Occupational Exposure to Hexavalent Chromium
Federal RegisterFeb 28, 2006
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DEPARTMENT OF LABOR
Occupational Safety and Health Administration
29 CFR Parts 1910, 1915, 1917, 1918, and 1926
[Docket No. H054A]
RIN 1218-AB45
Occupational Exposure to Hexavalent Chromium
AGENCY:
Occupational Safety and Health Administration (OSHA), Department of Labor.
ACTION:
Final rule.
SUMMARY:
The Occupational Safety and Health Administration (OSHA) is amending the existing standard which limits occupational exposure to hexavalent chromium (Cr(VI)). OSHA has determined based upon the best evidence currently available that at the current permissible exposure limit (PEL) for Cr(VI), workers face a significant risk to material impairment of their health. The evidence in the record for this rulemaking indicates that workers exposed to Cr(VI) are at an increased risk of developing lung cancer. The record also indicates that occupational exposure to Cr(VI) may result in asthma, and damage to the nasal epithelia and skin.
The final rule establishes an 8-hour time-weighted average (TWA) exposure limit of 5 micrograms of Cr(VI) per cubic meter of air (5 μg/m
3
). This is a considerable reduction from the previous PEL of 1 milligram per 10 cubic meters of air (1 mg/10 m
3
, or 100 μg/m
3
) reported as CrO
3
, which is equivalent to a limit of 52 μg/m
3
as Cr(VI). The final rule also contains ancillary provisions for worker protection such as requirements for exposure determination, preferred exposure control methods, including a compliance alternative for a small sector for which the new PEL is infeasible, respiratory protection, protective clothing and equipment, hygiene areas and practices, medical surveillance, recordkeeping, and start-up dates that include four years for the implementation of engineering controls to meet the PEL.
The final standard separately regulates general industry, construction, and shipyards in order to tailor requirements to the unique circumstances found in each of these sectors.
The PEL established by this rule reduces the significant risk posed to workers by occupational exposure to Cr(VI) to the maximum extent that is technologically and economically feasible.
DATES:
This final rule becomes effective on May 30, 2006. Start-up dates for specific provisions are set in § 1910.1026(n) for general industry; § 1915.1026(l) for shipyards; and § 1926.1126(l) for construction. However, affected parties do not have to comply with the information collection requirements in the final rule until the Department of Labor publishes in the
Federal Register
the control numbers assigned by the Office of Management and Budget (OMB). Publication of the control numbers notifies the public that OMB has approved these information collection requirements under the Paperwork Reduction Act of 1995.
ADDRESSES:
In compliance with 28 U.S.C. 2112(a), the Agency designates the Associate Solicitor for Occupational Safety and Health, Office of the Solicitor, Room S-4004, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210, as the recipient of petitions for review of these standards.
FOR FURTHER INFORMATION CONTACT:
Mr. Kevin Ropp, Director, OSHA Office of Communications, Room N-3647, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210; telephone (202) 693-1999.
SUPPLEMENTARY INFORMATION:
The following table of contents lays out the structure of the preamble to the final standards. This preamble contains a detailed description of OSHA's legal obligations, the analyses and rationale supporting the Agency's determination, including a summary of and response to comments and data submitted during the rulemaking.
I. General
II. Pertinent Legal Authority
III. Events Leading to the Final Standard
IV. Chemical Properties and Industrial Uses
V. Health Effects
A. Absorption, Distribution, Metabolic Reduction and Elimination
1. Deposition and Clearance of Inhaled Cr(VI) From the Respiratory Tract
2. Absorption of Inhaled Cr(VI) Into the Bloodstream
3. Dermal Absorption of Cr(VI)
4. Absorption of Cr(VI) by the Oral Route
5. Distribution of Cr(VI) in the Body
6. Metabolic Reduction of Cr(VI)
7. Elimination of Cr(VI) From the Body
8. Physiologically-Based Pharmacokinetic Modeling
9. Summary
B. Carcinogenic Effects
1. Evidence From Chromate Production Workers
2. Evidence From Chromate Pigment Production Workers
3. Evidence From Workers in Chromium Plating
4. Evidence From Stainless Steel Welders
5. Evidence From Ferrochromium Workers
6. Evidence From Workers in Other Industry Sectors
7. Evidence From Experimental Animal Studies
8. Mechanistic Considerations
C. Non-Cancer Respiratory Effects
1. Nasal Irritation, Nasal Tissue Ulcerations and Nasal Septum Perforations
2. Occupational Asthma
3. Bronchitis
4. Summary
D. Dermal Effects
E. Other Health Effects
VI. Quantitative Risk Assessment
A. Introduction
B. Study Selection
1. Gibb Cohort
2. Luippold Cohort
3. Mancuso Cohort
4. Hayes Cohort
5. Gerin Cohort
6. Alexander Cohort
7. Studies Selected for the Quantitative Risk Assessment
C. Quantitative Risk Assessments Based on the Gibb Cohort
1. Environ Risk Assessments
2. National Institute for Occupational Safety and Health (NIOSH) Risk Assessment
3. Exponent Risk Assessment
4. Summary of Risk Assessments Based on the Gibb Cohort
D. Quantitative Risk Assessments Based on the Luippold Cohort
E. Quantitative Risk Assessments Based on the Mancuso, Hayes, Gerin, and Alexander Cohorts
1. Mancuso Cohort
2. Hayes Cohort
3. Gerin Cohort
4. Alexander Cohort
F. Summary of Risk Estimates Based on Gibb, Luippold, and Additional Cohorts
G. Issues and Uncertainties
1. Uncertainty With Regard to Worker Exposure to Cr(VI)
2. Model Uncertainty, Exposure Threshold, and Dose Rate Effects
3. Influence of Smoking, Race, and the Healthy Worker Survivor Effect
4. Suitability of Risk Estimates for Cr(VI) Exposures in Other Industries
H. Conclusions
VII. Significance of Risk
A. Material Impairment of Health
1. Lung Cancer
2. Non-Cancer Impairments
B. Risk Assessment
1. Lung Cancer Risk Based on the Gibb Cohort
2. Lung Cancer Risk Based on the Luippold Cohort
3. Risk of Non-Cancer Impairments
C. Significance of Risk and Risk Reduction
VIII. Summary of the Final Economic Analysis and Regulatory Flexibility Analysis
IX. OMB Review Under the Paperwork Reduction Act of 1995
X. Federalism
XI. State Plans
XII. Unfunded Mandates
XIII. Protecting Children from Environmental Health and Safety Risks
XIV. Environmental Impacts
XV. Summary and Explanation of the Standards
(a) Scope
(b) Definitions
(c) Permissible Exposure Limit (PEL)
(d) Exposure Determination
(e) Regulated Areas
(f) Methods of Compliance
(g) Respiratory Protection
(h) Protective Work Clothing and Equipment
(i) Hygiene Areas and Practices
(j) Housekeeping
(k) Medical Surveillance
(l) Communication of Chromium (VI) Hazards to Employees
(m) Recordkeeping
(n) Dates
XVI. Authority and Signature
XVII. Final Standards
I. General
This final rule establishes a permissible exposure limit (PEL) of 5 micrograms of Cr(VI) per cubic meter of air (5 μg/m
3
) as an 8-hour time-weighted average for all Cr(VI) compounds. After consideration of all comments and evidence submitted during this rulemaking, OSHA has made a final determination that a PEL of 5 μg/m
3
is necessary to reduce the significant health risks posed by occupational exposures to Cr(VI); it is the lowest level that is technologically and economically feasible for industries impacted by this rule. A full explanation of OSHA's rationale for establishing this PEL is presented in the following preamble sections: V (Health Effects), VI (Quantitative Risk Assessment), VII (Significance of Risk), VIII (Summary of the Final Economic Analysis and Regulatory Flexibility Analysis), and XV (Summary and Explanation of the Standard, paragraph (c), Permissible Exposure Limit).
OSHA is establishing three separate standards covering occupational exposures to Cr(VI) for: general industry (29 CFR 1910.1026); shipyards (29 CFR 1915.1026), and construction (29 CFR 1926.1126). In addition to the PEL, these three standards include ancillary provisions for exposure determination, methods of compliance, respiratory protection, protective work clothing and equipment, hygiene areas and practices, medical surveillance, communication of Cr(VI) hazards to employees, recordkeeping, and compliance dates. The general industry standard has additional provisions for regulated areas and housekeeping. The Summary and Explanation section of this preamble (Section XV, paragraphs (d) through (n)) includes a full discussion of the basis for including these provisions in the final standards.
Several major changes were made to the October 4, 2004 proposed rule as a result of OSHA's analysis of comments and data received during the comment periods and public hearings. The major changes are summarized below and are fully discussed in the Summary and Explanation section of this preamble (Section XV)
Scope.
As proposed, the standards apply to occupational exposures to Cr(VI) in all forms and compounds with limited exceptions. OSHA has made a final determination to exclude from coverage of these final standards exposures that occur in the application of pesticides containing Cr(VI) (e.g., the treatment of wood with preservatives). These exposures are already covered by the Environmental Protection Agency. OSHA is also excluding exposures to portland cement and exposures in work settings where the employer has objective data demonstrating that a material containing chromium or a specific process, operation, or activity involving chromium cannot release dusts, fumes, or mists of Cr(VI) in concentrations at or above 0.5 μg/m
3
under any expected conditions of use. OSHA believes that the weight of evidence in this rulemaking demonstrates that the primary risk in these two exposure scenarios can be effectively addressed through existing OSHA standards for personal protective equipment, hygiene, hazard communication and the PELs for portland cement or particulates not otherwise regulated (PNOR).
Permissible Exposure Limit.
OSHA proposed a PEL of 1 μg/m
3
but has now determined that a PEL 5 μg/m
3
is the lowest level that is technologically and economically feasible.
Exposure Determination.
OSHA did not include a provision for exposure determination in the proposed shipyard and construction standards, reasoning that the obligation to meet the proposed PEL would implicitly necessitate performance-based monitoring by the employer to ensure compliance with the PEL. However, OSHA was convinced by arguments presented during the rulemaking that an explicit requirement for exposure determination is necessary to ensure that employee exposures are adequately characterized. Therefore OSHA has included a provision for exposure determination for general industry, shipyards and construction in the final rule. In order to provide additional flexibility in characterizing employee exposures, OSHA is allowing employers to choose between a scheduled monitoring option and a performance-based option for making exposure determinations.
Methods of Compliance.
Under the proposed rule employers were to use engineering and work practice controls to achieve the proposed PEL unless the employer could demonstrate such controls are not feasible. In the final rule, OSHA has retained this exception but has added a provision that only requires employers to use engineering and work practice controls to reduce or maintain employee exposures to 25 μg/m
3
when painting aircraft or large aircraft parts in the aerospace industry to the extent such controls are feasible. The employer must then supplement those engineering controls with respiratory protection to achieve the PEL. As discussed more fully in the Summary of the Final Economic Analysis and Regulatory Flexibility Analysis (Section VIII) and the Summary and Explanation (Section XV) OSHA has determined that this is the lowest level achievable through the use of engineering and work practice controls alone for these limited operations.
Housekeeping.
In the proposed rule, cleaning methods such as shoveling, sweeping, and brushing were prohibited unless they were the only effective means available to clean surfaces contaminated with Cr(VI). The final standard has modified this prohibition to make clear only
dry
shoveling, sweeping and brushing are prohibited so that effective wet shoveling, sweeping, and brushing would be allowed. OSHA is also adding a provision that allows the use of compressed air to remove Cr(VI) when no alternative method is feasible.
Medical Surveillance.
As proposed and continued in these final standards, medical surveillance is required to be provided to employees experiencing signs or symptoms of the adverse health effects associated with Cr(VI) exposure or exposed in an emergency. In addition, for general industry, employees exposed above the PEL for 30 or more days a year were to be provided medical surveillance. In the final standard, OSHA has changed the trigger for medical surveillance to exposure above the action level (instead of the PEL) for 30 days a year to take into account the existing risks at the new PEL. This provision has also been extended to the standards for shipyards and construction since those employers now will be required to perform an exposure determination and thus will be able to determine which employees are exposed above the action level 30 or more days a year.
Communication of Hazards.
In the proposed standard, OSHA specified the sign for the demarcation of regulated areas in general industry and the label for contaminated work clothing or equipment and Cr(VI) contaminated waste and debris. The proposed standard also listed the various elements to be covered for employee training. In order to simplify requirements under this section of the final standard and reduce confusion between this standard and the Hazard Communication Standard, OSHA has removed the requirement for special signs and labels and the specification of employee training elements. Instead, the final standard requires that signs, labels and training be in accordance with the Hazard Communication Standard (29 CFR 1910.1200). The only additional training elements required in the final rule are those related specifically to the contents of the final Cr(VI) standards. While the final standards have removed language in the communication of hazards provisions to make them more consistent with OSHA's existing Hazard Communication Standard, the employers obligation to mark regulated areas (where regulated areas are required), to label Cr(VI) contaminated clothing and wastes, and to train on the hazards of Cr(VI) have not changed.
Recordkeeping.
In the proposed standards for shipyards and construction there were no recordkeeping requirements for exposure records since there was not a requirement for exposure determination. The final standard now requires exposure determination for shipyards and construction and therefore, OSHA has also added provisions for exposure records to be maintained in these final standards. In keeping with its intent to be consistent with the Hazard Communication Standard, OSHA has removed the requirement for training records in the final standards.
Dates.
In the proposed standard, the effective date of the standard was 60 days after the publication date; the start-up date for all provisions except engineering controls was 90 days after the effective date; and the start-up date for engineering controls was two years after the effective date. OSHA believes that it is appropriate to allow additional time for employers, particularly small employers, to meet the requirements of the final rule. The effective and start-up dates have been extended as follows: the effective date for the final rule is changed to 90 days after the publication date; the start-up date for all provisions except engineering controls is changed to 180 days after the effective date for employers with 20 or more employees; the start-up date for all provisions except engineering controls is changed to one year after the effective date for employers with 19 or fewer employees; and the start-up date for engineering controls is changed to four years after the effective date for all employers.
II. Pertinent Legal Authority
The purpose of the Occupational Safety and Health Act, 29 U.S.C. 651
et seq.
(“the Act”) is to,
* * * assure so far as possible every working man and woman in the nation safe and healthful working conditions and to preserve our human resources. 29 U.S.C. 651(b).
To achieve this goal Congress authorized the Secretary of Labor (the Secretary) to promulgate and enforce occupational safety and health standards. 29 U.S.C. 654(b) (requiring employers to comply with OSHA standards), 655(a) (authorizing summary adoption of existing consensus and federal standards within two years of the Act's enactment), and 655(b) (authorizing promulgation, modification or revocation of standards pursuant to notice and comment).
The Act provides that in promulgating health standards dealing with toxic materials or harmful physical agents, such as this standard regulating occupational exposure to Cr(VI), the Secretary,
* * * shall set the standard which most adequately assures, to the extent feasible, on the basis of the best available evidence that no employee will suffer material impairment of health or functional capacity even if such employee has regular exposure to the hazard dealt with by such standard for the period of his working life. 29 U.S.C. § 655(b)(5).
The Supreme Court has held that before the Secretary can promulgate any permanent health or safety standard, she must make a threshold finding that significant risk is present and that such risk can be eliminated or lessened by a change in practices.
Industrial Union Dept., AFL-CIO
v.
American Petroleum Institute
, 448 U.S. 607, 641-42 (1980) (plurality opinion) (“The Benzene case”). The Court further observed that what constitutes “significant risk” is “not a mathematical straitjacket” and must be “based largely on policy considerations.” The Benzene case, 448 U.S. at 655. The Court gave the example that if,
* * * the odds are one in a billion that a person will die from cancer * * * the risk clearly could not be considered significant. On the other hand, if the odds are one in one thousand that regular inhalation of gasoline vapors that are 2% benzene will be fatal, a reasonable person might well consider the risk significant. * * *
Id.
OSHA standards must be both technologically and economically feasible.
United Steelworkers
v.
Marshall
, 647 F.2d 1189, 1264 (D.C. Cir. 1980) (“The Lead I case”). The Supreme Court has defined feasibility as “capable of being done.”
American Textile Mfrs. Inst.
v.
Donovan
, 425 U.S. 490, 509 (1981) (“The Cotton dust case”). The courts have further clarified that a standard is technologically feasible if OSHA proves a reasonable possibility,
* * * within the limits of the best available evidence * * * that the typical firm will be able to develop and install engineering and work practice controls that can meet the PEL in most of its operations.
See
The Lead I case, 647 F.2d at 1272.
With respect to economic feasibility, the courts have held that a standard is feasible if it does not threaten massive dislocation to or imperil the existence of the industry.
See
The Lead case, 647 F.2d at 1265. A court must examine the cost of compliance with an OSHA standard “in relation to the financial health and profitability of the industry and the likely effect of such costs on unit consumer prices.”
Id.
[The] practical question is whether the standard threatens the competitive stability of an industry, * * * or whether any intra-industry or inter-industry discrimination in the standard might wreck such stability or lead to undue concentration.
Id
. (
citing Industrial Union Dept.,
AFL-CIO
v.
