Occupational Exposure to Hexavalent Chromium

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:

Proposed rule; request for comments and scheduling of informal public hearings.

SUMMARY:

The Occupational Safety and Health Administration (OSHA) proposes to amend its existing standard for employee exposure to hexavalent chromium (Cr(VI)). The basis for issuance of this proposal is a preliminary determination by the Assistant Secretary that employees exposed to Cr(VI) face a significant risk to their health at the current permissible exposure limit and that promulgating this proposed standard will substantially reduce that risk. The information gathered so far in this rulemaking indicates that employees exposed to Cr(VI) well below the current permissible exposure limit are at increased risk of developing lung cancer. Occupational exposures to Cr(VI) may also result in asthma, and damage to the nasal epithelia and skin.

This document proposes an 8-hour time-weighted average permissible exposure limit of one microgram of Cr(VI) per cubic meter of air (1 mg/m

3

) for all Cr(VI) compounds. OSHA also proposes other ancillary provisions for employee protection such as preferred methods for controlling exposure, respiratory protection, protective work clothing and equipment, hygiene areas and practices, medical surveillance, hazard communication, and recordkeeping. OSHA is proposing separate regulatory texts for general industry, construction, and shipyards in order to tailor requirements to the circumstances found in each of these sectors.

DATES:

Written comments.

The Agency invites interested persons to submit written comments regarding the proposed rule, including comments on the information collection determination described in Section X of the preamble (OMB Review under the Paperwork Reduction Act of 1995), by mail, facsimile, or electronically. All comments, whether submitted by mail, facsimile, or electronically through the Internet, must be sent by January 3, 2005.

Informal public hearings.

The Agency plans to hold an informal public hearing in Washington, DC, beginning on February 1, 2005. OSHA expects the hearing to last from 9:30 a.m. to 5:30 p.m.; however, the exact daily schedule is at the discretion of the presiding administrative law judge.

Notice of intention to appear to provide testimony at the informal public hearing.

Interested persons who intend to present testimony at the informal public hearing in Washington, DC, must notify OSHA of their intention to do so no later than December 3, 2004.

Hearing testimony and documentary evidence.

Interested persons who request more than 10 minutes to present their testimony, or who will be submitting documentary evidence at the hearing, must provide the Agency with copies of their full testimony and all documentary evidence they plan to present by January 3, 2005. See Section XVI below for details on the format and how to file a notice of intention to appear, submit documentary evidence at the hearing, and request an appropriate amount of time to present testimony.

ADDRESSES:

Written comments.

Interested persons may submit three copies of written comments to the Docket Office, Docket H054A, Room N-2625, OSHA, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210; telephone (202) 693-2350. If written comments are 10 pages or fewer, they may be faxed to the OSHA Docket Office, facsimile number (202) 693-1648. Comments may also be submitted electronically through the Internet at

http://ecomments.osha.gov.

Supplemental information such as studies and journal articles cannot be attached to electronic submissions. Instead, three copies of each study, article, or other supplemental document must be sent to the OSHA Docket Office at the address above. These materials must clearly identify the associated electronic comments to which they will be attached in the docket by the following information: Name of person submitting comments; date of comment submission; subject of comments; and docket number to which comments belong.

Informal public hearings.

The informal public hearing to be held in Washington, DC, will be held in the Frances Perkins Building, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210.

Notice of intention to appear to provide testimony at the informal public hearing.

Interested persons who intend to present testimony at the informal public hearing in Washington, DC, may submit three copies of their notice of intention to appear to the Docket Office, Docket H054A, Room N-2625, OSHA, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210. Notices may also be submitted electronically through the Internet at

http://ecomments.osha.gov.

OSHA Docket Office and Department of Labor hours of operation are 8:15 a.m. to 4:45 p.m.

Hearing testimony and documentary evidence.

Interested persons who request more than 10 minutes in which to present their testimony, or who will be submitting documentary evidence at the informal public hearing must submit three copies of the testimony and the documentary evidence to the Docket Office, Docket H054A, Room N-2625, OSHA, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210. Written testimony may also be submitted electronically through the Internet at

http://ecomments.osha.gov.

Please note that security-related problems may result in significant delays in receiving comments and other materials by regular mail. Telephone the OSHA Docket Office at (202) 693-2350 for information regarding security procedures concerning delivery of materials by express delivery, hand delivery, and messenger service.

All comments and submissions will be available for inspection and copying in the OSHA Docket Office at the address above. Most comments and submissions will be posted on OSHA's Web page (

http://www.osha.gov

). Contact the OSHA Docket Office at (202) 693-2350 for information about materials not available on the OSHA Web page and for assistance in using this Web page to locate docket submissions. Because comments sent to the docket or to OSHA's Web page are available for public inspection, the Agency cautions interested parties against including in these comments personal information such as social security numbers and birth dates.

FOR FURTHER INFORMATION CONTACT:

For general information and press inquiries, contact Mr. George Shaw, Office of Communications, Room N-3647, OSHA, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210; telephone (202) 693-1999. For technical inquiries, contact Ms. Amanda Edens, Directorate of Standards and Guidance, Room N-3718, OSHA, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210; telephone (202) 693-2093 or

fax (202) 693-1678. For hearing information contact Ms. Veneta Chatmon, Office of Communications, Room N-3647, OSHA, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210; telephone (202) 693-1999.

SUPPLEMENTARY INFORMATION:

For additional copies of this

Federal Register

document, contact the Office of Publications, Room N-3101, OSHA, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210; telephone (202) 693-1888. Electronic copies of this

Federal Register

, as well as news releases and other relevant documents, are available at OSHA's Home page at

http://www.osha.gov.

I. General

The preamble to the proposed standard on occupational exposure to chromium (VI) discusses events leading to the proposal, health effects of exposure, the degree and significance of the risk presented, a summary of the analysis of technological and economic feasibility, regulatory impact, and regulatory flexibility, and the rationale behind the specific provisions set forth in the proposed standard. The discussion follows this outline:

I. General

II. Issues

III. Pertinent Legal Authority

IV. Events Leading to the Proposed Standards

V. Chemical Properties and Industrial Uses

VI. Health Effects

VII. Preliminary Quantitative Risk Assessment

VIII. Significance of Risk

IX. Summary of the Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis

X. OMB Review under the Paperwork Reduction Act of 1995

XI. Federalism

XII. State Plans

XIII. Unfunded Mandates

XIV. Protecting Children from Environmental Health and Safety Risks

XV. Environmental Impacts

XVI. Public Participation—Notice of Hearing

XVII. Summary and Explanation of the Standards

XVIII. Authority and Signature

XIX. Proposed Standards

II. Issues

OSHA requests comment on all relevant issues, including health effects, risk assessment, significance of risk determination, technological and economic feasibility, and the provisions of the proposed regulatory text. OSHA is especially interested in responses, supported by evidence and reasons, to the following questions:

Health Effects

1. OSHA has described a variety of studies addressing the major adverse health effects that have been associated with exposure to Cr(VI). Has OSHA adequately identified and documented all critical health impairments associated with occupational exposure to Cr(VI)? Are there any additional studies or other data that would controvert the information discussed or significantly enhance the determination of material health impairment or the assessment of exposure-response relationships? Submit any relevant information, and explain your reasoning for recommending the inclusion of any studies you suggest.

