[Code of Federal Regulations]
[Title 29, Volume 6]
[Revised as of July 1, 2006]
From the U.S. Government Printing Office via GPO Access
[CITE: 29CFR1910.1027]
[Page 138-232]
TITLE 29--LABOR
CHAPTER XVII--OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT
OF LABOR
PART 1910_OCCUPATIONAL SAFETY AND HEALTH STANDARDS (CONTINUED)--Table of
Contents
Subpart Z_Toxic and Hazardous Substances
Sec. 1910.1027 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
[micro]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
[[Page 139]]
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 [micro]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.
[[Page 140]]
(5) Employee Notification of Monitoring Results. (i) The employer
must, within 15 working days after the receipt of the results of any
monitoring performed under this section, notify each affected employee
of these results either individually in writing or by posting the
results in an appropriate location that is accessible to 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 I--Separate Engineering Control Airborne Limits (SECALs) for
Processes in Selected Industries
------------------------------------------------------------------------
SECAL
Industry Process ([micro]g/
m\3\)
------------------------------------------------------------------------
Nickel cadmium battery........... Plate making, plate 50
preparation.
All other processes...... 15
Zinc/Cadmium refining*........... Cadmium refining, 50
casting, melting, oxide
production, sinter plant.
Pigment manufacture.............. Calcine, crushing, 50
milling, blending.
All other processes...... 15
Stabilizers*..................... Cadmium oxide charging, 50
crushing, drying,
blending.
Lead smelting*................... Sinter plant, blast 50
furnace, 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
[[Page 141]]
(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) Respiratory protection--(1) General. For employees who use
respirators required by this section, the employer must provide
respirators that comply with the requirements of this paragraph.
Respirators must be used during:
(i) Periods necessary to install or implement feasible engineering
and work-practice controls when employee exposure levels exceed the PEL.
[[Page 142]]
(ii) Maintenance and repair activities, and brief or intermittent
operations, for which employee exposures exceed the PEL and engineering
and work-practice controls are not feasible or are not required.
(iii) Activities in regulated areas specified in paragraph (e) of
this section.
(iv) Work operations for which the employer has implemented all
feasible engineering and work-practice controls and such controls are
not sufficient to reduce employee exposures to or below the PEL.
(v) Work operations for which an employee is exposed to cadmium at
or above the action level, and the employee requests a respirator.
(vi) Work operations for which an employee is exposed to cadmium
above the PEL and engineering controls are not required by paragraph
(f)(1)(ii) of this section.
(vii) Emergencies.
(2) Respirator program. (i) The employer must implement a
respiratory protection program in accordance with 29 CFR 1910.134 (b)
through (d) (except (d)(1)(iii)), and (f) through (m).
(ii) No employees must use a respirator if, based on their most
recent medical examination, the examining physician determines that they
will be unable to continue to function normally while using a
respirator. If the physician determines that the employee must be
limited in, or removed from, their current job because of their
inability to use a respirator, the limitation or removal must be in
accordance with paragraphs (l) (11) and (12) of this section.
(iii) If an employee has breathing difficulty during fit testing or
respirator use, the employer must provide the employee with a medical
examination in accordance with paragraph (l)(6)(ii) of this section to
determine if the employee can use a respirator while performing the
required duties.
(3) Respirator selection. (i) The employer must select the
appropriate respirator from Table 2 of this section.
Table 2--Respiratory Protection for Cadmium
------------------------------------------------------------------------
Airborne concentration or
condition of use \a\ Required respirator type \b\
------------------------------------------------------------------------
10 X or less................. A half mask, air-purifying equipped with
a HEPA \c\ 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 A self-contained breathing apparatus with
concentrations. 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.
------------------------------------------------------------------------
\a\ Concentrations expressed as multiple of the PEL.
\b\ Respirators 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 (10x5 ug/m(3) =
50 ug/m(3)). A full facepiece respirator is required when eye
irritation is experienced.
\c\ HEPA means High-efficiency Particulate Air.
\d\ Fit testing, qualitative or quantitative, is required.
SOURCE: Respiratory Decision Logic, NIOSH, 1987.
(ii) The employer must provide an employee with a powered air-
purifying respirator instead of a negative-pressure respirator when an
employee who is entitled to a respirator chooses to use this type of
respirator and such a respirator provides adequate protection to the
employee.
(h) Emergency situations. The employer shall develop and implement a
[[Page 143]]
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.
[[Page 144]]
(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 [micro]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
[[Page 145]]
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 ([beta]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
([beta]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 ([beta]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 [micro]g/g Cr, [beta]2-M level
to be at or below 300 [micro]g/g Cr and CdB level to be at or below 5
[micro]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, [beta]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 [micro]g/g
Cr, the level of [beta]2-M to exceed 300 [micro]g/g Cr, or
the level of CdB to exceed 5 [micro]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
[[Page 146]]
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
[micro]g/g Cr, [beta]2-M level falls to or below 300
[micro]g/g Cr and CdB level falls to or below 5 [micro]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
[micro]g/g Cr, or the level of CdB to be in excess of 15 [micro]g/lwb,
or the level of [beta]2-M to be in excess of 1,500 [micro]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 [micro]g/g Cr; or CdB exceeds 15 [micro]g/lwb; or
[beta]2-M exceeds 1500 [micro]g/g Cr, and in addition CdU
exceeds 3 [micro]g/g Cr or CdB exceeds 5 [micro]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
[micro]g/g Cr, [beta]2-M level falls to or below 300
[micro]g/g Cr and CdB level falls to or below 5 [micro]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 [micro]g/g Cr,
[beta]2-M level to be at or below 300 [micro]g/g Cr and CdB
level to be at or below 5 [micro]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 [micro]g/g Cr, the level of
[beta]2-M to exceed 300 [micro]g/g Cr, or the level of CdB to
exceed 5 [micro]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 [micro]g/g Cr, or the level of CdB
to be in excess of 10 [micro]g/lwb, or the level of [beta]2-M
to be in excess of 750 [micro]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
[[Page 147]]
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 [micro]g/g Cr; or CdB exceeds 10 [micro]g/lwb; or
[beta]2-M exceeds 750 [micro]g/g Cr, and in addition CdU
exceeds 3 [micro]g/g Cr or CdB exceeds 5 [micro]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
[micro]g/g Cr, [beta]2-M level falls to or below 300
[micro]g/g Cr and CdB level falls to or below 5 [micro]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, [beta]2-M,
or CdB to be in excess of the levels specified in paragraphs (l)(3)(ii)
or (iii);
[[Page 148]]
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 [micro]g/g Cr,
CdB did not exceed 5 [micro]g/lwb, and [beta]2-M did not
exceed 300 [micro]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
[beta]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 [micro]g/g Cr, CdB levels no
longer exceed 5 [micro]g/lwb, and [beta]2-M levels no longer
exceed 300 [micro]g/g Cr, the employer shall provide biological
monitoring for CdU, CdB, and [beta]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, [beta]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
[[Page 149]]
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
[beta]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
[[Page 150]]
obtain a written, 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.
[[Page 151]]
(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
[beta]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 [micro]g/g Cr, CdB falls to or below 5
[micro]g/lwb, and [beta]2-M falls to or below 300 [micro]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 [micro]g/g Cr, CdB falls
to or below 5 [micro]g/lwb, and [beta]2-M falls to or below
300 [micro]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:
[[Page 152]]
(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:
[[Page 153]]
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.
1910.1020(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 29 CFR 1910.1020.
(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,
[[Page 154]]
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 29
CFR 1910.1020.
(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
29 CFR 1910.1020.
(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
29 CFR 1910.1020 (h).
(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 60 days after the effective date of this standard. 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 120 days after the effective date of this standard.
(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
[[Page 155]]
soon as possible after the results of exposure monitoring are known and
in any event no later than 90 days after the effective date of this
section. 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 150 days after the effective date of this section.
(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 150 days after the effective date of this
section.
(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 1 year after the effective date of this section.
(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 two (2) years after the
effective date of this section. 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 60 days after the effective date of this section.
(B) Change rooms, showers, and lunchroom facilities shall be
completed as soon as possible and in any event no later than 1 year
after the effective date of this section.
(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 90
days after the effective date of this standard. 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 180 days after the effective date of this standard.
(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 90 days after the effective date
of this standard. 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 180 days after the effective
date of this standard.
(q) Appendices. 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. 1910.1027--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
[micro]g/m\3\, 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.
[[Page 156]]
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.
[[Page 157]]
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 ([beta]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 [beta]2-M associated
with cadmium exposure it is unlikely that [beta]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 [beta]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
[[Page 158]]
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 ([beta]2-M), a
low molecular weight protein. Excess [beta]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 [beta]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 [beta]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 [micro]g
Cd/gram creatinine in urine and 5 [micro]gCd/liter whole blood,
respectively. These levels were derived from broad-based population
studies.
Three issues confront the physicians in the use of
[beta]2-M as a marker of kidney dysfunction and material
impairment. First, there are a few other causes of elevated levels of
[beta]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 [beta]2-M to degrade so that low
levels would result in workers with tubular dysfunction. For example,
regarding the degradation of [beta]2-M, workers with acidic
urine (pH<6) might have [beta]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 pH6 (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 [beta]2-M levels greater than 300
[micro]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 [beta]2-M at low levels has
often been considered difficult, however, many laboratories have the
capability of detecting excess [beta]2-M using simple kits,
such as the Phadebas Delphia test, that are accurate to levels of 100
[micro]g [beta]2-M/g Cr U (Ex. L-140-1).
Specific recommendations for ways to measure [beta]2-M
and proper handling of urine samples to prevent degradation of
[beta]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
([beta]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 ([beta]2-M) taken from
employees is performed in laboratories with demonstrated proficiency for
that particular analyte. (See appendix F.)
[[Page 159]]
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/m\3\ 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/m\3\ 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 ([beta]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 [micro]g/gram creatinine
(g Cr), or CdB is greater than 15 [micro]g/liter whole blood (lwb), or
[beta]2-M is greater than 1500 [micro]g/g Cr, and CdB is
greater than 5 [micro]g/lwb or CdU is greater than 3 [micro]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;
[[Page 160]]
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 [beta]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 [beta]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 number 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.