Hodgson
, 499 F.2d 467 (D.C. Cir. 1974)).
The courts have further observed that granting companies reasonable time to comply with new PEL's may enhance economic feasibility.
Id.
While a standard must be economically feasible, the Supreme Court has held that a cost-benefit analysis of health standards is not required by the Act because a feasibility analysis is. The Cotton dust case, 453 U.S. at 509. Finally, unlike safety standards, health standards must eliminate risk or reduce it to the maximum extent that is technologically and economically feasible. See
International Union, United Automobile, Aerospace & Agricultural Implement Workers of America, UAW
v.
OSHA
, 938 F.2d 1310, 1313 (D.C. Cir. 1991); Control of Hazardous Energy Sources (Lockout/Tagout), Final rule; supplemental statement of reasons, (58 FR 16612, March 30, 1993).
III. Events Leading to the Final Standard
OSHA's previous standards for workplace exposure to Cr(VI) were adopted in 1971, pursuant to section 6(a) of the Act, from a 1943 American National Standards Institute (ANSI) recommendation originally established to control irritation and damage to nasal
tissues (36 FR at 10466, 5/29/71; Ex. 20-3). OSHA's general industry standard set a permissible exposure limit (PEL) of 1 mg chromium trioxide per 10 m
3
air in the workplace (1 mg/10 m
3
CrO
3
) as a ceiling concentration, which corresponds to a concentration of 52 μg/m
3
Cr(VI). A separate rule promulgated for the construction industry set an eight-hour time-weighted-average PEL of 1 mg/10 m
3
CrO
3
, also equivalent to 52 μg/m
3
Cr(VI), adopted from the American Conference of Governmental Industrial Hygienists (ACGIH) 1970 Threshold Limit Value (TLV) (36 FR at 7340, 4/17/71).
Following the ANSI standard of 1943, other occupational and public health organizations evaluated Cr(VI) as a workplace and environmental hazard and formulated recommendations to control exposure. The ACGIH first recommended control of workplace exposures to chromium in 1946, recommending a time-weighted average Maximum Allowable Concentration (later called a Threshold Limit Value) of 100 μg/m
3
for chromic acid and chromates as Cr
2
O
3
(Ex. 5-37), and later classified certain Cr(VI) compounds as class A1 (confirmed human) carcinogens in 1974. In 1975, the NIOSH Criteria for a Recommended Standard recommended that occupational exposure to Cr(VI) compounds should be limited to a 10-hour TWA of 1 μg/m
3
, except for some forms of Cr(VI) then believed to be noncarcinogenic (Ex. 3-92). The National Toxicology Program's First Annual Report on Carcinogens identified calcium chromate, chromium chromate, strontium chromate, and zinc chromate as carcinogens in 1980 (Ex. 35-157).
During the 1980s, regulatory and standards organizations came to recognize Cr(VI) compounds in general as carcinogens. The Environmental Protection Agency (EPA) Health Assessment Document of 1984 stated that,
* * * using the IARC [International Agency for Research on Cancer] classification scheme, the level of evidence available for the combined animal and human data would place hexavalent chromium (Cr VI) compounds into Group 1, meaning that there is decisive evidence for the carcinogenicity of those compounds in humans (Ex. 19-1, p. 7-107).
In 1988 IARC evaluated the available evidence regarding Cr(VI) carcinogenicity, concluding in 1990 that
* * * [t]here is sufficient evidence in humans for the carcinogenicity of chromium[VI] compounds as encountered in the chromate production, chromate pigment production and chromium plating industries, [and] sufficient evidence in experimental animals for the carcinogenicity of calcium chromate, zinc chromates, strontium chromate and lead chromates (Ex. 18-3, p. 213).
In September 1988, NIOSH advised OSHA to consider all Cr(VI) compounds as potential occupational carcinogens (Ex. 31-22-22). ACGIH now classifies water-insoluble and water-soluble Cr(IV) compounds as class A1 carcinogens (Ex. 35-207). Current ACGIH standards include specific 8-hour time-weighted average TLVs for calcium chromate (1 μg/m
3
), lead chromate (12 μg/m
3
), strontium chromate (0.5 μg/m
3
), and zinc chromates (10 μg/m
3
), and generic TLVs for water soluble (50 μg/m
3
) and insoluble (10 μg/m
3
) forms of hexavalent chromium not otherwise classified, all measured as chromium (Ex. 35-207).
In July 1993, OSHA was petitioned for an emergency temporary standard to reduce occupational exposures to Cr(VI) compounds (Ex. 1). The Oil, Chemical, and Atomic Workers International Union (OCAW) and Public Citizen's Health Research Group (Public Citizen), citing evidence that occupational exposure to Cr(VI) increases workers' risk of lung cancer, petitioned OSHA to promulgate an emergency temporary standard to lower the PEL for Cr(VI) compounds to 0.5 μg/m
3
as an eight-hour time-weighted average (TWA). Upon review of the petition, OSHA agreed that there was evidence of increased cancer risk from exposure to Cr(VI) at the existing PEL, but found that the available data did not show the “grave danger” required to support an emergency temporary standard (Ex. 1-C). The Agency therefore denied the request for an emergency temporary standard, but initiated Section 6(b)(5) rulemaking and began performing preliminary analyses relevant to the rule.
In 1997, Public Citizen petitioned the United States Court of Appeals for the Third Circuit to compel OSHA to complete rulemaking lowering the standard for occupational exposure to Cr(VI). The Court denied Public Citizen's request, concluding that there was no unreasonable delay and dismissed the suit.
Oil, Chemical and Atomic Workers Union and Public Citizen Health Research Group
v.
OSHA
, 145 F.3d 120 (3rd Cir. 1998). Afterwards, the Agency continued its data collection and analytic efforts on Cr(VI) (Ex. 35-208, p. 3). In 2002, Public Citizen again petitioned the Court to compel OSHA to commence rulemaking to lower the Cr(VI) standard (Ex. 31-24-1). Meanwhile on August 22, 2002, OSHA published a Request for Information on Cr(VI) to solicit additional information on key issues related to controlling exposures to Cr(VI) (FR 67 at 54389), and on December 4, 2002 announced its intent to proceed with developing a proposed standard (Ex. 35-306). On December 24, 2002, the Court granted Public Citizen's petition, and ordered the Agency to proceed expeditiously with a Cr(VI) standard.
See Public Citizen Health Research Group
v.
Chao
, 314 F.3d 143 (3rd Cir. 2002)). In a subsequent order, the Court established a compressed schedule for completion of the rulemaking, with deadlines of October 4, 2004 for publication of a proposed standard and January 18, 2006 for publication of a final standard (Ex. 35-304).
In 2003, as required by the Small Business Regulatory Enforcement Act (SBREFA), OSHA initiated SBREFA proceedings, seeking the advice of small business representatives on the proposed rule. The SBREFA panel, including representatives from OSHA, the Small Business Administration (SBA), and the Office of Management and Budget (OMB), was convened on December 23, 2003. The panel conferred with representatives from small entities in chemical, alloy, and pigment manufacturing, electroplating, welding, aerospace, concrete, shipbuilding, masonry, and construction on March 16-17, 2004, and delivered its final report to OSHA on April 20, 2004. The Panel's report, including comments from the small entity representatives (SERS) and recommendations to OSHA for the proposed rule, is available in the Cr(VI) rulemaking docket (Ex. 34). The SBREFA Panel made recommendations on a variety of subjects. The most important recommendations with respect to alternatives that OSHA should consider included: A higher PEL than the PEL of 1; excluding cement from the scope of the standard; the use of SECALs for some industries; different PELS for different Hexavalent chromium compounds; a multi-year phase-in to the standards; and further consideration to approaches suited to the special conditions of the maritime and construction industries. OSHA has adapted many of these recommendations: The PEL is now 5; cement has been excluded from the scope of the standard; a compliance alternative, similar to a SECAL, has been used in aerospace industry; the standard allows four years to phase in engineering controls; and a new performance based monitoring approach for all industries, among other changes, all of which should make it easier for all
industries with changing work place conditions to meet the standard in a cost effective way. A full discussion of all of the recommendations, and OSHA's responses to them, is provided in Section VIII of this Preamble.
In addition to undertaking SBREFA proceedings, in early 2004, OSHA provided the Advisory Committee on Construction Safety and Health (ACCSH) and the Maritime Advisory Committee on Occupational Safety and Health (MACOSH) with copies of the draft proposed rule for review. OSHA representatives met with ACCSH in February 2004 and May 2004 to discuss the rulemaking and receive their comments and recommendations. On February 13, 2004, ACCSH recommended that portland cement should be included within the scope of the proposed standard (Ex. 35-307, pp. 288-293) and that identical PELs should be set for construction, maritime, and general industry (Ex. 35-307, pp. 293-297). On May 18, 2004, ACCSH recommended that the construction industry should be included in the current rulemaking, and affirmed its earlier recommendation regarding portland cement. OSHA representatives met with MACOSH in March 2004. On March 3, 2004, MACOSH collected and forwarded additional exposure monitoring data to OSHA to help the Agency better evaluate exposures to Cr(VI) in shipyards (Ex. 35-309, p. 208). MACOSH also recommended a separate Cr(VI) standard for the maritime industry, arguing that maritime involves different exposures and requires different means of exposure control than general industry and construction (Ex. 35-309, p. 227).
In accordance with the Court's rulemaking schedule, OSHA published the proposed standard for hexavalent chromium on October 4, 2004 (69 FR at 59306). The proposal included a notice of public hearing in Washington, DC (69 FR at 59306, 59445-59446). The notice also invited interested persons to submit comments on the proposal until January 3, 2005. In the proposal, OSHA solicited public input on 65 issues regarding the human health risks of Cr(VI) exposure, the impact of the proposed rule on Cr(VI) users, and other issues of particular interest to the Agency (69 FR at 59306-59312).
OSHA convened the public hearing on February 1, 2005, with Administrative Law Judges John M. Vittone and Thomas M. Burke presiding. At the conclusion of the hearing on February 15, 2005, Judge Burke set a deadline of March 21, 2005, for the submission of post hearing comments, additional information and data relevant to the rulemaking, and a deadline of April 20, 2005, for the submission of additional written comments, arguments, summations, and briefs. A wide range of employees, employers, union representatives, trade associations, government agencies and other interested parties participated in the public hearing or contributed written comments. Issues raised in their comments and testimony are addressed in the relevant sections of this preamble (
e.g.
, comments on the risk assessment are discussed in section VI; comments on the benefits analysis in section VIII). On December 22, 2005, OSHA filed a motion with the U.S. Court of Appeals for the Third Circuit requesting an extension of the court-mandated deadline for the publication of the final rule by six weeks, to February 28, 2006 (Ex. 48-13). The Court granted the request on January 17, 2006 (Ex. 48-15).
As mandated by the Act, the final standard on occupational exposure to hexavalent chromium is based on careful consideration of the entire record of this proceeding, including materials discussed or relied upon in the proposal, the record of the hearing, and all written comments and exhibits received.
OSHA has developed separate final standards for general industry, shipyards, and the construction industry. The Agency has concluded that excess exposure to Cr(VI) in any form poses a significant risk of material impairment to the health of workers, by causing or contributing to adverse health effects including lung cancer, non-cancer respiratory effects, and dermal effects. OSHA determined that the TWA PEL should not be set above 5 μg/m
3
based on the evidence in the record and its own quantitative risk assessment. The TWA PEL of 5 μg/m
3
reduces the significant risk posed to workers by occupational exposure to Cr(VI) to the maximum extent that is technologically and economically feasible. (See discussion of the PEL in Section XV below.)
IV. Chemical Properties and Industrial Uses
Chromium is a metal that exists in several oxidation or valence states, ranging from chromium (−II) to chromium (+VI). The elemental valence state, chromium (0), does not occur in nature. Chromium compounds are very stable in the trivalent state and occur naturally in this state in ores such as ferrochromite, or chromite ore (FeCr
2
O
4
). The hexavalent, Cr(VI) or chromate, is the second most stable state. It rarely occurs naturally; most Cr(VI) compounds are man made.
Chromium compounds in higher valence states are able to undergo “reduction” to lower valence states; chromium compounds in lower valence states are able to undergo “oxidation” to higher valence states. Thus, Cr(VI) compounds can be reduced to Cr(III) in the presence of oxidizable organic matter. Chromium can also be reduced in the presence of inorganic chemicals such as iron.
Chromium does exist in less stable oxidation (valence) states such as Cr(II), Cr(IV), and Cr(V). Anhydrous Cr(II) salts are relatively stable, but the divalent state (II, or chromous) is generally relatively unstable and is readily oxidized to the trivalent (III or chromic) state. Compounds in valence states such as (IV) and (V) usually require special handling procedures as a result of their instability. Cr(IV) oxide (CrO
2
) is used in magnetic recording and storage devices, but very few other Cr(IV) compounds have industrial use. Evidence exists that both Cr(IV) and Cr(V) are formed as transient intermediates in the reduction of Cr(VI) to Cr(III) in the body.
Chromium (III) is also an essential nutrient that plays a role in glucose, fat, and protein metabolism by causing the action of insulin to be more effective. Chromium picolinate, a trivalent form of chromium combined with picolinic acid, is used as a dietary supplement, because it is claimed to speed metabolism.
Elemental chromium and the chromium compounds in their different valence states have various physical and chemical properties, including differing solubilities. Most chromium species are solid. Elemental chromium is a steel gray solid, with high melting and boiling points (1857 °C and 2672 °C, respectively), and is insoluble in water and common organic solvents. Chromium (III) chloride is a violet or purple solid, with high melting and sublimation points (1150 °C and 1300 °C, respectively), and is slightly soluble in hot water and insoluble in common organic solvents. Ferrochromite is a brown-black solid; chromium (III) oxide is a green solid; and chromium (III) sulfate is a violet or red solid, insoluble in water and slightly soluble in ethanol. Chromium (III) picolinate is a ruby red crystal soluble in water (1 part per million at 25 °C). Chromium (IV) oxide is a brown-black solid that decomposes at 300 °C and is insoluble in water.
Cr(VI) compounds have mostly lemon yellow to orange to dark red hues. They are typically crystalline, granular, or powdery although one compound (chromyl chloride) exists in liquid form. For example, chromyl chloride is a dark
red liquid that decomposes into chromate ion and hydrochloric acid in water. Chromic acids are dark red crystals that are very soluble in water. Other examples of soluble chromates are sodium chromate (yellow crystals) and sodium dichromate (reddish to bright orange crystals). Lead chromate oxide is typically a red crystalline powder. Zinc chromate is typically seen as lemon yellow crystals which decompose in hot water and are soluble in acids and liquid ammonia. Other chromates such as barium, calcium, lead, strontium, and zinc chromates vary in color from light yellow to greenish yellow to orange-yellow and exist in solid form as crystals or powder.
The Color Pigments Manufacturers Association (CPMA) provided additional information on lead chromate and some other chromates used in their pigments (Ex. 38-205, pp. 12-13). CPMA describes two main lead chromate color groups: the chrome yellow pigments and the orange to red varieties known as molybdate orange pigments. The chrome yellow pigments are solid solution crystal compositions of lead chromate and lead sulfate. Molybdate orange pigments are solid solution crystal compositions of lead chromate, lead sulfate, and lead molybdate (Ex. 38-205, p. 12). CPMA also describes a basic lead chromate called “chrome orange,” and a lead chromate precipitated “onto a core” of silica (Ex. 38-205, p. 13).
OSHA re-examined available information on solubility values in light of comments from the CPMA and Dominion Color Corporation (DCC) on qualitative solubility designations and CPMA's claim of low bioavailability of lead chromate due to its extremely low solubility (Exs. 38-201-1, p. 4; 38-205, p. 95). There was not always agreement or consistency with the qualitative assignments of solubilities. Quantitative values for the same compound also differ depending on the source of information.
The Table IV-1 is the result of OSHA's re-examination of quantitative water solubility values and qualitative designations. Qualitative designations as well as quantitative values are listed as they were provided by the source. As can be seen by the Table IV-1, qualitative descriptions vary by the descriptive terminology chosen by the source.
BILLING CODE 4510-26-P
ER28FE06.000
ER28FE06.001
BILLING CODE 4510-26-C
OSHA has made some generalizations to describe the water solubilities of chromates in subsequent sections of this
Federal Register
notice. OSHA has divided Cr(VI) compounds and mixtures into three categories based on solubility values. Compounds and mixtures with water solubilities less than 0.01 g/l are referred to as water insoluble. Compounds and mixtures between 0.01 g/l and 500 g/l are referred to as slightly
soluble. Compounds and mixtures with water solubility values of 500 g/l or greater are referred to as highly water soluble. It should be noted that these boundaries for insoluble, slightly soluble, and highly soluble are arbitrary designations for the sake of further description elsewhere in this document. Quantitative values take precedence over qualitative designations. For example, zinc chromates would be slightly soluble where their solubility values exceed 0.01 g/l.
