods of being able to determine cadmium body burdens in specific 
organs (e.g., liver, kidney) in vivo (Ellis et al. 1983). Neutron 
bombardment of the target transforms cadmium-113 to cadmium-114, 
which promptly decays (<10-14 sec) to its ground state, 
emitting gamma rays that are measured using large gamma detectors; 
appropriate shielding and instrumentation are required when using 
this method.
    IDMS analysis, a definitive but laborious method, is based on 
the change in the ratio of 2 isotopes of cadmium (cadmium 111 and 
112) that occurs when a known amount of the element (with an 
artificially altered ratio of the same isotopes [i.e., a cadmium 111 
``spike''] is added to a weighed aliquot of the sample (Michiels and 
De Bievre 1986).

5.1.2  Methods Developed for CDB Determinations

    A variety of methods have been used for preparing and analyzing 
CDB samples; most of these methods rely on one of the analytical 
techniques described above. Among the earliest reports, Princi 
(1947) and Smith et al. (1955) employed a colorimetric procedure to 
analyze for CDB and CDU. Samples were dried and digested through 
several cycles with concentrated mineral acids (HNO3 and 
H2SO4) and hydrogen peroxide (H2O2). The digest 
was neutralized, and the cadmium was complexed with 
diphenylthiocarbazone and extracted with chloroform. The dithizone-
cadmium complex then was quantified using a spectrometer.
    Colorimetric procedures for cadmium analyses were replaced by 
methods based on atomic absorption spectroscopy (AAS) in the early 
1960s, but many of the complex sample preparation procedures were 
retained. Kjellstrom (1979) reports that in Japanese, American and 
Swedish laboratories during the early 1970s, blood samples were wet 
ashed with mineral acids or ashed at high temperature and wetted 
with nitric acid. The cadmium in the digest was complexed with metal 
chelators including diethyl dithiocarbamate (DDTC), ammonium 
pyrrolidine dithiocarbamate (APDC) or diphenylthiocarbazone 
(dithizone) in ammonia-citrate buffer and extracted with methyl 
isobutyl ketone (MIBK). The resulting solution then was analyzed by 
flame AAS or graphite-furnace AAS forcadmium determinations using 
deuterium-lamp background correction.
    In the late 1970s, researchers began developing simpler 
preparation procedures. Roels et al. (1978) and Roberts and Clark 
(1986) developed simplified digestion procedures. Using the Roberts 
and Clark method, a 0.5 ml aliquot of blood is collected and 
transferred to a digestion tube containing 1 ml concentrated 
HNO3. The blood is then digested at 110  deg.C for 4 hours. The 
sample is reduced in volume by continued heating, and 0.5 ml 30% 
H2O2 is added as the sample dries. The residue is 
dissolved in 5 ml dilute (1%) HNO3, and 20 l of sample 
is then analyzed by graphite-furnace AAS with deuterium-background 
correction.
    The current trend in the preparation of blood samples is to 
dilute the sample and add matrix modifiers to reduce background 
interference, rather than digesting the sample to reduce organic 
content. The method of Stoeppler and Brandt (1980), and the 
abbreviated procedure published in the American Public Health 
Association's (APHA) Methods for Biological Monitoring (1988), are 
straightforward and are nearly identical. For the APHA method, a 
small aliquot (50-300 l) of whole blood that has been 
stabilized with ethylenediaminetetraacetate (EDTA) is added to 1.0 
ml 1MHNO3, vigorously shaken and centrifuged. Aliquots (10-25 
l) of the supernatant then are then analyzed by graphite-
furnace AAS with appropriate background correction.
    Using the method of Stoeppler and Brandt (1980), aliquots (50-
200 l) of whole blood that have been stabilized with EDTA 
are pipetted into clean polystyrene tubes and mixed with 150-600 
l of 1 M HNO3. After vigorous shaking, the solution is 
centrifuged and a 10-25 l aliquot of the supernatant then 
is analyzed by graphite-furnace AAS with appropriate background 
correction.
    Claeys-Thoreau (1982) and DeBenzo et al. (1990) diluted blood 
samples at a ratio of 1:10 with a matrix modifier (0.2% Triton X-
100, a wetting agent) for direct determinations of CDB. DeBenzo et 
al. also demonstrated that aqueous standards of cadmium, instead of 
spiked, whole-blood samples, could be used to establish calibration 
curves if standards and samples are treated with additional small 
volumes of matrix modifiers (i.e., 1% HNO3, 0.2% ammonium 
hydrogenphosphate and 1 mg/ml magnesium salts).
    These direct dilution procedures for CDB analysis are simple and 
rapid. Laboratories can process more than 100 samples a day using a 
dedicated graphite-furnace AAS, an auto-sampler, and either a 
Zeeman- or a deuterium-background correction system. Several authors 
emphasize using optimum settings for graphite-furnace temperatures 
during the drying, charring, and atomization processes associated 
with the flameless AAS method, and the need to run frequent QC 
samples when performing automated analysis.

5.1.3  Sample Collection and Handling

    Sample collection procedures are addressed primarily to identify 
ways to minimize the degree of variability that may be introduced by 
sample collection during medical monitoring. It is unclear at this 
point the extent to which collection procedures contribute to 
variability among CDB samples. Sources of variation that may result 
from sampling procedures include time-of-day effects and 
introduction of external contamination during the collection 
process. To minimize these sources, strict adherence to a sample 
collection protocol is recommended. Such a protocol must include 
provisions for thorough cleaning of the site from which blood will 
be extracted; also, every effort should be made to collect samples 
near the same time of day. It is also important to recognize that 
under the recent OSHA blood-borne pathogens standard (29 CFR 
1910.1030), blood samples and certain body fluids must be handled 
and treated as if they are infectious.

5.1.4  Best Achievable Performance

    The best achievable performance using a particular method for 
CDB determinations is assumed to be equivalent to the performance 
reported by research laboratories in which the method was developed.
    For their method, Roberts and Clark (1986) demonstrated a limit 
of detection of 0.4 g Cd/l in whole blood, with a linear 
response curve from 0.4 to 16.0 g Cd/l. They report a 
coefficient of variation (CV) of 6.7% at 8.0 g/l.
    The APHA (1988) reports a range of 1.0-25 g/l, with a 
CV of 7.3% (concentration not stated). Insufficient documentation 
was available to critique this method.
    Stoeppler and Brandt (1980) achieved a detection limit of 0.2 
g Cd/l whole blood, with a linear range of 0.4-12.0 
g Cd/l, and a CV of 15-30%, for samples at <1.0 g/
l. Improved precision (CV of 3.8%) was reported for CDB 
concentrations at 9.3 g/l.

5.1.5  General Method Performance

    For any particular method, the performance expected from 
commercial laboratories may be somewhat lower than that reported by 
the research laboratory in which the method was developed. With 
participation in appropriate proficiency programs and use of a 
proper in-house QA/QC program incorporating provisions for regular 
corrective actions, the performance of commercial laboratories is 
expected to approach that reported by research laboratories. Also, 
the results reported for existing proficiency programs serve as a 
gauge of the likely level of performance that currently can be 
expected from commercial laboratories offering these analyses.
    Weber (1988) reports on the results of the proficiency program 
run by the Centre de Toxicologie du Quebec (CTQ). As indicated 
previously, participants in that program receive 18 blood samples 
per year having cadmium concentrations ranging from 0.2-20 
g/l. Currently, 76 laboratories are participating in this 
program. The program is established for several analytes in addition 
to cadmium, and not all of these laboratories participate in the 
cadmium proficiency-testing program.
    Under the CTQ program, cadmium results from individual 
laboratories are compared against the consensus mean derived for 
each sample. Results indicate that after receiving 60 samples (i.e., 
after participation for approximately three years), 60% of the 
laboratories in the program are able to report results that fall 
within 1 g/l or 15% of the mean, whichever is 
greater. (For this procedure, the 15% criterion was applied to 
concentrations exceeding 7 g/l.) On any single sample of 
the last 20 samples, the percentage of laboratories falling within 
the specified range is between 55 and 80%.
    The CTQ also evaluates the performance of participating 
laboratories against a less severe standard: 2 
g/l or 15% of the mean, whichever is greater (Weber 1988); 
90% of participating laboratories are able to satisfy this standard 
after approximately 3 years in the program. (The 15% criterion is 
used for concentrations in excess of 13 g/l.) On any single 
sample of the last 15 samples, the percentage of laboratories 
falling within the specified range is between 80 and 95% (except for 
a single test for which only 60% of the laboratories achieved the 
desired performance).
    Based on the data presented in Weber (1988), the CV for analysis 
of CDB is nearly constant at 20% for cadmium concentrations 
exceeding 5 g/l, and increases for cadmium concentrations 
below 5 g/l. At 2 g/l, the reported CV rises to 
approximately 40%. At 1 g/l, the reported CV is 
approximately 60%.
    Participating laboratories also tend to overestimate 
concentrations for samples exhibiting concentrations less than 2 
g/l (see Figure 11 of Weber 1988). This problem is due in 
part to the proficiency evaluation criterion that allows reporting a 
minimum 2.0 g/l for evaluated CDB samples. 
There is currently little economic or regulatory incentive for 
laboratories participating in the CTQ program to achieve greater 
accuracy for CDB samples containing cadmium at concentrations less 
than 2.0 g/l, even if the laboratory has the experience and 
competency to distinguish among lower concentrations in the samples 
obtained from the CTQ.
    The collective experience of international agencies and 
investigators demonstrate the need for a vigorous QC program to 
ensure that CDB values reported by participating laboratories are 
indeed reasonably accurate. As Friberg (1988) stated:

``Information about the quality of published data has often been 
lacking. This is of concern as assessment of metals in trace 
concentrations in biological media are fraught with difficulties 
from the collection, handling, and storage of samples to the 
chemical analyses. This has been proven over and over again from the 
results of interlaboratory testing and quality control exercises. 
Large variations in results were reported even from `experienced' 
laboratories.''

    The UNEP/WHO global study of cadmium biological monitoring set a 
limit for CDB accuracy using the maximum allowable deviation method 
at Y=X(0.1X+1) for a targeted concentration of 10 
g Cd/l (Friberg and Vahter 1983). The performance of 
participating laboratories over a concentration range of 1.5-12 
g/l was reported by Lind et al. (1987). Of the 3 QC runs 
conducted during 1982 and 1983, 1 or 2 of the 6 laboratories failed 
each run. For the years 1983 and 1985, between zero and 2 
laboratories failed each of the consecutive QC runs.
    In another study (Vahter and Friberg 1988), QC samples 
consisting of both external (unknown) and internal (stated) 
concentrations were distributed to laboratories participating in the 
epidemiology research. In this study, the maximum acceptable 
deviation between the regression analysis of reported results and 
reference values was set at Y=X(0.05X+0.2) for a 
concentration range of 0.3-5.0 g Cd/l. It is reported that 
only 2 of 5 laboratories had acceptable data after the first QC set, 
and only 1 of 5 laboratories had acceptable data after the second QC 
set. By the fourth QC set, however, all 5 laboratories were judged 
proficient.
    The need for high quality CDB monitoring is apparent when the 
toxicological and biological characteristics of this metal are 
considered; an increase in CDB from 2 to 4 g/l could cause 
a doubling of the cadmium accumulation in the kidney, a critical 
target tissue for selective cadmium accumulation (Nordberg and 
Nordberg 1988).
    Historically, the CDC's internal QC program for CDB cadmium 
monitoring program has found achievable accuracy to be 
10% of the true value at CDB concentrations 
5.0 g/l (Paschal 1990). Data on the performance 
of laboratories participating in this program currently are not 
available.

5.1.6  'Observed CDB Concentrations

    As stated in Section 4.3, CDB concentrations are representative 
of ongoing levels of exposure to cadmium. Among those who have been 
exposed chronically to cadmium for extended periods, however, CDB 
may contain a component attributable to the general cadmium body 
burden.

5.1.6.1  CDB Concentrations Among Unexposed Samples

    Numerous studies have been conducted examining CDB 
concentrations in the general population, and in control groups used 
for comparison with cadmium-exposed workers. A number of reports 
have been published that present erroneously high values of CDB 
(Nordberg and Nordberg 1988). This problem was due to contamination 
of samples during sampling and analysis, and to errors in analysis. 
Early AAS methods were not sufficiently sensitive to accurately 
estimate CDB concentrations.
    Table 4 presents results of recent studies reporting CDB levels 
for the general U.S. population not exposed occupationally to 
cadmium. Other surveys of tissue cadmium using U.S. samples and 
conducted as part of a cooperative effort among Japan, Sweden and 
the U.S., did not collect CDB data because standard analytical 
methodologies were unavailable, and because of analytic problems 
(Kjellstrom 1979; SWRI 1978).

                                                Table 4.--Blood Cadmium Concentrations of U.S. Population Not Occupationally Exposed to Cadmiuma                                                
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                          Lower 95th     Upper 95th                             
                                           No. in                           Smoking       Arithmetic mean      Absolute     Geometric   percentile of  percentile of                            
                Study No.                   study     Sex       Age         habitsb     (S.D.)c    range or   mean (GSD)e   distributionf  distributionf          Reference         
                                             (n)                                                              (95% CI)d                                                                         
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
1.......................................        80  M       4 to 69      NS,S                      1.13        0.35-3.3   0.982.1     (0.5-5.0)                         g(0)         g(5.8)  Ellis et al. (1983).      
3.......................................        24  M       Adults       NS                                               0.62.1     (0.5-7.3)                         g(0)         g(5.6)  Mueller et al. (1989).    
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
aConcentrations reported in g Cd/l blood unless otherwise stated.                                                                                                                      
bNS--never smoked; S--current cigarette smoker.                                                                                                                                                 
cA.S.D.--Arithmetic Standard Deviation.                                                                                                                                                         
dC.I.--Confidence Interval.                                                                                                                                                                     
eG.S.D.--Geometric Standard Deviation.                                                                                                                                                          
f Based on assumed lognormal distribution.                                                                                                                                                      
g Based on assumed normal distribution.                                                                                                                                                         

    Arithmetic and/or geometric means and standard deviations are 
provided in Table 4 for measurements among the populations defined 
in each study listed. The range of reported measurements and/or the 
95% upper and lower confidence intervals for the means are presented 
when this information was reported in a study. For studies reporting 
either an arithmetic or geometric standard deviation along with a 
mean, the lower and upper 95th percentile for the distribution also 
were derived and reported in the table.
    The data provided in Table 4 from Kowal et al. (1979) are from 
studies conducted between 1974 and 1976 evaluating CDB levels for 
the general population in Chicago, and are considered to be 
representative of the U.S. population. These studies indicate that 
the average CDB concentration among those not occupationally exposed 
to cadmium is approximately 1 g/l.
    In several other studies presented in Table 4, measurements are 
reported separately for males and females, and for smokers and 
nonsmokers. The data in this table indicate that similar CDB levels 
are observed among males and females in the general population, but 
that smokers tend to exhibit higher CDB levels than nonsmokers. 
Based on the Kowal et al. (1979) study, smokers not occupationally 
exposed to cadmium exhibit an average CDB level of 1.4 g/l.
    In general, nonsmokers tend to exhibit levels ranging to 2 
g/l, while levels observed among smokers range to 5 
g/l. Based on the data presented in Table 4, 95% of those 
not occupationally exposed to cadmium exhibit CDB levels less than 5 
g/l.