2. Using currently available epidemiologic and experimental studies, OSHA has made a preliminary determination that all Cr(VI) compounds (

e.g.

, water soluble, insoluble and slightly soluble) possess carcinogenic potential and thus present a lung cancer risk to exposed workers. Is this determination correct? Are there additional data OSHA should consider in evaluating the carcinogenicity or relative carcinogenic potencies of different Cr(VI) compounds?

Risk Assessment

3. In its preliminary assessment of risk, OSHA has relied primarily on two epidemiologic cohort studies of chromate production workers to estimate the lung cancer risk to workers exposed to Cr(VI) (Exs. 31-22-11; 33-10). Are there any other studies that you believe are better suited to estimating the risk to exposed workers; if so, please provide the studies and explain why you believe they are better.

4. OSHA is aware of two cohorts (i.e., Alexander cohort, Ex. 31-16-3, and Pastides cohort, Ex. 35-279) in which a sizable number of workers were probably exposed to low Cr(VI) air levels (

e.g.

, <10 μg/m

3

) more consistent with concentrations found in the workplace today. However, OSHA believes the period of follow-up observation (median <10 yr), the young age (<45 yr at end of follow-up) and the low number of observed lung cancers (≤15 lung cancers) severely limits these cohorts as primary data sets for quantitative risk analysis. Other limitations to the Alexander study include a lack of data on workers who were employed between 1940 and 1974, but whose employment ended prior to 1974, and on exposures prior to 1974. Are there updated analyses available for the Alexander and Pastides cohorts? How many years do these cohorts need to be followed and how many lung cancers need to be observed in order for these data sets to provide insight into the shape of the exposure-response curve at lower levels of Cr(VI) exposure (

e.g.

, 0.5 to 5 μg/m

3

)? In the case of the Alexander cohort, is there additional information on cohort members' exposures prior to 1974 or workers who left prior to 1974 that could improve the analysis? Are there other cohorts available to look at low exposures?

5. OSHA has relied upon a linear relative risk model and cumulative Cr(VI) exposure for estimating the lifetime occupational lung cancer risk among Cr(VI)-exposed workers. In particular, OSHA has made a preliminary determination that a threshold model is not appropriate for estimating the lung cancer risk associated with Cr(VI). However, there is some evidence that pathways (

e.g.

, extracellular reduction, DNA repair, cell apoptosis, etc.) may exist within the lung that protect against Cr(VI)-induced respiratory carcinogenesis, and may potentially introduce non-linearities into the Cr(VI) exposure-cancer response. Is there convincing scientific evidence of a non-linear exposure-response relationship in the range of occupational exposures of interest to OSHA? If so, are there sufficient data to define a non-linear approach that would provide more reliable predictions of risk than the linear relative risk model used by OSHA?

6. OSHA's estimates of lung cancer risk are based on workers primarily exposed to highly water-soluble sodium chromate and sodium dichromate. OSHA has preliminarily concluded that the risk for workers exposed to equivalent levels of other Cr(VI) compounds will be of a similar magnitude or, in the case of some Cr(VI) compounds, possibly greater than the risks projected in the OSHA quantitative risk assessment. Is this determination appropriate? Are there sufficient data to reliably quantify the risk from occupational exposure to specific Cr(VI) compounds? If so, explain how the risk could be estimated.

7. The preliminary quantitative risk assessment relies on two (Gibb and Luippold) cohort studies in which most workers were exposed higher Cr(VI) levels than the PEL proposed by OSHA, for shorter durations than a working lifetime exposure. The risks estimated by OSHA for lifetime exposure to the proposed PEL, therefore, carry the assumption that a cumulative exposure achieved by short duration exposure to higher Cr(VI) air levels (

e.g.

, exposed 3 years to 15 μg/m

3

) leads to the same risk as an equivalent cumulative exposure achieved by longer duration exposure to

lower Cr(VI) exposure (e.g, exposed 45 years to 1 μg/m

3

). OSHA preliminarily finds this assumed exposure equivalency to represent an uncertainty in the estimates of risk but does not have information that indicates this uncertainty introduces serious error in its predictions of risk. Does the OSHA exposure-response assessment based on the higher Cr(VI) air levels and/or shorter durations experienced by the Gibb and Luippold cohorts lead to a serious underprediction or overprediction in estimated risks for the occupational exposure scenarios of interest to OSHA? Please provide any data to support your rationale.

8. OSHA has made a preliminary determination that suitable data are not available for making quantitative risk estimates for the non-cancer adverse health effects associated with exposure to Cr(VI) (

e.g.

, nasal septum ulcerations and perforations, asthma, irritant and allergic contact dermatitis). Are there suitable data for a quantitative estimation of risk for non-cancer adverse effects that OSHA should include in its final quantitative risk assessment? If so, what models or approaches should be used?

9. Are there other factors OSHA should take into consideration in its final quantitative risk assessment to better characterize the risks associated with exposure to Cr(VI)?

Technologic and Economic Feasibility

10. In its Preliminary Economic Analysis of the proposed standard, OSHA presents a profile of the affected worker population. In that profile are estimates of the number of affected workers by application group and job category and the distribution of exposures by job category. Are there additional data that will enable the Agency to refine its profile of the worker population exposed to Cr(VI)? If so, how should OSHA use these data in making such revisions?

11. What are the job categories in which employees are potentially exposed to Cr(VI) in your company or industry? For each job category, provide a brief description of the operation and describe the job activities that may lead to Cr(VI) exposure. How many employees are exposed, or have the potential for exposure, to Cr(VI) in each job category in your company or industry? What are the frequency, duration and levels of exposures to Cr(VI) at each job category in your company or industry? Where commenters are able to provide exposure data, OSHA requests that, where possible, exposure data be personal samples with clear descriptions of the length of the sample and analytical method. Exposure data that provide information concerning the controls in place are more valuable than exposure data without such information.

12. Have there been technological changes within your industry that have influenced the magnitude, frequency, or duration of exposure to Cr(VI) or the means by which employers attempt to control exposures? Describe in detail these technological changes and their effects on Cr(VI) exposures and methods of control.

