`[Federal Register Volume 62, Number 7 (Friday, January 10, 1997)]
[Rules and Regulations]
[Pages 1494-1619]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-198]



[[Page 1493]]

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Part II





Department of Labor





_______________________________________________________________________



Occupational Safety and Health Administration



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29 CFR Parts 1910, 1915 and 1926



Occupational Exposure to Methylene Chloride; Final Rule

  Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules 
and Regulations  

[[Page 1494]]



DEPARTMENT OF LABOR

Occupational Safety and Health Administration

29 CFR Parts 1910, 1915 and 1926

RIN 1218-AA98


Occupational Exposure to Methylene Chloride

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

ACTION: Final rule.

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

SUMMARY: The Occupational Safety and Health Administration (OSHA) 
hereby amends its existing regulations for employee exposure to 
methylene chloride (MC), (also known as methylene dichloride, 
dichloromethane or DCM). OSHA has determined, based on animal and human 
data, that the current permissible exposure limits (PELs) allow 
employee exposure to a significant risk of material impairment of 
health. OSHA is reducing the existing 8-hour time-weighted average 
(TWA) exposure from 500 parts MC per million parts (ppm) of air to 25 
ppm. Also, OSHA is deleting the existing ceiling limit concentration of 
1,000 ppm and is reducing the existing short-term exposure limit from 
2,000 ppm (measured over five minutes in any 2 hour period) to 125 ppm, 
measured as a 15-minute TWA. In addition, the Agency is setting an 
``action level'' of 12.5 ppm, measured as an 8-hour TWA. The final rule 
also contains provisions for exposure control, personal protective 
equipment, employee exposure monitoring, training, medical 
surveillance, hazard communication, regulated areas, and recordkeeping. 
Together, these provisions will substantially reduce significant risk 
to the extent feasible. This standard applies to all employment in 
general industry, shipyards and construction. Small employers, for 
purposes of the Regulatory Flexibility Act, 5 U.S.C. 601, are defined 
as firms with fewer than twenty employees. The final standard will 
prevent an estimated 31 cancer deaths per year and an estimated three 
deaths per year from acute central nervous system and 
carboxyhemoglobinemic effects, and will also reduce cardiovascular 
disease and material impairment of the central nervous system. The 
estimated cost, on an annualized basis, is $101 million per year.

DATES: This final rule becomes effective April 10, 1997.
    Compliance: Start-up dates for specific provisions are set in 
Sec. 1910.1052(n) of the regulatory text. However, affected parties do 
not have to comply with the information collection requirements in 
Sec. 1910.1052(d) exposure monitoring, Sec. 1910.1052(e) regulated 
areas, Sec. 1910.1052(j) medical surveillance, Sec. 1910.1052(l) 
employee information and training; and Sec. 1910.1052(m) recordkeeping, 
until the Department of Labor publishes in the Federal Register the 
control numbers assigned by the Office of Management and Budget (OMB). 
Publication of the control numbers notifies the public that OMB has 
approved these information collection requirements under the Paperwork 
Reduction Act of 1995.
    Comments: Interested parties may submit comments on the information 
collection requirements for this standard until March 11, 1997.

ADDRESSES: In compliance with 28 U.S.C. 2112(a), the Agency designates 
the Associate Solicitor for Occupational Safety and Health, Office of 
the Solicitor, Room S-4004, U.S. Department of Labor, 200 Constitution 
Avenue, NW., Washington, D.C. 20210, as the recipient of petitions for 
review of the standard.
    Comments on the paperwork requirements of this final rule are to be 
submitted to the Docket Office, Docket No. ICR96-15, U.S. Department of 
Labor, Room N-2625, 200 Constitution Ave., NW., Washington D.C. 20210, 
telephone (202) 219-7894. Written comments limited to 10 pages or less 
in length may also be transmitted by facsimile to (202) 219-5046.
    Copies of the referenced information collection request are 
available for inspection and copying in the Docket Office and will be 
mailed immediately to persons who request copies by telephoning Vivian 
Allen at (202) 219-8076. For electronic copies of the Methylene 
Chloride Final Standard and the Information Collection Request, contact 
OSHA's WebPage on Internet at http://www.osha.gov/.

FOR FURTHER INFORMATION CONTACT: Bonnie Friedman, Director, OSHA Office 
of Public Affairs, Room N-3647, U.S. Department of Labor, 200 
Constitution Avenue, NW, Washington, D.C. 20210; Telephone (202) 219-
8148.

SUPPLEMENTARY INFORMATION:

Collections of Information: Comment Request

    The Department of Labor, as part of its continuing effort to reduce 
paperwork and respondent burden, conducts a preclearance consultation 
program to provide the general public and Federal agencies with an 
opportunity to comment on proposed and/or continuing collections of 
information in accordance with the Paperwork Reduction Act of 1995 
(PRA95) (44 U.S.C. 3506(c)(2)(A)). This program helps to ensure that 
requested data can be provided in the desired format, reporting burden 
(time and financial resources) is minimized, collection instruments are 
clearly understood, and the impact of collection requirements on 
respondents can be properly assessed. Currently, OSHA is soliciting 
comments concerning the proposed approval for the paperwork 
requirements of the Methylene Chloride Final Standard. Written comments 
should:
     Evaluate whether the proposed collection of information is 
necessary for the proper performance of the functions of the agency, 
including whether the information will have practical utility;
     Evaluate the accuracy of the agency's estimate of the 
burden of the proposed collection of information, including the 
validity of the methodology and assumptions used;
     Enhance the quality, utility, and clarity of the 
information to be collected; and
     Minimize the burden of the collection of information on 
those who are to respond, including through the use of appropriate 
automated, electronic, mechanical, or other technological collection 
techniques or other forms of information technology, e.g., permitting 
electronic submissions of responses.
    Background: The Methylene Chloride Standard and its information 
collection requirements are designed to provide protection for 
employees from adverse health effects associated with occupational 
exposure to MC. The standard requires employers to monitor employee 
exposure to MC and inform employees of monitoring results. If 
monitoring results are above the 8-hour TWA PEL or the STEL, then 
employers must also inform employees of the corrective action that will 
be taken to reduce employee exposure to or below the 8-hour PEL or 
STEL. Employers may also be required to provide medical surveillance to 
employees who are or may be exposed to MC. Employers are also required 
to provide information and training to employees on the following: 
health effects of MC, specifics regarding use of MC in the workplace, 
the contents of the standard, and means the employee can take to 
protect themselves from overexposure to MC.
    Current Actions: This notice requests public comment on the 
paperwork requirements in the Methylene Chloride Final Standard. The 
Agency previously sought clearance on three Methylene

[[Page 1495]]

Chloride Notice of Proposed Rulemaking Information Collection Requests: 
Shipyards, 1218-0177; Construction, 1218-0178; and General Industry, 
1218-0179. Since the information requirements are identical for each 
industry, the Agency has combined these three packages into one 
entitled Methylene Chloride Sec. 1910.1052, OMB number 1218-0179.
    Type of Review: Revision of a currently approved collection.
    Agency: Occupational Safety and Health Administration.
    Title: Methylene Chloride Sec. 1910.1052.
    OMB Number: 1218-0179.
    Agency Number: Methylene Chloride Docket Number H-71.
    Recordkeeping: Employers must maintain employee medical records for 
at least the duration of employment plus thirty years. Employee 
exposure monitoring records must be maintained for at least 30 years. 
Objective data, data showing that any materials in the workplace 
containing MC will not release MC at levels which exceed the action 
level or the STEL under foreseeable condition of exposures, must be 
maintained as long as the employer is relying on the data in support of 
the initial monitoring exemption.
    Affected Public: Business or other for-profit, Federal government, 
State and Local governments.
    Total Respondents: 92,000.
    Frequency: On Occasion.
    Total Responses: Initial 719,948; Recurring 299,620.
    Average Time per Response: 0.26 hour.
    Estimated Total Burden Hours: Initial 188,728; Recurring 74,299.
    Estimated Total Burden Cost: Initial $32,496,380; Recurring 
$12,282,420.
    Comments submitted in response to this notice will be summarized 
and/or included in the request for the Office of Management and Budget 
approval of the information collection request; they will also become a 
matter of public record.

Federalism

    This standard has been reviewed in accordance with Executive Order 
12612, 52 FR 41685 (October 30, 1987), regarding Federalism. This Order 
requires that agencies, to the extent possible, refrain from limiting 
State policy options, consult with States prior to taking any actions 
that would restrict State policy options, and take such actions only 
when there is a clear constitutional authority and the presence of a 
problem of national scope. The Order provides for preemption of State 
law only if there is a clear Congressional intent for the Agency to do 
so. Any such preemption is to be limited to the extent possible.
    Section 18 of the Occupational Safety and Health Act (OSH Act), 
expresses Congress' clear intent to preempt State laws with respect to 
which Federal OSHA has promulgated occupational safety or health 
standards. Under the OSH Act, a State can avoid preemption only if it 
submits, and obtains Federal approval of, a plan for the development of 
such standards and their enforcement. Occupational safety and health 
standards developed by such State Plan-States must, among other things, 
be at least as effective in providing safe and healthful employment and 
places of employment as the Federal standards. Where such standards are 
applicable to products distributed or used in interstate commerce, they 
may not unduly burden commerce and must be justified by compelling 
local conditions (See section 18(c)(2)).
    The final MC standard is drafted so that employees in every State 
will be protected by general, performance-oriented standards. States 
with occupational safety and health plans approved under section 18 of 
the OSH Act will be able to develop their own State standards to deal 
with any special problems which might be encountered in a particular 
state. Moreover, the performance nature of this standard, of and by 
itself, allows for flexibility by States and employers to provide as 
much leeway as possible using alternative means of compliance.
    This final MC rule addresses a health problem related to 
occupational exposure to MC which is national in scope.
    Those States which have elected to participate under section 18 of 
the OSH Act would not be preempted by this regulation and will be able 
to deal with special, local conditions within the framework provided by 
this performance-oriented standard while ensuring that their standards 
are at least as effective as the Federal Standard.

State Plans

    The 23 States and two territories with their own OSHA-approved 
occupational safety and health plans must adopt a comparable standard 
within six months of the publication of this final standard for 
occupational exposure to methylene chloride or amend their existing 
standards if it is not ``at least as effective'' as the final Federal 
standard. The states and territories with occupational safety and 
health state plans are: Alaska, Arizona, California, Connecticut (for 
State and local government employees only), Hawaii, Indiana, Iowa, 
Kentucky, Maryland, Michigan, Nevada, New Mexico, New York (for State 
and local government employees only), North Carolina, Oregon, Puerto 
Rico, South Carolina, Tennessee, Utah, Vermont, Virginia, the Virgin 
Islands, Washington, and Wyoming. Until such time as a State standard 
is promulgated, Federal OSHA will provide interim enforcement 
assistance, as appropriate, in these states and territories.

Unfunded Mandates

    The MC final rule has been reviewed in accordance with the Unfunded 
Mandates Reform Act of 1995 (UMRA) (2 U.S.C. 1501 et seq.) and 
Executive Order 12875. As discussed below in the Summary of the Final 
Economic Analysis (FEA) (Section VIII of this document), OSHA estimates 
that compliance with the revised MC standard will require the 
expenditure of slightly more than $100 million each year by employers 
in the private sector. Therefore, the MC final rule establishes a 
federal private sector mandate and is a significant regulatory action, 
within the meaning of Section 202 of UMRA (2 U.S.C. 1532). OSHA has 
included this statement to address the anticipated effects of the MC 
final rule pursuant to Section 202.
    OSHA standards do not apply to state and local governments, except 
in states that have voluntarily elected to adopt an OSHA State Plan. 
Consequently, the MC standard does not meet the definition of a 
``Federal intergovernmental mandate'' (Section 421(5) of UMRA (2 U.S.C. 
658(5)). In addition, the Agency has concluded, based on review of the 
rulemaking record, that few, if any, of the affected employers are 
state, local and tribal governments. Further, OSHA has found that any 
impact on such entities would be insignificant. In sum, the MC standard 
does not impose unfunded mandates on state, local and tribal 
governments.
    The anticipated benefits and costs of this final standard are 
addressed in the Summary of the FEA (Section VIII of this document), 
below, and in the FEA [Ex. 129]. In addition, pursuant to Section 205 
of the UMRA (2 U.S.C. 1535), having considered a reasonable number of 
alternatives as outlined in this Preamble and in the FEA [Ex. 129], the 
Agency has concluded that the final rule is the most cost-effective 
alternative for implementation of OSHA's statutory objective of 
reducing significant risk to the extent feasible. This is discussed at 
length in the FEA [Ex. 129] and in the Summary and Explanation (Section 
X of

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this document) for the various provisions of the MC standard.

I. General

    The preamble to the final rule on occupational exposure to 
Methylene Chloride (MC) discusses the events leading to the final rule, 
the physical and chemical properties of MC, the health effects of 
exposure, the degree and significance of the risk presented by MC 
exposure, the Final Economic Analysis and Regulatory Flexibility 
Analysis, and the rationale behind the specific provisions set forth in 
the final standard. The discussion follows this outline:

I. General
II. Pertinent Legal Authority
III. Events Leading to the Final Standard
IV. Chemical Identification
V. Health Effects
VI. Quantitative Risk Assessment
VII. Significance of Risk
VIII. Summary of the Final Economic Analysis
IX. Environmental Impact
X. Summary and Explanation of the Final Standard
    A. Scope and Application
    B. Definitions
    C. Permissible Exposure Limits
    D. Exposure Monitoring
    E. Regulated Areas
    F. Methods of Compliance
    G. Respiratory Protection
    H. Protective Clothing and Equipment
    I. Hygiene Facilities
    J. Medical Surveillance
    K. Hazard Communication
    L. Employee Information and Training
    M. Recordkeeping
    N. Dates
    O. Appendices
XI. Authority and Signature
XII. Final Rule and Appendices
Appendix A: Substance Safety Data Sheet and Technical Guidelines for 
Methylene Chloride
Appendix B: Medical Surveillance for Methylene Chloride
Appendix C: Questions and Answers--Methylene Chloride Control in 
Furniture Stripping

II. Pertinent Legal Authority

    The purpose of the Occupational Safety and Health Act, 29 U.S.C. 
651 et seq. (``the Act'') is to ``assure so far as possible every 
working man and woman in the nation safe and healthful working 
conditions and to preserve our human resources.'' 29 U.S.C. 
Sec. 651(b). To achieve this goal, Congress authorized the Secretary of 
Labor to promulgate and enforce occupational safety and health 
standards. U.S.C. Secs. 655(a) (authorizing summary adoption of 
existing consensus and federal standards within two years of the 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 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. Sec. 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 purposes than any national consensus standard it 
supersedes. See 58 FR 16612-16616 (March 30, 1993).
    The Supreme Court has noted that a reasonable person would consider 
a fatality risk of 1/1000 to be a significant risk, and would consider 
a risk of one in one billion to be insignificant. Industrial Union 
Department v. American Petroleum Institute, 448 U.S. 607, 646 (1980) 
(the ``Benzene decision''). So a risk of 1/1000 (10-3) represents 
the uppermost end of a million-fold range suggested by the Supreme 
Court, somewhere below which the boundary of acceptable versus 
unacceptable risk must fall. The Court further stated that ``while the 
Agency must support its findings that a certain level of risk exists 
with substantial evidence, we recognize that its determination that a 
particular level of risk is significant will be based largely on policy 
considerations.'' See, e.g., International Union, UAW v. Pendergrass, 
878 F.2d 389 (D.C. Cir. 1989) (formaldehyde standard); Building and 
Constr. Trades Department, AFL-CIO v. Brock, 838 F.2d 1258, 1265 (D.C. 
Cir. 1988) (asbestos standard).
    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 cost 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 668. However, health standards must also meet the 
``feasibility mandate'' of Section 6(b)(5) 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 hazards. ATMI, 452 U.S. 
at 509.
    Section 6(b)(5) also directs OSHA to base health standards on ``the 
best available evidence,'' including research, demonstrations, and 
experiments. 29 U.S.C. Sec. 655(b)(5). OSHA shall consider ``in 
addition to the attainment of the highest degree of health and safety 
protection * * * the latest scientific data * * * feasibility and 
experience gained under this and other health and safety laws.'' Id.
    Section 6(b)(7) of the Act authorizes OSHA to include among a 
standard's requirements labeling, monitoring, medical testing and other 
information gathering and transmittal provisions. 29 U.S.C. 
Sec. 655(b)(7).

III. Events Leading to the Final Standard

    The present OSHA standard for MC requires employers to ensure that 
employee exposure does not exceed 500 ppm as an 8-hour TWA, 1000 ppm as 
a ceiling concentration, and 2000 ppm as a maximum peak for a period 
not to exceed five minutes in any two hours (29 CFR 1910.1000, Table Z-
2). This standard was adopted by OSHA in 1971 pursuant to section 6(a) 
of the OSH Act, 29 U.S.C. 655, from an existing Walsh-Healey Federal 
Standard. The source of this Walsh-Healey Standard [Ex. 7-1] was the 
American National Standards Institute (ANSI) standard for acceptable 
concentrations of MC (ANSI-Z37.23-1969), which was intended to protect 
workers from injury to the neurological system including loss of 
awareness and functional deficits linked to anesthetic and irritating 
properties of MC which had been observed from excessive, acute or large 
chronic exposures to MC in humans and experimental animals.
    In 1946, the American Conference of Governmental Industrial 
Hygienists (ACGIH) recommended a Threshold Limit Value (TLV) of 500 ppm 
for MC [Ex. 2]. In 1975, the ACGIH lowered the

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recommended TLV to 100 ppm [Ex. 7-11].
    In March 1976, the National Institute for Occupational Safety and 
Health (NIOSH) published ``Criteria for a recommended standard for 
Methylene Chloride'' [Ex. 2], which recommended a reduction of 
occupational exposures to MC to 75 ppm as an 8-hour TWA, and a lower 
peak exposure not to exceed 500 ppm. Further exposure reduction based 
on the ambient level of carbon monoxide was also recommended.
    In February 1985, the National Toxicology Program (NTP) reported 
the final results of animal studies indicating that MC is a potential 
cancer causing agent [Ex. 7-8]. Subsequently, the U.S. Environmental 
Protection Agency (EPA), upon receipt of the NTP studies, initiated a 
risk assessment evaluation to determine whether or not MC presents an 
unreasonable risk to human health or the environment and to determine 
if regulatory actions are needed to eliminate or reduce exposures.
    On May 14, 1985, EPA announced its determination that MC was a 
probable human carcinogen. EPA classified MC as Group B2, in accordance 
with its interim guidelines for cancer risk (49 FR 46294), and hence 
announced the initiation of a 180-day priority review (50 FR 20126) 
under section 4(f) of the Toxic Substances Control Act (TSCA). In 
meeting its mandate under section 4(f) of TSCA to initiate a regulatory 
action, on October 17, 1985, EPA published an Advance Notice of 
Proposed Rulemaking (ANPR) (50 FR 42037) for the purpose of collecting 
the necessary information required for initiating a rulemaking. In this 
notice, EPA established December 16, 1985, as its deadline for 
receiving comments.
    On April 11, 1985, the U.S. Consumer Product Safety Commission 
(CPSC) released its risk assessment findings for MC and began to 
consider a regulatory action to ban MC containing products and to 
develop a voluntary hazard communication program for consumers.
    On December 18, 1985, the U.S. Food and Drug Administration (FDA) 
published a proposal to ban the use of MC as an ingredient in aerosol 
cosmetic products (50 FR 51551). This proposal was based on a risk 
assessment that used the NTP animal data.
    On July 19, 1985, Owen Bieber, President of International Union, 
United Automobile, Aerospace and Agricultural Implement Workers of 
America (UAW), petitioned OSHA to act expeditiously on reducing 
workers' exposure to MC. Specifically, Mr. Bieber requested that OSHA: 
(1) Publish a hazard alert; (2) issue an emergency temporary standard 
(ETS); and (3) begin work on a new permanent standard for controlling 
MC exposure. Subsequently, the following unions joined UAW in 
petitioning OSHA to act on revising the current standard:

A. International Union, Allied Industrial Workers of America;
B. Glass, Pottery, Plastics and Allied Workers International Union;
C. United Furniture Workers of America;
D. The Newspaper Guild;
E. Communication Workers of America; and
F. United Steelworkers of America.

    In March 1986, as a preliminary response to this petition, OSHA 
issued ``Guidelines for Controlling Exposure to Methylene Chloride.'' 
That document, which was canceled by OSHA Notice ADM 8 (July 12, 1994), 
provided information to employers and workers on risks of MC exposure 
and methods for controlling such exposure [Ex. 8-11].
    In April 1986, NIOSH published a Current Intelligence Bulletin #46 
(CIB) on MC reflecting the findings of the NTP study [Ex. 8-26]. The 
CIB concluded that MC should be regarded as a potential occupational 
carcinogen and that exposure should be controlled to the lowest 
feasible level.
    On August 20, 1986, the CPSC issued a proposed rule [51 FR 29778] 
``that would declare household products containing other than 
contaminant levels of MC to be hazardous substances.'' The CPSC noted 
the proposal was prompted by evidence that inhalation of MC vapor 
increased the incidence of various malignant and benign tumors in rats 
and mice. Accordingly, the Commission proposed to require that 
household products which can expose consumers to MC vapor be treated as 
hazardous substances and be labeled as provided by section 2(p)(1) of 
the Federal Hazardous Substances Act (FHSA) (15 U.S.C. 1261(p)(1)). The 
FHSA requires the use of labels which (1) indicate that exposure to a 
product may present a cancer risk; (2) explain the factors (such as 
level and duration of exposure) that control the degree of risk; and 
(3) explain the precautions to be taken.
    On November 17, 1986, OSHA denied the petition for an Emergency 
Temporary Standard, but agreed that work on a permanent standard should 
commence [Ex. 3A]. On November 24, 1986, OSHA announced, in an Advance 
Notice of Proposed Rulemaking (ANPR) [51 FR 42257], that it was 
considering revision of the occupational health standard for MC. The 
Agency based this action on animal studies which indicated that the PEL 
of 500 ppm did not provide adequate protection against potential cancer 
risks and other adverse health effects. The ANPR summarized OSHA's 
information regarding the production and use of MC, occupational 
exposure to MC, and the potential adverse health effects associated 
with MC exposure. In addition, the notice invited interested parties to 
submit comments, recommendations, data, and information on a variety of 
issues related to the regulation of MC. OSHA received 43 comments in 
response to the ANPR. Those comments are discussed, as appropriate, 
below.
    On December 5, 1986, the FDA reopened the comment period for 30 
days on the above-cited proposal to ban the use of MC in cosmetic 
products [51 FR 43935]. The reopening enabled interested parties to 
submit comments on studies received after the close of the initial 
comment period regarding MC comparative pharmacokinetics, metabolism, 
and genotoxicity.
    On September 14, 1987, the CPSC issued a statement of 
interpretation and enforcement policy, in lieu of continuing with 
rulemaking, which expressed the Commission's determination that 
consumer products containing MC and capable of exposing consumers to 
significant amounts of MC may pose cancer risk to humans and, 
therefore, are subject to the above- described hazardous substance 
labeling requirements. The CPSC explicitly retained the option of 
resuming the rulemaking if voluntary compliance with and enforcement of 
the Commission's interpretation did not adequately induce firms to 
label their products appropriately.
    In 1988, based on the response to the ANPR, OSHA began contacting 
small businesses and conducting a number of site visits, to develop a 
clear understanding of how revisions to OSHA's MC standard would affect 
small entities. For example, on April 27, 1989, OSHA participated in a 
NIOSH conference on MC controls for the furniture stripping industry 
(54 FR 11811, March 22, 1989) to learn how that industry, which is 
dominated by small businesses, was dealing with MC exposure. That 
conference focused on the progress of a NIOSH pilot program aimed at 
developing affordable engineering controls for the furniture stripping 
industry. OSHA continued to seek input from small businesses throughout 
the MC rulemaking, as discussed below in the Preamble and in the Final 
Economic Analysis [Ex. 129].
    Also, in 1988, ACGIH officially lowered the TLV for MC to 50 ppm as 
an 8-hour TWA. OSHA considered whether the TLV recommended by the

[[Page 1498]]

ACGIH would be an appropriate OSHA standard. The ACGIH is a 
professional society devoted to administrative and technical aspects of 
occupational and environmental health. Voting members of ACGIH are 
scientists who work for government agencies or educational 
institutions. Every year the ACGIH adopts new or revised TLVs for 
several substances by a majority vote, not by consensus. OSHA has not 
adopted the MC TLV (50 ppm) as the 8-hour TWA PEL because the Agency's 
criteria for setting standards differ from those used by the ACGIH. 
OSHA standards must eliminate significant risks to the extent feasible, 
whereas the ACGIH sets limits under which it is believed that nearly 
all workers may be repeatedly exposed day after day without adverse 
health effects. Also, as evidenced by their ``Documentation of the 
TLVs,'' the ACGIH does not perform quantitative risk assessments. This 
difference between OSHA and ACGIH practice is critical because the 
Supreme Court has required OSHA to perform quantitative risk 
assessments when data permit, and to use these assessments to set 
exposure limits.
    On June 29, 1989, the FDA issued a final rule that banned the use 
of MC in cosmetic products [54 FR 27328]. The Agency based its final 
rule on scientific studies that showed inhalation of MC caused cancer 
in laboratory animals. The FDA concluded, accordingly, ``that continued 
use of MC in cosmetic products may pose a significant risk to human 
health * * * '' The Agency considered comments and information 
regarding the application of a physiologically-based pharmacokinetic 
model to the prediction of human cancer risk. The FDA determined that 
the risk assessment developed using animal studies should not be 
changed to reflect the ``pharmacokinetic and metabolic data and 
hypothesized GST metabolic mechanism of carcinogenicity.''
    On August 8, 1990, the Consumer Product Safety Commission (CPSC) 
issued a General Order (55 FR 32282) that required manufacturers, 
importers, packagers and private labelers of consumer products 
containing 1% or more of MC to report to the CPSC information on the 
labeling and marketing of those products. The CPSC indicated that the 
information obtained would aid the Commission in evaluating the CPSC's 
policy concerning the labeling of MC-containing products as hazardous 
substances, pursuant to the Federal Hazardous Substances Act.
    On November 11, 1990, then-President Bush signed the Clean Air Act 
Amendments (CAAA) of 1990. Title VI of the CAAA requires the phaseout 
of ozone-depleting chemicals by the year 2000 (section 604) and 
requires the EPA to determine which alternatives to ozone-depleting 
chemicals are safe for use (section 612). MC was among the potential 
substitutes studied by the EPA. In addition, section 112 of the CAAA 
requires the EPA to address the residual risks of MC and other 
specified Hazardous Air Pollutants (HAPs) by establishing Maximum 
Achievable Control Technology (MACT) standards. In particular, section 
112(d) requires EPA to promulgate National Emission Standards for 
Hazardous Air Pollutants (NESHAP) (40 CFR part 63) over a 10-year 
period. In addition, EPA regulates MC as a priority pollutant under the 
Clean Water Act as amended (33 U.S.C. 1251, et seq.)
    On February 12-13, 1991, EPA convened an international conference 
on ``Reducing Risk in Paint Stripping'' that was well attended by 
representatives of small businesses which use MC or its substitutes in 
a wide range of operations. OSHA actively participated in the workgroup 
and panel discussions to elicit information regarding the anticipated 
impacts of a revised MC standard on paint stripping operations.
    OSHA determined, based on animal and human data, that the existing 
PELs for MC did not adequately protect employee health. Accordingly, on 
November 7, 1991, OSHA issued a notice of proposed rulemaking (NPRM) 
(56 FR 57036) to address the significant risks of MC-induced health 
effects. The proposed rule required employers to reduce occupational 
exposure to MC and to institute ancillary measures, such as employee 
training and medical surveillance, for further protection of MC-exposed 
workers. The provisions of the proposed rule are discussed in detail in 
the Summary and Explanation, Section X, below. The Agency published a 
correction notice on January 6, 1992 (57 FR 387). The NPRM solicited 
comments on the proposed rule and raised 48 specific issues to elicit 
information about MC health effects, use, and exposure controls, as 
well as input regarding the appropriateness and impacts of particular 
provisions. The written comment period, which ended on April 6, 1992, 
produced 58 comments, including several hearing requests.
    On February 11, 1992, then-President Bush announced an accelerated 
phaseout schedule for ozone depleting substances and ordered the EPA to 
accelerate its review of substitutes (such as MC) whose use would 
reduce damage to the ozone layer.
    On May 19, 1992, OSHA presented the MC proposal to the newly 
reconstituted Advisory Committee on Construction Safety and Health 
(ACCSH) for consultation. The Advisory Committee established a MC work 
group to generate information and recommendations regarding MC use and 
exposure in the construction industry.
    In response to the hearing requests and to concerns raised by 
commenters, the Agency issued a notice of informal public hearing (57 
FR 24438, June 9, 1992), which scheduled hearings to start in 
Washington, D.C. on September 16, 1992 and in San Francisco, California 
on October 14, 1992. That notice also reopened the written comment 
period until August 24, 1992. The hearing notice raised 16 issues, 
based on the NPRM comments, which solicited input regarding the human 
health risks of MC exposure and the impact of the proposed rule on MC 
users. San Francisco was selected as a hearing site to facilitate 
participation by small businesses, particularly foam blowers and 
furniture refinishers, for whom attendance at the Washington, D.C. 
hearing would have been economically burdensome.
    On July 28, 1992, the MC work group's report was presented to the 
ACCSH and was adopted as the Advisory Committee's recommendation to 
OSHA. Based on the input from the ACCSH, OSHA issued a supplemental 
hearing notice (57 FR 36964, August 17, 1992) which raised MC use, 
exposure and control issues specific to the construction industry. The 
supplemental notice extended the deadline for submission of comments 
regarding the construction issues until September 22, 1992.
    OSHA convened public hearings in Washington, D.C. on September 16-
24, 1992 and in San Francisco on October 14-16, 1992, with 
Administrative Law Judge James Guill presiding. At the conclusion of 
the hearings, Judge Guill set a post hearing period for the submission 
of additional data, which ended on January 14, 1993, and for the 
submission of additional briefs, arguments and summations, which ended 
on March 15, 1993. The posthearing comment period elicited 35 comments.
    On March 31, 1993, pursuant to section 112 of the CAAA, the EPA 
issued a notice (58 FR 16808) requesting information on the anticipated 
impacts of a National Emission Standard for Hazardous Air Pollutants 
(NESHAP) for the halogenated solvent cleaning-vapor degreasing source 
category. This notice characterized MC as the third most commonly used 
halogenated solvent,

[[Page 1499]]

based on 1991 data. On November 29, 1993, the EPA issued a notice of 
proposed rulemaking (58 FR 62566) describing MACT rules for the use of 
MC and other HAPs in halogenated solvent cleaning-vapor degreasing 
operations.
    On March 11, 1994, OSHA reopened the rulemaking record for 45 days 
(59 FR 11567) to receive public comment on reports related to 
engineering controls for MC exposure in the furniture refinishing 
industry, MC carcinogenicity, and the availability of water-based 
substitutes for MC-based adhesives in the manufacture of flexible foam 
products. In particular, OSHA solicited input regarding the extent to 
which it was feasible for small businesses with furniture stripping 
operations to comply with the proposed PELs using engineering controls 
addressed in an OSHA contractor's report [Ex. 114]. The limited 
reopening, which ended on April 25, 1994, elicited 29 comments.
    OSHA has evaluated the impact of the final rule on the identified 
application groups (except for farm equipment [Ex. 115-23], insofar as 
this rulemaking does not address agricultural employment). The Agency's 
analysis and conclusions are presented in the Final Economic Assessment 
for this rulemaking [Ex.129], summarized in Section VIII, below.
    On March 18, 1994, the EPA issued a final rule (59 FR 13044) which 
addressed the use of MC as a substitute for ozone-depleting chemicals 
being phased out under section 612 of the CAAA of 1990. The EPA has 
found the use of MC to be acceptable in the production of flexible 
polyurethane foam; polyurethane integral skin foams; metal cleaning; 
electronics cleaning; precision cleaning; and adhesives, coatings and 
inks. That Agency expressed concern regarding MC toxicity, stating 
``methylene chloride use will be subject to future controls for 
hazardous air pollutants under Title III section 112 of the CAA. In 
addition, use of the compound must conform to all relevant workplace 
safety standards * * * Use is also subject to waste disposal 
requirements under RCRA (59 FR at 13088).'' The EPA also noted that it 
is encouraging companies to decrease emissions of MC through the ``30/
50'' pollution prevention program, under which companies voluntarily 
commit to reduce emissions 33 percent by the end of 1992 and 50 percent 
by the end of 1995 (59 FR at 13093).
    On April 21, 1994, the Department of Housing and Urban Development 
(HUD) issued a notice (59 FR 19084) announcing that funds were 
available for the removal of lead-based paint. That notice explicitly 
provided that paint removal activities funded by HUD could not use 
products containing MC.
    On May 31, 1994, Judge Guill closed and certified the hearing 
record for OSHA's MC rulemaking.
    Pursuant to section 112(d) of the CAAA, the EPA has already 
finalized NESHAP rulemakings that cover halogenated solvent cleaning 
(59 FR 61801, December 4, 1994, 40 CFR part 63, subpart T), aerospace 
manufacture and rework facilities (September 1, 1995, 40 CFR part 63, 
subpart ) and wood furniture manufacturing (60 FR 62930, December 7, 
1995, 40 CFR part 63, subpart JJ). MC-related NESHAP proceedings for 
several industries (e.g., pharmaceuticals, flexible polyurethane foam, 
polycarbonates and nylon 6 are currently underway.
    Pursuant to its CAAA, CWA, RCRA and PPA mandates, EPA has proposed 
effluent limitation guidelines for the pharmaceutical industry (60 FR 
21592, May 2, 1995) which characterize MC as one of the most 
significant priority pollutants to be addressed under the CWA. In 
particular, EPA has addressed the use of stream stripping and 
distillation technology to recover MC from wastewater for reuse or sale 
for use in other industries. That Agency has also proposed requirements 
for compliance monitoring of MC that, due to dilution with wastewater, 
would be found at levels below current analytical limits of detection.
    OSHA has attempted to consider the foreseeable impact of EPA action 
on the use of MC because EPA-driven changes in such use would affect 
the data on which OSHA relies to estimate the impact of this final 
rule. In brief, while EPA action to reduce HAP exposure may encourage 
employers to reduce or eliminate MC use, simultaneous EPA efforts to 
reduce the emission of ozone-depleting chemicals may encourage 
employers to maintain or increase MC use. Given the time frame for EPA 
action and that Agency's need to coordinate proceedings that arise from 
several statutory mandates, it is inappropriate to draw conclusions 
regarding the impact of EPA regulatory action on the need for OSHA 
action.
    OSHA has also consulted with EPA to determine whether any potential 
overlapping or conflicting requirements exist in OSHA's MC standard and 
various EPA NESHAPs, and has committed to continue working with EPA on 
future NESHAP compliance issues. OSHA discussed the MC regulation with 
project officers for all recent, current and planned NESHAPs projects 
and has determined that there are no overlapping or conflicting 
requirements in the NESHAPs and OSHA's MC standard. Indeed, employers 
can choose among a variety of means to comply which would not entail 
any conflict in OSHA and EPA regulations.
    In particular, OSHA conducted a thorough analysis of the EPA 
Solvent Degreasing NESHAP. OSHA determined, and EPA agreed, that there 
are no conflicting requirements in the two regulations. OSHA does not 
require or recommend specific compliance strategies. One common method 
of reducing worker exposure is local exhaust ventilation. In addition, 
some of the alternative compliance strategies suggested in the EPA 
solvent degreasing NESHAP include reducing room draft. OSHA has 
determined that even if an employer chooses reducing room draft as its 
compliance strategy for the EPA NESHAP, employers may use some local 
exhaust ventilation to reduce worker MC exposures and still be in 
compliance with both the OSHA MC standard and the EPA NESHAP. There are 
also other combinations of compliance strategies that can be utilized 
to comply with both regulations. OSHA plans further discussion of this 
issue in its compliance assistance documents. The purpose of these 
documents is to assist employers in selecting among the many 
appropriate control strategies which satisfy requirements under both 
OSHA and EPA regulations.
    On October 25, 1995, OSHA reopened the rulemaking record (60 FR 
54462) to obtain input regarding studies submitted by the Halogenated 
Solvents Industry Alliance (HSIA) [Ex. 118-125] which address the use 
of animal data to estimate human cancer risk from MC exposure. The 
comments received on those studies [Exs. 126-1 through 126-37] are 
discussed in relation to the Quantitative Risk Assessment (Section VI), 
below.
    The rulemaking record contains 129 exhibits, and 2717 pages of 
hearing transcript. A wide range of employees, employers, union 
representatives, trade associations, government agencies and other 
interested parties contributed to the development of the rulemaking 
record. The Agency appreciates these efforts to help OSHA develop a 
record that provides a sound basis for the promulgation of this final 
rule.
    Throughout the ten years since OSHA initiated MC proceedings, the 
Agency has sought and evaluated input regarding the anticipated impact 
of a MC health standard on small entities. For example, Issue K of 
OSHA's Advance Notice of Proposed

[[Page 1500]]

Rulemaking for MC (ANPRM) (51 FR 42257, November 24, 1986) solicited 
comments, recommendations, data and information regarding the 
anticipated impacts of a MC standard on small entities. Responses from 
manufacturers of flexible polyurethane foam [Exs. 10-4 and 10-17] and 
industrial paint removers [Ex. 10-7] indicated that rulemaking 
regarding MC would affect small entities. Based on the response to the 
ANPRM, OSHA initiated contacts with small businesses and conducted a 
number of site visits, to develop a clear understanding of how 
revisions to OSHA's MC standard would affect small entities.
    Based on OSHA's contacts with small business and the response to 
the ANPRM, the Preliminary Regulatory Impact Analysis (PRIA) for the MC 
NPRM (56 FR 57036, November 7, 1991) considered small firms to be those 
with fewer than 20 total employees. In addition, the PRIA estimated 
that 45 percent of establishments using MC were ``small businesses.''
    Issue 25 of the NPRM for MC stated that OSHA had analyzed the 
impacts of the proposed rule on small businesses and had adapted the 
standard to take into account the circumstances of small businesses, 
where appropriate. The performance-oriented language covering the 
demarcation of regulated areas (proposed paragraph (e)(4)) and the 30/
10 days of exposure thresholds for medical surveillance (proposed 
paragraph (i)(1)(i)) reflected the Agency's determination to avoid 
imposing unnecessary burdens on small entities. In addition, Issue 25 
solicited information regarding anticipated small business impacts so 
that OSHA could update the initial regulatory flexibility analysis 
performed pursuant to 5 U.S.C. 604 of the Regulatory Flexibility Act.
    Small businesses, particularly in the furniture refinishing [Exs. 
19-1, 19-4, 19-6, 19-8, 19-10 and 19-11] and polyurethane foam blowing 
industries [Ex. 19-3], expressed concern that the proposed rule would 
impose excessive compliance burdens on their operations. Based in part 
on these concerns, the Agency convened informal public hearings (57 FR 
24438, June 9, 1992) in Washington, D.C. and San Francisco, CA. San 
Francisco was selected as a hearing site to facilitate participation by 
small businesses, particularly foam blowers and furniture refinishers, 
for whom attendance at the Washington, D.C. hearing would have been 
economically burdensome.
    Hearing Notice Issue 8 solicited comments and testimony, with 
supporting documentation, regarding the impact of the proposed rule on 
small businesses, particularly in the furniture refinishing sector. A 
significant number of small businesses participated in the Washington, 
D.C. and San Francisco hearings, providing OSHA with useful testimony 
and posthearing submissions. For example, Harold Markey of the Markey 
Restoration Company proposed [Tr. 2660, 2672, 10/16/92] that 
``furniture refinishing businesses be exempt from [25 ppm PEL] due to 
the financial hardship that enforcement would cause.'' In addition, Mr. 
Markey expressed appreciation for OSHA's efforts to facilitate his 
participation in the hearing. As discussed above, OSHA subsequently 
solicited (59 FR 11567, March 11, 1994) additional input regarding the 
extent to which it was feasible for small businesses with furniture 
stripping operations to comply with the proposed PELs using the 
engineering controls addressed in an OSHA contractor's report [Ex. 
114].
    OSHA has had numerous contacts with furniture refinishers, 
particularly with members of the National Association of Furniture 
Refinishers and Refurbishers (NAFRR), the trade association for the 
industry. In 1994, OSHA was represented at the NAFRR's annual 
conference in Williamsburg, VA. The Agency has continued to provide 
assistance to NAFRR members and other furniture refinishers regarding 
appropriate industrial hygiene measures for workplaces where MC is 
used. For example, OSHA has disseminated information about the 
engineering controls developed by NIOSH for the furniture stripping 
industry. OSHA will continue to strive for a cooperative relationship 
with the small businesses affected by the MC final rule through careful 
compliance with the Small Business Regulatory Enforcement Fairness Act 
(SBREFA) (5 U.S.C. Chapter 8) and the Regulatory Flexibility Act (5 
U.S.C. 601, et seq.), as amended. In addition, the Agency's ``Outreach 
Program'' for the MC final rule will involve a commitment of 
significant consultation and other resources by OSHA and other 
concerned parties, building on the relationships established during the 
rulemaking.
    OSHA has developed a multifaceted outreach plan to provide 
information and compliance assistance to the regulated community. In 
particular, OSHA:

--Has developed a booklet which summarizes the provisions of the MC 
standard;
--Has developed a compliance directive for the MC standard which 
answers compliance-related questions about the MC standard;
--Is developing compliance guides directed at assisting small 
businesses in complying with the MC standard, consistent with section 
212 of the Small Business Regulatory Enforcement Fairness Act of 1996;
--Has recruited interested trade associations to assist in the 
distribution of MC standard-related information, and the convening of 
workshops to help small businesses understand available compliance 
strategies;
--Has spoken to trade association meetings and distributed MC standard-
related materials;
--Has contacted manufacturers of MC to develop a strategy for inclusion 
of OSHA MC-standard information in existing product stewardship 
programs; and
--Is working with individuals interested in conducting workshops for 
impacted industries, such as polyurethane foam manufacturers and 
furniture refinishers, to train small businesses on compliance with 
OSHA and EPA regulations.

    All 50 states and the territories covered by the OSH Act provide 
free consultation services for small businesses to assist them in 
achieving compliance with OSHA standards. Those services are funded by 
federal OSHA but supplied by the states in state plan states and by 
private contractors in other areas. Those consultation services will 
provide free assistance for small business so it will be easier to come 
into compliance with the MC standard.
    OSHA will also set up Cooperative Assessment Programs (CAP's) for 
individual employers to assist them in achieving compliance in a 
reasonable manner. In a CAP, an OSHA industrial hygienist works with 
the employer and employee representatives, to determine a reasonable 
number of cost-effective engineering controls and work practices to 
bring the employer into compliance. A reasonable schedule is determined 
for the implementation of those controls. Good faith efforts to 
implement a CAP are generally considered to be in compliance with the 
provisions of the standard. OSHA has had success in implementing CAP's 
for the arsenic, lead and other standards. Employers have found that 
working with OSHA or CAP's has led to cost effective compliance with 
OSHA standards.

IV. Chemical Identification

    Methylene chloride (MC), also called dichloromethane (DCM) 
[Chemical Abstracts Service Registry Number 75-09-2] is a halogenated 
aliphatic hydrocarbon with a chemical formula of CH2Cl2, a 
molecular weight of 84.9, a

[[Page 1501]]

boiling point of 39.8 deg.C (104 deg.F) at 760 mm Hg, a specific 
gravity of 1.3, a vapor density of 2.9 and a vapor pressure of 350 mm 
Hg at 20 deg.C (68 deg.F). Concentration of MC in saturated air at 
25 deg.C reaches 550,000 ppm. MC has low water solubility (1.3 gm per 
100 gm of water at 20 deg.C), an extensive oil and fat solubility, and 
a low flammability potential. It is used as a flame suppressant in 
solvent mixtures (lower explosive limit of 12% and upper explosive 
limit of 19%). It is a colorless volatile liquid with a chloroform-like 
odor and its odor threshold varies between 100 and 300 ppm. Contact 
with strong oxidizers, caustics and active metal powder may cause 
explosions and fires. Decomposition products during combustion or fire 
include phosgene, hydrogen chloride and carbon monoxide.

V. Health Effects

A. Introduction

    The toxicology of MC is summarized below. A more detailed review of 
MC toxicology can be found in the NPRM [56 FR 57036].

B. Absorption and Disposition of Methylene Chloride

    Inhalation is the most significant route of entry for MC in 
occupational settings. The quantity of MC taken into the body depends 
on the concentration of MC in inspired air, the breathing rate, the 
duration of exposure to MC, and the solubility of MC in blood and 
tissues. Because MC is volatile, inhalation exposures to MC can be 
quite high, especially in poorly ventilated spaces.
    Dermal absorption of MC is a slow process relative to inhalation. 
In the NPRM, OSHA described the rate of skin absorption of pure MC as 
insignificant relative to inhalation. In contrast, Mr. Harvey Clewell, 
in comments prepared for the U.S. Navy [Ex. 19-59], stated that 
substantial occupational exposure could occur through the dermal route 
when the employee is exposed to high concentrations of MC vapor and 
protective clothing is not worn [Ex. 19-59]. Mr. Clewell provided a 
physiologically-based pharmacokinetic (PBPK) model to describe the 
potential absorption through skin exposed to high vapor concentrations 
of MC. Where the employee is protected from inhalation exposure by use 
of an air-supplied respirator and the skin (exposed surface area = two 
hands) is unprotected in high MC-vapor concentrations, the primary 
route of exposure in this case will be dermal exposure. Mr. Clewell has 
determined that sufficient MC may be absorbed by the dermal route over 
an 8-hour shift to give an internal concentration which would exceed 
that experienced by workers exposed to MC through inhalation of 25 ppm 
for 8 hours.
    In the NPRM, OSHA also indicated that the burning sensation 
associated with dermal exposure to liquid MC would likely lead 
employers and employees to limit skin absorption. However, exposure to 
high concentrations of vapor may not be associated with a burning 
sensation, and there is evidence in the record [Tr. 2468-70, 10/15/92] 
to suggest that employees are exposed to liquid MC without protective 
clothing. OSHA believes that dermal exposure to liquid and high vapor 
concentrations of MC should be limited to the extent feasible to 
protect the employee from overexposure. For this reason, in this 
standard OSHA has required that employers provide personal protective 
clothing and equipment appropriate to the hazard. For example, if an 
employee will be at risk of hand contact with liquid MC, impermeable 
gloves must be provided.

C. Metabolism of MC

    Once MC is absorbed into the body, it is widely distributed in the 
body fluids and in various tissues. The uptake and elimination of MC 
has been well described in human and animal studies [Exs. 7-156, 7-157, 
7-174].
    The carcinogenic mechanism of action for MC has not been clearly 
established. Although it has not been proven whether MC is carcinogenic 
through a genotoxic or non-genotoxic mechanism, current evidence 
supports the hypothesis that MC is a genotoxic carcinogen. Genotoxic 
carcinogens typically are reactive compounds or metabolized to reactive 
compounds. MC is unreactive in the body until it is metabolized. 
Therefore, many investigators believe that one or more of the 
metabolites of MC, and not MC itself, is the ultimate carcinogen.
    It has been established by Kubic and Anders [Ex. 7-167] and Ahmed 
and Anders [Ex. 7-25] that MC is metabolized by rat liver enzymes in 
vitro by two distinct pathways. The first pathway is the mixed function 
oxidase system (MFO pathway) associated with the microsomal cell 
fraction and the second is the glutathione dependent pathway localized 
primarily in the cytoplasm and mediated by glutathione-S-transferase 
(GST pathway). The metabolism of MC is illustrated in Figure 1.

BILLING CODE 4510-26-P

[[Page 1502]]

[GRAPHIC] [TIFF OMITTED] TR10JA97.000


BILLING CODE 4510-26-C

[[Page 1503]]

    The MFO pathway metabolizes MC via a cytochrome-P450 dependent 
oxidative dehalogenation [Ex. 7-167] which produces formyl chloride. 
The formyl chloride decomposes to give chloride ion and carbon 
monoxide. It has been postulated that if the MFO pathway contributes to 
the carcinogenicity of MC, it is through the production of the reactive 
compound, formyl chloride. The end product of the MFO pathway, carbon 
monoxide, can be detected in the blood and breath of humans and animals 
exposed to MC, and has been used as a surrogate measure of MC exposure 
in humans.
    The GST pathway metabolizes MC to formaldehyde and chloride ions 
via a postulated S-chloromethylglutathione conjugate [Ex. 7-25]. 
Formaldehyde is further metabolized to carbon dioxide in mammalian 
systems. Potential reactive metabolites in this pathway are the S-
chloromethylglutathione conjugate and formaldehyde (known to react with 
protein, RNA and DNA).
    Animal data indicate that the MFO pathway is saturated at ambient 
concentrations less than 500 ppm, while the GST pathway remains linear 
throughout the exposure levels examined [Exs. 7-161, 7-171]. Saturation 
of the MFO pathway in humans has been estimated to occur at a level 
which is within the range of the animal data (estimates range from 200 
to 1000 ppm MC) [Exs. 7-114, 7-115, 8-32]. The GST pathway is not 
thought to be saturated for any of the species investigated at doses up 
to 4000 ppm.

D. Carcinogenicity

    The evidence for the carcinogenicity of MC has been derived from 
mutagenicity studies, animal bioassays and human epidemiological 
studies. OSHA analyzed data from each of these sources in determining 
that MC is carcinogenic to test animals and a potential occupational 
carcinogen. The evidence that OSHA evaluated in making this 
determination is summarized below. Additional evidence pertaining to 
the hazard identification of MC is discussed in the Quantitative Risk 
Assessment, Section VI, below.
1. Mutagenicity Studies
    Mutagenicity and genotoxicity studies are useful in describing the 
possible carcinogenic mechanism of action of MC. Evidence for the 
interaction of MC or MC metabolites with DNA (producing mutations or 
toxicity) is consistent with a genotoxic mechanism for the carcinogenic 
action of MC, rather than a non-genotoxic action (i.e., by acting as a 
promoter, increasing cell turnover). The EPA reviewed the literature on 
the mutagenic potential of MC in their ``Health Assessment Document for 
Dichloromethane (Methylene Chloride)'' (HAD) [Ex. 4-5] and studies 
conducted by ECETOC in the ``Technical Analysis of New Methods and Data 
Regarding Dichloromethane Hazard Assessments'' [Ex. 7-129].
    As described in the MC Notice of Proposed Rulemaking (56 FR 57036), 
the documentation of positive responses in the production of mutations 
in bacteria, yeast and Drosophila, chromosomal aberrations in CHO cells 
and sister chromatid exchanges (SCE) in CHO and V79 cells and equivocal 
responses in other systems indicated the potential genotoxicity of MC.
    A paper submitted to the record by Dr. Trevor Green [Ex. L-107], 
for the Halogenated Solvents Industry Alliance (HSIA), investigated the 
role of metabolites of the GST pathway in the bacterial mutagenicity of 
MC. The authors of this study found that in glutathione-deficient 
strains of Salmonella typhimurium there was approximately a two-fold 
decrease in mutations. Mutation rates returned to normal when bacteria 
were supplemented with exogenous glutathione. They also investigated 
whether individual metabolites in the GST pathway were likely to be 
responsible for mutagenesis. Experiments in S. typhimurium strains were 
consistent with the S-chloromethylglutathione conjugate as the 
mutagenic moiety. Experiments in Escherichia coli strains implicated 
formaldehyde as the active mutagen. Overall, these results support the 
hypothesis that MC may act as a genotoxic carcinogen, but the ultimate 
reactive species still remains to be identified.
    Dillon et al. [Ex. 21-89] also conducted experiments on the 
mechanism of MC mutagenicity in bacterial cells, using wild type and 
glutathione-deficient Salmonella typhimurium TA100. Dose-related 
increases in mutagenicity were observed with and without metabolic 
(cytosolic or microsomal) activation. The authors characterized the 
mutagenicity as marginally highest in the presence of cytosol at the 
highest MC concentrations. The glutathione-deficient strain was 
slightly less responsive to MC-induced mutation than the wild type. In 
contrast to the study by Green, Dillon et al. found that MC 
mutagenicity was not appreciably enhance by the addition of microsomal 
or cytosolic liver fractions or exogenous glutathione. They concluded 
that it was not clear to what extent, if any, glutathione was involved 
in MC mutagenicity, and noted that ``* * * the residual glutathione 
present in the glutathione-deficient strain may have been sufficient to 
facilitate the mutagenic responses observed.''
    The differing results in these studies suggest that the exact 
mechanism of MC mutagenicity, even in bacterial cells, has not been 
determined with certainty. However, OSHA has concluded that the 
evidence that MC is genotoxic is compelling. Additional studies 
supporting classification of MC as a genotoxin were submitted to the 
Agency in late 1995 and are discussed in the Quantitative Risk 
Assessment, Section VI, below.
2. Animal Studies
    The evidence for the carcinogenicity of MC has been derived 
primarily from data obtained in chronic toxicity studies in rodents. 
Table V-1 contains a summary of the major bioassays. These bioassays 
have been conducted in three rodent species (rat, mouse and hamster) 
using two routes of administration (oral and inhalation) and a wide 
range of doses (from 5 mg/kg/d, oral to 4000 ppm inhaled for 6 hr/d, 5 
d/wk).
    The National Toxicology Program conducted two 2-year inhalation 
bioassays [Ex. 7-8] using B6C3F1 mice and Fischer 344 rats. In the NTP 
mouse study [Ex. 7-8], groups of 50 male and 50 female B6C3F1 mice were 
exposed to 0, 2000 or 4000 ppm MC, 6 hr/day, 5 d/wk for 102 weeks. All 
animals were necropsied and examined histopathologically.
    Treated male and female mice had increased incidences of alveolar 
or bronchiolar adenomas and carcinomas as compared with control 
animals. In addition, there was an increased number of lung tumors per 
tumor-bearing animal (multiplicity of tumors) with increasing dose of 
MC.
    In the liver, the toxic effects of MC were expressed as cytologic 
degeneration in male and female mice which was not present in the 
controls. An increased incidence of hepatocellular adenomas and 
carcinomas (combined) was observed in male mice. The incidence of 
hepatocellular carcinomas in male mice was statistically significantly 
increased at 4000 ppm. Female mice also experienced dose-related 
increases in the incidences of hepatocellular adenomas and carcinomas. 
An increased multiplicity of liver tumors was also found in both male 
and female mice.