5.1.6.2  CDB Concentrations Among Exposed Workers

    Table 5 is a summary of results from studies reporting CDB 
levels among workers exposed to cadmium in the work place. As in 
Table 4, arithmetic and/or geometric means and standard deviations 
are provided if reported in the listed studies. The absolute range, 
or the 95% confidence interval around the mean, of the data in each 
study are provided when reported. In addition, the lower and upper 
95th percentile of the distribution are presented for each study in 
which a mean and corresponding standard deviation were reported. 
Table 5 also provides estimates of the duration, and level, of 
exposure to cadmium in the work place if these data were reported in 
the listed studies. The data presented in Table 5 suggest that CDB 
levels are dose related. Sukuri et al. (1983) show that higher CDB 
levels are observed among workers experiencing higher work place 
exposure. This trend appears to be true of every one of the studies 
listed in the table.
    CDB levels reported in Table 5 are higher among those showing 
signs of cadmium-related kidney damage than those showing no such 
damage. Lauwerys et al. (1976) report CDB levels among workers with 
kidney lesions that generally are above the levels reported for 
workers without kidney lesions. Ellis et al. (1983) report a similar 
observation comparing workers with and without renal dysfunction, 
although they found more overlap between the 2 groups than Lauwerys 
et al.

                                                              Table 5--Blood Cadmium in Workers Exposed to Cadmium in the Workplace                                                             
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                Concentrations of Cadmium in blooda                             
                                                                                        Mean      ----------------------------------------------------------------------------------------------
  Study         Work environment (worker population        Number    Employment    concentration                         Absolute                                                               
  number                     monitored)                   in study    in years     of cadmium in     Arithmetic mean     range or    Geometric    Lower 95th      Upper 95th                    
                                                                       (mean)     air (g/ (S.D.)b     (95%        mean      percentile of   percentile of      Reference   
                                                                                        m3)                               C.I.)c      (GSD)d      rangee ()f      rangee ()f                    
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
1........  Ni-Cd battery plant and Cd production plant:                     3-40    90                                                                               Lauwerys et al. 
                                                                                                                                                                                 1976.          
           (Workers without kidney lesions).............        96  ............  ...............  21.41.9  ..........  ..........            (18)            (25)                  
           (Workers with kidney lesions)................        25  ............  ...............  38.83.8  ..........  ..........            (32)            (45)                  
2........  Ni-Cd battery plant:                                                                                                                                                 Adamsson et al. 
                                                                                                                                                                                 (1979).        
           (Smokers)....................................         7           (5)             10.1             22.7        7.3-67.2                                                              
           (Nonsmokers).................................         8           (9)              7.0              7.0        4.9-10.5                                                              
3........  Cadmium alloy plant:                                                                                                                                                 Sukuri et al.   
                                                                                                                                                                                 1982.          
           (High exposure group)........................         7        (10.6)    [1,000-5 yrs;  20.87.1  ..........  ..........           (7.3)            (34)                  
           (Low exposure group).........................         9         (7.3)        40-5 yrs]  7.11.1   ..........  ..........           (5.1)           (9.1)                  
4........  Retrospective study of workers with renal            19         15-41                                                                                ..............  Roels et al.    
            problems:                                                                                                                                                            1982.          
           (Before removal).............................  ........        (27.2)  ...............  39.93.7      11-179  ..........            (34)            (46)                  
           (After removal)..............................  ........        (4.2)g  ...............  14.15.6    5.7-27.4  ..........           (4.4)            (24)                  
5........  Cadmium production plant:                                                                                                                                            Ellis et al.    
                                                                                                                                                                                 1983.          
           (Workers without renal dysfunction)..........        33          1-34  ...............  155.7          7-31  ..........           (5.4)            (25)                  
           (Workers with renal dysfunction).............        18         10-34  ...............  248.5         10-34  ..........           (9.3)            (39)                  
6........  Cd-Cu alloy plant............................        75      Up to 39  ...............  ...................  ..........  8.85.3    2.2-18.8  ..........           (1.3)            (19)  Mueller et al.  
                                                                                                                                                                                 1989.          
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
aConcentrations reported in g Cd/l blood unless otherwise stated.                                                                                                                      
bS.D.--Standard Deviation.                                                                                                                                                                      
cC.I.--Confidence Interval.                                                                                                                                                                     
dG.S.D.--Geometric Standard Deviation.                                                                                                                                                          
e Based on assumed lognormal distribution.                                                                                                                                                      
f Based on assumed normal distribution.                                                                                                                                                         
g Years following removal.                                                                                                                                                                      

    The data in Table 5 also indicate that CDB levels are higher 
among those experiencing current occupational exposure than those 
who have been removed from such exposure. Roels et al. (1982) 
indicate that CDB levels observed among workers experiencing ongoing 
exposure in the work place are almost entirely above levels observed 
among workers removed from such exposure. This finding suggests that 
CDB levels decrease once cadmium exposure has ceased.
    A comparison of the data presented in Tables 4 and 5 indicates 
that CDB levels observed among cadmium-exposed workers is 
significantly higher than levels observed among the unexposed 
groups. With the exception of 2 studies presented in Table 5 (1 of 
which includes former workers in the sample group tested), the lower 
95th percentile for CDB levels among exposed workers are greater 
than 5 g/l, which is the value of the upper 95th percentile 
for CDB levels observed among those who are not occupationally 
exposed. Therefore, a CDB level of 5 g/l represents a 
threshold above which significant work place exposure to cadmium may 
be occurring.

5.1.7  Conclusions and Recommendations for CDB

    Based on the above evaluation, the following recommendations are 
made for a CDB proficiency program.

5.1.7.1  Recommended Method

    The method of Stoeppler and Brandt (1980) should be adopted for 
analyzing CDB. This method was selected over other methods for its 
straightforward sample-preparation procedures, and because 
limitations of the method were described adequately. It also is the 
method used by a plurality of laboratories currently participating 
in the CTQ proficiency program. In a recent CTQ interlaboratory 
comparison report (CTQ 1991), analysis of the methods used by 
laboratories to measure CDB indicates that 46% (11 of 24) of the 
participating laboratories used the Stoeppler and Brandt methodology 
(HNO3 deproteinization of blood followed by analysis of the 
supernatant by GF-AAS). Other CDB methods employed by participating 
laboratories identified in the CTQ report include dilution of blood 
(29%), acid digestion (12%) and miscellaneous methods (12%).
    Laboratories may adopt alternate methods, but it is the 
responsibility of the laboratory to demonstrate that the alternate 
methods meet the data quality objectives defined for the Stoeppler 
and Brandt method (see section 5.1.7.2 below).

5.1.7.2  Data Quality Objectives

    Based on the above evaluation, the following data quality 
objectives (DQOs) should facilitate interpretation of analytical 
results.
    Limit of Detection. 0.5 g/l should be achievable using 
the Stoeppler and Brandt method. Stoeppler and Brandt (1980) report 
a limit of detection equivalent to 0.2 g/l in 
whole blood using 25 l aliquots of deproteinized, diluted 
blood samples.
    Accuracy. Initially, some of the laboratories performing CDB 
measurements may be expected to satisfy criteria similar to the less 
severe criteria specified by the CTQ program, i.e., measurements 
within 2 g/l or 15% (whichever is greater) of the target 
value. About 60% of the laboratories enrolled in the CTQ program 
could meet this criterion on the first proficiencey test (Weber 
1988).
    Currently, approximately 12 laboratories in the CTQ program are 
achieving an accuracy for CDB analysis within the more severe 
constraints of 1 g/l or 15% (whichever is 
greater). Later, as laboratories gain experience, they should 
achieve the level of accuracy exhibited by these 12 laboratories. 
The experience in the CTQ program has shown that, even without 
incentives, laboratories benefit from the feedback of the program; 
after they have analyzed 40-50 control samples from the program, 
performance improves to the point where about 60% of the 
laboratories can meet the stricter criterion of 1 
g/l or 15% (Weber 1988). Thus, this stricter target 
accuracy is a reasonable DQO.
    Precision. Although Stoeppler and Brandt (1980) suggest that a 
coefficient of variation (CV) near 1.3% (for a 10 g/l 
concentration) is achievable for within-run reproducibility, it is 
recognized that other factors affecting within- and between-run 
comparability will increase the achievable CV. Stoeppler and Brandt 
(1980) observed CVs that were as high as 30% for low concentrations 
(0.4 g/l), and CVs of less than 5% for higher 
concentrations.
    For internal QC samples (see section 3.3.1), laboratories should 
to attain an overall precision near 25%. For CDB samples with 
concentrations less than 2 g/l, a target precision of 40% 
is reasonable, while precisions of 20% should be achievable for 
concentrations greater than 2 g/l. Although these values 
are more strict than values observed in the CTQ interlaboratory 
program reported by Webber (1988), they are within the achievable 
limits reported by Stoeppler and Brandt (1980).

5.1.7.3  Quality Assurance/Quality Control

    Commercial laboratories providing measurement of CDB should 
adopt an internal QA/QC program that incorporates the following 
components: Strict adherence to the selected method, including all 
calibration requirements; regular incorporation of QC samples during 
actual runs; a protocol for corrective actions, and documentation of 
these actions; and, participation in an interlaboratory proficiency 
program. Note that the nonmandatory QA/QC program presented in 
Attachment 1 is based on the Stoeppler and Brandt method for CDB 
analysis. Should an alternate method be adopted, the laboratory 
should develop a QA/QC program satisfying the provisions of Section 
3.3.1.

5.2  Measuring Cadmium in Urine (CDU)

    As in the case of CDB measurement, proper determination of CDU 
requires strict analytical discipline regarding collection and 
handling of samples. Because cadmium is both ubiquitous in the 
environment and employed widely in coloring agents for industrial 
products that may be used during sample collection, preparation and 
analysis, care should be exercised to ensure that samples are not 
contaminated during the sampling procedure.
    Methods for CDU determination share many of the same features as 
those employed for the determination of CDB. Thus, changes and 
improvements to methods for measuring CDU over the past 40 years 
parallel those used to monitor CDB. The direction of development has 
largely been toward the simplification of sample preparation 
techniques made possible because of improvements in analytic 
techniques.

5.2.1  Units of CDU Measurement

    Procedures adopted for reporting CDU concentrations are not 
uniform. In fact, the situation for reporting CDU is more 
complicated than for CDB, where concentrations are normalized 
against a unit volume of whole blood.
    Concentrations of solutes in urine vary with several biological 
factors (including the time since last voiding and the volume of 
liquid consumed over the last few hours); as a result, solute 
concentrations should be normalized against another characteristic 
of urine that represents changes in solute concentrations. The 2 
most common techniques are either to standardize solute 
concentrations against the concentration of creatinine, or to 
standardize solute concentrations against the specific gravity of 
the urine. Thus, CDU concentrations have been reported in the 
literature as ``uncorrected'' concentrations of cadmium per volume 
of urine (i.e., g Cd/l urine), ``corrected'' concentrations 
of cadmium per volume of urine at a standard specific gravity (i.e., 
g Cd/l urine at a specific gravity of 1.020), or 
``corrected'' mass concentration per unit mass of creatinine (i.e., 
g Cd/g creatinine). (CDU concentrations [whether 
uncorrected or corrected for specific gravity, or normalized to 
creatinine] occasionally are reported in nanomoles [i.e., nmoles] of 
cadmium per unit mass or volume. In this protocol, these values are 
converted to g of cadmium per unit mass or volume using 89 
nmoles of cadmium=10 g.)
    While it is agreed generally that urine values of analytes 
should be normalized for reporting purposes, some debate exists over 
what correction method should be used. The medical community has 
long favored normalization based on creatinine concentration, a 
common urinary constituent. Creatinine is a normal product of tissue 
catabolism, is excreted at a uniform rate, and the total amount 
excreted per day is constant on a day-to-day basis (NIOSH 1984b). 
While this correction method is accepted widely in Europe, and 
within some occupational health circles, Kowals (1983) argues that 
the use of specific gravity (i.e., total solids per unit volume) is 
more straightforward and practical (than creatinine) in adjusting 
CDU values for populations that vary by age or gender.
    Kowals (1983) found that urinary creatinine (CRTU) is lower in 
females than males, and also varies with age. Creatinine excretion 
is highest in younger males (20-30 years old), decreases at middle 
age (50-60 years), and may rise slightly in later years. Thus, 
cadmium concentrations may be underestimated for some workers with 
high CRTU levels.
    Within a single void urine collection, urine concentration of 
any analyte will be affected by recent consumption of large volumes 
of liquids, and by heavy physical labor in hot environments. The 
absolute amount of analyte excreted may be identical, but 
concentrations will vary widely so that urine must be corrected for 
specific gravity (i.e., to normalize concentrations to the quantity 
of total solute) using a fixed value (e.g., 1.020 or 1.024). 
However, since heavy-metal exposure may increase urinary protein 
excretion, there is a tendency to underestimate cadmium 
concentrations in samples with high specific gravities when 
specific-gravity corrections are applied.
    Despite some shortcomings, reporting solute concentrations as a 
function of creatinine concentration is accepted generally; OSHA 
therefore recommends that CDU levels be reported as the mass of 
cadmium per unit mass of creatinine (g/g CTRU).
    Reporting CDU as g/g CRTU requires an additional 
analytical process beyond the analysis of cadmium: Samples must be 
analyzed independently for creatinine so that results may be 
reported as the ratio of cadmium to creatinine concentrations found 
in the urine sample. Consequently, the overall quality of the 
analysis depends on the combined performance by a laboratory on 
these 2 determinations. The analysis used for CDU determinations is 
addressed below in terms of g Cd/l, with analysis of 
creatinine addressed separately. Techniques for assessing creatinine 
are discussed in Section 5.4.
    Techniques for deriving cadmium as a ratio of CRTU, and the 
confidence limits for independent measurements of cadmium and CRTU, 
are provided in Section 3.3.3.

5.2.2  Analytical Techniques Used to Monitor CDU

    Analytical techniques used for CDU determinations are similar to 
those employed for CDB determinations; these techniques are 
summarized in Table 3. As with CDB monitoring, the technique most 
suitable for CDU determinations is atomic absorption spectroscopy 
(AAS). AAS methods used for CDU determinations typically employ a 
graphite furnace, with background correction made using either the 
deuterium-lamp or Zeeman techniques; Section 5.1.1 provides a 
detailed description of AAS methods.

5.2.3  Methods Developed for CDU Determinations

    Princi (1947), Smith et al. (1955), Smith and Kench (1957), and 
Tsuchiya (1967) used colorimetric procedures similar to those 
described in the CDB section above to estimate CDU concentrations. 
In these methods, urine (50 ml) is reduced to dryness by heating in 
a sand bath and digested (wet ashed) with mineral acids. Cadmium 
then is complexed with dithiazone, extracted with chloroform and 
quantified by spectrophotometry. These early studies typically 
report reagent blank values equivalent to 0.3 g Cd/l, and 
CDU concentrations among nonexposed control groups at maximum levels 
of 10 g Cd/l--erroneously high values when compared to more 
recent surveys of cadmium concentrations in the general population.
    By the mid-1970s, most analytical procedures for CDU analysis 
used either wet ashing (mineral acid) or high temperatures (>400 
deg.C) to digest the organic matrix of urine, followed by cadmium 
chelation with APDC or DDTC solutions and extraction with MIBK. The 
resulting aliquots were analyzed by flame or graphite-furnace AAS 
(Kjellstrom 1979).
    Improvements in control over temperature parameters with 
electrothermal heating devices used in conjunction with flameless 
AAS techniques, and optimization of temperature programs for 
controlling the drying, charring, and atomization processes in 
sample analyses, led to improved analytical detection of diluted 
urine samples without the need for sample digestion or ashing. Roels 
et al. (1978) successfully used a simple sample preparation, 
dilution of 1.0 ml aliquots of urine with 0.1 N HNO3, to 
achieve accurate low-level determinations of CDU.
    In the method described by Pruszkowska et al. (1983), which has 
become the preferred method for CDU analysis, urine samples were 
diluted at a ratio of 1:5 with water; diammonium hydrogenphosphate 
in dilute HNO3 was used as a matrix modifier. The matrix 
modifier allows for a higher charring temperature without loss of 
cadmium through volatilization during pre-atomization. This 
procedure also employs a stabilized temperature platform in a 
graphite furnace, while nonspecific background absorbtion is 
corrected using the Zeeman technique. This method allows for an 
absolute detection limit of approximately 0.04 g Cd/l 
urine.