------------------------------------------------------------------------
[[Page 161]]
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.
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) ([micro]g/g creatinine)................... <=3 3 and <=15 15
[beta]2-microglobulin ([beta]2-M) ([micro]g/g creatinine)........ <=300 300 and 1500*
Cadmium in blood (CdB) ([micro]g/liter whole blood).............. <=5 5 and <=15 15
----------------------------------------------------------------------------------------------------------------
* If an employee's [beta]2-M levels are above 1,500 [micro]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 [micro]g/g
creatinine or CdB level must also be >5 [micro]g/liter whole blood.
Applicable Beginning January 1, 1999
----------------------------------------------------------------------------------------------------------------
Monitoring result categories
Biological marker ----------------------------------------------
A B C
----------------------------------------------------------------------------------------------------------------
Cadmium in urine (CdU) ([micro]g/g creatinine)................... <=3 3 and <=7 7
[beta]2-microglobulin ([beta]2-M) ([micro]g/g creatinine)........ <=300 300 and 750*
Cadmium in blood (CdB) ([micro]g/liter whole blood).............. <=5 5 and <=10 10
----------------------------------------------------------------------------------------------------------------
* If an employee's [beta]2-M levels are above 750 [micro]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 [micro]g/g
creatinine or CdB level must also be >5 [micro]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.
[[Page 162]]
------------------------------------------------------------------------
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 ............ X X
exposure.
(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 ............ X X
removal.
(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 ------ [micro]g/g Cr--Normal Levels: <=3 [micro]g/g
Cr.
Cadmium in Blood ------ [micro]g/lwb--Normal Levels: <=5 [micro]g/
lwb.
Beta-2-microglobulin in Urine ------ [micro]g/g Cr--Normal Levels:
<=300 [micro]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
[[Page 163]]
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 ([micro]g/g Cr), cadmium blood greater than 10 micrograms per
liter of whole blood ([micro]g/lwb), or beta-2-microglobulin greater
than 1000 micrograms per gram of creatinine ([micro]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 [micro]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. 1910.1027--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: (H2 O=@ 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
[[Page 164]]
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: (H2 O=1@20 [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: (H2 O=1@ 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.
Chemcail name: Cadmium chloride.
Formula: CdC12.
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.
[[Page 165]]
Boiling point (760 mm Hg): 960 degrees C.
Melting point: 568 degrees C.
Specific Gravity: (H2 O=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. 1910.1027 [Reserved]
Appendix D to Sec. 1910.1027--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?
[[Page 166]]
[ ] 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
[[Page 167]]
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?
________________________________________________________________________
________________________________________________________________________
[[Page 168]]
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 approximated 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. 1910.1027--Cadmium in Workplace Atmospheres
Method Number: ID-189
Matrix: Air
OSHA Permissible Exposure Limits: 5 [micro]g/m\3\ (TWA), 2.5 [micro]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-[micro]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 [micro]g/m\3\ for a 200 L sample by Flame AAS, 0.007
[micro]g/m\3\ for a 60 L sample by AAS-HGA
Quantitative: 0.70 [micro]g/m\3\ for a 200 L sample by Flame AAS, 0.025
[micro]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 [micro]g/m\3\ for a 400 L air vol, 1.25
to 5.0 [micro]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-[micro]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-[micro]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-[micro]m mixed cellulose ester membrane filters for the collection
of air samples. These cadmium air filter samples
[[Page 169]]
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 [micro]g (0.004 [micro]g/mL) and
0.14 [micro]g (0.014 [micro]g/mL) cadmium, respectively, for a 10 mL
solution volume. These correspond, respectively, to 0.2 [micro]g/m\3\
and 0.70 [micro]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 [micro]g/m\3\ and 0.025 [micro]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 [micro]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 [micro]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
[micro]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
[[Page 170]]
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-[micro]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.
[[Page 171]]
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 [micro]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
[micro]S.
3.5.2. Concentrated nitric acid, HNO3.
3.5.3. Concentrated hydrochloric acid, HCl.
3.5.4. Ammonium phosphate, monobasic, NH4 H2
PO4.
3.5.5. Magnesium nitrate, Mg(NO3)2 [middot]
6H2 O.
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 [micro]g/mL: Use a
commercially available certified 1,000 [micro]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
NH4 H2 PO4 and 0.15 g
Mg(NO3)2 [middot] 6H2 O 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 H2 O mixture:
Carefully add a measured volume of concentrated HNO3 to an
equal volume of DI H2 O.
3.5.10. Nitric acid, 10% v/v: Carefully add 100 mL of concentrated
HNO3 to 500 mL of DI H2 O 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 [micro]g/mL
cadmium standard stock solutions by making appropriate serial dilutions
of 1,000 [micro]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 [micro]g/mL by making appropriate serial dilutions
of the dilute stock solutions with the
[[Page 172]]
same diluting solution. A suggested method of preparation of the working
standards is given below.
------------------------------------------------------------------------
Std Final
Working standard solution Aliquot vol.
------------------------------------------------------------------------
([micro]g/mL) ([micro]g/ (mL) (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 [micro]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.
------------------------------------------------------------------------
Std Final
Working standard solution Aliquot vol.
------------------------------------------------------------------------
(ng/mL) (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 [micro]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
[micro]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 [micro]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
[[Page 173]]
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 [micro]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-[micro]L aliquot of the
working standard, sample or reagent blank solution onto the L'vov
platform along with a 10-[micro]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 [micro]g) unless a prior
conversion is made.
3.12.1. Correct for baseline drift and noise in flame AAS analysis
by subtracting each
[[Page 174]]
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 ([micro]g/mL or ng/mL) of cadmium in
each working standard.
3.12.3. Determine the concentration ([micro]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 [micro]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 ([micro]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 [micro]g/m\3\) by using one of the following equations:
mg/m\3\ = Wbc/(Air vol sampled, L)
or
[micro]g/m\3\ = (Wbc)(1,000 ng/[micro]g)/(Air vol sampled, L)
Where:
Wbc = blank corrected total [micro]g cadmium in the sample.
(1[micro]g=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 = [[verbar]
Bias[verbar]+(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-[micro]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
[[Page 175]]
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, NH4 H2
PO4 and magnesium nitrate,
Mg(NO3)26H2 O, 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
[micro]g/mL cadmium standard stock solutions by making appropriate
serial dilutions of a commercially available 1,000 [micro]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 [micro]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 [micro]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 [micro]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
[micro]g/mL cadmium standard was made prior to analysis. The 2.0
[micro]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 [micro]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 [micro]g/mL cadmium standards versus their concentration is 772.7
abs. units/([micro]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/([micro]g/mL))
= 0.0041 [micro]g/mL for the qualitative detection limit.
Cld=(10)(1.05 abs. units)/(772.7 abs. units/[micro]g/mL))
=0.014 [micro]g/mL for the quantitative detection limit.
The qualitative and quantitative detection limits for the flame AAS
analytical technique are 0.041 [micro]g and 0.14 [micro]g cadmium,
respectively, for a 10 mL solution volume. These correspond,
respectively, to 0.2 [micro]g/m\3\ and 0.70 [micro]g/m\3\ 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 [micro]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 [micro]g/mL, is
slightly greater than the calculated quantitative detection limit, 0.014
[micro]g/mL. The standard of highest concentration in the working range,
2.0 [micro]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
[micro]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
[[Page 176]]
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
[micro]g/m\3\ and 0.025 [micro]g/m\3\ 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 [micro]L of 10, 50, 100 and 200 [micro]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 [micro]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
[micro]g/m\3\ 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[micro]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%.
[[Page 177]]
4.9. Analytical Method Recovery for AAS-HGA Analysis
4.9.1. Three sets of spiked MCEF samples were prepared by injecting
15[micro]L of 5, 10 and 20 [micro]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 [micro]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
[micro]g/m\3\ 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.
[[Page 178]]
Table I--Cd Detection Limit Study
[Flame AAS Analysis]
------------------------------------------------------------------------
Absorbance
STD ([micro]g/mL) reading at 228.8 Statistical
nm analysis
------------------------------------------------------------------------
Reagent blank................... 5 2 n=6.
4 3 mean=3.50.
4 3 std dev=1.05.
CV=0.30.
0.001........................... 6 6 n=6.
2 4 mean=5.00.
6 6 std dev=1.67.
CV=0.335.
0.002........................... 5 7 n=6.
7 3 mean=5.50.
7 4 std dev=1.76.
CV=0.320.
0.005........................... 7 7 n=6.
8 8 mean=7.33.
8 6 std dev=0.817.
CV=0.111.
0.010........................... 10 9 n=6.
10 13 mean=10.3.
10 10 std dev=1.37.
CV=0.133.
0.020........................... 20 23 n=6.
20 22 mean=20.8.
20 20 std dev=1.33.
CV=0.064.
0.050........................... 42 42 n=6.
42 42 mean=42.5.
42 45 std dev=1.22.
CV=0.029.
0.10............................ 84 n=3.
80 mean=82.3.
83 std dev=2.08.
CV=0.025.
------------------------------------------------------------------------
Table II--Cd Standard Working Range Study
[Flame AAS Analysis]
------------------------------------------------------------------------
Absorbance
STD ([micro]g/mL) reading at 228.8 Statistical
nm analysis
------------------------------------------------------------------------
Reagent blank................... 5 2 n=6.
4 3 mean=3.50.
4 3 std dev=1.05.
CV=0.30.
0.020........................... 20 23 n=6.
20 22 mean=20.8.
20 20 std dev=1.33.
CV=0.064.
0.050........................... 42 42 n=6.
42 42 mean=42.5.
42 45 std dev=1.22.
CV=0.029.
0.10............................ 84 n=3.
80 mean=82.3.
83 std dev=2.08.
CV=0.025.
0.20............................ 161 n=3.
161 mean=160.0.
158 std dev=1.73.
CV=0.011.
0.50............................ 391 n=3.
389 mean=391.0.
393 std dev=2.00.
CV=0.005.