[[Page 1504]]



                                Table V-1.--Methylene Chloride Lifetime Bioassays                               
----------------------------------------------------------------------------------------------------------------
                                                  Route and dosing      Dosage (No. of                          
           Reference             Species/strain       schedule             animals)               Comments      
----------------------------------------------------------------------------------------------------------------
NTP (1985)....................  B6C3F1 mouse....  Inhalation 6 hr/  0, 2000, 4000 ppm (50  Lung and liver tumors
                                                   day, 5 days/      mice/ sex/dose).       both sexes, both    
                                                   week.                                    doses.              
Serota (NCA) (1986)...........  B6C3F1 mouse....  Daily in water..  0 (125M, 100F), 60     No tumors observed.  
                                                                     (200M, 100F), 125                          
                                                                     (100M, 50F), 185                           
                                                                     (100M, 50F), and 250                       
                                                                     (125M, 50F) mg/kg/d.                       
NTP (1985)....................  Fischer 344 rat.  Inhalation 6 hr/  0, 1000, 2000 and      Mammary and          
                                                   day, 5 days/      4000 ppm (50 rats/     integumentary       
                                                   week.             sex/dose).             fibromas and        
                                                                                            fibrosarcomas in    
                                                                                            both sexes.         
Burek (DOW) (1980)............  Sprague-Dawley    Inhalation 6 hr/  0, 500, 1500 and 3500  Malignant salivary   
                                 rat.              day, 5 days/      ppm (95 rats/sex/      gland tumors at 3500
                                                   week.             dose).                 ppm, dose-related   
                                                                                            increase in mammary 
                                                                                            tumors.             
Nitschke (DOW) (1982).........  Sprague-Dawley    Inhalation 6 hr/  0, 50, 200 and 500     No tumors observed.  
                                 rat.              day, 5 days/      ppm (70 rats/ sex/                         
                                                   week.             dose.                                      
Serota (NCA) (1986)...........  Fischer 344 rat.  Daily in water..  0, 5, 50, 125 and 250  No tumors observed.  
                                                                     mg/kg/d (135/sex at                        
                                                                     0, 85/sex/dose).                           
Burek (DOW) (1980)............  Syrian Golden     Inhalation 6 hr/  0, 500, 1500, 3500     No tumors observed.  
                                 hamster.          day, 5 days/      ppm (90 hamsters/sex/                      
                                                   week.              dose).                                    
----------------------------------------------------------------------------------------------------------------

    The dose-related increase in the incidence of lung and liver tumors 
in mice, and the increased multiplicity of these tumors, present the 
strongest evidence for the carcinogenicity of MC. NTP concluded that, 
based on the evidence from these lung and liver tumors, there was clear 
evidence of the carcinogenicity of MC in both male and female mice.
    In a second two-year bioassay, the NTP examined the effects of 
inhalation of MC at 0, 1000, 2000 and 4000 ppm in F344 rats [Ex. 7-8]. 
Body weights of all exposure groups were comparable. The highest dose 
female rats experienced reduced survival after 100 weeks of exposure.
    The incidence of mammary tumors in the high dose group in both 
sexes was statistically significantly higher than in control animals 
(concurrent and historical). The incidence of mammary fibroadenomas 
alone and the combined incidence of fibroadenomas and adenomas in male 
and female rats occurred with statistically significant positive 
trends. When subcutaneous fibromas or sarcomas in the male rat, which 
were believed to have originated in the mammary chain, were included in 
comparisons, differences between control and exposed animals were even 
greater.
    MC-exposed male and female rats also showed increased incidence of 
liver effects, characterized by hemosiderosis, hepatocytomegaly, 
cytoplasmic vacuolization and necrosis. Neoplastic nodules alone and 
combined incidence of neoplastic nodules and hepatocellular carcinomas 
in female rats occurred with significant positive trends by the life 
table test. Pair-wise comparisons did not indicate statistically 
significant effects at any one dose. Although this is suggestive of a 
carcinogenic response in the female rat liver, NTP did not use this 
response in their determination of the carcinogenicity of MC.
    NTP based its determination of the carcinogenicity of MC in the rat 
on the mammary tumor incidence data. NTP has concluded that the 
increased incidences of mammary gland tumors in the female rats 
provided clear evidence of carcinogenicity and, in the male rats, some 
evidence of carcinogenicity.
    The Dow Chemical Company [Ex. 7-151] conducted experiments in which 
Sprague-Dawley rats and Syrian Golden hamsters were exposed to 0, 50, 
1500 or 3500 ppm MC, 6 hr/d, 5 d/wk for 2 years. A dose-related 
statistically-significant increase in the number of mammary tumors per 
tumor-bearing female rat was observed. These results support the NTP 
findings of increased mammary tumors in F344 rats. The background 
mammary tumor response in the Sprague-Dawley rat is higher than in F344 
rats, so a quantitative analysis of risk is easier to perform on the 
data from the NTP study.
    A statistically significant increase in male rat salivary tumors 
was also observed in this study, although the authors believed that 
this response should be discounted because of the presence of 
sialodacryoadenitis virus in the rats. OSHA believes that the presence 
of this virus in the rats would complicate the interpretation of the 
data, and so has relied on the NTP studies for its quantitative risk 
assessments.
    No statistically significant excess incidence of tumors was 
observed in either sex of hamsters at any exposure level. This suggests 
that hamsters are less sensitive to the carcinogenic effects of MC than 
either mice or rats. Metabolism data gathered in hamsters indicate that 
hamsters have less capability to metabolize MC by the GST pathway than 
rats or hamsters (or humans). This correlation between lack of GST 
metabolism capacity and lack of tumor response supports the hypothesis 
that GST metabolism is important in MC carcinogenesis and also 
indicates that it would not be protective to use the hamster response 
to MC as the basis for a carcinogenic risk assessment.
    A second inhalation study in Sprague-Dawley rats conducted by 
investigators at Dow Chemical [Ex. 7-173], with exposures up to 500 
ppm, showed an increase in the number of mammary tumors per tumor-
bearing animal in female rats at the highest dose level only. This 
study extended the finding of excess mammary tumors in rats to the 500 
ppm level. However, because of the high background rates of mammary 
tumors in Sprague-Dawley rats, the NTP study showed a clearer dose-
response relationship between MC exposure and incidence of mammary 
tumors.
    In a study conducted for the National Coffee Association [Ex. 7-
180], no statistically significant increased incidence of tumors was 
observed in B6C3F1 mice or F344 rats exposed to up to 250 mg/kg/d MC in 
drinking water. These studies used the drinking water route of exposure 
instead of inhalation and exposed animals to lower doses (on an mg/kg/d 
basis) than the NTP and high-dose Dow studies. These factors most 
likely accounted for the lack of a positive tumor response. The NCA 
studies were used by Reitz et al. in the development of the 
physiologically-

[[Page 1505]]

based pharmacokinetic models for MC. Specifically, these studies helped 
to determine that the lack of tumor development was consistent with 
model predictions of the amount of GST metabolites in lung and liver of 
mice and that the MFO pathway was most likely not primarily responsible 
for the mouse tumor response.
    The Agency believes that the NTP studies show the clearest evidence 
of a carcinogenic effect of MC and has used these studies as the basis 
of its risk assessment for the following reasons: (1) The studies were 
well conducted and underwent extensive peer review. (2) The inhalation 
route of exposure was used, which is the most appropriate route for 
extrapolation to occupational exposures. (3) Dose-related, 
statistically significant increases in tumor incidence were observed in 
both sexes in mice and in female rats. OSHA believes that because of 
the clear tumor response, and quality of the studies, the NTP studies 
provide the best data for quantitative cancer risk assessment. OSHA 
concludes from these studies that MC causes cancer in two species of 
test animals by the inhalation route, and that a clear dose-response 
has been demonstrated.
3. Epidemiological Studies
    Epidemiological studies of occupational exposure to MC have been 
conducted in the manufacturing of triacetate fibers, photographic film 
production, and the manufacturing of paint and varnish. Those studies 
were reviewed by OSHA in the preamble to the proposed rule [56 FR 
57075] and are summarized and updated in this document. In addition, an 
epidemiological study of MC exposure and astrocytic brain cancer is 
reviewed in this text.
    a. Studies of triacetate fiber production workers. Ott et al. [Ex. 
7-76] performed a retrospective cohort study using a cellulose 
diacetate and triacetate plant in Rock Hill, South Carolina to examine 
the effects of MC on a working population. In particular, Ott et al. 
evaluated the effects that were possibly mediated through the 
metabolism of MC to carboxyhemoglobin. Employees at this plant had MC 
exposures close to OSHA's time weighted average (TWA) permissible 
exposure limit (PEL) of 500 ppm. Ott et al. used workers in a plant in 
Narrows, Virginia as a comparison population because it had operations 
similar to those at the Rock Hill plant, but did not use MC. In this 
study, Ott et al. compared the number of deaths within the exposed 
cohort with the United States population and the Narrows, Virginia 
referent group. Ott et al. observed that the overall mortality of the 
cohort was comparable to that of the age, sex, and race-matched U.S. 
population. Comparing exposed and referent cohorts, statistical 
differences in risk were observed in white men for ``all causes'' (risk 
ratio=2.2, p<0.01), ``diseases of the circulatory system'' (risk 
ratio=2.2, p<0.5), and ``ischemic heart disease'' (risk ratio=3.1, 
p<0.05).
    In interpreting the results of this study, Ott noted that there may 
have been differences in hiring practices in the two plants which could 
have contributed to the observed differences in mortality. In their 
conclusion, Ott et al. stated that a healthy worker effect (HWE) and 
the low power of their study did not permit them to dismiss the 
possibility of increased health risks within the working population 
exposed to MC.
    Dr. Mirer of UAW testified [Tr. 1896-6, 9/24/92] that there is some 
evidence that there is excess work-related heart disease mortality in 
epidemiological studies that have observed SMRs greater than 80% for 
ischemic heart disease or any other cardiovascular disease. 
Furthermore, when the MC epidemiological studies are looked at 
together, there is evidence, although limited, that MC exposure has an 
effect on cardiovascular mortality.
    On the other hand, Kodak [Ex. 91D] questioned the appropriateness 
of the referent population in the Rock Hill study, alleging that the 
SMR for ischemic heart disease in the referent population was unusually 
low, and that this fact, rather than an effect of MC exposure, caused 
the observed differences in ischemic heart disease rates.
    In contrast, NIOSH considered the Rock Hill study to be suggestive 
of an effect of MC on risk of cardiac disease. According to NIOSH [Tr. 
879, 9/21/92] the Ott study did not use appropriate analytic techniques 
that would allow the acute effects of MC on cardiac disease risk to be 
examined. Furthermore, NIOSH suggested [Tr. 969, 9/21/92] that future 
epidemiological studies should examine risks from MC exposure during 
the period when employees are actively working.
    In an update to the Rock Hill study, Lanes et al. followed the Ott 
et al. cohort through September 1986 [Ex. 7-260] and December 1990 [Ex. 
106]. Lanes et al. used the population of York County, South Carolina 
as the comparison group. Statistically significant excess mortality was 
observed for cancer of the liver and biliary passages (SMR=5.75, 
CI:1.82-13.78) in the study group. Excess mortality was also observed 
for buccal cavity and pharynx cancer (SMR=2.31, 95% CI:0.39-7.60) and 
melanoma (SMR=2.28, CI:0.38-7.51), although mortality from these causes 
did not reach statistical significance. No excess mortality was 
observed for ischemic heart disease (SMR=0.90, CI:0.62-1.27).
    Examination of the liver and biliary cancers indicated that the 
workers had ten or more years of employment and at least 20 years since 
first employment (4 observed v. 0.35 expected). Three of the four 
employees who died from liver/biliary cancer had tumor sites in the 
intrahepatic and common bile duct, common bile duct, and ampulla of 
Vater. Approximate durations of employment for these three cases were 
28 years, 20 years, and less than one year. No medical record for the 
third case could be obtained. However, an autopsy report indicated 
adenocarcinoma of the liver for this case. To estimate the expected 
number of biliary cancer deaths, Lanes et al. used Surveillance, 
Epidemiology, and End Results (SEER) mortality rates of the continental 
United States. The computed risk estimate, based on 0.15 cases 
expected, was SMR=20 (95% CI:5.2-56.0).
    The authors hypothesized that the biliary duct cancer cases may 
have been due to factors such as oral contraceptive use, gallstones, or 
ulcerative colitis. However, it appeared that medical records showed no 
indication of gallstones or ulcerative colitis in workers who died of 
biliary cancer. Moreover, although these factors were not specifically 
controlled for, there is no reason to believe the rates of these 
factors would be different in the exposed cohort compared to the 
general U.S. population.
    Lanes et al. updated their study through December 31, 1990 [Ex. 
106] using the National Death Index and focused on mortality from 
pancreatic cancer, biliary and liver cancer, and ischemic heart 
disease. Lanes et al. ascertained fifty more death certificates from 
the end of the last follow-up period on September 1, 1986. As before, 
York County, South Carolina was used as the comparison population.
    The overall SMR from all causes of death was 0.90, and for 
malignant neoplasms, the SMR was 0.82. In this follow-up, the SMR for 
liver and biliary cancer dropped from 5.75 to 2.98 (95% CI:0.81-7.63). 
No additional deaths from biliary or liver cancer were observed. In the 
original and updated studies combined, four deaths from biliary/liver 
cancer were observed and 0.64 were expected. Using a Poisson 
distribution, Lanes et al. calculated the probability of failing to 
observe any liver/biliary

[[Page 1506]]

cancer deaths in this update if the ``true'' value of the SMR for 
liver/biliary cancer was 5.75 (from the previous study) and then 
expecting 3.68 deaths in this follow-up (0.64 x 5.75). They estimated 
the probability that this update would have no observed biliary/liver 
cancer deaths if the true SMR were 5.75, as e-3.68=0.025. On the 
other hand, if MC had no effect on liver and biliary cancer mortality, 
Lanes et al. estimated that the probability of observing zero deaths 
would have been 0.527 (e-0.64). Lanes et al. used the likelihood 
ratio (0.527/0.025=21.08) to compare these two hypotheses. The authors 
concluded that the null hypothesis that the SMR=1.0 was 21 times more 
probable than the hypothesis that the SMR=5.75.
    Because of the small number of cases involved and the instability 
of the numbers generated in this type of statistical analysis, OSHA 
believes that this study, overall, is suggestive (but not definitive) 
of an association between occupational exposure to MC and elevation of 
human cancer risk. Furthermore, the Agency has determined that the 
study results are not inconsistent with the results of the NTP cancer 
bioassay.
    Hoechst-Celanese [Ex. 19-65, pp. 6-8; Ex. 19-19] was concerned that 
OSHA considered the incidence of biliary cancer as evidence of a 
positive effect. They argued that the reported excess in biliary tract 
cancer did not support the conclusion that MC exposure is associated 
with an increased risk of cancer. Specifically, they noted that,

    (1) Biliary cancers have not been reported in any of the animal 
cancer studies of MC; (2) no statistically significant increase in 
biliary cancers was seen in the Cumberland study (described below); 
(3) no statistically significant excess in biliary cancers was 
reported in the Kodak studies (described below); (4) It was unlikely 
that MC could have been responsible for the biliary tract cancer 
observed in one employee who had been exposed to MC for less than 
one year; and (5) the Rock Hill study did not control for other 
chemical exposures.

Comments by the Halogenated Solvents Industry Alliance (HSIA) [Ex. 19-
45, p. 47] were in accord with those of Hoechst-Celanese.
    Dr. Shy, on behalf of Kodak, asserted [Tr. 1303, 9/22/92; Ex. 91F] 
that MC exposure failed to meet Bradford Hill's criteria for causality 
(e.g., biological plausibility, dose-response, and consistency) for 
producing biliary tract cancer. Dr. Shy acknowledged that animal 
bioassays have demonstrated liver tumors from MC exposure, but he noted 
that there is no evidence in humans that liver and biliary tract 
cancers have the same etiology. Furthermore, Dr. Shy argued that,
    (1) the results from the Lanes study is not supported by in vitro 
or pharmacokinetic studies.
    (2) a dose-response relationship could not be determined from the 
Lanes study because there were no direct measurements of worker 
exposure to MC.
    (3) the observed association between MC exposure and liver/biliary 
cancer was an isolated finding and the existence of a causal 
relationship could not be concluded.
    (4) the excess biliary tract cancer in the Lanes study was not 
consistent with the other three epidemiological studies (Hearne, 1987, 
1990, 1992; Hearne, 1992; Gibbs, 1992).
    Dr. Shy did recognize that there was a strong association between 
MC exposure and biliary tract cancer in the Lanes study (SMR=20). 
Moreover, the 20 year time interval between first exposure and death 
from biliary tract cancer provided evidence that ``exposure preceded 
cancer with an appropriate interval for induction of the tumor [Ex. 
91F].''
    OSHA disagrees with the conclusions reached by Dr. Shy. The Agency 
believes that the risks of biliary cancer observed in these studies is 
consistent with risks derived from its pharmacokinetic analysis (see 
the Quantitative Risk Assessment, Section VI). Since the occupational 
exposures in these studies are likely to have been among the highest in 
any of the epidemiologic cohorts, there is no evidence that the 
increased biliary/liver cancer result is inconsistent with other 
reported epidemiological findings. Regarding the biological 
plausibility, the Agency notes that human biliary cells appear to 
contain high concentrations of the mRNA for GST (the enzyme many 
investigators believe to be responsible for MC-induced carcinogenesis) 
[Exs. 124 and 124A]. Although this requires more investigation to 
determine if there is a direct relationship, OSHA believes there is a 
plausible mechanistic argument for MC causality in human biliary tract 
cancers. The Agency agrees with Dr. Shy, however, that the lack of 
dose-response data and the small number of cases in this cohort limit 
the strength of conclusions that can be drawn from this study. After 
weighing these considerations, the Agency has determined that there is 
suggestive evidence of a causal role for MC in these cases of biliary 
cancer.
    Gibbs et al. conducted a study of another cellulose acetate and 
triacetate fibers plant in Cumberland, Maryland [Ex. 54] to evaluate 
the possible relationship between MC exposure and biliary/liver cancer. 
This plant, which ceased to operate in 1982, had operations similar to 
the plant in Rock Hill, and it was assumed to have had similar MC 
exposure levels as well. However, exposure measurements were not 
submitted for the Cumberland plant and it is unknown whether the 
Cumberland employees experienced the same exposures as their Rock Hill 
counterparts.
    The Gibbs study investigated the mortality of 3,211 workers who 
were employed at this plant on or after January 1970. There were 2,187 
men and 1,024 women in the cohort. Most of the workers in the cohort 
were hired prior to 1979 (2,566 total). The study population was 
divided into three subcohorts based on their estimated exposure to MC: 
1) 834 men and 146 women in the ``high exposure'' group (estimated to 
be 350-700 ppm), 2) 1095 men and 832 women in the ``low but never high 
exposure'' group (estimated to be 50-100 ppm), and 3) 256 men and 46 
women in the ``no exposure'' group. This cohort was followed through 
December 1989. The observed mortality was compared to expected death 
rates for Allegany County, Maryland (where the plant was located and 
where most of the cohort deaths occurred), the State of Maryland, and 
the United States.
    The author of this study believed that the county rates were the 
most appropriate to use because the city of Cumberland is located in a 
rural area of Maryland and the state rates may have been influenced by 
rates in large urban areas such as Baltimore. In addition, local rates 
tend to adjust for social, economic, ethnic, and cultural factors which 
may be related to disease risk, access to medical care, etc. However, 
if the fiber plant was the major employer in this rural area, then 
county rates may reflect the cohort's mortality rather than the 
background risk, in which case, state rates or U.S. population rates 
would be more appropriate. The overall mortality rate for the high MC-
exposed group was below the expected rates for Allegany County, 
Maryland, and the U.S. population.
    As in the Rock Hill study, mortality from biliary tract cancer was 
observed in the Cumberland study, although no statistically significant 
elevated incidence of biliary cancer was found (two cases of biliary 
tract cancer were observed). In the high exposure group, there was one 
death (1.24 expected with Allegany rates (SMR=80.5) and 1.42 expected 
with Maryland rates (SMR=70.4)). In the low MC-exposed group, there was 
also one death from biliary/liver cancer. For the high MC-

[[Page 1507]]

exposed subcohort, Gibbs et al. estimated SMRs of 80.4, 70.3, and 75.1 
when comparisons were made with Allegany County, Maryland, and U.S. 
rates, respectively. In the low MC-exposed subcohort, the SMRs using 
Allegany and Maryland rates were 75.4 and 76.4, respectively. This 
cohort should be followed for a longer period of time to help clarify 
the suggested association between MC exposure and biliary cancer 
observed in the Rock Hill cohort.
    Statistically significant excess mortality was also observed from 
prostate, uterine, and cervical cancers, although these also 
represented small numbers of cases: 13, 2, and 1, respectively.
    The excess of prostate cancer in the Gibbs et al. study suggested 
an exposure-response relationship (3 deaths in no MC-exposure group, 9 
in low MC-exposure group, and 13 in high MC-exposure group). According 
to Gibbs et al. and Shy [Tr. 1303, 9/22/92; Exs. 19-64, 91F], this 
response may have been related to other chemical exposures 
(occupational or non- occupational). In support of this hypothesis, no 
other epidemiological or animal studies of MC exposure have suggested a 
relationship between prostate cancer and MC. Hoechst-Celanese [Ex. 19-
65, pp. 10-12; Ex. 91D, p. 12] cautioned OSHA not to overinterpret the 
excess of prostate cancer in the Cumberland study for the following 
reasons:

    (1) of all the epidemiological studies, only the Cumberland 
study has shown an excess of prostate cancer; (2) of the thirteen 
high subcohort men who died of prostate cancer, twelve worked in the 
extrusion area of the Cumberland plant before methylene chloride was 
used as a solvent in cellulose triacetate fiber production. Thus, 
these men may have had longer exposure to other chemicals; (3) the 
study did not control for other personal risk factors; (4) Gibbs 
reported an increased incidence of prostate cancer elsewhere in the 
textile industry; and (5) the large number of statistical tests may 
have increased the probability of finding the death rate of a 
specific cause to be elevated or depressed.

    OSHA believes that the increased risk of prostate cancer should be 
noted as a possible positive effect of MC exposure on cancer risk, 
particularly considering the exposure-response relationship. However, 
because of potential confounding factors and lack of corroborating 
findings in other studies, OSHA believes this is suggestive rather than 
conclusive evidence of a human carcinogenic effect.
     b. Studies of film production workers.
In their original study of film production workers, Friedlander et al. 
[Ex. 4-27] conducted both a proportionate mortality study and a 
retrospective mortality cohort study to determine if workers exposed to 
MC experienced an increased risk for specific causes of mortality. The 
cohort in these studies consisted of workers who worked in any 
department in film production that used MC as its primary solvent for 
approximately thirty years. The cohort was followed through 1976.
    Proportionate mortality analysis for those workers ever employed in 
the study area versus a comparison group of workers in other Kodak Park 
departments produced a proportionate mortality ratio (PMR) of 143.88 
for liver (intrahepatic ducts-primary) cancer. For ischemic heart 
disease, Friedlander et al. calculated a PMR of 94.74. No statistically 
significant differences were observed at p  0.05.
    For the cohort mortality study, Friedlander et al. used rates from 
the 1964-70 hourly males age group exposed to MC in the film department 
and the other Kodak Park departments for internal comparison. Mortality 
rates for New York State, excluding New York City, males age group were 
used for external comparisons.
    Forty-five deaths from circulatory diseases were observed in the 
MC-exposed cohort versus 38.5 expected in the Kodak Park referent 
group. Also, 6 deaths from respiratory diseases were reported in the 
MC-exposed group versus 3.2 expected for the Kodak Park comparison 
group. No liver deaths were observed in this cohort. Thirty-three 
deaths from ischemic heart disease were observed in this cohort 
compared with 28.7 expected in the Kodak Park population. None of these 
observed differences in mortality reached statistical significance.
    Hearne et al. conducted several updates to the cohort study 
involving MC exposure and mortality among workers in film production 
areas at the Kodak plant in Rochester, New York [Exs. 7-122, 7-163, 49 
A-1]. In the first update, the study cohort was followed through 1983. 
Two referent groups were utilized in this study: the general population 
of upstate New York men, excluding New York City, and Kodak Park 
employees.
    No statistically significant findings were observed for any cause 
of death. However, Hearne et al. did find a relatively large number (8 
observed) of pancreatic cancer deaths compared with the New York State 
(3.2 expected) and Kodak (3.1 expected) populations. This observation 
did not achieve statistical significance and a dose-response 
relationship was not observed when Hearne et al. considered latency and 
dose.
    Hearne et al. then updated this study through 1988 [Ex. 7-163] and 
1990 [Ex. 49 A-2]. In the 1988 update, nonsignificant deficits in 
observed-expected ratios for lung and liver cancer were found. Also, 
overall mortality from 1964 to 1988 was significantly less than in both 
referent groups. Since 1986, the number of pancreatic cancer deaths 
remained the same. As before, dose-response analysis showed no 
statistically significant pattern when latency or dose were considered.
    The 1990 update showed that deaths due to liver cancer, lung 
cancer, and ischemic heart disease were below the expected numbers in 
both referent groups. Also, no additional pancreatic cancer deaths were 
observed in this second update. Since the start of the follow-up, 
Hearne et al. observed 8 deaths from pancreatic cancer compared with 
4.5 expected (SMR = 1.78, p = 0.17).
    Hearne et al. [Ex. 49 A-1] conducted a second Kodak cohort study 
involving workers in cellulose triacetate preparation and film base 
manufacturing between 1946 and 1970. Hearne et al. addressed the 
potential selection bias in the 1964-70 Kodak cohort by including only 
workers exposed primarily to MC after it was introduced in these areas 
and making the study more complete by adding workers in the Dope 
Department, which prepares the viscous cellulose triacetate mixture 
used in the film base coating, and the Distilling Department, which 
redistills and reblends solvents recovered from the coating operations.
    The 1,311 men in the cohort were followed through 1990. An 
occupational control group could not be formed because death rates for 
Kodak employees before 1964 were unavailable. Instead, male residents 
of upstate New York living outside of the five New York City counties 
were used.
    Hearne et al. combined exposures by job and time period with 
occupational history information to produce a career exposure estimate 
for each individual in the study for dose-response analyses. The mean 
career individual exposure was approximately 40 ppm for 17 years and 
the average interval between first exposure and end of follow-up was 
about 32 years.
    Total mortality for this cohort was 22% below the expected 
mortality (statistically significant). Circulatory diseases and 
ischemic heart disease mortality were also statistically significantly 
below expectation. For lung cancer there were 22 deaths (28.7 expected) 
and for liver/biliary cancer

[[Page 1508]]

there was one death (1.5 expected). Hearne et al. found that the number 
of pancreatic cancer deaths observed (4) was similar to the expected 
number (4.4). In this cohort, the number of observed deaths was greater 
than expected for diseases of the colon/rectum (13 observed v. 10.8 
expected), brain (5 v. 2.3), and for leukemia (7 v. 3.4), but were not 
statistically significant.
    Hearne et al. concluded that the findings in the 1964-70 cohort 
were consistent with the 1946-70 cohort: mortality from all causes, 
cancer (including lung and liver malignancies), and ischemic heart 
disease was lower than expected. Also, since the number of observed 
pancreatic cancer deaths in this cohort was similar to the expected 
number, Hearne et al. believed that this provided further evidence that 
the earlier finding of an excess of pancreatic cancer in the 1964-70 
cohort was due to chance or to factors other than MC exposure.
    Kodak [Tr. 1287-88, 9/22/92] also investigated the risk of adverse 
health effects during active occupational exposure to MC, as suggested 
by NIOSH [Tr. 970, 9/21/92]. Using person-years of active employment 
only in their analysis, Hearne observed 27 deaths (36 were expected in 
the internal Kodak reference group) from ischemic heart disease in the 
1964-70 Kodak cohort; in the 1946-70 cohort, Kodak recorded 33 deaths 
compared with 43 expected in the New York State comparison population.
    NIOSH testified [Tr. 877-83, 9/21/92] that the healthy worker 
effect (HWE) could have obscured any excess mortality from ischemic 
heart disease caused by MC exposure. NIOSH has stated that the HWE may 
be particularly strong for cardiovascular diseases.
    The HWE is likely to be less of a factor when occupational 
comparison groups are used. Kodak's use of the Kodak Park employees as 
a comparison group should reduce the HWE in its studies. However, there 
are two potential problems with using occupational comparison groups in 
this instance:
    (1) Cancer rates are more stable in larger populations, so 
comparison with state and national rates may be more appropriate.
    (2) Due to the volume of MC used in the Kodak plant, the 
occupational comparison group may be exposed to air- or water-borne 
environmental concentrations of MC which could obscure the impact of 
occupational exposure to MC on cancer incidence.
    c. Study of workers in paint and varnish manufacturing. The NPCA 
submitted to the record an epidemiological study of employees who 
worked for at least one year in the manufacture of paint or varnish 
[Ex. 10-29B]. OSHA's review of this study was published in the proposed 
rule [56 FR 57077]. Although no statistically significant excess of 
mortality was reported, OSHA noted that there were 4 pancreatic cancers 
(1.93 expected) and 15 cancers of digestive organs and peritoneum 
(10.66 expected) among MC-exposed workers.
    d. Astrocytic brain cancer among workers in electronic equipment 
production and repair. In its March 11, 1994 Notice of Limited 
Reopening of the Rulemaking Record, OSHA solicited comments on a case-
control study submitted to the Agency by the National Cancer Institute 
(NCI) [Exs. 112 and 113].
    Heineman et al. conducted a case-control study to examine the 
potential association between brain cancer and exposure to organic 
solvents as a group and six chlorinated aliphatic hydrocarbons (CAHs) 
including MC. Cases were defined as white males who died from brain or 
other central nervous system tumors in southern Louisiana, northern New 
Jersey, and Philadelphia, Pennsylvania. Controls were randomly selected 
from death certificates and included white males who died of causes 
other than brain tumors, cerebrovascular diseases, epilepsy, suicide, 
and homicide. Controls were frequency-matched to cases by age, year of 
death, and geographic area.
    Four-digit Standard Industrial Classification (SIC) and 4-digit 
Standard Occupational Classification (SOC) codes were employed to code 
occupational histories of study subjects. These codes linked work 
histories to job-exposure matrices which ``characterized likely 
exposure to the six CAHs and to organic solvents'' [Ex. 112]. Gomez et 
al. [Ex. 112] used an algorithm to assign estimates of probability and 
intensity of exposure to each industry/occupation combination in 
subjects' work histories. As noted by Gomez et al., these estimates 
were based on ``occupation alone, industry alone, or both occupation 
and industry, depending on the specificity of the exposure environment 
that could be inferred from the occupational (SOC) code.''
    The following surrogate measures of dose, for each substance, were 
used to summarize ``likely'' exposure histories for each study subject: 
duration of employment in occupation/industry combinations considered 
exposed, a cumulative exposure score, and ``average'' intensity of 
exposure. Odds ratios were calculated for exposure intensity categories 
to refrain from using weights. These categories did not include 
duration in jobs with lower intensity for subjects with high or medium 
intensity jobs. In their statistical analyses, Heineman et al. 
controlled for age, geographic area, and employment in electronics-
related occupations/industries.
    Astrocytic brain cancer was not found to be associated with 
``ever'' being exposed to organic solvents as a group or to any of the 
six CAHs examined in this study. However, as probability of exposure to 
organic solvents as a group, and MC in particular, increased, the risk 
of brain cancer increased (chi-squared statistics for trend for organic 
solvents and MC were 1.93 and 2.29 (p<0.05), respectively). For MC 
there was a 2.4-fold increase in risk for subjects with a high 
probability of exposure (confidence interval=1.0-5.9).
    Risk of brain cancer significantly increased with duration of 
exposure for subjects with high probabilities of MC exposure (OR=6.1; 
CI=1.1-43.8). Heineman et al. found that, in the high probability of MC 
exposure category, risk significantly increased with duration (chi for 
trend=2.58, p<0.01). Similar results were seen for organic solvents and 
methyl chloroform for all probabilities combined (chi-squared 
statistics for trend were 2.35 (p<0.01) and 1.87 (p<0.05), 
respectively).
    Lagging exposure by 10 years produced findings analogous to those 
noted above. Higher risks and a sharper increase with duration was 
observed for organic solvents when exposure was lagged by 20 years (all 
probabilities: 2-20 years, OR=1.3 (95% CI=0.9-2.0); 21+ years, OR=2.8 
(1.1-3.7); p for trend=0.006; high probability: 2-20 years, OR=1.2 (95% 
CI=0.7-1.9); 21+ years, OR=3.1 (1.3-7.4), p=0.009).
    Subjects with a high probability of MC exposure experienced a 
statistically significant increased risk as the cumulative exposure 
score increased (chi-squared statistics for trend=2.18, p<0.05). 
However, risk did not increase monotonically with cumulative exposure.
    Lagging exposure 20 years supported the odds ratios and the trends 
for organic solvents, particularly in men with a high probability of 
exposure (low cumulative score: OR=1.1 (95% CI=0.5-2.3); medium: OR=1.4 
(0.8-2.5); high: OR=2.2 (1.0-4.5); p for trend=0.02). Few individuals 
had high cumulative scores when exposure was lagged 20 years for the 
individual CAHs.
    Compared with jobs with medium or low intensity exposures to 
organic solvents and all six CAHs, risk of brain cancer was higher for 
subjects who

[[Page 1509]]

worked in jobs with high intensity exposures. Brain cancer was 
associated most strongly, and increased with probability of exposure, 
among subjects who worked 20 or more years with high intensity exposure 
to MC (all probabilities: OR=6.7, CI=1.3-47.4; high probability: 
OR=8.8, CI=1.0-200.0).
    Since many subjects were determined to have been exposed to more 
than one of the CAHs, sometimes even in the same job, Heineman et al. 
used logistic regression to examine, simultaneously, the effects of MC, 
carbon tetrachloride, tetrachloroethylene, and trichloroethylene, 
controlling for age, geographic area, and employment in electronics-
related occupations/industries. MC was the only substance to show a 
statistically significant increase in risk as the probability of 
exposure increased (low: OR=0.9, CI=0.5-1.6); medium: OR=1.4, CI=0.6-
3.1; high: OR=2.4, CI=0.9-6.4; chi-squared statistics for trend=2.08, 
p<0.05). Risks associated with MC increased when adjustments for 
exposure to the other agents were made. In addition, subjects employed 
for 20 years or more in jobs with high average intensity MC exposure 
showed an eight-fold excess of brain cancer (OR=8.5, CI=1.3-55.5), 
taking all probabilities into consideration.
    Among the six CAHs examined in this study Heineman et al. found the 
strongest association between brain cancer and MC-exposure, for which 
relative risks rose with probability, duration, and average intensity 
of exposure, though not with the cumulative exposure index.
    According to Heineman et al., the major weakness of this study was 
not having direct information on exposure to solvents. Next-of-kin 
data, poor specificity of some work histories for specific solvents, 
and the interchangeability of solvents may have resulted in 
misclassification of individuals with respect to any of the exposure 
measurements used in this study. However, Heineman et al. pointed out 
that the potential sources of error probably did not significantly bias 
risk estimates away from the null or generate the observed trends.
    Another limitation of this study, pointed out by Heineman et al., 
was that over one-third of the next-of-kin of eligible cases and 
controls were not interviewed. According to Heineman et al., this could 
have artificially created the associations seen in this study ``only by 
underrepresenting cases who were unexposed, and/or controls who were 
exposed, to solvents in general, and MC in particular'' [Ex. 113]. 
Heineman further remarked that differential misclassification was 
probably not a problem in this study because occupational histories 
came from next-of-kin of both cases and controls.
    In light of the limitations of this study, however, Heineman et al. 
commented that the consistency of exposure-response trends for MC was 
surprising and suggestive. Moreover, Heineman et al. believed that the 
trends and consistency of the associations between brain cancer and MC 
could not be explained by chance alone.
    Several commenters [Exs. 115-1, 115-31, 115-32, 115-36] indicated 
that Heineman et al. relied too heavily on next-of-kin information. 
Information provided by next-of-kin concerning jobs held, job 
descriptions, dates of employment, and hours worked per week may be 
flawed with recall bias. Next-of-kin may not be able to accurately 
recall job-related information, especially for jobs held early in life. 
If next-of-kin for cases or controls had better recall than the other 
group, differential misclassification could occur. HSIA [Ex. 115-36] 
stated that even small differences in error rates between cases and 
controls could produce false associations. Both HSIA and NIOSH [Ex.115-
31] agreed that this indirect source of exposure information was likely 
to produce some degree of misclassification. However, NIOSH noted that 
misclassification ``is a typical problem in population based case-
control studies of this type [Ex. 115-31]'' and that this 
misclassification could also explain the fact that no associations were 
found between brain cancer and the cumulative exposure score.
    Organization Resources Counselors (ORC) [Ex. 115-2] and Abbott 
Laboratories [Ex. 115-30] were concerned that the lack of exposure 
verification made this NCI study unreliable for setting MC exposure 
limits. ORC stated that exposure values were assigned to all SIC and 
SOC codes, and not developed based on job history information, which 
would have given the study more validity. Kodak also expressed some 
concern regarding this study due to lack of accurate records of past 
exposures, reliance on expert judgement to a large degree, use of next-
of-kin to determine potential exposure, and undocumented qualifications 
of those making judgements concerning the different occupations and 
industries involved. In addition, Kodak felt that the exposure data 
were ``at best, unsubstantiated semi-qualitative judgements of 
likelihood and intensity of exposure [Ex. 115-1].'' Organization 
Resources Counselors [Ex. 115-2] and Abbott Laboratories [Ex. 115-30] 
asserted that it was impossible to tell if those who died of cancer had 
been exposed to MC because there was no exposure verification. Vulcan 
Chemicals [Ex. 115-32] criticized the investigators for not going to 
work sites and determining the actual magnitude of exposure to the 
CAHs. HSIA [Ex. 115-36] argued that ``concordance of proxy reports with 
actual work histories may range from 0-50% for decedents' first jobs 
and from 50-70% for last jobs.'' OSHA believes that exposure 
verification would have increased the validity of the findings of this 
study. However, lack of exposure verification does not nullify the 
results of the study. The Agency believes that the associations 
observed are suggestive of a human carcinogenic effect of MC.
    Another issue that Kodak [Ex. 115-1] and Vulcan [Ex. 115-32] 
emphasized was the possible exposure to other chemicals or sources of 
potential human carcinogens, such as ionizing radiation, 
electromagnetic fields, smoking history, and place of residence. Vulcan 
[Ex. 115-32] noted that there may have been selection bias in this 
study because of the large ratio of astrocytic brain cancer tumors to 
the total number of brain tumors. Although they offered no explanation 
of how this selection bias would operate, Vulcan did suggest that this 
issue should be investigated further.
    Vulcan was also concerned that the matching of controls and cases 
with respect to occupations and socioeconomic status may be inadequate. 
In particular, Vulcan criticized the Heineman study for not presenting 
the occupations of the control group and for not matching the 
socioeconomic status of the two groups. Similarly, Kodak [Ex. 115-1] 
stated that some adjustment should have been made in order to match 
across educational levels.
    Kodak [Ex. 115-1] also believed that the estimates of trends 
observed in this study could have been affected, if workers in the 
longest duration or the higher probability of exposure categories had 
longer dates of employment, worked in more stable industries, and had 
better health benefits, better access to medical care, and more 
sophisticated diagnostic procedures. OSHA believes that there is no 
evidence that this is the case in this study.
    HSIA [Ex. 115-36] criticized the methodology for assessing the 
number of industries with exposures to CAHs. HSIA argued that Gomez et 
al. did not fully explain how they determined that workplaces in the 
specific SICs would have CAH exposures. According to HSIA, Gomez et al. 
reported inaccurate

[[Page 1510]]

information regarding industry use of MC. HSIA cited EPA's ``Toxic Air 
Pollutant/Source Crosswalk, A Screening Tool for Locating Possible 
Sources Emitting Toxic Air Pollutants (EPA-450/4-87-023A, Dec. 1987)'' 
which revealed a higher number of SIC codes using MC. In conclusion, 
HSIA asserted that Gomez et al.'s ``exposure scenario'' was incorrect.
    Several commenters [Exs. 115-1, 115-31, 115-36] argued that the 
Heineman et al. study should only be considered a hypothesis-generating 
study and should not be used to adjust the PEL.
    OSHA agrees with NIOSH that the Heineman et al. study was well-
conducted because there was a systematic attempt to estimate exposure 
by work experience. Furthermore, there was a remarkably high 
correlation between exposure to MC and brain tumors. OSHA concludes 
that the results from this study strongly suggest a possible 
association between MC and brain cancer. However, in the absence of 
quantified exposure data for these workers, it remains relatively 
speculative to attempt to estimate a quantitative dose-response 
relationship. Therefore, OSHA concludes that the risk estimate based on 
the animal data is the best available and accordingly it retains that 
estimate for its significant risk analysis.
    e. Summary of epidemiological studies. Considered as a whole, the 
available epidemiologic evidence did not demonstrate a strong, 
statistically significant cancer risk associated with occupational 
exposures to MC. However, the positive trend for biliary tract/liver 
cancer deaths, the association between occupational MC exposure and 
astrocytic brain cancer and the statistically significant excess 
prostate cancer results are suggestive of an association between MC 
exposure and cancer risk. In addition, the non-positive epidemiological 
studies summarized here are not of sufficient power to rule out the 
positive results from the animal studies. This issue is addressed 
further in the Quantitative Risk Assessment section of this document.
    In summary, the epidemiological results are suggestive of an 
association between occupational exposure to MC and elevated cancer 
risk which offers supporting evidence to the positive animal bioassay 
results.
4. Conclusion
    OSHA concludes from the mutagenicity, animal bioassay and human 
epidemiology data that MC causes cancer in test animals and that it is 
a potential occupational carcinogen. The Agency has determined that, 
because of the quality of the studies, the clear dose-response 
relationship and the appropriateness of the route of administration, 
the NTP rodent bioassay data are the best available for quantitative 
cancer risk assessment.
    OSHA also concludes that the epidemiology data, in some cases, 
suggest a positive association between human MC exposure and cancer 
incidence, but the dose-response relationships are not clear. The 
Agency has determined that the remaining epidemiology data (the non-
positive studies) are not of sufficient power to rule out the results 
obtained in the animal bioassay data and that the animal data provide 
the best available data for quantitative risk assessment.

E. Other Toxic Responses

1. Central Nervous System Toxicity
    MC acts on the central nervous system (CNS) as a CNS depressant. 
CNS depression has been described in humans exposed to MC 
concentrations as low as 175 ppm (8-hour TWA). This depression in CNS 
activity was manifested as increased tiredness, decreased alertness and 
decreased vigilance. These effects could compromise worker safety by 
leading to an increased likelihood of accidents following MC exposure.
    a. Animal studies. In the NPRM, OSHA reviewed two animal studies of 
MC CNS toxicity (briefly summarized below) and concluded that the CNS 
was potentially susceptible to reversible and irreversible effects due 
to MC exposure.
    Savolainen et al. [Ex. 7-178] studied biochemical changes in the 
brains of rats exposed to MC. Rats were exposed to 500 ppm MC for 6 hr/
d. On the fifth day, after 3 and 4 hours of exposure to MC, levels of 
acid proteinase in rat brains were significantly increased, but no 
change in brain RNA levels was reported. The authors suggested that the 
increase in acid proteinase may have been the result of increased 
levels of CO from metabolism of MC. OSHA believes that this study shows 
that MC can cause specific changes in the neurological system at a 
biochemical level. The Agency intends to monitor the scientific 
literature for additional developments on these effects, but has not 
used this information in setting the MC exposure limits because it is 
presently unclear how changes in acid proteinase are related to the 
observed CNS depressive effects of MC in humans.
    Rosengren et al. [Ex. 7-56] looked at the effects of MC on glial 
cell marker proteins and DNA concentrations in gerbil brains after 
continuous exposure to 210, 350 or 700 ppm MC. Because of high 
mortality in the 2 higher doses, no data were collected at 700 ppm and 
exposure was terminated after 10 weeks at 350 ppm. Exposure to 210 ppm 
was continued for three months. Exposure to MC was followed by four 
months of no exposure before animals were examined for irreversible CNS 
effects. The authors found increased levels of glial cell marker 
proteins in the frontal cerebral cortex and sensory motor cortex after 
exposure to 350 ppm MC. These findings are consistent with glial cell 
hypertrophy or glial cell proliferation. Levels of DNA were decreased 
in the hippocampus of gerbils exposed to both 210 and 350 ppm and in 
the cerebellar hemispheres after 350 ppm MC. Decreased DNA 
concentrations indicate decreased cell density resulting from cell 
death or inhibition of DNA synthesis.
    The neurotoxic mechanism of action of MC in gerbil brains is not 
understood. However, since the metabolism of MC to CO was determined to 
be saturated at both 210 and 350 ppm (COHb levels were equivalent at 
both exposure concentrations), the changes in glial cell proteins and 
DNA concentrations was attributed to either a direct effect of MC or an 
effect of a metabolite of the GST pathway. Although this study 
describes biochemical changes in the CNS subsequent to MC exposure, the 
high mortality of the experimental animals and the lack of MC toxicity 
data in the gerbil make it difficult to determine the significance of 
this study for extrapolation to other species. It is also unclear how 
these effects would relate to CNS depression observed in humans after 
MC exposure. In addition, continuous exposure to MC has been shown in 
other experimental situations [Exs. 7-14 and 7-130] to elicit more 
severe health effects than exposure to similar or higher concentrations 
when the animals are allowed a recovery period (for example, 6 hours' 
exposure per day). Exposure on a 6 or 8-hour per day schedule is also 
more like occupational exposure scenarios and therefore those 
experiments are generally easier to interpret when assessing risk to 
workers.
    In summary, OSHA believes that the rat and gerbil data described 
above shows that MC can cause specific changes in the neurological 
system at a biochemical level. The Agency intends to monitor the 
scientific literature for additional developments on these effects to 
determine if these types of effects have implications for human CNS 
risks.

[[Page 1511]]

    b. Human studies. The CNS depressant effects of MC have been well 
described in the literature [Exs. 7-4, 7-153, 7-154, 7-160, 7-175, 7-
182, 7-183, 7-184]. MC causes CNS depression which is characterized by 
tiredness, difficulty in maintaining concentration, decreased task 
vigilance, dizziness, headaches, and, at high concentrations, loss of 
consciousness and death. Accidental human overexposures to MC [Exs. 7-
18, 7-19] (for example, at concentrations greater than 10,000 ppm) have 
resulted in narcosis and death. CNS depression has been described after 
humans were exposed to experimental MC concentrations as low as 200 ppm 
[Ex. 7-175] and occupational concentrations as low as 175 ppm [Ex. 7-
153].
    i. Experimental studies. CNS depression was detected in human 
subjects exposed to MC at concentrations as low as 200 ppm for 4 hours 
or 300 ppm for 1.5 hours [Exs. 7-4, 7-160, 7-175, 7-182 and 7-184]. In 
these experiments, which measured subtle CNS depression (such as dual 
task performance and visual evoked response), it was not possible to 
determine a no observed effect level (NOEL), because the lowest 
experimental concentration used (200 ppm) elicited CNS effects. Since a 
NOEL was not determined for the CNS effects of MC, those effects may 
occur at lower exposures or after exposure for shorter durations.
    The HSIA questioned whether bias was introduced into the results of 
these studies by inadequate procedures to establish a ``double blind.'' 
This criticism raises a legitimate concern about the validity of the 
study. However, since Putz et al. did not describe the blinding 
procedures used in their experiments, the Agency concludes that there 
is not enough evidence publicly available to make the conclusion that 
the study is biased. OSHA believes that these studies were well 
conducted and is relying on the quality of the studies overall as 
evidence of the validity of the results. Absent evidence demonstrating 
the inadequacy of the blinding procedures, OSHA has determined that 
these studies show that MC can cause mild CNS depression in humans 
exposed at concentrations as low as 200 ppm.
    NIOSH expressed concern regarding the potential for neurobehavioral 
impairment (expressed as CNS depression) at lower exposures and shorter 
durations, particularly in relation to the setting of a STEL for MC 
[Exs. 23-18 and 94]. In order to assess the potential impact of the CNS 
effects of MC, NIOSH looked at data gathered from several studies and 
compared breath concentrations of MC (as a surrogate for brain tissue 
MC concentrations) at different ambient exposure levels with the CNS 
depression described by Putz et al. [Ex. 7-175]. NIOSH concluded that:

    At the proposed STEL of 125 ppm, increased uptake of MC in 
active workers may place them in the breath concentration range 
associated with mild neurobehavioral impairment. Although there are 
insufficient data to draw firm conclusions, extrapolation from 
existing studies suggests that the proposed STEL of 125 ppm may not 
fully protect physically active workers from CNS impairment. 
Therefore, a lower STEL should be considered, if feasible.

In response to concerns raised by NIOSH, the HSIA [Ex. 105] noted that 
NIOSH's analysis of breath MC concentration versus neurobehavioral 
impairment ``seemed highly speculative.'' HSIA emphasized that the 
exposures which produced the reported neurobehavioral effects were 
observed only after 2 to 4 hours of exposure and that the effects were 
observed only when difficult tasks were measured.
    To support their position, the HSIA asked Mr. Richard Reitz to use 
a PBPK model to estimate the concentration of MC in brain tissue. This 
analysis [Ex. 105] indicated that at exposures of 200 ppm for 15 
minutes with persons exercising at 50 watts, the brain concentration of 
MC would be predicted to be similar to that observed in the Putz et al. 
study for subjects engaged in ``light activity'' for 2 hours at 200 ppm 
MC, which did not produce measurable CNS depression. (Putz et al. did 
not detect CNS depression in subjects exposed to 200 ppm for 2 hours). 
The model also predicted that 15-minute exposures to 125 ppm while the 
subject was exercising at 50 watts would produce brain MC 
concentrations substantially less than that predicted for the 4 hour 
exposure to 200 ppm MC.
    OSHA considered the PBPK analysis presented by the HSIA, but was 
concerned that there has been no experimental validation of the 
predicted brain MC concentrations or any evidence as to what MC 
concentration would produce detectable CNS depression. OSHA believes 
the primary value of both the NIOSH and HSIA analyses is in 
demonstrating the relative effect that exercise and duration of 
exposure is likely to have on brain (or breath) concentrations of MC. 
The PBPK analysis clearly demonstrates that increasing exercise level 
increases brain concentration of MC, which is consistent with the 
detected CNS depression. Workers engaged in strenuous activity while 
exposed to MC should take special precautions, such as frequent breaks 
in fresh air, especially if dizziness or lightheadedness occurs.
    Although OSHA found the PBPK model to be useful for demonstrating 
the interaction between exercise and brain concentration of MC, the 
Agency did not use the model quantitatively (for example, in 
determining the STEL). OSHA believes that the data suggest that there 
may be CNS effects at levels below those tested. There are no studies 
which directly address whether there are CNS effects after exposure to 
STEL concentrations of MC. To the extent that these effects occur, the 
STEL would not be protective. Mild and reversible CNS depression was 
detected at 200 ppm for 4 hours and 300 ppm for 1.5 hours. The Agency 
shares NIOSH's concern, based on extrapolation of breath MC 
concentrations, that the proposed STEL may not be adequately protective 
for physically-active workers.
    OSHA concludes that there are clearly sufficient data to determine 
that a 125 ppm 15-minute STEL is needed to prevent a significant risk 
of material impairment to the CNS. Impairment of the CNS would also 
increase the risk from accidents. Measured data show risks at 200 ppm 
for four hours of exposure. A lower level at shorter duration is needed 
to avoid that risk. NIOSH's calculations show that for active workers a 
level lower than 125 ppm may be needed. However, because of feasibility 
concerns, which would be greater at lower levels and the suggestion 
that short duration of exposure (i.e., 15-minutes) may mitigate the 
effects, OSHA is retaining the proposed level, but will carefully 
monitor and follow up data to determine if this level eliminates 
significant risk.
    ii. Occupational exposure studies. In the NPRM, OSHA summarized 
studies which it believed described a neuropathy associated with 
chronic occupational exposure to solvents. Weiss [Ex. 7-196] described 
the case of a 39-year old chemist who worked for 5 years with airborne 
concentrations of MC as high as 660 ppm to 3600 ppm in a room with poor 
ventilation. After 3 years of exposure, the worker developed 
neurological symptoms, characterized by restlessness, palpitations, 
forgetfulness, poor concentration, sleep disorders, and finally, 
acoustical delusions and optical hallucinations. No hepatic damage or 
cardiac toxicity was found. At the first appearance of symptoms, 
cessation of exposure produced an immediate cessation of symptoms. 
Later, longer and longer periods were required after termination of 
exposure in order to alleviate the

[[Page 1512]]

symptoms. The increasing persistence of symptoms is consistent with a 
diagnosis of toxic encephalosis.
    Hanke et al. [Ex. 7-195] examined 32 floor tile setters who were 
exposed primarily to MC at concentrations from 400 to 5300 ppm for an 
average tenure of 7.7 years. Clinical examination of 14 of the workers 
who had neurological symptoms (headache, vertigo, sleep disturbance, 
digestive complaints and lapses in concentration and memory) revealed 
changes in the EEG patterns of the exposed workers which persisted over 
a weekend pause in exposure. These EEG changes were characteristic of a 
toxic encephalosis produced by chronic intoxication with a halogenated 
solvent (MC). The persistence of the EEG changes over the weekend break 
indicated a prolonged effect of MC exposure on EEG patterns. 
(Additional changes in the EEG found during exposure could be 
attributed to an acute effect of MC). Although these studies represent 
a small number of cases with very high chronic exposures, the evidence 
is suggestive of a relationship between chronic MC exposure and toxic 
encephalosis.
    In a case study report, Barrowcliff et al. [Ex. 7-123] attributed 
cerebral damage in a case study to CO poisoning caused by exposure to 
MC. Axelson [Ex. 7-150] has described an increased number of 
neuropsychiatric disorders among occupations with high solvent 
exposures.
    In the NPRM, OSHA expressed the opinion that these studies, taken 
together, ``provide suggestive evidence of a permanent toxicity 
[different from the observed reversible CNS depression] which may be 
the result of chronic exposure to MC.'' NIOSH stated that this 
assessment was too speculative and stated,

in the Hanke study, MC was apparently only one component of a 
solvent mixture and may not have been the only neurotoxic agent* * * 
In addition, the observation interval of 2.5 days was not long 
enough to provide convincing evidence of irreversible effect, 
regardless of the active agent.

Upon reexamination of these studies, OSHA agrees with NIOSH [Ex. 19-46] 
that although a prolonged effect (over a weekend break in exposure) of 
MC on EEG patterns has been demonstrated, these studies do not support 
a determination that MC exposure is associated with irreversible brain 
damage in humans.
    OSHA reviewed several other studies of occupational exposure to MC 
for evidence of CNS effects of MC. The first study was provided as an 
English translation of a Czechoslovakian paper by Kuzelova et al. [Ex. 
7-26]. These investigators examined workers in a film production plant 
who were exposed to MC concentrations from 29 to 4899 ppm. Several 
workers suffered frank MC intoxication and many workers showed signs of 
MC-induced CNS depression. Toxicity associated with chronic MC exposure 
was observed in workers exposed to MC for up to two years, but the 
authors recommended continuing studies of the long-term health effects.
    OSHA believes that this study shows CNS depression in workers 
exposed to MC. The Agency agrees with the authors that this study was 
not sufficient to adequately characterize the long-term CNS health 
effects that may be induced by MC exposure.
    Cherry et al. [Ex. 7-154] studied the effects of occupational 
exposure to MC at 28 to 175 ppm in two exposed populations. In a 1981 
study, the authors found a marginal increase in self-reported 
neurological symptoms among exposed workers. This increase disappeared 
when an appropriate reference group was used for comparison. However, 
in a 1983 investigation, Cherry [Ex. 7-153] showed statistically 
significant increases in tiredness and deficits in reaction time and 
digit symbol substitution which correlated with MC in blood. Ambient MC 
exposures for this population ranged from 28 to 175 ppm for the full 
shift. This study demonstrated CNS effects due to occupational MC 
exposures below 200 ppm (the lowest dose which was administered in the 
experimental studies).
    The HSIA [Ex. 105, p. 34] commented as follows:

    Decades of experience with worker populations exposed even at 
levels up to the current 500 ppm TWA have provided no evidence that 
such workers have higher rates of accidents or other signs of 
significant neurobehavioral impairment.

    To the contrary, OSHA believes that the occupational studies 
discussed above demonstrate that MC has an effect on the CNS at 
occupational exposure levels as low as 175 ppm.
    The Agency believes that the 1983 study by Cherry shows that 
occupational exposure to MC concentrations below the former 8-hour TWA 
PEL of 500 ppm can produce detectable CNS effects. Although the 1981 
study, which relied on self-report of neurological symptoms, did not 
demonstrate a CNS effect, the 1983 study examined more objective 
measures of CNS depression and correlated the observed effects with a 
direct measure of MC exposure. OSHA believes that this study 
demonstrates that, although the CNS depression may be mild, it is 
demonstrable in occupational settings and at concentrations in the 
range of the STEL (although the exposures in this study were over an 8-
hour work day). As described above, OSHA is sufficiently concerned 
about the potential for health effects at concentrations below the STEL 
of 125 ppm that it will continue to gather information and revisit this 
issue, if warranted.
2. Cardiac Toxicity
    As described in the section on the metabolism of MC, MC is 
metabolized in vivo (in animals and humans) to CO and CO2. 
Cardiovascular stress has been observed after exposure to CO, so it is 
reasonable to suspect that similar health effects would be observed 
after exposure to MC (and metabolism to CO) [Ex. 7-73,     4-33]. 
Carbon monoxide successfully competes with oxygen and blocks the oxygen 
binding site on hemoglobin, producing carboxyhemoglobin (COHb) and 
reducing delivery of oxygen to the tissues. This reduces the oxygen 
supply to the heart itself, which can result in myocardial infarction 
(heart attack) [Ex. 4-33].
    Generally, humans have a baseline level of COHb of less than 1% 
COHb due to the endogenous production of CO from normal metabolic 
processes. The measured level of COHb in the general non-smoking 
population is from 1% to 3% because of direct exposure to CO from 
combustion sources such as automobiles, etc. In smokers, COHb generally 
ranges from 2% to 10% because of the additional CO exposure during 
smoking. CO generated from exposure to MC would be additive to the COHb 
burden already experienced by an individual from direct exposure to CO. 
The cardiac health effects anticipated from exposure to MC itself or CO 
as the result of metabolism of MC are described below.
    a. Animal studies. There is no evidence from animal studies in the 
MC rulemaking record that MC has a direct toxic effect on cardiac 
tissue. After lethal doses of MC, death has been primarily attributed 
to CNS and respiratory depression [Exs. 7-27, 7-28]. Also, chronic 
studies (in which COHb levels have been maintained at 10% and higher) 
[Exs. 7-3, 7-8, 7-14, 7-130, 7-151] have not shown direct 
cardiotoxicity.
    Chlorinated solvents have been shown to sensitize the cardiac 
tissue to epinephrine- induced fatal cardiac arrhythmias [Ex. 7-226]. 
However, MC is less effective in sensitizing cardiac

[[Page 1513]]

tissue than other chlorinated analogues. MC caused sensitization of 
cardiac tissues only at doses well above doses which produce a narcotic 
effect. This finding indicates that compliance with an 8-hour TWA of 25 
ppm MC would likely be sufficient to protect against such 
sensitization.
    b. Human studies. The metabolism of MC to CO and measurement of 
COHb in human subjects exposed to MC were described in detail in the 
NPRM. In summary, it was found that exercising increased MC uptake and, 
subsequently, increased blood COHb levels compared to that of sedentary 
individuals [Ex. 7-222]. In addition, COHb levels due to smoking were 
found to be additive to the COHb produced by MC metabolism. Taken 
together, these results suggested that smokers or individuals engaged 
in physical exertion (as in a workplace) may be at increased risk from 
CO- induced toxicity from MC exposure. This risk may be especially 
elevated in individuals with silent or symptomatic cardiac disease who 
may be susceptible to very small increases in COHb because of an 
already impaired blood supply to the heart. Many American workers have 
silent or symptomatic heart disease. This increased OSHA's concern for 
the potential cardiac effects of MC and its metabolites.
    Elevated COHb has been measured in humans experimentally and 
occupationally exposed to MC [Exs. 7-4, 7-5-R0327, 7-102, 7-115, 7-157, 
7-159, 7-169, 7-174, 7-176]. The effects of elevated COHb are primarily 
increased risk of myocardial infarction, especially in susceptible 
individuals. Atkins and Baker [Ex. 7-198] described two cases of 
myocardial infarction in workers subsequent to CO exposure. COHb was 
measured at 30% and 24% in these individuals, which is much higher than 
normal general population levels of COHb. Humans exposed to MC would 
not be expected to experience COHb at those levels unless the exposure 
to MC was extremely high (greater than 500 ppm).
    In a laboratory study of humans with coronary artery disease, 
subjects were exposed to CO and observed for cardiac health effects 
during exercise. In subjects with 3 to 10% COHb, decreased exercise 
tolerance and increased anginal pain were observed [Ex. 7-198]. In an 
epidemiological study submitted to OSHA by NIOSH during the MC public 
hearings, the investigators observed a statistically significant excess 
of ischemic heart disease mortality among tunnel workers when compared 
with rates for the New York City population [Ex. 23-18]. This increase 
in mortality is supported by clinical findings. Allred et al. [Ex. 23-
18] observed that elevation of COHb from 0.6% to as low as 2% decreased 
time to myocardial ischemia and anginal pain during laboratory tests. 
OSHA believes that these studies, taken together, suggest that small 
increases in COHb can adversely affect persons with compromised cardiac 
health. The results observed in the tunnel workers are particularly 
relevant because they show an increased risk in a working population. 
NIOSH used these studies to support its recommendation that the COHb 
effects of MC be carefully considered in the MC rulemaking [Tr. 881-2, 
9/21/92]. OSHA agreed with NIOSH that the effects observed at low 
levels of COHb are cause for concern about the risks of MC metabolism 
to CO.
    In the NPRM, OSHA also reviewed case reports in which individuals 
exposed to MC experienced myocardial infarctions [Exs. 7-102, 7-73]. 
These case reports suggested that exposure to MC increased cardiac 
stress, although it was not determined whether this was a direct effect 
of MC or as the result of metabolism of MC to CO. OSHA believes that 
these case studies support the hypothesis that CO generated through 
metabolism of MC would have the same adverse health effects as direct 
CO exposure.
    Two epidemiological studies (in film coating and fiber production 
workers) [Exs. 7-75, 7-76, 7-122, 7-163] examined cardiac mortality due 
to occupational exposure to MC. Ott [Ex. 7-76] compared mortality from 
a plant in South Carolina that used MC to a reference plant in 
Virginia. An increased risk ratio for ischemic heart disease (risk 
ratio = 3.1) was observed in the MC-exposed workers compared to the 
reference population.
    This approach controls for the healthy worker effect by comparing 
two working populations, and excess risk was demonstrated. The authors 
believed that the apparent excess risk was due to geographical 
variability in the incidence of ischemic heart disease. The population 
from the reference plant was found to have an unusually low death rate 
due to ischemic heart disease in comparison to the general population 
rate.
    In an update of the study [Ex. 7-75], the ischemic heart disease 
rate in the exposed population was compared to that in the surrounding 
York County, S.C. population instead of a reference plant. No 
difference in ischemic heart disease rates was detected between exposed 
workers and controls, although this approach would not control for the 
healthy worker effect. The SMR was 0.94 (32 observed, 34.2 expected).
    NIOSH disagreed with the conclusion of the authors of this study, 
and indicated that the studies summarized above would be cause for 
concern regarding the cardiac effects of MC. NIOSH suggested that the 
raw data from the epidemiological studies of cellulose acetate film 
production workers and the studies of workers in cellulose acetate 
fiber manufacture be reviewed for cardiac mortality occurring during 
the period of occupational exposure for the workers. OSHA is concerned 
about the potential CO effects from metabolism of MC and will continue 
to monitor the scientific literature on this topic. However, the Agency 
is setting the exposure limits based on cancer and CNS effects and has 
not reached final conclusions on this issue.
3. Hepatic Toxicity
    Chlorinated hydrocarbons as a class, such as carbon tetrachloride 
and chloroform, are toxic to the liver. In general, chlorinated 
hydrocarbons cause cytotoxicity (cell death) in rodent livers. 
Therefore, there was suspicion that the liver would also be a target 
organ for MC (a chlorinated hydrocarbon) toxicity. OSHA evaluated the 
available literature on the hepatic effects of MC in animal and human 
studies.
    a. Animal studies. Studies of the effects of MC exposure on the 
rodent liver have not demonstrated significant acute liver toxicity, 
even at lethal or near-lethal doses. As summarized in the NPRM, Kutob 
et al. [Ex. 7-27] and Klaassen et al. [Ex. 7-28] conducted experiments 
on halogenated methanes and hepatotoxicity. MC was determined to be the 
least hepatotoxic of the halogenated methanes examined. The only injury 
described was a mild inflammatory response associated with lethal MC 
concentrations. These studies demonstrated that liver was not the 
primary target organ for the acute toxicity of MC.
    Weinstein et al. [Ex. 7-181] examined the hepatic effects of MC on 
female mice who were continuously exposed for up to 7 days to MC 
concentrations of up to 5000 ppm. Mild, nonlethal injury to the livers 
was noted, characterized by balloon degeneration of the rough 
endoplasmic reticulum (RER), transient severe triglyceride accumulation 
(fatty liver), partial inhibition of protein synthesis and breakdown of 
polysomes into individual ribosomes. The injury is similar to a mild 
form of carbon tetrachloride toxicity (a structural analog of MC) and 
suggests that although the toxicity due to MC is not as severe as that 
produced by carbon tetrachloride, the mechanism of toxicity may be 
similar.