5.2.4  Sample Collection and Handling

    Sample collection procedures for CDU may contribute to 
variability observed among CDU measurements. Sources of variation 
attendant to sampling include time-of-day, the interval since 
ingestion of liquids, and the introduction of external contamination 
during the collection process. Therefore, to minimize contributions 
from these variables, strict adherence to a sample-collection 
protocol is recommended. This a protocol should include provisions 
for normalizing the conditions under which urine is collected. Every 
effort also should be made to collect samples during the same time 
of day.
    Collection of urine samples from an industrial work force for 
biological monitoring purposes usually is performed using ``spot'' 
(i.e., single-void) urine with the pH of the sample determined 
immediately. Logistic and sample-integrity problems arise when 
efforts are made to collect urine over long periods (e.g., 24 hrs). 
Unless single-void urines are used, there are numerous opportunities 
for measurement error because of poor control over sample 
collection, storage and environmental contamination.
    To minimize the interval during which sample urine resides in 
the bladder, the following adaption to the ``spot'' collection 
procedure is recommended: The bladder should first be emptied, and 
then a large glass of water should be consumed; the sample may be 
collected within an hour after the water is consumed.

5.2.5  Best Achievable Performance

    Performance using a particular method for CDU determinations is 
assumed to be equivalent to the performance reported by the research 
laboratories in which the method was developed. Pruszkowska et al. 
(1983) report a detection limit of 0.04 g/l CDU, with a CV 
of <4% between 0-5 g/l. The CDC reports a minimum CDU 
detection limit of 0.07 g/l using a modified method based 
on Pruszkowska et al. (1983). No CV is stated in this protocol; the 
protocol contains only rejection criteria for internal QC parameters 
used during accuracy determinations with known standards (Attachment 
8 of exhibit 106 of OSHA docket H057A). Stoeppler and Brandt (1980) 
report a CDU detection limit of 0.2 g/l for their 
methodology.

5.2.6  General Method Performance

    For any particular method, the expected initial performance from 
commercial laboratories may be somewhat lower than that reported by 
the research laboratory in which the method was developed. With 
participation in appropriate proficiency programs, and use of a 
proper in-house QA/QC program incorporating provisions for regular 
corrective actions, the performance of commercial laboratories may 
be expected to improve and approach that reported by a research 
laboratories. The results reported for existing proficiency programs 
serve to specify the initial level of performance that likely can be 
expected from commercial laboratories offering analysis using a 
particular method.
    Weber (1988) reports on the results of the CTQ proficiency 
program, which includes CDU results for laboratories participating 
in the program. Results indicate that after receiving 60 samples 
(i.e., after participating in the program for approximately 3 
years), approximately 80% of the participating laboratories report 
CDU results ranging between 2 g/l or 15% of the 
consensus mean, whichever is greater. On any single sample of the 
last 15 samples, the proportion of laboratories falling within the 
specified range is between 75 and 95%, except for a single test for 
which only 60% of the laboratories reported acceptable results. For 
each of the last 15 samples, approximately 60% of the laboratories 
reported results within 1 g or 15% of the mean, 
whichever is greater. The range of concentrations included in this 
set of samples was not reported.
    Another report from the CTQ (1991) summarizes preliminary CDU 
results from their 1991 interlaboratory program. According to the 
report, for 3 CDU samples with values of 9.0, 16.8, 31.5 g/
l, acceptable results (target 2 g/l or 15% of 
the consensus mean, whichever is greater) were achieved by only 44-
52% of the 34 laboratories participating in the CDU program. The 
overall CVs for these 3 CDU samples among the 34 participating 
laboratories were 31%, 25%, and 49%, respectively. The reason for 
this poor performance has not been determined.
    A more recent report from the CTQ (Weber, private communication) 
indicates that 36% of the laboratories in the program have been able 
to achieve the target of 1 g/l or 15% for more 
than 75% of the samples analyzed over the last 5 years, while 45% of 
participating laboratories achieved a target of 2 
g/l or 15% for more than 75% of the samples analyzed over 
the same period.
    Note that results reported in the interlaboratory programs are 
in terms of g Cd/l of urine, unadjusted for creatinine. The 
performance indicated, therefore, is a measure of the performance of 
the cadmium portion of the analyses, and does not include variation 
that may be introduced during the analysis of CRTU.

5.2.7  Observed CDU Concentrations

    Prior to the onset of renal dysfunction, CDU concentrations 
provide a general indication of the exposure history (i.e., body 
burden)(see Section 4.3). Once renal dysfunction occurs, CDU levels 
appear to increase and are no longer indicative solely of cadmium 
body burden (Friberg and Elinder 1988).

5.2.7.1  Range of CDU Concentrations Observed Among Unexposed Samples 

    Surveys of CDU concentrations in the general population were 
first reported from cooperative studies among industrial countries 
(i.e., Japan, U.S. and Sweden) conducted in the mid-1970s. In 
summarizing these data, Kjellstrom (1979) reported that CDU 
concentrations among Dallas, Texas men (age range: <9-59 years; 
smokers and nonsmokers) varied from 0.11-1.12 g/l 
(uncorrected for creatinine or specific gravity). These CDU 
concentrations are intermediate between population values found in 
Sweden (range: 0.11-0.80 g/l) and Japan (range: 0.14-2.32 
g/l).
    Kowal and Zirkes (1983) reported CDU concentrations for almost 
1,000 samples collected during 1978-79 from the general U.S. adult 
population (i.e., nine states; both genders; ages 20-74 years). They 
report that CDU concentrations are lognormally distributed; low 
levels predominated, but a small proportion of the population 
exhibited high levels. These investigators transformed the CDU 
concentrations values, and reported the same data 3 different ways: 
g/l urine (unadjusted), g/l (specific gravity 
adjusted to 1.020), and g/g CRTU. These data are summarized 
in Tables 6 and 7.
    Based on further statistical examination of these data, 
including the lifestyle characteristics of this group, Kowal (1988) 
suggested increased cadmium absorption (i.e., body burden) was 
correlated with low dietary intakes of calcium and iron, as well as 
cigarette smoking.
    CDU levels presented in Table 6 are adjusted for age and gender. 
Results suggest that CDU levels may be slightly different among men 
and women (i.e., higher among men when values are unadjusted, but 
lower among men when the values are adjusted, for specific gravity 
or CRTU). Mean differences among men and women are small compared to 
the standard deviations, and therefore may not be significant. 
Levels of CDU also appear to increase with age. The data in Table 6 
suggest as well that reporting CDU levels adjusted for specific 
gravity or as a function of CRTU results in reduced variability.

   Table 6--Urine Cadmium Concentrations in the U.S. Adult Population:  
        Normal and Concentration-Adjusted Values By Age and Sex1        
------------------------------------------------------------------------
                              Geometric means (and geometric standard   
                                            deviations)                 
                         -----------------------------------------------
                                           SG-adjusted2      Creatine-  
                            Unadjusted     (g/l     adjusted   
                          (g/l)     at 1.020)    (g/g)
------------------------------------------------------------------------
Sex:                                                                    
    Male (n=484)........      0.55 (2.9)      0.73 (2.6)      0.55 (2.7)
    Female (n=498)......      0.49 (3.0)      0.86 (2.7)      0.78 (2.7)
Age:                                                                    
    20-29 (n=222).......      0.32 (3.0)      0.43 (2.7)      0.32 (2.7)
    30-39 (n=141).......      0.46 (3.2)      0.70 (2.8)      0.54 (2.7)
    40-49 (n=142).......      0.50 (3.0)      0.81 (2.6)      0.70 (2.7)
    50-59 (n=117).......      0.61 (2.9)      0.99 (2.4)      0.90 (2.3)
    60-69 (n=272).......      0.76 (2.6)      1.16 (2.3)      1.03 (2.3)
------------------------------------------------------------------------
1From Kowal and Zirkes 1983.                                            
2SC-adjusted is adjusted for specific gravity.                          


   Table 7--Urine Cadmium Concentrations in the U.S. Adult Population:  
      Cumulative Frequency Distribution of Urinary Cadmium (N=982)1     
                             [In percentage]                            
------------------------------------------------------------------------
                                            SG-adjusted      Creatine-  
 Range of concentrations    Unadjusted     (g/l     adjusted   
                          (g/l)     at 1.020)    (g/g)
------------------------------------------------------------------------
<0.5....................            43.9            28.0            35.8
0.6-1.0.................            71.7            56.4            65.6
1.1-1.5.................            84.4            74.9            81.4
1.6-2.0.................            91.3            84.7            88.9
2.1-3.0.................            97.3            94.4            95.8
3.1-4.0.................            98.8            97.4            97.2
4.1-5.0.................            99.4            98.2            97.9
5.1-10.0................            99.6            99.4            99.3
10.0-20.0...............            99.8            99.6           99.6 
------------------------------------------------------------------------
1Source: Kowal and Zirkes (1983).                                       

    The data in the Table 6 indicate the geometric mean of CDU 
levels observed among the general population is 0.52 g Cd/l 
urine (unadjusted), with a geometric standard deviation of 3.0. 
Normalized for creatinine, the geometric mean for the population is 
0.66 g/g CRTU, with a geometric standard deviation of 2.7. 
Table 7 provides the distributions of CDU concentrations for the 
general population studied by Kowal and Zirkes. The data in this 
table indicate that 95% of the CDU levels observed among those not 
occupationally exposed to cadmium are below 3 g/g CRTU.

5.2.7.2  Range of CDU Concentrations Observed Among Exposed Workers

    Table 8 is a summary of results from available studies of CDU 
concentrations observed among cadmium-exposed workers. In this 
table, arithmetic and/or geometric means and standard deviations are 
provided if reported in these studies. The absolute range for the 
data in each study, or the 95% confidence interval around the mean 
of each study, also are provided when reported. The lower and upper 
95th percentile of the distribution are presented for each study in 
which a mean and corresponding standard deviation were reported. 
Table 8 also provides estimates of the years of exposure, and the 
levels of exposure, to cadmium in the work place if reported in 
these studies. Concentrations reported in this table are in 
g/g CRTU, unless otherwise stated. 

                                                      Table 8--Urine Cadmium Concentrations in Workers Exposed to Cadmium in the Workplace                                                      
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                             Concentration of cadmium in Urinea                                 
                                                                                 Mean      -----------------------------------------------------------------------------------------------------
  Study      Work environment (worker population    Number    Employment    Concentration                         Absolute                                                                      
  number                 monitored)                in Study    in years     of cadmium in     Arithmetic mean     range or    Geometric    Lower 95th      Upper 95th                           
                                                      (n)       (mean)     air (g/ (S.D.)b     (95%        mean      percentile of   percentile of         Reference       
                                                                                 m3)                               C.I.)c      (GSD)d      rangee ()f      rangee ()f                           
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
1........  Ni-Cd battery plant and Cd production   ........          3-40    90  ...................  ..........  ..........  ..............  ..............  Lauwerys et al. 1976.  
            plant.                                                                                                                                                                              
           (Workers without kidney lesions)......        96  ............  ...............  16.316.  ..........  ..........             (0)            (44)  .......................
                                                                                                          7                                                                                     
           (Workers with kidney lesions).........        25  ............  ...............  48.242.  ..........  ..........             (0)           (120)  .......................
                                                                                                          6                                                                                     
2........  Ni-Cd battery plant...................  ........  ............  ...............  ...................  ..........  ..........  ..............  ..............  Adamsson et al. (1979).
           (Smokers).............................         7           (5)             10.1              5.5        1.0-14.7  ..........  ..............  ..............  .......................
           (Nonsmokers)..........................         8           (9)              7.0              3.6         0.5-9.3  ..........  ..............  ..............  .......................
3........  Cadmium salts production facility.....       148        (15.4)  ...............             15.8           2-150  ..........  ..............  ..............  Butchet et al. 1980.   
4........  Retrospective study of workers with           19         15-41  ...............  ...................  ..........  ..........  ..............  ..............  Roels et al. 1982.     
            renal problems.                                                                                                                                                                     
           (Before removal)......................  ........        (27.2)  ...............  39.428.    10.8-117  ..........             (0)            (88)  .......................
                                                                                                          1                                                                                     
           (After removal).......................  ........        (4.2)g  ...............  16.49.0     80-42.3  ..........           (1.0)            (32)  .......................
5........  Cadmium production plant..............  ........  ............  ...............  ...................  ..........  ..........  ..............  ..............  Ellis et al. 1983.     
           (Workers without renal dysfunction)...        33          1-34  ...............  9.46.9         2-27  ..........             (0)            (21)  .......................
           (Workers with renal dysfunction)......        18         10-34  ...............  22.812.        8-55  ..........             (1)            (45)  .......................
                                                                                                          7                                                                                     
6........  Cd-Cu alloy plant.....................        75      Up to 39           Note h  6.99.4   ..........  ..........             (0)            (23)  Mason et al. 1988.     
7........  Cadmium recovery operation............        45          (19)               87  9.36.9   ..........  ..........             (0)            (21)  Thun et al. 1989.      
8........  Pigment manufacturing plant...........        29        (12.8)         0.18-3.0  ...................     0.2-9.5         1.1  ..............  ..............  Mueller et al. 1989.   
9........  Pigment manufacturing plant...........        26        (12.1)   3.0  ...................  ..........  1.25aConcentrations are reported in g/g Cr.                                                                                                                                                
bS.D.--Standard Deviation.                                                                                                                                                                      
cC.I.--Confidence Interval.                                                                                                                                                                     
dG.S.D.--Geometric Standard Deviation.                                                                                                                                                          
e Based on assumed lognormal distribution.                                                                                                                                                      
f Based on assumed normal distribution.                                                                                                                                                         
g Years following removal.                                                                                                                                                                      
h Equivalent to 50 for 20-22 yrs.                                                                                                                                                               

    Data in Table 8 from Lauwerys et al. (1976) and Ellis et al. 
(1983) indicate that CDU concentrations are higher among those 
exhibiting kidney lesions or dysfunction than among those lacking 
these symptoms. Data from the study by Roels et al. (1982) indicate 
that CDU levels decrease among workers removed from occupational 
exposure to cadmium in comparison to workers experiencing ongoing 
exposure. In both cases, however, the distinction between the 2 
groups is not as clear as with CDB; there is more overlap in CDU 
levels observed among each of the paired populations than is true 
for corresponding CDB levels. As with CDB levels, the data in Table 
8 suggest increased CDU concentrations among workers who experienced 
increased overall exposure.
    Although a few occupationally-exposed workers in the studies 
presented in Table 8 exhibit CDU levels below 3 g/g CRTU, 
most of those workers exposed to cadmium levels in excess of the PEL 
defined in the final cadmium rule exhibit CDU levels above 3 
g/g CRTU; this level represents the upper 95th percentile 
of the CDU distribution observed among those who are not 
occupationally exposed to cadmium (Table 7).
    The mean CDU levels reported in Table 8 among occupationally-
exposed groups studied (except 2) exceed 3 g/g CRTU. 
Correspondingly, the level of exposure reported in these studies 
(with 1 exception) are significantly higher than what workers will 
experience under the final cadmium rule. The 2 exceptions are from 
the studies by Mueller et al. (1989) and Kawada et al. (1990); these 
studies indicate that workers exposed to cadmium during pigment 
manufacture do not exhibit CDU levels as high as those levels 
observed among workers exposed to cadmium in other occupations. 
Exposure levels, however, were lower in the pigment manufacturing 
plants studied. Significantly, workers removed from occupational 
cadmium exposure for an average of 4 years still exhibited CDU 
levels in excess of 3 g/g CRTU (Roels et al. 1982). In the 
single-exception study with a reported level of cadmium exposure 
lower than levels proposed in the final rule (i.e., the study of a 
pigment manufacturing plant by Kawada et al. 1990), most of the 
workers exhibited CDU levels less than 3 g/g CRTU (i.e., 
the mean value was only 1.3 g/g CRTU). CDU levels among 
workers with such limited cadmium exposure are expected to be 
significantly lower than levels of other studies reported on Table 
8.
    Based on the above data, a CDU level of 3 g/g CRTU 
appear to represent a threshold above which significant work place 
exposure to cadmium occurs over the work span of those being 
monitored. Note that this threshold is not as distinct as the 
corresponding threshold described for CDB. In general, the 
variability associated with CDU measurements among exposed workers 
appears to be higher than the variability associated with CDB 
measurements among similar workers.