Some major users of chromium are the metallurgical, refractory, and chemical industries. Chromium is used by the metallurgical industry to produce stainless steel, alloy steel, and nonferrous alloys. Chromium is alloyed with other metals and plated on metal and plastic substrates to improve corrosion resistance and provide protective coatings for automotive and equipment accessories. Welders use stainless steel welding rods when joining metal parts.
Cr(VI) compounds are widely used in the chemical industry in pigments, metal plating, and chemical synthesis as ingredients and catalysts. Chromates are used as high quality pigments for textile dyes, paints, inks, glass, and plastics. Cr(VI) can be produced during welding operations even if the chromium was originally present in another valence state. While Cr(VI) is not intentionally added to portland cement, it is often present as an impurity.
Occupational exposures to Cr(VI) can occur from inhalation of mists (e.g., chrome plating, painting), dusts (e.g., inorganic pigments), or fumes (e.g., stainless steel welding), and from dermal contact (e.g., cement workers).
There are about thirty major industries and processes where Cr(VI) is used. These include producers of chromates and related chemicals from chromite ore, electroplating, welding, painting, chromate pigment production and use, steel mills, and iron and steel foundries. A detailed discussion of the uses of Cr(VI) in industry is found in Section VIII of this preamble.
V. Health Effects
This section summarizes key studies of adverse health effects resulting from exposure to hexavalent chromium (Cr(VI)) in humans and experimental animals, as well as information on the fate of Cr(VI) in the body and laboratory research that relates to its toxic mode of action. The primary health impairments from workplace exposure to Cr(VI) are lung cancer, asthma, and damage to the nasal epithelia and skin. While this chapter on health effects does not describe all of the many studies that have been conducted on Cr(VI) toxicity, it includes a selection of those that are relevant to the rulemaking and representative of the scientific literature on Cr(VI) health effects.
A. Absorption, Distribution, Metabolic Reduction and Elimination
Although chromium can exist in a number of different valence states, Cr(VI) is the form considered to be the greatest health risk. Cr(VI) enters the body by inhalation, ingestion, or absorption through the skin. For occupational exposure, the airways and skin are the primary routes of uptake. The following discussion summarizes key aspects of Cr(VI) uptake, distribution, metabolism, and elimination.
1. Deposition and Clearance of Inhaled Cr(VI) From the Respiratory Tract
Various anatomical, physical and physiological factors determine both the fractional and regional deposition of inhaled particulate matter. Due to the airflow patterns in the lung, more particles tend to deposit at certain preferred regions in the lung. It is therefore possible to have a buildup of chromium at certain sites in the bronchial tree that could create areas of very high chromium concentration. A high degree of correspondence between the efficiency of particle deposition and the frequency of bronchial tumors at sites in the upper bronchial tree was reported in research by Schlesinger and Lippman that compared the distribution of cancer sites in published reports of primary bronchogenic tumors with experimentally determined particle deposition patterns (Ex. 35-102).
Large inhaled particles (>5 μm) are efficiently removed from the air-stream in the extrathoracic region (Ex. 35-175). Particles greater than 2.5 μm are generally deposited in the tracheobronchial regions, whereas particles less than 2.5 μm are generally deposited in the pulmonary region. Some larger particles (>2.5 μm) can reach the pulmonary region. The mucociliary escalator predominantly clears particles that deposit in the extrathoracic and the tracheobronchial region of the lung. Individuals exposed to high particulate levels of Cr(VI) may also have altered respiratory mucociliary clearance. Particulates that reach the alveoli can be absorbed into the bloodstream or cleared by phagocytosis.
2. Absorption of Inhaled Cr(VI) Into the Bloodstream
The absorption of inhaled chromium compounds depends on a number of factors, including physical and chemical properties of the particles (oxidation state, size, solubility) and the activity of alveolar macrophages (Ex. 35-41). The hexavalent chromate anions (CrO
4
)
2−
enter cells via facilitated diffusion through non-specific anion channels (similar to phosphate and sulfate anions). As demonstrated in research by Suzuki
et al.
, a portion of water soluble Cr(VI) is rapidly transported to the bloodstream in rats (Ex. 35-97). Rats were exposed to 7.3-15.9 mg Cr(VI)/m
3
as potassium dichromate for 2-6 hours. Following exposure to Cr(VI), the ratio of blood chromium/lung chromium was 1.44±0.30 at 0.5 hours, 0.81±0.10 at 18 hours, 0.85±0.20 at 48 hours, and 0.96±0.22 at 168 hours after exposure.
Once the Cr(VI) particles reach the alveoli, absorption into the bloodstream is greatly dependent on solubility. More soluble chromates are absorbed faster than water insoluble chromates, while insoluble chromates are poorly absorbed and therefore have longer resident time in the lungs. This effect has been demonstrated in research by Bragt and van Dura on the kinetics of three Cr(VI) compounds: highly soluble sodium chromate, slightly soluble zinc chromate and water insoluble lead chromate (Ex. 35-56). They instilled
51
chromium-labeled compounds (0.38 mg Cr(VI)/kg as sodium chromate, 0.36 mg Cr(VI)/kg as zinc chromate, or 0.21 mg Cr(VI)/kg as lead chromate) intratracheally in rats. Peak blood levels of
51
chromium were reached after 30 minutes for sodium chromate (0.35 μg chromium/ml), and after 24 hours for zinc chromate (0.60 μg chromium/ml) and lead chromate (0.007 μg chromium/ml). At 30 minutes after administration, the lungs contained 36, 25, and 81% of the respective dose of the sodium, zinc, and lead chromate. On day six, >80% of the dose of all three compounds had been cleared from the lungs, during which time the disappearance from lungs followed linear first-order kinetics. The residual amount left in the lungs on day 50 or 51 was 3.0, 3.9, and 13.9%, respectively. From these results authors concluded that zinc chromate, which is less soluble than sodium chromate, is more slowly absorbed from the lungs. Lead chromate was more poorly and slowly absorbed, as indicated by very low levels in blood and greater retention in the lungs. The authors also noted that the kinetics of sodium and zinc chromates were very similar. Zinc chromate, which is less soluble than sodium chromate, was slowly absorbed from the lung, but the maximal blood levels were higher than those resulting from an equivalent dose of sodium chromate. The authors
believe that this was probably the result of hemorrhages macroscopically visible in the lungs of zinc chromate-treated rats 24 hours following intratracheal administration. Boeing Corporation commented that this study does not show that the highly water soluble sodium chromate is cleared more rapidly or retained in the lung for shorter periods than the less soluble zinc chromate (Ex. 38-106-2, p. 18-19). This comment is addressed in the Carcinogenic Effects Conclusion Section V.B.9 dealing with the carcinogenicity of slightly soluble Cr(VI) compounds.
Studies by Langard
et al.
and Adachi
et al.
provide further evidence of absorption of chromates from the lungs (Exs. 35-93; 189). In Langard
et al.
, rats exposed to 2.1 mg Cr(VI)/m
3
as zinc chromate for 6 hours/day achieved steady state concentrations in the blood after 4 days of exposure (Ex. 35-93). Adachi
et al.
studied rats that were subject to a single inhalation exposure to chromic acid mist generated from electroplating at a concentration of 3.18 mg Cr(VI)/m
3
for 30 minutes which was then rapidly absorbed from the lungs (Ex. 189). The amount of chromium in the lungs of these rats declined from 13.0 mg immediately after exposure to 1.1 mg after 4 weeks, with an overall half-life of five days.
Several other studies have reported absorption of chromium from the lungs after intratracheal instillation (Exs. 7-9; 9-81; Visek
et al.
1953 as cited in Ex. 35-41). These studies indicated that 53-85% of Cr(VI) compounds (particle size <5 μm) were cleared from the lungs by absorption into the bloodstream or by mucociliary clearance in the pharynx; the rest remained in the lungs. Absorption of Cr(VI) from the respiratory tract of workers has been shown in several studies that identified chromium in the urine, serum and red blood cells following occupational exposure (Exs. 5-12; 35-294; 35-84).
Evidence indicates that even chromates encapsulated in a paint matrix may be released in the lungs (Ex. 31-15, p. 2). In a study of chromates in aircraft spray paint, LaPuma
et al.
measured the mass of Cr(VI) released from particles into water originating from three types of paint particles: solvent-borne epoxy (25% strontium chromate (SrCrO
4
)), water-borne epoxy (30% SrCrO
4
) and polyurethane (20% SrCrO
4
) (Ex. 31-2-1). The mean fraction of Cr(VI) released into the water after one and 24 hours for each primer averaged: 70% and 85% (solvent epoxy), 74% and 84% (water epoxy), and 94% and 95% (polyurethane). Correlations between particle size and the fraction of Cr(VI) released indicated that smaller particles (<5 μm) release a larger fraction of Cr(VI) versus larger particles (>5 μm). This study demonstrates that the paint matrix only modestly hinders Cr(VI) release into a fluid, especially with smaller particles. Larger particles, which contain the majority of Cr(VI) due to their size, appear to release proportionally less Cr(VI) (as a percent of total Cr(VI)) than smaller particles. Some commenters suggested that the above research shows that the slightly soluble Cr(VI) from aircraft spray paint is less likely to reach and be absorbed in the bronchoalveolar region of the lung than a highly soluble Cr(VI) form, such as chromic acid aerosol (Exs. 38-106-2; 39-43, 44-33). This issue is further discussed in the Carcinogenic Effects Conclusion Section V.B.9.a and in the Quantitative Risk Assessment Section VI.G.4.a.
A number of questions remain unanswered regarding encapsulated Cr(VI) and bioavailability from the lung. There is a lack of detailed information on the efficiency of encapsulation and whether all of the chromate molecules are encapsulated. The stability of the encapsulated product in physiological and environmental conditions over time has not been demonstrated. Finally, the fate of inhaled encapsulated Cr(VI) in the respiratory tract and the extent of distribution in systemic tissues has not been thoroughly studied.
3. Dermal Absorption of Cr(VI)
Both human and animal studies demonstrate that Cr(VI) compounds are absorbed after dermal exposure. Dermal absorption depends on the oxidation state of chromium, the vehicle and the integrity of the skin. Cr(VI) readily traverses the epidermis to the dermis (Exs. 9-49; 309). The histological distribution of Cr(VI) within intact human skin was studied by Liden and Lundberg (Ex. 35-80). They applied test solutions of potassium dichromate in petrolatum or in water as occluded circular patches of filter paper to the skin. Results with potassium dichromate in water revealed that Cr(VI) penetrated beyond the dermis and penetration reached steady state with resorption by the lymph and blood vessels by 5 hours. About 10 times more chromium penetrated when potassium dichromate was applied in petrolatum than when applied in water, indicating that organic solvents facilitate the absorption of Cr(VI) from the skin. Research by Baranowska-Dutkiewicz also demonstrated that the absorption rates of sodium chromate solutions from the occluded forearm skin of volunteers increase with increasing concentration (Ex. 35-75). The rates were 1.1 μg Cr(VI)/cm
2
/hour for a 0.01 molar solution, 6.4 μg Cr(VI)/cm
2
/hour for a 0.1 molar solution, and 10 μg Cr(VI)/cm
2
/hour for a 0.2 molar solution.
Additional studies have demonstrated that the absorption of Cr(VI) compounds can take place through the dermal route. Using volunteers, Mali found that potassium dichromate penetrates the intact epidermis (Exs. 9-49; 35-41). Wahlberg and Skog demonstrated the presence of chromium in the blood, spleen, bone marrow, lymph glands, urine and kidneys of guinea pigs dermally exposed to
51
chromium labeled Cr(VI) compounds (Ex. 35-81).
4. Absorption of Cr(VI) by the Oral Route
Inhaled Cr(VI) can enter the digestive tract as a result of mucocilliary clearance and swallowing. Studies indicate Cr(VI) is absorbed from the gastrointestinal tract. For example, in a study by Donaldson and Barreras, the six-day fecal and 24-hour urinary excretion patterns of radioactivity in groups of six volunteers given Cr(VI) as sodium chromate labeled with
51
chromium indicated that at least 2.1% of the Cr(VI) was absorbed. After intraduodenal administration at least 10% of the Cr(VI) compound was absorbed. These studies also demonstrated that Cr(VI) compounds are reduced to Cr(III) compounds in the stomach, thereby accounting for the relatively poor gastrointestinal absorption of orally administered Cr(VI) compounds (Exs. 35-96; 35-41). In the gastrointestinal tract, Cr(VI) can be reduced to Cr(III) by gastric juices, which is then poorly absorbed (Underwood, 1971 as cited in Ex. 19-1; Ex. 35-85).
In a study conducted by Clapp
et al.
, treatment of rats by gavage with an unencapsulated lead chromate pigment or with a silica-encapsulated lead chromate pigment resulted in no measurable blood levels of chromium (measured as Cr(III), detection limit = 10 μg/L) after two or four weeks of treatment or after a two-week recovery period. However, kidney levels of chromium (measured as Cr(III)) were significantly higher in the rats that received the unencapsulated pigment when compared to the rats that received the encapsulated pigment, indicating that silica encapsulation may reduce the gastrointestinal bioavailability of chromium from lead chromate pigments (Ex. 11-5). This study does not address the bioavailability of encapsulated chromate pigments from the lung where residence time could be different.
5. Distribution of Cr(VI) in the Body
Once in the bloodstream, Cr(VI) is taken up into erythrocytes, where it is reduced to lower oxidation states and forms chromium protein complexes during reduction (Ex. 35-41). Once complexed with protein, chromium cannot leave the cell and chromium ions are unable to repenetrate the membrane and move back into the plasma (Exs. 7-6; 7-7; 19-1; 35-41; 35-52). Once inside the blood cell, the intracellular Cr(VI) reduction to Cr(III) depletes Cr(VI) concentration in the red blood cell (Ex. 35-89). This serves to enhance diffusion of Cr(VI) from the plasma into the erythrocyte resulting in very low plasma levels of Cr(VI). It is also believed that the rate of uptake of Cr(VI) by red blood cells may not exceed the rate at which they reduce Cr(VI) to Cr(III) (Ex. 35-99). The higher tissue levels of chromium after administration of Cr(VI) than after administration of Cr(III) reflect the greater tendency of Cr(VI) to traverse plasma membranes and bind to intracellular proteins in the various tissues, which may explain the greater degree of toxicity associated with Cr(VI) (MacKenzie
et al.
1958 as cited in 35-52; Maruyama 1982 as cited in 35-41; Ex. 35-71).
Examination of autopsy tissues from chromate workers who were occupationally exposed to Cr(VI) showed that the highest chromium levels were in the lungs. The liver, bladder, and bone also had chromium levels above background. Mancuso examined tissues from three individuals with lung cancer who were exposed to chromium in the workplace (Ex. 124). One was employed for 15 years as a welder, the second and third worked for 10.2 years and 31.8 years, respectively, in ore milling and preparations and boiler operations. The cumulative chromium exposures for the three workers were estimated to be 3.45, 4.59, and 11.38 mg/m
3
-years, respectively. Tissues from the first worker were analyzed 3.5 years after last exposure, the second worker 18 years after last exposure, and the third worker 0.6 years after last exposure. All tissues from the three workers had elevated levels of chromium, with the possible exception of neural tissues. Levels were orders of magnitude higher in the lungs when compared to other tissues. Similar results were also reported in autopsy studies of people who may have been exposed to chromium in the workplace as well as chrome platers and chromate refining workers (Exs. 35-92; 21-1; 35-74; 35-88).
Animal studies have shown similar distribution patterns after inhalation exposure. For example, a study by Baetjer
et al.
investigated the distribution of Cr(VI) in guinea pigs after intratracheal instillation of slightly soluble potassium dichromate (Ex. 7-8). At 24 hours after instillation, 11% of the original dose of chromium from potassium dichromate remained in the lungs, 8% in the erythrocytes, 1% in plasma, 3% in the kidney, and 4% in the liver. The muscle, skin, and adrenal glands contained only a trace. All tissue concentrations of chromium declined to low or nondetectable levels in 140 days, with the exception of the lungs and spleen.
6. Metabolic Reduction of Cr(VI)
Cr(VI) is reduced to Cr(III) in the lungs by a variety of reducing agents. This serves to limit uptake into lung cells and absorption into the bloodstream. Cr(V) and Cr(IV) are transient intermediates in this process. The genotoxic effects produced by the Cr(VI) are related to the reduction process and are further discussed in the section V.B.8 on Mechanistic Considerations.
In vivo
and
in vitro
experiments in rats indicated that, in the lungs, Cr(VI) can be reduced to Cr(III) by ascorbate and glutathione. A study by Suzuki and Fukuda showed that the reduction of Cr(VI) by glutathione is slower than the reduction by ascorbate (Ex. 35-65). Other studies have reported the reduction of Cr(VI) to Cr(III) by epithelial lining fluid (ELF) obtained from the lungs of 15 individuals by bronchial lavage. The average overall reduction capacity was 0.6 μg Cr(VI)/mg of ELF protein. In addition, cell extracts made from pulmonary alveolar macrophages derived from five healthy male volunteers were able to reduce an average of 4.8 μg Cr(VI)/10
6
cells or 14.4 μg Cr(VI)/mg protein (Ex. 35-83). Postmitochondrial (S12) preparations of human lung cells (peripheral lung parenchyma and bronchial preparations) were also able to reduce Cr(VI) to Cr(III) (De Flora
et al.