[[Page 1514]]

    In subchronic experiments more severe effects were observed in the 
liver after continuous exposure. MacEwen et al. [Ex. 7-14] studied the 
effects of continuous exposure of mice, rats, dogs and rhesus monkeys 
to 1000 and 5000 ppm MC for up to 14 weeks. Fatty liver, icterus, 
elevated SGPT and ICDH were reported in dogs at both concentrations. 
These effects appeared at 6-7 weeks of exposure to 1000 ppm MC and at 3 
weeks of exposure to 5000 ppm. Monkeys were less sensitive to hepatic 
injury, and showed no changes in liver enzymes and only mild to 
moderate liver changes at 5000 ppm MC. No liver alterations were 
detectable in monkeys exposed to 1000 ppm MC. Mice and rats developed 
liver toxicity at both exposure levels, characterized by increased 
hemosiderin pigment, cytoplasmic vacuolization, nuclear degeneration 
and changes in cellular organization.
    Hepatic effects associated with chronic MC exposure were observed 
in lifetime cancer bioassays in three rodent species: rats, mice and 
hamsters. In studies conducted by the NTP and Dow Chemical Co., rats 
were exposed to inhalation concentrations of MC from 50 ppm to 4000 ppm 
6 hours per day, 5 days per week [Exs. 7-8, 7-151, 7-173]. Hepatic 
effects were observed after exposure to MC concentrations as low as 500 
ppm. These effects were characterized by increased fatty liver, 
cytoplasmic vacuolization and an increased number of multinucleated 
hepatocytes. At higher doses (greater than 1500 ppm), increased numbers 
of altered foci and hepatocellular necrosis became apparent.
    Serota et al. [Ex. 7-180] administered 5 to 250 mg MC/kg body 
weight to rats in drinking water. Hepatic toxicity similar to that 
observed in the inhalation studies was reported at doses from 50 to 250 
mg/kg.
    In mice, the chronic hepatic effects of MC were investigated in two 
bioassays: NTP [Ex. 7-8] and Serota et al. [Ex. 7-179]. In the NTP 
study, mice were exposed by inhalation to 2000 or 4000 ppm MC. 
Cytologic degeneration was observed in both male and female mice and 
increased incidences of hepatocellular adenomas and carcinomas were 
found at both concentrations. The carcinogenic effects of MC are 
described in greater detail above, in the discussion of MC 
carcinogenicity.
    In a drinking water study, Serota et al. found that mice exposed to 
50 to 250 mg/kg/d MC had dose-related increases in the fat content of 
the liver (a sign of liver toxicity). Although some proliferative 
hepatocellular lesions were identified in this study, they were 
distributed across all exposure groups. Hepatocellular tumor incidences 
were not elevated above historical control incidences.
    In the hamster, Burek et al. [Ex. 7-151] found minimal treatment-
related changes in the livers of the MC-exposed animals after exposure 
to 500, 1500 or 3500 ppm MC. A dose-related increase in hemosiderin was 
found in male hamsters at 6 months and at 3500 ppm at 12 months. No 
other changes in liver physiology were reported.
    OSHA believes that these studies demonstrate that the rodent liver 
is not sensitive to acute affects of MC, but that chronic exposure to 
MC caused toxic effects in rat and mouse liver and cancer in mouse 
liver. These studies appear to have been well conducted and the 
differences in toxicity observed across studies were likely due to 
differences in dose or route of exposure. The hamsters appeared to be 
insensitive to liver toxicity. OSHA believes that this is most likely 
due to inherent species differences in response to toxicants.
    b. Human studies. OSHA evaluated epidemiological studies and case 
reports to determine the extent of hepatic effects detected after 
exposure of humans to MC. Liver toxicity was measured as alterations in 
the blood levels of any of several normal liver enzymes in these 
studies.
    i. Epidemiological studies. In a cross-sectional analysis of the 
health of workers in an acetate fiber production plant in which workers 
were exposed to 140 to 475 ppm MC, Ott et al. [Ex. 4-33c] reported 
statistically significant increases in serum bilirubin and alanine 
aminotransferase (ALT) (also known as serum glutamic pyruvic 
transaminase (SGPT)) when compared with a reference group of industrial 
workers. The elevation in bilirubin levels showed a dose-response 
relationship, but the ALT levels were not associated with MC exposure. 
The authors felt that the increase in ALT in MC-exposed workers could 
not be attributed to MC because a dose-response relationship was not 
demonstrated and, therefore, the increase in ALT between the exposed 
and reference populations could be disregarded as a sign of liver 
toxicity. The authors concluded that although bilirubin elevation may 
be interpreted as a sign of liver toxicity, this interpretation was not 
supported by alterations in other liver parameters. OSHA feels that ALT 
cannot be disregarded as unrelated to MC exposure based on the lack of 
dose response within the exposure group. The high variability of this 
parameter and the low numbers of individuals within certain exposure 
subgroups (e.g., 10 men exposed at 280 ppm), make a dose-response 
relationship more difficult to demonstrate. Any mistake made in the 
characterization in an exposure group would result in obscuring the 
dose-response relationship. Although the evidence is not unequivocal, 
OSHA believes that the elevated bilirubin coupled with the elevated ALT 
values indicate suggestive evidence of a hepatotoxic response to MC 
exposure in this worker population.
    In an update to the study described above, Cohen et al. [Ex. 7-75] 
found 4 cases of liver/biliary duct cancer in workers with more than 10 
years of exposure to MC and after 20 years from first hire. Further 
description of this study can be found in the discussion of MC 
carcinogenicity, above.
    In an English translation of a 1968 Czechoslovakian study, Kuzelova 
et al. [Ex. 7-26] found no liver enzyme abnormalities in workers 
exposed to MC concentrations from 29 ppm to 4899 ppm for up to two 
years. In contrast, in an English translation of a German study which 
focussed on neurological changes due to MC exposure, Hanke et al. [Ex. 
7-195] observed pathological liver function tests and hepatomegaly 
(enlarged liver) in 4 of 14 floor tile setters examined. These workers 
were chronically exposed to MC at concentrations as high as 400 to 5300 
ppm. The average tenure of employment of these workers was 7.7 years. 
The authors of the Hanke study noted that although MC with its 
impurities could be responsible for the liver damage, the evidence was 
not conclusive. OSHA has determined that there is insufficient evidence 
from the Kuzelova and Hanke studies to conclude that MC causes chronic 
human hepatotoxic effects.
    ii. Case reports. In addition to the cross-sectional analyses of 
worker morbidity described above [Exs. 4-33c and 7-26], the 
relationship of MC exposure and hepatotoxicity has been studied by 
analysis of case reports. Welch [Ex. 7-73] collected 144 case reports 
of clinical disease reported subsequent to occupational MC exposure. 
Quantitative exposure estimates for individuals were unreliable, but 
the presence of MC in the work environment was ascertained for each 
employee. The most prevalent findings in these case reports were CNS 
symptoms, upper respiratory syndrome and alterations in liver enzymes. 
The patterns of alteration in liver enzymes were not consistent among 
individuals, but may be suggestive of a MC-associated hepatotoxic 
effect. One case of hepatitis of unknown etiology was identified. The 
case physician believed

[[Page 1515]]

that the hepatitis was secondary to solvent exposure. The solvents to 
which this employee was exposed included xylene and methylethyl ketone 
as well as MC. OSHA believes that the confounding solvent exposures in 
the hepatitis case and the unknown exposure histories of the 
individuals with altered liver enzymes limit the interpretation of 
these studies. OSHA has determined that these case reports provide 
insufficient evidence to conclude that MC was the causative agent in 
these cases.
    Analysis of cases of fatal and near-fatal human exposures [Exs. 7-
18, 7-19] indicated no apparent acute alterations of liver function. 
Acute concentrations of MC which caused narcosis and even death were 
not associated with changes in liver enzymes.
    OSHA concludes that limited evidence supports the hypothesis that 
MC causes human hepatotoxicity, based on the data in the Ott study. The 
remaining studies and case reports do not provide clear evidence of a 
causative role of MC in hepatotoxicity. The Agency has set the exposure 
limits based on cancer and CNS effects and has not reached final 
conclusions on this issue.
4. Reproductive Toxicity
    There are only limited data available regarding the potential 
adverse teratogenic or reproductive effects due to MC exposure. 
Teratogenicity studies have been conducted in rats and mice and limited 
epidemiology and case reports have been described for humans.
    a. Animal studies. A study [Ex. 4-5] using chicken embryos 
indicated that MC disrupts embryogenesis in a dose-related manner. 
Since the application of MC to the air space of chicken embryos is not 
comparable to MC administration to animals with a placenta, the 
exposure effect seen in the chick embryos can only be considered as 
suggestive evidence that an effect may also occur in mammalian systems.
    The teratogenicity of inhaled MC has also been studied in rats and 
mice [Exs. 7-20, 7-21, 7-22]. In 1975, Schwetz et al. [Ex. 7-21] 
conducted a study on Swiss Webster mice. Mice were exposed to 1250 ppm 
MC for 7 hours/day, on days 6-15 of gestation. On day 18 of gestation, 
Caesarian sectioning of dams was performed. A statistically significant 
increase in mean maternal body weight (11-15%) was observed in dams 
exposed to 1250 ppm MC; however, food consumption was not measured. The 
only effect on fetal development associated with MC exposure was a 
statistically significant increase in the number of fetuses which 
contained a single extra center of ossification in the sternum. The 
incidence of gross anomalies observed in the MC-exposed fetuses was not 
significantly different from that in the control litters. Maternal COHb 
level during exposure reached 12.6%; however, 24 hours after the last 
exposure, COHb had returned to control levels.
    In the same study by Schwetz et al. [Ex. 7-21], Sprague-Dawley rats 
were exposed to 1250 ppm MC via inhalation for 7 hours daily on days 6-
15 of gestation. No MC-associated effects were observed in food 
consumption or maternal body weight. Among litters from MC-exposed 
dams, the incidence of lumbar ribs or spurs was significantly decreased 
when compared to controls, while the incidence of delayed ossification 
of sternebrae was significantly increased compared to controls. No 
increased incidence of gross anomalies were observed in the fetuses 
from exposed rats compared to fetuses from control litters. No MC-
associated effects were observed on the average number of implantation 
sites per litter, litter size, the incidence of fetal resorptions, 
fetal sex ratios or fetal body measurements, in the 19 litters that 
were evaluated. As observed in the MC-exposed mice, there was 
significant elevation of the COHb level in the dams, but the level 
returned to control values within 24 hours of cessation of exposure.
    In 1980, Hardin and Manson [Ex. 7-22] evaluated the effect of MC 
exposure in Long-Evans rats after inhalation of 4500 ppm for 6 hours/
day, 7 days/week prior to and during gestation. Four exposure groups 
were described. The first group was exposed to MC for 12 to 14 days 
prior to gestation and during the first 17 days of pregnancy. The 
second group was exposed to MC only during the 12 to 14 days prior to 
gestation. The third group was exposed to MC only during the first 17 
days of pregnancy. The fourth group (control group) was exposed only to 
filtered air. The purpose of this study was to test whether MC exposure 
prior to and/or during gestation was more detrimental to reproductive 
outcome in female rats than exposure during gestation alone.
    In rats exposed to MC during gestation, there were signs of 
maternal toxicity, characterized by a statistically significant 
increase in maternal liver weights. The only fetal MC effects observed 
were statistically significant decreases in mean fetal body weights. No 
significantly increased incidence of skeletal or soft tissue anomalies 
was observed in the offspring.
    In 1980, Bornschein et al. [Ex. 7-224] tested some of the offspring 
of the Long-Evans rats from Hardin and Manson's study described above. 
All four treatment groups were used to assess the postnatal toxicity of 
MC exposure at 4500 ppm. The general activity measurements of groups of 
5-day old pups showed no exposure-related effects. At 10-days of age, 
however, significant MC-associated effects were observed in both sexes 
in the general activity test. These effects were still apparent in male 
rats at 150-days of age. This study showed that maternal exposure to MC 
prior to and/or during pregnancy altered the manner in which the 
offspring react and adapt to novel test environments at up to 150-days 
of age. These effects suggest that MC exposure prior to, or during 
pregnancy may influence the processes of orientation, reactivity, and/
or behavioral habituation. No changes in growth rate, long-term food 
and water consumption, wheel running activity or avoidance learning 
were reported.
    OSHA concluded from the animal studies that maternal exposure to 
high concentrations of MC during pregnancy may have some adverse 
effects on the offspring, in particular with regard to behavioral 
effects. The Agency has set the exposure limits based on cancer and CNS 
effects and has not reached final conclusions on this issue.
    b. Human studies. Limited data have been collected on the 
reproductive effects of MC in male workers. In a study reported in the 
Occupational Safety and Health Reporter [Ex. 7-43], a greater risk of 
male sterility was found in male workers exposed to MC. In 1988, Kelly 
[Ex. 7-165] reported 4 cases of oligospermia in MC-exposed workers. 
This study was described in detail in the NPRM. Although the study 
provided some evidence of an effect of MC on male fertility, the 
observations were based on a small number of cases and OSHA believes 
that more research is necessary before causative conclusions can be 
drawn about the human male reproductive toxicity of MC.
    The reproductive and developmental effects due to MC exposure in 
female workers have also been studied. According to information 
reported in an English translation of an abstract of a Russian article 
by Vozovaya et al. [Ex. 7-16], detectable levels of MC were found in 
the blood, milk, embryonal, fetal and placental tissues of nursing 
women exposed to MC in a rubber product plant. No other information was 
provided in the abstract. In a study by Taskinen et al. [Ex. 7-199], 
increased rates of spontaneous abortions were observed in female 
pharmaceutical

[[Page 1516]]

workers exposed to MC. Exposure data were not reported in this study 
and it is unclear what confounding factors or other chemical exposures 
were present. OSHA believes that more research is necessary in order to 
evaluate the potential effect of MC on pregnancy outcomes, and so has 
not reached a conclusion on this issue.
    Carbon monoxide has well known adverse reproductive effects in 
humans. Since MC is metabolized to CO, OSHA was concerned about the 
adverse reproductive effects of CO as a metabolite of MC. The EPA has 
reviewed the literature on the effects of maternal CO exposure on the 
development of the fetus in the Air Quality Criteria for Carbon 
Monoxide [Ex. 7-201]. Very high maternal CO exposures have resulted in 
fetal or infant death or severe neurological impairment of the 
offspring. CO reduces the amount of oxygen available to the tissues. 
The developing fetus is very sensitive to these effects. According to 
Fechter et al. [Ex. 7-200], low levels of CO exposure in animals have 
been shown to adversely affect the fetus, producing CNS damage or 
reduced fetal growth. These effects suggest that the fetus may be 
especially sensitive to the toxic effects of MC through its metabolism 
to CO.
    As described above, OSHA is sufficiently concerned about the 
potential for reproductive health effects of carbon monoxide as a 
result of MC metabolism that it has decided to continue to gather 
information and revisit this issue, if warranted.

F. Conclusion

    OSHA's determination that MC is a potential occupational carcinogen 
was based primarily on the positive findings of chronic inhalation 
bioassays in rodents. MC is carcinogenic to mice of both sexes, 
producing lung and liver neoplasms. In rats, MC produced dose-related 
increases in mammary tumors and increases in the number of tumors per 
tumor-bearing rat. The evidence in rodents is supported by 
epidemiologic findings from cellulose triacetate fiber production 
workers and a case-control study of individuals with astrocytic brain 
cancer. The study of fiber production workers suggests an association 
between liver and biliary cancer and long term (greater than 10 years) 
exposure to MC. The case-control study indicates an association between 
risk of astrocytic brain cancer and occupational exposure to MC. This 
evidence is further supported by the findings of genotoxic activity of 
MC in bacterial and mammalian cell systems. OSHA has set the 8-hour TWA 
PEL of 25 ppm primarily to protect employees from the risk of cancer 
due to MC exposure in the workplace.
    CNS depression has been demonstrated in humans and animals at 
relatively low inhalation concentrations of MC. The CNS depression 
observed in those studies was relatively mild, although the effects 
occurred at concentrations in the range of the STEL of 125 ppm. OSHA 
believes that the STEL will be protective against CNS depression for 
most employees exposed to MC most of the time, but the Agency is 
sufficiently concerned about the potential for CNS health effects at 
concentrations below the STEL and have decided to continue to gather 
information and revisit this issue, if warranted.

VI. Quantitative Risk Assessment

Summary

    After examining all the available data, both animal and human, and 
both quantitative and qualitative, OSHA has concluded that MC is a 
multi-species, multi-site carcinogen in various rodent species, and is 
likely to be so in humans, and that it most probably acts via one or 
more genotoxic metabolite(s). The evidence for this conclusion is quite 
strong: there exist several positive bioassays with low background 
incidence and dose-related increases; there is an unusually large 
amount of mechanistic information; and there are several positive 
epidemiological studies and no negative epidemiological studies of 
sufficient power to rule out the animal-based potency estimates.
    Furthermore, OSHA has conducted a quantitative risk assessment 
based on the highest-quality animal tumor data, constructing a state-
of-the-art physiologically-based pharmacokinetic (PBPK) model 
incorporating rodent and human metabolic information. That analysis 
shows a final estimate of risk of 3.62 deaths per 1000 workers 
occupationally exposed to 25 ppm MC for a working lifetime. [An 
alternative analysis, which incorporated all of the data used in the 
main analysis plus the assumption that human enzymes are even less 
active to MC (as compared to mice) than that predicted by the main 
analysis, gave a risk estimate of 1.23 deaths per 1000]. Both estimates 
are clearly well above any plausible upper boundary of the 
``significant risk'' range defined by the Supreme Court, used by OSHA 
in its prior rulemakings, and reported in the scientific/economic 
literature on risk. The estimated risk at the current PEL of 500 ppm is 
126 excess cancers per 1000 workers; clearly, the 25 ppm standard will 
effect a substantial reduction in a very high risk. The Final Economic 
Analysis shows that the average risk at current exposure levels is 
approximately 7.6 deaths per 1000 and ranges up to 126 per 1000; at 
post-regulatory exposure levels (which account for the fact that the 
action level will encourage some employers, where feasible, to lower 
exposures below 25 ppm), average risk is estimated to be 1.7 deaths per 
1000 (and nowhere higher than 3.62 per 1000 risk at the new PEL of 25 
ppm)--also a substantial reduction of a highly significant risk.
    Prior to the October 1995 record reopening, there was strong 
evidence to support the determination that MC is a human carcinogen, 
using well-established risk assessment models based on substantial 
biologically-based evidence and theories: there were two multi-site 
positive bioassays with dose-response trends and low background, and 
suggestive epidemiology with no clearly conflicting epidemiology. The 
only question was whether to use an administered-dose scaling or a PBPK 
model.
    Data submitted in the reopening of the record in late 1995 shed 
light both on the hazard identification and the quantitative risk 
assessment. Studies of isoenzyme activity and intracellular 
distribution across species were interpreted by the Halogenated 
Solvents Industry Alliance (HSIA) to suggest that MC is not a human 
carcinogen. OSHA has concluded that the HSIA interpretation of the 
studies is not supported by the evidence. There are numerous 
methodological problems with the studies: for example, in the 
experiment in which Graves et al. examined MC-induced mutations [Ex. 
123], OSHA agrees with Dr. Douglas Bell [Ex. 126-26] that insufficient 
numbers of doses and mutants were examined to reach any conclusions 
whatsoever regarding differences in mutation spectra between chemicals.
    More importantly, OSHA and most commenters agreed that the data 
showed a quantitative--and quantifiable--difference between mice and 
humans, not an infinite, qualitative one. In other words, there is 
substantial evidence that humans and mice metabolize MC similarly, only 
at different rates. HSIA's qualitative argument rests on two 
questionable assumptions, both of which are contradicted by other data: 
first, that the DNA single strand break assay is infinitely sensitive--
but the investigators do not even know if it is sensitive enough to 
show the 7-fold difference in enzyme activity between mice and humans 
that OSHA's main

[[Page 1517]]

PBPK analysis uses; and second, that the human isoenzyme most active 
against MC, although clearly present in human cells, is located in a 
different part of the cell. This interpretation: 1) contradicts some 
basic beliefs of comparative physiology (Why would the cell structures 
of humans and mice be so fundamentally different?); 2) would require 
OSHA to do a ``subcellular PBPK analysis'' to predict risk--no one has 
ever developed, let alone parameterized and validated, such a model; 
and 3) contradicts other data on activation by mouse cytosolic 
preparations--MC has been shown to have enhanced mutagenicity in 
bacterial and mammalian cell preparations when mouse cytosolic 
preparations were used to metabolize the MC. This requires metabolism 
by cytoplasmic (not nuclear) GST and for the metabolites to be stable 
enough to cross membranes and interact with DNA.
    Therefore, the new studies do not cast doubt on the MC hazard 
identification--in fact, they should probably increase the level of 
concern because it is now more clear that MC is likely to act by a 
genotoxic mechanism [animal tests are most relevant to humans when 
clear genotoxic agents are involved] and that that pathway exists in 
humans, and may be concentrated in cells of concern in human cancers, 
such as the bile duct epithelium. OSHA notes that an epidemiologic 
study of cellulose triacetate fiber workers has shown a statistically 
significant increase in biliary duct tumors [Ex. 7-260].
    On the other hand, the new data did reinforce OSHA's decision to 
proceed with a PBPK-based risk assessment and helped OSHA to 
incorporate the best available scientific data into a PBPK model. Here 
OSHA presents two PBPK-based risk analyses, both of which represent 
substantial refinements over the applied-dose risk assessment and over 
previous PBPK analyses. OSHA's final risk assessment incorporates all 
reliable data--OSHA's alternative analysis, in addition to the data in 
the final risk assessment, also incorporates some suggestive/sparse 
data found in new studies. As stated above, both analyses estimate 
risks at 25 ppm well in excess of any possible boundary line between 
significant and insignificant risk.
    Both of OSHA's PBPK analyses made two major advances: 1) the use of 
non-independent Monte Carlo simulation--Monte Carlo simulation is a 
well-developed computational technique that allows the modeler to take 
estimates of uncertainty in each of the many variables in a complex 
model and generate a quantitative estimate of the total uncertainty in 
the result. Others have used Monte Carlo simulation in PBPK modeling, 
but OSHA added information on the covariance structure of all the 
parameters, so that the uncertainty estimate would not be biased 
(exaggerated, probably) by incorrectly assuming that all the variables 
could simultaneously be at their lowest or highest values; and 2) the 
use of Bayesian analysis--this allows uncertainty distributions to be 
better estimated (narrowed) by cross-checking them against other 
independently-collected data from laboratory experiments, rather than 
simply guessing how big the uncertainties are and not refining the 
estimates as the model runs.
    Both these advances enabled OSHA to strike a balance between two 
unsatisfactory extremes--a) the extreme overconfidence of using 
estimates for each variable that did not allow for any uncertainty--or 
b) the extreme ``underconfidence'' of assuming that all uncertainties 
are independent of each other and of other laboratory data. The result 
is an analysis that tells what science knows and does not know about 
the relationship between ambient concentrations and the putative 
relevant dose measure (concentration of GST metabolites in the target 
organ) in mice and humans.
    Again, OSHA's final risk assessment regards the very limited human 
data base on GST-0 activity [a total of 39 liver samples and 5 lung 
samples] as useful, but insufficient to discard the traditional 
``allometric'' assumption (the well-validated assumption that, as a 
general rule, metabolic parameters scale proportional to a function of 
the animal's body weight). OSHA's alternative analysis accepts the 
limited human data at face value to extrapolate without using 
allometry. OSHA has concluded that the main analysis is better 
supported by available evidence than is the alternative analysis, but 
both yield significant risks. An important caveat is that both models 
are strictly applicable to humans who are physiologically similar to 
the six subjects analyzed by Dow (see the discussion later in this 
document for a fuller explanation). Since the population of 200,000 
workers will be much more heterogeneous than those six subjects, we 
regard these estimates as ``overconfident''--some workers exposed at 25 
ppm will have higher risks than 3.6 per 1000 (although some may have 
lower risks as well).

Introduction

    OSHA performs quantitative risk assessment, when information 
permits, to help determine the Permissible Exposure Limit (PEL) for 
toxic substances (contingent on the feasibility determination). The 
first step of assessing risks to human health is hazard identification. 
This step results in the determination that an exposure to a toxic 
substance causes, is likely to cause, or is unlikely or unable to 
cause, one or more specific adverse health effect(s) in workers. This 
identification also shows which studies have data that would allow a 
quantitative estimation of risk.
    If studies are available that contain information regarding the 
amount of exposure and disease, mathematical modeling allows 
extrapolation of the information in the study to conditions of concern 
in the workplace. OSHA uses these risk estimates to determine whether 
exposure results in significant risk, and whether the standards 
considered by OSHA substantially reduce the risk.
    This section describes the record evidence received during the 
public rulemaking concerning OSHA's quantitative risk assessment and 
the reasons OSHA has maintained or modified its opinion from the 
proposal. In the following sections, the evidence supporting and 
casting doubt on the hypothesis that MC is a probable carcinogen (the 
``Hazard Identification'' issues) is discussed first. Then the results 
of OSHA's quantitative risk assessments, conducted to estimate the 
carcinogenic potency of MC, are discussed.

A. Methylene Chloride Hazard Identification

    Animal and human evidence, summarized in the health effects 
section, indicates that MC can cause cancer, cardiac effects, central 
nervous system damage and other health effects. As described in the 
NPRM, OSHA's preliminary quantitative risk assessment was based on 
cancer and relied on rodent bioassay data for quantitation of risks. In 
1986, the National Toxicology Program (NTP) concluded that the mouse 
bioassay data provided ``clear evidence'' of carcinogenesis in male and 
female mice, based on the liver and lung tumors. The NTP also 
determined that the rat mammary tumors observed in the bioassay 
provided clear evidence of carcinogenesis in female rats and some 
evidence of carcinogenesis in male rats. This evidence of cancer in 
multiple species and in both sexes underlies the concern for MC as a 
potential human carcinogen. On the basis of these studies, IARC has 
classified MC as a 2B carcinogen, the EPA has classified MC as a B2 
carcinogen and NIOSH has

[[Page 1518]]

classified MC as a potential occupational carcinogen. OSHA concurred 
with these assessments.
    Animal bioassays are a critical tool in determining the potential 
hazard of a substance for humans. Virtually all of the toxic substances 
that have been demonstrated to be carcinogenic in humans are also 
carcinogenic in laboratory animals. Although it is possible that a 
substance may be carcinogenic in a laboratory species, but not in 
humans, it is reasonable to suspect that substances that cause cancer 
in multiple animal species and at multiple target organ sites would be 
carcinogenic in humans. Therefore, in the absence of sufficiently 
powerful negative epidemiological studies or mechanistic studies 
demonstrating that the purported carcinogenic mechanism of action of 
the substance is irrelevant to humans, OSHA and other federal agencies 
rely on well-conducted, high-quality bioassays as the primary basis for 
their hazard identification and risk assessment. This is the case with 
MC.
    During this rulemaking, some commenters have supported and others 
have questioned the hazard identification of MC as a potential human 
carcinogen. Most recently, some commenters contested the relevance of 
the mouse bioassay data for extrapolating to human cancer risks. 
Although these issues were raised by some rulemaking participants 
earlier in the rulemaking process, they were most thoroughly explored 
in connection with the information received by the Agency in late 1995. 
On October 24, 1995, OSHA reopened the MC record to receive comments on 
several studies submitted to the Agency by the Halogenated Solvents 
Industry Alliance (HSIA) pertaining to the mechanism of action of MC 
carcinogenesis in mice, and the implications of these studies for 
estimating human risks. The record closed on November 29, 1995, but was 
reopened in order to give the public additional opportunity to comment 
on the submitted studies. The record then closed on December 29, 1995. 
Thirty-seven comments were received on this topic and reviewed as part 
of this rulemaking.
    The papers submitted by the HSIA consisted of a cover letter [Ex. 
117], an overview of the sponsored research [Ex. 118] and seven 
research papers on the mechanism of MC carcinogenesis [Ex. 119-124A]. 
The hypothesis under investigation in these seven studies was that the 
pathways of MC metabolism and the mechanism of carcinogenesis in the 
mouse represented a unique situation that would not take place in 
humans, making the mouse unsuitable as the basis for extrapolating 
risks of cancer to humans. The specific studies are described briefly 
here and the comments received during the reopening of the rulemaking 
record are discussed in detail below.
1. Summary of Studies Submitted by HSIA
    Exhibit 119 ``Methylene Chloride: an inhalation study to 
investigate toxicity in the mouse lung using morphological, biochemical 
and Clara cell culture techniques,'' J.R. Foster, T. Green, L.L. Smith, 
S. Tittensor, and I. Wyatt, Toxicology 91 (1994) 221-234.
    This study investigated the potential role of MC as a mouse lung 
carcinogen via non-genotoxic mechanisms and the Clara cell as the cell 
of origin in mouse lung cancer. The hypothesis was that MC acts 
specifically to produce toxicity (vacuolation) in Clara cells which 
leads to cell proliferation and production of mouse lung tumors. The 
authors investigated the toxicity of MC in bronchiolar Clara cells by 
measuring the production of vacuoles after exposure to MC. The 
investigators also measured DNA synthesis in Clara cells isolated from 
mice exposed to MC as a measure of cell proliferation.
    The authors observed a transient vacuolation of bronchiolar Clara 
cells in mice exposed to 2000 and 4000 ppm MC, but not in mice exposed 
to 0, 125, 250, 500 or 1000 ppm MC. When the mixed function oxidase 
(MFO) pathway was inhibited, the bronchiolar cell vacuolation observed 
after exposure to 2000 and 4000 ppm MC was reduced. Inhibition of the 
glutathione S-transferase pathway (GST) had no effect on Clara cell 
vacuolation. The researchers also found that exposure of mice to 1000 
ppm MC or greater for 6 hours induced an increase in DNA synthesis in 
Clara cells cultured in vitro from exposed animals.
    Clara cells are present in mice, rats and humans, but appear to be 
more abundant in mice than other species. Clara cells contain enzymes 
for both the MFO and glutathione S-transferase (GST) pathways of MC 
metabolism. According to the authors, the results of this study suggest 
that metabolism of MC via the MFO pathway induces a transient toxicity 
in Clara cells and a transient increase in DNA synthesis.
    Exhibit 120 ``Methylene chloride-induced DNA damage: an 
interspecies comparison,'' R.J. Graves, C. Coutts and T. Green, 
Carcinogenesis, vol. 16 no. 8 pp. 1919-1926, 1995.
    This study investigated the role of MC as a mouse carcinogen via a 
genotoxic mechanism of action. The hypothesis under investigation was 
that MC is metabolized to a genotoxic carcinogen via the GST pathway to 
different extents in different species and that expression of this 
genotoxicity correlates with risk of developing cancer across species. 
The authors used production of single strand (ss) DNA breaks as a 
measure of genotoxicity. The researchers measured DNA ss breaks in lung 
and liver cells from mouse, rat, hamster and humans. They observed 
increased DNA ss breaks in mouse liver cells, after in vivo exposure to 
4000-8000 ppm MC for 6 hr and in mouse lung cells after exposure to 
2000-6000 ppm MC. Depletion of glutathione in the liver (after 
administration of buthionine sulfoximine) reduced the amount of ss 
breaks observed. No increase in ss breaks was observed in Clara cells 
isolated from mice exposed to MC in vivo. However, in experiments on 
isolated mouse Clara cells, the authors observed increased DNA ss 
breaks in cells exposed to concentrations of MC of 5 mM and above.
    No increases in ss breaks above control levels were detected in rat 
livers after exposure to 4000 ppm for 6 hr or in rat lungs after 
exposure to 4000 ppm for 3 hr. Increases in ss breaks were also not 
detected in hamster and human liver cells after exposure to MC in vitro 
at concentrations up to 90 and 120 mM.
    In Chinese hamster ovary (CHO) cells, MC plus mouse liver cytosol 
(which contains the GST enzymes) also induced ss breaks, while 
incubation of CHO cells with MC in the presence of mouse liver 
microsomes (which contain the MFO enzymes) did not increase ss breaks.
    The results suggest that mouse liver and lung cells are more 
susceptible to MC-induced ss breaks than cells from rats, hamsters or 
humans. Assuming that ss breaks are a relevant surrogate for 
carcinogenicity, the authors infer from this study that humans, rats 
and hamsters are insensitive to MC-induced liver cancer, because those 
species lack the high level of GST metabolic activity to MC found in 
the mouse liver cell and lung Clara cell.
    Exhibit 121 ``Isolation of two mouse theta glutathione S-
transferases active with methylene chloride,'' G.W. Mainwaring, J. Nash 
and T. Green, Zeneca Central Toxicology Laboratory, 1995.
    This study was conducted in order to characterize the mouse GST 
isozyme(s) responsible for MC metabolism. The results of this work 
could be used to explore the hypothesis that a particular GST isozyme 
was responsible for metabolizing MC to the carcinogenic metabolite and 
that there may be different concentrations of this enzyme across 
species.

[[Page 1519]]

    The researchers used a variety of chromatography methods to isolate 
two mouse glutathione S-transferases (MT-1 and MT-2, also known as T1-
1* and T2-2*, respectively) which metabolize MC, comparing the observed 
enzyme activity with that described in rats. Rats were found previously 
to have two GST isomers in the theta class (GST 5-5 and GST 12-12) 
which metabolized MC. The mouse MT-1 and MT-2 enzymes were found to be 
closely related to rat GST 5-5 and 12-12, respectively, and the 
specific activity of mouse MT-1 was found to be similar to rat GST 5-5. 
GST 12-12 and MT-2 were found to be extremely labile during 
purification, and so the specific activities of those isozymes have not 
been measured.
    The results of this study suggest that the mouse and rat contain 
GST theta enzymes similar in amino acid sequence and in specific 
activity (GST 5-5 and MT-1). The authors postulate that the greater 
conjugating activity seen in mice in other studies is ``probably due to 
a difference in expression of the enzyme or to a significant 
contribution from MT-2'' [Ex. 121].
    Exhibit 122 ``Mouse Liver glutathione S-Transferase Mediated 
Metabolism of Methylene Chloride to a Mutagen in the CHO/HPRT Assay,'' 
R.J. Graves and T. Green, Zeneca Central Toxicology Laboratory, 1995.
    This study investigated the mutagenicity of MC as a potential 
carcinogenic mechanism of action. The purposes of this study were to 
clarify the ability of MC to act as a mutagen, because studies in 
mammalian systems have yielded mixed results regarding the mutagenicity 
of MC, and to more fully characterize the metabolite purportedly 
responsible for MC mutagenicity by comparing the results to 
formaldehyde (one metabolite of MC by the GST pathway). Mutagenicity 
was measured by assaying CHO cells in vitro for mutations at the HPRT 
locus of DNA. Ss DNA breaks were also monitored. Cells were exposed in 
culture to MC mouse liver cytosol metabolites (which include metabolic 
enzymes for the GST but not the MFO pathway), formaldehyde (one of the 
MC GST metabolites) or 1,2-dibromoethane (1,2-DBE) (a reference 
genotoxin).
    Using standard techniques, MC GST metabolites were shown to be 
weakly mutagenic using the CHO/HPRT assay. Formaldehyde was also 
determined to be weakly mutagenic in this assay, but the effect was not 
as great as with MC GST metabolites. 1,2-DBE, as expected, showed a 
potent mutagenic response. The mutagenicity of MC GST metabolites and 
formaldehyde was increased when cell density was increased, cells were 
exposed in suspension rather than as attached cultures and cytosol 
concentration was optimized.
    MC mouse liver cytosol metabolites were observed to increase ss DNA 
breaks in CHO cells exposed in suspension, but caused only marginal 
increases in DNA-protein cross-links. In contrast, the researchers 
found that formaldehyde induced both DNA ss breaks and DNA-protein 
cross-links. Slight increases in ss DNA breaks were also seen with 
exposure to either MC alone or the cytosol fraction alone.
    Based on a comparison of the mutagenic effects of the three 
compounds, particularly on the lack of MC-induced DNA-protein cross-
linking in this experimental system, the authors concluded that 
formaldehyde does not play a major role in MC mutagenicity. 
Accordingly, the researchers viewed the results of this study as 
supporting the hypothesis that the DNA ss breaks induced by MC, and the 
resultant DNA mutations, are caused by interaction of S-chloromethyl-
glutathione (formed by the GST pathway) with DNA.
    Exhibit 123 ``DNA Sequence Analysis of Methylene Chloride-Induced 
HPRT Mutations in CHO Cells: Comparison with the Mutation Spectrum 
Obtained for 1,2-Dibromethane and Formaldehyde,'' R.J. Graves, P. 
Trueman, S. Jones and T. Green, Zeneca Central Toxicology Laboratory, 
1995.
    The purpose of this study was to describe the types of mutations 
induced by MC in order to further characterize the GST metabolite 
likely to cause MC mutations and therefore perhaps be responsible for 
the carcinogenicity of MC in the mouse. The spectrum of mutations in 
the HPRT locus of CHO DNA induced by MC plus mouse liver cytosol was 
compared to mutations induced by formaldehyde (a GST metabolite of MC) 
or 1,2-dibromoethane (1,2-DBE, a reference genotoxin).
    The results were expressed as a sequence analysis of 11 MC-induced 
mutations, 6 formaldehyde-induced mutations and 13 1,2-DBE-induced 
mutations. In comparing the distribution of types of mutations, the 
results suggested to the researchers that formaldehyde-induced DNA 
damage can contribute to MC mutagenicity, but that the majority of the 
mutations were derived from other types of DNA damage, probably via an 
interaction of S-chloromethylglutathione with DNA. The researchers 
noted that a glutathione conjugate also plays a role in the 
mutagenicity of 1,2-DBE. The increases above background mutation 
frequency detected through this study were 24.7-fold for 1,2-DBE, 4.7-
fold for formaldehyde, and 8-fold for MC.
    Exhibit 124 ``The distribution of glutathione S-transferase 5-5 in 
the lungs and livers of mice, rats and humans'' [Preliminary 
communication, T. Green, 1995].
    Exhibit 124A ``The distribution of theta class glutathione S-
transferases in the liver and lung of mouse, rat and human.'' G.W. 
Mainwaring, S.M. Williams, J.R. Foster and T. Green,1995.
    The preliminary communication [Ex. 124] and the unpublished report 
which followed [Ex. 124A] summarized the results of a study comparing 
the inter- and intra-cellular distribution of the messenger RNA (mRNA) 
for a glutathione S-transferase (GST) isoenzyme which metabolizes MC in 
the lungs and livers of mice, rats and humans. The purpose of the 
experiments summarized in these reports was to describe the 
distribution of the mRNA for the GST theta isozyme believed to be 
responsible for metabolism of MC to a carcinogenic metabolite in 
different species. The researchers believed that differences in 
distribution of the mRNA for this isozyme would correlate with 
differences in distribution (and activity) of the isozyme itself, and 
might explain differences in sensitivities of the species to the 
carcinogenicity of MC.
    The distribution of GST theta mRNA was visualized using DNA 
oligonucleotide anti-sense probes complementary to the nucleotide 
sequences for the GST theta isozymes. This technique is used to 
visualize the mRNA coding for a specific protein (such as the GST theta 
isozymes) within cells in tissues. The mRNA is a nucleotide sequence 
transcribed from the DNA containing the gene for the specific protein. 
After transcription, mRNA is transported to the cytoplasm, where it is 
translated into the amino acid sequence which becomes the specific 
protein (in this case, the GST theta isozyme). The finished protein 
then migrates to its final site of activity within the cell. 
Localization of the mRNA does not necessarily correspond to 
localization of the specific protein.
    The results of the study showed that the GST-specific mRNA could be 
found in lungs and livers of all three species. Mouse liver cells 
(particularly the nuclei) and mouse lung cells appeared (from the 
photomicrographs shown in the article) to stain more heavily for the 
GST mRNA than the lung or liver cells from rats or humans. Although the 
amount of GST-specific mRNA was not quantified in this study, the 
authors interpreted the photographs to suggest that, ``* * * mouse 
tissues are stained

[[Page 1520]]

much more heavily than sections from either rat or human.'' Based on 
the intracellular and intercellular distribution of the GST mRNA, the 
authors stated,

    The most significant findings are the presence of very high 
concentrations of GST 5-5 mRNA in specific cells and nuclei of mouse 
liver and lung. Metabolism of methylene chloride at high rates and 
within nuclei to a reactive but highly unstable glutathione 
conjugate is believed to facilitate alkylation of DNA by this 
metabolite. The lack of high or nuclear GST 5-5 concentrations in 
rat and human tissue, provides an explanation for the lack of 
genotoxicity in these species. [Ex. 124]

    In the letter submitting the studies summarized above to OSHA, HSIA 
characterized the studies as follows:

    This research, which is now complete, shows that B6C3F1 mice * * 
* are uniquely sensitive at high exposure levels to methylene 
chloride-induced lung and liver cancer, and that other species, 
including humans, are not at similar risk. [Ex. 117]

They went on to conclude:

    As a result of this research program, it appears that there are 
no foreseeable conditions of human exposure in which the 
carcinogenic effects seen in mice would be expected to occur in man. 
* * * The risk assessment that is the basis for the methylene 
chloride standard, which is in turn based on the increased liver and 
lung tumor incidence observed in the mouse bioassay, must be 
discarded in favor of scientific data that are relevant to human 
risk.

In response to the request by HSIA, OSHA has reviewed the cancer hazard 
identification of MC based on all of the evidence in the MC record, 
with particular emphasis on the validity of the conclusion stated 
immediately above. This review is presented below.
2. Carcinogenesis of Methylene Chloride
    a. Animal evidence. Several long-term MC bioassays have been 
conducted and are summarized in the Health Effects section. These 
included studies in which the route of exposure was inhalation [Burek 
et al., Ex. 4-25, Nitschke et al., Ex. 7-29, and NTP, Ex. 4-35] and two 
studies in which the route of exposure was drinking water [National 
Coffee Association, Exs. 7-30, 7-31]. In order to ensure full 
consideration of the data, OSHA analyzed in its preliminary assessment 
all data sets which showed an elevated incidence of tumors in a MC-
exposed group, compared to controls, whether or not the elevation of 
tumor response was statistically significant. This analysis and the 
individual datasets used were described in detail in the NPRM.
    In the NTP bioassay [Ex. 4-35], groups of 50 nine-week old 
B6C3F1 mice of each sex were exposed by inhalation to 0, 2000 or 
4000 ppm MC. Groups of 50 eight-week old F344/N rats of each sex were 
exposed to MC at concentrations of 0, 1000, 2000, or 4000 ppm. The 
inhalation exposures were administered 6 hours a day, 5 days a week for 
102 weeks. Food was provided to the animals ad libitum except during 
the exposure periods, while water was available at all times via an 
automatic watering system. All animals were observed twice a day for 
mortality and moribund animals were sacrificed. Clinical examinations 
were performed once a week for 3.5 months, then twice a month for 4.5 
months, and once a month thereafter. Each animal was also weighed 
weekly for 12 weeks, then monthly until the conclusion of the study at 
102 weeks. All animals were necropsied and histologically examined. 
Three different neoplastic lesions were observed to have significantly 
increased incidence over the controls: adenomas and carcinomas of the 
lung in male and female mice, adenomas and carcinomas of the liver in 
male and female mice, and mammary gland fibroadenomas and fibromas in 
male and female rats.
    HSIA and others argued that benign tumors, especially the mammary 
tumors in the rats, should not be counted as a carcinogenic response. 
The NTP has addressed that issue in its Technical Report [Ex. 4-35] and 
has concluded that the benign mammary tumors observed in the F344 
female rats are ``clear evidence'' of carcinogenicity and noted that 
such tumors may proceed to malignancy. OSHA agrees with this 
determination and has considered the rat mammary tumors as part of its 
cancer hazard identification for MC. However, OSHA's quantitative risk 
assessment does not consider rat mammary tumor responses.
    OSHA believes that the NTP studies provide the strongest evidence 
of carcinogenicity of MC in animals. Many commenters and hearing 
participants [Exs. 19-46, 7-128, 7-126, 25-E, 126-11,126-12, 126-16 and 
others] supported the use of the NTP mouse study as the basis for 
quantitative risk assessment. There are several reasons for this 
described in the proposal and earlier in this document. In brief, the 
NTP study used well established standard operating procedures that are 
generally considered a predictor of a potential carcinogenic response 
in humans. This study was also replicated by a second partial bioassay, 
conducted by NTP, in which groups of female mice were exposed to 2000 
ppm MC for 2 years. Statistically significant increases in alveolar/
bronchiolar and hepatocellular tumors were observed [Ex. 27].
    Before the 1995 record reopening, some commenters had raised 
specific arguments why a mouse study might not predict human 
carcinogenic response to MC. Mr. Krenson of Besway Systems [Tr. 397, 9/
17/92] objected to OSHA using the NTP mouse study as the basis for 
setting the PELs for MC. He believed that the mouse was irrelevant to 
human risk because the doses used were ``extremely high'' and that he 
believed that tests conducted on rats, hamsters and human 
epidemiological investigations showed ``no conclusive proof of cancer 
in human beings.'' OSHA disagrees with Mr. Krenson's conclusion. In 
general, high doses in rodent bioassay studies are appropriate to 
elicit a response due to the practical limitations on the number of 
animals that can be used in a study. In MC, there was no observed acute 
toxicity at the levels used in the study, which is an indication that 
the doses were not too high. Use of high doses in bioassay studies is 
common and its practical necessity has been affirmed by numerous expert 
bodies, including several committees of the National Academy of 
Sciences. In addition, for every known human carcinogen, positive 
results were obtained at high rodent doses. Also, quantitative 
comparisons, as conducted by Allen and Crump in 1988, demonstrate that, 
in general, observations of cancer potency from epidemiology studies 
agree with estimates of potency derived from rodent bioassay data. In 
the case of MC, statistically significant excess tumors were observed 
in mice after exposure to only 2000 ppm, or only four times the former 
PEL of 500 ppm (8-hour TWA), and excess tumors were seen in rats at 
4000 ppm. This level is within the range of human exposures experienced 
in occupational settings. Certainly the lower exposure showing 
substantial effect was not ``extremely high'' in relation to the 
exposure limit, as Mr. Krenson claimed.
    The HSIA and several others [Exs. 117, 126-1, 126-3, 126-5,126-
6,126-8,126-10, 126-13,126-20, 126-21, 126-29] also objected to using 
the mouse data as the basis of human risk assessment, based on the 
mechanism of action studies submitted to the Agency by HSIA on December 
6, 1995. OSHA's analysis of the individual studies follows, but 
overall, the Agency has determined that the mouse cancer data are 
appropriate for assessment of the cancer risks to humans (although, as 
discussed later in this section, OSHA has made extensive use of the 
submitted data to modify the quantitative

[[Page 1521]]

estimates of risk derived from the mouse model).
    b. Evidence pertaining to the mechanism of action of methylene 
chloride. Several lines of evidence relate to the mechanism of 
carcinogenesis of MC. The issues discussed in the papers submitted by 
the HSIA and subsequent comments can be divided into those pertaining 
to genotoxicity, those discussing potential non-genotoxic modes of 
action, and those related to the enzymatic metabolism of MC. Although 
some comments overlap these divisions, this organization is used in 
this discussion to simplify consideration of the issues.
    (1) Genotoxicity. It has not been conclusively demonstrated that MC 
or its metabolites act by a genotoxic mechanism in mice and rats. 
Substance-specific DNA adducts, which are among the strongest evidence 
of direct genotoxicity, have not been identified from MC exposure. 
However, evidence has been accumulating that MC is likely to be 
carcinogenic through a genotoxic mechanism of action. For example, DNA-
protein cross-links have been demonstrated in mouse liver [Ex. 21-16], 
increases in unscheduled DNA synthesis have been demonstrated in mouse 
lung [Ex. 126-25] and other evidence of MC metabolite interaction with 
mammalian DNA (such as increases in ss DNA breaks) has been observed. 
It is not necessary for a substance to bind covalently with DNA in 
order to act via a genotoxic mechanism, although evidence of covalent 
binding is a strong indication of genotoxicity. In the case of MC, 
although the reactive metabolites are presumed to exert a genotoxic 
effect by binding to DNA, no MC metabolite-DNA adducts have yet been 
identified. However, RNA adducts have been identified after MC 
exposure, which supports the hypothesis that MC acts by a genotoxic 
mechanism. Substance-specific DNA adducts have also not been identified 
for some other carcinogens which are presumed to act via a genotoxic 
mechanism.
    In addition, as discussed in the Health Effects section, MC has 
been found to be mutagenic in bacterial, yeast, Drosophila and 
mammalian systems; associated with chromosomal aberrations in CHO 
cells; and associated with sister chromatid exchanges in mammalian cell 
culture systems, such as CHO and V79 cells.
    Investigations of the role of metabolites of the GST pathway in the 
bacterial mutagenicity of MC found that in glutathione-deficient 
strains of Salmonella typhimurium MC-induced mutations were reduced 
[Ex. L107]. Mutation rates returned to normal when bacteria were 
supplemented with exogenous glutathione. This study supports the 
hypothesis that MC may act as a genotoxic carcinogen via its GST 
metabolites, although a study of similar design by Dillon et al. [Ex. 
21-89] did not replicate these results.
    (i) MC induced mutuations. Studies on the MC mechanism of 
carcinogenesis included two studies on the mutations induced by MC in 
the CHO/hypoxanthine phosphoribosyl transferase (HPRT) assay. In the 
1995 study by Graves et al. [Ex. 122], the investigators compared 
mutations induced by MC with those induced by formaldehyde and 1,2-
dibromoethane. The authors characterized the results of the studies as 
follows:

    Using the CHO/HPRT assay we have shown that MC is metabolized to 
a mutagen by mouse liver cytosol in a reaction which is dependent 
upon GST and GSH. Mutagenicity was enhanced by exposing the cells at 
high density in suspension rather than as attached cultures, which 
is consistent with the critical metabolites being extremely short-
lived.

The authors also observed that the MC-induced mutations were associated 
with an increase in DNA ss breaks. They remarked, ``The results suggest 
that MC-induced DNA ss breaks seen in other cell types are associated 
with DNA damage which can lead to mutation.''
    In a follow-on to the CHO/HPRT study, Graves et al. [Ex. 123] 
conducted a sequence analysis of HPRT mutations in CHO cells, comparing 
the spectrum of MC-induced mutations with those induced by 1,2-
dibromoethane or formaldehyde. The investigators analyzed 28 HPRT 
mutations: 13 from 1,2-dibromoethane experiments, 6 from formaldehyde 
experiments, and 11 from MC experiments. The authors characterized 
their results as follows,

    All three compounds induced primarily point mutations, with a 
small number of insertions and deletions. * * * The mutation 
sequence results for MC suggest that formaldehyde may also play a 
role in MC mutagenesis, although the majority of mutations arise 
from other types of DNA damage, probably DNA adducts formed by 
reaction of S-chloromethyl glutathione with DNA.

    Dr. Douglas A. Bell of NIEHS [Ex. 126-26] had specific comments 
regarding the study on the mutation spectra [Ex. 123]. He stated,

    This experiment is extremely weak scientifically and not of 
publication quality. It is unlikely that such a naive experiment 
could detect differences in spectra between the different chemicals 
tested. To test the hypothesis that there are chemical specific 
mutation spectra requires analysis of hundreds of mutants at several 
different doses. This exhibit contains no useful information for 
risk assessment.

    OSHA agrees with Dr. Bell that there are serious methodological 
problems with the paper. The Agency also agrees with Dr. Bell that the 
important information in these two studies is that MC increases the 
mutation frequency, showing a clear genotoxic effect.
    (ii) Single strand DNA breaks. In a 1995 study, Graves et al. [Ex. 
120] investigated the role of MC exposure in development of single 
strand (ss) DNA breaks in the lung and liver of mice and rats and in 
hamsters and human cell cultures. The authors observed a transient, 
dose-related increase in DNA ss breaks in mouse hepatocytes after 
inhalation exposure to MC. No increased amount of ss breaks was 
observed in rat liver cells exposed to MC as compared to control cells. 
The authors also reported a decrease in the amount of ss DNA breaks in 
liver and lung when a glutathione depletor was administered to mice 
immediately before MC exposure.
    In mouse and rat hepatocytes incubated with MC, the authors found 
increases in ss breaks, but no increases in ss breaks in hamster or 
human hepatocytes exposed in vitro were observed. No increase in DNA 
damage was observed in CHO cells exposed to MC plus mouse liver 
microsomes, while MC plus mouse liver cytosol induced detectable ss DNA 
breaks.
    The authors characterized their findings in the lung as follows:

    Here we show that Clara cells are also sensitive to MC-induced 
DNA ss breaks and that the DNA-damaging metabolites are derived from 
the GST pathway. * * * Overall, these findings support the proposal 
that Clara cells are the cell of origin of MC-induced mouse lung 
tumors.

For liver cancer, the investigators concluded:

    These studies suggest that humans (and rats and hamsters) are 
insensitive to MC-induced liver cancer.

    Commenters raised issues about the relevance and utility of ss DNA 
breaks in assessing the genotoxicity of MC. Dr. Karl T. Kelsey [Ex. 
126-34] and Dr. Miriam Poirier [Ex. 126-37] raised concerns about the 
sensitivity of the DNA ss break assay for detecting genotoxic effects.

Specifically, Dr. Kelsey stated,

    Reviewing the literature, considerable weight seems to fall upon 
the measure of DNA single strand breaks. I have serious concerns 
about this assay. It is well known that the assay is extraordinarily 
difficult to standardize and is sensitive only to very high doses of 
genotoxic compounds. This data,

[[Page 1522]]

therefore, is certainly not compelling; persuading any competent 
independent scientist of its relevance to humans would be difficult.

Dr. Poirier was concerned with the sensitivity of the DNA single strand 
break assay and the relevance of DNA ss breaks to carcinogenesis. She 
remarked that ss DNA breaks and mutagenicity are secondary indicators 
of DNA damage. She indicated that a better measure of genotoxicity 
would be formation of DNA adducts. Dr. Errol Zeiger [Ex. 126-28] of 
NIEHS agreed, stating,

    If the mechanism of carcinogenicity is through an alkylating S-
chloromethyl GSH complex, there should be evidence of DNA adducts in 
vitro and in vivo.

    OSHA agrees that DNA adducts are strong evidence of genotoxicity 
and that ss DNA breaks and mutagenicity are not as specific or relevant 
as indications of a genotoxic mechanism of action. However, the Agency 
has determined that, even in the absence of identified MC-specific DNA 
adducts, the accumulated evidence suggests that MC interacts with DNA 
via a genotoxic mechanism of action and that the GST pathway is a 
plausible carcinogenic pathway.
    Dr. Melnick [Ex. 126-33] stated, ``* * * it has not been 
demonstrated that the carcinogenicity of MC in mice is dependent solely 
on the induction of DNA single strand breaks.'' Dr. Andrew G. Salmon 
concurred with this analysis and also raised a serious concern about 
the ability of the assay even to detect increases in ss breaks, 
regardless of their relevance:

    Green's account states that ``mouse hepatocytes were * * * 20-
fold * * * more sensitive to the effects of methylene chloride 
[i.e., DNA strand breaks] than rat hepatocytes * * * '' and no 
breaks were detected in hamster or human liver cells. This is 
translated in the discussion to an assertion that not only humans 
and hamsters but also rats are completely immune to the carcinogenic 
effect of methylene chloride. However, the data simply do not 
support the assertion of a categorical difference as proposed by the 
HSIA. This particular work also raises a number of other issues, 
such as whether the liver is an appropriate model tissue, and 
whether single-strand breaks are an appropriate indicator of the 
type of genetic damage produced by the putative genotoxic 
metabolites of methylene chloride.

    OSHA agrees that the ss DNA break assay is not as sensitive as 
other methodologies for assessing the genotoxic potential of MC in 
different systems and therefore data from the ss DNA break study must 
be interpreted in a quantitative, not qualitative context, with 
allowance for uncertainty in assay sensitivity. It is also unclear 
whether ss DNA breaks are the appropriate surrogate measure for 
carcinogenic potential. In light of the issues raised by commenters, 
the Agency believes that the ss DNA break data should be interpreted 
with caution.
    (iii) DNA-protein cross-linking. Casanova and Heck [Ex. 21-16] 
observed DNA-protein crosslinks in mouse liver, but not mouse lung, 
after exposure to 500, 1500 and 4000 ppm. This study indicated that 
metabolites of MC have the ability to interact with DNA. However, the 
quantity of DNA-protein crosslinks did not show a strong correlation 
with tumor incidence, and so the DNA-protein crosslinks were not used 
as a dose-surrogate for MC exposure in OSHA's risk assessment.
    The Chemical Industry Institute of Toxicology (CIIT) [Ex. 126-25] 
submitted further evidence that MC exposure causes DNA-protein cross-
links in mouse liver but not mouse lung, hamster liver or hamster lung. 
These investigators also observed RNA adducts in mouse, rat and human 
cells after incubation with MC, but DNA-protein cross links were only 
observed in the mice. In addition, they submitted a pharmacokinetic 
model which modeled the DNA-protein cross-links as the dose surrogate 
for MC exposure. Finally, they made extensive comparisons of their 
model with the PBPK model submitted by Clewell [Ex. 96] and EPA's risk 
assessment for MC. Dr. Roger McClellan summarized the conclusions they 
reached as follows,

    The pharmacokinetic results suggest that at very low 
concentrations of DCM [methylene chloride], the yield of DPX [DNA-
protein cross-links] is almost linearly proportional to DCM 
concentration * * *
    DPX cannot be used directly as a surrogate for the internal dose 
in humans, however, because human hepatocytes, unlike mouse 
hepatocytes, do not appear to form DPX in measurable amounts in 
vitro. * * * These results suggest that the mouse may not be an 
appropriate animal model for human risk assessment due to its 
unusual susceptibility to DPX formation and to the fact that cell 
proliferation is a uniquely high-dose phenomenon that may occur only 
in this species.

    OSHA believes that this work provides more evidence for the 
formation of genotoxic metabolites in mouse liver after MC exposure. 
However, OSHA is not convinced that the DNA-protein cross-linking is 
the appropriate dose-surrogate for pharmacokinetic modeling. One of the 
strengths of Reitz's and subsequent PBPK models was that the dose 
surrogate used in the modeling was linearly related to tumor incidence. 
That is one reason that many investigators have focused on the GST 
pathway, instead of the MFO pathway of metabolism as the carcinogenic 
pathway. As explained by Dr. Lorenz Rhomberg [Ex. 126-16],

    * * * if this proportionality in the case of GST is broken by a 
deeper analysis, the rationale for focusing only on GST must be 
reevaluated.

Dr. Rhomberg was referring to results presented by HSIA on the 
distribution of GST theta isozymes within and among cells, but the same 
sentiment applies here; if OSHA were to abandon PBPK modeling using GST 
metabolites, all of the HSIA and other studies would have to be re-
evaluated and considerable more research might need to be done. 
Finally, in the CIIT study, RNA adducts, a more direct measure of 
genotoxicity than DNA ss breaks, were observed in human hepatocytes 
after incubation with MC. The amount of RNA adducts in human cells was 
only about 3-fold lower than the amount in mouse hepatocytes. It is 
therefore clear that human hepatocytes in this system are forming 
genotoxic metabolites after exposure to MC.
    OSHA notes that, in mouse lung, the DNA-protein cross-links were 
not observed, even though a clear dose-response relationship for tumors 
has been established at this site. OSHA is not convinced that the 
explanation for carcinogenesis in mice is DNA-protein cross-links in 
liver. Overall, it is unclear whether the interspecies difference in 
DNA-protein cross-linking is related in any way to the carcinogenic 
mechanism of action.
    OSHA concludes that there continue to be strong reasons for using 
the mouse data as the basis for its quantitative risk assessment 
because there is a clear dose-response relationship in the mouse liver 
and lung tumor incidence data; the mouse metabolizes MC by the same 
pathways as humans; PBPK models have been developed which account for 
inter-species differences in MC metabolism; statistical techniques have 
been developed to quantify the uncertainty and variability in the 
parameters used in the PBPK models; and there are no data that 
demonstrate that the mouse is an inappropriate model for assessing 
human cancer risks. In fact, OSHA finds further evidence in the studies 
described above which suggest that MC acts via a genotoxic mechanism in 
human cells as well as in mice and rats, which further supports OSHA's 
use of the mouse tumor incidence as the basis for quantitative risk.
    (iv) Interpreting the genotoxicity studies. Several other issues 
were raised regarding interpretation of the results of

[[Page 1523]]

these studies on the genotoxic mechanism of action of MC. NIOSH and 
others [Exs. 126-30, 126-11, 126-32] commented that, in general, the 
data presented by HSIA supported the hypothesis that the carcinogenic 
metabolite(s) of MC were derived from the GST pathway. They agreed with 
HSIA's interpretation of the data that the studies presented here 
helped to confirm that the mechanism of MC carcinogenesis is through 
one or more genotoxic metabolites of the GST pathway.
    Interpretation of short-term effects in explaining chronic 
mechanisms of action.
    Concerns were raised about the generalizability of the results of 
short-term genotoxicity assays to tumor incidence, especially when the 
observed effect is transient, as in the vacuolation of Clara cells, the 
appearance of ss DNA breaks in mouse liver and lung cells, etc. Dr. 
Mirer of the UAW [Ex. 126-31] commented,

    1. The evidence cited concerns acute effects which appear after 
a few hours of high level exposure of the animal to methylene 
chloride vapor, or the glassware (in vitro) mixing of homogenized 
animal or human tissue with the solvent. In a number of studies the 
effect in the whole animal is transient.
    2. There is no evidence to connect the acute toxic effect, or 
single strand breaks of DNA after acute exposure, to the chronic 
effect of lung or liver injury, or cancer. * * *

Dr. Maronpot [Ex. 126-22] was concerned that the vacuolation observed 
in Clara cells was not reproduced in the NIEHS mechanistic studies. 
HSIA responded to this concern by remarking that the vacuolation could 
only be found after single exposures to MC, and that the vacuolation of 
Clara cells was also associated with increased DNA synthesis in these 
cells. The fact that this response was only observed after single 
exposures to MC again raises the issue of the transience of this 
response and its relevance to MC carcinogenesis.
    Increased cell turnover.
    In these studies on genotoxicity, the authors remarked that 
increased cell turnover was observed in the lung (transient increase in 
DNA synthesis after single exposures to MC). Dr. Daniel Byrd [Ex. 126-
32] also commented on the DNA synthesis issue. Citing an HSIA study, he 
contended that there appeared to be a common mechanism of action 
between the lung and the liver since increased DNA synthesis was 
observed in both tissues. Dr. Maronpot of the NIEHS [Ex. 126-22] 
disagreed, stating,

    The purported ``liver growth'' in methylene chloride-exposed mice 
is actually an increase in liver weight attributable to accumulation of 
glycogen within hepatocytes. There is no evidence of replicative DNA 
synthesis (cell proliferation) in the liver of methylene chloride-
treated mice, and, hence, actual increases in the numbers of 
hepatocytes did not occur. * * * It is noteworthy that recovery to 
normal liver weight occurs within two weeks after cessation of exposure 
to methylene chloride.