5.2.8  Conclusions and Recommendations for CDU

    The above evaluation supports the following recommendations for 
a CDU proficiency program. These recommendations address only 
sampling and analysis procedures for CDU determinations 
specifically, which are to be reported as an unadjusted g 
Cd/l urine. Normalizing this result to creatinine requires a second 
analysis for CRTU so that the ratio of the 2 measurements can be 
obtained. Creatinine analysis is addressed in Section 5.4. Formal 
procedures for combining the 2 measurements to derive a value and a 
confidence limit for CDU in g/g CRTU are provided in 
Section 3.3.3.

5.2.8.1  Recommended Method

    The method of Pruszkowska et al. (1983) should be adopted for 
CDU analysis. This method is recommended because it is simple, 
straightforward and reliable (i.e., small variations in experimental 
conditions do not affect the analytical results).
    A synopsis of the methods used by laboratories to determine CDU 
under the interlaboratory program administered by the CTQ (1991) 
indicates that more than 78% (24 of 31) of the participating 
laboratories use a dilution method to prepare urine samples for CDU 
analysis. Laboratories may adopt alternate methods, but it is the 
responsibility of the laboratory to demonstrate that the alternate 
methods provide results of comparable quality to the Pruszkowska 
method.

5.2.8.2  Data Quality Objectives

    The following data quality objectives should facilitate 
interpretation of analytical results, and are achievable based on 
the above evaluation.
    Limit of Detection. A level of 0.5 g/l (i.e., 
corresponding to a detection limit of 0.5 g/g CRTU, 
assuming 1 g CRT/l urine) should be achievable. Pruszkowska et al. 
(1983) achieved a limit of detection of 0.04 g/l for CDU 
based on the slope the the curve for their working standards (0.35 
pg Cd/0.0044, A signal=1% absorbance using GF-AAS).
    The CDC reports a minimum detection limit for CDU of 0.07 
g/l using a modified Pruszkowska method. This limit of 
detection was defined as 3 times the standard deviation calculated 
from 10 repeated measurements of a ``low level'' CDU test sample 
(Attachment 8 of exhibit 106 of OSHA docket H057A).
    Stoeppler and Brandt (1980) report a limit of detection for CDU 
of 0.2 g/l using an aqueous dilution (1:2) of the urine 
samples.
    Accuracy. A recent report from the CTQ (Weber, private 
communication) indicates that 36% of the laboratories in the program 
achieve the target of 1 g/l or 15% for more 
than 75% of the samples analyzed over the last 5 years, while 45% of 
participating laboratories achieve a target of 2 
g/l or 15% for more than 75% of the samples analyzed over 
the same period. With time and a strong incentive for improvement, 
it is expected that the proportion of laboratories successfully 
achieving the stricter level of accuracy should increase. It should 
be noted, however, these indices of performance do not include 
variations resulting from the ancillary measurement of CRTU (which 
is recommended for the proper recording of results). The low cadmium 
levels expected to be measured indicate that the analysis of 
creatinine will contribute relatively little to the overall 
variability observed among creatinine-normalized CDU levels (see 
Section 5.4). The initial target value for reporting CDU under this 
program, therefore, is set at 1 g/g CRTU or 15% 
(whichever is greater).
    Precision. For internal QC samples (which are recommended as 
part of an internal QA/QC program, Section 3.3.1), laboratories 
should attain an overall precision of 25%. For CDB samples with 
concentrations less than 2 g/l, a target precision of 40% 
is acceptable, while precisions of 20% should be achievable for CDU 
concentrations greater than 2 g/l. Although these values 
are more stringent than those observed in the CTQ interlaboratory 
program reported by Webber (1988), they are well within limits 
expected to be achievable for the method as reported by Stoeppler 
and Brandt (1980).

5.2.8.3  Quality Assurance/Quality Control

    Commercial laboratories providing CDU determinations should 
adopt an internal QA/QC program that incorporates the following 
components: Strict adherence to the selected method, including 
calibration requirements; regular incorporation of QC samples during 
actual runs; a protocol for corrective actions, and documentation of 
such actions; and, participation in an interlaboratory proficiency 
program. Note that the nonmandatory program presented in Attachment 
1 as an example of an acceptable QA/QC program, is based on using 
the Pruszkowska method for CDU analysis. Should an alternate method 
be adopted by a laboratory, the laboratory should develop a QA/QC 
program equivalent to the nonmandatory program, and which satisfies 
the provisions of Section 3.3.1.

5.3  Monitoring -2-Microglobulin in Urine (B2MU).

    As indicated in Section 4.3, B2MU appears to be the best of 
several small proteins that may be monitored as early indicators of 
cadmium-induced renal damage. Several analytic techniques are 
available for measuring B2M.

5.3.1  Units of B2MU Measurement

    Procedures adopted for reporting B2MU levels are not uniform. In 
these guidelines, OSHA recommends that B2MU levels be reported as 
g/g CRTU, similar to reporting CDU concentrations. 
Reporting B2MU normalized to the concentration of CRTU requires an 
additional analytical process beyond the analysis of B2M: 
Independent analysis for creatinine so that results may be reported 
as a ratio of the B2M and creatinine concentrations found in the 
urine sample. Consequently, the overall quality of the analysis 
depends on the combined performance on these 2 analyses. The 
analysis used for B2MU determinations is described in terms of 
g B2M/l urine, with analysis of creatinine addressed 
separately. Techniques used to measure creatinine are provided in 
Section 5.4. Note that Section 3.3.3 provides techniques for 
deriving the value of B2M as function of CRTU, and the confidence 
limits for independent measurements of B2M and CRTU.

5.3.2  Analytical Techniques Used to Monitor B2MU

    One of the earliest tests used to measure B2MU was the radial 
immunodiffusion technique. This technique is a simple and specific 
method for identification and quantitation of a number of proteins 
found in human serum and other body fluids when the protein is not 
readily differentiated by standard electrophoretic procedures. A 
quantitative relationship exists between the concentration of a 
protein deposited in a well that is cut into a thin agarose layer 
containing the corresponding monospecific antiserum, and the 
distance that the resultant complex diffuses. The wells are filled 
with an unknown serum and the standard (or control), and incubated 
in a moist environment at room temperature. After the optimal point 
of diffusion has been reached, the diameters of the resulting 
precipition rings are measured. The diameter of a ring is related to 
the concentration of the constituent substance. For B2MU 
determinations required in the medical monitoring program, this 
method requires a process that may be insufficient to concentrate 
the protein to levels that are required for detection.
    Radioimmunoassay (RIA) techniques are used widely in immunologic 
assays to measure the concentration of antigen or antibody in body-
fluid samples. RIA procedures are based on competitive-binding 
techniques. If antigen concentration is being measured, the 
principle underlying the procedure is that radioactive-labeled 
antigen competes with the sample's unlabeled antigen for binding 
sites on a known amount of immobile antibody. When these 3 
components are present in the system, an equilibrium exists. This 
equilibrium is followed by a separation of the free and bound forms 
of the antigen. Either free or bound radioactive-labeled antigen can 
be assessed to determine the amount of antigen in the sample. The 
analysis is performed by measuring the level of radiation emitted 
either by the bound complex following removal of the solution 
containing the free antigen, or by the isolated solution containing 
the residual-free antigen. The main advantage of the RIA method is 
the extreme sensitivity of detection for emitted radiation and the 
corresponding ability to detect trace amounts of antigen. 
Additionally, large numbers of tests can be performed rapidly.
    The enzyme-linked immunosorbent assay (ELISA) techniques are 
similar to RIA techniques except that nonradioactive labels are 
employed. This technique is safe, specific and rapid, and is nearly 
as sensitive as RIA techniques. An enzyme-labeled antigen is used in 
the immunologic assay; the labeled antigen detects the presence and 
quantity of unlabeled antigen in the sample. In a representative 
ELISA test, a plastic plate is coated with antibody (e.g., antibody 
to B2M). The antibody reacts with antigen (B2M) in the urine and 
forms an antigen-antibody complex on the plate. A second anti-B2M 
antibody (i.e., labeled with an enzyme) is added to the mixture and 
forms an antibody-antigen-antibody complex. Enzyme activity is 
measured spectrophotometrically after the addition of a specific 
chromogenic substrate which is activated by the bound enzyme. The 
results of a typical test are calculated by comparing the 
spectrophotometric reading of a serum sample to that of a control or 
reference serum. In general, these procedures are faster and require 
less laboratory work than other methods.
    In a fluorescent ELISA technique (such as the one employed in 
the Pharmacia Delphia test for B2M), the labeled enzyme is bound to 
a strong fluorescent dye. In the Pharmacia Delphia test, an antigen 
bound to a fluorescent dye competes with unlabeled antigen in the 
sample for a predetermined amount of specific, immobile antibody. 
Once equilibrium is reached, the immobile phase is removed from the 
labeled antigen in the sample solution and washed; an enhancement 
solution then is added that liberates the fluorescent dye from the 
bound antigen-antibody complex. The enhancement solution also 
contains a chelate that complexes with the fluorescent dye in 
solution; this complex increases the fluorescent properties of the 
dye so that it is easier to detect.
    To determine the quantity of B2M in a sample using the Pharmacia 
Delphia test, the intensity of the fluorescence of the enhancement 
solution is measured. This intensity is proportional to the 
concentration of labeled antigen that bound to the immobile antibody 
phase during the initial competition with unlabeled antigen from the 
sample. Consequently, the intensity of the fluorescence is an 
inverse function of the concentration of antigen (B2M) in the 
original sample. The relationship between the fluorescence level and 
the B2M concentration in the sample is determined using a series of 
graded standards, and extrapolating these standards to find the 
concentration of the unknown sample.

5.3.3  Methods Developed for B2MU Determinations

    B2MU usually is measured by radioimmunoassay (RIA) or enzyme-
linked immunosorbent assay (ELISA); however, other methods 
(including gel electrophoresis, radial immunodiffusion, and 
nephelometric assays) also have been described (Schardun and van 
Epps 1987). RIA and ELISA methods are preferred because they are 
sensitive at concentrations as low as micrograms per liter, require 
no concentration processes, are highly reliable and use only a small 
sample volume.
    Based on a survey of the literature, the ELISA technique is 
recommended for monitoring B2MU. While RIAs provide greater 
sensitivity (typically about 1 g/l, Evrin et al. 1971), 
they depend on the use of radioisotopes; use of radioisotopes 
requires adherence to rules and regulations established by the 
Atomic Energy Commission, and necessitates an expensive 
radioactivity counter for testing. Radioisotopes also have a 
relatively short half-life, which corresponds to a reduced shelf 
life, thereby increasing the cost and complexity of testing. In 
contrast, ELISA testing can be performed on routine laboratory 
spectrophotometers, do not necessitate adherence to additional rules 
and regulations governing the handling of radioactive substances, 
and the test kits have long shelf lives. Further, the range of 
sensitivity commonly achieved by the recommended ELISA test (i.e., 
the Pharmacia Delphia test) is approximately 100 g/l 
(Pharmacia 1990), which is sufficient for monitoring B2MU levels 
resulting from cadmium exposure. Based on the studies listed in 
Table 9 (Section 5.3.7), the average range of B2M concentrations 
among the general, nonexposed population falls between 60 and 300 
g/g CRTU. The upper 95th percentile of distributions, 
derived from studies in Table 9 which reported standard deviations, 
range between 180 and 1,140 g/g CRTU. Also, the Pharmacia 
Delphia test currently is the most widely used test for assessing 
B2MU.

5.3.4  Sample Collection and Handling

    As with CDB or CDU, sample collection procedures are addressed 
primarily to identify ways to minimize the degree of variability 
introduced by sample collection during medical monitoring. It is 
unclear the extent to which sample collection contributes to B2MU 
variability. Sources of variation include time-of-day effects, the 
interval since consuming liquids and the quantity of liquids 
consumed, and the introduction of external contamination during the 
collection process. A special problem unique to B2M sampling is the 
sensitivity of this protein to degradation under acid conditions 
commonly found in the bladder. To minimize this problem, strict 
adherence to a sampling protocol is recommended. The protocol should 
include provisions for normalizing the conditions under which the 
urine is collected. Clearly, it is important to minimize the 
interval urine spends in the bladder. It also is recommended that 
every effort be made to collect samples during the same time of day.
    Collection of urine samples for biological monitoring usually is 
performed using ``spot'' (i.e., single-void) urine. Logistics and 
sample integrity become problems when efforts are made to collect 
urine over extended periods (e.g., 24 hrs). Unless single-void 
urines are used, numerous opportunities exist for measurement error 
because of poor control over sample collection, storage and 
environmental contamination.
    To minimize the interval that sample urine resides in the 
bladder, the following adaption to the ``spot'' collection procedure 
is recommended: The bladder should be emptied and then a large glass 
of water should be consumed; the sample then should be collected 
within an hour after the water is consumed.

5.3.5  Best Achievable Performance

    The best achievable performance is assumed to be equivalent to 
the performance reported by the manufacturers of the Pharmacia 
Delphia test kits (Pharmacia 1990). According to the insert that 
comes with these kits, QC results should be within 2 SDs 
of the mean for each control sample tested; a CV of less than or 
equal to 5.2% should be maintained. The total CV reported for test 
kits is less than or equal to 7.2%.

5.3.6  General Method Performance

    Unlike analyses for CDB and CDU, the Pharmacia Delphia test is 
standardized in a commercial kit that controls for many sources of 
variation. In the absence of data to the contrary, it is assumed 
that the achievable performance reported by the manufacturer of this 
test kit will serve as an achievable performance objective. The CTQ 
proficiency testing program for B2MU analysis is expected to use the 
performance parameters defined by the test kit manufacturer as the 
basis of the B2MU proficiency testing program.
    Note that results reported for the test kit are expressed in 
terms of g B2M/l of urine, and have not been adjusted for 
creatinine. The indicated performance, therefore, is a measure of 
the performance of the B2M portion of the analyses only, and does 
not include variation that may have been introduced during the 
analysis of creatinine.

5.3.7  Observed B2MU Concentrations

    As indicated in Section 4.3, the concentration of B2MU may serve 
as an early indicator of the onset of kidney damage associated with 
cadmium exposure.

5.3.7.1  Range of B2MU Concentrations Among Unexposed Samples

    Most of the studies listed in Table 9 report B2MU levels for 
those who were not occupationally exposed to cadmium. Studies noted 
in the second column of this table (which contain the footnote 
``d'') reported B2MU concentrations among cadmium-exposed workers 
who, nonetheless, showed no signs of proteinuria. These latter 
studies are included in this table because, as indicated in Section 
4.3, monitoring B2MU is intended to provide advanced warning of the 
onset of kidney dysfunction associated with cadmium exposure, rather 
than to distinguish relative exposure. This table, therefore, 
indicates the range of B2MU levels observed among those who had no 
symptoms of renal dysfunction (including cadmium-exposed workers 
with none of these symptoms). 