1984 as cited in Ex. 35-41).
7. Elimination of Cr(VI) From the Body
Excretion of chromium from Cr(VI) compounds is predominantly in the urine, although there is some biliary excretion into the feces. In both urine and feces, the chromium is present as low molecular weight Cr(III) complexes. Absorbed chromium is excreted from the body in a rapid phase representing clearance from the blood and at least two slower phases representing clearance from tissues. Urinary excretion accounts for over 50% of eliminated chromium (Ex. 35-41). Although chromium is excreted in urine and feces, the intestine plays only a minor part in chromium elimination, representing only about 5% of elimination from the blood (Ex. 19-1). Normal urinary levels of chromium in humans have been reported to range from 0.24-1.8 μg/L with a median level of 0.4 μg/L (Ex. 35-79). Humans exposed to 0.01-0.1 mg Cr(VI)/m
3
as potassium dichromate (8-hour time-weighted average) had urinary excretion levels from 0.0247 to 0.037 mg Cr(III)/L. Workers exposed mainly to Cr(VI) compounds had higher urinary chromium levels than workers exposed primarily to Cr(III) compounds. An analysis of the urine did not detect Cr(VI), indicating that Cr(VI) was rapidly reduced before excretion (Exs. 35-294; 5-48).
A half-life of 15-41 hours has been estimated for chromium in urine for four welders using a linear one-compartment kinetic model (Exs. 35-73; 5-52; 5-53). Limited work on modeling the absorption and deposition of chromium indicates that adipose and muscle tissue retain chromium at a moderate level for about two weeks, while the liver and spleen store chromium for up to 12 months. The estimated half-life for whole body chromium retention is 22 days for Cr(VI) (Ex. 19-1). The half-life of chromium in the human lung is 616 days, which is similar to the half-life in rats (Ex. 7-5).
Elimination of chromium was shown to be very slow in rats exposed to 2.1 mg Cr(VI)/m
3
as zinc chromate six hours/day for four days. Urinary levels of chromium remained almost constant for four days after exposure and then decreased (Ex. 35-93). After intratracheal administration of sodium dichromate to rats, peak urinary chromium concentrations were observed at six hours, after which the urinary concentrations declined rapidly (Ex. 35-94). The more prolonged elimination of the moderately soluble zinc chromate as compared to the more soluble sodium dichromate is consistent with the influence of Cr(VI) solubility on absorption from the respiratory tract discussed earlier.
Information regarding the excretion of chromium in humans after dermal exposure to chromium or its compounds is limited. Fourteen days after application of a salve containing water soluble potassium chromate, which resulted in skin necrosis and sloughing at the application site, chromium was found at 8 mg/L in the urine and 0.61 mg/100 g in the feces of one individual (Brieger 1920 as cited in Ex. 19-1). A slight increase over background levels of urinary chromium was observed in four
subjects submersed in a tub of chlorinated water containing 22 mg Cr(VI)/L as potassium dichromate for three hours (Ex. 31-22-6). For three of the four subjects, the increase in urinary chromium excretion was less than 1 μg/day over the five-day collection period. Chromium was detected in the urine of guinea pigs after radiolabeled sodium chromate solution was applied to the skin (Ex. 35-81).
8. Physiologically-Based Pharmacokinetic Modeling
Physiologically-based pharmacokinetic (PBPK) models have been developed that simulate absorption, distribution, metabolism, and excretion of Cr(VI) and Cr(III) compounds in humans (Ex. 35-95) and rats (Exs. 35-86; 35-70). The original model (Ex. 35-86) evolved from a similar model for lead, and contained compartments for the lung, GI tract, skin, blood, liver, kidney, bone, well-perfused tissues, and slowly perfused tissues. The model was refined to include two lung subcompartments for chromium, one of which allowed inhaled chromium to enter the blood and GI tract and the other only allowed chromium to enter the GI tract (Ex. 35-70). Reduction of Cr(VI) to Cr(III) was considered to occur in every tissue compartment except bone.
The model was developed from several data sets in which rats were dosed with Cr(VI) or Cr(III) intravenously, orally or by intratracheal instillation, because different distribution and excretion patterns occur depending on the route of administration. In most cases, the model parameters (
e.g.
, tissue partitioning, absorption, reduction rates) were estimated by fitting model simulations to experimental data. The optimized rat model was validated against the 1978 Langard inhalation study (Ex. 35-93). Chromium blood levels were overpredicted during the four-day inhalation exposure period, but blood levels during the post-exposure period were well predicted by the model. The model-predicted levels of liver chromium were high, but other tissue levels were closely estimated.
A human PBPK model recently developed by O'Flaherty
et al.
is able to predict tissue levels from ingestion of Cr(VI) (Ex. 35-95). The model incorporates differential oral absorption of Cr(VI) and Cr(III), rapid reduction of Cr(VI) to Cr(III) in major body fluids and tissues, and concentration-dependent urinary clearance. The model does not include a physiologic lung compartment, but can be used to estimate an upper limit on pulmonary absorption of inhaled chromium. The model was calibrated against blood and urine chromium concentration data from a group of controlled studies in which adult human volunteers drank solutions of soluble Cr(III) or Cr(VI).
PBPK models are increasingly used in risk assessments, primarily to predict the concentration of a potentially toxic chemical that will be delivered to any given target tissue following various combinations of route, dose level, and test species. Further development of the respiratory tract portion of the model, specific Cr(VI) rate data on extracellular reduction and uptake into lung cells, and more precise understanding of critical pathways inside target cells would improve the model value for risk assessment purposes.
9. Summary
Based on the studies presented above, evidence exists in the literature that shows Cr(VI) can be systemically absorbed by the respiratory tract. The absorption of inhaled chromium compounds depends on a number of factors, including physical and chemical properties of the particles (oxidation state, size, and solubility), the reduction capacity of the ELF and alveolar macrophages and clearance by the mucocliary escalator and phagocytosis. Highly water soluble Cr(VI) compounds (
e.g.
sodium chromate) enter the bloodstream more readily than highly insoluble Cr(VI) compounds (
e.g.
lead chromate). However, insoluble compounds may have longer residence time in lung. Absorption of Cr(VI) can also take place after oral and dermal exposure, particularly if the exposures are high.
The chromate (CrO
4
)
2−
enters cells via facilitated diffusion through non-specific anion channels (similar to phosphate and sulfate anions). Following absorption of Cr(VI) compounds from various exposure routes, chromium is taken up by the blood cells and is widely distributed in tissues as Cr(VI). Inside blood cells and tissues, Cr(VI) is rapidly reduced to lower oxidation states and bound to macromolecules which may result in genotoxic or cytotoxic effects. However, in the blood a substantial proportion of Cr(VI) is taken up into erythrocytes, where it is reduced to Cr(III) and becomes bound to hemoglobin and other proteins.
Inhaled Cr(VI) is reduced to Cr(III)
in vivo
by a variety of reducing agents. Ascorbate and glutathione in the ELF and macrophages have been shown to reduce Cr(VI) to Cr(III) in the lungs. After oral exposure, gastric juices are also responsible for reducing Cr(VI) to Cr(III). This serves to limit the amount of Cr(VI) systemically absorbed.
Absorbed chromium is excreted from the body in a rapid phase representing clearance from the blood and at least two slower phases representing clearance from tissues. Urinary excretion is the primary route of elimination, accounting for over 50% of eliminated chromium. Although chromium is excreted in urine and feces, the intestine plays only a minor part in chromium elimination representing only about 5% of elimination from the blood.
B. Carcinogenic Effects
There has been extensive study on the potential for Cr(VI) to cause carcinogenic effects, particularly cancer of the lung. OSHA reviewed epidemiologic data from several industry sectors including chromate production, chromate pigment production, chromium plating, stainless steel welding, and ferrochromium production. Supporting evidence from animal studies and mechanistic considerations are also evaluated in this section.
1. Evidence from Chromate Production Workers
The epidemiologic literature of workers in the chromate production industry represents the earliest and best-documented relationship between exposure to chromium and lung cancer. The earliest study of chromate production workers in the United States was reported by Machle and Gregorius in 1948 (Ex. 7-2). In the United States, two chromate production plants, one in Baltimore, MD, and one in Painesville, OH, have been the subject of multiple studies. Both plants were included in the 1948 Machle and Gregorius study and again in the study conducted by the Public Health Service and published in 1953 (Ex. 7-3). Both of these studies reported the results in aggregate. The Baltimore chromate production plant was studied by Hayes
et al.
(Ex. 7-14) and more recently by Gibb
et al.
(Ex. 31-22-11). The chromate production plant in Painesville, OH, has been followed since the 1950s by Mancuso with his most recent follow-up published in 1997. The most recent study of the Painesville plant was published by Luippold
et al.
(Ex. 31-18-4). The studies by Gibb and Luippold present historical exposure data for the time periods covered by their respective studies. The Gibb exposure data are especially interesting since the industrial hygiene data were collected on a routine basis and not for compliance purposes. These routine air
measurements may be more representative of those typically encountered by the exposed workers. In Great Britain, three plants have been studied repeatedly, with reports published between 1952 and 1991. Other studies of cohorts in the United States, Germany, Italy and Japan are also reported. The elevated lung cancer mortality reported in the great majority of these cohorts and the significant upward trends with duration of employment and cumulative exposure provide some of the strongest evidence that Cr(VI) is carcinogenic to workers. A summary of selected human epidemiologic studies in chromate production workers is presented in Table V-1.
BILLING CODE 4510-26-P
ER28FE06.002
ER28FE06.003
BILLING CODE 4510-26-C
The basic hexavalent chromate production process involves milling and mixing trivalent chromite ore with soda ash, sometimes in the presence of lime (Exs. 7-103; 35-61). The mixture is ‘roasted’ at a high temperature, which oxidizes much of the chromite to hexavalent sodium chromate. Depending on the lime content used in the process, the roast also contains other chromate species, especially calcium
chromate under high lime conditions. The highly water-soluble sodium chromate is water-extracted from the water-insoluble trivalent chromite and the less water-soluble chromates (
e.g.
, calcium chromate) in the ‘leaching’ process. The sodium chromate leachate is reacted with sulfuric acid and sodium bisulfate to form sodium dichromate. The sodium dichromate is prepared and packaged as a crystalline powder to be sold as final product or sometimes used as the starting material to make other chromates such as chromic acid and potassium dichromate.
a. Cohort Studies of the Baltimore Facility.
The Hayes
et al.
study of the Baltimore, Maryland chromate production plant was designed to determine whether changes in the industrial process at one chromium chemical production facility were associated with a decreased risk of cancer, particularly cancer of the respiratory system (Ex. 7-14). Four thousand two hundred and seventeen (4,217) employees were identified as newly employed between January 1, 1945 and December 31, 1974. Excluded from this initial enumeration were employees who: (1) were working as of 1945, but had been hired prior to 1945 and (2) had been hired since 1945 but who had previously been employed at the plant. Excluded from the final cohort were those employed less than 90 days; women; those with unknown length of employment; those with no work history; and those of unknown age. The final cohort included 2,101 employees (1,803 hourly and 298 salaried).
Hayes divided the production process into three departments: (1) The mill and roast or “dry end” department which consists of grinding, roasting and leaching processes; (2) the bichromate department which consists of the acidification and crystallization processes; and (3) the special products department which produces secondary products including chromic acid. The bichromate and special products departments are referred to as the “wet end”.
The construction of a new mill and roast and bichromate plant that opened during 1950 and 1951 and a new chromic acid and special products plant that opened in 1960 were cited by Hayes as “notable production changes” (Ex. 7-14). The new facilities were designed to “obtain improvements in process technique and in environmental control of exposure to chromium bearing dusts * * *” (Ex. 7-14).
Plant-related work and health histories were abstracted for each employee from plant records. Each job on the employee's work history was characterized according to whether the job exposure occurred in (1) a newly constructed facility, (2) an old facility, or (3) could not be classified as having occurred in the new or the old facility. Those who ever worked in an old facility or whose work location(s) could not be distinguished based upon job title were considered as having a high or questionable exposure. Only those who worked exclusively in the new facility were defined for study purposes as “low exposure”. Data on cigarette smoking were abstracted from plant records, but were not utilized in any analyses since the investigators thought them “not to be of sufficient quality to allow analysis.”
One thousand one hundred and sixty nine (1,169) cohort members were identified as alive, 494 not individually identified as alive and 438 as deceased. Death certificates could not be located for 35 reported decedents. Deaths were coded to the 8th revision of the International Classification of Diseases.
Mortality analysis was limited to the 1,803 hourly employees calculating the standardized mortality ratios (SMRs) for specific causes of death. The SMR is a ratio of the number of deaths observed in the study population to the number that would be expected if that study population had the same specific mortality rate as a standard reference population (
e.g.
, age-, gender-, calendar year adjusted U.S. population). The SMR is typically multiplied by 100, so a SMR greater than 100 represents an elevated mortality in the study cohort relative to the reference group. In the Hayes study, the expected number of deaths was based upon Baltimore, Maryland male mortality rates standardized for age, race and time period. For those where race was unknown, the expected numbers were derived from mortality rates for whites. Cancer of the trachea, bronchus and lung accounted for 69% of the 86 cancer deaths identified and was statistically significantly elevated (O=59; E=29.16; SMR=202; 95% CI: 155-263).
Analysis of lung cancer deaths among hourly workers by year of initial employment (1945-1949; 1950-1959 and 1960-1974), exposure category (low exposure or questionable/high exposure) and duration of employment (short term defined as 90 days-2 years; long term defined as 3 years +) was also conducted. For those workers characterized as having questionable/high exposure, the SMRs were significantly elevated for the 1945-1949 and the 1950-1959 hire periods and for both short- and long-term workers (not statistically significant for the short-term workers initially hired 1945-1949). For those characterized as low exposure, there was an elevated SMR for the long-term workers hired between 1950 and 1959, but based only on three deaths (not statistically significant). No lung cancer cases were observed for workers hired 1960-1974.
Case-control analyses of (1) a history of ever having been employed in selected jobs or combinations of jobs or (2) a history of specified morbid conditions and combinations of conditions reported on plant medical records were conducted. Cases were defined as decedents (both hourly and salaried were included in the analyses) whose underlying or contributing cause of death was lung cancer. Controls were defined as deaths from causes other than malignant or benign tumors. Cases and controls were matched on race (white/non-white), year of initial employment (+/−3 years), age at time of initial employment (+/−5 years) and total duration of employment (90 days-2 years; 3-4 years and 5 years +). An odds ratio (OR) was determined where the ratio is the odds of employment in a job involving Cr(VI) exposure for the cases relative to the controls.
Based upon matched pairs, analysis by job position showed significantly elevated odds ratios for special products (OR=2.6) and bichromate and special products (OR=3.3). The relative risk for bichromate alone was also elevated (OR=2.1, not statistically significant).
The possible association of lung cancer and three health conditions (skin ulcers, nasal perforation and dermatitis) as recorded in the plant medical records was also assessed. Of the three medical conditions, only the odds ratio for dermatitis was statistically significant (OR=3.0). When various combinations of the three conditions were examined, the odds ratio for having all three conditions was statistically significantly elevated (OR=6.0).
Braver
et al.
used data from the Hayes study discussed above and the results of 555 air samples taken during the period 1945-1950 by the Baltimore City Health Department, the U.S. Public Health Service, and the companies that owned the plant, in an attempt to examine the relationship between exposure to Cr(VI) and the occurrence of lung cancer (Ex. 7-17). According to the authors, methods for determining the air concentrations of Cr(VI) have changed since the industrial hygiene data were collected at the Baltimore plant between 1945 and 1959. The authors asked the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health
Administration (OSHA) to review the available documents on the methods of collecting air samples, stability of Cr(VI) in the sampling media after collection and the methods of analyzing Cr(VI) that were used to collect the samples during that period.
Air samples were collected by both midget impingers and high volume samplers. According to the NIOSH/OSHA review, high volume samplers could have led to a “significant” loss of Cr(VI) due to the reduction of Cr(VI) to Cr(III) by glass or cellulose ester filters, acid extraction of the chromate from the filter, or improper storage of samples. The midget impinger was “less subject” to loss of Cr(VI) according to the panel since neither filters nor acid extraction from filters was employed. However, if iron was present or if the samples were stored for too long, conversion from Cr(VI) to Cr(III) may have occurred. The midget impinger can only detect water soluble Cr(VI). The authors noted that, according to a 1949 industrial hygiene survey by the U.S. Public Health Service, very little water insoluble Cr(VI) was found at the Baltimore plant. One NIOSH/OSHA panel member characterized midget impinger results as “reproducible” and “accuracy * * * fairly solid unless substantial reducing agents (
e.g.
, iron) are present” (Ex. 7-17, p. 370). Based upon the panel's recommendations, the authors used the midget impinger results to develop their exposure estimates even though the panel concluded that the midget impinger methods “tend toward underestimation” of Cr(VI).