OSHA agrees with Dr. Maronpot that no data in the rulemaking record 
show increases in liver cell proliferation as the result of MC 
exposure, although increased DNA synthesis was actively searched for in 
the NIEHS mechanistic and other studies. The increased DNA synthesis 
observed in mouse Clara cells is a transient phenomenon that has not 
been clearly linked to carcinogenesis in the mouse. In any event, cell 
proliferation is not necessarily related in any way to carcinogenesis 
and is often uncorrelated with the doses used in bioassays and the 
tumor rates themselves. Many substances that cause prolonged cell 
proliferation do not cause tumor formation and vice versa [Ex. 126-22], 
and many experts believe that transient increases in cell 
proliferation, such as seen with MC, cannot account for the 
carcinogenic effect. Further discussion of cell turnover as a mechanism 
of carcinogenicity is discussed below under ``Non-genotoxic 
mechanisms.''
    Clara cell as the mouse lung tumor cell of origin.
    Another issue raised by commenters concerned the cell of origin of 
the mouse lung tumors. The mouse lung has a higher proportion of Clara 
cells than the human lung. The investigators hypothesized that if the 
Clara cell were the mouse lung tumor cell of origin, the risk estimated 
from the mouse lung tumor data may overstate human risk because humans 
have fewer Clara cells, and therefore fewer potential target cells.
    Green et al. have focused much of their research efforts into 
determining the mechanism of action of MC in mouse lung and liver. In 
lung tissue, as described above, they concentrated on experiments 
addressing the hypothesis that the mouse Clara cell is the cell of 
origin of the mouse lung tumors observed in the NTP bioassay. Dr. 
Daniel Byrd [Ex. 126-32] indicated that he believed that the data 
presented supported this conclusion. He stated, ``Mouse lung tumors 
most likely arise from damaged Clara cells, although a few pathologists 
continue to speculate that mouse lung tumors arise from other lung 
cells, such as Type II pneumocytes.''
    In contrast, Dr. Maronpot of the NIEHS [Ex. 126-22] disagreed with 
that statement, indicating that ``* * * current belief among 
researchers is that mouse lung tumors arise from Type II pneumocytes 
rather than Clara cells.'' Dr. Melnick [Ex. 126-33] suggested that the 
HSIA data are not consistent with the hypothesis that the Clara cell is 
the tumor cell of origin. He stated,

    DNA damage was detected in lungs of mice exposed to 2000 ppm 
methylene chloride; however, no significant increase in DNA single 
strand breaks was observed in Clara cells isolated from mice exposed 
to 4000 ppm methylene chloride. This observation does not support 
the conclusion that Clara cells were the cells of origin of 
methylene chloride-induced mouse lung tumors.

    In their paper, Graves et al. [Ex. 120] explain their results as 
follows,

    Attempts to measure DNA damage in Clara cells isolated from mice 
which had been exposed to MC in vivo were unsuccessful. * * * [I]t 
is possible that cells extensively damaged by MC do not survive the 
isolation procedure. The observation that the in vivo vacuolation of 
Clara cells observed after MC treatment is not seen in vitro when 
the cells are isolated from the damaged lungs supports this 
proposal.

    This means that the authors could induce ss breaks in the DNA of 
Clara cells in vitro, but in mice exposed to MC in vivo, it is not 
clear that the DNA ss breaks observed in lung tissue were concentrated 
in the Clara cells. In fact, the authors state,

    Since Clara cells represent only 5% of the total lung cell 
population, the DNA ss breaks observed in vivo may not exclusively 
result from damage to this cell population.

    OSHA believes that these issues raise serious doubts as to whether 
current evidence supports the determination that the Clara cell is the 
cell of origin of the mouse lung tumors. Although the absence of 
increased ss breaks is not necessarily an indication of lack of 
genotoxicity, the presence of ss breaks in lung tissue (and apparently 
not concentrated in Clara cells) reveals an inconsistency in HSIA's 
argument: either the ss breaks are irrelevant or Clara cells are not 
the cells of origin, or both. Further discussion of the issues 
surrounding identification of the Clara cell as cell of origin for 
mouse lung tumors is contained below under ``Non-genotoxic mechanisms 
of carcinogenesis.''
    Ability of MC reactive metabolites to cross membranes.
    Although no data were presented by the HSIA to address this issue 
directly, several of the HSIA papers and the accompanying letters 
postulate that the

[[Page 1524]]

reactive metabolites of the GST pathway are too short-lived to cross 
membranes. This argument is used in combination with the claim of high 
concentrations of the mRNA for the GST T1-1* in the nuclei of mouse 
cells (but not those of rats and humans) to support the contention that 
humans are not at risk of developing cancer after exposure to MC. The 
reasoning is as follows: (1) Mice are the only species to have high 
concentrations of GST T1-1* in the nucleus of lung and liver cells. (2) 
The reactive metabolites of the GST pathway are too short-lived to 
cross the nuclear membrane. (3) In order to produce a carcinogenic 
effect, reactive metabolites must be produced inside the nucleus in 
proximity to the DNA. (4) Because the mouse has high concentrations of 
these enzymes in the nucleus (and rats and humans do not), the mouse is 
uniquely susceptible to lung and liver cancer after exposure to MC. (5) 
Therefore, there is no risk of humans developing cancer after exposure 
to MC.
    Some commenters [Exs. 126-12, 126-30, 126-33] maintained that 
HSIA's submitted studies do not support this argument. As discussed 
subsequently, the probe used in these experiments measured GST T1-1* 
mRNA, not the isozyme itself. There is not necessarily a correlation 
between the intracellular concentration of mRNA and the concentration 
of enzyme at a specific locus. In addition, one would expect there to 
be higher mRNA outside the nucleus (since that is where the enzyme is 
transcribed from the mRNA), even if the enzyme were subsequently 
concentrated inside the nucleus. Additionally, as discussed previously, 
some of the evidence presented by HSIA suggests that the metabolites 
can be generated outside the cell (not simply outside the nuclear 
membrane) and interact with the DNA. Specifically, Dr. Dale Hattis [Ex. 
126-12] has remarked that,

    * * * as long as these reaction and detoxification processes are 
not infinitely fast (and in principle they cannot be infinitely 
fast), a finite fraction of the activated metabolite molecules must 
reach the DNA and react. Even though this chain of events is 
required by our basic understanding of the relevant kinetic 
processes, in this case we also have direct empirical evidence that 
active metabolites need not be generated in a cell's nucleus in 
order to reach DNA and do damage. The DNA sequence mutations of 
Graves and Green [Ex. 122] and Graves et al. [Ex. 123], and the DNA 
single strand breaks reported by Graves et al. [Ex. 120] for CHO 
cells were all produced by exposing mammalian cells to a tissue 
culture medium that had been supplemented with mouse metabolizing 
enzymes and methylene chloride. The active metabolites in those 
cases were necessarily generated from outside of the cells, not just 
in the cytoplasm of the cells that manifested the DNA damage. 
Therefore, the claim that the active glutathione transferase 
metabolite(s) must be generated in the nucleus and would be 
ineffective if generated in the cytoplasm is flatly contradicted by 
HSIA's own evidence.

    HSIA [Ex. 126-29] strongly disagreed that their results should be 
interpreted in this way and countered as follows:

    The investigators had to use a suspension assay to maximize the 
concentration ratio of methylene chloride to cells to about 10\14\, 
and to optimize the GST activity from mouse liver preparation. Only 
under these extreme nonphysiological conditions with a transformed 
cell line could any increase in mutation frequency be observed. 
There is absolutely no justification for assuming similar conditions 
in humans, where GST activity is absent or at very low levels in the 
cytoplasm and absent in the nucleus.

    OSHA disagrees with HSIA, however, and finds Dr. Hattis' and the 
other commenters' reasoning more sound. The results of these 
experiments indicate that the metabolites of MC are stable enough to 
cross the cellular and the nuclear membrane to interact with DNA. The 
Agency recognizes that these are not physiological conditions, but the 
conditions of the experiment do support the common-sense assumption 
that enzymatic metabolism takes place in the cytoplasm of mouse cells 
and show that some fraction of the GST metabolite(s) is stable enough 
to cross membranes in the cell. Thus, the Agency believes that the 
observed tumorigenesis in the mouse is not the exclusive result of 
nuclear MC metabolism.
    Other issues pertaining to genotoxicity.
    The remaining comments on these studies focused on more general 
issues such as the genotoxicity of MC and other factors related to the 
GST metabolic pathway and MC-induced carcinogenesis. Dr. Melnick [Ex. 
126-33] remarked:

    Some fundamental questions related to this mechanism and its 
uniqueness to mouse liver and mouse lung carcinogenesis are also not 
addressed by the present research. For example, why do tumors not 
develop in other organs in mice that also have high levels of GST 
theta (e.g., kidney)?

OSHA believes this is an important question that reduces the strength 
of HSIA's contention that the mouse responds in a unique way to MC. The 
investigators have attempted to explain differences in potency of MC 
with respect to liver and lung carcinogenesis by invoking differences 
in DNA repair rates and GST metabolism within the nuclei of critical 
cells. However, there are other tissues which, based on the HSIA 
hypothesis, ought to be prime candidates for carcinogenesis. The 
kidney, besides having high levels of GST theta, also has a slower rate 
of DNA repair than the liver. It would appear to be a logical site of 
carcinogenesis if HSIA's hypothesis is correct. OSHA believes that the 
lack of tumor response in this organ (and perhaps other logical sites) 
indicates that the hypothesis proposed by HSIA fails to account for all 
relevant observations.
    (2) Non-genotoxic mechanisms of carcinogenesis. Non-genotoxic 
mechanisms of action have also been hypothesized for MC. Increased cell 
turnover, due to cell death caused by MC toxicity, could theoretically 
increase the available number of sites for mutation and subsequent 
tumor formation. However, there is only limited evidence of increased 
cell turnover after MC exposure. Casanova and Heck [Ex. 21-16] observed 
increased DNA synthesis in lung tissue of mice exposed to MC. Green et 
al. [Ex. 105] observed Clara cell vacuolation, and both studies 
measured increased DNA synthesis on the first day of exposure to MC, 
but not on subsequent days of exposure. Clara cells may be targets of 
MC-induced toxicity because they contain higher levels of MC-
metabolizing enzymes and are therefore more likely to generate toxic MC 
metabolites (for example, carbon monoxide is known to poison MFO 
enzymes). Green et al. suggested that the Clara cell was the cell of 
origin of the lung tumors observed in the NTP mouse study, because of 
the metabolic properties of these cells and the increased cell turnover 
observed within a day of MC exposure (in addition to the DNA damage 
described above under the section entitled, ``Genotoxic mechanisms of 
carcinogenesis'').
    Green et al. further suggested that if the cell of origin of the 
mouse lung tumors was the Clara cell, humans would be at substantially 
less risk of lung cancer, because humans have proportionally fewer 
Clara cells than mice do. However, OSHA believes that there is no clear 
evidence confirming that Clara cells were the cell of origin of the 
mouse lung tumors (see discussion above). Other cell types in the lung, 
such as the Type II lung cell, also have relatively high metabolic 
activity and could be the site of origin of lung tumors. These cells 
have not been studied separately. Further studies are needed to clarify 
the role of the Clara cell and other lung cell types and cells in other 
tissues in MC carcinogenesis.
    (i) Increased cell division. In 1994, Foster et al. [Ex. 119] 
investigated increased cell division as the

[[Page 1525]]

mechanism of action of MC in mouse lung cells. Specifically, they 
examined the mechanism of MC action on the transient vacuolation of 
bronchiolar cells observed following single exposures to MC. In mice 
exposed to 2000 and 4000 ppm MC, they observed increased numbers of 
vacuolated cells in the bronchiolar epithelium. Pretreatment of mice 
with a cytochrome P450 inhibitor decreased the number of vacuolated 
cells, while pretreatment with a glutathione depletor did not. In a 
replication of the observation made by Green et al. and described 
above, the authors found increased cell division (measured as 
incorporation of [3H]-thymidine) in Clara cells isolated from mice 
exposed to 4000 ppm MC. They concluded:

    We believe that these results strongly support the supposition 
that the vacuolation of the Clara cells is due to a toxic metabolite 
produced by the CYP [cytochrome P-450] pathway of metabolism. 
Furthermore the most likely candidate for inducing the change is 
thought to be formyl chloride.

    OSHA agrees that these observations indicate that increased cell 
turnover occurs in Clara cells of mice. This may possibly be a partial 
explanation of the mechanism, but only a partial one. In cases where 
cytotoxicity has been considered to be an explanation for risk 
occurring only at ``high'' doses, this argument is confined to 
chemicals believed to act non-genotoxically. MC is likely to be a 
genotoxic carcinogen, so even if cell proliferation is a factor, the 
genotoxic mechanism would be the primary mechanism of concern. 
Genotoxic carcinogens are not generally believed to have a threshold 
and the dose-response function is believed to be approximately linear 
at low doses. In addition, the study focused on one type of cell, which 
may not be the cell of origin for lung tumors. Carcinogenicity in 
humans (as well as in mice and rats) seems to originate from various 
cell types in various tissues.
    (3) Metabolism of MC. As described above, the mechanism of 
carcinogenesis for MC is not known. Numerous studies over many years 
have explored numerous possible mechanisms and have provided 
substantial information regarding the metabolism and the probable 
metabolite responsible for the carcinogenic effect. As discussed in the 
Health Effects section, MC is metabolized by two pathways: the mixed 
function oxidase pathway (MFO) and the glutathione S-transferase (GST) 
pathway. Both pathways produce reactive intermediates which potentially 
could contribute to a genotoxic mechanism of carcinogenicity. During 
development of the PBPK model for MC, Reitz et al. found that tumor 
incidence correlated with the estimated amount of GST metabolite, as 
well as with the amount of parent compound administered, but not with 
the amount of MFO metabolite [Ex. 7-225]. The parent MC is not likely 
to act as a genotoxic carcinogen because it is a fairly non-reactive 
compound. In addition, MC blood levels in mice were lower than in rats, 
so if MC was the carcinogenic moiety, one would expect the risk of 
cancer in rats to be higher than mice, whereas the opposite was 
observed. Consideration of these factors has led many investigators to 
conclude that the GST pathway is responsible for carcinogenesis and 
that it is likely to produce a genotoxic carcinogenic moiety. OSHA has 
reviewed the data available on mechanism of action and has concluded 
that the most plausible assumption is that the GST pathway is 
responsible for the carcinogenic action of MC and that this should be 
taken into account in the quantitative risk assessment. This represents 
a case-specific departure from the default assumption that the 
administered dose of the parent compound is the relevant metric for 
exposure.
    (i) Specific GST isozyme(s) responsible for MC metabolism to the 
carcinogenic metabolite. Recent work sponsored by the HSIA was directed 
at further characterization of the metabolism of MC by the GST pathway 
[Exs. 121, 124, 124A]. Specifically, the HSIA work on MC metabolism has 
focused on the isolation and description of isozymes in the GST theta 
class of enzymes, which HSIA believes are responsible for the 
metabolism of MC to the carcinogenic metabolite in mice. Mainwaring et 
al. have shown that the GST isomer with the greatest specific activity 
for MC is a member of the theta class of GST. [Ex. 121] In rats, three 
members of the theta class have been identified, GST 5-5, GST 12-12 and 
GST 13-13. In humans, two theta class enzymes have been identified, GST 
T1-1 and GST T2-2 and in mice, two theta enzymes have been described, 
GST T1-1* and GST T2-2* (also known as GST MT-1 and GST MT-2). 
According to Mainwaring et al. [Ex. 121], rat GST 5-5 and mouse GST T1-
1* have similar specific activity toward MC and sequencing studies have 
shown ``* * *that rat 5-5, mouse T1-1* and human T1-1 are orthologous 
proteins as are rat 12-12 and mouse T2-2* and human T2-2'' [Ex. 124A].
    The hypothesis under investigation in this work was that the enzyme 
similar to rat GST 5-5 (mouse T1-1* and human T1-1) was the critical 
enzyme responsible for metabolism of MC to the carcinogenic metabolite, 
and that differences in the interspecies intra- and inter-cellular 
distributions of this isozyme and differences in genotoxicity would be 
important for characterizing the risk of carcinogenesis after exposure 
to MC.
    In order to examine the distribution of the GST isozymes of 
interest, the investigators used DNA oligonucleotide anti-sense probes 
complementary to three regions of the protein nucleotide sequences of 
rat GST 5-5, mouse GST T1-1* and human GST T1-1 to localize specific 
mRNA sequences in mouse, rat and human liver and lung tissue. They also 
used an antibody raised against rat GST 12-12 to localize the protein 
itself [Exs. 124, 124A]. In the full paper describing these experiments 
[Ex. 124A], Mainwaring characterized the results of this study, as 
follows:

    The mouse enzymes [T1-1* and T2-2*] were present in 
significantly higher concentrations in both liver and lung than the 
equivalent enzymes in rat and human tissues. In mouse liver, both 
enzymes were localized in limiting plate hepatocytes surrounding the 
central vein, in bile duct epithelial cells and in the nuclei of 
hepatocytes. In rat liver the distribution of GST 12-12 was 
comparable to that seen for T2-2* in the mouse. GST 5-5 was not 
localized in limiting plate hepatocytes or in nuclei of rat liver. 
The levels of human transferase T1-1 in the liver were very low, 
with an even distribution throughout the lobule. The GST 12-12 
antibody did reveal high concentrations of this enzyme in human bile 
ducts. The relative amounts of the theta enzymes in the lungs of the 
three species followed the pattern seen in the liver, with very high 
concentrations in Clara cells and ciliated cells of the mouse lung 
and much lower levels in the Clara cells only of rat lung. Low 
levels of human transferase T1-1 were detected in Clara cells and 
ciliated cells found at the alveolar/bronchiolar junction of one 
human lung sample. The enzyme was entirely absent from the large 
bronchioles.

Mainwaring et al. concluded that:

    This study has demonstrated a highly specific distribution of 
the theta class GSTs 5-5 and 12-12 in liver and lung tissue from 
mice, rats and humans. * * *it was apparent from these studies that 
both the distribution and concentration of theses enzymes differed 
markedly between the three species. Whilst neither mRNA levels nor 
protein concentrations necessarily correspond to active enzyme, the 
distribution shown by the mRNA for GST 12-12 was quantitatively 
reflected by the antibody to the protein of this enzyme, suggesting 
that these techniques do, in this case, reflect the distribution of 
active enzyme. Although an antibody to GST 5-5 is not available, it 
is reasonable to assume that mRNA levels for this enzyme are 
similarly representative of the distribution of active enzyme.
    An understanding of the cellular and sub-cellular distribution 
of GST 5-5 has provided

[[Page 1526]]

an explanation for the species specificity of the mouse lung and 
liver carcinogen methylene chloride, and has provided reassurance 
that humans are not at risk from exposure to this chemical.

    (ii) Issues raised pertaining to metabolic studies. Many commenters 
commended the HSIA for providing new information on the mechanism of 
action of MC and for confirming previous quantitative studies of the 
interspecies differences in MC metabolism. However, commenters also 
raised several specific issues regarding the conduct and interpretation 
of these experiments.
    Correlation of mRNA concentrations with enzyme concentrations.
    Mainwaring et al. [Ex. 124A] correlated the inter- and intra-
cellular distribution of the mRNA for GST 12-12 in the rat with the 
distribution of the antibody for GST 12-12. They stated that it is 
reasonable to assume that since the protein and mRNA for the 12-12 
isomer have similar distributions, the protein for the 5-5 isomer would 
distribute in the same manner as the mRNA for the 5-5 isomer. In 
support of their assumption, they noted that there is 80% homology 
between the 5-5 and 12-12 isomer. Some commenters believed that this 
was not a reasonable assumption and that there was no reason to believe 
that the distribution of the GST 5-5 isomer protein would correlate 
with the distribution of the GST 5-5 mRNA simply because there seemed 
to be a correlation in the 12-12 isomer protein and mRNA distributions 
[Exs. 126-7, 126-16]. OSHA concurs with these commenters, and until 
there is actual measurement of the GST 5-5 protein, OSHA does not 
believe that the question of the actual distribution of GST 5-5 isozyme 
will have been settled.
    More importantly, several commenters stressed that it was mRNA that 
was actually observed in these studies, and mRNA levels do not 
necessarily correspond to either protein levels or protein activity 
within a cell [Exs. 126-7, 126-16, 126-28, 126-30, 126-32]. Although 
Mainwaring et al. acknowledge this fact [Ex. 124A], the conclusions 
reached by the authors still suggest that measurement of mRNA is 
equivalent to measurement of enzyme activity. Referring to the 
conclusions drawn by Mainwaring et al., Dr. Lorenz Rhomberg [Ex. 126-
16] commented:

    This interpretation of mRNA distribution is profoundly in error 
and contradicts some of the most well established and fundamental 
principles of molecular biology.* * * Finding mRNA in the nucleus is 
unsurprising and uninformative about the eventual location of the 
protein products. Detecting mRNA only reveals that the cell may be 
presumed to be manufacturing the corresponding protein.

Dr. Rhomberg was also concerned that the concentration of GST T1-1* in 
the nucleus of mice may be an artifact of the experimental conditions, 
resulting, perhaps, from a burst of mRNA synthesis. The concern that 
the apparent nuclear concentration of GST may be an artifact was echoed 
by Dr. Douglas A. Bell of the National Institute for Environmental 
Health Sciences [Ex. 126-26]. He stated:

    Why the [intracellular] distribution should be different among 
species is unclear and unusual. Differences in processing of the 
nuclear RNA transcript from full length pre- mRNA may be the 
underlying cause of this phenomenon (or perhaps there is a 
transcribed pseudogene that is complicating the process).

    Because of the specific cellular mechanisms that would be required 
to concentrate a protein in the nucleus, Dr. Rhomberg [Ex. 126-16] 
indicated that translocation of the GST 5-5 protein to the nucleus only 
in mice seemed unlikely. He stated:

    It seems implausible * * * that for a series of orthologous 
proteins, such localization would be found in a particular species 
and not in other species.

OSHA agrees with the comments made by Dr. Rhomberg and Dr. Bell on this 
issue, and concludes that the concentration of mRNA at a particular 
cellular site does not necessarily correlate with concentration of the 
enzyme itself. OSHA believes that caution should be used when 
interpreting the results of these experiments.
    Attribution of GST metabolizing activity to a single GST isozyme.
    Concern was also raised about the validity of attributing all of 
the glutathione S-transferase metabolism of MC to one isomer of the 
theta class [Exs. 126-7, 126-12]. In particular, Dr. Dale Hattis noted 
that there was less enzyme activity eluting coincident with the peak 
identified as the 5-5 form than that eluting at pH 8, which was not 
believed to correspond to the 5-5 form. Dr. Ronald Brown described 
results from a paper by Blocki (1994) [Ex. 127-22] which showed that 
``expression of the [5-5] isozyme contributes 50% of the total GST 
activity toward this substrate.'' This leaves the question open as to 
whether isozymes which may have lower specific activity for MC but 
which may be expressed in much greater abundance (particularly 
 4-4), could contribute as much as the remaining 50% of the 
total GST metabolism (see Table VI-1, reproduced below from Dr. Brown's 
comment [Ex. 126-7], original source Blocki et al. (1994) [Ex. 127-
22]).

           Table VI-1.--Relative Contribution of Different Rat Liver Glutathione S-Transferases in Dichloromethane Metabolism to Formaldehyde           
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                       Glutathione S-transferases       
                                                                                                               -----------------------------------------
                                                                                                                   
                                                                                                                    Class         Class         Class   
--------------------------------------------------------------------------------------------------------------------------------------------------------
Comparative parameter (units)...............  1-1+1-2+2-2                                  3-3           3-4           4-4       b 5-5         b 13k    
Specific activity (nmol/min/mg of protein)..  <0.1                                           7            11            23      11,000             9    
% Cytosolic protein (% of total in liver)...  6.4                                          0.7           0.3           0.6           0.002         0.005
Total activity (nmol/min/g of liver protein)  <10                                           49            33           138          22             0.45 
% Total activityc...........................  <1.5                                          11             7            32          50             0.1  
--------------------------------------------------------------------------------------------------------------------------------------------------------
a Data from Meyers et al., 1991.                                                                                                                        
b Data for 13,000 molecular weight glutathione transferase from Blocki et al., 1992.                                                                    
c Assuming Vmax conditions for each.                                                                                                                    

    In addition, Mainwaring et al. [Ex. 124A] noted that the 
``substrate specificity of GST 12-12 is currently poorly 
characterized,'' although the purified enzyme has no activity toward 
MC. As described above, these enzymes appear to be very labile upon 
purification. Therefore, it is unclear how much the 12-12 isomer itself 
may contribute to MC metabolism. As Dr. Kenneth T. Bogen stated, ``* * 
* while the substrate specificity of GST 12-12 may currently be poorly 
characterized, current data do not appear to rule out GST 12-12 
specificity toward MC.''

[[Page 1527]]

    Limited human samples and human polymorphism in the GST theta 
genes.
    Several commenters expressed concern for the limited number of 
human samples (one pooled lung sample and less than 40 human liver 
samples have been assayed) and the potential effect of a known human 
polymorphism for the glutathione S-transferase theta class genes on 
risk estimations [Exs. 126-7, 126-16, 126-26, 126-35]. Specifically, 
commenters raised concerns that there may be a large subpopulation of 
GST conjugators who may be at increased risk from MC exposure that has 
not been adequately characterized in the limited number of human 
samples (especially lung samples) that have been tested. HSIA objected 
to these comments, stating,

    The human tissue data base for the metabolism of methylene 
chloride by the GST pathway is one of the largest, if not the 
largest, available for this type of risk assessment. To discount it 
based on arguments concerning hypothetical polymorphisms, as these 
commenters urge OSHA to do, would be contrary to the message 
consistently put forward by the National Academy of Sciences and 
regulatory authorities for the past decade. * * *''

    In fact, the National Academy of Sciences report cited by HSIA, 
``Science and Judgement in Risk Assessment'' does encourage agencies to 
make use of biologically-based models, but cautions that using them 
without adequately considering human variability would be a step 
backwards:

    EPA has not sufficiently accounted for interindividual 
variability in biologic characteristics when it has used various 
physiologic or biologically based risk-assessment models. The 
validity of many of these models and assumptions depends crucially 
on the accuracy and precision of the human biological 
characteristics that drive them. In a wide variety of cases, 
interindividual variation can swamp the simple measurement 
uncertainty or the uncertainty in modeling that is inherent in 
deriving estimates for the ``average'' person.

The Academy goes on to recommend specifically that making ``reasonable 
inferences'' about interindividual variation is required, rather than 
assuming that no such variation exists:

    Even when the alternative to the default model hinges on a 
qualitative, rather than a quantitative, distinction, such as the 
possible irrelevance to humans of the alpha-2u- globulin mechanism 
involved in the initiation of some male rat kidney tumors, the new 
model must be checked against the possibility that some humans are 
qualitatively different from the norm. Any alternative assumption 
might be flawed, if it turns out to be biologically inappropriate 
for some fraction of the human population.
    When EPA proposes to adopt an alternative risk-assessment 
assumption * * * it should consider human interindividual 
variability in estimating the model parameters or verifying the 
assumption of ``irrelevance.'' If the data are not available that 
would enable EPA to take account of human variability, EPA should be 
free to make any reasonable inferences about its extent and impact 
(rather than having to collect or await such data), but should 
encourage interested parties to collect and provide the necessary 
data.

    OSHA believes HSIA has misinterpreted the NAS recommendations, and 
further disagrees with HSIA that the polymorphism is ``hypothetical.'' 
Investigators have demonstrated this polymorphism in human GST and have 
shown how the polymorphism varies across races [Exs. 127-7, 127-9, 127-
17, 127-21, 127-23, 127-24, 127-25]. OSHA agrees with the commenters 
that a human polymorphism in the GST theta genes may increase concern 
for individuals that may be at higher risk from exposure to MC due to 
their genetic make-up. The Agency has considered sensitive 
subpopulations in the development of health standards, including this 
rulemaking. For example, the subpopulation of workers with silent or 
symptomatic heart disease was considered in assessing the cardiac risks 
of MC (due to its metabolism to carbon monoxide). The variation in 
enzyme activity raises additional uncertainty in the use of human data 
to support the hypothesis that mice are uniquely sensitive to MC 
carcinogenicity. However, for purposes of quantitative analysis, the 
Agency has not attempted to systematically adjust the risk estimates 
based on a ``high GST metabolizing'' individual because the frequency 
and impact of such polymorphisms have not been clearly worked out.
    Target site of MC carcinogenesis in mice versus humans.
    Drs. Brown and Melnick [Exs. 126-7, 126-33] also raised the 
possibility that the target site for MC carcinogenesis may be different 
in humans than in mice or rats. Specifically, research on the 
occurrence of theta isomers of GST in human blood was described. The 
characterization of GST metabolism in human erythrocytes [Exs. 127-11, 
127-12] suggests the possibility of the bone marrow as a potential 
target of MC carcinogenesis and also the potential for metabolism in 
the blood and translocation of the metabolites to a variety of 
potential targets. The HSIA discounted human blood metabolism of MC, 
stating,

    The `very high capacity to conjugate methylene chloride' 
mentioned by Brown is in fact very low, approximately 40-fold lower 
than the highest activity detected in human liver.

OSHA believes that although the specific activity in the blood may be 
lower than the human liver activity, the total activity of the GST 
enzymes in blood and marrow may be significant when one also considers 
the volume of these compartments. OSHA also notes that interspecies 
tumor site concordance is not necessarily expected, and it is prudent 
to consider any human tissues which have the potential to metabolize MC 
to the putative carcinogen.
    Concentration of protein complementary to rat GST 12-12 in human 
bile ducts.
    Dr. Bogen [Ex. 126-15] commented specifically on the human liver 
protein complementary to the antibody to rat GST 12-12 protein. In 
particular he was concerned that high concentrations of this enzyme 
were reported in bile ducts of the human liver. He noted,

    With regard to potential human carcinogenicity of MC relative to 
its known carcinogenic potential in mice, it seems to me that these 
particular data ought not to reduce regulatory concern, but rather 
ought to increase regulatory concern, in view of the fact that bile 
duct epithelium cells are the most likely stem cells for 
hepatocytes. * * * Thus hepatocellular bile-duct epithelial cells 
are likely to play an important role in liver carcinogenesis in both 
mice and humans.

    OSHA agrees with Dr. Bogen's concerns and also notes that in the 
cohort study of textile workers conducted by Hoescht-Celanese [Ex. 7-
260], an excess of biliary cancers was observed in those workers 
exposed to the highest concentrations of MC and those with the longest 
latency period between exposure and disease. If the HSIA theory is 
correct (i.e., a single isozyme is the culprit), then finding high 
levels of this isozyme in human bile duct is strong evidence 
implicating MC in human carcinogenesis.
    Interpretation of data as qualitative versus quantitative 
differences.
    Perhaps most importantly for the purposes of MC risk assessment, 
several commenters remarked that OSHA should use caution when 
interpreting the data from the HSIA submissions, because any 
interspecies differences are rightly considered first as quantitative 
rather than qualitative ones. In part, the commenters cautioned that 
one should pay special attention to the threshold of detection in all 
assays. As Dr. Andrew Salmon stated,

    Green and co-workers have consistently confused their inability 
to measure a result or parameter value due to its magnitude or 
frequency of occurrence being below their threshold for practical 
detection, with a true

[[Page 1528]]

zero value for the parameter or zero risk of an occurrence [Ex. 126-
36].

OSHA agrees that caution should be used when attempting to characterize 
a difference between species as an absolute qualitative difference. A 
much higher burden of proof is required to support a claim of zero risk 
than of diminished risk. (This higher burden is due to the need to 
consider assay sensitivity and other factors; the fact that the 
consequences of incorrectly concluding that humans are at zero risk are 
particularly dire only adds to the already high threshold of scientific 
evidence needed to successfully make such a claim). In the case of MC, 
humans clearly have the ability to metabolize MC via the GST pathway 
[Exs. 21-53, 127-16]. Even if the enzyme concentration of GST T1-1* 
itself actually occurs only in the nuclei of mouse lung or liver (as 
opposed to the concentration of mRNA, which may or may not be localized 
differently within mouse cells), it is still unclear what impact (if 
any) this fact would have on the characterization of human cancer risks 
for MC. OSHA believes that the statement that there are absolute 
species differences in the activity and intracellular distribution of 
GST 5-5 is highly speculative and is not supported by the data 
presented to date, because the data presented refers to the 
distribution of mRNA for GST 5-5, not the enzyme concentrations or 
activity levels of the enzyme; there is no quantification of the 
intracellular levels of the mRNA or enzyme levels, only photographic 
representations; and there is no evidence that any potential difference 
in enzyme activity (when those experiments are completed) would be 
greater than the difference already predicted from allometric scaling 
considerations.
    Conclusions reached by the HSIA.
    HSIA concluded from these studies that because of a qualitative 
inter-species difference in the distribution of the GST theta enzyme 
responsible for MC carcinogenesis, humans would not be at risk of 
developing cancer under ``foreseeable conditions of exposure.'' 
Although some commenters agreed with the conclusions reached by the 
HSIA [e.g., Exs. 126-10, 126-13, 126-20], many commenters strongly 
disagreed with this interpretation of these data pertaining to the risk 
assessment for MC. These commenters [e.g., Exs. 126-7, 126-11, 126-12, 
126-15, 126-16, 126-22, 126-26, 126-30, 126-36] were concerned that the 
question was in reality an issue of quantitation of enzyme, not a 
qualitative difference in metabolism. Dr. Lorenz Rhomberg commented:

    The question is, is there any basis for believing that the 
species difference in activity suggested by the mRNA data is greater 
than has been previously supposed?
    It should be emphasized that some degree of species difference 
in metabolic activity is expected even under the default cross-
species extrapolation methods. That is, in keeping with the general 
pattern of scaling of physiological processes across species, 
general metabolic rates are presumed to be lower on a per unit of 
tissue basis in larger animals. As a default, this pattern can be 
presumed to apply to individual metabolic pathways as well, although 
data on species-species activities can be used in place of such 
defaults if available.
    If species-species activities are discovered by experiment to be 
less in humans than in mice to the degree already anticipated by 
allometry, then the experiments are simply confirming the default 
and no change in the human risk estimates is warranted. If humans 
have a metabolic activity different than the allometric prediction, 
the incorporation of such estimates into PBPK models can show 
different human risks from those predicted under the default. The 
allometric prediction is that, on a per unit of tissue basis, humans 
should have about 7-fold lower activity than mice and about 4-fold 
lower activity than rats.
    Given the limit of detection of the assay methods, human 
metabolic activity (or mRNA levels) only a bit less than the 
allometric expectation of 7-fold less than mice are often difficult 
to distinguish from zero. That is, claims that humans have no 
activity (or no mRNA production) in certain tissues must be judged 
in the light of the fact that only a small change from the already 
acknowledged allometric difference can often make the human activity 
undetectable. A 20-fold mouse-human difference, for example, really 
only represents a 3-fold exaggeration of the 7-fold allometric 
pattern, yet many assays may fail to reliably characterize a 20-fold 
difference as a quantitative difference rather than a qualitative 
difference.
    For the above reasons, claims that human metabolic activity in 
activating methylene chloride are so low as to be essentially 
qualitatively different than mice should be interpreted with great 
caution. In fact, existing assays have great difficulty in detecting 
species differences in metabolic activity great enough to markedly 
challenge existing risk assessments.

Another commenter discussed the fact that cellular levels of the GST 5-
5 isoenzyme would be expected to be distributed unevenly across cells, 
putting some cells at greater or lesser risk. This would tend to 
average out over a tissue and would be best described by tissue 
metabolism data. Other commenters remarked that there was no need to 
adjust the risk estimates based on these studies because current 
pharmacokinetic models already account for interspecies differences in 
metabolism. Although OSHA has incorporated data from these studies, 
especially in its ``alternative analysis,'' OSHA agrees with Dr. 
Rhomberg and the other commenters who have taken exception to the HSIA 
conclusions.
    The Agency does not accept the HSIA characterization of the results 
of the summarized studies. OSHA has determined that no evidence has yet 
been presented that demonstrates that humans are not at risk of 
developing cancer after exposure to MC. At most, the presented studies 
suggest a quantitative inter-species difference in MC metabolism, which 
was established in previous scientific reports and is already accounted 
for by PBPK modeling. As discussed extensively in this document, OSHA 
has concluded that HSIA has undervalued certain strong evidence and has 
overemphasized some more speculative hypotheses. However, as is clear 
from this discussion OSHA has carefully considered all of the evidence. 
Substantial evidence in the record clearly supports OSHA's conclusions. 
Consequently, OSHA's approach of relying on the NTP mouse tumor data as 
the basis of its quantitative risk assessment continues to be the best 
approach to risk estimation.
    c. Conclusions regarding the carcinogenesis of MC. The HSIA 
submitted these documents to OSHA with a request that the Agency 
consider the mouse tumor data in light of these additional studies and 
reject use of the mouse tumor response data as the basis of the 
Agency's quantitative risk assessment. OSHA believes it has given 
proper weight to all the evidence, giving greater weight to that which 
is of the highest scientific quality. However, in light of HSIA's 
request, the Agency reopened the rulemaking record and reviewed all the 
new data. After submitting these documents for review, the HSIA [Ex. 
126-29] remarked on comments submitted to the docket by other 
scientists,

    In general, the comments submitted by R. Maronpot, R. Brown, L. 
Rhomberg, K. Bogen and D. Hattis exhibit a reluctance to use the 
large body of mechanistic data now available in assessing the 
potential carcinogenic risk posed by methylene chloride, even though 
most other commenters agree that the pathway responsible for its 
observed carcinogenicity in mouse liver and lung, as well as species 
variations in activity of this critical pathway, have now been 
identified. Much of the comment addressed here appears to be 
motivated by a desire to maintain the ``status quo'' for assessing 
carcinogenic risk based on default principles that were developed 
twenty years ago.

The HSIA goes on to say,


[[Page 1529]]


    Many of the conclusions reached by the commenters * * * are 
based, often erroneously, on single aspects of one or the other of 
these publications, rather than on the entire data base, as a 
``weight of evidence'' approach would demand and as is necessary to 
understand the results.

    OSHA finds it difficult to understand why HSIA believes that the 
scientists they listed are primarily interested in preserving the 
``status quo.'' Dr. Maronpot conducted the mechanistic studies on MC at 
NIEHS, which have generated mechanistic information useful to the risk 
assessment process. Dr. Rhomberg was instrumental in developing the 
pharmacokinetic approach used by the Environmental Protection Agency in 
its risk assessment of MC (an approach never used by the Agency 
previously). Dr. Hattis, Dr. Bogen and Dr. Brown are all experts in the 
application of pharmacokinetic modeling to risk assessment and have 
repeatedly called for incorporating more mechanistic and physiological 
data into pharmacokinetic models. These highly respected scientists, 
among others, reviewed the HSIA submissions critically and 
independently and reached conclusions different from those of the HSIA, 
conclusions which themselves depart significantly from the ``status 
quo.'' This does not suggest to OSHA that they are trying to preserve 
some status quo in risk assessment, and OSHA finds nothing in the 
comments of these experts to suggest that this is the case.
    In order to respond to HSIA's desire to have OSHA further review 
all of the data, the Agency has reviewed each submitted study carefully 
and critically on its own merits to determine how each piece of data 
fits into the overall picture of the mechanism of action for MC. OSHA 
believes that in this process the critical issues raised by the HSIA 
have received a full airing and the hazard identification and the risk 
assessment for MC have been improved because of it. OSHA believes, 
however, that looking only at the new studies submitted by HSIA, and 
examining them uncritically, would contradict every principle of 
scientific analysis.
    In summary, in order to accept the HSIA's supposition that MC is 
not carcinogenic in humans, one must believe the following:
    1. GST 5-5 is the only isozyme which can metabolize MC to the 
carcinogenic metabolite.
    2. DNA single strand breaks are relevant and a sufficient measure 
of the tumorigenicity of a compound.
    3. The absence of detectable increases in DNA ss breaks in a single 
experiment means that there are in fact no additional ss breaks.
    4. The limited number of human samples (one sample of pooled lung 
tissues being the absolute extreme of ``limited'' data) used to 
determine metabolic parameters are truly representative of the range of 
human variability.
    5. An apparent correlation in the distribution of the GST 12-12 
protein and GST 12-12 mRNA means that the distribution of GST 5-5 
protein will correlate similarly with the distribution of GST 5-5 mRNA.
    6. Visual interpretation of photomicrographs staining for GST mRNA 
gives a true and accurate measure of GST activity in the cell.
    And one must also ignore the following contradictory observations 
and conclusions about the mechanism of action (in addition to ignoring 
the suggestive epidemiologic evidence):
    1. Metabolites of GST can cross cell and nuclear membranes and 
interact with DNA to induce DNA ss breaks and mutations.
    2. GST mRNA and protein stain heavily in human bile duct cells 
(believed to be precursors of hepatocytes).
    3. Human lung tissue has been shown to stain for GST mRNA.
    4. Only 50% of the GST metabolism of MC can be accounted for by the 
GST 5-5 isozyme.
    5. The metabolic capacity of GST 12-12 for MC has not been 
characterized.
    OSHA concludes that these studies, even putting aside all technical 
objections to the methodology and interpretation of individual studies, 
do not change the conclusion that substantial evidence supports the 
carcinogenicity of MC. The bioassay results in mice are still 
qualitatively and quantitatively relevant to humans. Once the HSIA 
studies have been replicated and key components quantified (like the 
intracellular enzyme activity (instead of mRNA levels) of GST towards 
MC), the HSIA data may be useful in characterizing quantitative 
interspecies differences in MC GST metabolism. In particular, it would 
be useful to determine whether all of the evidence that HSIA submitted 
is consistent with an allometric difference (a difference expected 
based on the size of the animal) in sensitivity to MC or with a greater 
interspecies difference in sensitivity. (The specific activity of GST 
toward MC in mice is estimated to be about 7-fold that of humans, based 
on allometric considerations.) OSHA believes that its final risk 
assessment, which relies on an analysis of all available PBPK data, 
addresses both possible interpretations.

B. Selection of Database for Quantitative Risk Assessment

1. Animal Bioassays
    The first step in performing a quantitative assessment of 
carcinogenic risk based on animal data is to choose a data set or sets 
from which to define the dose-response relationship. In its NPRM, OSHA 
had chosen the NTP female mouse lung and liver tumors to determine its 
estimates of risk. OSHA chose these responses because they provided 
clear dose-response relationships, had low background tumor rates and 
were more sensitive measures of dose-response than corresponding male 
mouse tumor sites.
    The EPA, the CPSC and the FDA chose to use the combined incidence 
of adenomas and carcinomas of the lung and liver as the basis for their 
risk assessments. Specifically, the EPA [Exs. 25-D, 28] placed emphasis 
on the experimental species and sex group showing the highest risk: the 
number of female mice showing either adenoma or carcinoma in either 
lung or liver (or both). The CPSC [Ex. 25-I] pooled benign and 
malignant tumors of either the mammary gland, lung or liver and 
averaged male and female estimates to derive an overall risk estimate. 
The FDA [Ex. 6-1] used benign and malignant responses of female mice. 
The Crump report [Ex. 12] noted that it may be reasonable to combine 
lung and liver responses to give an indication of the potency of MC, 
due to the fact that metabolism of MC occurs by the same pathway in 
both lung and liver and thus results in the same ultimate metabolites. 
However, the report added that since both tissues have different 
background responses, combining responses may tend to complicate the 
interpretation of risk estimates.
    In OSHA's final rule, the NTP study (rat and mouse, inhalation) was 
chosen for quantitative risk assessment because it provided the best 
toxicological and statistical information on the carcinogenicity of MC 
[Exs. 12, 7-127] and because the study was of the highest data quality. 
In the NTP study, MC induced significant increases both in the 
incidence and multiplicity of alveolar/bronchiolar and hepatocellular 
neoplasms in male and female mice. In rats, dose-related, statistically 
significant increases in mammary tumors were also observed. OSHA chose 
the female mouse tumor response as the basis of its quantitative risk 
assessment, because of the high quality of data, the clear dose 
response of liver and lung

[[Page 1530]]

tumors and the low background tumor incidence. Although the female rat 
mammary tumor response was also dose-related, the data of high quality 
and amenable to quantitative risk assessment, the mouse data set had a 
clearer dose-response in both liver and lung tumors than the rat 
mammary tumor response and the mouse background tumor incidence was 
lower than in the rat. Therefore the mouse data set was chosen for 
quantitative analysis.
    OSHA included the lung adenomas in the quantitative analysis. The 
evidence suggests that the presence of benign tumors with the potential 
to progress to malignancies should be interpreted as representing a 
potentially carcinogenic response. This belief is supported by the 
OSTP's views on chemical carcinogenesis (50 FR 10371). OSTP stated that 
at certain tissue sites, such as the lung, most tumors diagnosed as 
benign really represent a stage in the progression to malignancy. 
Additionally, NIOSH, the EPA, the CPSC and the FDA have also included 
benign responses in their assessments. Therefore, it is appropriate and 
sometimes necessary to combine certain benign tumors with malignant 
ones occurring in the same tissue and the same organ site. In 
particular, OSTP also stated that ``the judgement of the pathologist as 
to whether the lesion is an adenoma or an adenocarcinoma is so 
subjective that it is essential they be combined for statistical 
purposes.'' (50 FR 10371).
    OSHA chose female mouse lung tumors as the specific tumor site for 
its final quantitative risk assessment. There is no a priori reason to 
prefer the mouse lung tumor response over the liver tumor response, 
because both data sets were of high quality, showed a clear dose-
response relationship and had low background tumor incidence. In fact, 
in the NPRM, the Agency reported estimates of risk generated using both 
sites. However, to reduce the complexity of the final PBPK analysis, 
which required highly intensive computations, OSHA chose one site (the 
female mouse lung tumor response) for its final risk estimates. The 
risks calculated using the female mouse liver response would likely be 
slightly lower than those calculated using the lung tumor response. On 
the other hand, pooling the total number of tumor-bearing animals 
having either a lung or liver tumor (or both) (which is the procedure 
EPA advocates [see its 1986 Guidelines for Cancer Risk Assessment]) 
would have yielded risk estimates higher than OSHA's final values.
    The NTP study has been described in the Health Effects section and, 
above, in the discussion regarding hazard identification.
2. Epidemiologic Data
    The epidemiology data are not as useful for quantitative risk 
assessment as the animal data because the animal data provide a clear 
dose-response, with fairly precise indices of exposure, which cannot be 
derived from the epidemiology data. All other things being equal, risk 
assessors would prefer to use epidemiologic data to assess cancer risk 
in humans over data from animal studies whenever good data on human 
risk exist. However, the uncertainty inherent in epidemiologic studies 
must be accounted for; in particular, ``positive'' studies often have 
lower confidence limits that do not rule out the no-effect hypothesis, 
while ostensibly ``negative'' studies often have UCLs that would 
support a substantial positive effect. OSHA believes (see discussion 
below) that the latter circumstance applies to some of the MC studies. 
Other factors, such as duration and intensity of a chemical exposure 
(which can rarely be controlled and accurately measured in an 
epidemiological study), difficulty in accurately defining the exposed 
population, and other confounding factors diffuse a study's predictive 
power of true risks.
    Frequently, animal studies indicate a positive response to a 
particular chemical when epidemiologic studies of exposures to the same 
chemical fail to exhibit a statistically significant increase in risk. 
When animal studies show a substance to be a carcinogen but 
epidemiologic studies are non-positive, the minimum risk which could be 
detected by the human study should be estimated to assess the strength 
of the epidemiologic study and justify its importance in the risk 
assessment process. Similarly, the animal-based potency estimate can be 
used to predict the number of human deaths investigators would likely 
have seen in an epidemiologic study if the animal-based estimate was 
correct; if the observed number of human deaths is markedly 
inconsistent with this predicted number, the relevance of the animal-
based estimate might well be called into question. If the human data 
are equivocal, or the epidemiologic study is not sufficiently sensitive 
to identify an increased risk predicted by a well-conducted animal 
bioassay, it is necessary to consider the animal data to protect 
workers from significant risk. OSHA concludes that the MC epidemiology 
studies do not have adequate information upon which to base a 
quantitative risk assessment. OSHA has, however, used the analyzed 
epidemiological data to determine whether the results are consistent 
with those estimated using the rodent models. This is discussed later 
in the document.
3. Conclusions
    After reviewing the animal data and the quantifiable epidemiology 
data, OSHA has determined that the NTP female mouse lung tumor response 
is the appropriate data set on which to base its quantitative risk 
assessment, and has determined that the most scientifically-appropriate 
way to use these data involves constructing a PBPK model to extrapolate 
from animals to humans. OSHA believes that the non-positive 
epidemiology data, in particular those from Kodak, are of in sufficient 
power to rule out the risk estimates derived from the animal data.

C. Choice of Dose-Response Model

    Several approaches have been used to estimate cancer risk from 
exposure to toxic agents. A standard approach uses mathematical models 
to describe the relationship between dose (airborne concentration or 
target tissue dose surrogate) and response (cancer). Generally, 
mathematical functions are fit to the data points observed at different 
exposure levels and these functions are used to estimate the risk that 
would occur at exposure levels below those observed. The shapes of 
these curves vary, ranging from linear extrapolations from the observed 
points through the origin (zero exposure and zero risk) to curves which 
may deviate far from linearity at the very highest or lowest doses. The 
use of a particular model or curve can be justified in part by 
statistical measures of ``goodness-of-fit'' to observed data points. 
That is, there are various statistical tests which measure how closely 
a predicted dose-response curve fits the observed data.
    The most commonly used model for low-dose extrapolation is the 
multistage model of carcinogenesis. This model, derived from a theory 
proposed by Armitage and Doll in 1961, is based on the biological 
assumption that cancer is induced by carcinogens through a series of 
independent stages. The Agency believes that this model conforms most 
closely to what we know about the etiology of cancer. There is no 
evidence that the multistage model is biologically inappropriate, 
especially for genotoxic carcinogens, which MC most likely is. The most 
recent data submitted by the HSIA [Exs. 117-124A] clearly add 
substantial support to the previous body

[[Page 1531]]

of evidence indicating that one or more metabolites of MC is a 
genotoxic carcinogen. The low-dose linearity feature of this model is 
scientifically required for any exposure that confers additional risk 
upon a pre-existing background level of risk produced by a similar or 
equivalent mechanism. Given the underlying connection between DNA 
mutations and cancer and the obvious background incidence of cancer in 
the human population, the overwhelming scientific consensus is that 
genotoxins follow low-dose linear functions.
    The multistage model is generally considered to be a conservative 
model because it is approximately linear at low doses and because it 
assumes no threshold for carcinogenesis, although there are other 
plausible models of carcinogenesis which are more conservative at low 
doses. ``No threshold'' means that any incremental amount of exposure 
to a carcinogen is associated with some amount of increased risk. 
``Approximately linear at low doses'' means that one unit of change in 
dose will result in one unit of change in risk at low doses.
    The most common approach for setting the parameters in the 
multistage model is to assume that the dose-response curve is described 
by a polynomial of k-1 degrees, where k is the number of dose groups 
tested. The multistage model thus takes the form

P(Cancer) = 1--exp(-f(dose)),

with f(dose) given by:

 f(dose) = a + b1(dose) + b2(dose)2 + ...+ bk-
1(dose)k-1.

    The number of stages is specified by k-1, and the parameters a (the 
background risk) and bi are estimated from the observed data.
    Alternatives to the multistage model include the tolerance 
distribution models such as the probit model, the logit model and the 
Weibull model. The tolerance distribution models generally predict 
dose-response relationships which are sigmoid in shape. Thus, these 
models will approach zero more rapidly than a linear multistage model. 
This means that at low doses, these models will predict lower risks 
than will a linear multistage model.
    In the MC rulemaking, most of the risk assessments submitted to the 
Agency used the linearized multistage model to predict risk. The 
differences in risk estimates were not generally due to the dose-
response model used, but to whether the risk assessor used 
pharmacokinetic modeling to estimate target tissue doses, and what 
assumptions were used in the pharmacokinetic modeling.

D. Selection of Dose Measure

1. Estimation of Occupational Dose
    The purpose of low dose extrapolation is to estimate risk of cancer 
at a variety of occupational exposures. This requires that the doses be 
converted into units comparable to those in which the experimental dose 
is measured.
    In its NPRM, OSHA first converted the experimental dose, measured 
in ppm, to an inhaled dose, measured in mg/kg/day. The female mouse 
body weight used in these calculations was 0.0308 kg. The breathing 
rate for mice was 0.05 m3/day. The Agency then assumed that 
equivalent doses in mg/kg/day would lead to equivalent risk. Once the 
experimental dose (in mice) had been converted to mg/kg/day, it was 
then converted to ppm using the human breathing rate of 9.6 m3/
workday and human body weight of 70 kg in order to estimate risks at 
various potential exposure levels. To determine the dose to humans 
corresponding to the risk estimated from the mouse data, OSHA used the 
following equations:
[GRAPHIC] [TIFF OMITTED] TR10JA97.001

OSHA assumed that risk estimates derived for mice at a given mg/kg/d 
would be equivalent to risks experienced by humans at that mg/kg/d. 
Doses in mg/kg/d in humans were converted to ppm to determine risk at 
various potential workplace exposures using the following equations:
[GRAPHIC] [TIFF OMITTED] TR10JA97.002

This process was used by K.S. Crump et al. in their risk assessment 
submitted to OSHA [Ex. 12]. Use of mg/kg/d as a measure of dose has 
been criticized by Mr. Harvey Clewell, representing the U.S. Navy [Ex. 
19-59]. He stated,

    Strictly speaking, the concept of a mg/kg/day dose applies only 
to exposures for which the term ``administered dose'' is well 
defined, which does not include inhalation exposure to a volatile, 
lipophilic chemical such as MC....If a non-pharmacokinetic dose 
surrogate is desired, the choice should be time-weighted average 
concentration (ppm) as used by the FDA.

Mr. Clewell preferred use of dose surrogates calculated in the PBPK 
models to estimate human risk. OSHA has given careful consideration to 
the issues raised by Mr. Clewell and, in the risk assessment presented 
here, considered dose surrogates estimated in PBPK models and time-
weighted average concentration in addition to the mg/kg/d dose 
presented in the NPRM.
    For all dose measures used to estimate human risk, the assumptions 
used by OSHA for body weights and exposure times and rates were those 
described above. In OSHA's final risk assessment, a Bayesian analysis 
was used and the prior distribution for breathing rate was centered on 
OSHA's preferred value of 9.6 m3/d.