                      Table 9--B-2-Microglobulin Concentrations Observed in Urine Among Those Not Occupationally Exposed to Cadmium                     
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                       Lower 95th            Upper 95th                                 
  Study No.         No. in study         Geometric mean      Geometric standard       percentile of         percentile of              Reference        
                                                                  deviation           distributiona         distributiona                               
--------------------------------------------------------------------------------------------------------------------------------------------------------
1............  133 mb...............  115 g/gc...  4.03................  12..................  1,140 g/gc.  Ishizaki et al. 1989.     
2............  161 fb...............  146 g/gc...  3.11................  23..................  940 g/gc...  Ishizaki et al. 1989.     
3............  10...................  84 g/g.....  ....................  ....................  ....................  Ellis et al. 1983.        
4............  203..................  76 g/l.....  ....................  ....................  ....................  Stewart and Hughes 1981.  
5............  9....................  103 g/g....  ....................  ....................  ....................  Chia et al. 1989.         
6............  47d..................  86 g/L.....  1.9.................  30 g/l.....  250 g/L....  Kjellstrom et al. 1977.   
7............  1,000e...............  68.1 g/gr    3.1 m & f...........  <10 g/gr     320 g/gr     Kowal 1983.               
                                       Crf.                                        Crh.                  Crh.                                           
8............  87...................  71 g/gi....  ....................  7h..................  200h................  Buchet et al. 1980.       
9............  10...................  0.073 mg/24h........  ....................  ....................  ....................  Evrin et al. 1971.        
10...........  59...................  156 g/g....  1.1j................  130.................  180.................  Mason et al. 1988.        
11...........  8....................  118 g/g....  ....................  ....................  ....................  Iwao et al. 1980.         
12...........  34...................  79 g/g.....  ....................  ....................  ....................  Wibowo et al. 1982.       
13...........  41 m.................  ....................  ....................  ....................  400 g/gr     Falck et al. 1983.        
                                                                                                         Crk.                                           
14...........  35n..................  67..................  ....................  ....................  ....................  Roels et al. 1991.        
15...........  31d..................  63..................  ....................  ....................  ....................  Roels et al. 1991.        
16...........  36d..................  77i.................  ....................  ....................  ....................  Miksche et al. 1981.      
17...........  18n..................  130.................  ....................  ....................  ....................  Kawada et al. 1989.       
18...........  32p..................  122.................  ....................  ....................  ....................  Kawada et al. 1989.       
19...........  18d..................  295.................  1.4.................  170.................  510.................  Thun et al. 1989.         
--------------------------------------------------------------------------------------------------------------------------------------------------------
a--Based on an assumed lognormal distribution                                                                                                           
b--m = males, f = females                                                                                                                               
c--Aged general population from non-polluted area; 47.9% population aged 50-69; 52.1%  70 years of age; values reported in study             
d--Exposed workers without proteinuria                                                                                                                  
e--492 females, 484 males                                                                                                                               
f--Creatinine-adjusted; males = 68.1 g/g Cr, females = 64.3 g/g Cr                                                                    
h--Reported in the study                                                                                                                                
i--Arithmetic mean                                                                                                                                      
j--Geometric standard error                                                                                                                             
k--Upper 95% tolerance limits: for Falck this is based on the 24 hour urine sample                                                                      
n--Controls                                                                                                                                             
p--Exposed synthetic resin and pigment workers without proteinuria; Cadmium in urine levels up to 10 g/g Cr                                    

    To the extent possible, the studies listed in Table 9 provide 
geometric means and geometric standard deviations for measurements 
among the groups defined in each study. For studies reporting a 
geometric standard deviation along with a mean, the lower and upper 
95th percentile for these distributions were derived and reported in 
the table.
    The data provided from 15 of the 19 studies listed in Table 9 
indicate that the geometric mean concentration of B2M observed among 
those who were not occupationally exposed to cadmium is 70-170 
g/g CRTU. Data from the 4 remaining studies indicate that 
exposed workers who exhibit no signs of proteinuria show mean B2MU 
levels of 60-300 g/g CRTU. B2MU values in the study by Thun 
et al. (1989), however, appear high in comparison to the other 3 
studies. If this study is removed, B2MU levels for those who are not 
occupationally exposed to cadmium are similar to B2MU levels found 
among cadmium-exposed workers who exhibit no signs of kidney 
dysfunction. Although the mean is high in the study by Thun et al., 
the range of measurements reported in this study is within the 
ranges reported for the other studies.
    Determining a reasonable upper limit from the range of B2M 
concentrations observed among those who do not exhibit signs of 
proteinuria is problematic. Elevated B2MU levels are among the signs 
used to define the onset of kidney dysfunction. Without access to 
the raw data from the studies listed in Table 9, it is necessary to 
rely on reported standard deviations to estimate an upper limit for 
normal B2MU concentrations (i.e., the upper 95th percentile for the 
distributions measured). For the 8 studies reporting a geometric 
standard deviation, the upper 95th percentiles for the distributions 
are 180-1140 g/g CRTU. These values are in general 
agreement with the upper 95th percentile for the distribution (i.e., 
631 g/g CRTU) reported by Buchet et al. (1980). These upper 
limits also appear to be in general agreement with B2MU values 
(i.e., 100-690 g/g CRTU) reported as the normal upper limit 
by Iwao et al. (1980), Kawada et al. (1989), Wibowo et al. (1982), 
and Schardun and van Epps (1987). These values must be compared to 
levels reported among those exhibiting kidney dysfunction to define 
a threshold level for kidney dysfunction related to cadmium 
exposure.

5.3.7.2  Range of B2MU Concentrations Among Exposed Workers

    Table 10 presents results from studies reporting B2MU 
determinations among those occupationally exposed to cadmium in the 
work place; in some of these studies, kidney dysfunction was 
observed among exposed workers, while other studies did not make an 
effort to distinguish among exposed workers based on kidney 
dysfunction. As with Table 9, this table provides geometric means 
and geometric standard deviations for the groups defined in each 
study if available. For studies reporting a geometric standard 
deviation along with a mean, the lower and upper 95th percentiles 
for the distributions are derived and reported in the table.

   Table 10.--2-Microglobulin Concentrations Observed in Urine Among Occupationally-Exposed Workers    
----------------------------------------------------------------------------------------------------------------
                                       Concentration of 2-microglobulin in                             
                                                          urine                                                 
                                    -------------------------------------------------                           
       Study number            N     Geometric mean    Geom.                                   Reference        
                                      (g/   Std. Dev.   L 95% of   U 95% of                            
                                          g)a                    rangeb     rangeb                              
----------------------------------------------------------------------------------------------------------------
1..........................   1,424             160       6.19        8.1      3,300  Ishizaki et al. 1989.     
2..........................   1,754             260       6.50         12      5,600  Ishizaki et al. 1989.     
3..........................      33             210  .........  .........  .........  Ellis et al. 1983.        
4..........................      65             210  .........  .........  .........  Chia et al. 1989.         
5..........................     c44           5,700       6.49       d300    d98,000  Kjellstrom et al. 1977.   
6..........................     148            e180  .........       f110       f280  Buchet et al. 1980.       
7..........................      37             160       3.90         17      1,500  Kenzaburo et al. 1979.    
8..........................     c45           3,300       8.70       d310    d89,000  Mason et al. 1988.        
9..........................     c10           6,100       5.99       f650    f57,000  Falck et al. 1983.        
10.........................     c11           3,900       2.96       d710    d15,000  Elinder et al. 1985.      
11.........................     c12             300  .........  .........  .........  Roels et al. 1991.        
12.........................      g8           7,400  .........  .........  .........  Roels et al. 1991.        
13.........................     c23          h1,800  .........  .........  .........  Roels et al. 1989.        
14.........................      10             690  .........  .........  .........  Iwao et al. 1980.         
15.........................      34              71  .........  .........  .........  Wibowo et al. 1982.       
16.........................     c15           4,700       6.49       d590    d93,000  Thun et al. 1989.         
----------------------------------------------------------------------------------------------------------------
aUnless otherwise stated.                                                                                       
bBased on an assumed lognormal distribution.                                                                    
cAmong workers diagnosed as having renal dysfunction; for Elinder this means 2 levels greater than 300 
  micrograms per gram creatinine (g/gr Cr); for Roels, 1991, range=31-35, 170 g2/gr  
  Cr and geometric mean=63 among healthy workers; for Mason 2>300 g/gr Cr.                    
dBased on a detailed review of the data by OSHA.                                                                
eArithmetic mean.                                                                                               
fReported in the study.                                                                                         
gRetired workers.                                                                                               
h1,800 g2/gr Cr for first survey; second survey=1,600; third survey=2,600; fourth             
  survey=2,600; fifth survey=2,600.                                                                             

    The data provided in Table 10 indicate that the mean B2MU 
concentration observed among workers experiencing occupational 
exposure to cadmium (but with undefined levels of proteinuria) is 
160-7400 g/g CRTU. One of these studies reports geometric 
means lower than this range (i.e., as low as 71 g/g CRTU); 
an explanation for this wide spread in average concentrations is not 
available.
    Seven of the studies listed in Table 10 report a range of B2MU 
levels among those diagnosed as having renal dysfunction. As 
indicated in this table, renal dysfunction (proteinuria) is defined 
in several of these studies by B2MU levels in excess of 300 
g/g CRTU (see footnote ``c'' of Table 10); therefore, the 
range of B2MU levels observed in these studies is a function of the 
operational definition used to identify those with renal 
dysfunction. Nevertheless, a B2MU level of 300 g/g CRTU 
appears to be a meaningful threshold for identifying those having 
early signs of kidney damage. While levels much higher than 300 
g/g CRTU have been observed among those with renal 
dysfunction, the vast majority of those not occupationally exposed 
to cadmium exhibit much lower B2MU concentrations (see Table 9). 
Similarly, the vast majority of workers not exhibiting renal 
dysfunction are found to have levels below 300 g/g CRTU 
(Table 9).
    The 300 g/g CRTU level for B2MU proposed in the above 
paragraph has support among researchers as the threshold level that 
distinguishes between cadmium-exposed workers with and without 
kidney dysfunction. For example, in the guide for physicians who 
must evaluate cadmium-exposed workers written for the Cadmium 
Council by Dr. Lauwerys, levels of B2M greater than 200-300 
g/g CRTU are considered to require additional medical 
evaluation for kidney dysfunction (exhibit 8-447, OSHA docket 
H057A). The most widely used test for measuring B2M (i.e., the 
Pharmacia Delphia test) defines B2MU levels above 300 g/l 
as abnormal (exhibit L-140-1, OSHA docket H057A).
    Dr. Elinder, chairman of the Department of Nephrology at the 
Karolinska Institute, testified at the hearings on the proposed 
cadmium rule. According to Dr. Elinder (exhibit L-140-45, OSHA 
docket H057A), the normal concentration of B2MU has been well 
documented (Evrin and Wibell 1972; Kjellstrom et al. 1977a; Elinder 
et al. 1978, 1983; Buchet et al. 1980; Jawaid et al. 1983; Kowal and 
Zirkes, 1983). Elinder stated that the upper 95 or 97.5 percentiles 
for B2MU among those without tubular dysfunction is below 300 
g/g CRTU (Kjellstrom et al. 1977a; Buchet et al. 1980; 
Kowal and Zirkes, 1983). Elinder defined levels of B2M above 300 
g/g CRTU as ``slight'' proteinuria.

5.3.8  Conclusions and Recommendations for B2MU

    Based on the above evaluation, the following recommendations are 
made for a B2MU proficiency testing program. Note that the following 
discussion addresses only sampling and analysis for B2MU 
determinations (i.e., to be reported as an unadjusted g 
B2M/l urine). Normalizing this result to creatinine requires a 
second analysis for CRTU (see section 5.4) so that the ratio of the 
2 measurements can be obtained.

5.3.8.1  Recommended Method

    The Pharmacia Delphia method (Pharmacia 1990) should be adopted 
as the standard method for B2MU determinations. Laboratories may 
adopt alternate methods, but it is the responsibility of the 
laboratory to demonstrate that alternate methods provide results of 
comparable quality to the Pharmacia Delphia method.

5.3.8.2  Data Quality Objectives

    The following data quality objectives should facilitate 
interpretation of analytical results, and should be achievable based 
on the above evaluation.
    Limit of Detection. A limit of 100 g/l urine should be 
achievable, although the insert to the test kit (Pharmacia 1990) 
cites a detection limit of 150 g/l; private conversations 
with representatives of Pharmacia, however, indicate that the lower 
limit of 100 g/l should be achievable provided an 
additional standard of 100 g/l B2M is run with the other 
standards to derive the calibration curve (section 3.3.1.1). The 
lower detection limit is desirable due to the proximity of this 
detection limit to B2MU values defined for the cadmium medical 
monitoring program.
    Accuracy. Because results from an interlaboratory proficiency 
testing program are not available currently, it is difficult to 
define an achievable level of accuracy. Given the general 
performance parameters defined by the insert to the test kits, 
however, an accuracy of 15% of the target value appears 
achievable.
    Due to the low levels of B2MU to be measured generally, it is 
anticipated that the analysis of creatinine will contribute 
relatively little to the overall variability observed among 
creatinine-normalized B2MU levels (see section 5.4). The initial 
level of accuracy for reporting B2MU levels under this program 
should be set at 15%.
    Precision. Based on precision data reported by Pharmacia (1990), 
a precision value (i.e., CV) of 5% should be achievable over the 
defined range of the analyte. For internal QC samples (i.e., 
recommended as part of an internal QA/QC program, section 3.3.1), 
laboratories should attain precision near 5% over the range of 
concentrations measured.

5.3.8.3  Quality Assurance/Quality Control

    Commercial laboratories providing measurement of B2MU should 
adopt an internal QA/QC program that incorporates the following 
components: Strict adherence to the Pharmacia Delphia method, 
including calibration requirements; regular use of QC samples during 
routine runs; a protocol for corrective actions, and documentation 
of these actions; and, participation in an interlaboratory 
proficiency program. Procedures that may be used to address internal 
QC requirements are presented in Attachment 1. Due to differences 
between analyses for B2MU and CDB/CDU, specific values presented in 
Attachment 1 may have to be modified. Other components of the 
program (including characterization runs), however, can be adapted 
to a program for B2MU.

5.4  Monitoring Creatinine in Urine (CRTU)

    Because CDU and B2MU should be reported relative to 
concentrations of CRTU, these concentrations should be determined in 
addition CDU and B2MU determinations.

5.4.1  Units of CRTU Measurement

    CDU should be reported as g Cd/g CRTU, while B2MU 
should be reported as g B2M/g CRTU. To derive the ratio of 
cadmium or B2M to creatinine, CRTU should be reported in units of g 
crtn/l of urine. Depending on the analytical method, it may be 
necessary to convert results of creatinine determinations 
accordingly.

5.4.2  Analytical Techniques Used To Monitor CRTU

    Of the techniques available for CRTU determinations, an 
absorbance spectrophotometric technique and a high-performance 
liquid chromatography (HPLC) technique are identified as acceptable 
in this protocol.

5.4.3  Methods Developed for CRTU Determinations

    CRTU analysis performed in support of either CDU or B2MU 
determinations should be performed using either of the following 2 
methods:
    1. The Du Pont method (i.e., Jaffe method), in which creatinine 
in a sample reacts with picrate under alkaline conditions, and the 
resulting red chromophore is monitored (at 510 nm) for a fixed 
interval to determine the rate of the reaction; this reaction rate 
is proportional to the concentration of creatinine present in the 
sample (a copy of this method is provided in Attachment 2 of this 
protocol); or
    2. The OSHA SLC Technical Center (OSLTC) method, in which 
creatinine in an aliquot of sample is separated using an HPLC column 
equipped with a UV detector; the resulting peak is quantified using 
an electrical integrator (a copy of this method is provided in 
Attachment 3 of this protocol).