The authors also cite other factors related to the industrial hygiene data that could have potentially influenced the accuracy of their exposure estimates (either overestimating or underestimating the exposure). These include: Measurements may have been taken primarily in “problem” areas of the plant; the plants may have been cleaned or certain processes shut down prior to industrial hygiene monitoring by outside groups; respirator use; and periodic high exposures (due to infrequent maintenance operations or failure of exposure control equipment) which were not measured and therefore not reflected in the available data.
The authors estimated exposure indices for cohorts rather than for specific individuals using hire period (1945-1949 or 1950-1959) and duration of exposure, defined as short (at least 90 days but less than three years) and long (three years or more). The usual exposure to Cr(VI) for both the short- and long-term workers hired 1945-1949 was calculated as the average of the mean annual air concentration for 1945-1947 and 1949 (data were missing for 1948). This was estimated to be 413 μg/m
3
. The usual exposure to Cr(VI) was estimated to be 218 μg/m
3
for the short and long employees hired between 1950 and 1959 based on air measurements in the older facility in the early 1950s.
Cumulative exposure was calculated as the usual exposure level times average duration. Short-term workers, regardless of length of employment, were assumed to have received 1.6 years of exposure regardless of hire period. For long-term workers, the average length of exposure was 12.3 years. Those hired 1945-1949 were assigned five years at an exposure of 413 μg/m
3
and 7.3 years at an exposure of 218 μg/m
3
. For the long-term workers hired between 1950 and 1959, the average length of exposure was estimated to be 13.4 years. The authors estimated that the cumulative exposures at which “significant increases in lung cancer mortality” were observed in the Hayes study were 0.35, 0.67, 2.93 and 3.65 mg/m
3
—years. The association seen by the authors appears more likely to be the result of duration of employment rather than the magnitude of exposure since the variation in the latter was small.
Gibb
et al.
relied upon the Hayes study to investigate mortality in a second cohort of the Baltimore plant (Ex. 31-22-11). The Hayes cohort was composed of 1,803 hourly and 298 salaried workers newly employed between January 1, 1945 and December 31, 1974. Gibb excluded 734 workers who began work prior to August 1, 1950 and included 990 workers employed after August 1, 1950 who worked less than 90 days, resulting in a cohort of 2,357 males followed for the period August 1, 1950 through December 31, 1992. Fifty-one percent (1,205) of the cohort was white; 36% (848) nonwhite. Race was unknown for 13% (304) of the cohort. The plant closed in 1985.
Deaths were coded according to the 8th revision of the International Classification of Diseases. Person years of observation were calculated from the beginning of employment until death or December 31, 1992, whichever came earlier. Smoking data (yes/no) were available for 2,137 (93.3%) of the cohort from company records.
Between 1950 and 1985, approximately 70,000 measurements of airborne Cr(VI) were collected utilizing several different sampling methods. The program of routine air sampling for Cr(VI) was initiated to “characterize ‘typical/usual exposures’ of workers” (Ex. 31-22-11, p. 117). Area samples were collected during the earlier time periods, while both area and personal samples were collected starting in 1977. Exposure estimates were derived from the area sampling systems and were adjusted to “an equivalent personal exposure estimate using job-specific ratios of the mean area and personal sampling exposure estimates for the period 1978-1985 * * *” (Ex. 31-22-11, p. 117). According to the author, comparison of the area and personal samples showed “no significant differences” for about two-thirds of the job titles. For several job titles with a “significant point source of contamination” the area sampling methods “significantly underestimated” personal exposure estimates and were adjusted “by the ratio of the two” (Ex. 31-22-11, p. 118).
A job exposure matrix (JEM) was constructed, where air sampling data were available, containing annual average exposure for each job title. Data could not be located for the periods 1950-1956 and 1960-1961. Exposures were modeled for the missing data using the ratio of the measured exposure for a job title to the average of all measured job titles in the same department. For the time periods where “extensive” data were missing, a simple straight line interpolation between years with known exposures was employed.
To estimate airborne Cr(III) concentrations, 72 composite dust samples were collected at or near the fixed site air monitoring stations about three years after the facility closed. The dust samples were analyzed for Cr(VI) content using ion chromatography. Cr(III) content was determined through inductively coupled plasma spectroscopic analysis of the residue. The Cr(III):Cr(VI) ratio was calculated for each area corresponding to the air sampling zones and the measured Cr(VI) air concentration adjusted based on this ratio. Worker exposures were calculated for each job title and weighted by the fraction of time spent in each air-monitoring zone. The Cr(III):Cr(VI) ratio was derived in this manner for each job title based on the distribution of time spent in exposure zones in 1978. Cr(VI) exposures in the JEM were multiplied by this ratio to estimate Cr(III) exposures.
Information on smoking was collected at the time of hire for approximately 90% of the cohort. Of the 122 lung cancer cases, 116 were smokers and four were non smokers at the time of hire. Smoking status was unknown for two lung cancer cases. As discussed below, these data were used by the study authors to adjust for smoking in their proportional hazards regression models used to determine whether lung cancer mortality in the worker cohort increased
with increasing cumulative Cr(VI) exposure.
A total of 855 observed deaths (472 white; 323 nonwhite and 60 race unknown) were reported. SMRs were calculated using U.S. rates for overall mortality. Maryland rates (the state in which the plant was located) were used to analyze lung cancer mortality in order to better account for regional differences in disease fatality. SMRs were not adjusted for smoking. In the public hearing, Dr. Gibb explained that it was more appropriate to adjust for smoking in the proportional hazards models than in the SMRs, because the analyst must make more assumptions to adjust the SMRs for smoking than to adjust the regression model (Tr. 124).
A statistically significant lung cancer SMR, based on the national rate, was found for whites (O=71; SMR=186; 95% CI: 145-234); nonwhites (O=47; SMR=188; 95% CI: 138-251) and the total cohort (O=122; SMR=180; 95% CI: 149-214). The ratio of observed to expected lung cancer deaths (O/E) for the entire cohort stratified by race and cumulative exposure quartile were computed. Cumulative exposure was lagged five years (only exposure occurring five years before a given age was counted). The cut point for the quartiles divided the cohort into four equal groups based upon their cumulative exposure at the end of their working history (0-0.00149 mgCrO
3
/m3-yr; 0.0015-0.0089 mgCrO
3
/m
3
-yr; 0.009-0.0769 mgCrO
3
/m
3
-yr; and 0.077-5.25 mgCrO
3
/m
3
-yr). For whites, the relative risk of lung cancer was significantly elevated for the second through fourth exposure quartiles with O/E values of 0.8, 2.1, 2.1 and 1.7 for the four quartiles, respectively. For nonwhites, the O/E values by exposure quartiles were 1.1, 0.9, 1.2 and 2.9, respectively. Only the highest exposure quartile was significantly elevated. For the total cohort, a significant exposure-response trend was observed such that lung cancer mortality increased with increasing cumulative Cr(VI) exposure.
Proportional hazards models were used to assess the relationship between chromium exposure and the risk of lung cancer. The lowest exposure quartile was used as the reference group. The median exposure in each quartile was used as the measure of cumulative Cr(VI) exposure. When smoking status was included in the model, relative lung cancer risks of 1.83, 2.48 and 3.32 for the second, third and fourth exposure quartiles respectively were estimated. Smoking, Cr(III) exposure, and work duration were also significant predictors of lung cancer risk in the model.
The analysis attempted to separate the effects into two multivariate proportionate hazards models (one model incorporated the log of cumulative Cr(VI) exposure, the log of cumulative Cr(III) exposure and smoking; the second incorporated the log of cumulative Cr(VI), work duration and smoking). In either regression model, lung cancer mortality remained significantly associated (p < .05) with cumulative Cr(VI) exposure even after controlling for the combination of smoking and Cr(III) exposure or the combination of smoking and work duration. On the other hand, lung cancer mortality was not significantly associated with cumulative Cr(III) or work duration in the multivariate analysis indicating lung cancer risk was more strongly correlated with cumulative Cr(VI) exposure than the other variables.
Exponent, as part of a larger submission from the Chrome Coalition, submitted comments on the Gibb paper prior to the publication of the proposed rule. These comments asked that OSHA review methodological issues believed by Exponent to impact upon the usefulness of the Gibb data in a risk assessment analysis. While Exponent states that the Gibb study offers data that “are substantially better for cancer risk than the Mancuso study * * * they believe that further scrutiny of some of the methods and analytical procedures is necessary (Ex. 31-18-15-1, p. 5).
The issues raised by Exponent and the Chrome Coalition (Ex. 31-18-14) concerning the Gibb paper are: selection of the appropriate reference population for compilation of expected numbers for use in the SMR analysis; inclusion of short term workers (< 1 year); expansion of the number of exposure groupings to evaluate dose response trends; analyzing dose response by peak JEM exposure levels; analyzing dose-response at exposures above and below the current PEL and calculating smoking-adjusted SMRs for use in dose-response assessments. Exponent obtained the original data from the Gibb study. The data were reanalyzed to address the issues cited above. Exponent's findings are presented in Exhibit 31-18-15-1 and are discussed below.
Exponent suggested that Gibb's use of U.S. and Maryland mortality rates for developing expectations for the SMR analysis was inappropriate. It suggested that Baltimore city mortality rates would have been the appropriate standard to select since those mortality rates would more accurately reflect the mortality experience of those who worked at the plant. Exponent reran the SMR analysis to compare the SMR values reported by Gibb (U.S. mortality rates for SMR analysis) with the results of an SMR analysis using Maryland mortality rates and Baltimore mortality rates. Gibb reported a lung cancer SMR of 1.86 (95% CI: 1.45-2.34) for white males based upon 71 lung cancer deaths using U.S. mortality rates. Reanalysis of the data produced a lung cancer SMR of 1.85 (95% CI: 1.44-2.33) for white males based on U.S. mortality rates, roughly the same value obtained by Gibb. When Maryland and Baltimore rates are used, the SMR drops to 1.70 and 1.25 respectively.
Exponent suggested conducting sensitivity analysis that excludes short-term workers (defined as those with one year of employment) since the epidemiologic literature suggests that the mortality of short-term workers is different than long-term workers. Short-term workers in the Gibb study comprise 65% of the cohort and 54% of the lung cancers. The Coalition also suggested that data pertaining to short-term employees' information are of “questionable usefulness for assessing the increased cancer risk from chronic occupational exposure to Cr(VI)” (Ex. 31-18-15-1, p. 5).
Lung cancer SMRs were calculated for those who worked for less than one year and for those who worked one year or more. Exponent defined short-term workers as those who worked less than one year “because it is consistent with the inclusion criteria used by others studying chromate chemical production worker cohorts” (Ex. 31-18-15-1, p. 12). Exponent also suggested that Gibb's breakdown of exposure by quartile was not the most “appropriate” way of assessing dose-response since cumulative Cr(VI) exposures remained near zero until the 50th to 60th percentile, “so there was no real distinction between the first two quartiles * * * (Ex. 31-18-15-1, p. 24). They also suggested that combining “all workers together at the 75th quartile * * * does not properly account for the heterogeneity of exposure in this group” (Ex. 31-18-15-1, p. 24). The Exponent reanalysis used six cumulative exposure levels of Cr(VI) compared with the four cumulative exposure levels of Cr(VI) in the Gibb analysis. The lower levels of exposure were combined and “more homogeneous” categories were developed for the higher exposure levels.
Using these re-groupings and excluding workers with less than one year of employment, Exponent reported that the highest SMRs are seen in the highest exposure group (1.5-<5.25 mg
CrO
3
/m
3
-years) for both white and nonwhite, based on either the Maryland or the Baltimore mortality rates. The authors did not find “that the inclusion of short-term workers had a significant impact on the results, especially if Baltimore rates are used in the SMR calculations' (Ex. 31-18-15-1, p. 28).
Analysis of length of employment and “peak” (
i.e.
, highest recorded mean annual) exposure level to Cr(VI) was conducted. Exponent reported that approximately 50% of the cohort had “only very low” peak exposure levels (<7.2 μg CrO
3
/m
3
or approximately 3.6 μg/m
3
of Cr(VI)). The majority of the short-term workers had peak exposures of <100 μg CrO
3
/m
3
. There were five peak Cr(VI) exposure levels (<7.2 μg CrO
3
/m
3
; 7.2-<19.3 μg CrO
3
/m
3
; 19.3-<48.0 μg CrO
3
/m
3
; 48.0-<105 μg CrO
3
/m
3
; 105-<182 μg CrO
3
/m
3
; and 182-<806 μg CrO
3
/m
3
) included in the analyses. Overall, the lung cancer SMRs for the entire cohort grouped according to the six peak exposure categories were slightly higher using Maryland reference rates compared to Baltimore reference rates.
The Exponent analysis of workers who were ever exposed above the current PEL versus those never exposed above the current PEL produced slightly higher SMRs for those ever exposed, with the SMRs higher using the Maryland standard rather than the Baltimore standard. The only statistically significant result was for all lung cancer deaths combined.
Assessment was made of the potential impact of smoking on the lung cancer SMRs since Gibb did not adjust the SMRs for smoking. Exponent stated that the smoking-adjusted SMRs are more appropriate for use in the risk assessment than the unadjusted SMRs. It should be noted that smoking adjusted SMRs could not be calculated using Baltimore reference rates. As noted by the authors, the smoking adjusted SMRs produced using Maryland reference rates are, by exposure, “reasonably consistent with the Baltimore-referenced SMRs” (Ex. 31-18-15-1, p. 41).
Gibb
et al.
included workers regardless of duration of employment, and the cohort was heavily weighted by those individuals who worked less than 90 days. In an attempt to clarify this issue, Exponent produced analyses of short-term workers, particularly with respect to exposures. Exponent redefined short-term workers as those who worked less than one year, to be consistent with the definition used in other studies of chromate producers. OSHA finds this reanalysis excluding short-term workers to be useful. It suggests that including cohort workers employed less than one year did not substantively alter the conclusions of Gibb
et al.
with regard to the association between Cr(VI) exposure and lung cancer mortality. It should be noted that in the Hayes study of the Baltimore plant, the cohort is defined as anyone who worked 90 days or more.
Hayes
et al.
used Baltimore mortality rates while Gibb
et al.
used U.S. mortality rates to calculate expectations for overall SMRs. To calculate expectations for the analysis of lung cancer mortality and exposure, Gibb
et al.
used Maryland state mortality rates. The SMR analyses provided by Exponent using both Maryland and Baltimore rates are useful. The data showed that using Baltimore rates raised the expected number of lung cancer deaths and, thus, lowered the SMRs. However, there remained a statistically significant increase in lung cancer risk among the exposed workers and a significant upward trend with cumulative Cr(VI) exposure. The comparison group should be as similar as possible with respect to all other factors that may be related to the disease except the determinant under study. Since the largest portion of the cohort (45%) died in the city of Baltimore, and even those whose deaths occurred outside of Baltimore (16%) most likely lived in proximity to the city, the use of Baltimore mortality rates as an external reference population is preferable.
Gibb's selection of the cut points for the exposure quartiles was accomplished by dividing the workers in the cohort into four equal groups based on their cumulative exposure at the end of their working history. Using the same method but excluding the short-term workers would have resulted in slightly different cumulative exposure quartiles. Exponent expressed a preference for a six-tiered exposure grouping. The impact of using different exposure groupings is further discussed in section VI.C of the quantitative risk assessment.
The exposure matrix of Gibb
et al.
utilizes an unusually high-quality set of industrial hygiene data. Over 70,000 samples taken to characterize the “typical/usual” working environment is more extensive industrial hygiene data then is commonly available for most exposure assessments. However, there are several unresolved issues regarding the exposure assessment, including the impact of the different industrial hygiene sampling techniques used over the sampling time frame, how the use of different sampling techniques was taken into account in developing the exposure assessment and the use of area vs. personal samples.
Exponent and the Chrome Coalition also suggested that the SMRs should have been adjusted for smoking. According to Exponent, smoking adjusted SMRs based upon the Maryland mortality rates produced SMRs similar to the SMRs obtained using Baltimore mortality rates (Ex. 31-18-15-1). The accuracy of the smoking data is questionable since it represents information obtained at the time of hire. Hayes abstracted the smoking data from the plant medical records, but “found it not to be of sufficient quality to allow analysis.” One advantage to using the Baltimore mortality data may be to better control for the potential confounding of smoking.
The Gibb study is one of the better cohort mortality studies of workers in the chromium production industry. The quality of the available industrial hygiene data and its characterization as “typical/usual” makes the Gibb study particularly useful for risk assessment.
b. Cohort Studies of the Painesville Facility.
The Ohio Department of Health conducted epidemiological and environmental studies at a plant in Painesville that manufactured sodium bichromate from chromite ore. Mancuso and Hueper (Ex. 7-12) reported an excess of respiratory cancer among chromate workers when compared to the county in which the plant was located. Among the 33 deaths in males who had worked at the plant for a minimum of one year, 18.2% were from respiratory cancer. In contrast, the expected frequency of respiratory cancer among males in the county in which the plant was located was 1.2%. Although the authors did not include a formal statistical comparison, the lung cancer mortality rate among the exposed workers would be significantly greater than the county rate.