[[Page 1532]]

2. mg/kg/d Versus Other Measures of Exposure
    Quantitative risk assessments based on animal data are conducted 
under the assumption that animals and humans have equal risks from 
lifetime exposures to a chemical when exposure is measured in the same 
unit for both species. Opinions vary, however, on what is the correct 
measure of exposure. For site-of-contact tumors, a ppm-to-ppm 
conversion is a generally accepted measure of dose. For systemic 
tumors, commonly used dose conversions include mg/kg/day (as used by 
OSHA in its MC NPRM), mg/surface area/day (with surface area 
approximated by BW2/3), mg/BW3/4/day, and mg/kg/lifetime. 
When adequate and appropriate pharmacokinetic or metabolic data are 
available, these data are sometimes used to estimate internal dose. In 
the case of MC, metabolic data have been gathered and pharmacokinetic 
models have been used by various investigators to estimate target 
tissue doses for MC.
    Some commenters [Exs. 19-28, 19-57] had expressed concern that OSHA 
used a surface area correction factor in its risk assessment in the 
NPRM. In fact, in the NPRM, OSHA extrapolated from mice to humans based 
on body weight rather than surface area. However, the Agency requested 
comment on which species conversion factor would be appropriate to use 
in OSHA's final risk assessment and whether incorporation of 
pharmacokinetic information should influence the choice of the 
conversion factor. Two commenters [Exs. 19-83, 23-21] referred to the 
interagency document on interspecies scaling which ultimately 
recommends BW3/4 as the appropriate extrapolation factor in the 
absence of appropriate pharmacokinetic information, although the 
document also indicates that extrapolation factors based on BW or 
BW2/3 would also be consistent with the available data (EPA Draft 
Report: ``A cross-species scaling factor for carcinogen risk assessment 
based on equivalence of mg/kg3/4/day.'' 57 FR 24152, June 5, 
1992).
    There was also considerable discussion as to whether it was 
appropriate to apply an extrapolation factor such as BW3/4 or 
BW2/3 in addition to PBPK modeling of dose, to account for 
pharmacodynamic differences between species (such as differences in DNA 
repair rates and other non-metabolic differences in interspecies 
susceptibility to an agent). The EPA applied the BW2/3 
extrapolation factor after incorporation of the PBPK data for MC in 
their 1987 draft update of the MC risk assessment. In their previous 
risk assessment, which did not incorporate PBPK data, EPA also used 
BW2/3 as the extrapolation factor. Since OSHA has preferred the BW 
extrapolation in other chemical-specific risk assessments and has used 
BW as the extrapolation factor in its best estimate of risk in the NPRM 
for MC, OSHA agrees with Dr. Lorenz Rhomberg's assessment [Ex. 28] that 
OSHA should continue to use body weight as its extrapolation factor in 
its final MC risk assessment. Thus, OSHA's risk estimate does not make 
any allowance for possible pharmacodynamic differences between rodents 
and humans, or within the diverse human population.
3. Pharmacokinetic Modeling of Dose
    OSHA discussed issues relating to the use of pharmacokinetic data 
in its NPRM. These issues were further explored during the hearings and 
in pre-hearing and post-hearing comments. In response to the ANPR [51 
FR 42257], Dow Chemical submitted documentation of a physiologically-
based pharmacokinetic model (PBPK) [Exs. 8-14d and 10-6a], developed 
for MC by Reitz and Anderson, which described the rates of metabolism 
of the MFO and GST pathways and the levels of MC and its metabolites in 
various tissues of rats, mice, hamsters and humans. This model was 
presented as a basis for converting an applied (external) dose of MC to 
an internal dose of active metabolite in the lung and liver in various 
species under various MC exposure scenarios. Since publication of the 
NPRM, several parties have submitted pharmacokinetic models or comments 
on modeling to the rulemaking record. These are discussed in detail 
below.
    a. General issues in PBPK modeling. Physiologically-based 
pharmacokinetic modeling can be a useful tool for describing the 
distribution, metabolism and elimination of a compound of interest 
under conditions of actual exposure and, if data are adequate, can 
allow extrapolation across dose levels, across routes of exposure and 
across species. One limitation of using PBPK modeling is a widespread 
lack of adequate and appropriate physiological and metabolic data to 
define the model. In particular, difficulties arise in attempting to 
define a model for which the mechanism of carcinogenesis has not been 
established, when it is unclear whether there would be tumor site 
concordance across species, and when the metabolic pathway(s) 
responsible for carcinogenesis has not been determined.
    The concentration of a chemical in air or the total inhaled dose 
(mg/kg/d) may not be the most biologically relevant dose to use in 
comparing toxicity across doses or across species. The dose measure 
that would be most useful in risk assessment is the dose to the target 
tissue of the chemical or metabolite that is known to directly cause 
the toxic effect. Generally, this quantity is unknown in almost every 
case because the proximate carcinogenic moiety is usually highly 
reactive, and therefore very difficult to measure in biological 
systems. Since the proximate toxic agent is unlikely to be a quantity 
readily measured in the laboratory, it is sometimes desirable to use 
dose surrogate concentrations, calculated by methods such as PBPK 
modeling, to obtain a more direct estimate of a dose-response 
relationship. Examples of dose surrogates that may be relevant to the 
toxic mechanism of action of a chemical are peak concentrations of a 
particular metabolite at a target tissue site, area under the 
concentration-time curve of a metabolite at a target site, and blood 
concentration of the parent chemical or a relevant metabolite.
    If the dose surrogate chosen is directly relevant to the mechanism 
of action of a chemical, there is greater confidence in the risk 
estimates generated using the dose surrogate than those generated using 
total inhaled concentration. If the mechanism of action of a chemical 
is uncertain, and therefore the relevance of the dose surrogate to 
carcinogenicity is in question, there is proportionally less confidence 
in the predicted risks estimated using that dose surrogate. Risk 
estimates from PBPK modeling can also be limited by the quality and 
quantity of available metabolic data. Since risk estimates are directly 
dependent upon the dose or dose surrogate chosen, reliable measures of 
all relevant physiological parameters and all relevant metabolic 
pathways in all target tissues from all species under investigation are 
critical. In addition, measures of the uncertainty and inter-individual 
variability of these parameters must be generated.
    In its NPRM, OSHA solicited information on the appropriateness of 
physiologically- based pharmacokinetic modeling for the MC risk 
assessment. Specifically, OSHA asked the following questions:
    (a) How can pharmacokinetics be best applied to the risk assessment 
of MC and what are the current limitations of this approach in the 
quantitation of health risks? What weight should OSHA give to 
pharmacokinetic data in its risk assessments and why?
    (b) Given that five separate risk assessments have utilized the 
pharmacokinetic models for MC in five

[[Page 1533]]

different ways (resulting in from 0 to 170 fold reduction in the final 
risk when compared with assessments not utilizing pharmacokinetic 
data), how can OSHA best utilize the existing pharmacokinetic data and 
still be certain of protecting worker health?
    (c) Which parameters in the pharmacokinetic models are most 
sensitive to errors in measurement or estimation? Can an increased 
database reduce the uncertainties in these parameters?
    (d) How much confidence can be placed in the human in vitro MC 
metabolism data, especially that for lung tissue? How will human 
variability in these parameters affect the extrapolation of risk from 
rodent species?
    (e) Are there any studies in progress which attempt to verify the 
predictive ability of the model in vivo, (e.g., by giving doses in a 
lifetime bioassay which will produce cancer in a species other than the 
B6C3F1 mouse and the F344 and Sprague-Dawley rats)?
    (f) OSHA recognizes the large areas of uncertainty which exist in 
applied dose risk assessment procedures. If pharmacokinetic modeling 
reduces these uncertainties, can the reduction in uncertainty be 
quantified? Are additional uncertainties introduced into the risk 
assessment process by the use of pharmacokinetic models?
    (g) By using the pharmacokinetic models in the risk assessment 
process, one is making an assumption about the carcinogenic mechanism 
of action of methylene chloride. Are there any new studies on the 
carcinogenic mechanism of action of MC which would support or refute 
this assumption?
    (h) If the carcinogenic process is, in fact, not the result of the 
metabolite(s) from the GST pathway alone, but is due to a combination 
of metabolites or a combination of the parent compound plus the 
metabolites, how would the pharmacokinetic model and the subsequent 
risk assessments be affected? Can these effects be quantified?
    (i) One of the assumptions made in the pharmacokinetic model is 
that the target tissues for MC are liver and lung. Can this model 
predict cancer incidences at other sites? If not, is there a way to 
factor in consideration of possible MC-induced human cancers at other 
sites than liver and lung?
    (j) OSHA solicits information supporting or refuting interspecies 
allometric scaling based on body weight or body surface area.
    OSHA reviewed comments and testimony on these issues from an expert 
witness [Ex. 25-E]; representatives of other U.S. government agencies, 
including NIOSH [Exs. 19-46, 41], EPA [Exs. 25-D, 28], CPSC [Ex. 25-I] 
and U.S. Navy [Exs. 19-59, 96]; the State of California [Ex. 19-17]; 
the Halogenated Solvents Industry Alliance (HSIA) [Exs. 19-45, 19-83, 
105]; and the UAW [Exs. 19-22, 23-13, 61]. Comments and testimony from 
the expert witness, the other government agencies and the Halogenated 
Solvents Industry Alliance generally reflected the opinion that the 
pharmacokinetic information was sufficiently developed in the case of 
MC to justify its use in estimating human cancer risks. The predominant 
view among these commenters and hearing participants was that the data 
collected for MC and the pharmacokinetic model developed by Reitz and 
Andersen adequately represented the metabolism of MC in mice. Many 
commenters also believed that it was reasonable to conclude that the 
lung and liver tumor incidence in the B6C3F1 mice was the result of the 
GST metabolite. As described in further detail below, OSHA generally 
agrees that the PBPK approach is reasonable to assess cancer risks of 
MC. In fact, the Agency has evaluated the submitted PBPK models, 
determined that there were several deficiences in each of those models, 
and improved upon those in its final quantification of risks.
    One rulemaking participant was strongly opposed to using 
pharmacokinetic data in the MC risk assessment. Dr. Franklin Mirer [Ex. 
61], representing the UAW, stated:

    The pharmacokinetic model advanced for methylene chloride 
carcinogenesis is incorrect and should not be used for quantitative 
risk assessment.

Dr. Mirer was particularly concerned that the PBPK model ignored the 
rat cancer bioassay data and that the model was based on a 
``mechanistic hypothesis.''
    Dr. Mirer reiterated his concerns in response to the October 24, 
1995 reopening of the rulemaking record [Ex. 126-31], stating,

    The simple message is that OSHA should give no additional weight 
to the pharmacokinetic argument. For OSHA to give the argument any 
additional weight would mean that OSHA was ignoring a substantial 
body of evidence regarding carcinogenicity of methylene chloride in 
additional animal species.

Dr. Mirer continued,

    The pharmacokinetic hypothesis is unconvincing even as an 
explanation of the differences in lung and liver tumors in mice and 
rats.

    OSHA shares Dr. Mirer's concerns that the mechanism of 
carcinogenicity for MC has not been clearly established and that using 
pharmacokinetic modeling may lead to risk estimates which ignore the 
rat tumor data. The Agency notes that it has used the NTP rat data in 
its hazard identification for MC. OSHA has also determined, however, 
that the mouse data represent the strongest data set on which to base a 
quantitative risk assessment, and notes that risk estimates based on 
the rat data (without PBPK-based adjustment of dose) are similar to 
OSHA's final risk estimates using mouse data and a PBPK analysis.
    The determination that the mouse data set was the strongest on 
which to base a quantitative risk assessment was made without regard to 
the availability of information on pharmacokinetics. Incorporating 
pharmacokinetic modeling into the risk assessment for MC is a logical 
extension of OSHA's risk assessment decisionmaking process and reflects 
the Agency's review of the totality of data on tumor incidence, 
metabolism and mechanism of action. The extensive data base on MC 
metabolism and mechanism of action, although by no means complete, was 
the determining factor in the decision to incorporate pharmacokinetics 
into its final risk assessment. The Agency is aware of very few 
chemicals of regulatory interest for which the available data could 
match this body of information. The specific criteria utilized by the 
Agency in making this determination are enumerated below.
    Comments on the specific issues enumerated above are discussed 
under the appropriate topics in the sections that follow.
    b. Criteria for using PBPK in quantitative risk assessment. OSHA 
evaluated several criteria before deciding to use PBPK analysis in its 
final quantitative risk assessment for MC. In future rulemakings in 
which the use of pharmacokinetic information in risk assessment is at 
issue, it will be necessary to evaluate at least the criteria described 
below before reaching conclusions, in order to avoid adopting an 
alternative hypothesis that is less (rather than more) reflective of 
the true situation than the more generic applied-dose assumption. 
Further, it may be appropriate to evaluate additional criteria in some 
cases, depending on the metabolism and mechanism of action of the 
chemical. The criteria which OSHA considered before incorporation of 
PBPK in the final risk estimate for MC were:
    (1) The predominant and all relevant minor metabolic pathways must 
be well described in several species, including humans. (Two metabolic 
pathways are responsible for the metabolism of MC in humans, mice, rats 
and hamsters).

[[Page 1534]]

    (2) The metabolism must be adequately modeled (Only two pathways 
are responsible for the metabolism of MC as compared to several 
potential routes of metabolism for other compounds, such as benzene and 
the dioxins. This simplified the resulting PBPK models).
    (3) There must be strong empirical support for the putative 
mechanism of carcinogenesis (e.g., genotoxicity) and the proposed 
mechanism must be plausible.
    (4) The kinetics for the putative carcinogenic metabolic pathway 
must have been measured in test animals in vivo and in vitro and in 
corresponding human tissues (lung and liver) at least in vitro, 
although in vivo human data would be the most definitive.
    (5) The putative carcinogenic metabolic pathway must contain 
metabolites which are plausible proximate carcinogens (for example, 
reactive compounds such as formaldehyde or S-chloromethylglutathione).
    (6) The contribution to carcinogenesis via other pathways must be 
adequately modeled or ruled out as a factor. For example, there must be 
a reasonable analysis of why reactive metabolites formed in a second 
pathway would not contribute to carcinogenesis (e.g., formyl chloride 
produced via the MFO pathway is likely to be too short-lived to be 
important in MC carcinogenesis).
    (7) The dose surrogate in target tissues (lung and liver in the 
case of MC) used in PBPK modeling must correlate with tumor responses 
experienced by test animals (mice, rats and hamsters).
    (8) All biochemical parameters specific to the compound, such as 
blood:air partition coefficients, must have been experimentally and 
reproducibly measured. This must be true especially for those 
parameters to which the PBPK model is most sensitive.
    (9) The model must adequately describe experimentally measured 
physiological and biochemical phenomena.
    (10) The PBPK models must have been validated with data (including 
human data) which were not used to construct the models.
    (11) There must be sufficient data, especially data from a broadly 
representative sample of humans, to assess uncertainty and variability 
in the PBPK modeling.
    In the case of MC, to a large extent these criteria were met. This 
made evaluation of existing PBPK models and further development of the 
modeling strategy a viable option. Therefore, the Agency evaluated 
existing PBPK models and then contracted with Drs. Andrew Smith, 
Frederic Bois, and Dale Hattis to help OSHA improve on the MC PBPK 
model in the record, which would extend the application of modeling 
techniques beyond those models which had been submitted to the Agency 
and incorporate all of the data available and appropriate for 
quantitative analysis in the record. OSHA's evaluation of existing PBPK 
models, the development of a modified MC PBPK analysis, and OSHA's 
final risk assessment are described later in this document.
    c. Choice of GST metabolic pathway as dose surrogate. The choice of 
``dose surrogate'' for the MC PBPK model is a critical factor in 
estimating PBPK-based risks. The dose or ``dose surrogate'' used in a 
risk assessment should be a biologically-important quantity, should 
have a plausible mechanism of action at the target tissue and should 
correlate with the response of interest. The simplest choice of dose is 
the applied dose or ambient concentration of the contaminant measured 
as ppm or as the inhaled quantity in mg/kg/day (as used in the 
Preliminary Quantitative Risk Assessment in the NPRM). Such quantities 
have the advantage of being easily and directly measurable during the 
bioassay. Other meaningful dose surrogates could include the 
concentration of parent compound in the target organ, the concentration 
of specific metabolites in the target organ, the area under the time-
concentration curve (integrated dose) of each metabolite and the parent 
compound, or peak blood or target organ levels of each metabolite and 
parent compound. These quantities are not as easily measured. Often 
only indirect measurements or computer modeling of these dose 
surrogates are available.
    In the PBPK model developed by Reitz et al. [Ex. 7-225], the dose 
surrogates that correlated with the tumor response were the parent 
compound (MC) concentration and the amount of GST metabolites formed in 
the lung and liver. Reitz et al. discounted the parent compound as the 
dose surrogate because MC is not a chemically reactive compound and 
direct-acting carcinogens (and metabolites of carcinogenic compounds) 
are generally hypothesized to be reactive (usually, electrophilic). 
They also discounted the parent compound as a relevant dose surrogate 
because parent MC concentration was higher in the rat blood than in the 
mouse for any dose of MC, while the cancer response of the mouse was 
greater than the rat. If parent MC were the critical compound for MC 
carcinogenesis, one would expect the cancer response across species to 
correlate with blood levels of the compound.
    (1) Metabolism via GST versus MFO pathway. Human metabolism of MC 
has been well studied. One clear finding from the human metabolic 
studies is that humans metabolize MC by both the MFO and GST pathways, 
as do mice, rats, and hamsters. Although human metabolism via the MFO 
pathway has been measured in vivo as well as in vitro, human MC 
metabolism via the GST pathway has been measured only in vitro. 
Metabolic data on the human GST pathway have been collected from 
several liver samples and one pooled lung sample (combined samples from 
four human subjects). However, it has not been possible to measure 
human GST metabolism of MC in vivo.
    Reitz et al. measured the metabolic constants (Km and 
Vmax) in vitro for the GST and the MFO metabolic pathways. Enzyme 
activities were determined by measuring the conversion of 36Cl-
labeled MC to water-soluble products. Metabolic constants were then 
compared across species (mouse, rat, hamster and human). In the liver, 
the MFO activity was highest in the hamster, followed by the mouse, 
human and rat. Human values were much more variable than those of the 
rodent species. Human Vmax for the liver MFO pathway ranged 
approximately an order of magnitude and human Km varied 
approximately three-fold. GST activity in the liver was determined for 
mouse and human tissues only. Mouse liver had approximately 18-fold 
greater activity (Vmax) than human liver, but the human tissue had 
about a three-fold greater affinity constant (Km) for MC than the 
mouse.
    In the lung, the activity of the MFO and GST enzymes was determined 
for a single substrate concentration. For the MFO pathway, mouse tissue 
had the highest activity, followed by hamster and rat. No MFO activity 
specific for MC was detected in the human lung tissue, although other 
MFO isozymes were demonstrated to be active in the tissue. For the GST 
pathway in lung, mouse tissue was the most active, followed by rat and 
human. No GST activity was detected in the hamster lung.
    In humans, the MFO pathway has been measured in vivo as well as in 
vitro [Ex. 7-225]. Human in vivo experimentation was conducted by 
several investigators. Metabolism via the MFO pathway is relatively 
easy to measure because the end product is carbon monoxide [Ex. 7-24]. 
The metabolic rates measured in vitro were not similar to those 
measured in vivo after exposure to known concentrations

[[Page 1535]]

of MC, which means that in vitro measurements in human tissue (in 
particular for the GST pathway for which there are no human in vivo 
data) could not be used directly as a measure of metabolism. Human in 
vivo and in vitro MFO metabolism data were important in developing the 
pharmacokinetic models because they provided human data for MC-specific 
metabolism which could be used to help validate the models. 
Unfortunately, the modeling of the putative critical pathway for 
carcinogenesis (the GST pathway) could not be validated for humans. 
This is a weakness in the PBPK modeling for MC shared by all of the 
models, including OSHA's final PBPK analysis.
    In the PBPK models submitted to OSHA, the human rate of metabolism 
of MC, particularly via the GST pathway, was based on data gathered 
from four liver samples and one pooled lung sample. Although the liver 
metabolic data were of the same magnitude as those collected by Green 
et al., Green's data were not considered in Reitz's model and the 
variability of those data was not assessed. Therefore, the estimates of 
the dose surrogates in Reitz's model were based on the average of four 
liver samples. Four liver samples are not nearly enough data to 
confidently estimate and account for human variability. Considerations 
of the variability and uncertainty of these data are discussed in more 
detail later in this document.
    The human lung data were even more limited. Four human lung samples 
were pooled to provide a single data point. This lack of lung tissue 
data is particularly critical in PBPK modeling when calculating the 
ratios of A1 and A2 (the distribution of metabolism between liver and 
lung tissue in humans). Errors in calculating these ratios will 
significantly affect the final risk estimates, as discussed by Mr. 
Harvey Clewell for the U.S. Navy [Ex. 96].
    HSIA submitted additional data on the human metabolism of MC in the 
form of a study of GST metabolism in human liver samples conducted by 
Bogaards et al. [Ex. 127-16]. The human GST liver metabolism data 
collected in this study were not directly comparable to the data 
collected by Reitz or Green, becausethe Bogaards data were measured 
using a colorimetric method which was not as sensitive as the 36Cl 
method. Under contract to OSHA, Dr. Andrew Smith and Dr. Frederic Bois 
compared the data from different laboratories and collected under 
different methodologies and developed a correction factor across 
methodologies so that they could use all of the human metabolic data 
available in OSHA's final PBPK model [Ex. 128]. There are now over 30 
data points for human liver in vitro metabolism by the GST pathway and 
5 human lung data points (the additional lung data points were reported 
in Green et al., Ex. 124A). OSHA determined that it was important to 
use as much of the available human data in its PBPK model for MC as 
scientifically justifiable. These data were used to estimate the 
variability and uncertainty surrounding the measures of human GST 
metabolism. Although the methodologies differed across studies, OSHA 
has adjusted and incorporated all of the available human data in its 
PBPK model.
    (2) Parallelogram approach. When the metabolic rates for the MFO 
pathway measured in vivo and in vitro within each species were 
compared, it was determined that those rates were not equivalent. This 
meant that, unlike the case for some other chemical compounds, the in 
vitro GST data could not substitute directly for an in vivo measurement 
of metabolism. Reitz and Andersen [Ex. 7-225] suggested a 
``parallelogram'' approach to the problem of non-comparability of in 
vitro and in vivo rates. This approach makes the assumption that the 
ratio of in vivo to in vitro measurements is roughly comparable across 
species (including humans). They measured metabolic rates of both 
pathways in vitro and in vivo in rodents and then used the average 
ratio of the in vitro to in vivo metabolic rate in three rodent species 
to extrapolate from in vitro rates in humans [Ex. 7-225] to an 
estimated in vivo value.

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    Ron Brown [Ex. 25-E], an expert witness for OSHA, was concerned 
that ``...the methodology used to extrapolate the in vitro data to the 
in vivo state is problematic and the accuracy of the human in vitro 
measurement of GST activity toward MC is uncertain.'' This may be due 
to the small sample size, variability in the laboratory analysis or 
inadequacy of the in vitro model. OSHA believes that this is a critical 
point of uncertainty in using the PBPK model for risk assessment. The 
Agency also notes that in the risk assessments using PBPK models 
submitted during the MC rulemaking, none used the parallelogram 
approach as the basis of determining human in vivo metabolic rates. 
Instead, allometric scaling was used to estimate human values. OSHA has 
conducted risk assessments using both the allometric approach (OSHA's 
final risk estimates) and the parallelogram approach (OSHA's 
alternative analysis). The Agency did this in order to determine what 
the risk estimates would be if all possible quantitative data were used 
to the fullest extent, regardless of the uncertainties in the data.
    OSHA agrees that evidence presented in the record generally 
supports the GST pathway as a plausible carcinogenic mechanism of 
action of MC. The Agency remains concerned, however, that sole reliance 
on the GST pathway may show insufficient consideration for potential 
contributions of the parent compound and/or metabolites of the MFO 
pathway to the carcinogenesis of MC. It is clear that ambient MC 
concentration is dose-related to tumor response. It has not been shown 
with any certainty that MC GST metabolites are related to tumor 
response across species. Thus, there is greater confidence that the 
lifetime bioassays predict MC carcinogenicity in humans than there is 
that cancer occurred through a specific mechanism, and even less 
confidence that the metabolic rates measured in vitro accurately 
measure differences in species that correlate to tumor development. 
This is particularly true for lung metabolism where only one pooled and 
five individual human samples were analyzed. Notwithstanding the 
uncertainties described above, the Agency believes that the hypothesis 
that GST is the carcinogenic pathway presents a plausible mechanism of 
action for MC and is sufficiently well-developed to warrant the use of 
PBPK modeling of the GST pathway as the dose surrogate of choice in the 
quantitative risk assessment for MC.
    d. Structure of the MC PBPK model. The PBPK models described below 
are based on the model originally submitted by Dr. Reitz on behalf of 
HSIA in 1992 [Ex. 7-225]. Over the years since the first submission of 
a MC PBPK model to OSHA, significant improvements have been made in 
model structure and in the data collected for PBPK modeling, especially 
in how the uncertainty and variability in the data are treated. The 
general structure of the models submitted to OSHA are described below, 
followed by a description of the parameters used in the various models. 
Next follows a description of how the variability, uncertainty, and 
sensitivity of the models to uncertainty have been assessed, noting the 
improvements that have been made in developing methods to handle these 
issues. This is followed by a comparison of the risk estimates 
generated by these models. Finally, OSHA's final risk assessment is 
described. This risk assessment incorporates lessons learned from 
previous models and uses all of the available, appropriate, 
quantifiable data in a Bayesian approach to modeling the dose metric 
for MC.
    In the PBPK model submitted by Dr. Reitz of HSIA [Ex. 7-225], a 
series of differential equations was used to model the mass balance of 
MC and its metabolites in five physiologically-defined compartments, 
including the lung, liver, richly perfused tissue, slowly perfused 
tissue, and fat. Metabolism via the MFO pathway was described by 
saturable Michaelis-Menten kinetic equations and GST metabolism was 
modeled using first-order nonsaturable kinetics. With the exception of 
the PBPK model sumitted by ICI [Ex. 14A], all of the PBPK models 
submitted to the Agency followed these assumptions regarding the 
metabolism of MC. The rate constants for the metabolic equations were 
estimated based on measurements of the partition coefficients, 
allometric approximations of the physiological constants (e.g., lung 
weight), and estimations (i.e., allometric scaling of rodent data, 
estimations made using the parallelogram approach, etc.) of the 
biochemical constants (e.g., Michaelis-Menten constants).
    NIOSH presented a PBPK model in 1993 [Ex. 94], also structurally 
based on the Reitz-Andersen model, but with modifications to the human 
breathing rate and cardiac output to account for uptake of MC in 
physically active workers, rather than at-rest humans or humans 
involved in light activity, and including an analysis of the 
variability of the human metabolic parameters. Specifically, NIOSH 
compared estimates derived from the arithmetic average of the human GST 
metabolism data with the individual human liver data points to estimate 
the uncertainty in an individual's risk of cancer from occupational MC 
exposure. This approach began to incorporate some necessary features, 
such as a special focus on physically active workers and the 
variability of human metabolic parameters, but did not attempt to 
quantify the uncertainty and variability of the individual parameters 
and their contribution to the uncertainty associated with the PBPK 
model.
    Mr. Harvey Clewell, representing the U.S. Navy, also submitted 
several PBPK models to OSHA. In his initial submission (1992), Mr. 
Clewell modified an existing PBPK model [Ex. 7-125] to include more 
recent data on the mouse blood/air partition coefficient [Ex. 19-59]. 
In a second PBPK model, he ``started from scratch'' to construct a 
model based on data derived from sources independent of the previous 
work of Reitz and Andersen [Ex. 23-14], which was described in Mr. 
Clewell's testimony [Tr. 2361,10/15/92]. This model was structurally 
similar to the model presented by HSIA with the following exceptions: 
it featured three lumped compartments (slowly perfused, moderately 
perfused and rapidly perfused) based on tissue kinetic constants rather 
than the earlier two lumped compartment models based on tissue blood 
volumes; and the mouse blood/air partition coefficient was corrected to 
19.4 instead of the earlier 8.29 on the basis of more recent data. A 
third model submitted by Mr. Clewell was identical in structure to the 
Reitz/Andersen model, but incorporated the more recent experimental 
data on the partition coefficients and the more recent mouse metabolism 
data [Ex. 96]. OSHA used Mr. Clewell's third model in its comparison of 
PBPK-derived risk estimates because of its similarity in structure to 
the original Reitz model and its incorporation of the most recent 
experimental data.
    In his third model, Clewell either derived probability 
distributions for each parameter from the literature or estimated 
distributions for those parameters for which data were not available, 
and conducted Monte Carlo simulations to derive output distributions 
for the dose surrogates. These distributions of dose surrogates were 
then used to derive four risk estimates: the doses input into the 
multistage dose-response analysis of the tumor bioassay were derived 
either from the mean or from the 95th percentile of the output 
distribution of PBPK parameters, and these in turn were coupled with 
the either the MLE or the UCL of the distribution of possible values of 
the multistage model

[[Page 1537]]

parameters. This analysis was an advance over that of previous models 
because it took into account some of the uncertainty and variability 
known to be associated with the data used in the PBPK model.
    After evaluating these submitted models, OSHA determined that 
Clewell's model provided the best prototype on which to base its final 
PBPK modeling approach for MC. Therefore, the Agency worked with Drs. 
Smith and Bois to review Clewell's model and with the assistance of Dr. 
Hattis, to develop a refined PBPK modeling approach with a more 
sophisticated analysis of variability and uncertainty (and other 
refinements as described below). In this way the Agency developed an 
approach which would incorporate what was learned in the development of 
earlier PBPK models and make use of as much of the available 
physiological and metabolic data in the record as possible. Clewell's 
model was chosen for comparison, because this was the only model to 
provide a systematic analysis of the uncertainty, variability and 
sensitivity of the model using Monte Carlo techniques. OSHA's final 
risk assessment approach is described in greater detail below.
    e. Choice of parameters for PBPK modeling. The definitions of the 
parameters used in the models described above are contained in Table 
VI-2. Note that not all parameters were used in each model and slightly 
different variable names were used by different investigators. For 
example, OSHA's final analysis contains a bone marrow compartment, 
while Clewell's model did not. OSHA refers to the blood flow for poorly 
(or slowly) perfused tissues as ``QppC,'' while Clewell used ``QSC.''

         Table VI-2.--Definitions of Pharmacokinetic Parameters         
------------------------------------------------------------------------
      Parameter (units)                        Definition               
------------------------------------------------------------------------
BW (kg)......................  Body weight in kg. Human body weights    
                                were assumed to be 70-kg (Reference     
                                Man). Mouse body weights were the       
                                average weight of mice in the NTP       
                                bioassay.                               
QPC unscaled (1/hr, 1 kg BW).  Breathing rate. QPC = QP(1/hr)/BW.75     
                                where QP = alveolar ventilation rate.   
                                Human QP was based on rate of 9.6 m3/8- 
                                hr (converted 1/hr and adjusted to      
                                alveolar ventilation (= 0.70 total      
                                ventilation) except in NIOSH and OSHA-  
                                modified models. Mouse QP = (24.3 1/    
                                hr)(0.70 alveolar/total).               
QCC unscaled (1/hr, 1 kg BW).  Cardiac output. QCC = QC(1/hr)/BW.75     
                                where QC = cardiac output in 1/hr. Reitz
                                set QC = QP. Clewell and NIOSH based    
                                human QC on Astrand et al. [Ex. 7-120]  
                                data on cardiac output and breathing    
                                rate vs. workload.                      
VPR (ratio, unitless)........  Alveolar ventilation/perfusion ratio.    
                                                                        
------------------------------------------------------------------------
                         Blood flows to tissues                         
                                                                        
------------------------------------------------------------------------
QGC or QgiC (fraction of       Blood flow to gastrointestinal tract as a
 cardiac output).               fraction of cardiac output. QGC = QG/QC.
QLC or QliC (fraction of       Blood flow to liver as a fraction of     
 cardiac output).               cardiac output. QLC = QL/QC.            
QFC or QfatC (fraction of      Blood flow to fat as a fraction of       
 cardiac output).               cardiac output. QFC = QF/QC.            
QSC or QppC (fraction of       Blood flow to slowly (or poorly) perfused
 cardiac output).               tissues as a fraction of cardiac output.
                                QSC = QS/QC.                            
QRC or QwpC (fraction of       Blood flow to rapidly (or well) perfused 
 cardiac output).               tissues as a fraction of cardiac output.
                                QRC = QR/QC.                            
QmarC (fraction of cardiac     Blood flow to bone marrow as a fraction  
 output).                       of cardiac output.                      
                                                                        
------------------------------------------------------------------------
                             Tissue volumes                             
                                                                        
------------------------------------------------------------------------
VGC or VgiC (fraction of body  Volume of GI tract as a fraction of body 
 weight).                       weight. VGC = VG/BW.                    
VLC or VliC (fraction of body  Volume of liver as a fraction of body    
 weight).                       weight. VLC = VL/BW.                    
VFC or VfatC (fraction of      Volume of fat as a fraction of body      
 body weight).                  weight. VFC = VF/BW.                    
VSC or VppC (fraction of body  Volume of slowly (or poorly) perfused    
 weight).                       tissues as a fraction of body weight.   
                                VSC = VS/BW.                            
VRC or VwpP (fraction of body  Volume of rapidly (or well) perfused     
 weight).                       tissues as a fraction of body weight.   
                                VRC = VR/BW.                            
VluC (fraction of body         Volume of lung as a fraction of body     
 weight).                       weight.                                 
VmarC (fraction of body        Volume of bone marrow as a fraction of   
 weight).                       body weight.                            
                                                                        
------------------------------------------------------------------------
                         Partition coefficients                         
                                                                        
------------------------------------------------------------------------
PB or Pblo...................  Blood/air partition coefficient.         
PG or Pgi....................  GI tract/blood partition coefficient (GI 
                                tract/air divided by PB).               
PL or Pli....................  Liver/blood partition coefficient (Liver/
                                air divided by PB).                     
PF or Pfat...................  Fat/blood partition coefficient (Fat/air 
                                divided by PB).                         
PS or Ppp....................  Slowly (or poorly) perfused tissue/blood 
                                partition coefficient (Slowly perfused  
                                tissue/air divided by PB).              
PR or Pwp....................  Rapidly (or well) perfused tissue/blood  
                                partition coefficient (Rapidly perfused 
                                tissue/air divided by PB).              
PLU or Plu...................  Lung/blood partition coefficient (Lung/  
                                air divided by PB).                     
Pmar.........................  Bone marrow:air partition coefficient.   
                                                                        
------------------------------------------------------------------------
                          Metabolic parameters                          
                                                                        
------------------------------------------------------------------------
VMAXC unscaled (mg/hr, 1 kg    MFO pathway Michaelis-Menten maximum     
 animal).                       velocity for MC metabolism. VMAXC = VMAX
                                (mg/hr)/BW.75.                          
KM (mg/l)....................  MFO pathway Michaelis-Menten affinity    
                                constant for MC metabolism.             

[[Page 1538]]

                                                                        
KFC, unscaled, (/hr, 1 kg      GST pathway 1st order kinetic rate       
 animal).                       constant for MC metabolism. KFC = KF (/ 
                                hr)(BW.25).                             
A1 (ratio)...................  Ratio of distribution of MFO pathway MC  
                                metabolism between lung and liver. A1 = 
                                VMAXC(lung)/VMAXC(liver).               
A2 (ratio)...................  Ratio of distribution of GST pathway MC  
                                metabolism between lung and liver. A2 = 
                                KFC(lung)/KFC(liver).                   
B1 (ratio)...................  Ratio of lung and liver tissue content of
                                microsomal protein.                     
B2 (ratio)...................  Ratio of lung and liver tissue content of
                                cytosolic protein.                      
Sp--Kf.......................  Allometric scaling power for body weight 
                                scaling of KFC from mice to humans.     
------------------------------------------------------------------------

    The MC physiologically-based pharmacokinetic (PBPK) models 
discussed here contain the following types of parameters as defined 
above: body weight, breathing rate, cardiac output, blood flows to 
tissue compartments (as a fraction of the cardiac output), volumes of 
tissue compartments (as a fraction of body weight), partition 
coefficients, the metabolic parameters (the Michaelis-Menten 
parameters, Vmax and Km, for the MFO pathway and the 1st-order rate 
constant, Kf, for the GST pathway) and the ratio of the pathway-
specific metabolic capacity between the major metabolic sites (lung and 
liver). Differences in model structure (such as choice of lumped tissue 
compartments) and differences in sources of data for individual 
parameters lead to differences in the parameter values used in 
different models.
    The parameter values (point estimates) used in the PBPK models 
reviewed by OSHA are presented in Table VI-3. The parameter 
distributions used by OSHA in its analysis are presented later.
    As far as OSHA could determine, the parameters chosen by HSIA were 
those presented in Reitz's 1989 paper [Ex. 21-53] except that OSHA's 
preferred values for breathing rates (based on 9.6 m3/workday) and 
8-hour human exposures were used. The model submitted by NIOSH used the 
parameters and computer code from the Reitz model, except for the human 
breathing rate, human cardiac output and human metabolic parameters. 
The parameters used by Clewell were summarized in his post-hearing 
submission [Ex. 96], which included more recent experimental data for 
the partition coefficients and mouse metabolic parameters and a 
different scaling for human cardiac output.

                          Table VI-3.--Parameters Used in PBPK Models Reviewed by OSHA                          
----------------------------------------------------------------------------------------------------------------
            Model                  Clewell [Ex. 96]            NIOSH [Ex. 23-18]           HSIA [Ex. 19-45]     
----------------------------------------------------------------------------------------------------------------
          Parameter               Mouse         Human         Mouse         Human         Mouse         Human   
----------------------------------------------------------------------------------------------------------------
BW (kg).....................        0.0345        70            0.0345      70              0.0345      70      
QPC, unscaled alveolar                                                                                          
 ventilation (1/hr, 1 kg                                                                                        
 animal)....................       29.0           35           29.0         43.1           29.0         35.0    
QCC, unscaled cardiac output                                                                                    
 (1/hr, 1 kg animal)........       16.5           18           29.0         20.9           29.0         35.0    
QGC a, flow to GI tract                                                                                         
 (fraction of cardiac                                                                                           
 output)....................        0.165          0.195        0.0          0.0            0.0          0.0    
QLC a, flow to liver                                                                                            
 (fraction of cardiac                                                                                           
 output)....................        0.035          0.07         0.24         0.2093         0.24         0.24   
QFC a, flow to fat (fraction                                                                                    
 of cardiac output).........        0.03           0.05         0.05         0.040          0.05         0.05   
QSC a, flow to slowly                                                                                           
 perfused tissues (fraction                                                                                     
 of cardiac output).........        0.25           0.24         0.19         0.4319         0.19         0.19   
QRC a, flow to rapidly                                                                                          
 perfused tissues (fraction                                                                                     
 of cardiac output).........        0.52           0.445        0.52         0.3188         0.52         0.52   
VGC, GI volume (fraction of                                                                                     
 BW)........................        0.031          0.045        0.0          0.0            0.0          0.0    
VLC, liver volume (fraction                                                                                     
 of BW).....................        0.046          0.023        0.04         0.0314         0.04         0.0314 
VFC, fat volume (fraction of                                                                                    
 BW)........................        0.100          0.16         0.07         0.231          0.07         0.231  
VSC, slowly perfused tissue                                                                                     
 volume (fraction of BW)....        0.513          0.48         0.75         0.621          0.75         0.621  
VRC, rapidly perfused tissue                                                                                    
 volume (fraction of BW)....        0.041          0.033        0.05         0.0371         0.05         0.0371 
VLUC, lung volume (fraction                                                                                     
 of BW).....................        0.008          0.006        0.012        0.011          0.012        0.011  
PB, blood/air part. coeff...       23.0           12.9          8.29         9.7            8.29         9.7    
PG, GI tract/air part. coeff        0.52           0.93        NA           NA             NA           NA      
PL, liver/blood part. coeff.        1.6            2.9          1.71         1.46           1.71         1.46   
PF, fat/blood part. coeff...        5.1            9.1         14.5         12.4           14.5         12.4    
PS, slowly perf./blood part.                                                                                    
 coeff......................        0.44           0.78         0.96         0.82           0.96         0.82   
PR, rapidly perf./blood                                                                                         
 part. coeff................        0.52           0.93         1.71         1.46           1.71         1.46   
PLU, lung/blood part. coeff.        0.46           0.82         1.71         1.46           1.71         1.46   
VMAXC mg/hr, 1 kg animal                                                                                        
 (unscaled).................       13.4            5.0         13.2          3.98                               
                                                                             1.15                               
                                                                             9.81                               
                                                                             4.71          13.2          4.9    
KM (mg/L)...................        1.35           0.4          0.396        0.72                               
                                                                             0.55                               
                                                                             0.26                               
                                                                             0.79           0.396        0.580  

[[Page 1539]]

                                                                                                                
KFC /hr, 1 kg animal                                                                                            
 (unscaled).................        1.5            1.5          1.73         1.56                               
                                                                             0.00                               
                                                                             1.62                               
                                                                             1.79           1.73         1.24   
A1 (Vmaxc(lung)/                                                                                                
 Vmaxc(liver))..............        0.41           0.015        0.416        0.00143        0.416        0.00143
A2 (KFC(lung)/KFC(liver))...        0.28           0.18         0.137        0.18           0.137        0.18   
----------------------------------------------------------------------------------------------------------------
a QGC + QLC + QFC + QSC + QRC MUST = 1.00.                                                                      

    f. Assessment of the sensitivity and uncertainty of the PBPK model. 
In the NPRM, OSHA expressed concern that, if PBPK models were used to 
adjust risk assessments, the uncertainty in PBPK modeling should be 
adequately addressed. Specifically, OSHA was concerned that the 
uncertainty in the mechanism of action and the lack of human lung 
metabolism data were the greatest obstacles to incorporation of 
pharmacokinetic data into the MC final risk assessment. Many of the 
uncertainties in model parameters have been quantified by various 
hearing participants and are summarized below. The quantification of 
these uncertainties, however, did not address OSHA's primary concerns 
regarding the mechanism of action and the distribution of metabolism 
between lung and liver. OSHA's analyses of the uncertainty and 
variability of parameters in the PBPK model are presented with its risk 
assessment later in this document.
    The concepts of uncertainty, variability and sensitivity in PBPK 
modeling were defined in comments submitted by the U.S. Navy [Ex. 19-
59]:

    As it relates to the issue of using PBPK modeling in risk 
assessment, uncertainty can be defined as the possible error in 
estimating the ``true'' value of a parameter for a representative 
(``average'') animal. Variability, on the other hand, should only be 
considered to represent true interindividual differences.
    The normalized sensitivity coefficient gives the percentage 
change in a model output due to a percentage change in the parameter 
value and represents the relative importance of the parameter to the 
model output under the conditions of the simulation.

Each of these quantities is of concern for risk assessment and PBPK 
modeling. For example, we know that there is variability or inter-
individual heterogeneity in the body weights of humans (and mice), yet 
we estimate risks for an average member of the population (70 kg in 
humans, average bioassay weight in mice). For many parameters, the 
interindividual variability may not be known and must be estimated.
    Uncertainty in estimation of the value of a parameter representing 
an average member of a population is primarily due to laboratory 
measurement and related errors. Measurement errors, in many cases, can 
be quantified or estimated so that the potential impact of this 
uncertainty on the outcome of the PBPK modeling can be assessed.
    The sensitivity of the model to particular parameters is useful for 
determining which experiments should be conducted to confirm parameters 
and to determine the amount of confidence that PBPK model outputs 
merit. For example, when a sensitivity analysis is conducted and it is 
determined that the model outcomes are not very sensitive to changes in 
the definitions of the lumped tissue volumes, it suggests that there is 
little need to conduct experiments to describe those relationships more 
precisely. Similarly, even though the lumped tissue volume does not 
represent a ``true'' biological quantity, there is confidence that its 
precise definition is not critically important in PBPK model outcomes. 
Therefore, if the only large (quantifiable) uncertainty resides in this 
measurement, one would have greater confidence that the model 
predictions were reasonably accurate. Therefore, it is instructive to 
understand which parameters influence the model outcomes to the 
greatest degree. Conversely, if the PBPK model outputs are sensitive to 
a parameter which has not been precisely described (such as the 
distribution of GST metabolism between lung and liver), the confidence 
in model outputs is correspondingly reduced.
    Various investigators have attempted to determine the sensitivity 
of the PBPK models to parameter values and to characterize the 
uncertainty and variability within parameters in the models. The first 
attempt to describe the sensitivity of the Reitz's original PBPK model 
was performed by the Consumer Product Safety Commission (CPSC).
    The CPSC conducted a sensitivity analysis of the metabolic 
parameters, Km, Vmax and Kf, in the ``Updated Risk Assessment for 
Methylene Chloride'' [Ex. 7-126]. They analyzed the sensitivity of the 
model by selecting alternative point estimates for the metabolic 
parameters and determining what the resulting ratio of GST metabolite 
at 4000 ppm vs. 1 ppm would be. This analysis shows how this ratio 
would vary if the metabolic parameters used in the model were higher or 
lower than the measured values as selected by CPSC. The results showed 
that the ratio of the GST metabolite in the liver at 4000 ppm to the 
GST metabolite at 1 ppm (or the ratio of the GST metabolite in the lung 
at 4000 ppm to the GST metabolite at 1 ppm) was relatively insensitive 
to the value of Kf (when CPSC varied Kf from 0.01 to 5.3, while Km and 
Vmax were held constant at Reitz-Andersen values).
    HSIA presented a sensitivity analysis of the PBPK parameters from 
the Reitz (HSIA) model in the testimony of Dr. Reitz [Ex. 23-21A]. 
Results were presented for mice at 4000 ppm, mice at 1 ppm, humans at 
1000 ppm and humans at 1 ppm. In the first analysis (mice at 4000 ppm), 
the most sensitive parameters were determined to be PB (blood:air 
partition coefficient) and Kf (metabolic parameter for the GST 
pathway). The authors observed that at high MC exposure levels the 
model output was at least an order of magnitude less sensitive to 
changes in the other sixteen parameters investigated.
    When mice were exposed to lower concentrations of MC (1 ppm) Vmax 
and Km for the MFO pathway were the most sensitive parameters 
(sensitivity coefficient was over 120% for each of these parameters). 
In addition, several other parameters were found to exert a significant 
influence on model outputs: QP, QL, PB, VLu, and KF.
    In humans, at high concentrations (> 1000 ppm) the results were 
similar to those observed in mice: the model was most sensitive to PB 
and KF, with

[[Page 1540]]

sensitivity coefficients of 87% and 97%, respectively. In addition, the 
human model was also sensitive to the value chosen for the QP 
(sensitivity coefficient = 43%).
    In humans, at 1 ppm MC, Km and Vmax for the MFO pathway were the 
most sensitive parameters out of the six parameters which had a 
significant effect upon model outputs: QP, QL, PB, Vmax, Km, and KF.
    This type of sensitivity analysis improves on that conducted by the 
CPSC, because it looks at more of the parameters. It is still 
deficient, however, because it examines the effect of each parameter 
individually, and because it does not examine the effect of uncertainty 
in two key parameters, A1 and A2 (the ratios of distribution of the MFO 
and GST pathways between lung and liver), on the outcomes of the 
modeling.
    Mr. Clewell [Ex. 19-59] also conducted a sensitivity analysis to 
determine the impact of uncertainty in PBPK parameters on the model 
outcomes. In contrast to the HSIA analysis, he examined the sensitivity 
of the outcomes to the ratios A1 and A2, and he chose a more realistic 
occupational exposure level (100 ppm). He found that for mice at 4000 
ppm, the most sensitive parameters for estimation of lung tumors were 
KF, A2, and PB. In the liver, the most sensitive parameters were KF and 
PB, which agrees with the results of the HSIA analysis. For humans at 
100 ppm, the most sensitive parameters for estimating lung tumors were 
KF and A2. Other parameters with significant effects on model outcomes 
were PB, QPC, BW, KM, QCC, and QLC. The most sensitive parameters for 
estimating liver tumors were VMAX, KF, QPC and BW, while PB, KM, QCC 
and QLC also produced significant effects on model outcomes.
    In all of these analyses, the PBPK models were clearly sensitive to 
the values chosen for the metabolic parameters, especially the GST 
metabolic parameter (KF). Other parameters with consistently 
significant impact on the outcomes of the model included breathing rate 
(QP) and distribution of GST metabolism between lung and liver (A2). 
These analyses suggest that additional studies to quantify the 
metabolic parameters (KF, KM and VMAX), breathing rates (QP) and 
distribution of GST metabolism between lung and liver (A2) would 
increase confidence in the model outcomes. Characterization of the 
distribution of metabolism between lung and liver is particularly 
critical because estimates for human lung metabolism were initially 
based on one pooled sample of lung tissue, and the variability and 
uncertainty of the value of this parameter has not been quantified.
    Some analysts [Ex. 21-52] have suggested that the uncertainty is 
increased in risk assessments based on PBPK as compared to applied-dose 
risk assessments, because some methods of quantifying the uncertainty 
result in rather broad distributions of uncertainties. OSHA, in 
contrast, agrees with most commenters that quantifying uncertainty in a 
PBPK model or risk assessment does not increase the uncertainty. The 
Agency stresses that the appearance of increasing uncertainty with the 
identification of sources of uncertainty almost certainly means that 
the original uncertainty was underestimated. (In fact, since many 
assessors have not attempted even to quantify the uncertainty in 
applied-dose risk assessments, the uncertainty has often been 
infinitely underestimated.) When conducting a risk assessment using 
PBPK that appears to increase the uncertainty over delivered-dose 
methodologies, the investigator should go back and recalibrate what the 
uncertainty in the original analysis likely was, in light of the 
sources of uncertainty identified using PBPK. This would tend to 
broaden the confidence limits of the traditional risk assessments, 
almost certainly beyond the limits generated in a thoughtful PBPK-based 
assessment. For example, many analyses using delivered dose assume that 
in the interspecies scaling factor, BWx, x is known with perfect 
certainty (e.g., it is known to equal 2/3 or 1.0). An analysis that 
uses an empirically-derived probability distribution for x, which might 
reasonably extend from approximately 0.6 to approximately 1.0, would 
yield a rather broad distribution of uncertainty in the resulting 
estimate of risk.
    The Agency also agrees that the primary uncertainties lie in the 
choice of the dose surrogate and assumptions regarding cross-species 
scaling. Clewell [Ex. 23-14] investigated the uncertainty of the PBPK 
parameters using Monte Carlo analyses of the assumed distributions of 
uncertainty of each parameter. The resulting estimates of dose 
surrogate values were characterized by a mean of the distribution and 
an upper 95th percentile estimate. Mr. Clewell stated [Ex. 19-59]:

    [T]he use of the 95th percentile of the distribution of 
estimates accounts for additional uncertainty concerning the true 
values of the PBPK parameters for the bioassay animals and humans.

Mr. Clewell recommended that OSHA use the upper 95th percentile of the 
Monte Carlo distribution of GST metabolites (from PBPK modeling) as an 
input to the multistage model to generate risk estimates, and then use 
of the MLE from the multistage model in those risk estimates, in 
accordance with previous OSHA risk assessments. He remarked that use of 
the upper 95th percentile of the PBPK output would be a reasonable 
mechanism to account for the uncertainty quantified in these analyses. 
Using the upper 95th percentile of the distribution of GST metabolites, 
Mr. Clewell's risk estimate for lifetime occupational exposure to 25 
ppm MC was 0.9 deaths per 1000 using the MLE of the multistage model, 
and 1.1 per 1000 using the 95th percentile upper confidence limit (UCL) 
from the multistage model. Using the mean of the distribtution of GST 
metabolites, his MLE risk estimate was 0.28 deaths per 1000 at the same 
exposure level, with an UCL of 0.35/1000.
    The HSIA disagreed with using the upper 95th percentile for 
estimating risks, and stated [Ex. 105]:
    [T]he analyses conducted by Clewell et al. indicate that 
consideration of model parameter variability does not contribute 
orders of magnitude to the uncertainty associated with PB-PK risk 
assessments. Further, the uncertainty associated with PB-PK risk 
assessments is significantly less than that associated with risk 
assessments that fail to consider pharmacokinetics. The uncertainty 
in PB-PK based procedures is simply more readily available for 
calculation.

    OSHA disagrees with the HSIA that the uncertainty and variability 
associated with PBPK risk assessments is significantly less than that 
associated with risk assessments that fail to consider 
pharmacokinetics. Quantification of uncertainty does not equate with 
reducing uncertainty in an analysis. In fact, at a different level, the 
assumptions made regarding mechanism of action of MC and extrapolation 
of lung metabolic rates from one human in vitro sample may serve to 
underestimate the uncertainty inherent in the PBPK-based risk 
assessment if the underlying assumptions are wrong. Also, as stated 
above, identification of uncertainty may lead us to recalibrate the 
uncertainty associated with traditional risk assessment methods. In any 
event, the possibility that using PBPK significantly reduces 
uncertainty does not affect the need to account for whatever 
uncertainty remains.
    In addition, OSHA agrees with Clewell that using the upper 95th 
percentile of the Monte Carlo distribution of GST metabolites as input

[[Page 1541]]

to the multistage model is a reasonable way to incorporate the 
quantifiable uncertainty and variability into a risk assessment. In its 
final risk estimates, OSHA has used the upper 95th percentile on the 
distribution of GST metabolites from the Bayesian analysis as the input 
to the multistage model, as described later in this document.

E. Other Risk Estimates Based on PBPK Models Prior to OSHA's Final 
Analysis.

    A PBPK model can produce estimates of target tissue doses (or dose 
surrogates) for different hypotheses of action of a chemical. The 
appropriate choice of target tissue dose can greatly influence risk 
estimates based on that dose. For MC, the dose surrogate that has been 
used most frequently to estimate cancer risks is the amount of GST 
metabolite produced. The amount of GST metabolite can then be used to 
extrapolate from a high bioassay dose of MC to a low occupational (or 
environmental) dose of MC and from mouse MC metabolic rates to human 
metabolic rates.
    In the NPRM, OSHA reviewed available risk assessments for MC that 
used PBPK modeling in a variety of ways. The Food and Drug 
Administration risk assessment [Ex. 6-1] was not adjusted to account 
for pharmacokinetic information. The Consumer Product Safety 
Commission, in its ``Updated risk assessment for methylene chloride'' 
[Ex. 7-126], used pharmacokinetic data to adjust for differences in 
metabolism in extrapolating from high dose (4000 ppm mouse bioassay) to 
low dose (1 ppm) exposures, but did not adjust for interspecies 
differences in the metabolism of MC. The resulting risk estimate was 
approximately 2-fold lower than a risk estimate using applied dose.
    The U.S. EPA analyzed the MC pharmacokinetic data in its documents, 
``Technical analysis of new methods and data regarding dichloromethane 
hazard assessment'' [Ex. 7-129] and ``Update to the Health Assessment 
Document and Addendum for dichloromethane (methylene chloride): 
pharmacokinetics, mechanism of action, and epidemiology'' [Ex. 7-128]. 
The EPA used the PBPK data to adjust its risk estimates in its 
Integrated Risk Information System (IRIS) database. Adjustments were 
made for high-to-low dose and cross-species extrapolation. EPA's risk 
estimates for low human exposures to MC were decreased by approximately 
a factor of 9 from its risk estimates made without consideration of 
PBPK data.
    The HSIA [Ex. 105] and ECETOC [Ex. 14] also submitted risk 
assessments based on PBPK data. The primary difference between the HSIA 
and the EPA risk estimates was that the HSIA did not use a surface area 
correction to account for interspecies differences other than 
pharmacokinetics (e.g., pharmacodynamic differences) while the EPA did. 
Also, HSIA's risk estimates used OSHA's preferred breathing rates and 
an occupational exposure scenario. ECETOC based its risk estimates on 
different measures of human MC metabolism. In a pre-hearing submission, 
``Using PB-PK Models for Risk Assessment with Methylene Chloride 
(Comparison of U.S. and U.K. procedures)'' [Ex. 19-83A], scientists 
from the U.S. and the U.K. compared methodologies for using PBPK data 
in the MC risk assessment and presented a consensus opinion that OSHA 
should use the methodology developed by Dr. Richard Reitz [Ex. 7-225] 
for the U.S. For this reason, OSHA evaluated Dr. Reitz's analysis, as 
presented by the HSIA, and did not separately consider the ECETOC risk 
assessment.
    As described previously, Clewell [Ex. 96] and NIOSH [Ex. 94] have 
submitted analyses of the PBPK data and risk assessments based on those 
analyses. Both of these analyses used PBPK modeling of the amount of 
GST metabolites produced in their estimates of carcinogenic risks.
    OSHA has evaluated the data in the rulemaking record and has 
concluded that, if PBPK modeling is used to adjust estimates of risk, 
the weight of evidence supports using the amount of GST metabolites as 
the preferred surrogate for target tissue dose. The amount of GST 
metabolites predicted by the PBPK model varies depending upon the 
values or distributions chosen for the parameters in the model.
    Of the risk assessments described above, OSHA has chosen to compare 
risks estimated using PBPK models submitted by Reitz et al., Clewell et 
al. and NIOSH with applied dose methodology using either of two scaling 
assumptions: the inhaled dose in mg/kg/day (the estimates of risk 
presented in the NPRM) and ppm-to-ppm extrapolation. OSHA evaluated the 
methodologies used in developing these risk estimates before developing 
its final risk estimates, which are presented in the next section.
    The risk estimates derived from using PBPK with the multistage 
dose-response model submitted to the Agency by Reitz et al., Clewell et 
al., and NIOSH, and the risk estimates derived from applied dose 
methodologies, are shown in Table VI-4.

  Table VI-4.--Lifetime Excess Risk Estimates (per 1000) From Occupational Exposure Based on Female Mouse Lung  
                                                   Tumor Data                                                   
----------------------------------------------------------------------------------------------------------------
                                                                     MLE (UCL)**                                
               Model               -----------------------------------------------------------------------------
                                              25 ppm                      50 ppm                  500 ppm       
----------------------------------------------------------------------------------------------------------------
OSHA NPRM Risk Assessment (mg/kg/   2.32 (2.97)...............  4.64 (5.92)..............  45.5 (57.7)          
 d, BW extrapolation) without PBPK                                                                              
 Adjustment.                                                                                                    
PPM to PPM extrapolation without    11.3 (14.4)...............  22.4 (28.5)..............  203 (251)            
 PBPK Adjustment.                                                                                               
PBPK Reitz female mouse lung--      0.43 (0.53)...............  0.93 (1.17)..............  14.3 (17.9)          
 Reitz human (HSIA assumptions).                                                                                
PBPK Reitz female mouse lung--      0.81 (1.02)...............  1.69 (2.12)..............  15.0 (18.7)          
 Dankovic average human (NIOSH                                                                                  
 assumptions).                                                                                                  
PBPK Clewell female mouse lung--    0.91 (1.14)...............  1.88 (2.36)..............  27.5 (34.2)          
 Clewell human (Navy assumptions)*.                                                                             
OSHA Final Risk Assessment (female  3.62......................  7.47.....................  125.8                
 mouse lung with PBPK).                                                                                         
----------------------------------------------------------------------------------------------------------------
* Upper 95th percentile of the GST metabolites distribution was used as input in the multistage model.          
** Maximum likelihood estimates and 95th percentile upper confidence limit (in parentheses) of the multistage   
  dose-response function.                                                                                       

    Of those risk estimates considered by OSHA prior to its final risk 
assessment, the risk estimates for lifetime occupational exposure to 
the 8-hour TWA PEL of 25 ppm ranged from 0.43 per 1000 to 11.3 per 
1000. The risk assessment presented in the NPRM was based on a body 
weight extrapolation from mice to humans of a mg/kg/day dose of MC. Mr. 
Harvey Clewell [Ex. 19-59] stated that this dose was not a useful dose 
for estimating risks from volatile solvents such as MC. He suggested 
that, if PBPK modeling was not used to estimate target tissue dose (his 
preferred

[[Page 1542]]

method of estimating risk), then a ppm-to-ppm extrapolation would be 
more appropriate. The ppm-to-ppm extrapolation resulted in an estimated 
risk of 11.3 deaths per 1000 after lifetime occupational exposure to 25 
ppm. However, the ppm-to-ppm extrapolation is generally preferred for 
site-of-contact tumors. Although it is possible that the MC lung tumors 
were the result of a site-of-contact mechanism of action, the data are 
more supportive of a systemic, genotoxic mechanism mediated through 
metabolites of MC. In addition, the liver tumors are clearly not the 
result of a site-of-contact carcinogen because the liver is not a site 
of contact during inhalation bioassays.
    Several commenters [Exs. 19-26, 19-28, 19-29, 19-45, 19-48, 19-57, 
19-59, 25-E, 25-I] suggested using PBPK modeling to estimate target 
tissue dose and to account for differences in metabolism at high and 
low doses and differences in metabolism of MC across species. OSHA 
compared three sets of parameters in the PBPK models submitted by 
interested parties to adjust the dose across species and across doses. 
The risk estimates for those models (using the MLE of the multistage 
model parameters) ranged from 0.43 to 0.91 deaths per 1000 after 
lifetime occupational exposure to 25 ppm. Mr. Clewell's risk estimate 
(0.91/1000 MLE), unlike the other PBPK analyses, represent the upper 
95th percentile of the Monte Carlo distribution of GST metabolites as 
input into the multistage model. The Monte Carlo simulation takes into 
account the assumed distribution of values for each parameter, 
including the parameters used to estimate human metabolism of MC. The 
other PBPK models used point estimates instead of distributions for the 
PBPK parameters, and therefore it is not known whether these are 
central estimates or upper bounds. OSHA agrees that the distributional 
approach used by Clewell is a reasonable way to account for the 
uncertainty and variability inherent in PBPK modeling, and that 
uncertainty and variability must be considered in any useful risk 
assessment. The Agency has used the upper 95th percentile on the 
distribution of GST metabolites from the Bayesian modeling, coupled 
with the MLEs of the multistage model parameters, for its final 
estimates of MC risk.
    OSHA has concluded that all the risk estimates presented above 
support an 8-hour TWA PEL of 25 ppm or lower. The risks estimated from 
the PBPK models were less than an order of magnitude different from 
estimates of risk based on applied dose methodology. Either with or 
without PBPK modeling , the estimates of risk at 25 ppm clearly 
indicate a significant risk.
    The risks estimated from these PBPK models and ppm-to-ppm 
extrapolation offer a range of risks which might be expected after 
lifetime occupational exposure to MC. OSHA has assessed these models 
and has decided to modify and expand on the submitted PBPK and 
uncertainty analyses in its final estimates of cancer risk, in order to 
give full consideration to all of the available data. This analysis is 
presented in the next section.