13. Has there been a trend within your industry to eliminate Cr(VI) from production processes, products and services? If so, comments are requested on the success of substitution efforts. Commenters should estimate the percentage reduction in Cr(VI), and the extent to which Cr(VI) is still necessary in their processes within product lines or production activities. OSHA also requests that commenters describe any technical, economic or other deterrents to substitution.

14. Does any job category or employee in your workplace have exposures to Cr(VI) that raw air monitoring data do not adequately portray due to the short duration, intermittent or non-routine nature, or other unique characteristics of the exposure? Please explain your response and indicate peak levels, duration and frequency of exposures for employees in these job categories.

15. OSHA requests the following information regarding engineering and work practice controls in your workplace or industry:

a. Describe the operations in which the proposed PEL is being achieved most of the time by means of engineering and work practice controls.

b. What engineering and work practice controls have been implemented in these operations?

c. For all operations in facilities where Cr(VI) is used, what engineering and work practice controls have been implemented? If you have installed engineering controls or adopted work practices to reduce exposure to Cr(VI), describe the exposure reduction achieved and the cost of these controls. Where current work practices include the use of regulated areas and hygiene facilities, provide data on the implementation of these controls, including data on the costs of installation, operation, and maintenance associated with these controls.

d. Describe additional engineering and work practice controls which could be implemented in each operation where exposure levels are currently above the proposed PEL to further reduce exposure levels.

e. When these additional controls are implemented, to what levels can exposure be expected to be reduced, or what per cent reduction is expected to be achieved?

f. What are the costs and amount of time needed to develop, install and implement these additional controls? Will the added controls affect productivity?

g. Are there any processes or operations for which it is not reasonably possible to implement engineering and work practice controls within two years to achieve the proposed PEL? If so, would allowing additional time for employers to implement engineering and work practice controls make compliance possible? How much additional time would be necessary?

16. OSHA requests information on whether there are any limited or unique conditions or job tasks in Cr(VI) manufacture or use where engineering and work practice controls are not available or are not capable of reducing exposure levels to or below the proposed PEL most of the time. Provide data and evidence to support your response.

17. In its Preliminary Economic Analysis, OSHA presents estimated baseline levels of use of personal protective equipment (PPE) and the incremental costs associated with the proposed standard. Are OSHA's estimated compliance rates reasonable? Are OSHA's estimates of PPE costs, and the assumptions underlying these estimates, consistent with current industry practice? Comments are solicited on OSHA's analysis of PPE costs.

18. In its Preliminary Economic Analysis, OSHA presents estimated baseline levels of communication of Cr(VI)-related hazards and the incremental costs associated with the additional requirements for communication in the proposed standard. OSHA requests information on hazard communication programs addressing Cr(VI) that are currently being implemented by employers and any necessary additions to those programs that are anticipated in response to the proposed standard. Are OSHA's baseline estimates and unit costs for training reasonable and consistent with current industry practice?

Effects on Small Entities

19. Will difficulties be encountered by small entities when attempting to comply with requirements of the proposed standard? Can any of the

proposal's requirements be deleted or simplified for small entities, while still protecting the health of employees? Would a longer time allowed for compliance for small entities make a difference to their ability to comply, and if so, why? (Information submitted in the SBREFA process is part of the record and need not be resubmitted).

Economic Impacts and Economic Feasibility

20. OSHA, in its Preliminary Economic Analysis, has estimated, by application group, compliance costs per affected entity and the likely impacts on revenues and profits under alternative market scenarios. OSHA requests that affected employers provide comment on OSHA's estimate of revenue, profit, and the impacts of costs for their industry or application group. Are there special circumstances—such as unique cost factors, foreign competition, or pricing constraints—that OSHA needs to consider when evaluating economic impacts for particular application groups? Comments are requested on OSHA's analysis of economic feasibility in the PEA.

Overlapping and Duplicative Regulations

21. Do any federal regulations duplicate, overlap, or conflict with the proposed Cr(VI) standard?

22. In some facilities, adjustments in ventilation systems to comply with the proposed PEL may require additional time and expense to retest these systems to ensure compliance with EPA requirements or state requirements. OSHA requests information and comment indicating how frequently retesting would be required, and the time and costs involved in such retesting.

Environmental Impacts

23. Submit any data, information, or comments pertaining to possible environmental impacts of adopting this proposal, such as the following:

a. Any positive or negative environmental effects that could result;

b. Any irreversible commitments of natural resources which could be involved; and

c. Estimates of the effect of the proposed standard on the levels of Cr(VI) in the environment.

In particular, consideration should be given to the potential direct or indirect impacts of the proposal on water and air pollution, energy use, solid waste disposal, or land use.

d. Some small entity representatives noted that OSHA PELs are sometimes used to set “fence line” standards for air pollutants. OSHA is unable to find evidence of states formally using this procedure, though some states may use such a procedure informally. Do any states or other air pollution authorities base standards on OSHA PELs? What effects might this have on the environment and on environmental compliance?

Provisions of the Standard

24. OSHA's safety and health advisory committees for Construction and Maritime advised the Agency to take into consideration the unique nature of their work environments by either settings separate standards or making accommodations for the differences in work environments in construction and maritime. To account for differences in the workplace environment for these different sectors OSHA has proposed separate standards for general industry, construction, and shipyards. Is this approach appropriate? What other approaches should the Agency consider? Please provide a rationale for your response.

25. OSHA has not proposed to cover agriculture, because the Agency is not aware of significant exposures to Cr(VI) in agriculture. Is this determination correct?

26. OSHA has proposed to regulate exposures to all Cr(VI) compounds. As discussed in the health effects section of this preamble, the Agency has made a preliminary determination that the existing data support coverage of all Cr(VI) compounds in the scope of the proposed standard. Is this an appropriate determination or are there additional data that support the exclusion of certain compounds from the scope of the final standard? If so, describe specifically how these data would support a decision to exclude certain compounds from the scope of the final rule.

27. OSHA has made a preliminary determination to exclude Cr(VI) exposures due to work with portland cement from the scope of the construction standard. OSHA believes that guidance efforts by the Agency may be more suitable for addressing the dermal hazards associated with portland cement use in construction settings. OSHA's Advisory Committee for Construction Safety and Health (ACCSH) advised OSHA to include construction cement work under the proposed standard because of the known hazards associated with wet cement and the large number of workers exposed to wet cement in construction work settings. In particular ACCSH advised OSHA that only certain provisions might be necessary for workers exposed to wet cement (

e.g.

, protective work clothing, hygiene areas and practices, medical surveillance for signs and symptoms of adverse health effects only, communication of hazards and recordkeeping for medical surveillance and training). Other provisions, ACCSH advised, might not be necessary (

e.g.