5.4.4  Sample Collection and Handling

    CRTU samples should be segregated from samples collected for CDU 
or B2MU analysis. Sample-collection techniques have been described 
under section 5.2.4. Samples should be preserved either to stabilize 
CDU (with HNO3) or B2MU (with NaOH). Neither of these 
procedures should adversely affect CRTU analysis (see Attachment 3).

5.4.5  General Method Performance

    Data from the OSLTC indicate that a CV of 5% should be 
achievable using the OSLTC method (Septon, L private communication). 
The achievable accuracy of this method has not been determined.
    Results reported in surveys conducted by the CAP (CAP 1991a, 
1991b and 1992) indicate that a CV of 5% is achievable. The accuracy 
achievable for CRTU determinations has not been reported.
    Laboratories performing creatinine analysis under this protocol 
should be CAP accredited and should be active participants in the 
CAP surveys.

5.4.6  Observed CRTU Concentrations

    Published data suggest the range of CRTU concentrations is 1.0-
1.6 g in 24-hour urine samples (Harrison 1987). These values are 
equivalent to about 1 g/l urine.

5.4.7  Conclusions and Recommendations for CRTU

5.4.7.1  Recommended Method

    Use either the Jaffe method (Attachment 2) or the OSLTC method 
(Attachment 3). Alternate methods may be acceptable provided 
adequate performance is demonstrated in the CAP program.

5.4.7.2  Data Quality Objectives

    Limit of Detection. This value has not been formally defined; 
however, a value of 0.1 g/l urine should be readily achievable.
    Accuracy. This value has not been defined formally; accuracy 
should be sufficient to retain accreditation from the CAP.
    Precision. A CV of 5% should be achievable using the recommended 
methods.

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Attachment 1--Nonmandatory Protocol for an Internal Quality Assurance/
Quality Control Program

    The following is an example of the type of internal quality 
assurance/quality control program that assures adequate control to 
satisfy OSHA requirements under this protocol. However, other 
approaches may also be acceptable.
    As indicated in Section 3.3.1 of the protocol, the QA/QC program 
for CDB and CDU should address, at a minimum, the following:
     Calibration;
     Establishment of control limits;
     Internal QC analyses and maintaining control; and
     Corrective action protocols.
    This illustrative program includes both initial characterization 
runs to establish the performance of the method and ongoing analysis 
of quality control samples intermixed with compliance samples to 
maintain control.

Calibration

    Before any analytical runs are conducted, the analytic 
instrument must be calibrated. This is to be done at the beginning 
of each day on which quality control samples and/or compliance 
samples are run. Once calibration is established, quality control 
samples or compliance samples may be run. Regardless of the type of 
samples run, every fifth sample must be a standard to assure that 
the calibration is holding.
    Calibration is defined as holding if every standard is within 
plus or minus () 15% of its theoretical value. If a 
standard is more than plus or minus 15% of its theoretical value, 
then the run is out of control due to calibration error and the 
entire set of samples must either be reanalyzed after recalibrating 
or results should be recalculated based on a statistical curve 
derived from the measurement of all standards.
    It is essential that the highest standard run is higher than the 
highest sample run. To assure that this is the case, it may be 
necessary to run a high standard at the end of the run, which is 
selected based on the results obtained over the course of the run.
    All standards should be kept fresh, and as they get old, they 
should be compared with new standards and replaced if they exceed 
the new standards by  15%.

Initial Characterization Runs and Establishing Control

    A participating laboratory should establish four pools of 
quality control samples for each of the analytes for which 
determinations will be made. The concentrations of quality control 
samples within each pool are to be centered around each of the four 
target levels for the particular analyte identified in Section 4.4 
of the protocol.
    Within each pool, at least 4 quality control samples need to be 
established with varying concentrations ranging between plus or 
minus 50% of the target value of that pool. Thus for the medium-high 
cadmium in blood pool, the theoretical values of the quality control 
samples may range from 5 to 15 g/l, (the target value is 10 
g/l). At least 4 unique theoretical values must be 
represented in this pool.
    The range of theoretical values of plus or minus 50% of the 
target value of a pool means that there will be overlap of the 
pools. For example, the range of values for the medium-low pool for 
cadmium in blood is 3.5 to 10.5 g/l while the range of 
values for the medium-high pool is 5 to 15 g/l. Therefore, 
it is possible for a quality control sample from the medium-low pool 
to have a higher concentration of cadmium than a quality control 
sample from the medium-high pool.
    Quality control samples may be obtained as commercially 
available reference materials, internally prepared, or both. 
Internally prepared samples should be well characterized and traced 
or compared to a reference material for which a consensus value for 
concentration is available. Levels of analyte in the quality control 
samples must be concealed from the analyst prior to the reporting of 
analytical results. Potential sources of materials that may be used 
to construct quality control samples are listed in Section 3.3.1 of 
the protocol.
    Before any compliance samples are analyzed, control limits must 
be established. Control limits should be calculated for every pool 
of each analyte for which determinations will be made and control 
charts should be kept for each pool of each analyte. A separate set 
of control charts and control limits should be established for each 
analytical instrument in a laboratory that will be used for analysis 
of compliance samples.
    At the beginning of this QA/QC program, control limits should be 
based on the results of the analysis of 20 quality control samples 
from each pool of each analyte. For any given pool, the 20 quality 
control samples should be run on 20 different days. Although no more 
than one sample should be run from any single pool on a particular 
day, a laboratory may run quality control samples from different 
pools on the same day. This constitutes a set of initial 
characterization runs.
    For each quality control sample analyzed, the value F/T (defined 
in the glossary) should be calculated. To calculate the control 
limits for a pool of an analyte, it is first necessary to calculate 
the mean, X, of the F/T values for each quality control sample in a 
pool and then to calculate its standard deviation, s. Thus, for the 
control limit for a pool, X is calculated as:

TR03JA94.003

and s is calculated as

TR03JA94.004

where N is the number of quality control samples run for a pool.
    The control limit for a particular pool is then given by the 
mean plus or minus 2 standard deviations (X 2s). The 
control limits may be no greater than 40% of the mean F/T value. If 
three standard deviations are greater than 40% of the mean F/T 
value, then analysis of compliance samples may not begin.\1\ 
Instead, an investigation into the causes of the large standard 
deviation should begin, and the inadequacies must be remedied. Then, 
control limits must be reestablished which will mean repeating the 
running 20 quality control samples from each pool over 20 days.
---------------------------------------------------------------------------

    \1\Note that the value, ``40%'' may change over time as 
experience is gained with the program.
---------------------------------------------------------------------------

Internal Quality Control Analyses and Maintaining Control

    Once control limits have been established for each pool of an 
analyte, analysis of compliance samples may begin. During any run of 
compliance samples, quality control samples are to be interspersed 
at a rate of no less than 5% of the compliance sample workload. When 
quality control samples are run, however, they should be run in sets 
consisting of one quality control sample from each pool. Therefore, 
it may be necessary, at times, to intersperse quality control 
samples at a rate greater than 5%.
    There should be at least one set of quality control samples run 
with any analysis of compliance samples. At a minimum, for example, 
4 quality control samples should be run even if only 1 compliance 
sample is run. Generally, the number of quality control samples that 
should be run are a multiple of four with the minimum equal to the 
smallest multiple of four that is greater than 5% of the total 
number of samples to be run. For example, if 300 compliance samples 
of an analyte are run, then at least 16 quality control samples 
should be run (16 is the smallest multiple of four that is greater 
than 15, which is 5% of 300).
    Control charts for each pool of an analyte (and for each 
instrument in the laboratory to be used for analysis of compliance 
samples) should be established by plotting F/T versus date as the 
quality control sample results are reported. On the graph there 
should be lines representing the control limits for the pool, the 
mean F/T limits for the pool, and the theoretical F/T of 1.000. 
Lines representing plus or minus () 2s should also be 
represented on the charts. A theoretical example of a control chart 
is presented in Figure 1. 

                   Figure 1.--Theoretical Example of a Control Chart for a Pool of an Analyte                   
                                                                                         1.162 (Upper Control   
                                                                                          Limit)                
                                                  X                                                             
                                                                                         1.096 (Upper 2
                                                                                          Line)                 
                      X                                                                                         
               X   .....                                                                 1.000 (Theoretical     
                                                                                          Mean)                 
                                    X      X                                             0.964 (Mean)           
                                                         X                           X                          
                                                                X                                               
                             X                                                           0.832 (Lower 2
                                                                                          Line)                 
                                                                       X                                        
                                                                                         0.766 (Lower Control   
                                                                                          Limit)                
March          2      2      3      5      6      9     10     13     16     17                                 
----------------------------------------------------------------------------------------------------------------

    All quality control samples should be plotted on the chart, and 
the charts should be checked for visual trends. If a quality control 
sample falls above or below the control limits for its pool, then 
corrective steps must be taken (see the section on corrective 
actions below). Once a laboratory's program has been established, 
control limits should be updated every 2 months.
    The updated control limits should be calculated from the results 
of the last 100 quality control samples run for each pool. If 100 
quality control samples from a pool have not been run at the time of 
the update, then the limits should be based on as many as have been 
run provided at least 20 quality control samples from each pool have 
been run over 20 different days.
    The trends that should be looked for on the control charts are:
    1. 10 consecutive quality control samples falling above or below 
the mean;
    2. 3 consecutive quality control samples falling more than 2s 
from the mean (above or below the 2s lines of the chart); or
    3. the mean calculated to update the control limits falls more 
than 10% above or below the theoretical mean of 1.000.
    If any of these trends is observed, then all analysis must be 
stopped, and an investigation into the causes of the errors must 
begin. Before the analysis of compliance samples may resume, the 
inadequacies must be remedied and the control limits must be 
reestablished for that pool of an analyte. Reestablishment of 
control limits will entail running 20 sets of quality control 
samples over 20 days.
    Note that alternative procedures for defining internal quality 
control limits may also be acceptable. Limits may be based, for 
example, on proficiency testing, such as  1 g 
or 15% of the mean (whichever is greater). These should be clearly 
defined.

Corrective Actions

    Corrective action is the term used to describe the 
identification and remediation of errors occurring within an 
analysis. Corrective action is necessary whenever the result of the 
analysis of any quality control sample falls outside of the 
established control limits. The steps involved may include simple 
things like checking calculations of basic instrument maintenance, 
or it may involve more complicated actions like major instrument 
repair. Whatever the source of error, it must be identified and 
corrected (and a Corrective Action Report (CAR) must be completed. 
CARs should be kept on file by the laboratory.

Attachment 2--Creatinine in Urine (JAFFE PROCEDURE)

    * Note: Numbered superscripts refer to the bibliography.
    Intended use: The CREA pack is used in the Du Pont ACA 
discrete clinical analyzer to quantitatively measure creatinine in 
serum and urine.
    Summary: The CREA method employs a modification of the kinetic 
Jaffe reaction reported by Larsen. This method has been reported to 
be less susceptible than conventional methods to interference from 
non-creatinine, Jaffe-positive compounds.\2\
---------------------------------------------------------------------------

    \2\Larsen, K, Clin Chem Acta 41, 209 (1972).
---------------------------------------------------------------------------

    A split sample comparison between the CREA method and a 
conventional Jaffe procedure on Autoanalyzer showed a good 
correlation. (See SPECIFIC PERFORMANCE CHARACTERISTICS).
    Autoanalyzer, is a registered trademark of Technicon 
Corp., Tarrytown, NY.
    Principles of Procedure: In the presence of a strong base such 
as NaOH, picrate reacts with creatinine to form a red chromophore. 
The rate of increasing absorbance at 510 nm due to the formation of 
this chromophore during a 17.07-second measurement period is 
directly proportional to the creatinine concentration in the sample.

TR03JA94.005

    Reagents: 

------------------------------------------------------------------------
   Compartmenta            Form            Ingredient        Quantityb  
------------------------------------------------------------------------
No. 2, 3, & 4.....  Liquid............  Picrate..........  0.11 mmol.   
6.................  Liquid............  NaOH (for pH                    
                                         adjustment)c .                 
------------------------------------------------------------------------
a. Compartments are numbered 1-7, with compartment #7 located closest to
  pack fill position #2.                                                
b. Nominal value at manufacture.                                        
c. See PRECAUTIONS.                                                     


    Precautions: Compartment #6 contains 75L of 10 N NaOH; 
avoid contact; skin irritant; rinse contacted area with water. 
Comply with OSHA'S Bloodborne Pathogens Standard while handling 
biological samples (29 CFR 1910.1039).
    Used packs contain human body fluids; handle with appropriate 
care.

FOR IN VITRO DIAGNOSTIC USE

MIXING & DILUTING

    Mixing and diluting are automatically performed by the 
ACA discrete clinical analyzer. The sample cup must 
contain sufficient quantity to accommodate the sample volume plus 
the ``dead volume''; precise cup filling is not required. 

                    Sample Cup Volumes (L)                     
------------------------------------------------------------------------
                              Standard                Microsystem       
      Analyzer       ---------------------------------------------------
                         Dead         Total        Dead         Total   
------------------------------------------------------------------------
II, III.............          120         3000           10          500
IV, SX..............          120         3000           30          500
V...................           90         3000           10          500
------------------------------------------------------------------------


    Storage of Unprocessed Packs: Store at 2-8 deg.C. Do not freeze. 
Do not expose to temperatures above 35 deg.C or to direct sunlight.
    Expiration: Refer to EXPIRATION DATE on the tray label.
    Specimen Collection: Serum or urine can be collected and stored 
by normal procedures.\3\
---------------------------------------------------------------------------

    \3\Tietz, NW, Fundamentals of Clinical Chemistry, W. B. Saunders 
Co., Philadelphia, PA, 1976, pp 47-52, 1211.
---------------------------------------------------------------------------

Known Interfering Substances\4\
---------------------------------------------------------------------------

    \4\Supplementary information pertaining to the effects of 
various drugs and patient conditions on in vivo or in vitro 
diagnostic levels can be found in ``Drug Interferences with Clinical 
Laboratory Tests,'' Clin. Chem 21 (5) (1975), and ``Effects of 
Disease on Clinical Laboratory Tests,'' Clin Chem, 26 (4) 1D-476D 
(1980).
---------------------------------------------------------------------------

     Serum Protein Influence--Serum protein levels exert a 
direct influence on the CREA assay. The following should be taken 
into account when this method is used for urine samples and when it 
is calibrated:
    Aqueous creatinine standards or urine specimens will give CREA 
results depressed by approximately 0.7 mg/dL [62 mol/L] \5\ 
and will be less precise than samples containing more than 3 g/dL 
[30 g/L] protein.
---------------------------------------------------------------------------

    \5\ Systeme International d'unites (S.I. Units) are in brackets.
---------------------------------------------------------------------------

    All urine specimens should be diluted with an albumin solution 
to give a final protein concentration of at least 3 g/dL [30 g/L]. 
Du Pont Enzyme Diluent (Cat. #790035-901) may be used for this 
purpose.
     High concentration of endrogenous bilirubin (>20 mg/dL 
[>342 mol/L]) will give depressed CREA results (average 
depression 0.8 mg/dL [71 mol/L]).\6\
---------------------------------------------------------------------------

    \6\Watkins, R. Fieldkamp, SC, Thibert, RJ, and Zak, B, Clin 
Chem, 21, 1002 (1975).
---------------------------------------------------------------------------

     Grossly hemolyzed (hemoglobin >100 mg/dL [>62 
mol/L]) or visibly lipemic specimens may cause falsely 
elevated CREA results.7,8
---------------------------------------------------------------------------

    \7\Kawas, EE, Richards, AH, and Bigger, R, An Evaluation of a 
Kinetic Creatinine Test for the Du Pont ACA, Du Pont Company, 
Wilmington, DE (February 1973). (Reprints available from DuPont 
Company, Diagnostic Systems)
    \8\Westgard, JO, Effects of Hemolysis and Lipemia on ACA 
Creatinine Method, 0.200 L, Sample Size, Du Pont Company, 
Wilmington, DE (October 1972).
---------------------------------------------------------------------------

     The following cephalosporin antibiotics do not 
interfere with the CREA method when present at the concentrations 
indicated. Systematic inaccuracies (bias) due to these substances 
are less than or equal to 0.1 mg/dL [8.84 mol/L] at CREA 
concentrations of approximately 1 mg/dL [88 mol/L]. 