F. OSHA's PBPK Analysis and Final Risk Estimates

    In developing an approach to PBPK modeling for MC, OSHA wished to 
use all of the available, appropriate and quantifiable biochemical and 
physiological data in its PBPK modeling and in assessing the 
uncertainty and variability in model parameters. The Agency determined 
that this approach would provide the best characterization of the 
variability and uncertainty in the data and the model. In addition, 
incorporation of as much of the available data as possible should give 
the most realistic PBPK model, and in turn, the most realistic risk 
estimate. Before development of OSHA's PBPK model, Clewell's approach 
(described above) was the most comprehensive pharmacokinetic approach 
submitted to the Agency. It addressed many of the issues of concern to 
the Agency, and OSHA believes that Clewell's approach was a reasonable 
template for using PBPK in risk assessment. However, since Clewell's 
work was done, PBPK modeling has continued to advance. Therefore OSHA 
modified Clewell's model to accommodate these advances and to allow 
incorporation of additional biochemical and physiological data that had 
been added to the rulemaking record. The following is a summary of 
OSHA's final (revised) PBPK analysis. A more detailed discussion can be 
found in the reports submitted to the Agency, reflecting OSHA's 
analysis in which the Agency was assisted by contractors [Ex. 128].
1. Review of Clewell's PBPK Analysis
    a. Clewell's analytical approach.
    Clewell et al. [Ex. 96] employed Monte Carlo techniques to 
investigate imprecision in estimates of human health risk from 
occupational exposure to MC, as a function of imprecision in parameter 
values of the PBPK and dose-response models. (As described below, OSHA 
and its contractors believe that Clewell et al. did not correctly parse 
out uncertainty and variability, so their analysis is described as 
accounting for ``imprecision'' rather than uncertainty or variability). 
In the Clewell et al. analysis, probability distributions were 
specified for each PBPK model parameter in an attempt to characterize 
imprecision. Computer-based techniques were used to obtain pseudo-
random samples from these statistical distributions, generating 
multiple sets of model parameter values. These sets of parameter values 
were then used to obtain a corresponding distribution of PBPK model 
predictions of various measures of internal dose for a simulated animal 
bioassay (e.g., GST metabolism in lungs of mice exposed to 2000 ppm and 
4000 ppm for 6 hrs/day, 5 days/wk). The mean of the mouse internal dose 
distribution was used as the dose input to obtain the MLE and UCL on 
the multistage model parameters, using the tumor incidence data from 
the NTP bioassay. The multistage model was run a second time using the 
upper 95th percentile of the mouse internal dose distribution as the 
dose input to obtain the MLE and UCL on the multistage model 
parameters. This yielded a total of four estimates of the parameters 
(qo, q1, and q2) of the mouse dose-response function: 1) 
Mean of internal dose distribution/MLE of multistage model parameters; 
2) Mean of internal dose distribution/UCL of multistage model 
parameters; 3) Upper 95th percentile of internal dose distribution/MLE 
of multistage model parameters; and 4) Upper 95th percentile of 
internal dose distribution/UCL of multistage model parameters.
    Each set of dose-response parameters obtained from the analysis of 
the mouse data was then used to calculate human risk estimates. The 
upper 95th percentile of the human internal dose distribution was used 
to calculate the dose surrogate at 25 ppm, 8 hr/d exposure and then 
substituted into the MLE and UCL of the multistage parameters to obtain 
the MLE and UCL estimates of risk. Similarly the mean of the human 
internal dose distribution was used in conjunction with the MLE and UCL 
of the multistage model parameters. Therefore, four human risk 
estimates were generated, based on the distribution of human internal 
doses and the dose- response function derived from the multistage 
analysis of the NTP mouse bioassay. The four human risk estimates are: 
1) upper 95th percentile of the human internal dose distribution/MLE of 
the multistage model parameters; 2) mean of human internal dose 
distribution/MLE of the multistage model parameters; 3) upper 95th 
percentile of the human internal dose

[[Page 1543]]

distribution/UCL of the multistage model parameters; and 4) mean of the 
human internal dose distribution/UCL of the multistage model 
parameters.
    A major finding of that analysis was that the mean estimate of 
added cancer risk for occupational exposure at the proposed PEL of 25 
ppm based on the PBPK-derived GST-lung dose surrogate (PBPK(mean) / 
potency(MLE) = 0.39 x 10 -3) was 6-fold lower than the 
corresponding OSHA estimate (MLE = 2.32 x 10 -3) based on 
administered dose scaled to body weight. The 95 percentile upper bound 
estimate of risk using the same PBPK distributions and the distribution 
of 95%UCLs on carcinogenic potency (PBPK(95%)/potency(95%) = 1.56 x 10 
-3), was nearly 2-fold less than OSHA's 95%UCL on risk (2.97 x 10 
-3).
    b. Clewell's PBPK model. The PBPK model used by Clewell et al. in 
performing their Monte Carlo analysis was slightly modified from the 
PBPK model developed by Andersen et al. and submitted to OSHA by HSIA 
[Ex. 328]. The primary modification was the addition of a separate 
compartment for the GI-tract. The general structure of this model has 
received considerable use by PBPK modelers. Nevertheless, there were 
several deficiencies in this model and in the subsequent statistical 
analysis that the Agency believed warranted major modification. These 
are described in the following section.
    c. Prior distributions for model parameters.Truncated normals were 
used as the form for all probability distributions except for metabolic 
constants, which were described by truncated lognormals. All 
distributions were truncated to prevent sampling of nonsensical values 
(e.g., negative values). Truncation in some instances was 2 standard 
deviations (SDs) from mean values, in others more than 4 SDs.
    A variety of sources of information were used as a basis for the 
probability distributions of the PBPK parameters in Clewell's model: 
literature summaries for most physiologic and anatomic parameters, 
direct laboratory measurement of partition coefficients based on vial 
equilibration studies, and statistical regression analyses of 
experimental data for fitted metabolic constants.
    Clewell et al. stated that the focus of their analysis was on 
characterizing the effect of ``uncertainty'' in parameter values on 
uncertainty in PBPK model predictions, uncertainty being defined as the 
possible error in estimating the ``true'' value of a parameter for a 
representative ``average'' animal. To maintain consistency with a focus 
on investigating effects of parameter uncertainty, a logical choice 
would have been to center their probability distributions using 
estimates of mean values for all model parameters and to use the 
standard error of the mean (SEM) to characterize dispersion. It it 
unclear whether this was done for blood flows, tissue volumes, 
inhalation rates or cardiac output, since Clewell et al. appear to have 
relied extensively on an unpublished review of scientific literature 
performed by S. Lindstedt for the ILSI Risk Science Institute 
Physiological Parameter Working Group.
    Based on Clewell's comments accompanying his PBPK model, it appears 
that standard errors were not used to characterize variability among 
individual replicates of measured equilibrium partition coefficients; 
instead, standard deviations were used. Nor does it appear that Clewell 
et al. consistently made use of standard errors in characterizing 
imprecision in their fitted metabolic constants. Inspection of the 
joint confidence region for their fitted estimates of mouse VmaxC and 
Km (for the MFO pathway), shown in Figure 6 of Ex. 399, suggest 
coefficients of variation (%CVs) for VmaxC of about 2%. Similarly, for 
KfC, the %CV in the fitted MLE appears to be about 3%. These %CVs are 
considerably smaller than the assumed values of 20% and 30%, 
respectively, used by Clewell et al. in their Monte Carlo analysis. On 
the other hand, their %CV for Km does coincide with that indicated by 
the joint confidence regions. One should also note the high degree of 
correlation among the fitted values for VmaxC and Km.
    In assessing variability in the ratio of in vitro MFO and GST 
metabolism in lung versus liver tissue (i.e., the A1 and A2 
parameters), Clewell et al. used the in vitro MC metabolism data of 
Reitz et al. (1989). Yet it appears that the %CV for these data is 24% 
when one uses SDs among replicates for MFO metabolism in lung and liver 
of mice. This is substantially less than the 50% assumed by Clewell. 
One obtains a %CV of 9% when using SEMs.
    It appears then, that some of the probability distributions used by 
Clewell et al. reflect variability beyond that readily identifiable as 
uncertainty in estimates of sample means. It may be that Clewell made a 
subjective inflation of variances. Though ad hoc, inflating variances 
would not be unreasonable given the sparse data on certain model 
parameters. Another possibility is that the distributions reflect 
variability due to both uncertainty and intersubject heterogeneity--
another reason to inflate variances, or alternately, use SDs rather 
than SEMs to describe the distributions of the parameters. If so, then 
it might be more appropriate to view the proportion of simulated 
estimates of risk that fall within a specified interval as the 
probability that the true risk for a randomly selected individual is in 
that interval. Yet strictly speaking this would require that the 
probability distributions reflect both the full range of uncertainty 
and heterogeneity in the population of interest, with the latter being 
unlikely based on inspection. If the analysis only considered 
imprecision due to uncertainty, as suggested in Clewell et al., then 
the resulting distribution should instead be viewed as describing the 
uncertainty in risk for a hypothetical ``average'' individual.
2. OSHA's Modifications to PBPK Analysis
    a. Basis for modifying approach of Clewell et al. In addition to 
the likelihood that Clewell et al. used broader distributions than 
those necessary to model uncertainty in the PBPK analysis (as opposed 
to modeling some hybrid of uncertainty and variability), the analytical 
approach they used (1992 and 1993) also has two well-known 
methodological limitations. Their representation of imprecision in 
fitted parameters (e.g., VmaxC, Km, KfC) is problematic because they 
estimated the variability in these parameters by optimizing the model 
fit to in vivo data, while assuming nominal values for all other model 
parameters. However, the organ volumes, blood flows, and partition 
coefficients for the mice used in the gas uptake studies and the humans 
used in the open chamber studies are clearly not known with exact 
precision, and are not, therefore, accurately represented by nominal 
values. Consequently, the variances of the fitted parameters will be 
underestimated with this approach, since full acknowledgment of 
variability in other model parameters will have been ignored. 
Furthermore, it is quite likely that the joint parameter space for 
fitted PBPK model parameters will exhibit a considerable degree of 
correlation. Importantly, failure to account for such covariances when 
performing Monte Carlo sampling may overstate variance in some model 
predictions by assuming independence where it does not exist. The 
implications of these methodological limitations on predicted risk are 
unclear, since they would seem to exert countervailing effects on 
estimating uncertainty. Thus, OSHA decided that it was important to 
perform an analysis that addressed these limitations. The

[[Page 1544]]

use of a Bayesian statistical framework provided a means of overcoming 
the above limitations.
    b. Bayesian Approach. A Bayesian analysis allows the logical 
combination of two forms of information: ``prior knowledge'' about 
parameter values drawn from the scientific literature, and data from 
experimental studies (e.g., the mouse gas uptake studies, or, for 
humans, the open chamber experiments performed by Dow Chemical 
company), all within the context of a PBPK model. Clearly, neither 
prior information about parameter values nor experimental data alone 
are capable of precisely determining all parameter values in the PBPK 
model. If prior information were sufficient, the additional experiments 
performed by Clewell et al. and Dow Chemical Co. would not have had to 
be done. But the available experimental data alone are insufficient to 
pin down all parameters of the model to reasonable values (which is why 
no attempt was made to simultaneously optimize all PBPK parameters to 
data). Fitting only two or three parameters while holding others 
constant so as to reduce dimensionality leads to the biases and 
underestimation of variance mentioned above.
    A second feature of this Bayesian approach is that it yields 
distributions for all of the PBPK model parameters together with 
information about their entire joint covariance structure. Thus, the 
Bayesian analysis outputs distributions of parameter values that are 
consistent with both all the available data as well as the prior 
information. It is then possible to use samples from the joint 
posterior distribution of the parameters to simulate formation of GST 
metabolites in lung tissue from different species and cancer risk, 
therefore producing posterior distributions for these endpoints. It 
should be noted that if no data are available (or if the data are not 
informative as to the likely value of the parameter), the posterior 
distribution is equivalent to the prior distribution and this approach 
is then equivalent to the standard Monte Carlo sampling from the prior 
distribution, as in Clewell et al. Alternately, Bayesian updating with 
a uniform prior distribution (i.e., complete ignorance about plausible 
values) used in conjunction with data leads to a posterior distribution 
proportional to the distribution of the data. The most important 
applications of the Bayesian approach arise when informative (e.g., 
physiological, anatomical) prior distributions exist, in parallel with 
experimental metabolic data. This is now the case with PBPK modeling of 
MC. In this case, Bayesian modeling results in all the information 
content of both prior distributions of parameter values and metabolic 
data being incorporated in the posterior distribution of parameter 
values, which will have reduced variance compared to the prior 
distribution. Distributions of parameter values for both human and 
mouse PBPK models, and the multistage cancer model, were determined 
with this technique.
    c. PBPK Model Modifications. OSHA's final risk estimates were based 
on the Bayesian analysis described here. The Clewell model formed the 
structural core of the analysis, although five additional structural 
modifications were made as described below. These modifications were 
necessary to make the PBPK model more physiologically realistic:
    (1) Bone marrow was treated as a separate compartment. In the 
Clewell model (as in many PBPK models), bone marrow tissue was combined 
with other tissues into a (presumably) kinetically homologous 
compartment. Based on blood perfusion rates, a reasonable choice would 
be to place marrow in the well-perfused tissue compartment. However, if 
the physicochemical affinity of the compartment is considered, it makes 
more sense to place marrow in the adipose tissue compartment, since red 
marrow (at least in humans) has a fat content of about 40% and yellow 
marrow has a fat content of 80%. In comparison, liver, brain, kidney 
and heart all have fat contents (in humans) well under 20% . In 
addition, bone marrow accounts for a significant percentage of body 
weight and receives a substantial fraction of cardiac output. 
Therefore, a strong argument can be made for treating bone marrow as a 
separate compartment, as OSHA has done here.
    (2) Partitioning MFO and GST metabolism between the lung and liver. 
Clewell made the MFO and GST metabolic constants for lung dependent on 
the fitted constants for the liver, so as to reduce the number of 
fitted parameters to be simultaneously estimated from rodent and human 
in vivo data. For example, A1 is defined as the ratio of lung to liver 
in vitro MFO enzymatic activity, normalized to microsomal protein,
[GRAPHIC] [TIFF OMITTED] TR10JA97.005

Similarly, A2 is the ratio of lung to liver in vitro GST enzymatic 
activity, normalized to cytosolic protein,
[GRAPHIC] [TIFF OMITTED] TR10JA97.006

This assumes that lung and liver have equivalent mg protein per mg 
tissue contents. Yet the data of Litterst et al. (1973) argue against 
such an assumption. Litterst et al. measured microsomal protein and 
soluble protein in lung and liver tissues of mice, rats, hamsters, 
guinea pigs and rabbits. These data indicated ratios of mg microsomal 
protein content of lung versus liver tissue of less than 0.3, and a 
similar ratio for soluble protein of about 0.7. Thus, some adjustment 
of the constants A1 and A2 are required.
    The equations used to compute a lung Vmax for the MFO pathway and a 
lung Kf for the GST pathway from a liver Vmax and Kf were thus modified 
to include an additional proportionality factor to account for 
differences in microsomal and cytosolic protein content of lung and 
liver tissue. Specifically,

[[Page 1545]]

[GRAPHIC] [TIFF OMITTED] TR10JA97.007


where B1 is the ratio of [mg microsomal protein per mg of lung tissue] 
to the same measure for liver tissue. A geometric mean and geometric 
standard deviation for B1 were derived from the data of Litterst et al. 
(1973) to use as input in the Bayesian prior distribution for this 
parameter. Notably, accounting for this difference in protein content 
leads to a proportionality factor approximately four-fold less than 
that used by the Clewell et al. (i.e., A1 x B1 = 0.41  x  0.27 = 0.11).
    Similarly, for Kflung.GST, 
    [GRAPHIC] [TIFF OMITTED] TR10JA97.008
    
Here too, the data of Litterst et al. (1973) were used to compute a 
ratio of mg soluble protein per mg lung to the same measure for liver, 
yielding a mean value of 0.68 for B2. For a human B2, the average of 
the ratios computed for mice, rats, hamsters, guinea pigs, and rabbits 
as per Litterst et al. (1973) was used.
    (3) Linkage of alveolar ventilation to cardiac output. In 
recognition of OSHA's interest in occupational exposures, Clewell used 
values of cardiac output and alveolar ventilation rates consistent with 
the performance of light work. However, they did not account for the 
altered distribution of regional blood flows known to occur in response 
to increases in work intensity [Exs. 7-115, 7-120, 21-81], as was done 
in subsequent MC PBPK work by Dankovic and Bailer [Ex. 23-18] (1994). 
In the latter analysis, alveolar ventilation (QP) was made dependent on 
cardiac output (QC) by making QP = QC  x  VPR, where VPR is the 
ventilation- perfusion ratio. VPR was treated as a random variable with 
an assigned prior probability distribution.
    (4) Linkage of work intensity to changes in physiology. Cardiac 
output, ventilation perfusion ratio, and percent of cardiac output 
delivered to tissues were made dependent on work intensity. Using the 
data of Astrand (1983) [Ex. 21-81]--and similar to what was done by 
Dankovic and Bailer (1994) [Ex. 23-18]--slope factors were derived to 
describe change in flows per change in work intensity as measured in 
watts. These slope factors were then used to modify resting flows for 
varying levels of work intensity. This approach was taken so that the 
influence of variability in work load (i.e, work load was treated as a 
random variable)--with concomitant adjustments to regional blood flows 
and ventilation rate--on delivered dose could be modeled.
    (5) Maintaining mass balance in sampling of fractional blood flows 
and compartment volumes. Monte Carlo sampling of fractional quantities 
such as the proportion of cardiac output delivered to different 
compartments, or the proportion of body weight represented by a given 
compartment, requires the imposition of some type of constraint to 
prevent random sampling leading to summed proportions greater than the 
whole (and thus causing nonsensical departures from mass balance). The 
following constraint was imposed: VppC = 0.82--ViC 's (0.82 is 
a nominal value for the fraction of body weight absent bone, blood, and 
stomach and intestinal contents), QwpC = 1--QiC 's (in the 
mouse model), and QppC = 1--QiC 's (in the human model). The 
use of either QwpC or QppC as the quantity to be made dependent on the 
other fractional flows has biological appeal--one expects that higher 
fractional blood flow to the poorly-perfused compartment (i.e., muscle 
and skin) should be accompanied by a lower fractional flow to the well-
perfused compartment, and vice versa. The choice of QwpC versus QppC as 
the one to be made dependent on others appeared to be unimportant in 
work with the mouse model. The choice was important in work with the 
human model. Here it was necessary to choose QppC, because of its large 
variance relative to QwpC (i.e., since QppC cannot be estimated 
precisely, it makes sense to let our greater knowledge of the other 
fractional flows inform us about plausible values of QppC).
    The above approach modifies the approach taken by Clewell et al. 
[Ex. 96]. Their approach was to randomly draw from the distributions 
for cardiac output and all fractional flows, use the random draws to 
compute the absolute flows to the individual compartments, and then to 
sum the individual flows to make a new cardiac output value for use in 
the simulation. On the other hand, OSHA's final analysis avoided 
arbitrarily modifying the prior distribution for cardiac output (which 
happens to be one of the relatively well-known parameters). 
Furthermore, Clewell did not make the fractional flows dependent on one 
another.
    d. Prior Probability Distributions. A skewed, lognormal-like 
distribution is generally observed for biological parameters. However, 
most, if not all, parameters are also positive and have physiological 
bounds. Thus, truncated lognormal distributions of the parameter values 
were used in this analysis. They do not differ appreciably from normal 
distributions for small values of the variance.
    In specifying prior distributions an attempt was made to 
characterize the variability of the mean parameter values for small 
groups of rodents and humans. This focus was adopted to make the prior 
distribution congruent with the data sets available for Bayesian 
analysis. For example, the rodent gas uptake data represent the 
aggregate pharmacokinetic behavior of groups of 5 mice. Prior 
distributions were therefore constructed to reflect the degree of 
variability in mean physiological and anatomical PBPK parameters for 
small groups of mice. A similar approach was taken in defining prior 
distributions for human physiologic and anatomic parameters, since the 
available experimental data reflected the averaged pharmacokinetic 
behavior of 6 subjects. In practice, this meant amassing studies 
reporting mean values for certain PBPK parameters (e.g., tissue 
weights, blood flows, cardiac output, minute ventilation), and then 
using these means as data for computing a geometric mean (GM) and 
geometric standard deviation (GSD) with which to estimate the parameter 
values for the truncated lognormal distributions. Sampling of all 
lognormal distributions was truncated at 2 GSDs, with one exception. 
Truncation of the blood:air partition coefficient was extended to 3 
GSDs based on results from preliminary runs.
    Table VI-5 presents a summary of the prior probability 
distributions used in the Bayesian fitting of the mouse and human data 
sets. The prior distributions for metabolic constants to be estimated 
from in vivo data were made very broad (i.e., assigned a GSD of 10) to 
reflect our ignorance of these values before examining the data. 
Similarly, the prior distributions for parameters of the multistage 
cancer model were broad uniform distributions, constrained to be 
positive, as required by the standard model.

[[Page 1546]]



                               Table VI-5.--Prior Distributions Used in Bayesian Analysis of Mouse and Human In-vivo Data                               
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                       Mouse priors                                 Human priors                        
                                           Parameter           -----------------------------------------------------------------------------------------
                                                                     GM            GSD                    GM                            GSD             
--------------------------------------------------------------------------------------------------------------------------------------------------------
Flows:                                                                                                                                                  
    QCC                         Cardiac Output (l/hr/kg--BW)..      a 34.8            1.14  4.2..........................  1.10                         
    VPR                         Alveolar Ventilation Perfusion       b 1.22           1.95  1.35.........................  1.15                         
                                 Rate.                                                                                                                  
Tissue Blood Flows (fraction                                                                                                                            
 of cardiac output):                                                                                                                                    
    QgiC                        GI Tract......................         0.165          1.30  0.191........................  1.25                         
    QliC                        Liver.........................         0.017          1.20  0.067........................  1.20                         
    QfatC                       Fat...........................         0.047          1.60  0.057........................  1.45                         
    QppC                        Poorly Perfused Tissues.......         0.276          1.25  0.198 c......................  1.55                         
    QwpC                        Well Perfused Tissues.........       c 0.369          1.10  0.443........................  1.25                         
    QmarC                       Bone Marrow...................         0.089          1.60  0.044........................  1.70                         
Tissue Volumes (fraction of                                                                                                                             
 body weight):                                                                                                                                          
    VgiC                        GI Tract......................         0.035          1.30  0.017........................  1.10                         
    VliC                        Liver.........................         0.045          1.20  0.026........................  1.10                         
    VfatC                       Fat...........................         0.077          1.40  0.204........................  1.20                         
    VppC                        Poorly Perfused Tissues.......       c 0.556          1.10  0.470 c......................  1.15                         
    VwpC                        Well Perfused Tissues.........         0.065          1.15  0.044........................  1.10                         
    VluC                        Lung..........................         0.008          1.30  0.008........................  1.15                         
    VmarC                       Bone Marrow...................         0.033          1.50  0.050........................  1.10                         
Equilibrium Partition                                                                                                                                   
 Coefficients:                                                                                                                                          
    Pblo                        Blood:Air.....................        13.7            1.80  8.4..........................  1.30                         
    Pgi                         GI Tract:Air..................        10.5            1.20  8.1..........................  1.60                         
    Pli                         Liver:Air.....................        22.9            2.00  9.9..........................  1.60                         
    Pfat                        Fat:Air.......................        98.2            1.40  97.6.........................  1.25                         
    Ppp                         Poorly Perfused Tissues:Air...         9.5            1.30  6.8..........................  1.60                         
    Pwp                         Well Perfused Tissues:Air.....        10.2            1.20  7.6..........................  1.40                         
    Plu                         Lung:Air......................        10.0            1.30  7.6..........................  1.50                         
    Pmar                        Bone Marrow:Air...............        62.0            1.60  48.8.........................  1.60                         
Metabolic Parameters:                                                                                                                                   
    VmaxC                       Maximum metabolic velocity of        750             10.00  75...........................  10.00                        
                                 MFO saturable pathway (mg/hr/                                                                                          
                                 kg--liver).                                                                                                            
    KM                          Affinity of MFO saturable              1.35          10.00  0.6..........................  10.00                        
                                 pathway (mg/l).                                                                                                        
    KFC                         First order rate constant for          1.5           10.00  Mouse post. d................  Mouse post. d                
                                 GST pathway (l/hr/kg-0.25).                                                                                            
    A1                          Ratio of lung to liver in-             0.405          1.67  0.0045.......................  4.50                         
                                 vitro MFO metabolic                                                                                                    
                                 velocities (nmol/min/gm--                                                                                              
                                 lung--micros.Prot)/ (nmol/min/                                                                                         
                                 gm--liver--micros.Prot).                                                                                               
    A2                          Ratio of lung to liver in-             0.282          1.67  0.122........................  3.60                         
                                 vitro GST metabolic                                                                                                    
                                 velocities (nmol/min/gm--                                                                                              
                                 lung--cytos.Prot)/ (nmol/min/                                                                                          
                                 gm--liver--cytos.Prot).                                                                                                
    B1                          Ratio of lung and liver tissue         0.271          1.25  0.297........................  1.10                         
                                 content of microsomal protein.                                                                                         
    B2                          Ratio of lung and liver tissue         0.721          1.25  0.807........................  1.20                         
                                 content of cytosolic protein.                                                                                          
    Sp--Kf                      Allometric scaling power for    ............  ............  -0.272 e.....................  0.08 e                       
                                 body weight scaling of KFC                                                                                             
                                 from mice to humans.                                                                                                   
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notes: (a) value computed for 0.025 kg mouse, 70 kg human; (b) unitless; (c) prior distribution not used, fractional flow made functionally dependent on
  others (see text); (d) human prior set equal to mouse posterior; (e) mean and standard deviation of a truncated normal distribution.                  

    While it is desirable to separate variability into components 
reflecting pure uncertainty (e.g., measurement error) versus 
interindividual heterogeneity and to propagate them separately, it is 
necessary to build from the start an adequate statistical model. The 
problem here is complicated by the fact that both the rodent and human 
in vivo data used for estimating metabolic constants reflected either 
aggregated or averaged pharmacokinetic behavior. Thus the prior 
distributions and the statistical model used here aggregate variability 
due to both finite precision in measured values and heterogeneity among 
average values for small groups of rodents or humans; they do not, it 
must be emphasized, reflect heterogeneity among the individual humans 
in a large, representative population.
    e. In Vivo Rodent and Human data. Bayesian updating of the 
distributions was performed using the same data sets used by Clewell et 
al. to obtain fitted estimates of mouse and human metabolic constants; 
namely, gas uptake studies with mice with or without pretreatment with 
a MFO inhibitor and the human open chamber inhalation studies. All 
mouse gas uptake studies were conducted with 5 female mice in

[[Page 1547]]

a single chamber. Thus, measured observations of decline in chamber 
concentration of MC represent the aggregate pharmacokinetic behavior of 
groups of 5 animals.
    The human in vivo data were obtained from Tables 2 and 3 in 
Andersen et al. (1991) [Ex. 21-94]. Briefly, these data represent 
exhaled breath and venous blood concentrations of MC for 6 male human 
volunteers exposed to MC concentrations of 100 or 350 ppm for a period 
of 6 hours. These data have only been reported as means and standard 
deviations of the six subjects, which is unfortunate. Thus, the 
available data reflect the average pharmacokinetic behavior of the 6 
subjects. When simulating the human data reported in Andersen et al. 
(1991), the work load was assumed to be zero watts (rest) and the 
averaged body weight of the 6 subjects was assumed to be known without 
error (86 kg).
    f. Simulating the Rodent Bioassay and Human Occupational Exposure. 
Distributions for GST metabolism in the lungs of mice exposed to 2000 
ppm or 4000 ppm exposures, for 6 hrs/day and 5 days/week, were obtained 
by simulating these two exposures (the ones used in the NTP bioassay) 
with 5000 realizations drawn from the joint posterior distribution of 
the mouse PBPK parameters.
    The quantity of metabolites formed during the 4th week (dynamic 
equilibrium reached) was divided by 7 to give an average measure per 
day. For use as an input dose to the multistage model, these posterior 
distributions were approximated by truncated lognormals.
    The same set of 5000 parameter vectors was used to simulate both 
2000 and 4000 ppm MC exposures. The control dose was always assumed to 
be 0. Thus, a 5000-by-3 matrix of doses was generated, where the three 
column vectors represent different realizations of a particular dose 
group (0, 2000 and 4000 ppm MC) and the row vectors represent different 
realizations of bioassay doses.
    This method of using the joint posterior distributions for the two 
doses in the mouse bioassay implies certain assumptions about the 
uncertainties. Most importantly, this approach (referred to in this 
document as the ``dependence case'') assumes that the posterior 
distributions primarily reflect uncertainty about a single average 
value equally applicable to all groups of approximately 50 mice (i.e., 
it assumes groups of 50 mice will have the same ``average'' 
physiological, anatomical, physicochemical and metabolic attributes, 
and that these average values are simply known to us with uncertainty). 
An alternative would be to model the ``independence case'' by using a 
different random draw from the vector of PBPK parameters for one dose 
group than for the other. This approach assumes that the posterior 
distributions primarily reflect heterogeneity in the average attributes 
of groups of 50 rodents. Under the dependence case, estimates of 
metabolized dose for the two exposures would tend to move in tandem for 
a given simulation (i.e., when one dose is estimated to be low relative 
to its average, so is the other; likewise, when one is high, so is the 
other), and in principle would therefore exhibit less variability in 
dose-response shape (e.g., linear, sublinear, supralinear).
    It appears that the dependence case is more reasonable than the 
independence case, by appealing to biological theory and by examining 
the results of the sensitivity analysis conducted as part of this risk 
assessment. The sensitivity analysis showed that predicted mouse GST 
metabolism at 2000 ppm was most sensitive to variation in the model 
parameter A2. Variability in A2 was primarily a consequence of 
uncertainty in using an in vitro ratio of enzymatic activity to make 
inferences about an in vivo ratio. Therefore, uncertainty rather than 
heterogeneity seems to dominate the distribution of mouse GST 
metabolism estimates. Besides, laboratory rodents have a carefully 
controlled genetic makeup, primarily so that they will differ little 
from each other physiologically; thus, groups of 50 rodents should have 
extremely similar average characteristics (the variance of the mean of 
a characteristic within a group of 50 rodents will be approximately 50 
times smaller than the (already small) inter-individual variance). OSHA 
has determined that this reasoning supports use of the dependence case 
in this analysis. (Note that the excess risk estimates using the 
dependence case are only about a factor of 1.5 higher than those using 
the independence case).
    Five human occupational exposures were simulated: constant exposure 
to 10, 25, 50, 100 or 500 ppm MC for 8-hrs per day and 5 days per week. 
Simulations were made up to 4 weeks of work, at which a dynamic 
equilibrium was reached, and as with mice, were performed using 5000 
parameter human vectors drawn from their joint posterior distribution, 
augmented by allowing for additional variability in human body weight 
and work intensity (the latter linked to changes in cardiac, 
ventilation-perfusion and regional blood flow as described above).
    g. Sensitivity Analysis. The influence of variability in mouse and 
human PBPK model parameters on variability in predicted mouse and human 
GST lung metabolism was assessed by computing pairwise correlation 
coefficients using each parameter vector (i.e., the marginal posterior 
distribution) and the corresponding vector of model predictions. For 
mice, the sensitivity to predicted GST--lung metabolism in the 
simulated 2000 ppm bioassay dose group was evaluated. For humans, 
predicted GST--lung metabolism for an occupational exposure to 25 ppm 
was considered. Pairwise correlation coefficients were computed using 
5000 parameter vectors drawn from the joint posterior distribution and 
the associated model output vector.
    Table VI-6 presents the results from the sensitivity analysis. The 
strongest pairwise correlation between predicted lung GST metabolism 
and any input parameter, for either mouse or human simulations, was A2. 
For the mouse simulation of a 2000 ppm exposure, B2 gave the next 
strongest pairwise correlation. The mouse parameters QlivC, VlivC, 
VmaxC, Pfat and QppC all exhibited more moderate (though not 
negligible) correlations. For the human occupational simulation, the 
parameters KfC, VmaxC, Sp__Kf, and B2 all exhibited moderate pairwise 
correlations with human lung GST metabolism. For both mice and human 
sensitivity analyses, there were a half-dozen or more parameters 
exhibiting weak (r between 0.1 and 0.2) correlations. It is important 
to note that all parameters are further correlated via their posterior 
joint distribution function. This explains why the sum of the 
regression coefficients (i.e., squares of the correlation coefficients) 
is greater than 1. Thus considerable care should be exercised in 
quantitatively estimating the ability of variability in any input 
parameter to explain variability in predicted GST metabolism, 
especially among parameters with similar pairwise correlation 
coefficients.

[[Page 1548]]



  Table VI-6.--Correlation Coefficients for Total GST Lung Metabolism From Monte Carlo Analysis Using Mouse and 
                                          Human Posterior Distributions                                         
----------------------------------------------------------------------------------------------------------------
                      Mouse 2000 PPM                                            Human 25 PPM                    
----------------------------------------------------------------------------------------------------------------
                                              Correlation                                            Correlation
                  Parameter                   coefficient                  Parameter                 coefficient
                                                  (r)                                                    (r)    
----------------------------------------------------------------------------------------------------------------
A2..........................................        0.860  A2                                              0.850
B2..........................................        0.530  KfC                                             0.315
QliC........................................        0.335  VmaxC                                          -0.291
VliC........................................       -0.248  Sp--Kf                                          0.232
VmaxC.......................................       -0.229  B2                                              0.221
Pfat........................................       -0.203  Pmar                                           -0.183
QppC........................................       -0.202  QfatC                                           0.180
VPR.........................................        0.193  B1                                              0.179
Pli.........................................       -0.173  VliC                                            0.161
A1..........................................       -0.149  VmarC                                           0.146
QgiC........................................       -0.145  Work                                            0.142
Pmar........................................        0.144  QwpC                                            0.141
VwpC........................................       -0.121  VfatC                                           0.136
KfC.........................................        0.120  QmarC                                           0.136
Pwp.........................................       -0.106  Km                                             -0.095
VluC........................................       -0.120  QC                                             -0.083
B1..........................................       -0.093  QliC                                           -0.083
QmarC.......................................       -0.083  A1                                             -0.071
Ppp.........................................       -0.076  QgiC                                           -0.065
VgiC........................................        0.074  Pfat                                           -0.061
Pgi.........................................        0.054  Pwp                                            -0.058
QC..........................................       -0.049  VluC                                           -0.052
BW..........................................       -0.042  Pgi                                            -0.050
Plu.........................................        0.039  VwpC                                            0.041
Km..........................................       -0.035  Pblood                                          0.039
tVmaxC......................................        0.024  dVPR/dW                                         0.039
QfatC.......................................        0.020  BW                                             -0.038
Pblood......................................        0.019  dQli/dW                                        -0.033
VfatC.......................................       -0.013  Plu                                             0.023
Vmar........................................       -0.007  Ppp                                             0.021
                                                           dQfat/dW                                        0.016
                                                           VgiC                                           -0.012
                                                           Pli                                            -0.010
                                                           dQgi/dW                                        -0.010
                                                           dQmar/dW                                       -0.009
                                                           VPR                                             0.006
                                                           dQC/dW                                         -0.000
                                                           dQwp/dW                                        -0.000
----------------------------------------------------------------------------------------------------------------

    h. Posterior PBPK Parameter Distributions. Table VI-7 lists the 
posterior distributions for mouse PBPK parameters obtained by Bayesian 
updating of the prior distributions using the available gas uptake 
data. Comparison of the prior and posterior probability distributions 
reveals that the gas uptake data retain considerable influence on the 
distributions of many of the important PBPK model parameters. Medians 
of the posterior distributions for VPR, Qfat, Pblood, Pmar, Km, A1, and 
A2 were all appreciably different than the medians for their 
corresponding prior distributions. Percent CVs for nearly all posterior 
distributions were considerably smaller than those of their prior 
distributions. As expected, the marginal variances for the metabolic 
constants were considerably greater than what was obtained under 
nonlinear maximum likelihood regression analysis with all other model 
parameters fixed at nominal values.

              Table VI-7. Prior and Posterior (Fitted) Distributions of the Mouse Model Parameters              
----------------------------------------------------------------------------------------------------------------
                                                  Central tendency                             Variability      
                                           ------------------------------    Maximum   -------------------------
                            Parameter                        Posterior      posterior                 Posterior 
                                            Prior median      median                     Prior %CV       %CV    
----------------------------------------------------------------------------------------------------------------
Flows:                                                                                                          
    QCC               Cardiac Output (l/hr/       34.8          34.4            37.6             18            9
                       kg__BW).                                                                                 
    VPR               Alveolar Ventilation         1.22          1.59            1.49            75           14
                       Perfusion Ratio.                                                                         
Tissue Blood Flows                                                                                              
 (fraction of                                                                                                   
 cardiac output):                                                                                               
    QgiC              GI Tract............         0.165         0.140           0.175           26           16

[[Page 1549]]

                                                                                                                
    QliC              Liver...............         0.017         0.020           0.017           19           16
    QfatC             Fat.................         0.047         0.090           0.098           43           19
    QppC              Poorly Perfused              0.276         0.290           0.243           22           18
                       Tissues.                                                                                 
    QwpC              Well Perfused                0.369       a 0.360           0.378                         a
                       Tissues.                                                                                 
    QmarC             Bone Marrow.........         0.089         0.100           0.090           51           27
Tissue Volumes                                                                                                  
 (fraction of body                                                                                              
 weight):                                                                                                       
    VgiC              GI Tract............         0.035         0.040           0.038           26           22
    VliC              Liver...............         0.045         0.050           0.050           18           12
    VfatC             Fat.................         0.077         0.070           0.055           35           24
    VppC              Poorly Perfused              0.556       b 0.540           0.569                         b
                       Tissues.                                                                                 
    VwpC              Well Perfused                0.065         0.070           0.065           14           12
                       Tissues.                                                                                 
    VluC              Lung................         0.008         0.010           0.007           27           22
    VmarC             Bone Marrow.........         0.033         0.040           0.037           42           29
Equilibrium                                                                                                     
 Partition                                                                                                      
 Coefficients:                                                                                                  
    Pblo              Blood:Air...........        13.7          18.5            13.1             66           18
    Pgi               GI Tract:Air........        10.5          11.3             9.5             19           17
    Pli               Liver:Air...........        22.9          28.2            23.9             79           32
    Pfat              Fat:Air.............        98.2         100.5           106.7             35           21
    Ppp               Poorly Perfused              9.5          12.1            13.1             27           17
                       Tissues:Air.                                                                             
    Pwp               Well Perfused               10.2          10.4            10.3             19           16
                       Tissues:Air.                                                                             
    Plu               Lung:Air............        10.0          11.3            12.5             27           22
    Pmar              Bone Marrow:Ait.....        62.0          70.4            89.2             50           25
Metabolic                                                                                                       
 Parameters:                                                                                                    
    VmaxC             Maximum metabolic          750           718             661             1413           12
                       velocity of MFO                                                                          
                       saturable pathway                                                                        
                       (mg/hr/kg__liver).                                                                       
    tVmaxC            Maximum metabolic            8.4           7.2            11.3             58           50
                       velocity of MFO                                                                          
                       saturable pathway                                                                        
                       in t-DCE pretreated                                                                      
                       mice.                                                                                    
    Km                Affinity of MFO              1.35          0.04            0.03          1413           97
                       saturable pathway                                                                        
                       (mg/l).                                                                                  
    KfC               First order rate             1.5           1.77            2.47          1413           24
                       constant for GST                                                                         
                       pathway (l/hr/                                                                           
                       kgcaret0.25).                                                                            
    A1                Ratio of lung to             0.405         0.28            0.30            54           31
                       liver in-vitro MFO                                                                       
                       metabolic                                                                                
                       velocities (nmol/                                                                        
                       min/                                                                                     
                       gm__lung__micros.Pr                                                                      
                       ot)/(nmol/min/                                                                           
                       gm__liver__micros.P                                                                      
                       rot).                                                                                    
    A2                Ratio of lung to             0.282         0.37            0.30            55           41
                       liver in-vitro GST                                                                       
                       metabolic                                                                                
                       velocities (nmol/                                                                        
                       min/                                                                                     
                       gm__lung__cytos.Pro                                                                      
                       t)/(nmol/min/                                                                            
                       gm__liver__cytos.Pr                                                                      
                       ot).                                                                                     
    B1                Ratio of lung and            0.271         0.26            0.29            23           18
                       liver tissue                                                                             
                       content of                                                                               
                       microsomal protein.                                                                      
    B2                Ratio of lung and            0.721         0.70            0.84            22          17 
                       liver tissue                                                                             
                       content of                                                                               
                       cytosolic protein.                                                                       
----------------------------------------------------------------------------------------------------------------
Notes: (a) functionally defined as 1__sum (other fractional flows); (b) functionally defined as 0.82__sum (other
  fractional volumes).                                                                                          

    Table VI-8 presents the corresponding set of results for human PBPK 
parameters. The human in vivo data also appeared to contain 
considerable information about many of the model parameters, as 
evidenced by shifts in medians and tightening of posterior 
distributions relative to priors. Fitted estimates of the metabolic 
constants were fairly precise, even for Km (Table VI-8); indeed, the 
fits were markedly superior to those shown in Andersen et al. [Ex. 21-
94] and Clewell et al. [Ex. 96].

                                  Table VI-8.--Prior and Posterior (Fitted) Distributions of the Human Model Parameters                                 
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                      Prior distribution                           Posterior distribution               
                                                          ----------------------------------------------------------------------------------------------
                                                                                                     Posteriors for Bayesian      Modified by exercise  
                                        Parameter                                                              fit            --------------------------
                                                                GM            GSD          %CV     ---------------------------                          
                                                                                                       Median         %CV         Median         %CV    
--------------------------------------------------------------------------------------------------------------------------------------------------------
Flows:                                                                                                                                                  
    QCC                         Cardiac Ouput (1/hr/             4.2             1.10           10         4.0              6         6.2             17
                                 kg__BW).                                                                                                               

[[Page 1550]]

                                                                                                                                                        
    VPR                         Alveolar Ventilation             1.35            1.15           15         1.03             1         1.37             9
                                 Perfusion Ratio.                                                                                                       
Tissue Blood Flows (fraction    .........................  ............  ............  ...........  ............  ...........  ............  ...........
 of cardiac output):                                                                                                                                    
    QgiC                        GI Tract.................        0.191           1.25           23         0.149           12         0.122           14
    QliC                        Liver....................        0.067           1.20           19         0.063           15         0.041           24
    QfatC                       Fat......................         .057           1.45           38         0.045           10         0.052           11
    QppC                        Poorly Perfused Tissues..        0.198           1.55            a         0.378          a 9       a 0.453           10
    Qwpc                        Well Perfused Tissues....        0.443           1.25           23         0.294            3         0.258            7
    QmarC                       Bone Marrow..............        0.044           1.70           57         0.071           38         0.072           38
Tissue Volumes (fraction of     .........................  ............  ............  ...........  ............  ...........  ............  ...........
 body weight):                                                                                                                                          
    VgiC                        GI Tract.................        0.017           1.10           10         0.018            8         0.018            8
    VliC                        Liver....................        0.026           1.10           10         0.026            8         0.026            8
    VfatC                       Fat......................        0.204           1.20           18         0.183           11         0.183           11
    VppC                        Poorly Perfused Tissues..        0.470           1.15            b         0.489          b 5       b 0.489            5
    VwpC                        Well Perfused Tissues....        0.044           1.10            9         0.47             7         0.047            7
    VluC                        Lung.....................        0.008           1.15           14         0.008           11         0.008           11
    VmarC                       Bone Marrow..............        0.050           1.10           10         0.049            8         0.049            8
Equilibrium Partition           .........................  ............  ............  ...........  ............  ...........  ............  ...........
 Coefficients:                                                                                                                                          
    PC.blood                    Blood:Air................        8.4             1.30           26        16.5              2        16.5              2
    PC.gi                       GI Tract:Air.............        8.1             1.60           50        10.7             36        10.7             36
    PC.li                       Liver:Air................        9.9             1.60           50        13.7             33        13.7             33
    PC.fat                      Fat:Air..................       97.6             1.25           22        84.4             12        84.4             12
    PC.pp                       Poorly Perfuse Tissue:Air        6.8             1.60           48        13.3             13        13.3             13
    PC.wp                       Well Perfused Tissue:Air.        7.6             1.40           35        13.1             14        13.1             14
    PC.lu                       Lung:Air.................        7.6             1.50           43         9.4             33         9.4             33
    PC.mar                      Bone Marrow:Air..........       48.8             1.60           49        47.8             27        47.8             27
Metabolic Parameters:           .........................  ............  ............  ...........  ............  ...........  ............  ...........
    VmaxC                       Maximum MFO metabolic           75.0            10.00         1413        97.2             11        97.2             11
                                 rate (mg/mg/hr/kg-liver).                                                                                              
    Km                          MFO Michaelis Menton             0.60           10.00         1413         0.52            39         0.52            39
                                 constant (mg/1).                                                                                                       
    Kf                          1st order rate constant          0.12            2.07           81         0.23            63         0.23            63
                                 for GST pathway (1/hr).                                                                                                
    A1                          [V/S]-lung/[V/S-MFO-liver        0.0045          4.50          226         0.024           77         0.024           77
    A2                          [V/S]-lung/[V/S]-GST-            0.236           2.04           83         0.364           49         0.364           49
                                 liver.                                                                                                                 
    B1                          [mg micr.Prot/gm lung]/          0.297           1.10           10         0.300            8         0.300            8
                                 [mg micr.Prot/gm liver].                                                                                               
    B2                          [mg cyt. Prot/gm lung]/          0.807           1.20           18         0.845           15         0.845           15
                                 [mg cyt.Prot/gm liver].                                                                                                
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notes (a) operationally defined as 1--sum (other fractional flows); (b) functionally defined as 0.82--sum (other fractional volumes).                   


[[Page 1551]]

    Tables VI-9 and VI-10 compare the posterior distributions for mice 
and human PBPK parameters with the distributions used by Clewell. For 
mice, there were appreciable differences in the median values for QCC, 
VPR, QfatC, QwpC, VwpC, VmaxC, Km, KfC, and the apparent A1 (i.e., A1 
x  B1). With the exception of VliC, Pblood, Pliv, Ppp and Km, the 
posterior distributions for all other parameters were tighter than the 
distributions used by Clewell. The human posterior distributions in 
Table VI-10 are somewhat different than those in Table VI-8, in that 
they reflect the influence of modeling variable work intensity on QC, 
VPR, and all regional blood flows. In comparing these modified 
posterior distributions to the distributions used by Clewell, one finds 
appreciable differences in median values for VPR, many of the 
fractional blood flows (QgiC, QliC, QppC, QwpC), VgiC, PCblood, PCliv, 
PCfat, VmaxC, KfC, and the apparent A2 (i.e., A2  x  B2). All human 
posterior distributions except for VliC, Pli, and Sp__Kf, had 
appreciably tighter distributions than those used by Clewell et al. 
[Ex. 96].

     Table VI-9.--Comparison of Mouse Probability Distributions Used by Clewell et al. With OSHA's Posterior    
                                            Probability Distributions                                           
----------------------------------------------------------------------------------------------------------------
                                                                 Central tendency              Variability      
                                                           -----------------------------------------------------
                                         Parameter           Clewell et                  Clewell et             
                                                             al. median    OSHA median    al. %CV      OSHA %CV 
----------------------------------------------------------------------------------------------------------------
Flows:                                                                                                          
    QCC                          Cardiac Output (1/hr/          a 41.5           34.4             9            9
                                  kg__BW).                                                                      
    VPR                          Alveolar Ventilation            b 1.76           1.59           58           14
                                  Perfusion Ratio.                                                              
Tissue Blood Flows (fraction of                                                                                 
 cardiac output):                                                                                               
    QgiC                         GI Tract.................         0.165          0.14           25           16
    QliC                         Liver....................         0.035          0.02           96           16
    QfatC                        Fat......................         0.030          0.09           60           19
    QppC                         Poorly Perfused Tissues..         0.250          0.29           40           18
    QwpC                         Well Perfused Tissues....         0.520        c 0.36           50            c
    QmarC                        Bone Marrow..............        NA              0.10           NA           27
Tissue Volumes (fraction of                                                                                     
 body weight):                                                                                                  
    VgiC                         GI Tract.................         0.031          0.04           30           22
    VliC                         Liver....................         0.046          0.05            6           12
    VfatC                        Fat......................         0.100          0.07           30           24
    VppC                         Poorly Perfused Tissues..         0.513        d 0.54           30            d
    VwpC                         Well Perfused Tissues....         0.041          0.07           30           12
    VluC                         Lung.....................         0.008          0.01           30           22
    VmarC                        Bone Marrow..............        NA              0.04           NA           29
Equilibrium Partition                                                                                           
 Coefficients:                                                                                                  
    Pblo                         Blood:Air................        23.0           18.5            15           18
    Pgi                          GI Tract:Air.............        11.4           11.3            30           17
    Pli                          Liver:Air................        38.7           28.2            20           32
    Pfat                         Fat:Air..................       107.0          100.5            30           21
    Ppp                          Poorly Perfused                   8.5           12.1            10           17
                                  Tissues:Air.                                                                  
    Pwp                          Well Perfused Tissues:Air        11.4           10.4            20           16
    Plu                          Lung:Air.................        10.0           11.3            30           22
    Pmar                         Bone Marrow:Air..........        NA             70.4            NA           25
Metabolic Parameters:                                                                                           
    VmaxC                        Maximum metabolic               970            718              20           12
                                  velocity of MFO                                                               
                                  saturable pathway (mg/hr/                                                     
                                  kg__liver).                                                                   
    Km                           Affinity of MFO saturable         1.35           0.04           30           97
                                  pathway (mg/l).                                                               
    KfC                          First order rate constant         1.5            1.77           30           24
                                  for GST pathway (l/hr/                                                        
                                  kg__0.25).                                                                    
    A1                           Ratio of lung to liver in-        0.405          0.28           50           31
                                  vitor MFO metabolic                                                           
                                  velocities (nmol/min/                                                         
                                  gm__lung__micros.Prot)/                                                       
                                  (nmol/min/                                                                    
                                  gm__liver__micros.Prot).                                                      
    A2                           Ratio of lung to liver in-        0.282          0.37           50           41
                                  vitro GST metabolic                                                           
                                  velocities (nmol/min/                                                         
                                  gm__lung__cytos.Prot)/                                                        
                                  (nmol/min/                                                                    
                                  gm__liver__cytos.Prot).                                                       
    B1                           Ratio of lung and liver           1              0.25            0           18
                                  tissue content of                                                             
                                  microsomal protein.                                                           
    B2                           Ratio of lung and liver           1              0.69            0           17
                                  tissue content of                                                             
                                  cytosolic protein.                                                            
----------------------------------------------------------------------------------------------------------------
Notes: (a) value computed for 0.025 kg mouse; (b) unitless; (c) functionally defined as 1--sum (other fractional
  flows); (d) functionally defined as 0.82--sum(other fractional volumes); (na) not applicable.                 


     Table VI-10. Comparison of Human Probability Distributions Used by Clewell et al. With OSHA's Posterior    
                                            Probability Distributions                                           
----------------------------------------------------------------------------------------------------------------
                                                                 Central tendency              Variability      
                                                           -----------------------------------------------------
                                         Parameter           Clewell et                  Clewell et             
                                                             al. median    OSHA median    al. %CV      OSHA %CV 
----------------------------------------------------------------------------------------------------------------
Flows:                                                                                                          

[[Page 1552]]

                                                                                                                
    QCC                       Cardiac Output (l/hr/kg__BW)       a 6.2         c 6.3              9         c 17
    VPR                       Alveolar Ventilation               b 1.95        c 1.36            18          c 9
                               Perfusion Ratio.                                                                 
Tissue Blood Flows (fraction                                                                                    
 of cardiac output):                                                                                            
    QgiC                      GI Tract....................         0.195       c 0.12            10         c 13
    QliC                      Liver.......................         0.070       c 0.04            35         c 23
    QfatC                     Fat.........................         0.050       c 0.05            30         c 15
    QppC                      Poorly Perfused Tissues.....         0.240       c 0.46            15         c 10
    QwpC                      Well Perfused Tissues.......         0.445    c, d 0.26            20       c, d 7
    QmarC                     Bone Marrow.................        NA           c 0.07            NA         c 45
Tissue Volumes (fraction of                                                                                     
 body weight):                                                                                                  
    VgiC                      GI Tract....................         0.045         0.017           10            8
    VliC                      Liver.......................         0.023         0.026            5            8
    VfatC                     Fat.........................         0.160         0.187           30           12
    VppC                      Poorly Perfused Tissues.....         0.480       e 0.483           30          e 5
    VwpC                      Well Perfused Tissues.......         0.033         0.047           10            7
    VluC                      Lung........................         0.006         0.008           10           12
    VmarC                     Bone Marrow.................        NA             0.050           NA            8
Equilibrium Partition                                                                                           
 Coefficients:                                                                                                  
    Pblo                      Blood:Air...................        12.9          16.5             15            2
    Pgi                       GI Tract:Air................        12.0          13.5             30           31
    Pli                       Liver:Air...................        37.4          13.6             20           34
    Pfat                      Fat:Air.....................       117.0          81.2             30           13
    Ppp                       Poorly Perfused Tissues:Air.        10.0          13.3             10           14
    Pwp                       Well Perfused Tissues:Air...        12.0          13.0             20           14
    Plu                       Lung:Air....................        10.6           9.1             30           32
    Pmar                      Bone Marrow:Air.............        NA            51.2             NA           35
Metabolic Parameters:                                                                                           
    VmaxC                     Maximum metabolic velocity          75.2          94.2             30           12
                               of MFO saturable pathway                                                         
                               (mg/hr/kg__liver).                                                               
    Km                        Affinity of MFO saturable            0.4           0.49            50           35
                               pathway (mg/l).                                                                  
    KfC                       First order rate constant            1.5           1.82            50           24
                               for GST pathway (l/hr/kg-                                                        
                               0.25).                                                                           
    A1                        Ratio of lung to liver in-           0.015         0.03            70           69
                               vitro MFO metabolic                                                              
                               velocities (nmol/min/                                                            
                               gm__lung__micros. Prot)/                                                         
                               (nmol/min/                                                                       
                               gm__liver__micros.Prot).                                                         
    A2                        Ratio of lung to liver in-           0.18          0.45            70           71
                               vitro GST metabolic                                                              
                               velocities (nmol/min/                                                            
                               gm__lung__cytos.Prot)/                                                           
                               (nmol/min/                                                                       
                               gm__liver__cytos.Prot).                                                          
    B1                        Ratio of lung and liver              1.0           0.31             0            8
                               tissue content of                                                                
                               microsomal protein.                                                              
    B2                        Ratio of lung and liver              1.0           0.84             0           14
                               tissue content of cytosolic                                                      
                               protein.                                                                         
    Sp__Kf                    Allometric scaling power for        -0.25         -0.267            0          22 
                               body weight scaling of KFC                                                       
                               from mice to humans.                                                             
----------------------------------------------------------------------------------------------------------------
Notes: (a) value computed for 70 kg human; (b) unitless; (c) posterior distributions adjusted for effects of    
  light activity; (d) functionally defined as 1--sum(other fractional flows); (d) functionally defined as 0.82--
  sum(other fractional volumes); (NA) not applicable.                                                           

    i. Alternative analysis using the ``parallelogram'' approach. 
Andersen et al. [Ex. 21-94] estimated a human first order rate constant 
(Kf) for glutathione (GST) metabolism of MC in the liver by allometric 
scaling of a fitted estimate of an in vivo mouse rate constant 
(KfCmouse). Specifically,
[GRAPHIC] [TIFF OMITTED] TR10JA97.009

where spKf was the allometric scaling power with value -0.25. In their 
Monte Carlo analysis, Clewell et al. followed the approach of Andersen 
et al., treating KfCmouse as a lognormally distributed random 
variable and spKf as a known constant. The Bayesian analysis summarized 
above also made use of the allometric scaling given by the equation 
above, but prior probability distributions were specified for both 
KfCmouse and spKf.
    Reitz et al. (1988, 1989) [Exs. 7-225 and 21-53] proposed an 
alternative approach for estimating an apparent in vivo human Kf. The 
approach, referred to as the ``parallelogram method,'' assumes there is 
a constant proportionality across species between in vitro and apparent 
in vivo metabolic rates when normalized for substrate concentration 
([S]). For example, the equation modeling the apparent in vivo rate of 
GSH conjugation (dMGST/dt) is given by:
[GRAPHIC] [TIFF OMITTED] TR10JA97.010

The constant proportionality between apparent in vivo rates of 
metabolism and in vitro rates implies

[[Page 1553]]

[GRAPHIC] [TIFF OMITTED] TR10JA97.011


where [V/S]GST denotes an in vitro enzymatic rate normalized to 
[S] and kp the in vivo--in vitro proportionality constant. This 
approach assumes a common value of kp across species, such that 
knowledge of a [V/S]GST-rodent and Kfrodent (sufficient to 
estimate a value for kp as the ratio of Kfrodent to [V/
S]GST-rodent)
     and knowledge of [V/S]GST-human
 is sufficient to estimate the remaining corner of a parallelogram, 
namely Kfhuman. Therefore, this approach assumes,
[GRAPHIC] [TIFF OMITTED] TR10JA97.012

or:
[GRAPHIC] [TIFF OMITTED] TR10JA97.013

    Reitz et al. [Ex. 21-53] obtained an estimate for Kfhuman 
using the parallelogram method that was very similar to the estimate 
obtained by Andersen et al. [Ex. 21-94] using allometric scaling. 
However, Reitz and coworkers estimated a mean [V/S]GST-human based 
on liver samples from only four human subjects--three of which had 
appreciable enzymatic activity and one with no detectable activity. 
More recent publications (Bogaards et al., 1993 [Ex. 127-16]; Graves et 
al., 1995 [Ex. 122]) and unpublished data (Green et al., 1987 [Ex. 14]) 
provide measured values of [V/S]GST on another 35 human subjects. 
These additional data demonstrate considerable variation in rates of 
GST metabolism among human subjects, consistent with a known human 
polymorphism for GST, described earlier in this Quantitative Risk 
Assessment. Moreover, these data indicated that, putting aside 
questions of interlaboratory comparability of measurements, three of 
the four human samples used by Reitz et al. had GST metabolic rates 
among the highest reported to date. Consequently, the mean [V/
S]GST-human used by Reitz and coworkers was greater than the mean 
estimable from the full complement of data on human GST activity.
    Since OSHA was interested in assessing the effect of accounting for 
the full complement of data on human GST activity on estimates of 
cancer risk, this additional analysis was performed, despite the 
Agency's reservations concerning the appropriateness of using the 
parallelogram approach in the MC risk assessment. Although this 
approach allows the use of all of the available data, the uncertainties 
in the ratio of in vitro to in vivo metabolic constants raise serious 
questions for the utility of this analysis. OSHA is presenting this 
analysis for purposes of comparison and notes that HSIA and Clewell 
used allometric adjustments in their final PBPK models.
    The use of a Kfhuman derived by the parallelogram method 
required: (1) modification of the human PBPK model; (2) specification 
of a prior probability distribution for Kfhuman; (3) replication 
of the Bayesian analysis of the human in vivo open chamber data using 
the new prior for Kfhuman; (4) simulation of the occupational 
exposure scenario using the joint posterior distributions from the new 
Bayesian analysis to obtain a posterior distribution for human GST lung 
metabolism; and (5) re-estimation of the extra cancer risk.
    (1) PBPK Model Modifications. The only structural modification to 
the PBPK models was to replace the parameter for allometric scaling of 
Kfmouse with a direct insert of a model parameter Kfhuman, 
having its own prior probability distribution.
    (2) Prior Probability Distributions. Mouse prior probability 
distributions were unchanged. Prior probability distributions for human 
model parameters were also unchanged, with the exception of prior 
distributions for KfC, spKf and A2. Prior probability distributions for 
KfC and spKf were replaced with a prior probability distribution for 
Kfhuman. The prior probability distribution for A2 was modified to 
account for additional data on human lung GST activity submitted to 
OSHA by HSIA [Ex. 122].
    The prior probability distribution for Kfhuman was derived 
using the equation:
[GRAPHIC] [TIFF OMITTED] TR10JA97.014

where errkp is an error term added to account for uncertainty in 
estimating the proportionality constant kp, as kmouse. Thus, 
to derive a prior probability distribution for Kfhuman, it was 
necessary to derive prior distributions for Kfrodent, [V/
S]GST-rodent, [V/S]GST-human and errkp, which in turn 
were propagated using Monte Carlo techniques in accordance with the 
relationships specified by the equation above.
    (i) Prior distribution for rodent Kf. The posterior probability 
distribution used in the main analysis for the apparent in vivo rodent 
KfC parameter was used as the basis for a prior probability 
distribution for Kfrodent. The posterior distribution was well 
described by a truncated lognormal distribution with a mean and 
standard deviation of 1.8 and 0.43 l/hr/bw /-0.25, and lower and 
upper truncations at 0.84 and 3.07 l/hr/bw /-0.25, respectively. 
The posterior distribution was converted to units of (hour) -1 by 
using Monte Carlo techniques to multiply the truncated lognormal by the 
scalar, (rodent body weight) -0.25.
    (ii) Prior for rodent liver GST [V/S]. A prior probability 
distribution for a low dose mouse [V/S]GST was obtained as the 
ratio of the fitted estimates of in vitro Vmax and Km 
reported by Reitz et al. for liver glutathione conjugation of MC. The 
fitted estimates of Vmax and Km and their associated standard 
errors were used to set the parameters for normal distributions. Monte 
Carlo techniques were used to obtain the ratio of these two 
distributions (i.e., Vmax/Km), under the assumption that the 
joint sample space for Vmax and Km was correlated with a 
 = 0.9. Correlation was induced because a reanalysis of the 
mouse in vitro reported in Reitz et al. showed that the joint parameter 
space for these two fitted parameters was highly correlated.
    (iii) Prior distribution for human GST [V/S]. There were four data 
sets reporting measured values of in vitro GST activity in liver 
samples from 39 human subjects. These data reflect work from different 
laboratories using (in some cases) different assay methods and 
different substrate concentrations. In order to make use of all the 
data to estimate central tendencies and population variability, it was 
necessary that all measurements be placed on a common scale.
    With respect to assay methods, two of the studies [Exs. 21-53 and 
122] reported measured values of [V/S]GST based on detection of 
[36]Cl from labelled MC. The other two studies [Exs. 14 and 127-16] 
reported values of [V/S]GST based on detection of formaldehyde, a 
known decomposition product from GSH conjugation with MC. In a 
comparison of these two methods, Green et al. [Ex. 14] reported results 
indicating a systematic difference in measured values of [V/S]GST, 
with the [36]Cl detection method appearing to give estimates 
approximately 1.7-fold higher than the formaldehyde detection method. 
In this analysis, the [36]Cl method was chosen as the common scale, 
since the mouse [V/S]GST data used above were based on this 
method. Thus, the formaldehyde assay results were multiplied by 1.7 to 
put them on the [36]Cl scale.
    Adjustments for both substrate concentration and nonlinear 
metabolism were made by converting all the

[[Page 1554]]

reported in vitro velocity data, [V]GST, to Vmax/Km 
ratios (i.e., low dose metabolic velocity), by the equation:
[GRAPHIC] [TIFF OMITTED] TR10JA97.015

The above equation follows from assuming in vitro kinetics can be 
reasonably modeled as a single-substrate Michaelis-Menton process 
(i.e., [V]GST = {Vmax x [S]}/{Km + [S]}). In making 
adjustments, assay specific substrate concentrations were used (i.e., 
[S], which ranged from 35 to 94 mM) along with the average estimate of 
an in vitro Km reported by Reitz et al. [Ex. 21-53] in analysis of data 
from two human subjects ( 44 mM). It is noteworthy that none of the 
human in vitro [V/S]gst data reported in Reitz et al. were truly 
reflective of linear kinetics, whereas the mice data were.
    After the two above adjustments were made, a lognormal distribution 
was fit to the transformed data yielding a GM of 0.031 l/min/mg 
protein, and a GSD of 2.72. This distribution models intersubject 
variability in in vitro metabolic activity. However, the prior 
probability distribution for [V/S]gst-human should reflect 
variation in means of six subjects, because the in vivo human data from 
Dow Chemical Company reflect the averaged pharmacokinetic behavior of 
tissue from six subjects. Thus, dispersion in the above distribution 
was adjusted to give the corresponding sampling distribution for means 
of n = 6.
    (iv) Prior distribution for error term.
    The in vivo and in vitro metabolic data on the MFO metabolic 
pathway, reported by Reitz et al. [Ex. 21-53], were used to estimate 
the uncertainty in assuming a constant kp across species. These 
were the only data for which both in vivo and in vitro information was 
available on several species and which was directly relevant to MC. To 
avoid artifacts due to the very imprecise fitted estimates of apparent 
in vivo Km's, in vivo / in vitro comparisons were constructed based on 
estimates of Vmax alone. These estimates were then normalized by the 
ratio obtained for mice, providing a measure of the error in using a 
mouse ratio to estimate ratios in three other species: rats (1.42), 
hamsters (0.64), and humans (0.41). The GM (0.72) and GSD (1.89) of 
these three values were used to set parameters for a lognormal 
distribution used as the prior probability distribution for errkp. 
Note that the human value of 0.41 reflected an average of separate 
estimates on four human subjects, with ratios ranging from 0.1 to 1.0.
    (v) Monte Carlo simulation to obtain a prior for human Kf. The 
above prior probability distributions for Kfmouse, [V/S]gst-
mouse, [V/S]GST and errkp were independently sampled by Monte 
Carlo techniques (n = 5000) and combined to give a prior distribution 
for Kfhuman for use in Bayesian analysis of the human open chamber 
data.
    (vi) Revised prior distribution for A2.
    A2 is the ratio of in vitro GST enzymatic activity in lung tissue 
to the same activity in liver tissue. In the main analysis, the prior 
probability distribution for A2 was derived according to the equation:
[GRAPHIC] [TIFF OMITTED] TR10JA97.016

    where errvivo/vitro is an error term to account for 
uncertainty in using a ratio of in vitro activity to make inferences 
about in vivo activity, and the data of Reitz et al. [Ex. 21-53] were 
used to estimate prior distributions for [V/S]GST-lung and [V/
S]GST-liver. This prior distribution was revised to account for 
additional human [V/S]GST-lung and [V/S]GST-liver data.
    (vii) Prior for human lung GST [V/S]. Previously, only a single 
measured value for [V]GST-lung from a pooled lung sample from two 
human subjects was available for estimating A2. Mainwaring et al. [Ex. 
124] recently submitted additional [V]GST-lung data to OSHA, 
consisting of measured values on three additional human subjects (0.00, 
0.06 and 0.21 nmol/min/mg protein). The value reported as 0.00 was 
assumed equal to one-half the detection limit for the assay. Since 
these new [V]GST-lung data were obtained using the formaldehyde 
detection assay, it was necessary to transform the values to the [36]Cl 
scale. Lacking direct information, it was assumed that the same HCOOH 
 [36]Cl correction factor derived for the liver data held for 
the lung data. A correction for substrate concentration was also made, 
under the assumption of equivalency in lung and liver in vitro Km's. 
The resulting transformed [V]GST-lung data were used to construct 
a prior probability distribution describing uncertainty in the mean of 
five 1 observations (GM = 0.00082, GSD = 1.61). Note that, in this 
case, an attempt was made to model pure uncertainty in a low dose [V/
S]GST-lung, without information indicating appreciable 
heterogeneity in the ratio of lung and liver enzymatic activity within 
an individual.
---------------------------------------------------------------------------

    \1\ Since the single observation of [V]GST-lung reported by 
Reitz et al. (1988) was from a pooled sample of lung tissue from two 
human subjects, the data point was treated as two observations with 
the same value.
---------------------------------------------------------------------------

    (viii) Prior probability distribution for uncertainty in human 
liver GST [V/S]. Because of the focus on uncertainty in A2, the prior 
probability distribution for [V/S]GST-liver derived above was 
modified to describe uncertainty about the mean, given a sample size of 
39 subjects.
    (ix) Uncertainty in using an in vitro ratio of lung and liver GST 
activity to make an inference about the corresponding ratio for 
apparent in vivo GST activity. A prior probability distribution for 
errvivo/vitro was derived using data on in vivo and in vitro 
ratios of liver MFO enzymatic activity for different species, as a 
surrogate for intra-species lung versus liver GST enzymatic activity. 
Thus, two key assumptions are made: (i) That relative enzymatic 
activity for liver tissue from two species is a reasonable surrogate 
for relative activities of lung versus liver tissue within a single 
species, and (ii) that the degree of consistency in ratios of in vivo 
versus in vitro enzymatic activity will be the same for either MFO or 
GST mediated processes.
    If the apparent in vivo Vmax for the MFO pathway in the lung was 
modeled as:
[GRAPHIC] [TIFF OMITTED] TR10JA97.017

    it follows that,
    [GRAPHIC] [TIFF OMITTED] TR10JA97.018
    
    where VmaxA denotes normalization of Vmax to unit tissue volume. 
Although there were insufficient data to

[[Page 1555]]

allow for a direct evaluation of the above equation, the data tabulated 
by Reitz et al. [Ex. 7-225] for MFO enzymatic activity in mice, rats 
and hamsters did allow an evaluation of the equality,
[GRAPHIC] [TIFF OMITTED] TR10JA97.019

    where the subscripts sp1 and sp2 denote species 1 and 2 (e.g., 
mouse and rat). Using the apparent in vivo Vmax and in vitro [V/S] data 
reported in Reitz et al. [Exs. 7-225 and 21-53], it was possible to 
compute mouse:rat, hamster:mouse and rat:hamster ratios for in vivo 
Vmax and in vitro [V/S] as shown in table VI-11, below.