Mancuso (Ex. 7-11) updated his 1951 study of 332 chromate production workers employed during the period 1931-1937. Age adjusted mortality rates were calculated by the direct method using the distribution of person years by age group for the total chromate population as the standard. Vital status follow-up through 1974 found 173 deaths. Of the 66 cancer deaths, 41 (62.1%) were lung cancers. A cluster of lung cancer deaths was observed in workers with 27-36 years since first employment.
Mancuso used industrial hygiene data collected in 1949 to calculate weighted average exposures to water-soluble (presumed to be Cr(VI)), insoluble (presumed to be principally Cr(III)) and
total chromium (Ex. 7-98). The age-adjusted lung cancer death rate increased from 144.6 (based upon two deaths) to 649.6 (based upon 14 deaths) per 100,000 in five exposure categories ranging from a low of 0.25-0.49 to a high of 4.0+ mg/m
3
-years for the insoluble Cr(III) exposures. For exposure to soluble Cr(VI), the age adjusted lung cancer rates ranged from 80.2 (based upon three deaths) to 998.7 (based upon 12 deaths) in five exposure categories ranging from <0.25 to 2.0+ mg/m
3
-years. For total chromium, the age-adjusted death rates ranged from 225.7 (based upon three deaths) to 741.5 (based upon 16 deaths) for exposures ranging from 0.50-0.99 mg/m
3
-years to 6.0+ mg/m
3
-years.
Age-adjusted lung cancer death rates also were calculated by classifying workers by the levels of insoluble Cr(III) and total chromium exposure. From the data presented, it appears that for a fixed level of insoluble Cr(III), the lung cancer risk appears to increase as the total chromium increases (Ex. 7-11).
Mancuso (Ex. 23) updated the 1975 study. As of December 31, 1993, 283 (85%) cohort members had died and 49 could not be found. Of the 102 cancer deaths, 66 were lung cancers. The age-adjusted lung cancer death rate per 100,000 ranged from 187.9 (based upon four deaths) to 1,254.1 (based upon 15 deaths) for insoluble Cr(III) exposure categories ranging from 0.25-0.49 to 4.00-5.00 mg/m
3
years. For the highest exposure to insoluble Cr(III) (6.00+ mg/m
3
years) the age-adjusted lung cancer death rate per 100,000 fell slightly to 1,045.5 based upon seven deaths.
The age-adjusted lung cancer death rate per 100,000 ranged from 99.7 (based upon five deaths) to 2,848.3 (based upon two deaths) for soluble Cr(VI) exposure categories ranging from <0.25 to 4.00+ mg/m
3
years. For total chromium, the age-adjusted lung cancer death rate per 100,000 ranged from 64.7 (based upon two deaths) to 1,106.7 (based upon 21 deaths) for exposure categories ranging from <0.50 to 6.00+ mg/m
3
years.
To investigate whether the increase in the lung cancer death rate was due to one form of chromium compound (presumed insoluble Cr(III) or soluble Cr(VI)), age-adjusted lung cancer mortality rates were calculated by classifying workers by the levels of exposure to insoluble Cr(III) and total chromium. For a fixed level of insoluble Cr(III), the lung cancer rate appears to increase as the total chromium increases for each of the six total chromium exposure categories, except for the 1.00-1.99 mg/m
3
-years category. For the fixed exposure categories for total chromium, increasing exposures to levels of insoluble Cr(III) showed an increased age-adjusted death rate from lung cancer in three of the six total chromium exposure categories.
For a fixed level of soluble Cr(VI), the lung cancer death rate increased as total chromium categories of exposure increased for three of the six gradients of soluble Cr(VI). For the fixed exposure categories of total chromium, the increasing exposure to specific levels of soluble Cr(VI) led to an increase in two of the six total chromium exposure categories. Mancuso concluded that the relationship of lung cancer is not confined solely to either soluble or insoluble chromium. Unfortunately, it is difficult to attribute these findings specifically to Cr(III) [as insoluble chromium] and Cr(VI) [as soluble chromium] since it is likely that some slightly soluble and insoluble Cr(VI) as well as Cr(III) contributed to the insoluble chromium measurement.
Luippold
et al.
conducted a retrospective cohort study of 493 former employees of the chromate production plant in Painesville, Ohio (Ex. 31-18-4). This Painesville cohort does not overlap with the Mancuso cohort and is defined as employees hired beginning in 1940 who worked for a minimum of one year at Painesville and did not work at any other facility owned by the same company that used or produced Cr(VI). An exception to the last criterion was the inclusion of workers who subsequently were employed at a company plant in North Carolina (number not provided). Four cohort members were identified as female. The cohort was followed for the period January 1, 1941 through December 31, 1997. Thirty-two percent of the cohort worked for 10 or more years.
Information on potential confounders was limited. Smoking status (yes/no) was available for only 35% of the cohort from surveys administered between 1960 and 1965 or from employee medical files. For those employees where smoking data were available, 78% were smokers (responded yes on at least one survey or were identified as smokers from the medical file). Information on race also was limited, the death certificate being the primary source of information.
Results of the vital status follow-up were: 303 deaths; 132 presumed alive and 47 vital status unknown. Deaths were coded to the 9th revision of the International Classification of Diseases. Cause of death could not be located for two decedents. For five decedents the cause of death was only available from data collected by Mancuso and was recoded from the 7th to the 9th revision of the ICD. There were no lung cancer deaths among the five recoded deaths.
SMRs were calculated based upon two reference populations: The U.S. (white males) and the state of Ohio (white males). Lung cancer SMRs stratified by year of hire, duration of exposure, time since first employment and cumulative exposure group also were calculated.
Proctor
et al.
analyzed airborne Cr(VI) levels throughout the facility for the years 1943 to 1971 (the plant closed April 1972) from 800 area air sampling measurements from 21 industrial hygiene surveys (Ex. 35-61). A job exposure matrix (JEM) was constructed for 22 exposure areas for each month of plant operation. Gaps in the matrix were completed by computing the arithmetic mean concentration from area sampling data, averaged by exposure area over three time periods (1940-1949; 1950-1959 and 1960-1971) which coincided with process changes at the plant (Ex. 31-18-1)
The production of water-soluble sodium chromate was the primary operation at the Painesville plant. It involved a high lime roasting process that produced a water insoluble Cr(VI) residue (calcium chromate) as byproduct that was transported in open conveyors and likely contributed to worker exposure until the conveyors were covered during plant renovations in 1949. The average airborne soluble Cr(VI) from industrial hygiene surveys in 1943 and 1948 was 0.72 mg/m
3
with considerable variability among departments. During these surveys, the authors believe the reported levels may have underestimated total Cr(VI) exposure by 20 percent or less for some workers due to the presence of insoluble Cr(VI) dust.
Reductions in Cr(VI) levels over time coincided with improvements in the chromate production process. Industrial hygiene surveys over the period from 1957 to 1964 revealed average Cr(VI) levels of 270 μg/m
3
. Another series of plant renovations in the early 1960s lowered average Cr(VI) levels to 39 μg/m
3
over the period from 1965 to 1972. The highest Cr(VI) concentrations generally occurred in the shipping, lime and ash, and filtering operations while the locker rooms, laboratory, maintenance shop and outdoor raw liquor storage areas had the lowest Cr(VI) levels.
The average cumulative Cr(VI) exposure (mg/m
3
-yrs) for the cohort was 1.58 mg/m
3
-yrs and ranged from 0.006 to 27.8 mg/m
3
-yrs. For those who died from lung cancer, the average Cr(VI) exposure was 3.28 mg/m
3
-yrs and ranged from 0.06 to 27.8 mg/m
3
-yrs.
According to the authors, 60% of the cohort accumulated an estimated Cr(VI) exposure of 1.00 mg/m
3
-yrs or less.
Sixty-three per cent of the study cohort was reported as deceased at the end of the follow-up period (December 31, 1997). There was a statistically significant increase for the all causes of death category based on both the national and Ohio state standard mortality rates (national: O=303; E=225.6; SMR=134; 95% CI: 120-150; state: O=303; E=235; SMR=129; 95% CI: 115-144). Fifty-three of the 90 cancer deaths were cancers of the respiratory system with 51 coded as lung cancer. The SMR for lung cancer is statistically significant using both reference populations (national O= 51; E=19; SMR 268; 95% CI: 200-352; state O=51; E=21.2; SMR 241; 95% CI: 180-317).
SMRs also were calculated by year of hire, duration of employment, time since first employment and cumulative Cr(VI) exposure, mg/m
3
-years. The highest lung cancer SMRs were for those hired during the earliest time periods. For the period 1940-1949, the lung cancer SMR was 326 (O=30; E=9.2; 95% CI: 220-465); for 1950-1959, the lung cancer SMR was 275 (O=15; E=5.5; 95% CI: 154-454). For the period 1960-1971, the lung cancer SMR was just under 100 based upon six deaths with 6.5 expected.
Lung cancer SMRs based upon duration of employment (years) increased as duration of employment increased. For those with one to four years of employment, the lung cancer SMR was 137 based upon nine deaths (E=6.6; 95% CI: 62-260); for five to nine years of employment, the lung cancer SMR was 160 (O=8; E=5.0; 95% CI: 69-314). For those with 10-19 years of employment, the lung cancer SMR was 169 (O=7; E=4.1; 95% CI: 68-349), and for those with 20 or more years of employment, the lung cancer SMR was 497 (O=27; E=5.4; 95% CI: 328-723).
Analyses of cumulative Cr(VI) exposure found the lung cancer SMR (based upon the Ohio standard) in the highest exposure group (2.70-27.80 mg/m
3
-yrs) was 463 (O=20; E=4.3; 95% CI: 183-398). In the 1.05-2.69 mg/m
3
-yrs cumulative exposure group, the lung cancer SMR was 365 based upon 16 deaths (E=4.4; 95% CI: 208-592). For the cumulative exposure groups 0.49-1.04, 0.20-0.48 and 0.00-0.19, the lung cancer SMRs were 91 (O=4; E=4.4; 95% CI: 25-234; 184 (O=8; E=4.4; 95% CI: 79-362) and 67 (O=3; E=4.5; 95% CI: 14-196). A test for trend showed a strong relationship between lung cancer mortality and cumulative Cr(VI) exposure (p=0.00002). The authors claim that the SMRs are also consistent with a threshold effect since there was no statistically significant trend for excess lung cancer mortality with cumulative Cr(VI) exposures less than about 1 mg/m
3
-yrs. The issue of whether the cumulative Cr(VI) exposure-lung cancer response is best represented by a threshold effect is discussed further in preamble section VI on the quantitative risk assessment.
The Painesville cohort is small (482 employees). Excluded from the cohort were six employees who worked at other chromate plants after Painesville closed. However, exceptions were made for employees who subsequently worked at the company's North Carolina plant (number not provided) because exposure data were available from the North Carolina plant. Subsequent exposure to Cr(VI) by other terminated employees is unknown and not taken into account by the investigators. Therefore, the extent of the bias introduced is unknown.
The 10% lost to follow-up (47 employees) in a cohort of this size is striking. Four of the forty-seven had “substantial” follow-up that ended in 1997 just before the end date of the study. For the remaining 43, most were lost in the 1950s and 1960s (most is not defined). Since person-years are truncated at the time individuals are lost to follow up, the potential implication of lost person years could impact the width of the confidence intervals.
The authors used U.S. and Ohio mortality rates for the standards to compute the expectations for the SMRs, stating that the use of Ohio rates minimizes bias that could occur from regional differences in mortality. It is unclear why county rates were not used to address the differences in regional mortality.
c. Other Cohort Studies.
The first study of cancer of the respiratory system in the U.S. chromate producing industry was reported by Machle and Gregorius (Ex. 7-2). The study involved a total of 11,000 person-years of observation between 1933 and 1947. There were 193 deaths; 42 were due to cancer of the respiratory system. The proportion of respiratory cancer deaths among chromate workers was compared with proportions of respiratory cancer deaths among Metropolitan Life Insurance industrial policyholders. A non-significant excess respiratory cancer among chromate production workers was found. No attempt was made to control for confounding factors (
e.g.
, age). While some exposure data are presented, the authors state that one cannot associate tumor rates with tasks (and hence specific exposures) because of “shifting of personnel” and the lack of work history records.
Baetjer reported the results of a case-control study based upon records of two Baltimore hospitals (Ex. 7-7). A history of working with chromates was determined from these hospital records and the proportion of lung cancer cases determined to have been exposed to chromates was compared with the proportion of controls exposed. Of the lung cancer cases, 3.4% had worked in a chromate manufacturing plant, while none of the controls had such a history recorded in the medical record. The results were statistically significant and Baetjer concluded that the data confirmed the conclusions reached by Machle and Gregorius that “the number of deaths due to cancer of the lung and bronchi is greater in the chromate-producing industry than would normally be expected” (Ex. 7-7, p. 516).
As a part of a larger study carried out by the U.S. Public Health Service, the morbidity and mortality of male workers in seven U.S. chromate manufacturing plants during the period 1940-1950 was reported (Exs. 7-1; 7-3). Nearly 29 times as many deaths from respiratory cancer (excluding larynx) were found among workers in the chromate industry when compared to mortality rates for the total U.S. for the period 1940-1948. The lung cancer risk was higher at the younger ages (a 40-fold risk at ages 15-45; a 30-fold risk at ages 45-54 and a 20-fold risk at ages 55-74). Analysis of respiratory cancer deaths (excluding larynx) by race showed an observed to expected ratio of 14.29 for white males and 80 for nonwhite males.
Taylor conducted a mortality study in a cohort of 1,212 chromate workers followed over a 24 year (1937-1960) period (Ex. 7-5). The workers were from three chromate plants that included approximately 70% of the total population of U.S. chromate workers in 1937. In addition, the plants had been in continuous operation for the study period (January 1, 1937 to December 31, 1960). The cohort was followed utilizing records of Old Age and Survivors Disability Insurance (OASDI). Results were reported both in terms of SMRs and conditional probabilities of survival to various ages comparing the mortality experience of chromate workers to the U.S. civilian male population. No measures of chromate exposure were reported although results are provided in terms of duration of employment. Taylor concluded that not only was there an excess in mortality from respiratory cancer, but from other causes as well, especially as duration of employment increased.
In a reanalysis of Taylor's data, Enterline excluded those workers born prior to 1889 and analyzed the data by follow-up period using U.S. rates (Ex. 7-4). The SMR for respiratory cancer for all time periods showed a nine-fold excess (O=69 deaths; E=7.3). Respiratory cancer deaths comprised 28% of all deaths. Two of the respiratory cancer deaths were malignant neoplasms of the maxillary sinuses, a number according to Enterline, “greatly in excess of that expected based on the experience of the U.S. male population.” Also slightly elevated were cancers of the digestive organs (O=16; E=10.4) and non-malignant respiratory disease (O=13; E=8.9).
Pastides
et al.
conducted a cohort study of workers at a North Carolina chromium chemical production facility (Ex. 7-93). Opened in 1971, this facility is the largest chromium chemical production facility in the United States. A low-lime process was used since the plant began operation. Three hundred and ninety eight workers employed for a minimum of one year between September 4, 1971 and December 31, 1989 comprised the study cohort. A self-administered employee questionnaire was used to collect data concerning medical history, smoking, plant work history, previous employment and exposure to other potential chemical hazards. Personal air monitoring results for Cr(VI) were available from company records for the period February 1974 through April 1989 for 352 of the 398 cohort members. A job matrix utilizing exposure area and calendar year was devised. The exposure means from the matrix were linked to each employee's work history to produce the individual exposure estimates by multiplying the mean Cr(VI) value from the matrix by the duration (time) in a particular exposure area (job). Annual values were summed to estimate total cumulative exposure.
Personal air monitoring indicated that TWA Cr(VI) air concentrations were generally very low. Roughly half the samples were less than 1 μg/m
3
, about 75 percent were below 3 μg/m
3
, and 96 percent were below 25 μg/m
3
. The average worker's age was 42 years and mean duration of employment was 9.5 years. Two thirds of the workers had accumulated less than 0.01 μg/m
3
-yr cumulative Cr(VI) exposure. SMRs were computed using National, State (not reported) and county mortality rates (eight adjoining North Carolina counties, including the county in which the plant is located). Two of the 17 recorded deaths in the cohort were from lung cancers. The SMRs for lung cancer were 127 (95% CI: 22-398) and 97 (95% CI: 17-306) based on U.S. and North Carolina county mortality rates, respectively. The North Carolina cohort is still relatively young and not enough time has elapsed to reach any conclusions regarding lung cancer risk and Cr(VI) exposure.
In 2005, Luippold
et al.
published a study of mortality among two cohorts of chromate production workers with low exposures (Ex. 47-24-2). Luippold
et al.
studied a total of 617 workers with at least one year of employment, including 430 at the North Carolina plant studied by Pastides
et al.