1.00............................ 760 n=3.
748 mean=753.3.
752 std dev=6.11.
CV=0.008.
2.00............................ 1416 n=3.
1426 mean=1414.3.
1401 std dev=12.6.
CV=0.009.
------------------------------------------------------------------------
Table III--Cd Detection Limit Study
[AAS-HGA Analysis]
------------------------------------------------------------------------
Peak area
readings x
STD (ng/mL) 10\3\ at Statistical analysis
228.8 nm
------------------------------------------------------------------------
Reagent blank...................... 0 0 n=6.
0 1 mean=0.167.
0 0 std dev=0.41.
CV=2.45.
0.1................................ 8 6 n=6.
5 7 mean=7.7.
13 7 std dev=2.8.
CV=0.366.
0.2................................ 11 13 n=6.
11 12 mean=11.8.
12 12 std dev=0.75.
CV=0.064.
0.5................................ 28 33 n=6.
26 28 mean=28.8.
28 30 std dev=2.4.
CV=0.083.
1.0................................ 52 55 n=6.
56 58 mean=54.8.
54 54 std dev=2.0.
CV=0.037.
2.0................................ 101 112 n=6.
110 110 mean=108.8.
110 110 std dev=3.9.
CV=0.036.
------------------------------------------------------------------------
Table IV--Cd Standard Working Range Study
[AAS-HGA Analysis]
------------------------------------------------------------------------
Peak area
readings x
STD (ng/mL) 10\3\ at Statistical analysis
228.8 nm
------------------------------------------------------------------------
0.2................................ 11 13 n=6.
11 12 mean=11.8.
12 12 std dev=0.75.
CV=0.064.
0.5................................ 28 33 n=6.
26 28 mean=28.8.
28 30 std dev=2.4.
CV=0.083.
1.0................................ 52 55 n=6.
56 58 mean=54.8.
54 54 std dev=2.0.
CV=0.037.
2.0................................ 101 112 n=6.
110 110 mean=108.8.
110 110 std dev=3.9.
CV=0.036.
[[Page 179]]
5.0................................ 247 265 n=6.
268 275 mean=265.5.
259 279 std dev=11.5.
CV=0.044.
10.0............................... 495 520 n=6.
523 513 mean=516.7.
516 533 std dev=12.7.
CV=0.025.
20.0............................... 950 953 n=6.
951 958 mean=941.8.
949 890 std dev=25.6.
CV=0.027.
30.0............................... 1269 1291 n=6.
1303 1307 mean=1293.
1295 1290 std dev=13.3.
CV=0.010.
40.0............................... 1505 1567 n=6.
1535 1567 mean=1552.
1566 1572 std dev=26.6.
CV=0.017.
------------------------------------------------------------------------
Table V--Analytical Method Recovery
[Flame AAS Analysis]
----------------------------------------------------------------------------------------------------------------
Test level 0.5x 1.0x 2.0x
--------------------------------------- Percent [micro]g ---------- Percent [micro]g ---------- Percent
[micro]g rec. taken [micro]g rec. taken [micro]g rec.
[micro]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 0.1x
-------------------------------------------------------- Percent rec.
[micro]g taken [micro]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 0.5x 1.0x 2.0x
---------------------------------------------- Percent ng ---------- Percent ng ---------- Percent
ng rec. taken rec. taken rec.
ng taken found ng found ng found
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------
[[Page 180]]
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. 1910.1027--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
[[Page 181]]
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.
[[Page 182]]
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 [micro]g/l. For CDU, the target values are 3, 7, and 15
[micro]g/g CRTU. For B2 MU, the target values are 300, 750
and 1500 [micro]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 [micro]g/l...... ........... 1 [micro]g/l or 15%
of the mean.
<=2 [micro]g/l............... .................... 40
2[micro]g/l....... .................... 20
[[Page 183]]
Cadmium in urine................. 0.5 [micro]g/g ........... 1 [micro]g/l or 15%
creatinine. of the mean.
<=2 [micro]g/l creatinine.... .................... 40
2[micro]g/l .................... 20
creatinine.
[beta]-2-microglobulin in urine: 100 [micro]g/g 5 15% of the mean.
100 [micro]g/g creatine. creatinine.
----------------------------------------------------------------------------------------------------------------
To satisfy the DQOs presented in Table 1, OSHA provides the
following guidelines:
1. Procedures for the collection and handling of blood and urine are
specified (Section 3.4.1 of this protocol);
2. Preferred analytic methods for the analysis of CDB, CDU and B2MU
are defined (and a method for the determination of CRTU also is
specified since CDU and B2MU results are to be normalized to the level
of CRTU).
3. Procedures are described for identifying laboratories likely to
provide the required analyses in an accurate and reliable manner;
4. These guidelines (Sections 3.2.1 to 3.2.3, and Section 3.3)
include recommendations regarding internal QA/QC programs for
participating laboratories, as well as levels of proficiency through
participation in an interlaboratory proficiency program;
5. Procedures for QA/QC record keeping (Section 3.3.2), and for
reporting QC/QA results are described (Section 3.3.3); and,
6. Procedures for interpreting medical monitoring results are
specified (Section 3.4.3).
Methods recommended for the biological monitoring of eligible
workers are:
1. The method of Stoeppler and Brandt (1980) for CDB determinations
(limit of detection: 0.5 [micro]g/l);
2. The method of Pruszkowska et al. (1983) for CDU determinations
(limit of detection: 0.5 [micro]g/l of urine); and,
3. The Pharmacia Delphia test kit (Pharmacia 1990) for the
determination of B2MU (limit of detection: 100 [micro]g/l urine).
Because both CDU and B2MU should be reported in [micro]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 [micro]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
[[Page 184]]
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 [micro]g/l blood or 15%
of the consensus mean (whichever is greater). For samples exhibiting a
consensus mean less than 1 [micro]g/l, the performance requirement is
defined as a concentration between the detection limit of the analysis
and a maximum of 2 [micro]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 [micro]g/l.
The performance requirement for CDU analysis is defined as an
analytical result
[[Page 185]]
within 1 [micro]g/l urine or 15% of the consensus
mean (whichever is greater). For samples exhibiting a consensus mean
less than 1 [micro]g/l urine, the performance requirement is defined as
a concentration between the detection limit of the analysis and a
maximum of 2 [micro]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 [micro]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 [micro]g/g CRTU.
There are no recommended performance checks for CRTU analyses. As
stated previously, laboratories performing CRTU analysis in support of
CDU or B2MU analyses should be accredited by the CAP, and participating
in the CAP's survey for CRTU.
Following the first review, the status of each participating
laboratory should be reevaluated at regular intervals (i.e.,
corresponding to receipt of results from each succeeding round of
proficiency testing and submission of reports from a participating
laboratory's internal QA/QC program).
After a year of collecting proficiency test results, the following
proficiency criterion should be added to the set of criteria used to
determine the participating laboratory's status (for analyzing CDB, CDU
and/or B2MU): A participating laboratory should not fail performance
requirements for more than 4 samples from the 6 most recent consecutive
rounds used to assess proficiency for CDB, CDU and/or B2MU separately
(i.e., a total of 18 discrete proficiency samples for each analyte).
Note that this requirement does not replace, but supplements, the
recommendation that a laboratory should satisfy the performance criteria
for at least 2 of the 3 samples tested for each round of the program.
3.2.3 Recommendations for Selecting Among Newly-Formed Laboratories (or
Laboratories That Previously Failed To Meet the Protocol Guidelines)
OSHA recommends that laboratories that have not previously provided
commercial analyses of CDB, CDU and/or B2MU (or have done so for a
period less than 2 years), or which have provided these analyses for 2
or more years but have not conformed previously with these protocol
guidelines, should satisfy the following provisions for each analyte for
which determinations are to be made prior to being selected to analyze
biological samples under the medical monitoring program:
1. Submit to the responsible physician an internal QA/QC plan
detailing the standard operating procedures to be adopted for satisfying
the QA/QC guidelines (guidelines for internal QA/QC programs are
detailed in Section 3.3.1);
2. Submit to the responsible physician the results of the initial
characterization analyses for each analyte for which determinations are
to be made;
3. Submit to the responsible physician the results, for the initial
6-month period, of the internal QA/QC program for each analyte for which
determinations are to be made (if no commercial analyses have been
conducted previously, a minimum of 2 mock standardization trials for
each analyte should be completed per month for a 6-month period);
4. Enroll in the CTQ program for the appropriate analyte for which
determinations are to be made, and arrange to have the CTQ program
submit the initial confirmation of participation and proficiency test
results directly to the designated physicians. Note that the designated
physician should receive results from 3 completed rounds from the CTQ
program before approving a laboratory for participation in the
biological monitoring program;
5. Laboratories seeking participation for CDU and/or B2MU analyses
should submit to the responsible physician documentation of
accreditation by the CAP for CRTU analyses performed in conjunction with
CDU and/or B2MU determinations (if CRTU analyses are conducted by a
contract laboratory, this laboratory should submit proof of CAP
accreditation to the responsible physician); and,
6. Documentation should be submitted on an appropriate form.
To participate in CDB, CDU and/or B2MU analyses, the laboratory
should satisfy the above criteria for a minimum of 2 of the 3
proficiency samples provided in each of the 3 rounds of the CTQ program
over a 6-month period; this procedure should be completed for each
appropriate analyte. Proficiency should be maintained for each analyte
to continue participation. Note that laboratories seeking participation
for CDU or B2MU also should address the performance requirements for
CRTU, which involves providing evidence of accreditation by the CAP and
participation in the CAP surveys (or an equivalent program).
The performance requirement for CDB analysis is defined as an
analytical result within 1 [micro]g/l or 15% of
the consensus mean (whichever is greater). For samples exhibiting a
consensus mean less than 1 [micro]g/l, the performance requirement is
defined as a concentration between the detection limit of the analysis
and a maximum of 2 [micro]g/l. The
[[Page 186]]
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 [micro]g/l.
The performance requirement for CDU analysis is defined as an
analytical result within 1 [micro]g/l urine or 15%
of the consensus mean (whichever is greater). For samples exhibiting a
consensus mean less than 1 [micro]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 [micro]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 [micro]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 [micro]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.