          Table VI-11.--Interspecies Comparison of MFO Activity         
------------------------------------------------------------------------
                                              Ratios of MFO enzymatic   
                                                      activity          
                                          ------------------------------
              Species ratio                            in               
                                           in vivo   vitro      Fold-   
                                             Vmax    [V/S]    Difference
------------------------------------------------------------------*-----
Rat: mouse...............................     0.49     0.36       1.36  
Mouse: hamster...........................     1.20     0.79       1.53  
Hamster: rat.............................     0.59     0.28       2.06  
------------------------------------------------------------------------
* Ratio of values in in vivo Vmax column to values in in vitro [V/S]    
  column.                                                               

    The assumption was made that the use of an in vitro ratio as a 
surrogate for an in vivo ratio is unbiased (i.e., errvivo/vitro 
should be centered on a value of 1). The mean of the three estimates of 
fold-difference (1.65) is our best estimate of a GSD for errvivo/
vitro. Thus, the prior probability distribution for errvivo/vitro 
was modeled as a lognormal variate with expected value 1.0 and GSD of 
1.65.
    (x) Monte Carlo simulation to obtain a prior probability 
distribution for A2. The above prior probability distributions for [V/
S]GST-lung, [V/S]GST-liver and errvivo/vitro were independently 
sampled by Monte Carlo techniques (n = 5000) and combined to give a 
prior probability distribution for A2 for use in Bayesian analysis with 
the human open chamber data. The resulting distribution was well 
described as a lognormal variate with a GM of 0.236 and a GSD of 2.0.
    (3) Human in vivo data and simulating occupational exposure. 
Bayesian updating was performed with the same human in vivo data used 
in the main analysis. These data consisted of time serial measurements 
of exhaled breath and venous blood concentrations of MC for 6 human 
volunteers exposed to 100 and 350 ppm MC for 6 hours. Unfortunately, 
the data have only been reported as averages of the 6 subject-specific 
observations at each time point. When simulating the human data, 
subjects were assumed to be at rest (i.e., work load set equal to 0), 
and the reported average body weight for the six subjects (86 kg) was 
assumed to be known without error.
    A single human occupational exposure was simulated: constant 
exposure to 25 ppm MC for 8-hours per day and 5 days per week.
    (4) Distribution of human metabolized dose and sensitivity 
analysis. The distribution for GST metabolism in the human lung 
resulting from simulated occupational exposure to 25 ppm MC had a 
median and mean of 0.139 and 0.192 mg/day/liter lung, about 3-fold less 
than values obtained using the allometrically scaled Kf.
    From the sensitivity analysis, Kf and A2' exhibited the strongest 
pairwise correlations with predicted lung GST metabolism, with all 
other parameters having considerably smaller correlation coefficients. 
Indeed, other than PC.mar (partition coefficient air:marrow), all other 
parameters were only weakly correlated with GST lung metabolism. These 
results differ somewhat from those obtained when using an 
allometrically scaled Kf, and reflect the effect of greater variability 
in a Kf based on the parallelogram method.
    (5) Posterior distributions in the ``parallelogram method'' 
analysis. The posterior distributions for many model parameters were 
considerably tighter than their corresponding prior distributions, most 
notably for fractional blood flow and partition coefficient parameters. 
Similar results were obtained in the main analysis. In general, medians 
and %CVs of the posterior distributions were similar to those in the 
main analysis, with the exception of Kf, which was expected, given its 
revised prior distribution. However, differences among the posterior 
distributions for Kf were less than expected due to an appreciable 
shift toward larger values (and some tightening) in the posterior 
distribution for the parallelogram-based Kf relative to its prior 
distribution. Thus, it would appear that the data had some information 
about plausible values of Kf.
    The results of the covariance analysis indicated that the 
covariance structure was fairly similar to the results from the main 
analysis, with moderate to high pairwise correlations among 15 pairs of 
parameters.

G. Results of OSHA's PBPK Risk Assessments; Discussion

    Summary statistics for OSHA's main analysis modifying the other 
analysis and the alternative (parallelogram) analysis are reported in 
Table VI-12. From the main analysis, the MLE of excess cancer risk 
obtained using the upper 95th percentile of the human internal dose 
distribution was 3.62/1000, for an occupational lifetime exposure to 25 
ppm MC. The MLE of cancer risk obtained using the mean of the human 
internal dose distribution was 1.24/1000. The alternative 
(parallelogram) analysis yielded slightly lower estimates of risk. In 
that analysis, the MLE of cancer risk using the upper 95th percentile 
of the human internal dose distribution was 1.23/1000. The MLE of 
cancer risk for the alternative analysis using the mean of the human 
internal dose distribution was 0.40/1000. After evaluating the 
methodologies and uncertainties in the two analyses, OSHA determined 
that the main analysis was most appropriate for the Agency's final risk 
assessment and the MLE of cancer risk using the upper 95th percentile 
of the human internal dose distribution was best supported as OSHA's 
final MC risk estimate. Therefore, OSHA's final risk estimate for 
occupational lifetime exposure to MC at 25 ppm is 3.62/1000.

    Table VI-12.--Summary Statistics on Estimates of Extra Cancer Risk From Occupational Exposure to 25 ppm MC for 8 hrs/day, 5 days/wk for 45 years    
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                     Summary statistics for distributions of extra risk                                 
      Computational approach      ----------------------------------------------------------------------------------------------------------------------
                                                   95% **                                   Mean                      %CV *       Skewness     Kurtosis 
--------------------------------------------------------------------------------------------------------------------------------------------------------
Maximum likelihood fitting:        3.62 *** per 1000.....................  1.24 per 1000.........................          103          2.2         10.2
 Dependence case.                                                                                                                                       

[[Page 1556]]

                                                                                                                                                        
Maximum likelihood fitting:        2.43 per 1000.........................  0.79 per 1000.........................          113          2.3        11.3 
 Independence case..                                                                                                                                    
--------------------------------------------------------------------------------------------------------------------------------------------------------
* %CV denotes coefficient of variation ([standard deviation/mean] x 100).                                                                               
** 95% denotes the 95th percentile value of the distribution of GST matabolites for extra cancer risk.                                                  
*** OSHA's final risk estimate.                                                                                                                         

    Figure VI-1 shows the end result of the main PBPK analysis: the 
cumulative distribution function of excess lifetime cancer risk 
(log10 scale) from exposure to 25 ppm MC, 8 hours per day, 5 days 
per week for 45 years, when estimated using the MLE of the dose-
response parameters, GST lung metabolism as the dose surrogate, and a 
human Kf based on allometric scaling and Bayesian prior information. As 
described in the main analysis, the ``dependence case'' was used. 
Several summary statistics can be discerned from this cumulative 
distribution function: (1) the 95th percentile of this hybrid 
distribution of uncertainty and heterogeneity gives a risk estimate of 
3.62 x 10-3 (point ``A'' in the figure); (2) the mean value of the 
distribution (point ``B'' in the figure) gives a risk estimate of 1.24 
x 10-3.

BILLING CODE 4510-26-P

[[Page 1557]]

[GRAPHIC] [TIFF OMITTED] TR10JA97.020



BILLING CODE 4510-26-C

[[Page 1558]]

    OSHA conducted the alternative analysis in order to determine the 
impact of basing the human GST metabolite distribution on allometry 
(human GST metabolic rates estimated based on the relative size of 
animals and humans) versus the parallelogram approach (human GST 
metabolic rates based on ratio of various rodent in vitro: in vivo 
metabolic rates applied to human in vitro rates) on risk estimates. As 
discussed in greater detail above, allometry predicts that one would 
expect that humans have approximately seven-fold less GST activity than 
mice. The parallelogram approach, on the other hand, predicts 
approximately 18-fold less GST activity in humans than in mice. After 
analyzing the available data, OSHA has determined that the allometric 
assumptions are best supported by the scientific literature, primarily 
because of the lack of human in vivo GST data and the lack of 
validation of the parallelogram approach. The Agency has therefore used 
that approach in its final (main) estimate of risk, but has also 
presented an alternative analysis using the parallelogram methodology.
    During the rulemaking, studies were submitted to the Agency by HSIA 
challenging the relevance of the mouse data for estimating human cancer 
risks. However, as described in detail previously, if one examines the 
HSIA data critically, it is clear that the studies most likely could 
not detect differences in metabolic activity (and hence in risk) 
between mice and humans of the magnitude predicted by allometry. For 
example, the lack of detection of an increase in DNA ss breaks in human 
cells compared to mouse cells could be explained because the 
methodology used could not detect an increase in ss breaks 7-fold 
smaller than that observed in mice. Clearly, an 18-fold difference, as 
predicted by the parallelogram method, would be even harder to detect.
    Moreover, if the human in vitro data are examined more closely, it 
becomes apparent that the in vitro: in vivo ratios calculated for the 
35 individual humans who have been studied were as low as 4.6 (the 
median value in this series was 24). Therefore, the use of allometry 
(ratio = 7) or the parallelogram approach (ratio = 18) would lead to 
risk estimates that clearly underestimate the risks for some 
individuals. In addition, RNA adduct data [Ex. 126-25] indicate that 
exposure of human cells to MC results in only a 3-fold lower amount of 
RNA adducts than formed in mouse cells. This ratio may not be a close 
surrogate for the GST ratio, but it does heighten concern that both 
PBPK approaches may be underestimating cancer risks from occupational 
exposure to MC, because humans may be appreciably less sensitive than 
mice.
    The distribution of risk presented in either the main or the 
alternative analysis most closely reflects uncertainty about risk for 
some randomly chosen worker (with respect to work intensity and body 
weight), chosen among the population of workers with physiologic, 
anatomic, and metabolic attributes similar to those of the average 
subject from the Dow human study group. The Dow pharmacokinetic data 
did not contain individual data on the 6 subjects, so the results 
obtained and the predictions made are conditioned by the use of 
averages. This means that the model is truly only applicable to people 
who physiologically and biochemically resemble the Dow group of six 
subjects. Although six subjects do not represent a large data base from 
which to draw a representative PBPK sample, this is much more human 
data than is usually available to base a risk assessment on. In fact, 
in OSHA's preliminary quantitative risk assessment, point estimates 
were used for body weight, breathing rates, etc. to represent the 
entire working population with a single ``average'' number. Therefore, 
this sample, although small, represents a significant improvement over 
the point estimates of human parameter values for PBPK modeling. 
Although these are the best data available, the small number of 
individuals upon which the human parameter values are based increases 
concern that the Agency may be underestimating risks for a significant 
portion of the working population by relying upon these values and 
using PBPK modeling to estimate human internal doses. OSHA considered 
making an ad hoc inflation of the variance of the distributions of 
human GST enzyme kinetics parameters in order to account for some of 
this unmeasured heterogeneity (as recommended by the NAS Committee 
report discussed above), but decided not to make this ``conservative'' 
choice but instead to rely on the unadjusted analyses.
    OSHA has chosen for its final risk estimate to couple one measure 
of central tendency (the MLE of the dose-response parameters) with a 
somewhat ``conservative'' measure (the 95th percentile of the 
distribution of human GST metabolites (internal dose)). Congress and 
the courts have permitted--indeed, encouraged--OSHA to consider 
``conservative'' responses to both uncertainty and human variability. 
The OSH Act addresses the latter when it refers, for example, to OSHA's 
responsibility to set standards such that ``no employee shall suffer 
material impairment of health* * *;'' a standard that only considered 
risk to the average employee clearly would not be responsive to the 
statute. Similarly, the 1980 ``Benzene decision'' affirmed that ``the 
Agency is free to use conservative assumptions in interpreting the data 
with respect to carcinogens, risking error on the side of over-
protection rather than under-protection.''
    In past rulemakings, OSHA has frequently estimated carcinogenic 
potency via the MLE of the multistage model parameters. The Agency has 
recently received comments, particularly in a public meeting in 
February 1996 on risk assessment issues surrounding the first phase of 
its ``PEL Update'' process, critical of the MLE on the grounds that 
this estimator can be highly unstable with respect to small 
fluctuations in the observed bioassay response rates. Although OSHA may 
in the future move to a different estimator, such as the mean value of 
the likelihood function of the multistage model parameters, such a 
change would have neglible practical impact in the case of MC. The 
observed data in the NTP mouse bioassay follow a nearly precisely 
linear trend, so the MLE, mean and UCL estimates are all very nearly 
equivalent to each other.
    However, OSHA needs to take particular care not to underestimate 
risk when it departs from a relatively simple methodology (in this 
case, the assumption that administered dose is the most relevant 
measure of exposure) in favor of a relatively more complex and 
computationally- intensive methodology (in this case, that the human 
lung GST metabolite, calculated via a PBPK model, is the most relevant 
measure of exposure). This is even more important in this particular 
PBPK analysis, because the variance of the output distributions 
represents an unknown hybrid of uncertainty in the various parameters 
and true heterogeneity among the humans exposed to MC. As Clewell 
stated with respect to his own PBPK analysis (see discussion above), 
the 95th percentile estimator provides a modicum of assurance that the 
risk to the average human--and hence the population risk--is not 
underestimated.
    Moreover, it is critical to use an estimator other than the central 
tendency here so that it will not be inevitable that the risk to a 
human of above-average susceptibility (due to enzyme kinetics that 
produce relatively more reactive metabolite per unit of administered 
dose, or due to other attributes related to body weight, organ

[[Page 1559]]

volumes, partition coefficients, etc.) is not underestimated, 
potentially by a substantial amount. Any ``conservatism'' introduced by 
using the 95th percentile of the PBPK output distribution is further 
attenuated by the unmeasured model uncertainty inherent in this more 
complex model structure. Several aspects of the model itself are known 
to be oversimplifications (e.g., assuming the lung is the only tissue 
at risk); therefore, the resulting risk distributions could be biased 
downward.
    Finally, it is important to note that there is no risk of 
``cascading conservatism'' with this 95th percentile estimator; the 
individual model parameters are permitted to vary over their entire 
ranges, and the selected percentile is only applied to the distribution 
resulting from the combined influence of all parameters. Furthermore, 
the newest refinements to the model ensure that the 95th percentile is 
not affected by any probability assigned to impossible combinations of 
parameters. The attention paid to issues of mass balance, covariance 
structure and truncation ensures that this percentile represents a 
fully plausible set of input parameters. In sum, the combination of the 
MLE of the multistage parameters and the 95th percentile of the PBPK 
output distribution represents a reasonable attempt to account for 
uncertainty and variability without unduly exacerbating the magnitude 
or the probability of underestimation of errors.

H. Comparison of Animal-Based Risk Estimates With ``Non-Positive'' 
Epidemiology Data

    Direct comparisons between animal bioassays and human 
epidemiological studies are difficult to make because experimental 
protocols between animal and human studies differ substantially. 
Animals are generally exposed to a fixed dose of a chemical, for 
several hours per day, from approximately 6-8 weeks of age until study 
termination, which is usually at 2 years. This would be chronologically 
equivalent to a human exposure that starts when a human is 
approximately 4-5 years old and continuing until the human is 
approximately 74 years old (assuming a 74 year average life-span for 
humans) [Ex. 89]. This clearly differs from the typical pattern of 
occupational exposure encountered in epidemiological studies of worker 
populations. For example, in the Kodak cohort, the workers were never 
exposed to a constant level of MC; exposure to MC for these workers did 
not start until their adult life; and most of them were exposed to the 
chemical for less than one third of their life-span.
    Exposure to MC has been found to induce lung and liver cancer in 
mice and mammary tumors in rats. As discussed above, there are positive 
epidemiology studies which suggest an association between MC exposure 
and cancer risk. Because exposure data are inadequate or unavailable, 
it is not possible to quantify the risks in these studies. OSHA 
acknowledges that there are also non-positive epidemiology studies.
    In 1986, Crump analyzed the preliminary results from the 1964-70 
Kodak cohort followed through 1984 and compared them to the rodent 
bioassay results. The results from the Kodak epidemiological study have 
also been used by Tollefson et al. [Ex. 7-249], Hearne [Ex. 91-D], and 
NIOSH to compare the predictions of excess cancer risk from the animal 
risk assessment models. In addition, Hearne used data from the 
cellulose triacetate fiber study in Cumberland, Maryland, and a 
different analytical approach, to validate the excess cancer risk 
predicted by the animal data [Ex. 91-D]. The details of these analyses 
can be found in the cited exhibits. OSHA has analyzed the different 
approaches to assessing the mouse bioassay in light of the epidemiology 
data and has determined that the approach taken by NIOSH (summarized 
below) represents the most comprehensive and clearest way to examine 
those data. OSHA also agrees with the conclusions reached by NIOSH, 
that the epidemiology results and the mouse bioassay data are not 
inconsistent with each other.
    NIOSH compared the confidence intervals for the standardized 
mortality ratios (SMRs) from the Kodak study with the predicted 
confidence intervals derived from OSHA's risk assessment models from 
the NPRM [Ex. 89]. To estimate predicted SMRs using the multistage 
model, NIOSH used the following approach:

    1. The expected excess number of deaths in each of the exposure 
groups was derived by multiplying the number of workers in each 
exposure group by the excess risk as determined by the multistage 
model (after correcting for dose equivalence between animals and 
humans, and differences in length of follow-up).
    2. This number of expected deaths, derived from the animal data, 
was then added to the expected (denoted Ep) number of deaths 
which were derived from the Kodak study, after correcting for the 
HWE, (this can be viewed as the background risk) to estimate the 
number of ``observed'' deaths that would have been predicted by the 
multistage model assuming it was valid for humans (denoted Op).
    3. Op was then divided by Ep to calculate predicted 
SMRs and 95% confidence intervals, where calculated.

    NIOSH's results indicated that the non-positive findings from the 
Kodak study were not inconsistent with the predicted risk estimates in 
OSHA's risk assessment. The predicted confidence intervals from the 
animal multistage model were completely nested within the observed 
confidence intervals from the Kodak study. This is not to suggest that 
results from this non-positive epidemiology study are equivalent to the 
positive results from the animal inhalation study. Rather, based on 
these findings, one can conclude that the non-positive results from the 
Kodak epidemiologic study were not of sufficient power to contradict 
risk predictions of the multistage model developed from the animal 
bioassay data (when appropriate adjustments for differences in study 
protocol were taken into account).
    Basically, the Kodak study examined approximately 1000 workers 
whose average MC exposure was 26 ppm. Therefore, the animal-based 
potency estimates would predict only about 3 excess cancer deaths in 
that cohort (the risk at 26 ppm is approximately 3 per 1000), even if 
they were followed for many decades after exposure ceased. This small 
predicted excess is clearly too small an increment to be observable 
with statistical confidence, considering the much larger background of 
cancer present in the human population. The differences between the 
NIOSH and Hearne analyses essentially represent different ways to 
estimate the ``signal-to-noise'' ratio for the Kodak study; OSHA 
believes that any reasonable method of estimating this ratio would 
conclude that the Kodak study has insufficient power to rule out a 
``signal'' of significant human risk.
    NIOSH's approach for adjusting for the healthy worker effect (HWE) 
was criticized in the comments to the record submitted by Hearne. 
Hearne stated that the HWE is unlikely to be present in long term 
cancer studies and therefore an adjustment for the HWE is not necessary 
[Ex. 91-D]. Hearne argued that since the HWE diminishes with time, the 
healthy worker effect would have been minimal in the 1946-70 Kodak 
cohort because the median follow-up period was 32 years and that only 
20% of the cohort members were still actively employed [Tr. 10/15/92].
    There is evidence in the literature showing that the HWE can be 
weaker for some types of cancer than for other causes of death; 
however, in this case NIOSH believed and OSHA agreed that the 
difference between control and

[[Page 1560]]

exposed populations reflected an HWE for cancer. In addition, results 
from a similar analysis done by NIOSH without the HWE adjustment did 
not contradict the results including the HWE adjustment. NIOSH 
testified [Tr. 985-6, 9/21/92] that there would be a difference in the 
results obtained when adjusting for HWE and the unadjusted results. 
However, the conclusions reached would not be different. In other 
words, the analysis still supported the conclusion that the 
epidemiologic and mouse bioassay results were not inconsistent with 
each other. OSHA supports NIOSH's position on the use of an adjustment 
factor for HWE in this cohort. Other criticisms of NIOSH's approach can 
be found in the hearing transcripts and post-hearing comments. OSHA has 
evaluated these methodological criticisms and has determined that NIOSH 
used the best available methodology in analyzing this issue and that 
their conclusions are supported by those arrived at independently by 
Crump and by Tollefson et al.
    Specifically, NIOSH predicted 23.25 deaths from cancers (at all 
sites) in the full cohort, after adjusting for the HWE. This value is 
closer to the observed number (22) than is the unadjusted expected 
number of deaths (29.61). Looking at lung cancer deaths separately, 
NIOSH predicted 22.36 deaths for the entire cohort (adjusted for HWE) 
compared with 22 observed and 28.67 expected by Hearne. Hearne observed 
no deaths from liver cancer in the entire cohort (1.14 deaths were 
expected). NIOSH predicted 0.88 deaths from liver cancer when they 
adjusted for the HWE.
    OSHA believes that NIOSH's approach in comparing results from an 
animal bioassay to those of an epidemiological study is the most 
reasonable comparison between data sets because it is more accurate and 
better addresses computational and experimental issues inherent in the 
data sets. The Agency has evaluated the extent to which the cancer risk 
calculated using the human data is consistent with the cancer risk 
calculated using animal data. Based on its review of those studies, 
OSHA concluded that the human epidemiology results are not inconsistent 
with the animal bioassays and has determined that the bioassays are the 
appropriate basis for its quantitative risk assessment.

I. Conclusions

    OSHA has determined that MC is a potential occupational carcinogen 
and has conducted a quantitative risk assessment in order to estimate 
human risks of cancer after occupational exposure to MC. The Agency 
reviewed all of the human and animal data on MC and determined that MC 
is carcinogenic in mice and in rats, causing tumors at multiple sites, 
in both species, and in both sexes of animals. Some epidemiologic data 
also indicate an association between MC exposure and excess cancer in 
exposed workers (statistically significant increases in biliary cancers 
in textile workers and astrocytic brain cancer in workers exposed to MC 
in solvent applications). Mechanistic data indicate that MC is likely 
to be metabolized to a genotoxic carcinogen. MC has been clearly shown 
to be metabolized by similar enzymatic pathways in rodents and humans, 
indicating that the metabolic processes which produce cancer in mice 
and rats are also present in humans. Finally, no data have been 
presented which demonstrate that the mouse is an inappropriate model 
for humans because of a physiological or biochemical component or 
process. Therefore, the Agency has determined that it is appropriate to 
assess the carcinogenic risks of MC using the NTP mouse bioassay dose-
response.
    The NTP mouse MC bioassays demonstrated a clear dose-tumor response 
relationship. OSHA determined that the NTP female mouse lung tumor 
response was the best data set on which to base a quantitative analysis 
because there was a clear dose-response, low background tumor incidence 
and it represented the most sensitive tumor site/sex combination.
    After examining the PBPK models submitted to the Agency, OSHA 
concluded that PBPK modeling estimates of the amount of GST metabolites 
produced are reasonable dose surrogates for MC and are supported by 
substantial scientific evidence in the record. For that reason, OSHA 
has used PBPK modeling in its final risk assessment. OSHA reviewed 
methodologies used in PBPK models submitted to the Agency and decided 
to modify and expand an existing model. Specifically, a Bayesian 
analysis was conducted as described above. Use of the Bayesian model 
analysis was a logical next step in development and use of 
pharmacokinetic models for MC. It has great advantages in accounting 
for the covariance of the PBPK parameters and incorporating 
distributions of physiological parameters obtained from the scientific 
literature. OSHA's final estimates of risk use the PBPK analysis 
described above and are based on the MLE of the dose-response 
parameters using the upper 95th percentile of the human internal dose 
distribution. For an occupational lifetime exposure to 25 ppm MC, OSHA 
estimates an excess risk of 3.6 MC-induced cancer deaths per 1000 
workers.

VII. Significance of Risk

A. Introduction.

    In the 1980 Benzene decision, the Supreme Court, in its discussion 
of the level of risk that Congress authorized OSHA to regulate, 
indicated its view of the boundaries of acceptable and unacceptable 
risk. The Court stated:

    It is the Agency's responsibility to determine in the first 
instance what it considers to be a ``significant'' risk. Some risks 
are plainly acceptable and others are plainly unacceptable. If for 
example, the odds are one in a billion that a person will die from 
cancer by taking a drink of chlorinated water, the risk clearly 
could not be considered significant. On the other hand, if the odds 
are one in a thousand that regular inhalation of gasoline vapors 
that are 2 percent benzene will be fatal, a reasonable person might 
well consider the risk significant and take the appropriate steps to 
decrease or eliminate it. (I.U.D. v. A.P.I., 448 U.S. 607, 655).

    So a risk of 1/1000 (10-3) is clearly significant. It 
represents the uppermost end of a million-fold range suggested by the 
Court, somewhere below which the boundary of acceptable versus 
unacceptable risk must fall.
    The Court further stated that ``while the Agency must support its 
findings that a certain level of risk exists with substantial evidence, 
we recognize that its determination that a particular level of risk is 
significant will be based largely on policy considerations.'' The Court 
added that the significant risk determination required by the OSH Act 
is ``not a mathematical straitjacket,'' and that ``OSHA is not required 
to support its findings with anything approaching scientific 
certainty.'' The Court ruled that ``a reviewing court [is] to give OSHA 
some leeway where its findings must be made on the frontiers of 
scientific knowledge [and that] . . . the Agency is free to use 
conservative assumptions in interpreting the data with respect to 
carcinogens, risking error on the side of overprotection rather than 
underprotection'' (448 U.S. at 655, 656).
    Nonetheless, OSHA has taken various steps that make it fairly 
confident its risk assessment methodology is not ``conservative'' (in 
the sense of erring on the side of overprotection). For example, there 
are several options for extrapolating human risks from animal data via 
interspecies scaling factors. The plausible factors range from body 
weight extrapolation (risks equivalent at equivalent body weights) to 
(body

[[Page 1561]]

weight)2/3 (risks equivalent at equivalent surface areas). 
Intermediate values have also been used, and the value of (body 
weight)3/4, which is supported by physiological theory and 
empirical evidence, is generally considered to be the midpoint of the 
plausible values. (Body weight)2/3 is the most conservative value 
in this series. Body weight extrapolation is the least conservative. 
OSHA has generally used body weight extrapolation in assessing risks 
from animal data, our approach which tends to be significantly less 
conservative than the other methodologies and most likely is less 
conservative even than the central tendency of the plausible values.
    Other examples in OSHA's risk assessment methodology where the 
Agency does not use a conservative approach are selection of the 
maximum likelihood estimator to parameterize the dose-response function 
rather than the upper 95% confidence limit, and the use of site-
specific tumor incidence rather than pooled tumor response in 
determining the dose-response function for a chemical agent.
    OSHA's overall analytic approach to regulating occupational 
exposure to particular substances is a four-step process consistent 
with recent court interpretations of the OSH Act, such as the Benzene 
decision, and rational, objective policy formulation. In the first 
step, OSHA quantifies the pertinent health risks, to the extent 
possible, performing quantitative risk assessments. The Agency 
considers a number of factors to determine whether the substance to be 
regulated poses a significant risk to workers. These factors include 
the type of risk posed, the quality of the underlying data, the 
plausibility and precision of the risk assessment, the statistical 
significance of the findings and the magnitude of risk [48 FR 1864, 
January 14, 1983]. In the second step, OSHA considers which, if any, of 
the regulatory options being considered will substantially reduce the 
identified risks. In the third step, OSHA looks at the best available 
data to set permissible exposure limits that, to the extent possible, 
both protect employees from significant risks and are also 
technologically and economically feasible. In the fourth and final 
step, OSHA considers the most cost-effective way to fulfill its 
statutory mandate by crafting regulations that allow employers to reach 
the feasible PEL as efficiently as possible.

B. Review of Data Quality and Statistical Significance

    The former OSHA standard for MC was designed to prevent irritation 
and injury to the neurological system of the employees exposed to MC. 
In 1985, the National Toxicology Program (NTP) released the results of 
their MC rodent lifetime bioassays. Those results indicated that MC is 
carcinogenic to rats and mice. As discussed in the Events Leading to 
the Final Standard section, based on the NTP findings, EPA now 
considers MC a probable human carcinogen, and NIOSH regards MC as a 
potential occupational carcinogen and recommends controlling the 
exposure to MC to the lowest feasible level. In 1988, ACGIH classified 
MC as an industrial substance suspected of carcinogenic potential for 
humans.
    As discussed in the Health Effects section, OSHA has determined, 
based on the NTP data, that MC is a potential occupational carcinogen. 
This conclusion is supported by high-quality data in both rodent 
species. Having determined, as discussed in the Quantitative Risk 
Assessment section, that the NTP study provided suitable data for 
quantitative analysis, OSHA performed quantitative risk assessments to 
determine if MC exposure at the current PEL presents a significant 
risk.
    As discussed in the Health Effects and Quantitative Risk Assessment 
sections, OSHA evaluated four MC rodent bioassays [Exs. 4-35, 4-25, 7-
29, 7-30, 7-31] to select the most appropriate bioassay as the basis 
for a quantitative risk assessment. These bioassays were conducted in 
three rodent species (rat, mouse, and hamster) using two routes of 
administration (oral and inhalation). The NTP study (rat and mouse, 
inhalation) was chosen for a quantitative risk assessment because it 
provides the clearest toxicological and statistical evidence of the 
carcinogenicity of MC [Exs. 12, 7-127] and because the studies were of 
the highest data quality. In the NTP study, MC induced significant 
increases both in the incidence and multiplicity of alveolar/
bronchiolar and hepatocellular neoplasms in male and female mice. In 
rats, dose-related, statistically significant increases in mammary 
tumors were also observed. OSHA chose the female mouse tumor response 
as the basis of its quantitative risk assessment, because of the high 
quality of data, the clear dose response of liver and lung tumors and 
the low background tumor incidence. OSHA chose female mouse lung tumors 
as the specific tumor site for its final quantitative risk assessment. 
There is no a priori reason to prefer the mouse lung tumor response 
over the liver tumor response because both data sets were of high 
quality, showed a clear dose-response relationship and had low 
background tumor incidence. In fact, in the NPRM, the Agency reported 
estimates of risk generated using both sites. However, to reduce the 
complexity of the final PBPK analysis, which required highly intensive 
computations, OSHA chose one site (the female mouse lung tumor 
response) for its final risk estimates. The risks calculated using the 
female mouse liver response would likely be only slightly lower than 
those calculated using the lung tumor response. On the other hand, 
pooling the total number of tumor-bearing animals having either a lung 
or liver tumor (or both) would have yielded risk estimates higher than 
OSHA's final values.
    Once the alveolar/bronchiolar neoplasms in female mice were chosen 
as the most appropriate data set, the multistage model of 
carcinogenesis was used to predict a lifetime excess risk of cancer 
from occupational exposure to MC at several concentration levels. The 
multistage model is a mechanistic model based on the biological 
assumption that cancer is induced by carcinogens through a series of 
stages. The model may be conservative, in the sense that it risks error 
on the side of overprotection rather than underprotection, because it 
assumes no threshold for carcinogenesis and because it is approximately 
linear at low doses, although there are other plausible models of 
carcinogenesis which are more conservative. The Agency believes that 
this model conforms most closely to what we know of the etiology of 
cancer. There is no evidence that the multistage model is biologically 
incorrect, especially for genotoxic carcinogens, which MC most likely 
is. OSHA's preference is consistent with the position of the Office of 
Science and Technology Policy which recommends that ``when data and 
information are limited, and when much uncertainty exists regarding the 
mechanisms of carcinogenic action, models or procedures that 
incorporate low-dose linearity are preferred when compatible with 
limited information'' [Ex. 7-227].
    In the NPRM, OSHA solicited comment and testimony on the 
application of physiologically-based pharmacokinetic (PBPK) modeling to 
refine the MC risk assessment. There was an intensive discussion of 
pharmacokinetic issues during the hearings and in comments and briefs 
submitted to OSHA. PBPK modeling is used to account for metabolic and 
pharmacokinetic differences between rodents and humans and when 
extrapolating from high experimental doses to lower occupational 
exposures. OSHA has evaluated several risk assessments produced using

[[Page 1562]]

pharmacokinetic models. Discussion of the major issues surrounding the 
use of PBPK in risk assessment can be found in the Quantitative Risk 
Assessment section. Although serious questions remain concerning the 
application of these models in the MC risk assessment, the Agency has 
used the estimates generated via PBPK modeling as its final estimate of 
the carcinogenic risk of MC exposure.
    In accepting PBPK analysis, the Agency wanted to be able to utilize 
all of the data available and appropriate for the analysis. OSHA was 
also concerned that the uncertainties and inter-individual 
variabilities in PBPK models were insufficiently quantified to allow 
analysis of the impact of those uncertainties on the risk. Several 
rulemaking participants have conducted sensitivity and uncertainty 
analyses, the most extensive of which was that submitted by Mr. Harvey 
Clewell on behalf of the U.S. Navy. These analyses show the impact of 
the variability and uncertainty of the parameters which are used in the 
PBPK model and suggest methods of quantifying the impact of that 
uncertainty on the risk estimates.
    OSHA has determined that the PBPK data are of sufficient weight to 
warrant reliance on PBPK modeling to develop a risk estimate in the 
specific case of MC, a chemical with more extensive information on 
metabolism than exists for most other substances. To that end, OSHA 
adopted a Bayesian approach in which all of the physiological and MC-
specific data could be used to generate a distribution of estimates of 
the carcinogenic risks of MC. OSHA used the mean and the upper 95th 
percentile estimator of the distribution of human PBPK parameters, 
coupled with the maximum likelihood estimator of cancer potency, to 
generate its final estimates of risks.
    As discussed in more detail in the Health Effects Section above, 
human data concerning the carcinogenicity of MC were presented in 
several epidemiology studies. In a study of cellulose triacetate fiber 
production (MC used as solvent) workers, an increased incidence of 
liver/biliary cancer [Ex. 7-260] was noted. Although the case numbers 
were small and the exposure information limited, this epidemiological 
evidence is consistent with findings from animal studies and indicates 
that there may be an association between human cancer risk and MC 
exposure. A study of workers in photographic film production was non-
positive [7-163]. However, the exposures experienced by these workers 
were likely to have been much less than those in the cellulose 
triacetate fiber plant and, as discussed in the quantitative risk 
assessment section, the study lacked the power to detect the magnitude 
of the increase in cancer deaths that would have been predicted given 
only the bioassay results. A case-control study conducted by the 
National Cancer Institute showed a statistically significant 
association between occupational MC exposure and development of 
astrocytic brain cancer. Exposure levels could not be determined in 
this study. The results of the epidemiological studies summarized here 
were not inconsistent with the results of the animal-based cancer 
potency estimate.

C. Material Impairment of Health

    MC is a potential occupational carcinogen. Cancer is a material 
impairment of health. OSHA has set the 8-hour TWA PEL primarily to 
reduce the risk to employees of developing cancer.
    The STEL of 125 ppm averaged over 15 minutes is primarily designed 
to protect against MC's non-cancer risks. As discussed in the Health 
Effects section, there are substantial risks of CNS effects and cardiac 
toxicity resulting from acute exposure to MC and its metabolites. CNS 
effects have been demonstrated in workers at concentrations as low as 
175 ppm [Ex. 7-153] and a STEL of 125 ppm for 15 minutes would thus be 
protective against the CNS effects described. Metabolism of MC to CO 
increases the body burden of COHb in exposed workers. Levels of COHb 
above 3% COHb may exacerbate angina symptoms and reduce exercise 
tolerance in workers with silent or symptomatic heart disease. Smokers 
are at higher risk for these effects because of the already increased 
COHb associated with smoking (COHb ranges from 2 to 10% in most 
smokers). Limiting short term exposure to 125 ppm for 15 minutes will 
keep COHb levels due to MC exposure below the 3% level, protecting the 
sub-population of workers with silent or symptomatic heart disease and 
also limiting the additional COHb burden in smokers.
    In addition to protecting against CNS and cardiac effects, there is 
evidence that reducing the GST metabolite production by reducing short 
term exposure to high concentrations of MC may also lower the cancer 
risk. This is because metabolism by the MFO pathway (not generally 
believed to be associated with carcinogenesis) appears to saturate 
beginning around 100 ppm. This means that exposure to higher 
concentrations of MC would lead to increased metabolism by the GST 
pathway (the putative carcinogenic pathway) and therefore, greater than 
proportionally increased risk.
    All of the health effects averted by reducing MC exposure are 
potentially or likely to be fatal, and this clearly represents 
``material impairment of health'' as defined by the OSH Act and case 
law.

D. Risk Estimates

    OSHA's final estimate of excess cancer risks at the current PEL of 
500 ppm (8-hour TWA) is 126 per 1000. The risk at the new PEL of 25 ppm 
is 3.62 per 1000. The risk at 25 ppm is similar to the risk estimated 
in OSHA's preliminary quantitative risk assessment based on applied 
dose of MC on a mg/kg/day basis (2.3 per 1000 workers) and clearly 
supports a PEL of 25 ppm. Risks greater than or equal to 10-\3\ are 
clearly significant and the Agency deems them unacceptably high. 
However, OSHA did not collect the data necessary to document the 
feasibility of a PEL below 25 ppm across all affected industry sectors, 
and so the Agency has set the PEL at 25 ppm in the final rule. OSHA 
intends in the future to gather more information pertaining to the 
feasibility of lower PELs.

E. ``Significant Risk'' Policy Issues

    Further guidance for the Agency in evaluating significant risk and 
narrowing the million-fold range provided in the ``Benzene decision'' 
is provided by an examination of occupational risk rates, legislative 
intent, and the academic literature on ``acceptable risk'' issues. For 
example, in the high risk occupations of mining and quarrying, the 
average risk of death from an occupational injury or an acute 
occupationally-related illness over a lifetime of employment (45 years) 
is 15.1 per 1,000 workers. The typical occupational risk of deaths for 
all manufacturing industries is 1.98 per 1,000. Typical lifetime 
occupational risk of death in an occupation of relatively low risk, 
like retail trade, is 0.82 per 1,000. (These rates are averages derived 
from 1984-1986 Bureau of Labor Statistics data for employers with 11 or 
more employees, adjusted to 45 years of employment, for 50 weeks per 
year).
    Congress passed the Occupational Safety and Health Act of 1970 
because of a determination that occupational safety and health risks 
were too high. Congress therefore gave OSHA authority to reduce 
significant risks when it is feasible to do so. Within this context, 
OSHA's final estimate of risk from occupational exposure to MC at the 
current 8-hour TWA PEL (126 per 1000) is substantially higher than 
other risks

[[Page 1563]]

that OSHA has concluded are significant, is substantially higher than 
the risk of fatality in some high-risk occupations, and is 
substantially higher than the example presented by the Supreme Court. 
Moreover, a risk of 3.62 per 1000 at 25 ppm is also clearly 
significant; therefore, the PEL must be set at least as low as the 
level of 25 ppm documented as feasible across all industries.
    Further, applying the rationale of the Benzene decision, the other 
risk assessments presented by OSHA and the risk estimates presented by 
rulemaking participants, including the HSIA (see Table VII-1, below), 
all support OSHA's conclusion that the human cancer risk for employees 
exposed to MC above 25 ppm as an 8-hour TWA is significant.

  Table VII-1.--Lifetime Excess Risk Estimates (per 1000) From Occupational Exposure Based on Female Mouse Lung 
                                                   Tumor Data                                                   
----------------------------------------------------------------------------------------------------------------
                                                                     MLE (UCL)**                                
               Model               -----------------------------------------------------------------------------
                                              25 ppm                      50 ppm                  500 ppm       
----------------------------------------------------------------------------------------------------------------
OSHA NPRM Risk Assessment (mg/kg/   2.32 (2.97)...............  4.64 (5.92)..............  45.5 (57.7)          
 d, BW extrapolation) without PBPK                                                                              
 Adjustment.                                                                                                    
PPM to PPM extrapolation without    11.3 (14.4)...............  22.4 (28.5)..............  203 (251)            
 PBPK Adjustment.                                                                                               
PBPK Reitz female mouse lung--      0.43 (0.53)...............  0.93 (1.17)..............  14.3 (17.9)          
 Reitz human (HSIA assumptions).                                                                                
PBPK Reitz female mouse lung--      0.81 (1.02)...............  1.69 (2.12)..............  15.0 (18.7)          
 Dankovic average human (NIOSH                                                                                  
 assumptions).                                                                                                  
PBPK Clewell female mouse lung--    0.91 (1.14)...............  1.88 (2.36)..............  27.5 (34.2)          
 Clewell human (Navy assumptions)*.                                                                             
OSHA Final Risk Assessment (female  3.62......................  7.47.....................  125.8                
 mouse lung with PBPK).                                                                                         
----------------------------------------------------------------------------------------------------------------
*Upper 95th percentile of the GST metabolites distribution was used as input in the multistage model.           
**Maximum likelihood estimates are 95th percentile upper confidence limit (in parentheses) of the multistage    
  dose-response function.                                                                                       

    In addition to being 100 to 1000 times higher than the risk levels 
generally regarded by other Federal Agencies as on the boundary between 
significant and insignificant risk (see, e.g., Travis et al., 1987), 
and 1000 times higher than the ``acceptable risk'' level Congress set 
in the 1990 Clean Air Act Amendments, the level of 10-3 is within 
the range where economic studies document a marked nonlinearity. In 
other words, individuals regard risks this high as qualitatively 
different from ``smaller'' risks. Although risks below 10-3 are 
not unambiguously significant, depending on the size of the affected 
population, the benefits associated with the risky activity, and other 
factors, this policy determination is not relevant to this regulation, 
since OSHA's final risk estimate is substantially greater than 1 per 
1000. Risks at or above 10-3 are always significant by any 
empirical, legal or economic argument available.2
---------------------------------------------------------------------------

    \2\ OSHA also conducted an alternative PBPK analysis that uses 
all of the available human data on MC metabolism, despite the very 
limited quantity of data available and the additional bias 
introduced by adopting the ``parallelogram'' assumptions for 
interspecies scaling (see Quantitative Risk Assessment for a 
discussion of this analysis and the uncertainties and biases 
therein). The risk estimate using this alternative method, 1.2 per 
1000, is also unambiguously significant.
---------------------------------------------------------------------------

    Because of the lack of documented feasibility data for potential 
PELs of less than 25 ppm, OSHA has concluded that there is not enough 
information available to support lowering the 8-hour TWA PEL or STEL 
further at this time. However, OSHA has integrated other protective 
provisions into the final standard to further reduce the risk of 
developing cancer among employees exposed to MC. Employees exposed to 
MC at the 8-hour TWA PEL limit without the supplementary provisions 
would remain at risk of developing adverse health effects, so that 
inclusion of other protective provisions, such as medical surveillance 
and employee training, is both necessary and appropriate. The action 
level will encourage those employers for whom it is feasible to do so 
to lower exposures below 12.5 ppm to further reduce significant risk. 
Consequently, the programs triggered by the action level will further 
decrease the incidence of disease beyond the predicted reductions 
attributable merely to a lower PEL. As a result, OSHA concludes that 
its 8-hour TWA PEL of 25 ppm and associated action level (12.5 ppm) and 
STEL (125 ppm) will reduce significant risk and that employers who 
comply with the provisions of the standard will be taking reasonable 
steps to protect their employees from the hazards of MC.
    The Agency notes that even at the final PELs, the risks to workers 
remain clearly significant. OSHA will be gathering information on the 
risks of, and feasibility of compliance with, PELs less than 25 ppm, to 
determine whether future rulemaking is appropriate in order to further 
reduce the MC risks to employees.

VIII. Summary of the Final Economic Analysis

    In its Final Economic and Regulatory Flexibility Analysis document, 
OSHA addresses the significant issues related to technological and 
economic feasibility and small business impacts raised in the 
rulemaking process. The Final Economic Analysis is also OSHA's most 
comprehensive explanation of the standard's practical impact on the 
regulated community; in the Final Economic Analysis, OSHA explains in 
detail the Agency's findings and conclusions concerning pre-standard 
(baseline) conditions, such as exposure levels, in establishments in 
the regulated community, and discusses how and why the requirements of 
the standard are expected to eliminate significant risk to the extent 
feasible. This document also sets forth OSHA's Final Regulatory 
Flexibility Analysis and the analyses required by Executive Order 
12866. This Federal Register preamble and the Final Economic Analysis 
are integrally related and together present the fullest statement of 
OSHA's reasoning concerning this standard. The Final Economic and 
Regulatory Flexibility Analysis, together with supporting appendix 
material, has been placed in the rulemaking docket for methylene 
chloride (Ex. 129).
    The purpose of the Final Economic Analysis is to:
     Describe the need for a standard governing occupational 
exposure to methylene chloride;
     Identify the establishments and industries potentially 
affected by the standard;
     Evaluate the costs, benefits, economic impacts and small 
business impacts of the standard on affected firms;
     Assess the technological and economic feasibility of the 
standard for affected establishments, industries, and small businesses;
     Evaluate the availability of effective non-regulatory 
approaches to the problem of occupational exposure to methylene 
chloride; and
     Present changes designed to reduce the impact of the 
standard on small

[[Page 1564]]

firms while meeting the objectives of the OSH Act.

Need for the Standard

    OSHA's final methylene chloride (MC) standard covers occupational 
exposures to this substance, one of the most widely used of all organic 
solvents, in general industry, construction, and shipyard employment. 
In all, about 237,000 employees are estimated to be exposed to MC. 
These workers are exposed to MC in many different ways, including the 
manufacturing, formulation, distribution, and use of MC-containing 
products. The most common uses of MC are in paint stripping, metal 
cleaning, and furniture stripping.
    Workers exposed to MC are at significant risk of developing cancer, 
heart and liver effects, and central nervous system impairments, as 
well as eye, skin, and mucous membrane irritation. Animal bioassays 
have shown MC to be carcinogenic in mice and rats of both sexes, and 
epidemiologic studies in workers have produced suggestive evidence of 
its carcinogenicity in humans. Acute overexposure to the vapors of MC 
can lead to central nervous system depression, respiratory paralysis, 
and death: OSHA receives fatality reports every year involving workers 
who have died using MC to perform such tasks as stripping floors and 
removing paint. To protect all MC-exposed workers from these adverse 
health effects, the final standard lowers the airborne concentration of 
MC to which workers may be exposed from the current permissible 
exposure limit (PEL) of 500 ppm as an 8-hour time-weighted average (8-
hour TWA) to 25 ppm, and from the Agency's current short-term limit of 
1000 ppm as an acceptable ceiling, or 2000 ppm as an acceptable peak 
above the acceptable ceiling for 5 minutes in any 2-hour period, to a 
short-term exposure limit (STEL) of 125 ppm, averaged over 15 minutes. 
(For a detailed discussion of the risks posed to workers by exposure to 
MC, see the Quantitative Risk Assessment and Significance of Risk 
sections of the preamble, above.)
    OSHA's final MC standard is similar in format and content to other 
health standards issued under Section (6)(b)(5) of the Act. In addition 
to setting PELs, the standard requires employers to monitor the 
exposures of workers; establish regulated areas when exposures may 
reasonably be expected to exceed one of these PELs; implement 
engineering and work practice controls to reduce employee exposures to 
MC; provide respiratory protection to supplement engineering controls 
where these are not feasible, are insufficient to meet the PELs, or in 
emergencies; provide other protective clothing and equipment as 
necessary for employee protection; make industrial hygiene facilities 
(such as eyewash and emergency showers) available in certain 
circumstances; provide medical surveillance; train workers about the 
hazards of MC (as required by OSHA's Hazard Communication Standard); 
and keep records relating to the standard. The contents of the standard 
are explained briefly in Chapter I of the Final Economic Analysis and 
in detail in the Summary and Explanation (Section X of the preamble, 
below).
    Chapter II of the economic analysis describes the uses of methylene 
chloride and the industries in which such use occurs. Employee 
exposures to MC are analyzed on the basis of ``application groups,'' 
i.e., groups of firms that use MC to perform a particular function, 
such as metal cleaning or industrial paint stripping, regardless of the 
particular industry in which the use takes place. The methodology used 
by OSHA in the analysis is appropriate when a ubiquitous chemical like 
MC is used to perform the same function in many kinds of firms in many 
industries, because the processes used, employee exposures generated, 
and controls in place or needed to achieve compliance are the same, 
whether the process takes place in a machine shop, on board ship, or on 
a construction site. For example, because the process of using MC to 
strip paint or coatings from an object is essentially the same whether 
the object being stripped is a spray paint booth, boat, church pew, or 
automobile, and the exposures generated during the process are similar 
in important respects, it is appropriate to analyze such activities as 
a group. However, OSHA's technological feasibility and cost analyses 
reflect the fact that job classifications and work processes may differ 
within a given application group. Table VIII-1 shows the application 
groups analyzed in the economic analysis, and the numbers of MC-using 
establishments, MC-exposed workers, and estimated volume of MC handled 
annually by establishments in each application group.

                              Table VIII-1.--Methylene Chloride Application Groups                              
----------------------------------------------------------------------------------------------------------------
                                                          Estimated                      Estimated    Estimated 
                                                        number of MC-      Estimated     number of    MC handled
                  Application group                         using            total        exposed     (millions 
                                                        establishments   employment *    workers *     of lbs)  
--------------------------------------------------------------*-------------------------------------------------
Methylene Chloride Manufacturing.....................              4             1,664           84       469.20
Distribution/Formulation of Solvents.................            320            84,004        1,701       189.65
Metal Cleaning:                                                                                                 
    Cold Degreasing and Other Cold Cleaning:                  23,717           901,232       94,537        32.56
        Open-Top Vapor Degreasing....................            278            27,105          608        14.87
        Conveyorized Vapor Degreasing................             45             2,920           75         1.13
        Semiconductors...............................            239           217,960        1,392         0.40
        Printed Circuit Boards.......................            141            77,795          298        13.98
Aerosol Packaging....................................             52             4,142          520        25.21
Paint Remover Manufacturing..........................             80             6,134          200       136.85
Paint Manufacturing..................................             49             8,909          229         3.54
Paint Stripping:                                                                                                
    Aircraft Stripping...............................            300           266,826        2,470        13.17
    Furniture Stripping..............................          6,152            23,592        7,872        23.26
    Other Industrial Paint Stripping.................         35,041         2,312,721       46,605        59.36
Flexible Polyurethane Foam Manufacturing.............            100             9,800          600        50.32
Plastics and Adhesives Manufacturing and Use.........          3,487         1,186,040       10,481        41.90
    Adhesive Production..............................            165            56,254          497  ...........
    Adhesive Use.....................................          1,753           596,291        5,269  ...........
    Injection Molding................................             80            27,211          240  ...........