(1994) (“Plant 1”) and 187 hired after the 1980 institution of exposure-reducing process and work practice changes at a second U.S. plant (“Plant 2”). A high-lime process was never used at Plant 1, and workers drawn from Plant 2 were hired after the institution of a low lime process, so that exposures to calcium chromate in both cohorts were likely minimal. Personal air-monitoring measures available from 1974 to 1988 for the first plant and from 1981 to 1998 for the second plant indicated that exposure levels at both plants were low, with overall geometric mean concentrations below 1.5 μg/m
3
and area-specific average personal air sampling values not exceeding 10 μg/m
3
for most years (Ex. 47-24-2, p. 383).
Workers were followed through 1998. By the end of follow-up, which lasted an average of 20.1 years for workers at Plant 1 and 10.1 years at Plant 2, 27 cohort members (4%) were deceased. There was a 41% deficit in all-cause mortality when compared to all-cause mortality from age-specific state reference rates, suggesting a strong healthy worker effect. Lung cancer was 16% lower than expected based on three observed vs. 3.59 expected cases, also using age-specific state reference rates (Ex. 47-24-2, p. 383). The authors stated that “[t]he absence of an elevated lung cancer risk may be a favorable reflection of the postchange environment”, but cautioned that longer follow-up allowing an appropriate latency for the entire cohort would be required to confirm this conclusion (Ex. 47-24-2, p. 381). OSHA received several written testimony regarding this cohort during the post-hearing comment period. These are discussed in section VI.B.7 on the quantitative risk assessment.
A study of four chromate producing facilities in New Jersey was reported by Rosenman (Ex. 35-104). A total of 3,408 individuals were identified from the four facilities over different time periods (plant A from 1951-1954; plant B from 1951-1971; plant C from 1937-1964 and plant D 1937-1954). No Cr(VI) exposure data was collected for this study. Proportionate mortality ratios (PMRs) and proportionate cancer mortality ratios (PCMRs), adjusted by race, age, and calendar year, were calculated for the three companies (plants A and B are owned by one company). Unlike SMRs, PMRs are not based on the expected mortality rates in a standardized population but, instead, merely represent the proportional distribution of deaths in the cohort relative to the general U.S. population. Analyses were done evaluating duration of work and latency from first employment.
Significantly elevated PMRs were seen for lung cancer among white males (170 deaths, PMR=1.95; 95% CI: 1.67-2.27) and black males (54 deaths, PMR=1.88; 95% CI: 1.41-2.45). PMRs were also significantly elevated (regardless of race) for those who worked 1-10, 11-20 and >20 years and consistently higher for white and black workers 11-20 years and >20 years since first hire. The results were less consistent for those with 10 or fewer years since first hire.
Bidstrup and Case reported the mortality experience of 723 workers at three chromate producing factories in Great Britain (Ex. 7-20). Lung cancer mortality was 3.6 times that expected (O=12; E=3.3) for England and Wales. Alderson
et al.
conducted a follow-up of workers from the three plants in the U.K. (Bolton, Rutherglen and Eaglescliffe) originally studied by Bidstrup (Ex. 7-22). Until the late 1950s, all three plants operated a “high-lime” process. This process potentially produced significant quantities of calcium chromate as a by-product as well as the intended sodium dichromate. Process changes occurred during the 1940s and 1950s. The major change, according to the author, was the introduction of the “no-lime” process, which eliminated unwanted production of calcium chromate. The no-lime process was introduced at Eaglescliffe 1957-1959 and by 1961 all production at the plant was by this process. Rutherglen operated a low-lime process from 1957/1959 until it closed in 1967. Bolton never changed to the low lime process. The plant closed in 1966. Subjects were eligible for entry into the study if they had received an X-ray examination at work and had been employed for a minimum of one year between 1948 and 1977. Of the 3,898 workers enumerated at the three plants, 2,715 met the cohort entrance criteria, (alive: 1,999; deceased: 602; emigrated: 35; and lost to follow-up: 79). Those lost to follow-up were not included in the analyses. Eaglescliffe contributed the greatest number of subjects to the study (1,418). Rutherglen contributed the
largest number of total deaths (369, or 61%). Lung cancer comprised the majority of cancer deaths and was statistically significantly elevated for the entire cohort (O=116; E=47.96; SMR= 240; p <0.001). Two deaths from nasal cancer were observed, both from Rutherglen.
SMRs were computed for Eaglescliffe by duration of employment, which was defined based upon plant process updates (those who only worked before the plant modification, those who worked both before and after the modifications, or those who worked only after the modifications were completed). Of the 179 deaths at the Eaglescliffe plant, 40 are in the pre-change group; 129 in the pre-/post-change and 10 in the post-change. A total of 36 lung cancer deaths occurred at the plant, in the pre-change group O=7; E=2.3; SMR=303; in the pre-/post-change group O=27; E=13; SMR=2.03 and in the post-change group O=2; E=1.07; SMR=187.
In an attempt to address several potential confounders, regression analysis examined the contributions of various risk factors to lung cancer. Duration of employment, duration of follow-up and working before or after plant modification appear to be greater risk factors for lung cancer, while age at entry or estimated degree of chromate exposure had less influence.
Davies updated the work of Alderson,
et al.
concerning lung cancer in the U.K. chromate producing industry (Ex. 7-99). The study cohort included payroll employees who worked a minimum of one year during the period January 1, 1950 and June 30, 1976 at any of the three facilities (Bolton, Eaglescliffe or Rutherglen). Contract employees were excluded unless they later joined the workforce, in which case their contract work was taken into account.
Based upon the date of hire, the workers were assigned to one of three groups. The first, or “early” group, consists of workers hired prior to January 1945 who are considered long term workers, but do not comprise a cohort since those who left or died prior to 1950 are excluded. The second group, “pre-change” workers, were hired between January 1, 1945 to December 31, 1958 at Rutherglen or to December 31, 1960 at Eaglescliffe. Bolton employees starting from 1945 are also termed pre-change. The cohort of pre-change workers is considered incomplete since those leaving 1946-1949 could not be included and because of gaps in the later records. For those who started after 1953 and for all men staying 5+ years, this subcohort of pre-change workers is considered complete. The third group, “post-change” workers, started after the process changes at Eaglescliffe and Rutherglen became fully effective and are considered a “complete” cohort. A “control” group of workers from a nearby fertilizer facility, who never worked in or near the chromate plant, was assembled.
A total of 2,607 employees met the cohort entrance criteria. As of December 31, 1988, 1,477 were alive, 997 dead, 54 emigrated and 79 could not be traced (total lost to follow-up: 133). SMRs were calculated using the mortality rates for England and Wales and the mortality rates for Scotland. Causes of death were ascertained for all but three decedents and deaths were coded to the revision of the International Classification of Diseases in effect at the time of death. Lung cancer in this study is defined as those deaths where the underlying cause of death is coded as 162 (carcinoma of the lung) or 239.1 (lung neoplasms of unspecified nature) in the 9th revision of the ICD. Two deaths fell into the latter category. The authors attempted to adjust the national mortality rates to allow for differences based upon area and social class.
There were 12 lung cancer deaths at Bolton, 117 at Rutherglen, 75 at Eaglescliffe and one among staff for a total of 205 lung cancer deaths. A statistically significant excess of lung cancer deaths (175 deaths) among early and pre-change workers is seen at Rutherglen and Eaglescliffe for both the adjusted and unadjusted SMRs. For Rutherglen, for the early period based upon 68 observed deaths, the adjusted SMR was 230 while the unadjusted SMR was 347 (for both SMRs p<0.001). For the 41 pre-change lung cancer deaths at Rutherglen, the adjusted SMR was 160 while the unadjusted SMR was 242 (for both SMRs p<0.001). At Eaglescliffe, there were 14 lung cancer deaths in the early period resulting in an adjusted SMR of 196 and an unadjusted SMR of 269 (for both SMRs p<0.05). For the pre-change period at Eaglescliffe, the adjusted SMR was 195 and the unadjusted was 267 (p<0.001 for both SMRs). At Bolton there is a non-significant excess among pre-change men. There are no apparent excesses in the post-change groups, the staff groups or in the non-exposed fertilizer group.
There is a highly significant overall excess of nasal cancers with two cases at Eaglescliffe and two cases at Rutherglen (O=4, Eadjusted=0.26; SMR=1538). All four men with nasal cancer had more than 20 years of exposure to chromates.
Aw reported on two case-control studies conducted at the previously studies Eaglescliffe plant (Ex. 245). In 1960, the plant, converted from a “high-lime” to a “no-lime” process, reducing the likelihood of calcium chromate formation. As of March 1996, 2,672 post-change workers had been employed, including 891 office personnel. Of the post-change plant personnel, 56% had been employed for more than one year. Eighteen lung cancer cases were identified among white male post-change workers (13 deceased; five alive). Duration of employment for the cases ranged from 1.5 to 25 years with a mean of 14.4. Sixteen of the lung cancer cases were smokers.
In the first case-control study reported, the 15 lung cancer cases identified up to September 1991 were matched to controls by age and hire date (five controls per case). Cases and controls were compared based upon their job categories within the plant. The results showed that cases were more likely to have worked in the kiln area than the controls. Five of the 15 cases had five or more years in the kiln area where Cr(VI) exposure occurred vs. six of the 75 controls. A second case-control study utilized the 18 lung cancer cases identified in post change workers up to March 1996. Five controls per case were matched by age (+/−5 years), gender and hire date. Both cases and controls had a minimum of one year of employment. A job exposure matrix was being constructed that would allow the investigators to “estimate exposure to hexavalent chromates for each worker in the study for all the jobs done since the start of employment at the site until 1980.” Starting in 1970 industrial hygiene sampling was performed to determine exposure for all jobs at the plant. Cr(VI) exposure levels for the period between 1960 and 1969 were being estimated based on the recall of employees regarding past working conditions relative to current conditions from a questionnaire. The author stated that preliminary analysis suggests that the maximum recorded or estimated level of exposure to Cr(VI) for the cases was higher than that of the controls. However, specific values for the estimated Cr(VI) exposures were not reported.
Korallus
et al.
conducted a study of 1,140 active and retired workers with a minimum of one year of employment between January 1, 1948 and March 31, 1979 at two German chromate production plants (Ex. 7-26). Workers employed prior to January 1, 1948 (either active or retired) and still alive at that date were also included in the cohort. The primary source for determining cause of death was medical
records. Death certificates were used only when medical records could not be found. Expected deaths were calculated using the male population of North Rhineland-Westphalia. Elevated SMRs for cancer of the respiratory system (50 lung cancers and one laryngeal cancer) were seen at both plants (O=21; E=10.9; SMR=192 and O=30; E=13.4; SMR=224).
Korallus
et al.
reported an update of the study. The cohort definition was expanded to include workers with one year of employment between January 1, 1948 and December 31, 1987 (Ex. 7-91). One thousand four hundred and seventeen workers met the cohort entrance criteria and were followed through December 31, 1988. While death certificates were used, where possible, to obtain cause of death, a majority of the cause of death data was obtained from hospital, surgical and general practitioner reports and autopsies because of Germany's data protection laws. Smoking data for the cohort were incomplete.
Process modifications at the two plants eliminated the high-lime process by January 1, 1958 at one location and January 1, 1964 at the second location. In addition, technical measures were introduced which led to reductions in the workplace air concentrations of chromate dusts. Cohort members were divided into pre- and post-change cohorts, with subcohorts in the pre-change group. SMRs were computed with the expected number of deaths derived from the regional mortality rates (where the plants are located). One plant had 695 workers (279 in the pre-change group and 416 in the post change group). The second plant had 722 workers (460 in the pre-change group and 262 in the post-change group). A total of 489 deaths were ascertained (225 and 264 deaths). Of the cohort members, 6.4% were lost to follow-up.
Lung cancer is defined as deaths coded 162 in the 9th revision of the International Classification of Diseases. There were 32 lung cancer deaths at one plant and 43 lung cancer deaths at the second plant. Lung cancer SMRs by date of entry (which differ slightly by plant) show elevated but declining SMRs for each plant, possibly due to lower Cr(VI) exposure as a result of improvements in production process. The lung cancer SMR for those hired before 1948 at Plant 1 is statistically significant (O=13; SMR=225; 95% CI: 122-382). The overall lung cancer SMR for Plant 1 is also statistically significantly elevated based upon 32 deaths (SMR=175; 95% CI: 120-246). At Plant 2, the only lung cancer SMR that is not statistically significant is for those hired after 1963 (based upon 1 death). Lung cancer SMRs for those hired before 1948 (O=23; SMR=344; 95% CI: 224-508) and for those hired between 1948 and 1963 (O=19; SMR=196; 95% CI: 1.24-2.98) are statistically significantly elevated. The overall lung cancer SMR at Plant 2 based upon 43 deaths is 239 (95% CI: 177-317). No nasal cavity neoplasms were found. A statistically significant SMR for stomach cancer was observed at Plant 2 (O=12; SMR=192; 95% CI: 104-324).
Recently, the mortality experience of the post-change workers identified by Korallus
et al.
was updated in a study by Birk
et al.
(Ex. 48-4). The study cohort consisted of 901 post-change male workers from two German chromate production plants (
i.e.
472 workers and 262 workers, respectively) employed for at least one year. Review of employment records led to the addition of employees to the previous Korallus cohort. Mortality experience of the cohort was evaluated through 1998. A total of 130 deaths were ascertained, of which 22 were due to cancer of the lung. Four percent of the cohort was lost to follow-up. Specific cause of death could not be determined for 14 decedents. The mean duration of Cr(VI) exposure was 10 years and the mean time since first exposure was 17 years. The proportion of workers who ever smoked was 65 percent.
The cohort lacked sufficient job history information and air monitoring data to develop an adequate job-exposure matrix required to estimate individual airborne exposures (Ex. 48-1-2). Instead, the researchers used the over 12,000 measurements of urinary chromium from routine biomonitoring of plant employees collected over the entire study period to derive individual cumulative urinary chromium estimates as an exposure surrogate. The approximate geometric average of all urinary chromium measurements in the two German plants from 1960 to 1998 was 7-8 μg/dl (Ex. 48-1-2, Table 5). There was a general plant-wide decline in average urinary chromium over time from 30 to 50 μg/dl in the 1960s to less than 5 μg/dl in the 1990s (Ex. 48-4, Figure 1). However, there was substantial variation in urinary chromium by work location and job group.
The study reported a statistically significant deficit in all cause mortality (SMR=80 95% CI: 67-95) and mortality due to heart disease (SMR=66 95% CI: 45-93) based on the age- and calendar year-adjusted German national population rates indicating a healthy worker population. However, the SMR for lung cancer mortality was elevated (SMR=148 95% CI: 93-225) against the same reference population (Ex. 48-4, Table 2). There was a statistically significant two-fold excess lung cancer mortality (SMR=209; 95% CI: 108-365; 12 observed lung cancer deaths) among workers in the highest cumulative exposure grouping (
i.e.
>200 μg Cr/L-yr). There was no increase in lung cancer mortality in the lower exposure groups, but the number of lung cancer deaths was small (
i.e.
≤5 deaths) and the confidence intervals were wide.
There were no obvious trends in lung cancer mortality with employment duration or time since first employed, but the results were, again, limited by the small number of study subjects per group. Logistic regression analysis showed that cumulative urinary chromium ≥ 200 μg Cr/L-yr was associated with a significantly higher risk of lung cancer death (OR=6.9; 95% CI: 2.6-18.2) when compared against workers exposed to lower cumulative urinary chromium exposures. This risk was unchanged after controlling for smoking status indicating that the elevated risks were unlikely to be confounded by smoking. Including a peak exposure score to the regression analysis did not result in additional risk beyond that associated with cumulative exposure alone. Some commenters felt this German post-change cohort provided evidence for an exposure threshold below which there is no risk of lung cancer. This issue is addressed in Section VI.B.7 of the quantitative risk assessment.
DeMarco
et al.
conducted a cohort study of chromate production workers in northern Italy to assess the existence of excess risk of respiratory cancer, specifically lung cancer (Ex. 7-54). The cohort was defined as males who worked for a minimum of one year from 1948 to 1985 and had at least 10 years of follow-up. Five hundred forty workers met the cohort definition. Vital status follow-up, carried out through June 30, 1985, found 427 cohort members alive, 110 dead and three lost to follow-up. Analysis utilizing SMRs based on Italian national rates was conducted. Of the 110 deaths, 42 were cancer deaths. The statistically significant SMR for lung cancer based upon 14 observed deaths with 6.46 expected was 217 (95% CI: 118-363).
Exposure estimates were based upon the duration of cumulative exposure and upon a risk score (low, medium, high and not assessed) assigned to the department in which the worker was primarily employed. A committee assigned the scores, based upon knowledge of the production process or on industrial hygiene surveys taken in
1974, 1982 and 1984. The risk score is a surrogate for the workplace concentrations of Cr(VI) in the different plant departments. Since no substantial changes had been made since World War II, the assumption was made that exposures remained relatively stable. Lung cancer SMRs based upon type of exposure increased with level of exposure (Low: O=1; E=1.43; SMR=70; Medium: O=5; E=202; SMR=2.48; High: O=6; E=1.4; SMR=420; Not Assessed: O=2; E=1.6; SMR=126). Only the SMR for those classified as having worked in departments characterized as high exposure was statistically significant at the p<0.05 level.