[[Page 187]]
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 2[sigma] from the
laboratory mean recovery), or on proficiency testing limits (e.g.,1[micro]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 [micro]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 [micro]g Cd/l,
and Bl CBM-2 at 12.38 [micro]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 [micro]g/l in
reconstituted urine.)
[[Page 188]]
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
data report. full 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 Report...... For all reports Date the sample was
of 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
[[Page 189]]
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 X
2[sigma] (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 the total number of samples analyzed):
[GRAPHIC] [TIFF OMITTED] TC28OC91.012
The standard deviation, [sigma], for these measurements is derived using
the following equation (note that 2[sigma] is twice this value):
[GRAPHIC] [TIFF OMITTED] TC28OC91.013
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)[Sigma]i, with
Ti being a consensus mean for the sample;
3. Mean of the measurements, (1/N)[Sigma]i, with
Mi being a sample measurement;
4. A measure of error defined by:
(1/N)[Sigma](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 X2[sigma], with X being the measured value and
2[sigma] 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:
[GRAPHIC] [TIFF OMITTED] TC28OC91.014
For these calculations, X p is the measurement and
confidence limits for CDU or B2MU, and Y q 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
[[Page 190]]
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 [micro]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.
[[Page 191]]
The average daily intake of cadmium by the U.S. population is estimated
to be 10-20 [micro]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 [micro]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 [micro]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 [micro]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).
[[Page 192]]
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 [beta]-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 [micro]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.
[[Page 193]]
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 [micro]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 [micro]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
[micro]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 [micro]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 [micro]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[sigma] 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 [micro]g Cd/l urine
(unadjusted), [micro]g Cd/l urine (adjusted for specific gravity), or
[micro]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 [micro]g/l (see Section 5.2.7).
Normalized for creatinine (CRTU), the average CDU concentration of the
general population is less than 1 [micro]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
[micro]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. [beta]-2-Microglobulin (B2M), currently the most widely used
assay for detecting kidney dysfunction, is the best characterized
[[Page 194]]
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 [micro]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 [micro]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
[micro]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
[[Page 195]]
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 [micro]g/l (2 ng/ml), while occupationally-exposed
workers can be at medical risk to cadmium toxicity if blood
concentrations exceed 5 [micro]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. Any matrix............. Perkin-Elmer (1982).... Not sensitive enough
Spectroscopy (FAAS). 0 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.
[[Page 196]]
=0. Blood.................. Stoeppler and Brandt
20 (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
Gamma Spectroscopy vivo method for
(NA). direct 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 [micro]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
[[Page 197]]
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 H2 SO4) and
hydrogen peroxide (H2 O2). 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% H2 O2 is added as the
sample dries. The residue is dissolved in 5 ml dilute (1%)
HNO3, and 20 [micro]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 [micro]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 [micro]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
[micro]l) of whole blood that have been stabilized with EDTA are
pipetted into clean polystyrene tubes and mixed with 150-600 [micro]l of
1 M HNO3. After vigorous shaking, the solution is centrifuged
and a 10-25 [micro]l aliquot of the supernatant then is analyzed by
graphite-furnace AAS with appropriate background correction.
[[Page 198]]
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 [micro]g Cd/l in whole blood, with a linear response
curve from 0.4 to 16.0 [micro]g Cd/l. They report a coefficient of
variation (CV) of 6.7% at 8.0 [micro]g/l.
The APHA (1988) reports a range of 1.0-25 [micro]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
[micro]g Cd/l whole blood, with a linear range of 0.4-12.0 [micro]g Cd/
l, and a CV of 15-30%, for samples at <1.0 [micro]g/l. Improved
precision (CV of 3.8%) was reported for CDB concentrations at 9.3
[micro]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 [micro]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
[micro]g/l or 15% of the mean, whichever is greater. (For this
procedure, the 15% criterion was applied to concentrations exceeding 7
[micro]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 [micro]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 [micro]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
[micro]g/l, and increases for cadmium
[[Page 199]]
concentrations below 5 [micro]g/l. At 2 [micro]g/l, the reported CV
rises to approximately 40%. At 1 [micro]g/l, the reported CV is
approximately 60%.
Participating laboratories also tend to overestimate concentrations
for samples exhibiting concentrations less than 2 [micro]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 [micro]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 [micro]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
[micro]g Cd/l (Friberg and Vahter 1983). The performance of
participating laboratories over a concentration range of 1.5-12
[micro]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
[micro]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 [micro]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 [micro]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).
[[Page 200]]
Table 4--Blood Cadmium Concentrations of U.S. Population Not Occupationally Exposed to Cadmium \a\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Lower 95th Upper 95th
Arithmetic mean Absolute Geometric mean percentile percentile
Study No. No. in Sex Age Smoking ( S.D.) (95% CI) thn-eq> GSD) \e\ distribution distribution
\c\ \d\ \f\ \f\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
1............................... 80 M 4 to 69.......... NS,S 1.13 0.35-3.3 0.98
1.71
88 F 4 to 69.......... NS,S 1.03 0.21-3.3 0.91
1.63
115 M/F 4 to 69.......... NS 0.95 0.21-3.3 0.85
1.59
31 M/F 4 to 69.......... S 1.54 0.4-3.3 1.37
1.65
2............................... 10 M Adults........... (?) 2.0
2.1
3............................... 24 M Adults........... NS ................ ........... 0.6 (1983).
1/87
20 M Adults........... S ................ ........... 1.2
2.13
64 F Adults........... NS ................ ........... 0.5
1.85
39 F Adults........... S ................ ........... 0.8
2.22
4............................... 32 M Adults........... S,NS ................ ........... 1.2
2.0
5............................... 35 M Adults........... (?) 2.1
2.1
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Concentrations reported in [micro]g Cd/l blood unless otherwise stated.
\b\ NS--never smoked; S--current cigarette smoker.
\c\ S.D.--Arithmetic Standard Deviation.
\d\ C.I.--Confidence interval.
\e\ GSD--Geometric Standard Deviation.
\f\ Based on an assumed lognormal distribution.
\g\ Based on an assumed normal distribution.
[[Page 201]]
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 [micro]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 [micro]g/l.
In general, nonsmokers tend to exhibit levels ranging to 2 [micro]g/
l, while levels observed among smokers range to 5 [micro]g/l. Based on
the data presented in Table 4, 95% of those not occupationally exposed
to cadmium exhibit CDB levels less than 5 [micro]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 i 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 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.
[[Page 202]]
Table 5--Blood Cadmium in Workers Exposed to Cadmium in the Workplace
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Concentrations of Cadmium in blood \a\
Mean -------------------------------------------------------------------------------------------
Work environment Number Employment concentration Arithmetic mean Absolute Lower 95th Upper 95th
Study number (worker population in study in years of cadmium in ( S.D.) (95% C.I.) mean (GSD) of range of range Reference
m\3\) \b\ \c\ \d\ \e\ ( ) \f\ \e\ ( ) \f\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
1................................. Ni-Cd battery plant and ........ 3-40 <=90 ................ .......... .......... ........... ........... Lauwerys et al. 1976.
Cd production plant:
(Workers without 96 ............ ............... 21.4
1.9
(Workers with kidney 25 ............ ............... 38.8
3.8
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; 20.8
7.1
(Low exposure group).. 9 (7.3) 40-5 yrs] 7.1
1.1
4................................. Retrospective study of 19 15-41 ............... ................ .......... .......... ........... ........... Roels et al. 1982.
workers with renal
problems:
(Before removal)...... ........ (27.2) ............... 39.9
3.7
(After removal)....... ........ \g\(4.2) ............... 14.1
5.6
5................................. Cadmium production ........ ............ ............... ................ .......... .......... ........... ........... Ellis et al. 1983.
plant:
(Workers without renal 33 1-34 ............... 155.7
(Workers with renal 18 10-34 ............... 248.5
6................................. Cd-Cu alloy plant...... 75 Up to 39 ............... ................ .......... 8.8
5.3
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Concentrations reported in [micro]g Cd/l blood unless otherwise stated.
\b\ S.D.--Standard Deviation.
\c\ C.I.--Confidence Interval.
\d\ GSD--Geometric Standard Deviation.
\e\ Based on an assumed lognormal distribution.
\f\ Based on an assumed normal distribution.
\g\ Years following removal.
[[Page 203]]
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 [micro]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
[micro]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 [micro]g/l should be achievable using the
Stoeppler and Brandt method. Stoeppler and Brandt (1980) report a limit
of detection equivalent to <=0.2 [micro]g/l in whole blood using 25
[micro]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 [micro]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 proficiency 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 [micro]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 [micro]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 [micro]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
[micro]g/l), and CVs of less than 5% for higher concentrations.
For internal QC samples (see Section 3.3.1), laboratories should
attain an overall precision near 25%. For CDB samples with
concentrations less than 2 [micro]g/l, a target precision of 40% is
reasonable, while precisions of 20% should be achievable for
concentrations greater than 2 [micro]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
[[Page 204]]
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., [micro]g Cd/l urine), ``corrected''
concentrations of cadmium per volume of urine at a standard specific
gravity (i.e., [micro]g Cd/l urine at a specific gravity of 1.020), or
``corrected'' mass concentration per unit mass of creatinine (i.e.,
[micro]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
[micro]g of cadmium per unit mass or volume using 89 nmoles of
cadmium=10 [micro]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 ([micro]g/g CTRU).
Reporting CDU as [micro]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
[micro]g Cd/l, with analysis of creatinine addressed separately.
Techniques for assessing creatinine are discussed in Section 5.4.
[[Page 205]]
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 [micro]g Cd/l, and CDU concentrations among
nonexposed control groups at maximum levels of 10 [micro]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 preatomization. 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
[micro]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
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 [micro]g/l CDU, with a CV of <4%
between 0-5 [micro]g/l. The CDC reports a minimum CDU detection limit of
0.07 [micro]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 [micro]/l for their methodology.