, permissible exposure levels, exposure assessment, methods of compliance and respiratory protection). Should OSHA expand the scope of the construction proposal to include Cr(VI) exposures from portland cement? If so, what would be the best approach for addressing the dermal hazards from Cr(VI) faced by these workers? If Cr(VI) exposure from portland cement work in construction is included in the final standard, should only certain provisions such as those outlined by ACCSH be considered?

28. OSHA has proposed to include exposure to Cr(VI) from portland cement in the scope of the standard for general industry. The Agency believes that the potential for airborne exposure to Cr(VI) in general industry due to work with portland cement, as indicated by the profile of exposed workers presented in Table IX-2 of this preamble, is higher than in the construction industry. OSHA acknowledges, however, that the exposure profile indicates that no workers are exposed to Cr(VI) at levels over the proposed action level. Given the low level of airborne exposure among cement workers in general industry, should OSHA exclude exposures to Cr(VI) from portland cement from the scope of the general industry standard? OSHA seeks data to help inform this issue, and solicits comments on particular provisions of the general industry and construction standards that may or may not be appropriate for cement workers.

29. OSHA has proposed to exempt from coverage Cr(VI) exposures occurring in the application of pesticides in general industry (such as the treatment of wood with chromium copper arsenate (CCA)) because pesticide application is regulated by EPA, and section 4(b)(1) of the OSH Act precludes OSHA from regulating where other Federal agencies exercise their statutory authority to do so. OSHA has proposed to cover exposures resulting from use of treated materials. Is this approach appropriate? Are there any instances where EPA-regulated pesticide application occurs in construction or shipyard workplaces?

30. Describe any additional industries, processes, or applications that should be exempted from the Cr(VI) standard and provide detailed reasons for any requested exemption. In

particular, are the epidemiologic and experimental studies sufficient to support OSHA's the inclusion of various industries or processes under the scope of the proposed standard? Please provide the rationale and supporting data for your response.

31. Can the proposed Cr(VI) standard for the construction industry be modified in any way to better account for the workplace conditions in that industry, while still providing appropriate protection to Cr(VI)-exposed workers in that industry? Would an alternative approach similar to that used in OSHA's asbestos standard, where the application of specified controls in certain situations would be considered adequate to meet the requirements of the standard, be useful? Is there enough information available to define such technology specifications?

32. Can the proposed Cr(VI) standard for shipyards be modified in any way to better account for the workplace conditions in that industry, while still providing appropriate protection to Cr(VI)-exposed workers in that industry?

33. OSHA has proposed a TWA PEL for Cr(VI) of 1.0 μg/m

3

. The Agency has made a preliminary determination that this is the lowest level that is both technologically and economically feasible and is necessary to reduce significant risks of material health impairment from exposure to Cr(VI). Is this PEL appropriate and is it adequately supported by the existing data? If not, what PEL would be more appropriate or would more adequately protect employees from Cr(VI)-associated health risks? Provide evidence to support your response.

34. Should different PELs be established for different Cr(VI) compounds? If so, how should they be established? Where possible, provide specific detail about how different PELs could be established and how the Agency should apply those PELs in instances where workers may be exposed to more than one Cr(VI) compound.

35. OSHA has proposed an action level for Cr(VI) exposure in general industry, but not in construction or shipyards. Is this an appropriate approach? Should OSHA set an action level for exposure to Cr(VI) in construction and shipyards? Should the proposed action level in general industry be retained in the final rule?

36. If an action level is included in the final rule, is the proposed action level for general industry (0.5 μg/m

3

) the appropriate level for the PEL under consideration? If not, at what level should the action level be set?

37. If an action level is included in the final rule, which provisions should be triggered by exposure above the action level? Indicate the basis for your position and include any supporting information.

38. If no action level is included in the final rule, which provisions should apply to all Cr(VI)-exposed workers? Which provisions should be triggered by the PEL? Are there any other appropriate triggers for the requirements of the standard?

39. Should OSHA set a short-term exposure limit (STEL) or ceiling for exposure to Cr(VI)? If so, please specify the appropriate air concentration and the rationale for its selection.

40. Do you conduct initial air monitoring or do you rely on objective data to determine Cr(VI) exposures? Describe any other approaches you have implemented for assessing an employee's initial exposure to Cr(VI).

41. Describe any follow-up or subsequent exposure assessments that you conduct. How often do you conduct such follow-up or subsequent exposure assessments? Please comment on OSHA's estimate of baseline industry practice and the projected costs for initial and periodic exposure assessment. Are OSHA's estimates consistent with current industry practice?

42. Do shipyard employers presently measure their employees' exposure to Cr(VI)? If not, do they use some alternative method of identifying which employees may be over-exposed to Cr(VI)?

43. OSHA has proposed specific requirements for exposure assessment in general industry, but has not proposed that these requirements apply to construction or shipyard employers. Should requirements for exposure assessment in construction or shipyards be included in the final Cr(VI) standard? Are there any advantages to requiring construction or shipyard employers to measure their employees' exposures to Cr(VI)? If so, would the exposure assessment requirements proposed for general industry be appropriate? Would construction or shipyard employers encounter situations where monitoring would be infeasible if they were required to follow the exposure assessment requirements proposed for employers in general industry? Indicate the basis for your position and include any supporting information. What types of exposure assessment strategies are effective for assessing worker exposures at construction and shipyard worksites?

44. Should requirements for exposure assessment in general industry be included in the final Cr(VI) standard, or would the performance-oriented requirement proposed for construction and shipyards be more appropriate? Indicate the basis for your position and include any supporting information.

45. OSHA has proposed that exposure monitoring in general industry be conducted at least every six months if exposures are above the action level but below the PEL, and at least every three months if exposures are at or above the PEL. Are these proposed frequencies appropriate? If not, what frequency of monitoring would be more appropriate, and why?

46. OSHA has proposed that regulated areas be established in general industry wherever an employee's exposure to airborne concentrations of Cr(VI) is, or can reasonably be expected to be, in excess of the PEL. OSHA seeks comments on this provision and in particular:

a. Describe any work settings where establishing regulated areas could be problematic or infeasible. If establishing regulated areas is problematic, what approaches might be used to warn employees in such work settings of high risk areas (i.e., areas where the airborne concentrations of Cr(VI) exceed the PEL?).

b. Should OSHA add hazards from eye or skin contact as a trigger for establishing regulated areas? Explain the basis for your position, and include any supporting information. c. Describe any methods currently used that have been found to be effective in establishing regulated areas.

47. OSHA has not proposed requirements for establishment of regulated areas in construction or shipyards. Should requirements for regulated areas for construction or shipyards be included in the final Cr(VI) standard? If so, would the requirements for regulated areas proposed for general industry be appropriate? Are there any particular problems in construction or shipyard settings that make regulated areas problematic or infeasible? If requirements for regulated areas for construction or shipyards are not included in the final Cr(VI) standard, should OSHA include requirements for warning signs or other measures to alert employees of the presence of Cr(VI)? If so, what practical means could be used to determine where and when such labeling would be required? What potential difficulties might be encountered by using such an approach? Indicate the basis for your position and include any supporting information.