A cohort study of workers at a chromium compounds manufacturing plant in Tokyo, Japan by Satoh
et al.
included males employed between 1918 and 1975 for a minimum of one year and for whom the necessary data were available (Ex. 7-27). Date and cause of death data were obtained from the death certificate (85%) or from other “reliable” written testimony (15%). Of the 1,061 workers identified, 165 were excluded from the study because information was missing. A total of 896 workers met the cohort inclusion criteria and were followed through 1978. The causes of 120 deaths were ascertained. SMRs based on age-cause specific mortality for Japanese males were calculated for four different time periods (1918-1949; 1950-1959; 1960-1969 and 1970-1978) and for the entire follow-up period (1918-1978). An elevated SMR for lung cancer is seen for the entire follow-up period (O=26; E=2.746; SMR=950). A majority of the lung cancer deaths (20) occurred during the 1970-1978 interval.
Results from the many studies of chromate production workers from different countries indicate a relationship between exposure to chromium and malignant respiratory disease. The epidemiologic studies done between 1948 and 1952 by Machle and Gregorius (Ex. 7-2), Mancuso and Hueper (Ex. 7-12) and Brinton,
et al.
(Ex. 7-1) suggest a risk for respiratory cancer among chromate workers between 15 and 29 times expectation. Despite the potential problems with the basis for the calculations of the expectations or the particular statistical methods employed, the magnitude of the difference between observed and expected is powerful enough to overcome these potential biases.
It is worth noting that the magnitude of difference in the relative risks reported in a mortality study among workers in three chromate plants in the U.K. (Ex.7-20) were lower than the relative risks reported for chromate workers in the U.S. during the 1950s and 1960s. The observed difference could be the result of a variety of factors including different working conditions in the two countries, a shorter follow-up period in the British study, the larger lost-to-follow-up in the British study or the different statistical methods employed. While the earlier studies established that there was an excess risk for respiratory cancer from exposure to chromium, they were unable to specify either a specific chromium compound responsible or an exposure level associated with the risk. Later studies were able to use superior methodologies to estimate standardized lung cancer mortality ratios between chromate production cohorts and appropriate reference populations (Exs. 7-14; 7-22; 7-26; 7-99; 7-91). These studies generally found statistically increased lung cancer risk of around two-fold. The studies usually found trends with duration of employment, year of hire, or some production process change that tended to implicate chromium exposure as the causative agent.
Some of the most recent studies were able to use industrial hygiene data to reconstruct historical Cr(VI) exposures and show statistically significant associations between cumulative airborne Cr(VI) and lung cancer mortality (Exs. 23; 31-22-11; Ex. 31-18-4). Gibb
et al.
found the significant association between Cr(VI) and lung cancer was evident in models that accounted for smoking. The exposure'response relationship from these chromate production cohorts provide strong evidence that occupational exposure to Cr(VI) dust can increase cancer in the respiratory tract of workers.
The Davies, Korallus, (German cohort), Luippold (2003), and Luippold (2005) studies examine mortality patterns at chromate producing facilities where one production process modification involved conversion from a high-lime to a low-lime or a lime-free process (Exs. 7-99; 7-91; 31-18-4). In addition to process modification, technical improvements also were implemented that lowered Cr(VI) exposure. One of the plants in the Davies study retained the high-lime process and is not discussed. The lung cancer SMRs for one British plant and both of the German plants decline from early, to pre-change to post change time periods. In the remaining British plants, the lung cancer SMR is basically identical for the early and pre-change period, but does decline in the post-change time period. The lung cancer SMR in the Luippold 2003 cohort also declined over time as the amount of lime was reduced in the roasting process. Other modifications at the Painesville plant that reduced airborne Cr(VI) exposure, such as installation of covered conveyors and conversion from batch to continuous process, occurred at the same time (Ex. 35-61). The workers in the Luippold (2005) study were not exposed to Cr(VI) in facilities using a high-lime process. This study did not show excess risk; however, this may be a consequence of short follow-up time (< 20 years for most workers) or the small size of the study (< 4 expected lung cancers), as discussed further in Section VI.B.7. In general, it is not clear whether reduced levels of the high-lime byproduct, calcium chromate, or the roasting/leaching end product, sodium dichromate, that resulted from the various process changes is the reason for the decrease in lung cancer SMRs in these cohorts. It should be noted that increased lung cancer risk was experienced by workers at the Baltimore plant (
e.g.
, Hayes and Gibb cohorts) even though early air monitoring studies suggest that a high lime process was probably not used at this facility (Ex. 7-17).
2. Evidence From Chromate Pigment Production Workers
Chromium compounds are used in the manufacture of pigments to produce a wide range of vivid colors. Lead and zinc chromates have historically been the predominant hexavalent chromium pigments, although others such as strontium and barium chromate have also been produced. These chromates vary considerably in their water solubility with lead and barium chromates being the most water insoluble. All of the above chromates are less water-soluble than the highly water-soluble sodium chromate and dichromate that usually serve as the starting material for chromium pigment production. The reaction of sodium chromate or dichromate with the appropriate zinc or lead compound to form the corresponding lead or zinc chromate takes place in solution. The chromate pigment is then precipitated, separated, dried, milled, and packaged. Worker exposures to chromate pigments are greatest during the milling and packaging stages.
There have been a number of cohort studies of chromate pigment production workers from the United States, the United Kingdom, France, Germany, the Netherlands, Norway and Japan. Most of the studies found significantly elevated lung cancers in workers exposed to Cr(VI) pigments over many years when compared against standardized reference populations. In general, the
studies of chromate pigment workers lack the historical exposure data found in some of the chromate production cohorts. The consistently higher lung cancers across several worker cohorts exposed to the less water-soluble Cr(VI) compounds complements the lung cancer findings from the studies of workers producing highly water soluble chromates and adds to the further evidence that occupational exposure to Cr(VI) compounds should be regarded as carcinogenic. A summary of selected human epidemiologic studies in chromate production workers is presented in Table V-2.
BILLING CODE 4510-26-P
ER28FE06.004
BILLING CODE 4510-26-C
Langard and Vigander updated a cohort study of lung cancer incidence in 133 workers employed by a chromium pigment production company in Norway (Ex. 7-36). The cohort was originally studied by Langard and Norseth (Ex. 7-33). Twenty four men had more than three years of exposure to chromate dust. From 1948, when the company was founded, until 1951, only lead chromate pigment was produced.
From 1951 to 1956, both lead chromate and zinc chromate pigments were produced and from 1956 to the end of the study period in 1972 only zinc chromate was produced. Workers were exposed to chromates both as the pigment and its raw material, sodium dichromate.
The numbers of expected lung cancers in the workers were calculated using the age-adjusted incidence rates for lung cancer in the Norwegian male population for the period 1955-1976. Follow-up using the Norwegian Cancer Registry through December 1980, found the twelve cancers of which seven were lung cancers. Six of the seven lung cancers were observed in the subcohort of 24 workers who had been employed for more than three years before 1973. There was an increased lung cancer incidence in the subcohort based on an observed to expected ratio of 44 (O=6; E=0.135). Except for one case, all lung cancer cases were exposed to zinc chromates and only sporadically to other chromates. Five of the six cases were known to be smokers or ex-smokers. Although the authors did not report any formal statistical comparisons, the extremely high age-adjusted standardized incidence ratio suggests that the results would likely be statistically significant.
Davies reported on a cohort study of English chromate pigment workers at three factories that produced chromate pigments since the 1920s or earlier (Ex. 7-41). Two of the factories produced both zinc and lead chromate. Both products were made in the same sheds and all workers had mixed exposure to both substances. The only product at the third factory was lead chromate.
Cohort members are defined as males with a minimum of one year of employment first hired between 1933 and 1967 at plant A; 1948 and 1967 at plant B and 1946-1961 at plant C. The analysis excludes men who entered employment later than 1967 because of the short follow-up period. Three hundred and ninety six (396) men from Factory A, 136 men from Factory B and 114 men from Factory C were followed to mid-1977. Ninety-four workers with 3-11 months employment during 1932-1945 at Factory A were also included. Expectations were based upon calendar time period-, gender- and age-specific national cancer death rates for England and Wales. The author adjusted the death rates for each factory for local differences, but the exact methods of adjustment were not explicit.
Exposure to chromates was assigned as high for those in the dry departments where pigments were ground, blended and packed; medium for those in the wet departments where precipitates were washed, pressed and stove dried and in maintenance or cleaning which required time in various departments; or low for those jobs which the author states involved “slight exposure to chromates such as most laboratory jobs, boiler stoking, painting and bricklaying” (Ex. 7-41, p. 159). The high and medium exposure categories were combined for analytical purposes.
For those entering employment from 1932 to 1954 at Factory A, there were 18 lung cancer deaths in the high/medium exposure group, with 8.2 deaths expected. The difference is significant at p<.01. In the low exposure group, the number of observed and expected lung cancer deaths was equal (two deaths). There were no lung cancer deaths at Factory A for those hired between 1955-1960 and 1961-1967.
For those entering employment between 1948 and 1967 at Factory B, there were seven observed lung cancer deaths in the high/medium exposure group with 1.4 expected which is statistically significant at p<.001. At Factory C (which manufactured only lead chromate), there was one death in the high/medium exposure group and one death in the low exposure group for those beginning employment between 1946 and 1967.
The author points out that:
There has been no excess lung cancer mortality amongst workers with chromate exposure rated as “low”, nor among those exposed only to lead chromate. High and medium exposure-rated workers who in the past had mixed exposure to both lead and zinc chromate have experienced a marked excess of lung cancer deaths, even if employed for as little as one year (Ex. 7-41, p. 157).
It is the author's opinion that the results “suggest that the manufacture of zinc chromate may involve a lung cancer hazard” (Ex. 7-41, p. 157).
Davies updated the lung cancer mortality at the three British chromate pigment production factories (Ex. 7-42). The follow-up was through December 31, 1981. The cohort was expanded to include all male workers completing one year of service by June 30, 1975 but excluded office workers.
Among workers at Factory A with high and medium exposure, mortality was statistically significantly elevated over the total follow-up period among entrants hired from 1932 to 1945 (O/E=2.22). A similar, but not statistically significant, excess was seen among entrants hired from 1946 to 1954 (O/E=2.23). The results for Factory B showed statistically significantly elevated lung cancer mortality among workers classified with medium exposures entering service during the period from 1948 to 1960 (O/E=3.73) and from 1961 to 1967 (O/E=5.62). There were no lung cancer deaths in the high exposure group in either time period. At Factory C, analysis by entry date (early entrant and the period 1946-1960) produced no meaningful results since the number of deaths was small. When the two periods are combined, the O/E was near unity. The author concluded that in light of the apparent absence of risk at Factory C, “it seems reasonable to suggest that the hazard affecting workers with mixed exposures at factories A and B * * * is attributable to zinc chromates” (Ex. 7-42, p. 166). OSHA disagrees with this conclusion, as discussed in section V.9.
Davies also studied a subgroup of 57 chromate pigment workers, mostly employed between 1930 and 1945, who suffered clinical lead poisoning (Ex. 7-43). Followed through 1981, there was a statistically significantly elevated SMR for lung cancer based upon four cases (O=4; E=2.8; SMR=145).
Haguenoer studied 251 French zinc and lead chromate pigment workers employed for six months or more between January 1, 1958 and December 31, 1977 (Ex. 7-44). As of December 31, 1977, 50 subjects were identified as deceased. Cause of death was obtained for 30 of the 50 deaths (60%). Lung cancer mortality was significantly elevated based on 11 fatalities (SMR=461; 95% CI: 270-790). The mean time from first employment until detection of cancer was 17 years. The mean duration of employment among cases was 15 years.
The Haguenoer cohort was followed up in a study by Deschamps
et al.
(Ex. 234). Both lead and zinc chromate pigments were produced at the plant until zinc chromate production ceased in 1986. The cohort consisted of 294 male workers employed for at least six months between 1958 and 1987. At the end of the follow-up, 182 cohort members were alive, 16 were lost to follow-up and 96 were dead. Because of French confidentiality rules, the cause of death could not be obtained from the death certificate; instead physicians and hospital records were utilized. Using cause of death data from sources other than death certificates raises the potential for misclassification bias. Cause of death could not be obtained for five decedents. Data on smoking habits was not available for a number of workers and was not used in the analysis.
Since individual work histories were not available, the authors made the assumption that the exposure level was the same for all workers during their
employment at the plant. Duration of employment was used as a surrogate for exposure. Industrial hygiene measurements taken in 1981 provide some idea of the exposure levels at the plant. In the filtration department, Cr(VI) levels were between 2 and 3 μg/m
3
; in the grinding department between 6 and 165 μg/m
3
; in the drying and sacking department between 6 and 178 μg/m
3
; and in the sacks marking department more than 2000 μg/m
3
.
The expected number of deaths for the SMR analysis was computed from age-adjusted death rates in the northern region of France where the plant was located. There was a significant increase in lung cancer deaths based on 18 fatalities with five expected (SMR=360; 95% CI: 213-568). Using duration of employment as a surrogate for exposure, statistically significant SMRs were seen for the 10-15 years of exposure (O=6, SMR=720, 95% CI: 264-1568), 15-20 years (O=4, SMR=481, 95% CI: 131-1231), and 20+ years (O=6, SMR=377, 95% CI: 1.38-8.21) time intervals. There was a significantly elevated SMR for brain cancer based upon two deaths (SMR=844, 95% CI: 102-3049). There was a non-statistically significant increase for digestive tract cancer (O=9, SMR=130) consisting of three esophageal cancers, two stomach cancers and four colon cancers.
Equitable Environmental Health, Inc., on behalf of the Dry Color Manufacturers Association, undertook a historical prospective mortality study of workers involved in the production of lead chromate (Exs. 2-D-3; 2-D-1). The cohort was defined as male employees who had been exposed to lead chromate for a minimum of six months prior to December 1974 at one of three facilities in West Virginia, Kentucky or New Jersey. The New Jersey facility had a unit where zinc chromate was produced dating back to 1947 (Ex. 2-D-3). Most workers rotated through this unit and were exposed to both lead and zinc chromates. Two men were identified at the New Jersey facility with exposure solely to lead chromate; no one with exposure only to zinc chromate was identified.
Subsequent review of the data found that the Kentucky plant also produced zinc chromates from the late 1930s to early 1964. During the period 1961-1962, zinc chromates accounted for approximately 12% of chromate production at the plant. In addition, strontium chromate and barium chromate also were produced at the plant.
The cohort consisted of 574 male employees from all three plants (Ex. 2-D-1). Eighty-five deaths were identified with follow up through December 1979. Six death certificates were not obtained. SMRs were reported based on U.S. white male death rates. There were 53 deaths from the New Jersey plant including a statistically significant SMR for cancer of the trachea, bronchus and lung based upon nine deaths (E=3.9; SMR=231; 95% CI: 106-438). One lung cancer decedent worked solely in the production of lead chromates. Three of the lung cancer deaths were black males. In addition, there were six deaths from digestive system cancers, five of which were stomach cancers reported at the New Jersey plant. The SMR for stomach cancer was statistically significantly elevated (O=5; E=0.63; SMR=792; 99% CI: 171-2243). There were 21 deaths from the West Virginia plant, three of which were cancer of the trachea, bronchus and lung (E=2.3; SMR=130; 95% CI: 27-381). There were 11 deaths at the Kentucky plant, two of which were cancer of the trachea, bronchus and lung (E=0.9; SMR=216; 95% CI: 26-780).
Sheffet
et al.
examined the lung cancer mortality among 1,946 male employees in a chromate pigment factory in Newark, NJ, who were exposed to both lead chromate and zinc chromate pigments (Ex. 7-48). The men worked for a minimum of one month between January 1, 1940 and December 31, 1969. As of March 31, 1979, a total of 321 cohort members were identified as deceased (211 white males and 110 non-white males). Cause of death could not be ascertained for 37 white males and 12 non-white males. The proportion of the cohort lost to follow up was high (15% of white males and 20% of non-white males).
Positions at the plant were classified into three categories according to intensity of exposure: high (continuous exposure to chemical dust), moderate (occasional exposure to chemical dust or to dry or wet pigments) and low (infrequent exposure by janitors or office workers). Positions were also classified by type of chemical exposure: chromates, other inorganic substances, and organics. The authors state that in almost all positions individuals “who were exposed to any chemicals were also exposed to hexavalent chromium in the form of airborne lead and zinc chromates (Ex. 7-48, p. 46).” The proportion of lead chromate to zinc chromate was approximately nine to one. Calculations, based upon air samples during later years, give an estimate for the study period of more than 2000 μg airborne chromium/m
3
for the high exposure category, between 500 and 2000 μg airborne chromium/m
3
and less than 100 μg airborne chromium/m
3
for the low exposure category. Other suspected carcinogens present in the workplace air at much lower levels were nickel sulfate and nickel carbonate.
Because of the large proportion of workers lost to follow-up (15% of white males and 20% of non-white males) and the large numbers of unknown cause of death (21% of white males and 12% of non-white males), the authors calculated three separate mortality expectations based upon race-, gender-, age-, and time-specific U.S. mortality ratios. The first expectation was calculated upon the assum
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