[[Page 206]]
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 [micro]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 [micro]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 [micro]g/l,
acceptable results (target of 2 [micro]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 [micro]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
[micro]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 [micro]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 [micro]g/l (uncorrected for creatinine or specific gravity).
These CDU concentrations are intermediate between population values
found in Sweden (range: 0.11-0.80 [micro]g/l) and Japan (range: 0.14-
2.32 [micro]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: [micro]g/l urine (unadjusted), [micro]g/
l (specific gravity adjusted to 1.020), and [micro]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.
[[Page 207]]
Table 6--Urine Cadmium Concentrations in the U.S. Adult Population: Normal and Concentration-Adjusted Values by
Age and Sex \1\
----------------------------------------------------------------------------------------------------------------
Geometric means (and geometric standard
deviations)
-----------------------------------------------
SG-adjusted Creatine-
Unadjusted \2\ [micro]g/l adjusted
([micro]g/l) at 1.020) ([micro]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)
----------------------------------------------------------------------------------------------------------------
\1\ From Kowal and Zirkes 1983.
\2\ SC-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\
----------------------------------------------------------------------------------------------------------------
Creatine-
Unadjusted SG-adjusted adjusted
Range of concentrations ([micro]g/l) ([micro]g/l at ([micro]g/g)
percent 1.020) percent percent
----------------------------------------------------------------------------------------------------------------
<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
----------------------------------------------------------------------------------------------------------------
\1\ Source: 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 [micro]/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 [micro]/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 [micro]/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 [micro]/g CRTU, unless otherwise stated.
[[Page 208]]
Table 8--Urine Cadmium Concentrations in Workers Exposed to Cadmium in the Workplace
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Concentration of cadmium in Urine \a\
Mean --------------------------------------------------------------------------------------------------------
Work environment (worker Number Employment Concentration Arithmetic mean Absolute Lower 95th Upper 95th
Study number population monitored) in Study in years of cadmium in ( S.D.) (95% C.I.) mean (GSD) of range of range Reference
m\3\) \b\ \c\ \d\ \e\ ( ) \f\ \e\ ( ) \f\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
1.................. Ni-Cd battery plant and ........ 3-40 <= 90 ................ .......... .......... ........... ........... Lauwerys et al. 1976.
Cd production plant.
(Workers without kidney 96 ............ ............... 16.3
16.7
(Workers with kidney 25 ............ ............... 48.2
42.6
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 148 (15.4) ............... 15.8 2-150 .......... ........... ........... Butchet et al. 1980.
facility.
4.................. Retrospective study of 19 15-41 ............... ................ .......... .......... ........... ........... Roels et al. 1982.
workers with renal
problems.
(Before removal)........ ........ (27.2) ............... 39.4
28.1
(After removal)......... ........ (4.2) \g\ ............... 16.4
9.0
5.................. Cadmium production plant. ........ ............ ............... ................ .......... .......... ........... ........... Ellis et al. 1983.
(Workers without renal 33 1-34 ............... 9.4
6.9
(Workers with renal 18 10-34 ............... 22.8
12.7
6.................. Cd-Cu alloy plant........ 75 Up to 39 Note h 6.9
9.4
7.................. Cadmium recovery 45 (19) 87 9.3
6.9
8.................. Pigment manufacturing 29 (12.8) 0.18-3.0 ................ 0.2-9.5 1.1 ........... ........... Mueller et al. 1989.
plant.
9.................. Pigment manufacturing 26 (12.1) <=3.0 ................ .......... 1.251 [micro]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
[micro]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
[micro]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 [micro]g/l, a target precision of 40% is acceptable, while precisions
of 20% should be achievable for CDU concentrations greater than 2
[micro]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 [beta]-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
[micro]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 [micro]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
[[Page 211]]
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 [micro]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 [micro]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 [micro]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
[micro]g/g CRTU. Also, the Pharmacia Delphia test currently is the most
widely used test for assessing B2MU.
[[Page 212]]
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 [micro]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 distribution \a\ distribution \a\
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
1................................. 133 m \b\........... 115 [micro]g/g \c\.. 4.03................ 12.................. 1,140 [micro]g/g \c\ Ishizaki et al. 1989.
2................................. 161 f \b\........... 146 [micro]g/g \c\.. 3.11................ 23.................. 940 [micro]g/g \c\.. Ishizaki et al. 1989.
[[Page 213]]
3................................. 10.................. 84 [micro]g/g....... .................... .................... .................... Ellis et al. 1983.
4................................. 203................. 76 [micro]g/l....... .................... .................... .................... Stewart and Hughes 1981.
5................................. 9................... 103 [micro]g/g...... .................... .................... .................... Chia et al. 1989.
6................................. 47 \d\.............. 86 [micro]g/L....... 1.9................. 30 [micro]g/1....... 250 [micro]g/L...... Kjellstrom et al. 1977.
7................................. 1,000 \e\........... 68.1 [micro]g/gr Cr 3.1 m & f........... < 10 [micro]g/gr Cr 320 [micro]g/gr Cr Kowal 1983.
\f\. \h\. \h\.
8................................. 87.................. 71 [micro]g/g \i\... .................... 7 \h\............... 200 \h\............. Buchet et al. 1980.
9................................. 10.................. 0.073 mg/24h........ .................... .................... .................... Evrin et al. 1971.
10................................ 59.................. 156 [micro]g/g...... 1.1 \j\............. 130................. 180................. Mason et al. 1988.
11................................ 8................... 118 [micro]g/g...... .................... .................... .................... Iwao et al. 1980.
12................................ 34.................. 79 [micro]g/g....... .................... .................... .................... Wibowo et al. 1982.
13................................ 41 m................ .................... .................... .................... 400 [micro]g/gr Cr Falck et al. 1983.
\k\.
14................................ 35 \n\.............. 67.................. .................... .................... .................... Roels et al. 1991.
15................................ 31 \d\.............. 63.................. .................... .................... .................... Roels et al. 1991.
16................................ 36 \d\.............. 77 \i\.............. .................... .................... .................... Miksche et al. 1981.
17................................ 18 \n\.............. 130................. .................... .................... .................... Kawada et al. 1989.
18................................ 32 \p\.............. 122................. .................... .................... .................... Kawada et al. 1989.
19................................ 18 \d\.............. 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 male.
f--Creatinine adjusted; males = 68.1 [micro]g/g Cr, females = 64.3 [micro]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 [micro]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 [micro]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
[micro]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-
[[Page 214]]
1140 [micro]g/g CRTU. These values are in general agreement with the
upper 95th percentile for the distribution (i.e., 631 [micro]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 [micro]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--B-2-Microglobulin Concentrations Observed in Urine Among Occupationally-Exposed workers
----------------------------------------------------------------------------------------------------------------
Concentration of B-2-Microglobulin in
urine
--------------------------------------------
Study No. N Geometric Reference
mean Geom std L 95% of U 95% of
([micro]g/ dev range \b\ range \b\
g) \a\
----------------------------------------------------------------------------------------------------------------
1................................. 1,42 160 6.19 8.1 3,300 Ishizaki et al., 1989.
4
2................................. 1,75 260 6.50 12 5,600 Ishizaki et al., 1989.
4
3................................. 33 210 ........ ......... ......... Ellis et al., 1983.
4................................. 65 210 ........ ......... ......... Chia et al., 1989.
5................................. \c\ 44 5,700 6.49 \d\ 300 \d\ Kjellstrom et al.,
98,000 1977.
6................................. 148 \e\ 180 ........ \f\ 110 \f\ 280 Buchet et al., 1980.
7................................. 37 160 3.90 17 1,500 Kenzaburo et al.,
1979.
8................................. \c\ 45 3,300 8.7 \d\ 310 \d\ Mason et al., 1988.
89,000
9................................. \c\ 10 6,100 5.99 \f\ 650 \f\ Falck et al., 1983.
57,000
10................................. \c\ 11 3,900 2.96 \d\ 710 \d\ Elinder et al., 1985.
15,000
11................................. \c\ 12 300 ........ ......... ......... Roels et al., 1991.
12................................. \g\ 8 7,400 ........ ......... ......... Roels et al., 1991.
13................................. \c\ 23 \h\ 1,800 ........ ......... ......... Roels et al., 1989.
14................................. 10 690 ........ ......... ......... Iwao et al., 1980.
15................................. 34 71 ........ ......... ......... Wibowo et al., 1982.
16................................. \c\ 15 4,700 6.49 \d\ 590 \d\ Thun et al., 1989.
93,000
----------------------------------------------------------------------------------------------------------------
\a\ Unless otherwise stated.
\b\ Based on an assumed lognormal distribution.
\c\ Among workers diagnosed as having renal dysfunction; for Elinder this means [beta] 2 levels greater than 300
micrograms per gram creatinine ([micro]g/gr Cr); for Roels, 1991, range = 31 - 35, 170 [micro]g[beta]2/gr Cr
and geometric mean = 63 among healthy workers; for Mason [beta]2 > 300 [micro]g/gr Cr.
\d\ Based on a detailed review of the data by OSHA.
\e\ Arthmetic mean.
\f\ Reported in the study.
\g\ Retired workers.
\h\ 1,800 [micro]g[beta]2/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
[micro]g/g CRTU. One of these studies reports geometric means lower than
this range (i.e., as low as 71 [micro]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 [micro]g/g CRTU
[[Page 215]]
(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 [micro]g/g CRTU appears to be a meaningful threshold for
identifying those having early signs of kidney damage. While levels much
higher than 300 [micro]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 [micro]g/g CRTU (Table 9).
The 300 [micro]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 [micro]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
[micro]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 [micro]g/g CRTU (Kjellstrom et al.
1977a; Buchet et al. 1980; Kowal and Zirkes, 1983). Elinder defined
levels of B2M above 300 [micro]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 [micro]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 [micro]g/l urine should be
achievable, although the insert to the test kit (Pharmacia 1990) cites a
detection limit of 150 [micro]g/l; private conversations with
representatives of Pharmacia, however, indicate that the lower limit of
100 [micro]g/l should be achievable provided an additional standard of
100 [micro]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
[[Page 216]]
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 [micro]g Cd/g CRTU, while B2MU should be
reported as [micro]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 analysise 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.