48. Under the proposed standard, employers are required to use engineering and work practice controls

to reduce and maintain employee exposure to Cr(VI) to or below the PEL unless the employer can demonstrate that employees are not exposed above the PEL for 30 or more days per year, or the employer can demonstrate that such controls are not feasible. Is this approach appropriate for Cr(VI)? Indicate the basis for your position and include any supporting information.

49. In OSHA's Cadmium standard (29 CFR 1010.1027), the Agency established separate engineering control air limits (SECALs) for certain processes in selected industries. SECALs were established where compliance with the PEL by means of engineering and work practice controls was infeasible. For these industries, a SECAL was established at the lowest feasible level that could be achieved by engineering and work practice controls. The PEL was set at a lower level, and could be achieved by any allowable combination of controls. SECALs thus allowed OSHA to establish a lower PEL for cadmium than would otherwise have been possible, given technological feasibility constraints. Should OSHA establish SECALs for Cr(VI) in any industries or processes? If so, in what industries or processes, and at what levels? Provide rationale to support your position.

50. The proposed standard prohibits the use of job rotation for the sole purpose of lowering employee exposures to Cr(VI). Are there any circumstances where this practice should be allowed in order to meet the proposed PEL?

51. OSHA is proposing that employers provide appropriate protective clothing and equipment when a hazard is present or is likely to be present from skin or eye contact with Cr(VI). OSHA would expect an employer to exercise common sense and appropriate expertise to determine if a hazard is present or likely to be present. Is this approach appropriate? Are there other approaches that would be better for characterizing eye and skin contact with Cr(VI)? For example, are there methods to measure dermal exposure that could be used to routinely monitor worker exposure to Cr(VI) that OSHA should consider including in the final standard?

52. For employers whose employees are exposed to Cr(VI), what approaches do you currently use to assess potential hazards from eye or skin contact with Cr(VI)? What protective clothing and equipment do you use to protect employees from eye or skin contact with Cr(VI)? What does this protective clothing and equipment cost? Who pays for the protective clothing and equipment?

53. Should OSHA require the use of protective clothing and equipment for those employees who are exposed to airborne concentrations of Cr(VI) in excess of the PEL? If so, what type of protective clothing and equipment might be necessary?

54. OSHA has proposed to require that employers pay for protective clothing and equipment provided to employees. The Agency seeks comment on this provision, in particular:

a. Should OSHA refrain from requiring employer payment, and follow the outcome of the rulemaking addressing employer payment for personal protective equipment (64 FR 15401 (3/31/99))?

b. Are there circumstances where employers should not be required to pay for clothing and equipment used to protect employees from Cr(VI) hazards, such as situations where it is customary for employees to provide their own protective clothing and equipment (i.e., “tools of the trade”)?

c. OSHA realizes that there is frequent turnover in the construction industry, where employees frequently move from jobsite to jobsite. This is an important factor because an employer with a high-turnover workplace would have to buy protective clothing and equipment for more employees if the protective clothing and equipment could only be used by one employee. The Agency requests comment on whether this proposal's requirement for employer payment for protective clothing and equipment is appropriate in the construction industry. Are there any alternative approaches that would be responsive to the turnover situation and would also be protective of construction workers? Are there any other issues specific to the construction industry that OSHA should be consider in this rulemaking?

d. At some ports, employees are hired for jobs in shipyards, longshoring, and marine terminals through a labor pool, and a single employee may work for five different employers in the same week. How do these factors affect who is required to pay for protective clothing and equipment? Are there any other issues specific to shipyards, longshoring, or marine terminals that OSHA should consider in this rulemaking?

55. OSHA is proposing that washing facilities capable of removing Cr(VI) from the skin be provided to affected employees, but does not propose that showers be required. Should OSHA include requirements to provide showers to employees exposed to Cr(VI)? If so, under what circumstances should showers be required? Describe work situations where showers are either unnecessary for employee protection or that present obstacles to their implementation and describe any such obstacles.

56. OSHA has not included housekeeping provisions in the proposed Cr(VI) standard for construction or shipyards. The Agency has made a preliminary determination that the housekeeping requirements proposed for general industry are likely to be difficult to implement in the construction and shipyard environments. Is this an appropriate determination? If not, what practicable housekeeping measures can construction and shipyard employers take to reduce employee exposure to Cr(VI) at the work site? What housekeeping activities are currently being performed?

57. Is medical surveillance being provided to Cr(VI)-exposed employees at your worksite? If so,

a. What exposure levels or other factors trigger medical surveillance?

b. What tests or evaluations are included in the medical surveillance program?

c. What benefits have been achieved from the medical surveillance program?

d. What are the costs of the medical surveillance program? How do your current costs compare with OSHA's estimated unit costs for the physical examination and employee time involved in the medical surveillance program? Please comment on OSHA's baseline assumptions and cost estimates for medical surveillance.

e. How many employees are included in your medical surveillance program?

f. In what North American Industry Classification System (NAICS) code does your workplace fall?

58. OSHA has proposed that medical surveillance be triggered in general industry in the following circumstances: (1) When exposure to Cr(VI) is above the PEL for 30 days or more per year; (2) after an employee experiences signs or symptoms of the adverse health effects associated with Cr(VI) exposure (

e.g.

, dermatitis, asthma); or (3) after exposure in an emergency. OSHA seeks comments as to whether or not these are appropriate triggers for offering medical surveillance and whether there are additional triggers that should be included. Should OSHA require that medical surveillance be triggered in general industry only upon an employee experiencing signs and symptoms of disease or after exposure in an emergency, as in the construction and maritime standards? OSHA also solicits comment on the optimal frequency of medical surveillance.

59. OSHA has proposed that medical surveillance be triggered in construction and shipyards in the following circumstances: (1) after an employee experiences signs or symptoms of the adverse health effects associated with Cr(VI) exposure (

e.g.

, dermatitis, asthma); or (2) after exposure in an emergency. Should medical surveillance in construction or shipyards be triggered by exposure to Cr(VI) above the PEL for 30 days or more per year, as proposed for general industry? OSHA seeks comments as to whether or not the proposed triggers are appropriate for offering medical surveillance and whether there are additional triggers that should be included.

60. OSHA has not included certain biological tests (

e.g.