------------------------------------------------------------------------
                            Peak serum levela,b,c    Drug concentration 
        Antibiotic         ---------------------------------------------
                              mg/dL      [mmol/L]     mg/dL     [mmol/L]
------------------------------------------------------------------------
Cephaloridine.............    1.4         0.3              25        6.0
Cephalexin................  0.6-2.0     0.2-0.6            25        7.2
Cephamandole..............  1.3-2.5     0.3-0.5            25        4.9
Cephapirin................    2.0        D0.4              25        5.6
Cephradine................  1.5-2.0     0.4-0.6            25        7.1
Cefazolin.................  2.5-5.0     0.55-1.1           50      11.0 
------------------------------------------------------------------------
aPhysicians' Desk Reference, Medical Economics Company, 33 Edition,     
  1979.                                                                 
bHenry, JB, Clinical Diagnosis and Management by Laboratory Methods,    
  W.B. Saunders Co., Philadelphia, PA 1979, Vol. III.                   
cKrupp, MA, Tierney, LM Jr., Jawetz, E, Roe, RI, Camargo, CA, Physicians
  Handbook, Lange Medical Publications, Los Altos, CA, 1982 pp 635-636. 

     The following cephalosporin antibiotics have been shown 
to affect CREA results when present at the indicated concentrations. 
System inaccuracies (bias) due to these substances are greater that 
0.1 mg/dL [8.84 mol/L] at CREA concentrations of:
      

------------------------------------------------------------------------
                  Peak serum levela,b          Drug concentration       
  Antibiotic    --------------------------------------------------------
                   mg/dL      [mmol/L]     mg/dL    [mmol/L]     Effect 
------------------------------------------------------------------------
Cephalothin....    1-6       0.2-1.5           100       25.2  
                                                                  20-25%
Cephoxitin.....    2.0         0.5             5.0        1.2  
                                                                  35-40%
------------------------------------------------------------------------
aHenry, JB, Clinical Diagnosis and Management by Laboratory Methods,    
  W.B. Saunders Co., Philadelphia, PA 1979, Vol. III.                   
bSarah, AJ, Koch, TR, Drusano, GL, Celoxitin Falsely Elevates Creatinine
  Levels, JAMA 247, 205-206 (1982).                                     

     The single wavelength measurement used in this method 
eliminates interference from chromophores whose 510 nm absorbance is 
constant throughout the measurement period.
     Each laboratory should determine the acceptability of 
its own blood collection tubes and serum separation products. 
Variations in these products may exist between manufacturers and, at 
times, from lot to lot.

    Procedure: 

                             Test Materials                             
------------------------------------------------------------------------
                            II, III Du    IV, SX Du Pont  V Du Pont Cat.
          Item             Pont Cat. No.     Cat. No.           No.     
------------------------------------------------------------------------
ACA CREA                                                      
 Analytical Test Pack...       701976901       701976901       701976901
Sample System Kit or....       710642901       710642901       713697901
Micro Sample System Kit                                                 
 and....................       702694901       710356901              NA
Micro Sample System                                                     
 Holders................       702785000              NA              NA
DYLUX                                                         
 Photosensitive.........  ..............  ..............  ..............
Printer Paper...........       700036000              NA              NA
Thermal Printer Paper...              NA       710639901       713645901
Du Pont Purified Water..       704209901       710615901       710815901
Cell Wash Solution......       701864901       710664901       710864901
------------------------------------------------------------------------

Test Steps

    The operator need only load the sample kit and appropriate test 
pack(s) into a properly prepared ACA discrete clinical 
analyzer. It automatically advances the pack(s) through the test 
steps and prints a result(s). See the Instrument Manual of the 
ACA analyzer for details of mechanical travel of the test 
pack(s).

Preset Creatinine (CREA)--Test Conditions

 Sample Volume: 200 L
 Diluent: Purified Water
 Temperature: 37.0  0.1 deg.C
 Reaction Period: 29 seconds
 Type of Measurement: Rate
 Measurement Period: 17.07 seconds
 Wavelength: 510 nm
 Units: mg/dL [mol/L]

CALIBRATION

    The general calibration procedure is described in the 
Calibration/Verification chapter of the Manuals.
    The following information should be considered when calibrating 
the CREA method.
 Assay Range: 0-20 mg/mL [0-1768 mol/L] \9\.
---------------------------------------------------------------------------

    \9\ For the results in S.I. units [mol/L] the 
conversion factory is 88.4.
---------------------------------------------------------------------------

 Reference Material: Protein containing primary 
standards\10\ or secondary calibrators such as Du Pont Elevated 
Chemistry Control (Cat. #790035903) and Normal Chemistry Control 
(Cat.\#790035905)\11\.
---------------------------------------------------------------------------

    \10\Refer to the Creatinine Standard Preparation and Calibration 
Procedure available on request from a Du Pont Representative.
    \11\If the Du Pont Chemistry Controls are being used, prepare 
them according to the instructions on the product insert sheets.
---------------------------------------------------------------------------

 Suggested Calibration Levels: 1,5,20, mg/mL [88, 442, 1768 
mol/L].
 Calibration Scheme: 3 levels, 3 packs per level.
 Frequency: Each new pack lot. Every 3 months for any one 
pack lot.

       

                Preset Creatinine (CREA) Test Conditions                
------------------------------------------------------------------------
                                                          ACA 
           Item               ACA II analyzer   III, IV, SX, V
                                                             analyzer   
------------------------------------------------------------------------
Count by...................  One (1)...................  NA             
                             [Five (5)]................                 
Decimal point location.....  0.0 mg/dL.................  000.0 mg/dL    
                             [000.0 mol/L]....  [000 mol/L]      
Assigned starting point or   999.8.....................  -1.000 E1      
 offset Co                   [9823.]...................  [-8.840 E2]    
Scale factor or assigned...  0.2000....................  2.004 E-1a     
                             mg/dL/counta..............                 
Linear Term C1a............  [0.3536 mol/L/     [1.772E1]      
                              count].                                   
------------------------------------------------------------------------
a The preset scale factor (linear term) was derived from the molar      
  absorptivity of the indicator and is based on an absorbance to        
  activity relationship (sensitivity) of 0.596 (mA/min)/(U/L). Due to   
  small differences in filters and electronic components between        
  instruments, the actual scale factor (linear term) may differ slightly
  from that given above.                                                

Quality Control

    Two types of quality control procedures are recommended:
     General Instrument Check. Refer to the Filter Balance 
Procedure and the Absorbance Test Method described in the ACA 
Analyzerinstrument Manual. Refer also to the ABS Test Methodology 
literature.
    Creatinine Method Check. At least once daily run a CREA test on 
a solution of known creatinine activity such as an assayed control 
or calibration standard other than that used to calibrate the CREA 
method. For further details review the Quality Assurance Section of 
the Chemistry Manual. The result obtained should fall within 
acceptable limits defined by the day-to-day variability of the 
system as measured in the user's laboratory. (See SPECIFIC 
PERFORMANCE CHARACTERISTICS for guidance.) If the result falls 
outside the laboratory's acceptable limits, follow the procedure 
outlined in the Chemistry Troubleshooting Section of the Chemistry 
Manual.
    A possible system malfunction is indicated when analysis of a 
sample with five consecutive test packs gives the following results:
       

------------------------------------------------------------------------
                      Level                                  SD         
------------------------------------------------------------------------
1 mg/dL..........................................  >0.15 mg/dL          
[88 mol/L]..............................  [>13 mol/L] 
20 mg/dL.........................................  >0.68 mg/dL          
[1768 mol/L]............................  [>60 mol/L] 
------------------------------------------------------------------------

    Refer to the procedure outlined in the Trouble Shooting Section 
of the Manual.

Results

    The ACA analyzer automatically calculates and prints 
the CREA result in mg/dL [mol/L].

Limitation of Procedure

    Results >20 mg/dL [1768 mol/L]:

     Dilute with suitable protein base diluent. Reassay. 
Correct for diluting before reporting.
    The reporting system contains error messages to warn the 
operator of specific malfunctions. Any report slip containing a 
letter code or word immediately following the numerical value should 
not be reported. Refer to the Manual for the definition of error 
codes.

Reference Interval


                                                                        
                                                                        
                                                                        
SERUM:a,b                                                               
  Males                              0.8-1.3 md/dL                      
                                     [71-115 mol/L]            
  Females                            0.6-1.0 md/dL                      
                                     [53-88 mol/L]             
URINE:c                                                                 
  Males                              0.6-2.5 g/24 hr                    
                                     [53-221 mmol/24 hr]                
  Females                            0.6-1.5 g/24 hr                    
                                     [53-133 mmol/24 hr]                
                                                                        
a Gadsden, RH, and Phelps, CA, A Normal Range Study of Amylase in Urine 
  and Serum on the Du Pont ACA, Du Pont Company, Wilmington, DE (March  
  1978). (Reprints available from DuPont Company, Diagnostic Systems)   
b Reference interval data obtained from 200 apparently healthy          
  individuals (71 males, 129 females) between the ages of 19 and 72.    
c Dicht, JJ, Reference Intervals for Serum Amylase and Urinary          
  Creatinine on the Du Pont ACA Discrete Clinical Analyzer, Du
  Pont Company, Wilmington, DE (November 1984).                         

    Each laboratory should establish its own reference intervals for 
CREA as performed on the analyzer.

Specific Performance Characteristics\12\
---------------------------------------------------------------------------

    \12\ All specific performance characteristics tests were run 
after normal recommended equipment quality control checks were 
performed (see Instrument Manual).
---------------------------------------------------------------------------

      

                            Reproducibilitya                            
------------------------------------------------------------------------
                                                  Standard deviation (% 
                                                           CV)          
             Material                  Mean    -------------------------
                                                Within-run   Between-day
------------------------------------------------------------------------
Lyophilized......................          1.3   0.05 (3.7)   0.05 (3.7)
Control..........................        [115]        [4.4]        [4.4]
Lyophilized......................         20.6   0.12 (0.6)   0.37 (1.8)
Control..........................       [1821]       [10.6]      [32.7] 
------------------------------------------------------------------------
a Specimens at each level were analyzed in duplicate for twenty days.   
  The within-run and between-day standard deviations were calculated by 
  the analysis of variance method.                                      


                   Correlation--Regression Statisticsa                  
------------------------------------------------------------------------
                                                     Correlation        
    Comparative method        Slope      Intercept   coefficient     n  
------------------------------------------------------------------------
Autoanalyzer...         1.03    0.03[2.7]        0.997     260
------------------------------------------------------------------------
a Model equation for regression statistics is:                          


Result of ACA Analyzer = Slope (Comparative method result) + 
intercept

Assay Range *

0.0-20.0 mg/dl
[0-1768 mol]


     * See REPRODUCIBILITY for method performance within the assay 
range.Analytical Specificity

    See KNOWN INTERFERING SUBSTANCES section for details.

Bibliography

    Larsen, K, Clin Chem Acta 41, 209 (1972).
    Tietz, NW, Fundamentals of Clinical Chemistry, W. B. Saunders 
Co., Philadelphia, PA, 1976, pp 47-52, 1211.
    Supplementary information pertaining to the effects of various 
drugs and patient conditions on in vivo or in vitro diagnostic 
levels can be found in ``Drug Interferences with Clinical Laboratory 
Tests,'' Clin. Chem 21 (5) (1975), and ``Effects of Disease on 
Clinical Laboratory Tests,'' Clin Chem, 26 (4) 1D-476D (1980).
    Watkins, R. Fieldkamp, SC, Thibert, RJ, and Zak, B, Clin Chem, 
21, 1002 (1975).
    Kawas, EE, Richards, AH, and Bigger, R, An Evaluation of a 
Kinetic Creatinine Test for the Du Pont ACA, Du Pont Company, 
Wilmington, DE (February 1973). (Reprints available from DuPont 
Company, Diagnostic Systems)
    Westgard, JO, Effects of Hemolysis and Lipemia on ACA Creatinine 
Method, 0.200 L, Sample Size, Du Pont Company, Wilmington, 
DE (October 1972).
    Physicians' Desk Reference, Medical Economics Company, 33 
Edition, 1979.
    Henry, JB, Clinical Diagnosis and Management by Laboratory 
Methods, W.B. Saunders Co., Philadelphia, PA 1979, Vol. III.
    Krupp, MA, Tierney, LM Jr., Jawetz, E, Roe, RI, Camargo, CA, 
Physicians Handbook, Lange Medical Publications, Los Altos, CA, 1982 
pp 635-636.
    Sarah, AJ, Koch, TR, Drusano, GL, Celoxitin Falsely Elevates 
Creatinine Levels, JAMA 247, 205-206 (1982).
    Gadsden, RH, and Phelps, CA, A Normal Range Study of Amylase in 
Urine and Serum on the Du Pont ACA, Du Pont Company, Wilmington, DE 
(March 1978). (Reprints available from DuPont Company, Diagnostic 
Systems)
    Dicht, JJ, Reference Intervals for Serum Amylase and Urinary 
Creatinine on the Du Pont ACA Discrete Clinical Analyzer, 
Du Pont Company, Wilmington, DE (November 1984).

Attachment 3--Analysis of Creatinine for the Normalization of Cadmium 
and Beta-2-Microglobulin Concentrations in Urine (OSLTC Procedure)

Matrix: Urine
Target Concentration: 1.1 g/L (this amount is representative of 
creatinine concentrations found in urine).
Procedure: A 1.0 mL aliquot of urine is passed through a C18 SEP-
PAK (Waters Associates). Approximately 30 mL of HPLC (high 
performance liquid chromatography) grade water is then run through 
the SEP-PAK. The resulting solution is diluted to volume in a 100-mL 
volumetric flask and analyzed by HPLC using an ultraviolet (UV) 
detector.
Special Requirements: After collection, samples should be 
appropriately stabilized for cadmium (Cd) analysis by using 10% high 
purity (with low Cd background levels) nitric acid (exactly 1.0 mL 
of 10% nitric acid per 10 mL of urine) or stabilized for Beta-2-
Microglobulin (B2M) by taking to pH 7 with dilute NaOH (exactly 1.0 
mL of 0.11 N NaOH per 10 mL of urine). If not immediately analyzed, 
the samples should be frozen and shipped by overnight mail in an 
insulated container.

    Date: January 1992.
Chemists: David B. Armitage,
Duane Lee,
Organic Service Branch II, OSHA Technical Center, Salt Lake City, Utah.