6.0 References
Adamsson E, Piscator M, and Nogawa K. (1979). Pulmonary and
gastrointestinal exposure to cadmium oxide dust in a battery factory.
Environmental Health Perspectives, 28, 219-222.
American Conference of Governmental Industrial Hygienists (ACGIH).
(1986). Documentation of the Threshold Limit Values and Biological
Exposure Indices. 5th edition. p. BEI-55.
Bernard A, Buchet J, Roels H, Masson P, and Lauwerys R. (1979).
Renal excretion of proteins and enzymes in workers exposed to cadmium.
European Journal of Clinical Investigation, 9, 11-22.
Bernard A and Lauwerys R. (1990). Early markers of cadmium
nephrotoxicity: Biological significance and predictive value.
Toxocological and Environmental Chemistry, 27, 65-72.
Braunwald E, Isselbacher K, Petersdorf R, Wilson J, Martin J, and
Fauci A (Eds.).
[[Page 217]]
(1987). Harrison's Principles of Internal Medicine. New York: McGraw-
Hill Book Company.
Buchet J, Roels H, Bernard I, and Lauwerys R. (1980). Assessment of
renal funcion of workers exposed to inorganic lead, cadmium, or mercury
vapor. Journal of Occupational Medicine, 22, 741-750.
CAP. (1991). Urine Chemistry, Series 1: Survey (Set U-B).
College of American Pathologists.
CAP. (1991). Urine Chemistry, Series 1: Survey (Set U-C). College of
American
Pathologists.
CAP. (1992). Urine Chemistry, Series 1: Survey (Set U-A). College of
American Pathologists.
CDC. (1986). Centers for Disease Control, Division of Environmental
Health Laboratory Sciences, Center for Environmental Health, Atlanta,
Georgia. Docket No. 106A. Lake Couer d'Alene, Idaho cadmium and lead
study: 86-0030, Specimen collection and shipping protocol.
CDC. (1990). Centers for Disease Control, Nutritional Biochemistry
Branch. 4/27/90 Draft SOP for Method 0360A ``Determination of cadmium in
urine by graphite furnace atomic absorption spectrometry with Zeeman
background correction.
Centre de Toxicologie du Quebec. (1991). Interlaboratory comparison
program report for run 2. Shipping date 3/11/91. Addition BLR
9/19.
Chia K, Ong C, Ong H, and Endo G. (1989). Renal tubular function of
workers exposed to low levels of cadmium. British Journal of Industrial
Medicine, 46, 165-170.
Claeys-Thoreau F. (1982). Determination of low levels of cadmium and
lead in biological fluids with simple dilution by atomic absorption
spectrophotometry using Zeeman effect background absorption and the
L'Vov platform. Atomic Spectroscopy, 3, 188-191.
DeBenzo Z, Fraile R, and Carrion N. (1990). Electrothermal
atomization atomic absorption spectrometry with stabilized aqueous
standards for the determination of cadmium in whole blood. Analytica
Chimica Acta, 231, 283-288.
Elinder C, Edling C, Lindberg E, Kagedal B, and Vesterberg O.
(1985). Assessment of renal function in workers previously exposed to
cadmium. British Journal of Internal Medicine, 42, 754.
Ellis K, Cohn S, and Smith T. (1985). Cadmium inhalation exposure
estimates: Their significance with respect to kidney and liver cadmium
burden. Journal of Toxicology and Environmental Health, 15, 173-187.
Ellis K, Yasumura S, Vartsky D, and Cohn S. (1983). Evaluation of
biological indicators of body burden of cadmium in humans. Fundamentals
and Applied Toxicology, 3, 169-174.
Ellis K, Yeun K, Yasumura S, and Cohn S. (1984). Dose-response
analysis of cadmium in man: Body burden vs kidney function.
Environmental Research, 33, 216-226.
Evrin P, Peterson A, Wide I, and Berggard I. (1971).
Radioimmunoassay of B-2-microglobulin in human biological fluids.
Scandanavian Journal of Clinical Laboratory Investigation, 28, 439-443.
Falck F, Fine L, Smith R, Garvey J, Schork A, England B, McClatchey
K, and Linton J. (1983). Metallothionein and occupational exposure to
cadmium. British Journal of Industrial Medicine, 40, 305-313.
Federal Register. (1990). Occupational exposure to cadmium: Proposed
rule. 55/22/4052-4147, February 6.
Friberg, Exhibit 29, (1990). Exhibit No. 29 of the OSHA Federal
Docket H057A. Washington, DC.
Friberg L. (1988). Quality assurance. In T. Clarkson (Ed.),
Biological Monitoring of Toxic Metals (pp. 103-105). New York: Plenum
Press.
Friberg L, and Elinder C. (1988). Cadmium toxicity in humans. In
Essential and Trace Elements in Human Health and Disease (pp. 559-587).
Docket Number 8-660.
Friberg L, Elinder F, et al. (1986). Cadmium and Health: A
Toxicological and Epidemiological Appraisal. Volume II, Effects and
Response. Boca Raton, FL: CRC Press.
Friberg L, Piscator M, Nordberg G, and Kjellstrom T. (1974). Cadmium
in the Environment (2nd ed.). Cleveland:CRC.
Friberg L and Vahter M. (1983). Assessment of exposure to lead and
cadmium through biological monitoring: Results of a UNEP/WHO global
study. Environmental Research, 30, 95-128.
Gunter E, and Miller D. (1986). Laboratory procedures used by the
division of environmental health laboratory sciences center for
environmental health, Centers for Disease Control for the hispanic
health and nutrition examination survey (HHANES). Atlanta, GA: Centers
for Disease Control.
Harrison. (1987). Harrison's Principles of Internal Medicine.
Braunwald, E; Isselbacher, KJ; Petersdorf, RG; Wilson, JD; Martin, JB;
and Fauci, AS Eds. Eleventh Ed. McGraw Hill Book Company. San Francisco.
Henry J. (1991). Clinical Diagnosis and Management by Laboratory
Methods (18th edition). Philadelphia: WB Saunders Company.
IARC (1987). IRAC Monographs on the Evaluation of Carcinogenic Risks
to Humans. Overall Evaluation of Carcinogenicity: Update of Volume 1-42.
Supplemental 7, 1987.
Ishizaki M, Kido T, Honda R, Tsuritani I, Yamada Y, Nakagawa H, and
Nogawa K. (1989). Dose-response relationship between urinary cadmium and
B-2-microglobulin in a Japanese environmentally cadmium exposed
population. Toxicology, 58, 121-131.
Iwao S, Tsuchiya K, and Sakurai H. (1980). Serum and urinary B-2-
microglobulin among cadmium-exposed workers. Journal of Occupational
Medicine, 22, 399-402.
Iwata K, Katoh T, Morikawa Y, Aoshima K, Nishijo M, Teranishi H, and
Kasuya M.
[[Page 218]]
(1988). Urinary trehalase activity as an indicator of kidney injury due
to environmental cadmium exposure. Archives of Toxicology, 62, 435-439.
Kawada T, Koyama H, and Suzuki S. (1989). Cadmium, NAG activity, and
B-2-microglobulin in the urine of cadmium pigment workers. British
Journal of Industrial Medicine, 46, 52-55.
Kawada T, Tohyama C, and Suzuki S. (1990). Significance of the
excretion of urinary indicator proteins for a low level of occupational
exposure to cadmium. International Archives of Occupational
Environmental Health, 62, 95-100.
Kjellstrom T. (1979). Exposure and accumulation of cadmium in
populations from Japan, the United States, and Sweden. Environmental
Health Perspectives, 28, 169-197.
Kjellstrom T, Evrin P, and Rahnster B. (1977). Dose-response
analysis of cadmium-induced tubular proteinuria. Environmental Research,
13, 303-317.
Kjellstrom T, Shiroishi K, and Evrin P. (1977). Urinary B-2-
microglobulin excretion among people exposed to cadmium in the general
environment. Environmental Research, 13, 318-344.
Kneip T, & Crable J (Eds.). (1988). Method 107. Cadmium in blood.
Methods for biological monitoring (pp.161-164). Washington, DC: American
Public Health Association.
Kowal N. (1988). Urinary cadmium and B-2-microglobulin: Correlation
with nutrition and smoking history. Journal of Toxicology and
Environmental Health, 25, 179-183.
Kowal N, Johnson D, Kraemer D, and Pahren H. (1979). Normal levels
of cadmium in diet, urine, blood, and tissues of inhabitants of the
United States. Journal of Toxicology and Environmental Health, 5, 995-
1014.
Kowal N and Zirkes M. (1983). Urinary cadmium and B-2-microglobulin:
Normal values and concentration adjustment. Journal of Toxicology and
Environmental Health, 11, 607-624.
Lauwerys R, Buchet J, and Roels H. (1976). The relationship between
cadmium exposure or body burden and the concentration of cadmium in
blood and urine in man. International Archives of Occupational and
Environmental Health, 36, 275-285
Lauwerys R, Roels H, Regniers, Buchet J, and Bernard A. (1979).
Significance of cadmium concentration in blood and in urine in workers
exposed to cadmium. Environmental Research, 20, 375-391.
Lind B, Elinder C, Friberg L, Nilsson B, Svartengren M, and Vahter
M. (1987). Quality control in the analysis of lead and cadmium in blood.
Fresenius' Zeitschrift fur Analytical Chemistry, 326, 647-655.
Mason H, Davison A, Wright A, Guthrie C, Fayers P, Venables K, Smith
N, Chettle D, Franklin D, Scott M, Holden H, Gompertz D, and Newman-
Taylor A. (1988). Relations between liver cadmium, cumulative exposure,
and renal function in cadmium alloy workers. British Journal of
Industrial Medicine, 45, 793-802.
Meridian Research, Inc. (1989). Quantitative Assessment of Cancer
Risks Associated with Occupational Exposure to Cd. Prepared by Meridian
Research, Inc. and Roth Associates, Inc. for the Occupational Safety &
Health Administration. June 12, 1989.