, blood or urine monitoring, skin patch testing for sensitization, expiratory flow measurements for airway restriction) as a part of the medical evaluations required to be provided to employees offered medical surveillance under the proposed standard. OSHA has preliminarily determined that the general application of these tests is of uncertain value as an early indicator of potential Cr(VI)-related health effects. However, the proposed standard does allow for the provision of any tests (which could include urine or blood tests) that are deemed necessary by the physician or other licensed health care professional. Are there any tests (

e.g.

, urine tests, blood tests, skin patch tests, airway flow measurements, or others) that should be included under the proposed standard's medical surveillance provisions? If there are any that should be included, explain the rationale for their inclusion, including the benefit to worker health they might provide, their utility and ease of use in an occupational health surveillance program, and associated costs.

61. OSHA has not included requirements for medical removal protection (MRP) in the proposed standard. OSHA has made a preliminary determination that there are few instances where temporary worker removal and MRP will be useful. The Agency seeks comment as to whether the final Cr(VI) standard should include provisions for the temporary removal and extension of MRP benefits to employees with certain Cr(VI)-related health conditions. In particular, what endpoints should be considered for temporary removal and for what maximum amount of time should MRP benefits be extended? OSHA also seeks information on whether or not MRP is currently being used by employers with Cr(VI)-exposed workers, and the costs of such programs.

62. OSHA has proposed that employers provide hazard information to employees in accordance with the Agency's Hazard Communication standard (29 CFR 1910.1200), and has also proposed additional requirements regarding signs, labels, and additional training specific to work with Cr(VI). Should OSHA include these additional requirements in the final rule, or are the requirements of the Hazard Communication standard sufficient?

63. OSHA has proposed that bags or containers of laundry contaminated with Cr(VI) bear warning labels. Will this cause you to alter your current laundry practices? Are there laundries in your area that would accept such laundry? Would laundering costs increase? If so, by how much?

64. OSHA requests comment on the time allowed for compliance with the provisions of the proposed standard. Is the time proposed sufficient, or is a longer or shorter phase-in of requirements appropriate? Identify any industries, processes, or operations that have special needs for additional time, the additional time required and the reasons for the request.

65. Some other OSHA health standards have included appendices that address topics such as the hazards associated with the regulated substance, health screening considerations, occupational disease questionnaires, and PLHCP obligations. OSHA has not proposed to include any appendices with the Cr(VI) rule because the Agency has made a preliminary determination that such topics would be best addressed with guidance materials. What would be the advantage of including such appendices in the final rule? If you believe they should be included, what information should be included? What would be the disadvantage of including these appendices in the final rule?

III. 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 to promulgate and enforce occupational safety and health standards. 29 U.S.C. 655(a)(authorizing summary adoption of existing consensus and federal standards within two years of Act's enactment), 655(b)(authorizing promulgation of standards pursuant to notice and comment), 654(b)(requiring employers to comply with OSHA standards).

A safety or health standard is a standard “which requires conditions or the adoption of or use of one or more practices, means, methods, operations or processes, reasonably necessary or appropriate to provide safe or healthful employment or places of employment 29 U.S.C. 652(8).

A standard is reasonably necessary or appropriate within the meaning of Section 652(8) if it substantially reduces or eliminates significant risk, and is economically feasible, technologically feasible, cost effective, consistent with prior Agency action or supported by a reasoned justification for departing from prior Agency actions, supported by substantial evidence, and is better able to effectuate the Act's purpose than any national consensus standard it supersedes. See 58 Fed. Reg. 16612-16616 (March 30, 1993).

OSHA has generally considered, at minimum, fatality risk of 1/1000 over a 45-year working lifetime to be a significant health risk.

See

the Benzene standard,

Industrial Union Dep't

v.

American Petroleum Institute,

448 U.S. 607, 646 ((1980); the Asbestos standard,

International Union, UAW

v.

Pendergrass,

878 F.2d 389, 393 (D.C. Cir. 1989).

A standard is technologically feasible if the protective measures it requires already exist, can be brought into existence with available technology, or can be created with technology that can reasonably be expected to be developed.

American Textile Mfrs. Institute

v.

OSHA,

452 U.S. 490, 513 (1981)(“ATMI”) American Iron and Steel Institute v. OSHA, 939 F.2d 975, 980 (D.C. Cir. 1991)(“AISI”).

A standard is economically feasible if industry can absorb or pass on the costs of compliance without threatening its long-term profitability or competitive structure.

See

ATMI, 452 U.S. at 530 n. 55; AISI, 939 F. 2d at 980.

A standard is cost effective if the protective measures it requires are the least costly of the available alternatives that achieve the same level of protection. ATMI, 453, U.S, at 514 n. 32; International

Union, UAW

v.

OSHA,

37 F.3d 665, 668 (D.C., Cir 1994)(“LOTO III”).

All standards must be highly protective. See 58 FR 16614-16615; LOTO III, 37 F. 3d at 669. However, health standards must also meet the “feasibility mandate” of Section 6(b)(7) of the Act, 29 U.S.C. 655(b)(5). Section 6(b)(5) requires OSHA to select “The most protective standard consistent with feasibility” that is needed to reduce significant risk when regulating health standards. ATMI, 452 U.S. at 509.

Section 6(b)(5) also directs OSHA to base health standard on “the best available evidence,” including research, demonstrations, and experiments. 29 U.S.C. 655(b)(5). OSHA shall consider “in addition to the attainment of the highest degree of health and safety protection * * * feasibility and experience gained under this and other health and safety laws.”

Id.

Section 6(b)(7) authorizes OSHA to include among a standard's requirements labeling, monitoring, medical testing and other information gathering and transmittal provisions. 29 U.S.C. 655(b)(7).

Finally, whenever practical, standards shall “be expressed in terms of objective criteria and of the performance desired.”

Id.

IV. Events Leading to the Proposed Standards

OSHA's present standards for workplace exposure to Cr(VI) were adopted in 1971, pursuant to section 6(a) of the OSH Act, from a 1943 American National Standards Institute (ANSI) recommendation originally established to control irritation and damage to nasal tissues (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 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 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 “There 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, p. 8). 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 (HRG), 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, OSHA was sued by HRG for unreasonable delay in issuing a Cr(VI) standard. The U.S. Court of Appeals for the Third Court ruled in OSHA's favor and the Agency continued its data collection and analytic efforts on Cr(VI) (Ex. 35-208, p. 3). OSHA was sued again in 2002 by HRG for continued unreasonable delay in issuing a Cr(VI) standard (Ex. 31-24-1). In August 2002, OSHA published a Request for Information on Cr(VI) to solicit additional information on key issues related to controlling exposures to Cr(VI)(67 FR 54389 (8/22/02)), and on December 4, 2002 announced its intent to proceed with developing a proposed standard (Ex. 307). The Court ruled in favor of HRG on December 24, 2002, ordering the Agency to proceed expeditiously with a Cr(VI) standard (Ex. 35-208). On April 2, 2003 the Court set deadlines of October 4, 2004 for publication of a proposed standard and January 18, 2006 for publication of a final standard (Ex. 35-306).