1. General Discussion

1.1. Background
    1.1.1.  History of procedure
    Creatinine has been analyzed by several methods in the past. The 
earliest methods were of the wet chemical type. As an example, 
creatinine reacts with sodium picrate in basic solution to form a 
red complex, which is then analyzed colorimetrically (Refs. 5.1. and 
5.2.).
    Since industrial hygiene laboratories will be analyzing for Cd 
and B2M in urine, they will be normalizing those concentrations to 
the concentration of creatinine in urine. A literature search 
revealed several HPLC methods (Refs. 5.3., 5.4., 5.5. and 5.6.) for 
creatinine in urine and because many industrial hygiene laboratories 
have HPLC equipment, it was desirable to develop an industrial 
hygiene HPLC method for creatinine in urine. The method of Hausen, 
Fuchs, and Wachter was chosen as the starting point for method 
development. SEP-PAKs were used for sample clarification and cleanup 
in this method to protect the analytical column. The urine aliquot 
which has been passed through the SEP-PAK is then analyzed by 
reverse-phase HPLC using ion-pair techniques.
    This method is very similar to that of Ogata and Taguchi (Ref. 
5.6.), except they used centrifugation for sample clean-up. It is 
also of note that they did a comparison of their HPLC results to 
those of the Jaffe method (a picric acid method commonly used in the 
health care industry) and found a linear relationship of close to 
1:1. This indicates that either HPLC or colorimetric methods may be 
used to measure creatinine concentrations in urine.
    1.1.2.  Physical properties (Ref. 5.7.)
    Molecular weight: 113.12
    Molecular formula: C4-H7-N3-O
Chemical name: 2-amino-1,5-dihydro-1-methyl-4H-imidazol-4-one
    CAS#: 60-27-5
    Melting point: 300  deg.C (decomposes)
    Appearance: white powder
    Solubility: soluble in water; slightly soluble in alcohol; 
practically insoluble in acetone, ether, and chloroform
    Synonyms: 1-methylglycocyamidine, 1-methylhydantoin-2-imide
    Structure: see Figure #1

TR03JA94.006

1.2  Advantages
    1.2.1.  This method offers a simple, straightforward, and 
specific alternative method to the Jaffe method.
    1.2.2.  HPLC instrumentation is commonly found in many 
industrial hygiene laboratories.

2. Sample Stabilization Procedure

2.1. Apparatus
    Metal-free plastic container for urine sample.
2.2. Reagents
    2.2.1. Stabilizing Solution--1) Nitric acid (10%, high purity 
with low Cd background levels) for stabilizing urine for Cd analysis 
or 2) NaOH, 0.11 N, for stabilizing urine for B2M analysis.
    2.2.2. HPLC grade water
2.3. Technique
    2.3.1. Stabilizing solution is added to the urine sample (see 
section 2.2.1.). The stabilizing solution should be such that for 
each 10 mL of urine, add exactly 1.0 mL of stabilizer solution. 
(Never add water or urine to acid or base. Always add acid or base 
to water or urine.) Exactly 1.0 mL of 0.11 N NaOH added to 10 mL of 
urine should result in a pH of 7. Or add 1.0 mL of 10% nitric acid 
to 10 mL of urine.
    2.3.2. After sample collection seal the plastic bottle securely 
and wrap it with an appropriate seal. Urine samples should be frozen 
and then shipped by overnight mail (if shipping is necessary) in an 
insulated container. (Do not fill plastic bottle too full. This will 
allow for expansion of contents during the freezing process.)
2.4. The Effect of Preparation and Stabilization Techniques on 
Creatinine Concentrations
    Three urine samples were prepared by making one sample acidic, 
not treating a second sample, and adjusting a third sample to pH 7. 
The samples were analyzed in duplicate by two different procedures. 
For the first procedure a 1.0 mL aliquot of urine was put in a 100-
mL volumetric flask, diluted to volume with HPLC grade water, and 
then analyzed directly on an HPLC. The other procedure used SEP-
PAKs. The SEP-PAK was rinsed with approximately 5 mL of methanol 
followed by approximately 10 mL of HPLC grade water and both rinses 
were discarded. Then, 1.0 mL of the urine sample was put through the 
SEP-PAK, followed by 30 mL of HPLC grade water. The urine and water 
were transferred to a 100-mL volumetric flask, diluted to volume 
with HPLC grade water, and analyzed by HPLC. These three urine 
samples were analyzed on the day they were obtained and then frozen. 
The results show that whether the urine is acidic, untreated or 
adjusted to pH 7, the resulting answer for creatinine is essentially 
unchanged. The purpose of stabilizing the urine by making it acidic 
or neutral is for the analysis of Cd or B2M respectively. 

         Comparison of Preparation and Stabilization Techniques         
------------------------------------------------------------------------
                                             w/o SEP-PAK   with SEP- PAK
                  Sample                         (g/L           (g/L    
                                             creatinine)    creatinine) 
------------------------------------------------------------------------
Acid......................................           1.10           1.10
Acid......................................           1.11           1.10
Untreated.................................           1.12           1.11
Untreated.................................           1.11           1.12
pH7.......................................           1.08           1.02
pH7.......................................           1.11           1.08
------------------------------------------------------------------------

2.5. Storage
    After 4 days and 54 days of storage in a freezer, the samples 
were thawed, brought to room temperature and analyzed using the same 
procedures as in section 2.4. The results of several days of storage 
show that the resulting answer for creatinine is essentially 
unchanged. 

                                                  Storage Data                                                  
----------------------------------------------------------------------------------------------------------------
                                                              4 days                         54 days            
                                                 ---------------------------------------------------------------
                     Sample                       W/o SEP-PAK g/  With SEP-PAK g/ W/o SEP-PAK g/  With SEP-PAK g/
                                                   L creatinine    L creatinine    L creatinine    L creatinine 
----------------------------------------------------------------------------------------------------------------
Acid............................................            1.09            1.09            1.08            1.09
Acid............................................            1.10            1.10            1.09            1.10
Acid............................................  ..............  ..............            1.09            1.09
Untreated.......................................            1.13            1.14            1.09            1.11
Untreated.......................................            1.15            1.14            1.10            1.10
Untreated.......................................  ..............  ..............            1.09            1.10
pH 7............................................            1.14            1.13            1.12            1.12
pH 7............................................            1.14            1.13            1.12            1.12
pH 7............................................  ..............  ..............            1.12           1.12 
----------------------------------------------------------------------------------------------------------------

2.6. lnterferences
    None.
2.7. Safety precautions
    2.7.1. Make sure samples are properly sealed and frozen before 
shipment to avoid leakage.
    2.7.2. Follow the appropriate shipping procedures.

    The following modified special safety precautions are based on 
those recommended by the Centers for Disease Control (CDC)(Ref. 
5.8.) and OSHA's Bloodborne Pathogens standard (29 CFr 1910.1039).

    2.7.3. Wear gloves, lab coat, and safety glasses while handling 
all human urine products. Disposable plastic, glass, and paper 
(pipet tips, gloves, etc.) that contact urine should be placed in a 
biohazard autoclave bag. These bags should be kept in appropriate 
containers until sealed and autoclaved. Wipe down all work surfaces 
with 10% sodium hypochlorite solution when work is finished.
    2.7.4. Dispose of all biological samples and diluted specimens 
in a biohazard autoclave bag at the end of the analytical run.
    2.7.5. Special care should be taken when handling and dispensing 
nitric acid. Always remember to add acid to water (or urine). Nitric 
acid is a corrosive chemical capable of severe eye and skin damage. 
Wear metal-free gloves, a lab coat, and safety glasses. If the 
nitric acid comes in contact with any part of the body, quickly wash 
with copious quantities of water for at least 15 minutes.
    2.7.6. Special care should be taken when handling and dispensing 
NaOH. Always remember to add base to water (or urine). NaOH can 
cause severe eye and skin damage. Always wear the appropriate 
gloves, a lab coat, and safety glasses. If the NaOH comes in contact 
with any part of the body, quickly wash with copious quantities of 
water for at least 15 minutes.

3. Analytical Procedure

3.1. Apparatus
    3.1.1. A high performance liquid chromatograph equipped with 
pump, sample injector and UV detector.
    3.1.2. A C18 HPLC column; 25 cm  x  4.6 mm I.D.
    3.1.3. An electronic integrator, or some other suitable means of 
determining analyte response.
    3.1.4. Stripchart recorder.
    3.1.5. C18 SEP-PAKs (Waters Associates) or equivalent.
    3.1.6. Luer-lock syringe for sample preparation (5 mL or 10 mL).
    3.1.7. Volumetric pipettes and flasks for standard and sample 
preparation.
    3.1.8. Vacuum system to aid sample preparation (optional).
3.2. Reagents
    3.2.1. Water, HPLC grade.
    3.2.2. Methanol, HPLC grade.
    3.2.3. PlC B-7 (Waters Associates) in small vials.
    3.2.4. Creatinine, anhydrous, Sigma Chemical Corp., purity not 
listed.
    3.2.5. 1-Heptanesulfonic acid, sodium salt monohydrate.
    3.2.6. Phosphoric acid.
    3.2.7. Mobile phase. It can be prepared by mixing one vial of 
PlC B-7 into a 1 L solution of 50% methanol and 50% water. The 
mobile phase can also be made by preparing a solution that is 50% 
methanol and 50% water with 0.005M heptanesulfonic acid and 
adjusting the pH of the solution to 3.5 with phosphoric acid.
3.3. Standard preparation
    3.3.1. Stock standards are prepared by weighing 10 to 15 mg of 
creatinine. This is transferred to a 25-mL volumetric flask and 
diluted to volume with HPLC grade water.
    3.3.2. Dilutions to a working range of 3 to 35 g/mL are 
made in either HPLC grade water or HPLC mobile phase (standards give 
the same detector response in either solution).
3.4. Sample preparation
    3.4.1. The C18 SEP-PAK is connected to a Luer-lock syringe. It 
is rinsed with 5 mL HPLC grade methanol and then 10 mL of HPLC grade 
water. These rinses are discarded.
    3.4.2. Exactly 1.0 mL of urine is pipetted into the syringe. The 
urine is put through the SEP-PAK into a suitable container using a 
vacuum system.
    3.4.3. The walls of the syringe are rinsed in several stages 
with a total of approximately 30 mL of HPLC grade water. These 
rinses are put through the SEP-PAK into the same container. The 
resulting solution is transferred to a 100-mL volumetric flask and 
then brought to volume with HPLC grade water.
3.5. Analysis (conditions and hardware are those used in this 
evaluation.)
    3.5.1. Instrument conditions 

Column..........  Zorbax ODS, 5-6 m particle size; 25
                   cm  x  4.6 mm I.D.                                   
Mobile phase....  See Section 3.2.7.                                    
Detector........  Dual wavelength UV; 229 nm (primary) 254 nm           
                   (secondary),                                         
Flow rate.......  0.7 mL/minute.                                        
Retention time..  7.2 minutes.                                          
Sensitivity.....  0.05 AUFS.                                            
Injection volume  20 L.                                        
                                                                        

    3.5.2. Chromatogram (See Figure #2).
3.6. Interferences
    3.6.1. Any compound that has the same retention time as 
creatinine and absorbs at 229 nm is an interference.
    3.6.2. HPLC conditions may be varied to circumvent 
interferences. In addition, analysis at another UV wavelength (i.e. 
254 nm) would allow a comparison of the ratio of response of a 
standard to that of a sample. Any deviations would indicate an 
interference.

TR03JA94.007

3.7. Calculations
    3.7.1. A calibration curve is constructed by plotting detector 
response versus standard concentration (See Figure #3).
    3.7.2. The concentration of creatinine in a sample is determined 
by finding the concentration corresponding to its detector response. 
(See Figure #3).
    3.7.3. The g/mL creatinine from section 3.7.2. is then 
multiplied by 100 (the dilution factor). This value is equivalent to 
the micrograms of creatinine in the 1.0 mL stabilized urine aliquot 
or the milligrams of creatinine per liter of urine. The desired 
unit, g/L, is determined by the following relationship:

TR03JA94.008


                                                                        
        g/        mg/L                                         
             mL         ---------                                       
 g/L=  -------------  =                                                 
            1000           1000                                         
                                                                        

    3.7.4. The resulting value for creatinine is used to normalize 
the urinary concentration of the desired analyte (A) (Cd or B2M) by 
using the following formula. 

                                                                        
                           g A/L                               
   g A/g          (experimental)                               
     creatinine=     -------------------------                          
                           g/L creatinine                               
                                                                        

Where A is the desired analyte. The protocol of reporting such 
normalized results is g A/g creatinine.
3.8. Safety precautions. See section 2.7.
4. Conclusions
    The determination of creatinine in urine by HPLC is a good 
alternative to the Jaffe method for industrial hygiene laboratories. 
Sample clarification with SEP-PAKs did not change the amount of 
creatinine found in urine samples. However, it does protect the 
analytical column. The results of this creatinine in urine procedure 
are unaffected by the pH of the urine sample under the conditions 
tested by this procedure. Therefore, no special measures are 
required for creatinine analysis whether the urine sample has been 
stabilized with 10% nitric acid for the Cd analysis or brought to a 
pH of 7 with 0.11 NaOH for the B2M analysis.
5. References
    5.1. Clark, L.C.; Thompson, H.L.; Anal. Chem. 1949, 21, 1218.
    5.2. Peters, J.H.; J. Biol. Chem. 1942, 146, 176.
    5.3. Hausen, V.A.; Fuchs, D.; Wachter, H.; J. Clin. Chem. Clin. 
Biochem. 1981, 19, 373-378.
    5.4. Clark, P.M.S.; Kricka, L.J.; Patel, A.; J. Liq. Chrom. 
1980, 3(7), 1031-1046.
    5.5. Ballerini, R.; Chinol, M.; Cambi, A.; J. Chrom. 1979, 179, 
365-369.
    5.6. Ogata, M.; Taguchi, T.; Industrial Health 1987, 25, 225-
228.
    5.7. ``Merck Index'', 11th ed.; Windholz, Martha Ed.; Merck: 
Rahway, N.J., 1989; p. 403.
    5.8. Kimberly, M.; ``Determination of Cadmium in Urine by 
Graphite Furnace Atomic Absorption Spectrometry with Zeeman 
Background Correction.'' Centers for Disease Control, Atlanta, 
Georgia, unpublished, update 1990.

PART 1926 -- [Amended]

Subpart Z--Toxic and Hazardous Substances

    1. The authority citation for subpart Z of 29 CFR part 1926 
continues to read as follows:
    Authority: Sections 6 and 8, Occupational Safety and Health Act, 
29 U.S.C. 655, 657; Secretary of Labor's Orders Nos. 12-71 (36 FR 
8754), 8-76 (41 FR 25059), 9-83 (48 FR 35736) or 1-90 (55 FR 9033) 
as applicable; and 29 CFR part 1911.
    Section 1926.1102 not issued under 29 U.S.C. 655 or 29 CFR part 
1911; also issued under 5 U.S.C. 653.
    Section 1926.1103 through 1926.1118 also issued under 29 U.S.C. 
653.
    Section 1926.1128 also issued under 29 U.S.C. 653.
    Section 1926.1145 and 1926.1147 also issued under 29 U.S.C. 653.
    Section 1926.1148 also issued under 29 U.S.C. 653.

    2. In part 1926, Sec. 1926.63, Cadmium, is redesignated as 
Sec. 1926.1127.
    3. In paragraph (m)(4)(iii)(H) of (newly redesignated) 
Sec. 1926.1127, the reference to ``Sec. 1910.20(g)(1) and (2)'' is 
changed to read ``Sec. 1926.33(g) (1) and (2)''; in Sec. 1926.1127(n) 
(1)(iii), (3)(iii), and (5)(i), the reference to ``29 CFR 1910.20'' is 
changed to read ``Sec. 1926.33 of this part''; and in 
Sec. 1926.1127(n)(6), the reference to ``29 CFR 1910.20(h)'' is changed 
to read ``Sec. 1926.33(h) of this part.''
[FR Doc. 93-31820 Filed 12-30-93; 8:45 am]
BILLING CODE 4510-26-F