Meridian Research, Inc and Roth Associates, Inc. (1989).
Quantitative Assessment of the Risk of Kidney Dysfunction Associated
with Occupational Exposure to Cd. Prepared by Meridian Research, Inc.
and Roth Associates, Inc. for the Occupational Safety & Health
Administration. July 31 1989.
Micheils E and DeBievre P. (1986). Method 25-Determination of
cadmium in whole blood by isotope dilution mass spectrometry. O'Neill I,
Schuller P, and Fishbein L (Eds.), Environmental Carcinogens Selected
Methods of Analysis (Vol. 8). Lyon, France: International Agency for
Research on Cancer.
Mueller P, Smith S, Steinberg K, and Thun M. (1989). Chronic renal
tubular effects in relation to urine cadmium levels. Nephron, 52, 45-54.
NIOSH. (1984a). Elements in blood or tissues. Method 8005 issued 5/
15/85 and Metals in urine. Method 8310 issued 2/15/84 In P. Eller (Ed.),
NIOSH Manual of Analytical Methods (Vol. 1, Ed. 3). Cincinnati, Ohio:
US-DHHS.
NIOSH. (1984b). Lowry L. Section F: Special considerations for
biological samples in NIOSH Manual of Analytical Methods (Vol. 1, 3rd
ed). P. Eller (Ed.). Cincinnati, Ohio: US-DHHS.
Nordberg G and Nordberg M. (1988). Biological monitoring of cadmium.
In T. Clarkson, L. Friberg, G. Nordberg, and P. Sager (Eds.), Biological
Monitoring of Toxic Metals, New York: Plenum Press.
Nogawa K. (1984). Biologic indicators of cadmium nephrotoxicity in
persons with low-level cadmium exposure. Environmental Health
Perspectives, 54, 163-169.
OSLTC (no date). Analysis of Creatinine for the Normalization of
Cadmium and Beta-2-Microglobulin Concentrations in Urine. OSHA Salt Lake
Technical Center. Salt Lake City, UT. Paschal. (1990). Attachment 8 of
exhibit 106 of the OSHA docket H057A.
Perkin-Elmer Corporation. (1982). Analytical Methods for Atomic
Absorption Spectroscopy.
Perkin-Elmer Corporation. (1977). Analytical Methods Using the HGA
Graphite Furnace.
Pharmacia Diagnostics. (1990). Pharmacia DELFIA system B-2-
microglobulin kit insert. Uppsala, Sweden: Pharmacia Diagnostics.
Piscator M. (1962). Proteinuria in chronic cadmium poisoning.
Archives of Environmental Health,5, 55-62.
[[Page 219]]
Potts, C.L. (1965). Cadmium Proteinuria--The Health Battery Workers
Exposed to Cadmium Oxide dust. Ann Occup Hyg, 3:55-61, 1965.
Princi F. (1947). A study of industrial exposures to cadmium.
Journal of Industrial Hygiene and Toxicology, 29, 315-320.
Pruszkowska E, Carnick G, and Slavin W. (1983). Direct determination
of cadmium in urine with use of a stabilized temperature platform
furnace and Zeeman background correction. Clinical Chemistry, 29, 477-
480.
Roberts C and Clark J. (1986). Improved determination of cadmium in
blood and plasma by flameless atomic absorption spectroscopy. Bulletin
of Environmental Contamination and Toxicology, 36, 496-499.
Roelandts I. (1989). Biological reference materials. Soectrochimica
Acta, 44B, 281-290.
Roels H, Buchet R, Lauwerys R, Bruaux P, Clays-Thoreau F,
Laafontaine A, Overschelde J, and Verduyn J. (1978). Lead and cadmium
absorption among children near a nonferrous metal plant. Environmental
Research, 15, 290-308.
Roels H, Djubgang J, Buchet J, Bernard A, and Lauwerys R. (1982).
Evolution of cadmium-induced renal dysfunction in workers removed from
exposure. Scandanavian Journal of Work and Environmental Health, 8, 191-
200.
Roels H, Lauwerys R, and Buchet J. (1989). Health significance of
cadmium induced renal dysfunction: A five year follow-up. British
Journal of Industrial Medicine, 46, 755-764.
Roels J, Lauwerys R, Buchet J, Bernard A, Chettle D, Harvey T, and
Al-Haddad I. (1981). In vivo measurements of liver and kidney cadmium in
workers exposed to this metal: Its significance with respect to cadmium
in blood and urine. Environmental Research, 26, 217-240.
Roels H, Lauwerys R, Buchet J, Bernard A, Lijnen P, and Houte G.
(1990). Urinary kallikrein activity in workers exposed to cadmium, lead,
or mercury vapor. British Journal of Industrial Medicine, 47, 331-337.
Sakurai H, Omae K, Toyama T, Higashi T, and Nakadate T. (1982).
Cross-sectional study of pulmonary function in cadmium alloy workers.
Scandanavian Journal of Work and Environmental Health, 8, 122-130.
Schardun G and van Epps L. (1987). B-2-microglobulin: Its
significance in the evaluation of renal function. Kidney International,
32, 635-641.
Shaikh Z, and Smith L. (1984). Biological indicators of cadmium
exposure and toxicity. Experentia, 40, 36-43.
Smith J and Kench J. (1957). Observations on urinary cadmium and
protein excretion in men exposed to cadmium oxide dust and fume. British
Journal of Industrial Medicine, 14, 240-245.
Smith J, Kench J, and Lane R. (1955). Determination of Cadmium in
urine and observations on urinary cadmium and protein excretion in men
exposed to cadmium oxide dust. British Journal of Industrial Medicine,
12, 698-701.
SWRI (Southwest Research Institute). (1978). The distribution of
cadmium and other metals in human tissues. Health Effects Research Lab,
Research Triangle Park, NC, Population Studies Division. NTIS No. PB-
285-200.
Stewart M and Hughes E. (1981). Urinary B-2-microglobulin in the
biological monitoring of cadmium workers. British Journal of Industrial
Medicine, 38, 170-174.
Stoeppler K and Brandt M. (1980). Contributions to automated trace
analysis. Part V. Determination of cadmium in whole blood and urine by
electrothermal atomic absorption spectrophotometry. Fresenius'
Zeitschrift fur Analytical Chemistry, 300, 372-380.
Takenaka et al. (1983). Carcinogencity of Cd Chloride Aerosols in
White Rates. INCI 70: 367-373, 1983.
Thun M, Osorio A, Schober S, Hannon W, Lewis B, and Halperin W.
(1989). Nephropathy in cadmium workers: Assessment of risk from airborne
occupational exposure to cadmium. British Journal of Industrial
Medicine, 46, 689-697.
Thun M, Schnorr T, Smith A, Halperin W, and Lemen R. (1985).
Mortality among a cohort of US cadmium production workers--an update.
Journal of the National Cancer Institute, 74, 325-333.
Travis D and Haddock A. (1980). Interpretation of the observed age-
dependency of cadmium body burdens in man. Environmental Research, 22,
46-60.
Tsuchiya K. (1967). Proteinuria of workers exposed to cadmium fume.
Archives of Environmental Health, 14, 875-880.
Tsuchiya K. (1976). Proteinuria of cadmium workers. Journal of
Occupational Medicine, 18, 463-470.
Tsuchiya K, Iwao S, Sugita M, Sakurai H. (1979). Increased urinary
B-2-microglobulin in cadmium exposure: Dose-effect relationship and
biological significance of B-2-microglobulin. Environmental Health
Perspectives, 28, 147-153.
USEPA. (1985). Updated Mutagenicity and Carcinogenicity Assessments
of Cd: Addendum to the Health Assessment Document for Cd (May 1981).
Final Report. June 1985.
Vahter M and Friberg L. (1988). Quality control in integrated human
exposure monitoring of lead and cadmium. Fresenius' Zeitschrift fur
Analytical Chemistry, 332, 726-731.
Weber J. (1988). An interlaboratory comparison programme for several
toxic substances in blood and urine. The Science of the Total
Environment, 71, 111-123.
Weber J. (1991a). Accuracy and precision of trace metal
determinations in biological fluids. In K. Subramanian, G. Iyengar, and
K.
[[Page 220]]
Okamot (Eds.), Biological Trace Element Research-Multidisciplinary
Perspectives, ACS Symposium Series 445. Washington, DC: American
Chemical Society.
Weber J. (1991b). Personal communication about interlaboratory
program and shipping biological media samples for cadmium analyses.
Wibowo A, Herber R, van Deyck W, and Zielhuis R. (1982). Biological
assessment of exposure in factories with second degree usage of cadmium
compounds. International Archives of Occupational Environmental Health,
49, 265-273.
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 [micro]g/l, (the target value is 10 [micro]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 [micro]g/l while the range of values for the
medium-high pool is 5 to 15 [micro]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
[[Page 221]]
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 [sigma]. Thus, for the control limit
for a pool, X is calculated as:
[GRAPHIC] [TIFF OMITTED] TC15NO91.186
and [sigma] is calculated as
[GRAPHIC] [TIFF OMITTED] TC15NO91.187
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 3[sigma]).
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 () [sigma] 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[sigma] Line)
..... X
X ..... ..... ..... ..... ..... ..... ..... ..... ..... ..... 1.000 (Theoretical
Mean)
..... ..... ..... X X ..... ..... ..... ..... ..... ..... 0.964 (Mean)
..... ..... ..... ..... ..... ..... X ..... ..... ..... X
..... ..... ..... ..... ..... ..... ..... X
..... ..... X ..... ..... ..... ..... ..... ..... ..... ..... 0.832 (Lower
2[sigma] Line)
..... ..... ..... ..... ..... ..... ..... ..... X
..... ..... ..... ..... ..... ..... ..... ..... ..... ..... ..... 0.766 (Lower
Control Limit)
March 2 2 3 5 6 9 10 13 16 17
----------------------------------------------------------------------------------------------------------------
[[Page 222]]
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 2[sigma]
from the mean (above or below the 2[sigma] 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 [micro]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)
Intended use: The CREA pack is used in the Du Pont ACA
[reg] 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.\1\
A split sample comparison between the CREA method and a conventional
Jaffe procedure on Autoanalyzer [reg] showed a good
correlation. (See Specific Performance Characteristics).