OSHA initiated Small Business Regulatory Enforcement Act (SBREFA) proceedings in 2003, 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).

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 in early 2004. OSHA representatives met with ACCSH in February 2004 and May 2004 to discuss the rulemaking and receive their comments and recommendations. On February 13, ACCSH recommended that portland cement should be included

within the scope of the proposed standard (Ex. 35-308, pp. 288-293) and that identical PELs should be set for the construction, maritime, and general industries (Ex. 35-308, pp. 293-297). The Committee recommended on May 18 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, MACOSH decided to collect and forward additional exposure monitoring data to OSHA to help the Agency better evaluate exposures to Cr(VI) in shipyards (Ex. 310, 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. 310, p. 227).

V. 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. They range from very soluble to insoluble in water. 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 potassium chromate (lemon yellow crystals), sodium chromate (yellow crystals), and sodium dichromate (reddish to bright orange crystals). Nickel chromate, lead chromate oxide, and zinc chromate are completely insoluble in water. The nickel chromate (black crystals) dissolves in nitric acid and hydrogen peroxide. Lead chromate oxide is a red crystalline powder. The zinc chromate (lemon yellow crystals) decomposes in hot water and is soluble in acids and liquid ammonia. Examples of slightly soluble Cr(VI) compounds are barium (light yellow), calcium (yellow), lead (yellow to orange-yellow), and strontium (yellow) chromates, and zinc chromate hydroxide (yellow). They all exist in solid form as crystals or powder. Potassium zinc chromate hydroxide (greenish-yellow crystals) is also slightly soluble in water.

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 (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 IX of this preamble.

VI. Health Effects

The studies of adverse health effects resulting from exposure to hexavalent chromium (Cr(VI)) in humans and experimental animals are summarized in the section below. Section VI includes 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. This chapter on health effects will not attempt to describe every study ever conducted on Cr(VI) toxicity. Instead, only the most important articles and reviews of studies will be evaluated.

A. Absorption, Distribution, Metabolic Reduction and Elimination

Chromium can exist in a number of valence states from −2 to +6 valence. The most common forms are the elemental metal Cr(0), trivalent Cr(III), and hexavalent Cr(VI). Chromium exists naturally in the environment in

chromite ore as Cr(III). Cr(0) and Cr(VI), as well as Cr(III) are produced during industrial processes. Cr(VI) is the form considered to be the greatest health risk. A small amount of Cr(III) is needed for optimal insulin receptor function in human tissues but much larger amounts may be harmful. Much less is known about the toxicity of Cr(0), but it is believed to be converted to Cr(III) in the body and is not considered to be a serious 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.

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. Schlesinger and Lippman have shown a high degree of correlation between sites of greatest particle deposition in the tracheobronchial airways and increased incidence of bronchial tumors (Ex. 35-102). It is possible to have a buildup of chromium at certain sites in the bronchial tree that could create areas of very high chromium concentration. This would especially be true for occupational environments that are particularly dusty or contain other irritating aerosols.

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 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 anion (CrO

4

)

2−

enter cells via facilitated diffusion through non-specific anion channels (similar to phosphate and sulfate anions). Suzuki

et al.

have demonstrated that Cr(VI) is rapidly and extensively transported to the bloodstream in rats (Ex. 35-97). They exposed rats 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. Bragt and van Dura demonstrated that more soluble chromates are absorbed faster than less soluble chromates (Ex. 35-56). Insoluble chromates are poorly absorbed and therefore have longer resident time in the lungs. They studied the kinetics of three Cr(VI) compounds: Sodium chromate, zinc chromate and lead chromate. 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 due to irritative properties of the zinc chromate used, as it caused hemorrhages in the lungs which were macroscopically visible as early as 24 hours after intratracheal administration.

The studies by Langard

et al.

and Adachi

et al.

provide further evidence of absorption of chromates from the lungs (Exs. 35-93; 189). 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 that are encapsulated in a paint matrix may be released in the lungs (Ex. 31-15, p. 2). LaPuma

et al.

measured the mass of Cr(VI) released from particles into water originating from three types of paint particles: solvent-borne expoxy (25% strontium chromate (SrCrO

4

)), water-borne expoxy (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 m) 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.

A number of questions remain unanswered regarding encapsulated Cr(VI) and bioavailability from the lung. There is a lack of detailed information on the encapsulation process. The efficiency of encapsulation and whether all of the chromate molecules are

encapsulated is not known. The stability of the encapsulated product in physiological and environmental conditions has not been demonstrated. It would be useful to know if any processes can break the encapsulation during its use. Finally, the fate of inhaled encapsulated and unencapsulated Cr(VI) in the respiratory tract as well as the systemic tissues needs to be more 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. 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.

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 exposed to

51

chromium labeled Cr(VI) compounds (Ex. 35-81). In this study radiolabeled sodium chromate solution was dermally applied to guinea pigs and

51

Cr was monitored by scintillation counting in tissues. These studies demonstrate that the absorption of Cr(VI) compounds can take place through the dermal route. Also, the absorption of Cr(VI) can be facilitated by organic solvents.

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. 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). The mechanism by which Cr(VI) is carried across the intestinal wall and the site of absorption are not known and may well depend upon the efficiency of defense mechanisms (Mertz, 1969 as cited in Ex. 19-1).

Kuykendall

et al.

studied the absorption of Cr(VI) in human volunteers after oral administration of potassium dichromate (Ex. 35-77). They reported the bioavailability based on 14-day urinary excretion to be 6.9% (range 1.2-18%) for Cr(VI). Other investigators have also reported absorption of Cr(VI) compounds after oral administration (Exs. 35-76; 31-22-13; 35-91).

Studies with

51

chromium in animals also indicate that chromium and its compounds are poorly absorbed from the gastrointestinal tract after oral exposure. When radioactive sodium chromate (Cr(VI)) was given orally to rats, the amount of chromium in the feces was greater than that found when sodium chromate was injected directly into the small intestine. These results are consistent with evidence that the gastric environment has a capacity to reduce Cr(VI) to Cr(III) and therefore decrease the amount of Cr(VI) absorbed from the GI tract.

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. The binding of chromium compounds by proteins in the blood has been studied in some detail (Exs. 5-24; 35-41; 35-52). It was found that intravenously injected anionic Cr(VI) passes through the membrane of red blood cells and binds to the globin fraction of hemoglobin. It has been hypothesized that before Cr(VI) is bound by hemoglobin, it is reduced to Cr(III) by an enzymatic reaction within red blood cells. Once inside the blood cell, 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). According to Aaseth

et al.

, the intracellular Cr(VI) reduction 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. The highest lung level reported was 456 mg/10 g tissue in the first worker, 178 in the second worker, and 1,920 for the third worker. There were significant chromium levels in the tissue of the second worker even though he had not been exposed to chromium for 18 years. 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. The distribution of Cr(VI) compared with Cr(III) was investigated in guinea pigs after intratracheal instillation of potassium dichromate or chromium trichloride (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. After chromium trichloride instillation, 69% of the dose remained in the lungs at 20 minutes, while only 4% was found in the blood and other tissues, with the remaining 27% cleared from the lungs and swallowed. The only tissue that contained a significant amount of chromium two days after instillation of chromium trichloride was the spleen. After 30 and 60 days, 30 and 12%, respectively, of the Cr(III) was retained in the lungs, while only 2.6 and 1.6%, respectively, of the Cr(VI) dose was retained in the lungs.

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 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. 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). As discussed earlier, Cr(VI) is also reduced to Cr(III) in the gastric environment by the gastric juice (Ex. 35-85) and ascorbate after oral exposure (Ex. 35-82).

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 0.05-1.7 mg Cr(III)/m

3

as chromium sulfate and 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) and 92 days for Cr(III) (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 less 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 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

O'Flaherty developed physiologically-based pharmacokinetic (PBPK) models 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. Soluble Cr(VI) compounds enter the bloodstream more readily than highly insoluble Cr(VI) compounds. 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, Maryland and one in Painesville, Ohio 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, Ohio 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 consistently elevated lung cancer mortality reported in these cohorts and the significant upward trends with duration of employment and cumulative exposure provide some of the strongest evidence that Cr(VI) be regarded as carcinogenic to workers. A summary of selected human epidemiologic studies in chromate production workers is presented in Table VI-1.

Table VI-1.—Summary of Selected Epidemiologic Studies of Lung Cancer in Workers Exposed to Hexavalent Chromium—Chromate Production

Reference/exhibit number

Study population

Reference population

Chromium (VI) exposure

Lung Cancer Risk

Hayes

et al.

(1979, Ex. 7-14)

Braver

et al.

(1985, Ex. 7-17).

1803 male workers initially employed 3 or more months 1945-1974 at old and new Baltimore MD production facility; follow-up through 1977

Baltimore City mortality

Primarily sodium chromate and dichromate production. Avg Cr(VI) of 21 to 413 μg/m

3

and avg duration 1.6 yr to 13 yr depending on subcohort, plant, and year employed

—O/E of 2.0 (p<0.01) based on 59 lung cancer deaths.

—Increased risk with duration of employment.

Gibb

et al.

(2000, Ex. 31-22-11)

2357 male workers initially employed 1950-1974 only at new Baltimore MD production facility; follow-up through 1992

U.S. mortality

Primarily sodium chromate and dichromate. Mean cumulative Cr(VI) of 0.070 mg/m

3

− yr and work duration of 3.1 yr

—O/E of 1.86 (p<0.01) based on 71 lung cancer deaths.

—Significant upward mortality trend with cumulative Cr(VI) exposure.

Mancuso (1997, Ex. 23)

Mancuso (1975, Ex. 7-11).

Mancuso and Heuper (1951, Ex. 7-13).

Bourne and Yee (1950, Ex. 7-98).

332 male workers employed at Painesville OH facility 1931-1937; follow-up through 1993

Mortality rate directly calculated using the distribution of person years by age group for the entire exposed population as the standard

Primarily sodium chromate and dichromate production with some calcium chromate as a result of using high lime process. Most cumulative soluble Cr(VI) between 0.25 and 4.0 mg/m

3

− yr based on 1949 survey

O/E not calculated but significant increase in age-adjusted lung cancer death rate with cumulative chromium exposure based on 66 deaths.

Luippold

et al.

(2003, Ex. 31-18-4)

492 male workers employed one year between 1940 and 1972 at Painesville OH facility; follow-up through 1997

U.S. and Ohio Mortality Rates

Primarily sodium chromate and dichromate production with minor calcium chromate. Mean cumulative soluble Cr(VI) of 1.58 mg/m

3

− yr

—O/E of 2.41(p<0.01) based on Ohio rates and 51 deaths.

—Significant upward mortality trend with cumulative Cr(VI) exposure

Davies

et al.

(1991, Ex. 7-99)

Alderson

et al.

(1981, Ex. 7-22).

Bistrup and Case (1956, Ex. 7-20).

2298 male chromate production workers employed for one year between 1950 and 1976 at three different UK plants; follow-up through 1989

Cancer mortality of England, Wales and Scotland and unexposed local workers

Principally sodium chromate and dichromate production with some calcium chromate before switch from high lime to no lime process. Avg soluble Cr(VI) in early 1950s from 2 to 880 μg/m

3

depending on job

—O/E of 1.97 (p<0.01) pre-process change based on 175 deaths.

—SMR of 1.02 (NS) post-process change based on 14 deaths.

—Increased risk for high exposed compared with less exposed.

Korallus

et al.

(1993, Ex. 7-91).

Korallus

et al.

(1982, Ex. 7-26).

1417 chromate production workers employed for one year between 1948 and 1987 at two different German plants; follow-up through 1988

Mortality rates for North Rhine-Westphalia region of Germany where plants located

Principally sodium chromate and dichromate production with some calcium chromate before switch from high lime to no lime process. Annual mean Cr(VI) between 6.2 and 38 μg/m

3

after 1977. Cr(VI) exposure not reported before 1977

—O/E of 2.27 (p<0.01) pre-process change based on 66 deaths.

—O/E of 1.25 (NS) post-process change based on 9 deaths.

Observed/Expected (O/E)

Relative Risk (RR)

Not Statistically Significant (NS)

Odds Ratio (OR)

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 was abstracted from plant records, but was not utilized in any analyses since the investigators thought it “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 × 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 1950-1959, 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 μg/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.

In an attempt 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.

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.

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). 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. SMRs were not adjusted for smoking.

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

/m

3

-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 asking 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 are 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 suggests that Gibb's use of U.S. and Maryland mortality rates for developing expectations for the SMR analysis was inappropriate and 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 employee's 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 <1 year and for those who worked one year or more. Exponent defined short-term workers as those who worked a minimum of 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 (<07.2 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 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 is 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 preamble section VII.C of the preliminary quantitative risk assessment.

The exposure matrix of Gibb

et al.

does utilize a unique 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 still 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.

Despite the potential methodological limitations of the Gibb study, this 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 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 VII on the preliminary 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 1989 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. 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 administered 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 age was 42 years and mean duration of employment was 9.5 years. Two thirds of the workers had accumulated less than 0.01mg/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.

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. 35-245). 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 1

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