*Note: Numbered subscripts refer to the bibliography and lettered
subscripts refer to footnotes.
Autoanalyzer [reg], 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.
[GRAPHIC] [TIFF OMITTED] TC15NO91.188
Reagents:
----------------------------------------------------------------------------------------------------------------
Compartment \a\ Form Ingredient Quantity \b\
----------------------------------------------------------------------------------------------------------------
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.
[[Page 223]]
Precautions: Compartment 6 contains 75[micro]L 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 and Diluting:
Mixing and diluting are automatically performed by the ACA
[reg] 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 ([micro]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.\2\
Known Interfering Substances \3\
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 [micro]mol/L] \d\ and
will be less precise than samples containing more than 3 g/dL [30 g/L]
protein.
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 [micro]mol/L]) will give depressed
CREA results (average depression 0.8 mg/dL [71 [micro]mol/L]).\4\
Grossly hemolyzed (hemoglobin 100 mg/
dL [62 [micro]mol/L]) or visibly lipemic specimens may cause
falsely elevated CREA results. \5,6\
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 [micro]mol/L] at CREA
concentrations of approximately 1 mg/dL [88 [micro]mol/L].
----------------------------------------------------------------------------------------------------------------
Peak serum level Drug concentration
\7,8,9\ ---------------------
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
----------------------------------------------------------------------------------------------------------------
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 [micro]mol/L] at CREA concentrations of:
----------------------------------------------------------------------------------------------------------------
Peak serum level Drug concentration
\8,10\ --------------------------------
Antibiotic ------------------------
mg/dL [mmol/L] mg/dL [mmol/L] Effect
----------------------------------------------------------------------------------------------------------------
Cephalothin............................................ 1-6 0.2-1.5 100 25.2 [darr]20-
25%
Cephoxitin............................................. 2.0 0.5 5.0 1.2 [uarr]35-
40%
----------------------------------------------------------------------------------------------------------------
[[Page 224]]
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.
d. Systeme International d'unites (S.I. Units) are in brackets.
Procedure:
Test Materials
----------------------------------------------------------------------------------------------------------------
II, III Du IV, SX Du Pont V Du Pont Cat.
Item Pont Cat. No. Cat. No. No.
----------------------------------------------------------------------------------------------------------------
ACA [reg] 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 [reg] 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 [reg]
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 [reg] analyzer for details of mechanical travel of
the test pack(s).
Preset Creatinine (CREA)--Test Conditions
Sample Volume: 200 [micro]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 [[micro]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 [micro]mol/L] \e\.
Reference Material: Protein containing primary
standards \f\ or secondary calibrators such as Du Pont Elevated
Chemistry Control (Cat. 790035903) and Normal Chemistry Control
(Cat.790035905) \g\.
Suggested Calibration Levels: 1,5,20, mg/mL [88, 442,
1768 [micro]mol/L].
Calibration Scheme: 3 levels, 3 packs per level.
Frequency: Each new pack lot. Every 3 months for any
one pack lot.
e. For the results in S.I. units [[micro]mol/L] the conversion
factory is 88.4.
f. Refer to the Creatinine Standard Preparation and Calibration
Procedure available on request from a Du Pont Representative.
g. If the Du Pont Chemistry Controls are being used, prepare them
according to the instructions on the product insert sheets.
Preset Creatinine (CREA) Test Conditions
------------------------------------------------------------------------
ACA [reg] II ACA [reg] III, IV,
Item analyzer SX, V analyzer
------------------------------------------------------------------------
Count by...................... One (1).......... NA
[Five (5)].......
Decimal Point................. 0.0 mg/dL........ 000.0 mg/dL
Location...................... [000.0 [micro]mol/ [000 [micro]mol/L]
L].
Assigned Starting............. 999.8............ -1.000 E1
Point or Offset Co............ [9823.].......... [-8.840 E2]
Scale Factor or Assigned...... 0.2000........... 2.004 E-1 \h\
mg/dL/count \h\..
Linear Term C1 h.............. [0.3536 [1.772E1]
[micro]mol/L/
count].
------------------------------------------------------------------------
h. 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
Analyzer Instrument Manual. Refer also to the ABS Test Methodology
literature.
Creatinine Method Check. At least once daily run
a CREA test on a solution of
[[Page 225]]
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 [micro]mol/L]........................ [13 [micro]mol/L]
20 mg/dL................................. 0.68 mg/dL
[1768 [micro]mol/L]...................... [60 [micro]mol/L]
------------------------------------------------------------------------
Refer to the procedure outlined in the Trouble Shooting Section of
the Manual.
Results: The ACA [reg] analyzer automatically calculates
and prints the CREA result in mg/dL [[micro]mol/L].
Limitation of Procedure: Results 20 mg/dL [1768 [micro]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: \11,i\
Males 0.8-1.3 md/dL
[71-115 [micro]mol/L]
Females 0.6-1.0 md/dL
[53-88 [micro]mol/L]
Urine: \12\
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]
i. Reference interval data obtained from 200 apparently healthy
individuals (71 males, 129 females) between the ages of 19 and 72.
Each laboratory should establish its own reference intervals for
CREA as performed on the analyzer.
Specific Performance Characteristics \j\
Reproducibility \k\
------------------------------------------------------------------------
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]
------------------------------------------------------------------------
Correlation--Regression Statistics \l\
----------------------------------------------------------------------------------------------------------------
Correlation
Comparative method Slope Intercept coefficient n
----------------------------------------------------------------------------------------------------------------
Autoanalyzer [reg]............................................... 1.03 0.03[2.7] 0.997 260
----------------------------------------------------------------------------------------------------------------
j. All specific performance characteristics tests were run after
normal recommended equipment quality control checks were performed (see
Instrument Manual).
k. 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.
l. Model equation for regression statistics is:
[GRAPHIC] [TIFF OMITTED] TC15NO91.189
Assay Range \m\
0.0-20.0 mg/dl
[0-1768 [micro]mol]
m. See REPRODUCIBILITY for method performance within the assay
range.
[[Page 226]]
Analytical Specificity
See KNOWN INTERFERING SUBSTANCES section for details.
Bibliography
\1\ Larsen, K, Clin Chem Acta 41, 209 (1972).
\2\ Tietz, NW, Fundamentals of Clinical Chemistry, W. B. Saunders
Co., Philadelphia, PA, 1976, pp 47-52, 1211.
\3\ 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).
\4\ Watkins, R. Fieldkamp, SC, Thibert, RJ, and Zak, B, Clin Chem,
21, 1002 (1975).
\5\ 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)
\6\ Westgard, JO, Effects of Hemolysis and Lipemia on ACA Creatinine
Method, 0.200 [micro]L, Sample Size, Du Pont Company, Wilmington, DE
(October 1972).
\7\ Physicians' Desk Reference, Medical Economics Company, 33
Edition, 1979.
\8\ Henry, JB, Clinical Diagnosis and Management by Laboratory
Methods, W.B. Saunders Co., Philadelphia, PA 1979, Vol. III.
\9\ Krupp, MA, Tierney, LM Jr., Jawetz, E, Roe, RI, Camargo, CA,
Physicians Handbook, Lange Medical Publications, Los Altos, CA, 1982 pp
635-636.
\10\ Sarah, AJ, Koch, TR, Drusano, GL, Celoxitin Falsely Elevates
Creatinine Levels, JAMA 247, 205-206 (1982).
\11\ 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)
\12\ Dicht, JJ, Reference Intervals for Serum Amylase and Urinary
Creatinine on the Du Pont ACA [reg] 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
[reg] (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.
Dated: January 1992.
David B. Armitage,
Duane Lee,
Chemists.
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.)
[[Page 227]]
Molecular weight: 113.12
Molecular formula: C4-H7-N3-0
Chemical name: 2-amino-1,5-dihydro-1-methyl-4H-imidazol-4-one
CAS No.: 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
[GRAPHIC] [TIFF OMITTED] TC28OC91.015
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 & Stabilization Techniques
------------------------------------------------------------------------
w/o SEP- with SEP-
Sample PAK g/L PAK g/L
creatinine creatinine
------------------------------------------------------------------------
Acid............................................ 1.10 1.10
Acid............................................ 1.11 1.10
Untreated....................................... 1.12 1.11
Untreated....................................... 1.11 1.12
pH 7............................................ 1.08 1.02
pH 7............................................ 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 of creatinine is essentially unchanged.
[[Page 228]]
Storage Data
----------------------------------------------------------------------------------------------------------------
4 days 54 days
---------------------------------------------------
Sample w/o SEP-PAK with SEP- w/o SEP-PAK with SEP-
g/L PAK g/L g/L PAK g/L
creatinine creatinine creatinine 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. Interferences
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. PIC B-7 [reg] (Waters Associates) in small vials.
3.2.4. Creatinine, anhydrous, Sigma hemical 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 PIC 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.
[[Page 229]]
3.3.2. Dilutions to a working range of 3 to 35 [micro]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 [reg] ODS, 5-6 [micro]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[micro]l
3.5.2. Chromatogram (see Figure 2)
[[Page 230]]
[GRAPHIC] [TIFF OMITTED] TC28OC91.016
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.
3.7. Calculations
[[Page 231]]
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).
[GRAPHIC] [TIFF OMITTED] TC28OC91.017
[[Page 232]]
3.7.3. The [micro]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 units, g/L, is
determined by the following relationship:
[GRAPHIC] [TIFF OMITTED] TC15NO91.190
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.
[GRAPHIC] [TIFF OMITTED] TC15NO91.191
Where A is the desired analyte. The protocol of reporting such
normalized results is [micro]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 N
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.
[57 FR 42389, Sept. 14, 1992, as amended at 57 FR 49272, Oct. 30, 1992;
58 FR 21781, Apr. 23, 1993; 61 FR 5508, Feb. 13, 1996; 63 FR 1288, Jan.
8, 1998; 70 FR 1142, Jan. 5, 2005; 71 FR 16672, 16673, Apr. 3, 2006]