[[Page 1565]]

                                                                                                                
    Lamination.......................................          1,323           450,031        4,070  ...........
    Mold Release.....................................            165            56,254          497  ...........
Ink Use:                                                                                                        
    Ink and Ink Solvent Manufacturing................             15             2,010           58         3.68
    Ink Solvent Use in Printing......................         11,869           197,619       39,481         3.68
Pesticide Manufacturing and Formulation..............             60             1,440          120         9.58
Pharmaceutical Manufacturing.........................            108            70,223        1,431        39.53
Solvent Recovery.....................................             34               932          137        32.10
Film Base Manufacturing..............................              1            45,000          500         8.90
Polycarbonate Manufacturing..........................              4             1,898           67         6.70
Construction.........................................          9,504            63,115       24,896         2.44
Shipyards............................................             25            85,212        3,040         0.47
      Total, all application groups..................         91,624         5,598,293      237,496           **
----------------------------------------------------------------------------------------------------------------
* In most cases, the estimated number of establishments in each application group was based on the volume flow  
  of MC in 1990 divided by the estimated MC use per facility. The estimated number of establishments was        
  multiplied by the total number of employees per establishment and exposed employees per establishment as      
  reported in CONSAD's survey.                                                                                  
** Netting out rehandling, estimated total consumption equals 469.2 million pounds manufactured, minus 129.1    
  million pounds exported, + 19.3 million pounds imported, + 32.10 million pounds recovered from used solvent.  
  The column does not sum to 391.5 million pounds because non-consumptive uses such as production, distribution 
  and formulation, and solvent recovery are included.                                                           
 Sources: CONSAD, HSIA, PRMA, Office of Regulatory Analysis.                                                    

    In all, OSHA analyzed 28 application groups. These application 
groups include, among others, methylene chloride manufacturing, paint 
manufacturing, metal cleaning, polyurethane foam manufacturing, 
plastics and adhesives manufacturing, ink use, pharmaceuticals, and 
construction and shipyards. A total of 91,624 establishments are 
estimated to be potentially affected by the standard. These 
establishments employ a total of 5.6 million employees, of whom 237,496 
are estimated to be exposed to MC in the course of their work. The 
application groups with the largest numbers of directly exposed 
employees are the Metal Cleaning, All Other Industrial Paint Stripping, 
and Ink Solvent Use groups. In many facilities, MC is used only by a 
small number of employees; the average number of MC-exposed employees 
per establishment covered by the final rule is only 2.6 employees.
    Chapter III of the analysis assesses the technological feasibility 
of the final standard's requirements, and particularly its PELs, for 
firms in the 28 application groups identified in the Industry Profile. 
OSHA finds, based on an analysis of exposure data taken on workers 
performing the MC-related tasks identified for each application group, 
that compliance with the standard is technologically feasible for 
establishments in every application group studied. With few exceptions, 
employers will be able to achieve compliance with both PELs through the 
use of engineering controls and work practices. The few exceptions are 
certain maintenance activities, such as vessel cleaning, which have 
traditionally involved the use of respiratory protection, and 
operations in two applications where the supplemental use of 
respirators may be necessary. These operations are centrifuge unloading 
and dryer loading at one bulk pharmaceutical manufacturing facility 
operated by Abbott Laboratories, and operations involving access to and 
entering of the roll coating machine used by the Eastman Kodak Company 
to make film base.
    The exposure data relied on by OSHA in making its technological 
feasibility determinations have been compiled in a database that 
contains thousands of MC exposure results (see Appendix B of this 
analysis) taken by OSHA compliance officers, consultation program 
consultants, MC-using companies, and interested parties. These data 
show that many facilities in many of the affected application groups 
have already achieved the reductions in employee exposures required by 
the final rule. In addition, the exposures of many employees in many 
job categories in a number of the application groups have been reduced 
to levels that are close to those required by the standard. OSHA's 
analysis of technological feasibility analyzes employee exposures at 
the operation or task level to the extent that such data are available. 
In other words, the analysis identifies relevant exposure data on a 
job-category-by-job category basis to permit the Agency to pinpoint 
those MC-exposed workers and job operations that are not yet under good 
process control and will thus need additional controls (including 
improved housekeeping, maintenance procedures, and employee work 
practices) to achieve compliance. Costs are then developed (see Chapter 
V of the economic analysis) for the improved controls needed to reach 
the new levels.
    The benefits that will accrue to MC-exposed employees and their 
employers are substantial and take a number of forms. Chapter IV of the 
analysis describes these benefits, both in quantitative and qualitative 
form. First, based on a physiologically-based pharmacokinetic (PBPK) 
model, OSHA estimated that, if all 237,000 employees were exposed at 
the existing 8-hour TWA exposure limit of 500 ppm for an occupational 
lifetime of 45 years, a total of 29,862 excess cancer deaths would 
occur, or 126 excess cancer deaths per 1,000 workers. If, however, the 
237,000 employees were exposed to the final standard's PEL of 25 ppm 
for 45 years, 8533 excess cancer deaths would be expected (3.6 per 
thousand workers). However, few workers are currently being exposed to 
500 ppm of MC as an 8-hour TWA. The actual exposure levels of most 
affected workers are considerably lower, and, when these exposure 
levels, rather than 500 ppm, are used as the baseline, the PBPK model 
estimates that 1405 cancer deaths will be averted over a 45-year 
period. By reducing the total number of MC-related cancer deaths from 
1,804 deaths to 399 deaths over 45 years, the standard will

[[Page 1566]]

save an average of 31 cancer deaths per year. Table VIII-2 shows these 
risk estimates.

               Table VIII-2.--Lung Cancer Risk Over 45 Years for Workers Exposed At Current Exposure Levels and at the Levels Expected After Implementation of the Final Standard               
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                    0-12.5      12.5-25       25         25-50      50-100      100-200     200-350     350-500     500+***          Total      
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Lifetime Excess Cancer Risk (per thousand workers)*.............        0.91        2.71        3.60        5.53       11.98       28.45       61.75      104.44      125.78  ..................
Baseline Number of Workers Exposed..............................  141,323      26,464         162      22,839      23,903      14,803       3,281       1,297       3,422                237,495
Estimated Excess Deaths in Baseline (Existing PEL)**............      129          72           1         126         286         421         203         135         430                  1,804
Predicted Number of Workers Exposed at New PEL..................  159,825      28,441      49,229           0           0           0           0           0           0                237,495
Predicted Excess Deaths at New PEL**............................      146          77         176           0           0           0           0           0           0                    399
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
*Based on OSHA's final estimate using the PBPK model, as presented in the Quantitative Risk Assessment section of the Preamble.                                                                 
**Computed as level of lifetime risk times the number of exposed workers.                                                                                                                       
***For workers exposed to levels of greater than the current PEL of 500 ppm, the risk estimate is that associated with a lifetime exposure to 500 ppm.                                          
Source: Office of Regulatory Analysis; OSHA; Department of Labor.                                                                                                                               

    In addition to cancer deaths, the standard is estimated to prevent 
3 deaths per year from MC's acute central nervous system and 
carboxyhemoglobinemic effects. (Carboxy-hemoglobinemia is the inability 
of the blood to carry sufficient oxygen to supply the heart muscle; 
because methylene chloride interferes with the blood's ability to carry 
oxygen, exposure to it places susceptible individuals, such as those 
with silent cardiovascular disease, pregnant women, and smokers, at 
greater risk.) OSHA receives reports every year of workers who have 
succumbed to MC's acute CNS toxicity while they were engaged in such 
tasks as floor stripping. For example, the Agency recently received a 
fatality report on two young workers who died after pouring 14 gallons 
of MC on a squash court they were refinishing. Both of these employees 
lost consciousness, collapsed, and subsequently died of respiratory 
failure. In addition, MC exposures above the level at which the final 
rule's STEL is set--125 ppm--are also associated with acute central 
nervous system effects, such as dizziness, staggered gait, and 
diminished alertness, all effects that can lead to workplace accidents. 
OSHA estimates that as many as 30,000 to 54,000 workers will be 
protected by the final rule's STEL from experiencing CNS effects and 
episodes of carboxyhemoglobinemia every year. Moreover, exposure to the 
liquid or vapor forms of MC can lead to eye, skin, and mucous membrane 
irritation, and these material impairments will also be averted by 
compliance with the final rule. Finally, contact of the skin with MC 
can lead to percutaneous absorption and systemic toxicity and thus lead 
to additional cases of cancer that have not been taken into account in 
the benefits assessment presented in Chapter IV of the Final Economic 
Analysis.
    The costs employers in the affected application groups are 
estimated to incur to comply with the standard total $101 million in 
1994 dollars. These costs, which are presented in Chapter V of the full 
economic analysis, are annualized over a 10-year horizon at a discount 
rate of 7 percent. Table VIII-3 shows annualized costs by provision of 
the standard; the most costly

[[Page 1567]]

provisions are those requiring engineering controls, protective 
clothing and eye protection, and medical surveillance for MC-exposed 
workers. These three provisions together account for approximately 75 
percent of the standard's compliance costs.

              Table VIII-3.--Annualized Costs by Provision              
------------------------------------------------------------------------
                                                             Annualized 
                         Provision                              Costs   
------------------------------------------------------------------------
Engineering Controls......................................   $38,773,642
Respirators...............................................     6,374,083
Monitoring................................................     9,849,577
Protective Clothing and Eye Protection....................    29,578,340
Emergency Eyewash and Shower..............................     3,183,486
Medical Surveillance......................................     7,986,493
Leak and Spill Detection Program..........................     3,703,286
Regulated Areas...........................................       150,884
Recordkeeping.............................................       652,121
Training..................................................       196,656
Understanding Regulation and Developing Training..........       777,132
                                                           -------------
      Subtotal............................................   101,225,701
Costs of Substitution.....................................       237,336
                                                           -------------
      Total...............................................   101,463,037
------------------------------------------------------------------------
Source: Office of Regulatory Analysis; OSHA; Department of Labor.       

    Table VIII-4 analyzes compliance costs by application group and 
shows that the Cold Cleaning application group, which is in the larger 
Metal Cleaning grouping, and the Furniture Stripping application group, 
which is in the larger Paint Stripping category, will incur the largest 
costs of compliance (though not necessarily the largest economic 
impacts). These costs reflect the high exposures and relative lack of 
control measures currently existing in many establishments in these two 
application groups. In other words, because MC exposures are poorly 
controlled in so many cold cleaning and furniture stripping facilities, 
employers in these industries will be required by the standard to 
implement control measures to protect their employees from the 
significant risk of MC exposure.

Table VIII-4.--Annualized Costs by Methylene Chloride Application Groups
------------------------------------------------------------------------
                                                             Annualized 
                     Application group                          costs   
------------------------------------------------------------------------
Methylene Chloride Manufacturing..........................         8,150
Distribution/Formulation of Solvents......................       794,099
Metal Cleaning:                                                         
  Cold Degreasing and Other Cold Cleaning.................    26,950,869
  Open-Top Vapor Degreasing...............................       371,096
  Conveyorized Vapor Degreasing...........................        97,253
  Semiconductors..........................................       247,666
  Printed Circuit Boards..................................       217,479
Aerosol Packaging.........................................       297,999
Paint Remover Manufacturing...............................       229,724
Paint Manufacturing.......................................        89,697
Paint Stripping:                                                        
  Aircraft Stripping......................................     8,148,754
  Furniture Stripping.....................................    10,689,840
  All Other Industrial Paint Stripping....................    24,413,924
Flexible Polyurethane Foam Manufacturing..................     4,252,861
Plastics and Adhesives Manufacturing and use..............     5,417,950
  Adhesive Production                                                   
  Adhesive Use                                                          
  Injection Molding                                                     
  Lamination                                                            
  Mold Release                                                          
Ink and Ink Solvent Manufacturing.........................        23,518
Ink Solvent Use...........................................     3,360,723
Pesticide Manufacturing and Formulation...................       106,060
Pharmaceutical Manufacturing..............................       311,708
Solvent Recovery..........................................        49,829
Film Base Manufacturing...................................        47,454
Polycarbonate Manufacturing...............................         4,651
Construction..............................................    14,922,000
Shipyards.................................................       518,544
                                                           -------------
      Total, all application groups.......................   101,463,037
------------------------------------------------------------------------
Source: Office of Regulatory Analysis; OSHA; Department of Labor.       

    Chapter VI of the economic analysis analyzes the impacts of 
compliance costs on firms in affected application groups. The standard 
is clearly economically feasible: on average, annualized compliance 
costs amount only to 0.18 percent of estimated sales and 3.79 percent 
of profits. For all but three application groups--polyurethane foam 
blowing, furniture stripping, and construction--compliance costs are 
less than 3 percent of profits, and for all but one application group--
furniture stripping--annualized compliance costs are less than 0.5 
percent of the value of sales. Table VIII-5 shows average compliance 
cost impacts across the many Standard Industrial Classification (SIC) 
codes potentially involved in the application groups studied.

 Table VIII-5.--Screening Analysis to Identify Possible Economic Impact 
                        of the Final MC Standard                        
------------------------------------------------------------------------
                                                   Annualized costs of  
                                   Number of           compliance       
       Application group        establishments -------------------------
                                   complying     As percent   As percent
                                                  of sales    of profit 
------------------------------------------------------------------------
Manufacture of MC.............              4           (*)         0.04
Distribution/Formulation of                                             
 Solvents.....................            320          0.04         0.55
Metal Cleaning:                                                         
    Cold Degreasing and Other                                           
    Cold Cleaning.............         23,717          0.01         0.18
    Open-Top Vapor Degreasing.            278          0.01         0.22
    Conveyorized Vapor                                                  
     Degreasing...............             45          0.02         0.35
    Semiconductors............            239           (*)         0.05
    Printed Circuit Boards....            141          0.02         0.41
Aerosol Packaging.............             50          0.01         0.13
Paint Remover Manufacturing...             80          0.02         0.06
Paint Manufacturing...........             49          0.01         0.04
Paint Remover Use (Paint                                                
 Stripping):                                                            
    Aircraft Stripping (Large                                           
     Firms)...................             75          0.07         1.34
    Aircraft Stripping ( Small                                          
     Firms)...................            225          0.08         2.12
    Furniture Stripping.......          6,152          2.04      **39.40

[[Page 1568]]

                                                                        
    All Other Industrial Paint                                          
     Stripping................         35,041          0.01         0.11
Flexible Polyurethane Foam                                              
 Manufacturing................            100          0.32       **9.23
Plastics and Adhesives                                                  
 Manufacturing and Use........          3,487          0.03         0.52
Ink and Ink Solvent                                                     
 Manufacturing................             15           (*)         0.03
Ink Solvent Use...............         11,869          0.03         0.05
Pesticide Manufacturing and                                             
 Formulation..................             60          0.01         0.35
Pharmaceutical Manufacturing..            108           (*)         0.03
Solvent Recovery..............             37          0.05         0.85
Film Base.....................              1           (*)         0.01
Polycarbonates................              4           (*)          (*)
Construction..................          9,504          0.35       **9.67
Shipyards.....................             25          0.07         1.72
All Application groups........         91,625          0.18         3.79
------------------------------------------------------------------------
* = less than .005%.                                                    
** These relatively high impacts on profits assume that no price        
  increase is possible. In all three cases, price increases of 2.1      
  percent or less would fully restore profits. In all of these          
  application groups, most firms will be able to increase prices to     
  offset their regulatory costs. In furniture stripping, a substantial  
  portion of the market is for antique refinishing that involves MC use,
  a service which is relatively price insenstive. Soft flexible foam of 
  the kind MC is used to make is an essential material in the           
  construction of cushions of all types. In the construction sector, MC 
  based paint stripping and foam blowing are essential operations of    
  many of the jobs in which they are used.                              
                                                                        
Sources: CONSAD; Dun & Bradstreet; Office of Regulatory Analysis, OSHA, 
  Department of Labor.                                                  

    It is important to understand that OSHA's methodology tends to 
overestimate the economic impacts of the standard, for a number of 
reasons. For example, OSHA's cost methodology does not take into 
account the many simple and virtually cost-less improvements in 
employee work practices and housekeeping procedures that would enable 
many employers to achieve compliance with the final rule's PELs. In 
flexible polyurethane foam manufacturing, for example, OSHA's costs may 
be overestimated because it was assumed that no firms would substitute 
away from MC entirely, even though some firms have already done so (as 
described in Chapter III, Technological Feasibility). Despite the fact 
that OSHA's cost estimates are likely to be overestimates, OSHA decided 
to examine in greater detail the three application groups shown by the 
economic analysis to have the highest costs as a percentage of profits, 
i.e., furniture stripping, polyurethane foam manufacturing, and 
construction.
    In the furniture refinishing application group, compliance costs 
are 2.0 percent of the value of revenues and 39 percent of the value of 
before-tax profits. Approximately half of all furniture refinishing 
sales derive from antique refinishing, a market niche that is unlikely 
to be sensitive to a 2.0 percent change in price. Even in the area of 
used furniture refinishing, which constitutes the remaining half of the 
furniture refinishing market, a 2.0 percent price increase would be 
unlikely to significantly alter the amount of furniture being 
refinished. In general, price increases of this magnitude would be 
expected to result only in a very small drop in the demand for 
furniture refinishing. If this were not the case, normal business 
fluctuations, such as drops in the relative cost of new furniture or a 
major increase in the price of methylene chloride (such as has occurred 
in recent years) would also have had major impacts on the industry.
    In construction and polyurethane foam manufacturing, compliance 
costs for the average firm are 9.2 and 9.7 percent of profits, 
respectively. However, to offset these costs, construction firms would 
need only to increase their revenues by 0.35 percent and foam blowing 
operations would need only to increase the price of their products by 
0.32 percent. In construction, such price increases are unlikely to 
present a problem, since the use of MC is essential on many larger 
construction projects. For example, it is difficult to believe that 
demand for remodeling or renovation projects would be seriously altered 
by a 0.35 percent increase in the cost of the paint stripping portion 
of the job. In flexible polyurethane foam manufacturing, either MC or 
an appropriate substitute is essential to the production of low 
density, or soft, foam, and foam, in turn, is essential to the 
production of many kinds of furniture. Demand for such products is 
unlikely to change as a result of an 0.32 percent increase in the price 
of flexible foam. OSHA therefore concludes that even marginal firms in 
these three sectors--furniture stripping, construction, and flexible 
foam blowing-- are unlikely to close as a result of the compliance 
costs of this standard.
    To ensure that the analysis of average impacts presented in the 
economic analysis did not obscure potentially significant economic 
impacts at the 4-digit SIC level, OSHA performed an in-depth analysis 
of the 4-digit SICs potentially involved in the Cold Cleaning and All 
Other Industrial Paint Stripping application groups. The results of 
this in-depth analysis are presented in Appendix D of the full economic 
analysis. In all, a total of 162 4-digit SICs potentially impacted by 
the standard in the Cold Cleaning group and more than 200 4-digit SICs 
in the Other Industrial Paint Stripping group were analyzed. Across all 
of the Cold Cleaning SICs, the average impact of the costs of 
compliance is 0.06 percent of revenues and 1.12 percent of profits. The 
largest impacts on profits occur in SIC 3412, Metal Barrels, Drums, and 
Pails, and SIC 3494, Valves and Pipe Fittings not elsewhere classified; 
in these cases, impacts on profits are 13.3 and 15.1 percent, 
respectively. In both of these cases, however, these impacts are 
explained by extremely low profit margins (less than .02 percent of 
sales, i.e., less than $2 per $10,000 in sales, in 1994). As a result, 
a price increase of less than one cent per $100 of revenue would leave 
profits unchanged. Such a price increase is feasible because an

[[Page 1569]]

increase of this magnitude is unlikely to lead to significant changes 
in the demand for metal barrels or valves and pipe fittings. In no 
other 4-digit Cold Cleaning SIC did impacts reach even 5 percent of 
profits.
    Across all 200-plus Industrial Paint Stripping SICs, the average 
impact of the costs of compliance on revenues is 0.03 percent. The 
largest impact of costs on sales is 0.33 percent and occurs in SIC 
7532, Auto Top, Body Repair, and Paint Shops (discussed further below). 
The average impacts of costs on profits across these SICs is 0.17 
percent. The largest impacts on profits occur in SIC 3412, SIC 3494 
(both discussed above), and in SIC 7532, Auto Tops, Body Repair and 
Paint Shops; in all three of these SICs, cost impacts are between 6 and 
8 percent of profits. Again, the explanation for these impacts in SICs 
3412 and 3494 is that their profit margin in 1994 was vanishingly low. 
The resulting price increases required to maintain profits are also 
extremely small, and OSHA concludes that such an increase is likely to 
take place in these cases. In SIC 7532, the other relatively high 
impact SIC, profit margins are relatively high (approximately 4.4 
percent), and thus a small decline of this magnitude would have 
relatively little impact.

Summary of the Regulatory Flexibility Analysis

    In its 1991 proposal, OSHA requested comments and information that 
would assist the Agency in identifying small-business users of MC and 
in structuring the final standard so that these users would be able to 
achieve the standard's worker protection goals in ways that would be 
technologically and economically feasible for them (56 FR 57041 to 
57043). OSHA anticipated that, as stated in the proposal, the standard 
might have a significant economic impact on small entities in at least 
two application groups: firms with fewer than 20 employees that engage 
in stripping of paint from aircraft, and firms with fewer than 20 
employees that engage in furniture stripping.3 OSHA also requested 
comment concerning the standard's impact on small employers in light of 
the Regulatory Flexibility Act's mandate to consider and minimize 
impacts on small businesses, consistent with the purposes and criteria 
of the standard's enabling legislation (56 FR 57115 to 57121).
---------------------------------------------------------------------------

    \3\ As a result of data and information received from commenters 
and other information in the record, the Final Economic Analysis 
does not identify significant impacts or technologic or economic 
feasibility problems for aircraft stripping operations of any size.
---------------------------------------------------------------------------

    Many commenters identified additional application groups that 
include small establishments likely to have difficulty achieving all of 
the standard's protective goals if the requirements of the standard 
were structured in a one-size-fits-all manner. These commenters 
provided considerable data and identified many possible modifications 
and alternatives to the proposed standard that they believed would 
facilitate compliance and mitigate the standard's impact on MC-using 
establishments with fewer than 20 employees.
    None of the comments concerning small employer issues, whether in 
the context of economic or technological feasibility or the Regulatory 
Flexibility Act, disagreed with OSHA's basic premise that the fewer-
than-20-employee cut-off was appropriate to distinguish between large 
and small MC-using businesses, was a useful way of characterizing the 
compliance abilities and limitations of affected employers and is an 
appropriate definition for purposes of the Regulatory Flexibility Act. 
Use of this numerical cut-off point captures 61 percent of all 
establishments potentially affected by the final rule. MC-users with 
fewer than 20 workers tend to have the characteristics of ``mom-and-
pop'' businesses, whereas establishments with 20 or more workers are 
generally more sophisticated in terms of the technology they use and 
their management resources. The 20-employee threshold has also proved 
to be an agreed-on and useful cut-off point in past OSHA rulemakings 
(see, for example, the permit-required confined spaces standard (58 FR 
4547) and the process safety management standard (57 FR 6402)).
    During Executive Order 12866 review, the Office of Advocacy of the 
Small Business Administration expressed its views concerning OSHA's 
small business definition. In a letter to OMB, the SBA's Chief Counsel 
for Advocacy stated in a letter dated August 16, 1996, that ``[t]he 
regulatory alternatives developed, using OSHA's size standard of less 
than 20 employees, were somewhat beneficial to two of the three 
industries [furniture stripping, polyurethane foam blowing, and 
construction]. These industries, i.e., furniture stripping and 
construction, are predominantly micro businesses that fall into OSHA's 
definition of small'' (Ex. 130). The Office of Advocacy was concerned, 
however, that the 20-employee cut-off did not adequately deal with the 
MC-using polyurethane foam manufacturing sector. (In this application 
group, the majority of establishments likely to experience significant 
economic impacts fall into the 20 to 99- employee size category.) 
``[T]he characteristics of the manufacturing sector indicate that the 
[20 employee] size standard was not appropriate in that industry for 
the purposes of regulatory flexibility.'' Id. The SBA concluded that 
OSHA should consider taking additional steps to address implementation 
burdens and the needs of the polyurethane foam manufacturing sector.
    Working with OMB and the SBA's Office of Advocacy to resolve this 
concern, OSHA reexamined the potential impacts of the standard on 
polyurethane foam manufacturing establishments in the 20 to 99 employee 
size category in the context of economic impact issues. As explained 
more fully in the Final Economic and Regulatory Flexibility Analysis, 
OSHA concluded that, even though members of this group were not small 
employers, some accommodation would be necessary to assure that 
employees working in establishments of this size in this industry would 
not receive less protection than all other MC-exposed employees. 
Accordingly, OSHA extended the engineering control implementation date 
for this group of establishments by one year. This extended phase-in is 
designed to enable this group of employers to plan for and accumulate 
the capital to finance needed controls, install them, and ensure their 
effective and consistent operation before the compliance deadline.
    OSHA's extensive feasibility studies and focus on small business 
issues resulted in a number of modifications that have made the 
standard more cost-effective for business while maintaining protection 
for workers. In addition, OSHA conducted an alternative screening 
analysis to measure the final rule's potential impacts on 
establishments in the regulated community using the SBA's size 
standards. For most application groups, this meant that OSHA examined 
the standard's economic impacts on firms at the 500 employee level. 
(Financial data are not available for cut-off points higher than 500 
employees; thus, OSHA used that cut-off for all application groups.) In 
some cases, the SBA size standards are defined in terms of annual 
revenues, and for SICs so defined, OSHA translated these revenue 
figures into the appropriate employee size category. This SBA-based 
alternative screening analysis enabled the Agency to determine whether, 
by failing to look

[[Page 1570]]

at potential impacts among firms in other size classes, significant 
impacts had been overlooked. The analysis conducted using the SBA size 
standards confirmed that any potentially significant economic impacts 
associated with the final rule occur among firms in the fewer-than-20-
employee category, with one exception, i.e., firms in the 20-99 
employee size category in the polyurethane foam manufacturing industry. 
(See the full Final Economic Analysis for additional detail.)
    For the final rule, OSHA has analyzed the costs of compliance as a 
percentage of profits, and costs as a percentage of revenues, for firms 
with fewer than 20 employees in every application group. This analysis 
identified significant economic impacts on a substantial number of 
small entities, and the Agency has accordingly conducted a full Final 
Regulatory Flexibility Analysis in accordance with the Regulatory 
Flexibility Act, as amended in 1996. The three application groups for 
which such impacts were identified were Furniture Stripping, 
Polyurethane Foam Blowing, and Construction. Table VIII-6 shows the 
results of this analysis in detail.
    The full regulatory flexibility analysis is presented in Chapter VI 
of the Final Economic and Regulatory Flexibility Analysis. The 
remainder of this section briefly summarizes that analysis.
    This rule is needed to prevent cancer deaths and other illnesses, 
as discussed in greater detail in the Health Effects Section (Section V 
of this Preamble). Section III of this preamble, Events Leading to the 
Final Standard, summarizes OSHA's efforts to assure input to this 
rulemaking by affected small firms. Table VIII-6 identifies the 
affected small firms by sector. OSHA estimates that a total of 56,000 
small firms will be affected by this standard.

 Table VIII-6.--Sceening Analysis of Potential Economic Impacts on Small
                                  Firms                                 
------------------------------------------------------------------------
                                                 Costs as a   Costs as a
                                   Number of     percentage   percentage
       Application group             small       of profits    of sales 
                                establishments   for small    for small 
                                   affected        firms        firms   
------------------------------------------------------------------------
Manufacture of MC.............              0            NA           NA
Distribution/Formulation of                                             
 Solvents.....................            139          3.0%          0.2
Metal Cleaning:                                                         
    Cold Degreasing and Other                                           
     Cold Cleaning............          9,223           0.9          0.0
    Open-Top Vapor Degreasing.              0            NA           NA
    Conveyorized Vapor                                                  
     Degreasing...............             11           2.4          0.1
    Semiconductors............              0            NA           NA
    Printed Circuit Boards....             20           2.0          0.1
Aerosol Packaging.............             10           0.7          0.1
Paint Remover Manufacturing...             34           0.3          0.1
Paint Manufacturing...........              7           0.1          0.0
Paint Remover Use (Paint                                                
 Stripping):                                                            
    Aircraft Stripping (Large                                           
     Firms)...................              0            NA           NA
    Aircraft Stripping ( Small                                          
     Firms)...................             75           4.5          0.1
    Furniture Stripping.......          5,901         41.5*          2.2
    All Other Industrial Paint                                          
     Stripping................         25,441           0.8          0.0
Flexible Polyurethane Foam                                              
 Manufacturing................              8         60.3*          1.7
Plastics and Adhesives                                                  
 Manufacturing and Use........            498           1.8          0.1
Ink and Ink Solvent                                                     
 Manufacturing................              3            NA           NA
Ink Solvent Use...............          5,395           0.1          0.1
Pesticide Manufacturing and                                             
 Formulation..................             40           6.6          0.2
Pharmaceutical Manufacturing..              0            NA           NA
Solvent Recovery..............             17           2.7          0.1
Film Base.....................              0            NA           NA
Polycarbonates................              0            NA           NA
Construction..................          9,085         19.9*          0.5
Shipyards.....................              0            NA           NA
All Application groups........         55,908           8.2         0.3 
------------------------------------------------------------------------
NA=No small firms in this application group.                            
* These relatively high impacts on profits assume that no price increase
  is possible. In all three cases, price increases of 2.1 percent or    
  less would fully restore profits. In all of these application groups, 
  most firms will be able to increase prices to offset their regulatory 
  costs. In furniture stripping, a susbtantial portion of the market is 
  for antique refinishing that involves MC use, a service which is      
  relatively price insensitive. Soft flexible foam of the kind MC is    
  used to make is an essential material in the construction of cushions 
  of all types. In the construction sector, MC based paint stripping and
  foam blowing are essential operations of many of the jobs in which    
  they are used.                                                        
 Sources: CONSAD; Dun & Bradstreet; Office of Regulatory Analysis, OSHA,
  Department of Labor.                                                  

    The Summary and Explanation section of this preamble provides a 
description of the compliance requirements associated with this rule, 
and a paperwork burden analysis of the record keeping requirements is 
provided in the Collection of Information Request for Comment section 
at the beginning of this preamble. Based on comments regarding 
anticipated effects on small businesses, OSHA has reduced the final 
rule's overall paperwork requirements from those proposed and has 
refined some paperwork requirements to simplify compliance for small 
entities.
    OSHA considered numerous regulatory alternatives and modifications 
to the requirements of the proposed standard (ranging from higher PELs, 
to 40-hour rather than 8-hour time weighted average exposure limits, to 
delayed implementation dates) that commenters believed might minimize 
significant economic impacts on small businesses. OSHA rejected those 
alternatives that clearly decreased the safety of workers in small 
establishments, but the Agency also adopted many regulatory changes 
that will improve small employers' ability to provide their employees 
with the same level of protection as that afforded workers in larger 
establishments. As

[[Page 1571]]

explained more fully in the Final Economic Analysis and summarized in 
Table VIII-7, the final standard contains delayed implementation dates, 
reduced paperwork requirements, streamlined medical surveillance 
provisions and other accommodations that, in the Agency's judgment, 
will minimize any significant economic impacts of the standard on small 
employers to the extent necessary to enable them to meet the standard's 
protective goals.

 Table VIII-7. Changes Made Since the Proposed Regulation To Reduce the 
              Final Standard's Impacts on Small Businesses              
------------------------------------------------------------------------
     Change to proposed regulation          Impact on small businesses  
------------------------------------------------------------------------
Firms with fewer than 20 employees       More performance oriented and  
 given 3 years (rather than 1) to         flexible, reduces costs to    
 achieve PEL using engineering controls.  small businesses in first two 
                                          years by 30 to 40 %, allows   
                                          small businesses time to plan 
                                          major expenditures.           
Allows the use of licensed health care   Provides greater flexibility.  
 professionals in addition to                                           
 physicians for medical surveillance.                                   
Laboratory tests are at the discretion   Reduces costs of medical       
 of physician rather than automatically   surveillance by more than 14  
 required.                                percent, more performance     
                                          oriented.                     
Employees under 45 are required to have  Reduces costs of medical       
 a physical every three years rather      surveillance by 30 percent.   
 than annually.                                                         
Respirators required in regulated areas  Decreases respirator use and   
 only when PEL is likely to be exceeded.  costs for small business.     
If MC is used less than 30 days per      Significantly reduces costs of 
 year, monitoring may be conducted with   monitoring for establishments 
 direct reading instruments.              making limited use of MC; this
                                          provision will be especially  
                                          helpful in construction.      
Written compliance plans are no longer   Reduces paperwork.             
 required.                                                              
Hazard communication requirements do     Reduces paperwork and costs.   
 not go beyond what is already required                                 
 by hazard communication standard.                                      
Employee re-training only as needed      More performance oriented,     
 rather than annually.                    reduces costs of training 80  
                                          percent.                      
Simplified recordkeeping for small       Reduces paperwork.             
 businesses for exposure monitoring                                     
 data.                                                                  
------------------------------------------------------------------------

IX. Environmental Impact

    This section analyzes the impact on the environment of changing the 
standard for methylene chloride (MC) to an eight-hour time weighted 
average (TWA8) permissible exposure limit (PEL) of 25 parts per million 
(ppm), with a 125 ppm 15-minute short-term exposure limit (STEL) and 
ancillary requirements. It is based principally on information 
collected for OSHA by CONSAD Research Corporation and its 
subcontractor, PEI Associates Inc., and reported in Economic Analysis 
of Draft Regulatory Standard for Methylene Chloride, 1990, OSHA Docket, 
Ex. 15, and also draws upon other materials in the OSHA docket.
    Current uses of methylene chloride involve releases to the air 
through venting of storage tanks or drums and through evaporation of MC 
during the performance of various activities such as paint stripping 
and cold cleaning indoors or outdoors. The volume of MC emitted as a 
percentage of MC used varies greatly among industries. Some processes, 
such as polyurethane foam manufacturing and paint stripping, typically 
release 100 percent of the MC to the atmosphere (Ex. 15). Other uses, 
such as solvent recovery and the manufacture of methylene chloride, 
involve less than 1 percent of the MC used being emitted to the 
atmosphere (Ex. 15). In addition, air, water, or solid waste pollution 
may occur as a result of the disposal of waste residues containing MC. 
Additional details by application group are presented in CONSAD's 
report [Ex. 15].
    Future environmental releases of methylene chloride resulting from 
the final standard will largely be a function of how it affects the 
demand for methylene chloride and for its substitutes. The demand for 
methylene chloride has been declining (e.g., generally, it is no longer 
being used in formulating hairsprays). Any regulatory action by OSHA is 
expected to further reduce the demand for MC and thus the extent of its 
environmental releases.
    Although it is technically possible to substitute 
chlorofluorocarbons (CFCs) for methylene chloride in electronics and 
foam blowing, OSHA does not expect the revision of the MC standard to 
have any such effect. CFC products are significantly more expensive 
than MC products and are themselves being phased out or banned because 
of their effects on the environment.
    To the extent that firms might have to use greater quantities of 
substitute chemicals to get the same effects formerly obtained with MC, 
waste residues and disposal costs would increase. On the other hand, 
increases in MC leak prevention and recycling would improve the 
environment.
    The Paint Remover Manufacturers Association (PRMA) has charged that 
the standard would cause ``massive amounts'' of methylene chloride to 
be emitted into the atmosphere (Ex. 19-11). In Chapter III, OSHA noted 
that it could find no convincing argument by PRMA as to why the total 
amount emitted after installation of exhaust ventilation would differ 
significantly from the amount now simply leaking into the atmosphere.
    At informal public hearings, PRMA stated that ``an exposure level 
of 25 PPM is so low that it brings into the issue the formation of 
vapor clouds with levels of greater than 25 PPM that could move in and 
around the neighborhood,'' allegedly through decomposition of the MC 
[Tr. 245, 9/17/92]. There is no evidence that this hypothetical 
situation has ever occurred. PRMA may have confused decomposition with 
diffusion [Tr. 940-941, 9/21/92]. At Eastman Kodak Company, which 
currently emits more methylene chloride into the atmosphere than any 
furniture stripper possibly could, the chemical has diffused so rapidly 
that no clouds of MC have been formed [Tr. 1237-1238, 9/22/92].
    Generally, it is not expected that any significant environmental 
impact will result from revision of the methylene chloride standard.

X. Summary and Explanation of the Final Standard

Introduction

    The final standard for occupational exposure to methylene chloride 
(MC) is different in several important respects from the proposed MC 
standard

[[Page 1572]]

published in the Federal Register in 1991 (56 FR 57036). For example, 
the standard has been written in plain language, is more performance-
oriented than the proposal, and substantially reduces the amount of 
paperwork employers will have to complete. Employers will thus find 
compliance with the standard easier, their paperwork less extensive, 
and their obligations clearer and less burdensome. These changes are 
discussed in greater detail in the appropriate sections of this Summary 
and Explanation. OSHA seeks input from users of the standard on whether 
these changes are helpful and what other changes could be made to 
future standards to increase their user-friendliness. OSHA will also be 
conducting a number of compliance assistance and outreach projects in 
connection with this standard to assist employers and employees to 
comply.
    As part of the Agency's new approach to standards writing, OSHA has 
included an introductory paragraph in the standard to provide readers 
with information on MC, its health effects and principal uses, and the 
reasons OSHA is regulating this toxic substance. This introductory 
language is non-mandatory and is intended only to provide information 
and enhance compliance.
    This final rule is an occupational health standard that establishes 
requirements to control employee exposure to MC, a chemical compound 
found in many different types of industries. OSHA has determined that 
this standard is necessary because exposure to MC places employees at 
significant risk of developing exposure-related adverse health effects. 
These effects include cancer, effects on the heart and central nervous 
system, and skin and eye irritation. Employee exposure to MC can occur 
through inhalation or through skin absorption or contact with the skin. 
This substance is frequently used as a solvent in many different kinds 
of jobs, including furniture stripping, foam blowing, film 
manufacturing and metal degreasing.
    Although the final rule covers many different types of workplaces 
where MC is used, the extent of coverage depends on the magnitude of 
employee exposure. Although all covered employers, i.e., those with MC 
in the workplace, must determine initially the extent to which their 
employees are exposed to MC, those with exposures at or below the 
action level will only have to document the results of this initial 
determination, provide employee information and training, and provide 
means of protecting employees from contact with liquid MC. The 
standard's other requirements, such as those for engineering controls, 
medical surveillance, etc. apply only to workplaces where employee 
exposures to MC exceed the action level.

Paragraph (a) Scope and application

    This standard applies to all occupational exposures in workplaces 
covered by OSHA in general industry, construction and shipyards where 
MC is produced, released, stored, handled, or used.
    As discussed in the Health Effects and Significance of Risk 
sections of this preamble, OSHA has determined that exposure to MC at 
the former PEL creates a significant risk that employees' health will 
be materially impaired. Possible adverse health effects include cancer, 
cardiac effects, central nervous system effects, and skin or eye 
irritation. Exposures to MC are found in various general industry, 
construction, and shipyard facilities, and OSHA has determined that 
there are feasible measures to control them in each of these types of 
employment.
    In the proposal's Authority section, OSHA preliminarily determined, 
under Section 4(b)(2) of the OSH Act, that it would be appropriate for 
the MC standard to supersede any corresponding longshoring standards in 
Sec. 1910.16 and 29 CFR part 1918. The Agency therefore proposed to add 
a new paragraph (m) to Sec. 1910.19. In addition, in questions raised 
by the Agency in its Notice of Public Hearing, OSHA requested input 
regarding the use of MC in longshoring. However, OSHA has subsequently 
proposed (59 FR 28594, June 2, 1994) to revise its marine terminal 
(part 1917) and longshoring (part 1918) standards. Those proposed 
standards (proposed Secs. 1910.16(b)(2), 1917.1(b)(2)(xiv), and 
1918.1(b)(1)) would apply OSHA's toxic substance standards (part 1910, 
subpart Z) only when the packaging in which a substance is being 
transported in the maritime environment has broken open. This language, 
based on the existing marine terminal standard 
(Sec. 1910.16(b)(2)(ii)), reflects the view that hazardous substances, 
when properly packaged, do not pose significant exposure risks for the 
shipyard employees transporting them in closed packages.
    Therefore, as revised, final rule Sec. 1910.19(m) states that 
Sec. 1910.1052 will address MC exposure in marine terminal and 
longshore employment only where leaking or broken packages allow MC 
exposure that is not addressed through compliance with 29 CFR parts 
1917 and 1918. Given the promulgation of Sec. 1910.19(m), the Agency 
has determined that it is unnecessary to mention marine terminals and 
longshoring in final rule Sec. 1910.1052(a), Scope and application.
    OSHA has not learned of any circumstances in which marine terminal 
or longshore employees have been exposed to MC because of damage to 
packaging. The Agency, accordingly, anticipates that the MC final rule 
will have little or no impact on the marine terminal and longshoring 
industries.
    In developing this rule, OSHA has consulted with its Shipyard 
Employment Standards Advisory Committee (SESAC) to obtain information 
on MC use and exposure in shipyards and has taken the Committee's input 
into consideration in developing the standard. In particular, OSHA has 
relied on data provided by SESAC in assessing the technological 
feasibility and costs of compliance of the standard for shipyards 
covered by the rule.
    Since the construction industry is also included in the scope of 
the final rule, OSHA is required to consult the Advisory Committee on 
Construction Safety and Health (ACCSH) in accordance with section 107 
of the Contract Work Hours and Safety Standards Act (40 U.S.C. 333) 
(the Construction Safety Act) and 29 CFR 1911.10. On July 28, 1992, 
OSHA formally consulted with ACCSH regarding the construction-specific 
aspects of occupational exposure to MC. The Agency solicited comment 
and testimony regarding ACCSH's recommendations through a Federal 
Register notice (57 FR 36964, August 17, 1992). One of ACCSH's 
suggestions was that the rule specifically require originators of 
contract bids to stipulate a requirement for compliance with the MC 
standard in their bids. OSHA has not adopted this suggestion in the 
final rule because construction contracts already require compliance 
with all relevant Federal regulations. The specific suggestions made by 
ACCSH and OSHA's responses to ACCSH's input are discussed below in the 
relevant paragraphs of the Summary and Explanation.
    In the proposal, the scope and application paragraph included an 
exemption for employers with workplaces where MC products were present 
but objective data were available to demonstrate that the product could 
not release MC above the action level or STEL under those foreseeable 
conditions of processing, use, and handling that would cause the 
greatest possible release. This concept remains in the final standard, 
although the provision has been moved to the

[[Page 1573]]

exposure monitoring section (paragraph (d)), because this provision 
constitutes, in effect, an exception to the standard's requirement for 
initial monitoring.
    The Air Transport Association [Ex. 19-75] requested that airlines 
be excluded from the general industry standard, and that a separate 
standard covering MC use in the airline industry be developed. OSHA has 
specifically determined that the exposures, work operations, and means 
of compliance for aircraft-related MC uses are similar to those in many 
other establishments and thus that there is no substantive basis for 
the requested exemption. Consequently, OSHA has concluded that no 
industry-specific standard for airlines is warranted. MC uses in the 
airline industry are discussed in the section of the final economic 
analysis entitled ``Aircraft Stripping.''

Paragraph (b) Definitions

    This paragraph includes definitions of a number of terms used in 
the regulatory text of the final standard. Although some of these terms 
are in common use, OSHA believes that these definitions will help to 
ensure that their meaning in the context of the standard is clear.
    Action level means an airborne concentration of MC of 12.5 ppm, 
measured as an 8-hour time-weighted average. One purpose of the action 
level is to relieve the burden on employers by providing a cut-off 
point below which many of the compliance activities in the standard are 
not required. In addition, due to the variable nature of employee 
exposures to airborne concentrations of MC, compliance with an action 
level provides employers with greater assurance that their employees 
will not be exposed to MC concentrations above the permissible exposure 
limits.
    The action level also increases the cost-effectiveness and 
performance orientation of the standard while improving employee 
protection. The standard will encourage employers who can, in a cost-
effective manner, identify approaches or innovative methodologies to 
reduce their employees' exposures to levels below the action level, 
because this will eliminate the costs associated with exposure 
monitoring and medical surveillance, two provisions of the standard 
that are triggered by exposure exceeding the action level. At the same 
time, the employees of such employers will be protected because their 
MC exposures will be less than half of those permitted by the 
permissible exposure limit. Employees of those employers who are not 
able to lower exposures below the action level will have the additional 
protection provided by medical surveillance, exposure monitoring, and 
the other provisions of the standard that are triggered by the action 
level.
    The statistical basis for using an ``action level'' has been 
discussed in connection with several other OSHA health standards [see, 
for example, acrylonitrile (29 CFR 1910.1045) and ethylene oxide (29 
CFR 1910.1047)]. In brief, although all employee exposure measurements 
on a given day may fall below the permissible exposure limit, some 
probability exists that on unmeasured days the employee's actual 
exposure may exceed the permissible exposure limit. Where exposure 
measurements are above the action level, the employer cannot reasonably 
be confident that the employee may not be overexposed on a given day. 
Therefore, requiring periodic employee exposure measurements to begin 
at the action level provides the employer with a reasonable degree of 
confidence in the results of his or her exposure measurement program 
[Ex. 7-248]. OSHA's decision to set the action level at one-half the 
PEL is based on its successful experience using this fraction as the 
action level in many standards, such as arsenic, ethylene oxide, vinyl 
chloride and benzene.
    OSHA received comments from a number of rulemaking participants 
[Exs. 19-16, 19-20, 19-22, 19-31, 19-47, 19-75] suggesting that the 
proposed PELs and, by association, the action level, be revised. For 
instance, Hukill Chemical Corporation [Ex. 19-47] argued that the 
action level should be set at 100 ppm because it believes that: 1) CNS 
effects from MC are not observed in humans until 300 ppm; and 2) there 
is no evidence of excess cancer mortality in humans up to a level of 
475 ppm. As explained in the Health Effects and Quantitative Risk 
Assessment sections of this preamble, OSHA disagrees with this 
commenter because the Agency has determined that significant risks 
exist at levels substantially below those referred to by the commenter 
and therefore that the suggested levels would not be adequately 
protective.
    The Pharmaceutical Manufacturers Association (PMA) [Ex. 19-25] 
commented that the action level of 12.5 ppm is appropriate, but 
requested an exemption from ``various requirements of the standard'' if 
exposure occurs on fewer than 30 days a year. In particular, PMA 
suggested that periodic monitoring be required only when there is 
exposure above the PEL or STEL for at least 10 days a year or at or 
above the action level for at least 30 days a year. OSHA has considered 
this issue, along with similar concerns raised by ACCSH, and agreed 
that in cases where exposure occurs only on a few days per year, it was 
appropriate to alter the exposure monitoring requirements. 
Specifically, paragraph (d)(2)(iii) would permit employers whose 
employees are exposed to MC on fewer than 30 days per year to forego 
the initial monitoring required by paragraph (d)(2), provided that the 
employer has taken measurements that give immediate results (such as 
those taken by detector tube) and that provide sufficient information 
about exposures to determine what (if any) control measures are 
necessary. In addition, the medical surveillance requirement (paragraph 
(j)), with the exceptions described in the final rule, applies only 
where employees are exposed above the action level on at least 30 days 
within a year or above the PELs on at least 10 days within a year.
    Newport News Shipbuilding [Ex. 19-37] suggested that the action 
level be set at 15 ppm. However, adopting this suggestion would not be 
consistent with the statistical basis for establishing the action level 
at one-half the PEL, as described above. In addition, Markey 
Restoration Company [Tr. 2671-72,
10/16/92] recommended that the action level be eliminated based on the 
costs of medical surveillance triggered by that level. As noted above, 
an action level is based on the probability of exceeding the PEL and is 
designed to enhance both employee protection and the standard's cost-
effectiveness, and OSHA does not believe it would serve either 
employers or employees to eliminate this concept from the final rule.
    The UAW [Tr. 1885-86, 9/24/92] questioned the statistical arguments 
underpinning the action level that OSHA has used for some years. 
According to the UAW's calculations, the action level should actually 
be set at one-tenth the PEL to accomplish the purpose OSHA intended. 
Accordingly, the UAW argued that: ``[I]f you leave it [the action 
level] at 1/2, [there is] almost the virtual certainty that workers are 
overexposed on that job.'' In response, OSHA notes that its experience 
with action levels set at one-half the 8-hour TWA PEL has been 
favorable and that employers and employees have benefitted from the use 
of the action level concept. In particular, it is OSHA's experience 
that, for most workplaces, variability is normally such that an action 
level set at one-half the TWA PEL is appropriate. The final standard 
thus continues this practice.
     Emergency means any occurrence, such as but not limited to, 
equipment failure, rupture of containers, or failure of control 
equipment, which results, or is likely to result in an uncontrolled

[[Page 1574]]

release of MC. The word ``uncontrolled'' was changed from 
``unexpected'' in the proposal to be more descriptive and to be 
consistent with the Hazard Communication Standard (29 CFR 1910.1200) 
and the Hazardous Waste Operations and Emergency Response Standard (29 
CFR 1910.120). Incidental releases of MC--i.e., those where the 
substance can be absorbed, neutralized, or otherwise controlled at the 
time of release by maintenance personnel or other employees working in 
the immediate release area--are not considered to be emergencies within 
the scope of this standard. Dow Chemical Company [Ex. 19-31] indicated 
that the examples of emergencies provided in the proposal (purging 
lines and cleaning sludge from tanks) should not be included in the 
final rule. Other commenters [Exs. 19-25, 19-28, 19-57] agreed with Dow 
that the examples provided with the definition in the proposal were 
inappropriate. In particular, Eli Lilly and Company [Ex. 19-28, p. 7] 
stated

    Lilly agrees with the concept that an emergency should be tied 
to unexpected releases. It is therefore curious and illogical that 
the examples given--purging of lines and cleaning tanks--are not 
unexpected events. To the contrary, in the pharmaceutical industry 
these are planned events which could even occur daily.

    On the other hand, the Upjohn Company [Ex. 19-49] commented as 
follows:

    The language ``unexpected significant release'' is very vague 
and will not result in any consistent interpretation as to what type 
of a release meets this definition. We would recommend that the 
language be changed to ``* * * which may lead to employee exposure 
at or above the eight hour, timed-weighted average (TWA) or at or 
above the short-term exposure limit (STEL).''

    OSHA acknowledges that the language in question could be 
misunderstood and has deleted the parenthetical listing of some 
examples of emergency situations. Furthermore, the Agency recognizes 
that emergency situations, by their very nature, are difficult to 
anticipate and describe. Therefore, OSHA has not provided examples of 
emergency situations in the final rule. Instead, the final rule lists 
situations that OSHA does not consider emergencies, because these will 
help employers to identify situations in their workplaces that do 
constitute emergencies. OSHA recognizes that emergencies have certain 
aspects in common but that other aspects are specific to a given 
workplace. For example, employee exposure must be uncontrolled for an 
emergency to exist. Provisions of the standard that include 
requirements that employers must meet in case of an emergency include 
Methods of Compliance, Respiratory Protection, Medical Surveillance, 
and Employee Information and Training.
    Employee exposure is defined as that exposure to airborne MC which 
occurs or which would occur if the employee were not using respiratory 
protective equipment. This definition is consistent with OSHA's 
previous use of the term ``employee exposure'' in other health 
standards.
    Methylene chloride (MC), or dichloromethane, means an organic 
compound with the chemical formula, CH2Cl2. Its Chemical Abstracts 
Registry Number is 75-09-2. Its molecular weight is 84.9 g/mole. Other 
information regarding the characteristics of MC may be found in the 
appendices to the final standard. MC is a colorless, volatile, liquid 
with a chloroform-like odor and is not flammable by standard tests in 
air, but will burn under extreme conditions. It has a boiling point of 
39.85 C (104 F) at standard atmospheric pressure, a lower explosive 
limit of 12% and an upper explosive limit of 19.5% in air. It is 
completely miscible with most organic solvents but is sparingly soluble 
in water (1.3% by weight at room temperature). It has an extensive oil 
and fat solubility. Decomposition products during combustion or fire 
include phosgene, hydrochloric acid and carbon monoxide.
    Physician or other licensed health care professional is defined as 
a person whose legally permitted scope of practice allows him or her to 
independently provide or be delegated the responsibility to provide 
some or all of the health care services required by final rule 
paragraph (j), Medical Surveillance. Use of this phrase is designed to 
increase the flexibility of the standard; the proposal used the more 
restrictive term ``physician.'' OSHA intends that employers should 
consider the opinion of the applicable state licensing board, which 
defines the scope of practice for licensed health care professionals, 
when they are determining the appropriate provider to supply some or 
all of the medical services required by the standard. The new 
terminology recognizes that there are many services that non-physicians 
can provide, that some non-physicians have particular expertise in 
diagnosing and treating occupationally related diseases, and that the 
use of these providers is often a cost-effective and protective 
approach to the provision of medical care.
    Regulated area means an area, demarcated by the employer, where an 
employee's exposure to airborne concentrations of MC exceeds or can 
reasonably be expected to exceed either the eight (8)-hour time-
weighted average limit or the short-term exposure limit. The wording of 
this definition has been changed slightly from that in the proposal for 
clarity. The requirements for regulated areas are discussed below in 
relation to paragraph (e).
    OSHA has added a definition for symptom to the final rule to 
clarify what is meant by that term when it is referred to in the 
regulatory text. MC has a wide range of possible adverse health 
effects. This definition clarifies what portion of that range would be 
considered a symptom for purposes of the standard. The covered symptoms 
would include indications of central nervous system effects, such as 
headaches, disorientation, dizziness, fatigue, and decreased attention 
span; cardiac effects, such as chest pain and shortness of breath; and 
skin effects, such as chapping, erythema, or skin burns.
    The definitions of ``Assistant Secretary,'' ``Authorized Person,'' 
``Director'' and ``This section'' are consistent with OSHA's previous 
uses of these terms in other health standards.
    The Boeing Company [Ex. 19-26] suggested that a definition be added 
for ``work area'' to preclude unnecessary monitoring in areas that do 
not contain MC. OSHA does not believe that this is necessary. If there 
is no MC present in an area, no monitoring needs to be performed for 
MC. In addition, the focus of this standard is employee exposure, as 
measured by personal monitoring, and not particular locations.

Paragraph (c) Permissible Exposure Limits

    OSHA is promulgating an 8-hour time-weighted average (TWA) 
permissible exposure limit (PEL) of 25 ppm, and a short-term exposure 
limit (STEL) of 125 ppm averaged over 15 minutes, as proposed. OSHA has 
determined, based on evidence in the record, that occupational exposure 
to MC at the current 500 ppm 8-hour TWA PEL presents a significant risk 
of material health impairment, and particularly of cancer, to exposed 
employees and that compliance with the new standard will substantially 
reduce that risk. In combination with the STEL, the 8-hour TWA PEL and 
the other industrial hygiene provisions of the standard will also 
protect exposed employees from the other health effects caused by 
exposure to MC.
    The basis for the 8-hour permissible exposure limit is discussed 
above in the sections on Health Effects and Significance of Risk, as 
well as in the economic analysis. OSHA believes that

[[Page 1575]]

compliance with the new 25 ppm 8-hour TWA PEL is feasible and necessary 
to protect exposed employees from this significant risk of material 
health impairment.
    OSHA received comments from a number of rulemaking participants 
suggesting that the proposed PELs and, by association, the action level 
be revised. The arguments for revising the proposed PELs were based on 
interpretations of the scientific support for given PELs and the 
feasibility of particular PELs in certain situations. Some commenters 
felt that the current level of 500 ppm does not provide adequate 
protection for employees and agreed that the PEL should be set at 25 
ppm [Exs. 19-15, 19-49]. Specifically, Striptech International, Inc. 
[Ex. 19-15] stated:

    The OSHA proposed 25 ppm standard for MC does substantially 
eliminate significant risk and it is feasible and definitely 
appropriate. The technology exists to enable the industries using MC 
to comply or to use an alternate method.

    However, a number of rulemaking participants [Exs. 19-22, 19-23, 
19-36, 19-38, Tr. 530, 9/18/92, Tr. 1776, 9/24/92, Tr. 1869, 9/24/92] 
suggested that OSHA set the 8-hour TWA PEL below 25 ppm, because they 
believe that the proposed 25 ppm limit would not adequately protect 
workers. For example, the UAW stated that setting a PEL at 25 ppm 
``will permit too much exposure to methylene chloride, therefore 
placing workers at great risk, contrary to the requirements of the OSHA 
Act'' [Tr. 1869, 9/24/92]. The UAW stated that the proposed limit 
``would permit 2 deaths per thousand workers,'' and therefore suggested 
setting a PEL of 10 ppm, which the union felt would be feasible through 
specified engineering and work practice controls [Ex. 19-22, Tr. 1869, 
9/24/92]. Scott Schneider, representing the IUE, also suggested that 
``because of the evidence of health effects from low level exposures'' 
to MC, the PEL should be lowered below 25 ppm [Ex. 19-38]. The IUE and 
the ACTWU both supported the UAW recommendation of 10 ppm [Tr. 530, 9/
18/92, Tr. 1776, 9/24/92].
    The Laborers' Safety and Health Fund of North America [Ex. 19-36] 
suggested that worker exposure should be controlled to the lowest 
feasible level, which is consistent with NIOSH's position. NIOSH 
recommended ``that occupational exposure to methylene chloride, which 
is a potential occupational carcinogen and may induce ischemic heart 
disease, be reduced below the proposed PEL to the lowest feasible 
level'' [Tr. 868, 9/21/94]. OSHA agrees with these commenters that a 
significant risk remains at 25 ppm, but believes that this level is the 
lowest level for which OSHA can currently document feasibility across 
the affected application groups and industries.
    OSHA's primary justification for the new standard is the risk of 
cancer associated with exposure to MC. Some commenters stated that the 
carcinogenicity of MC has not been proven and therefore that 
carcinogenicity should not be the basis for setting the PEL [Exs. 19-
18, 19-29, 19-31, 19-45]. In particular, Kodak [Ex. 19-18] stated that 
it ``does not believe that the human or animal data demonstrate a need 
to establish methylene chloride exposure limits at the levels proposed 
by OSHA in order to adequately protect employee health.'' Mr. Bixenman, 
representing Benco Sales, testified [Tr. 2638, 10/16/92] ``And surely 
with our current level of technology, if methylene chloride were a 
human carcinogen, it could be established without question with actual 
diagnosed cases.'' Also, the Air Transport Association stated [Ex. 19-
75]:

    [T]he limited findings regarding cancer in mice at high MC 
dosage is weak justification for the proposed regulatory action. 
None of our members have found permanent health symptoms related to 
the use of MC, while usage at some facilities goes back at least 30 
years. We have no data or experience connecting heart disease with 
MC use.

    As discussed more extensively in the Quantitative Risk Assessment 
section, above, OSHA has based its assessment of MC cancer risk on the 
determination (supported by the NTP, EPA, and other agencies) that 
there is clear evidence of MC carcinogenicity in mice and rats. 
Although there are a few substances for which clear evidence of 
carcinogenicity in rodents has been deemed to be irrelevant to humans 
due to compelling evidence of mechanisms of action unique to the 
species tested, no such evidence exists for MC. In fact, as discussed 
in the Risk Assessment section, mechanistic evidence adds to the 
weight-of-the-evidence suggesting that MC is also carcinogenic in 
humans.
    OSHA's final risk estimate indicates a risk of 7.5 deaths per 1000 
workers exposed to MC at 50 ppm over a working lifetime and a risk of 
3.6 deaths per thousand workers exposed to MC at 25 ppm over a working 
lifetime. OSHA has determined, using quantitative risk assessment, that 
the estimated risk of developing cancer warrants setting the 8-hour TWA 
PEL at 25 ppm and a 15-minute STEL at 125 ppm; in fact, at the 25 ppm 
PEL the residual risk still greatly exceeds any significant risk 
threshold, and only the lack of documentation of the feasibility of 
lower PELs across the affected industries has convinced the Agency not 
to reduce the PEL even further at this time.
    OSHA disputes the contention of Mr. Bixenman that ``actual 
diagnosed cases'' are a precondition for establishing that a particular 
substance is carcinogenic to humans. Due to the natural background rate 
of all cancers, epidemiologic studies of groups are the only way to 
analyze human cause-effect relationships. As discussed in the 
Quantitative Risk Assessment section, OSHA has concluded that some of 
the available epidemiologic studies suggest a positive association 
between MC exposure and human cancer and that no epidemiologic studies 
of sufficient power exist to cast serious doubt on such conclusions.
    Several commenters preferred a PEL of 50 ppm, which is the current 
ACGIH threshold limit value for MC, because they felt that a 25 ppm PEL 
would be either too costly to implement or the technology to achieve 
such a level of control was not available [Exs. 19-2, 19-3, 19-12, 19-
14, 19-15, 19-29, 19-31, 19-35, 19-37, 19-39, 19-48, 19-50, 19-56, 19-
57]. For example, Abbott Laboratories [Ex. 19-29] commented that 
specific processes in the pharmaceutical industry ``cannot be 
controlled through existing conventional engineering controls.'' Also, 
AMETEK [Ex. 19-12] stated that ``It will be hard for many industries to 
reach the 50 ppm level and extremely difficult, if not, impossible, for 
most to reach the 25 ppm level.'' Therefore, this commenter proposed 
``that OSHA set the PEL for methylene chloride at 50 ppm (8-hour TWA) 
with no AL [action level] and leave the STEL at 125 ppm (15-minute 
average) as originally written.'' AMETEK contended that this approach 
``combines aspects of both ACGIH guidelines and OSHA's proposed 
standard into a regulation which would be both protective of worker 
health and economically feasible for industry'' [Ex 19-12].
    Many other commenters argued for a PEL of at least 100 ppm [Exs. 
19-1, 19-4, 19-10, 19-11, 19-16, 19-24, 19-47, 19-51, 19-52, 19-53, 19-
54, 19-67, 19-75, 19-79, 98, 115-3, Tr. 397, 9/17/92, Tr. 2216, 10/14/
92, Tr. 2627, 10/16/92, Tr. 2671, 10/16/92, Tr. 2702, 10/16/92]. For 
example, Besway Systems, Inc., testified [Tr. 397, 9/17/92]: ``We would 
like to see a PEL for these companies of 200 ppm, which we've been able 
to show is safe and economically attainable in our real life 
experience. We

[[Page 1576]]

believe that the absolute maximum PEL for our industry should be set at 
100 ppm eight hour time weighted average. . . .'' Also, Benco Sales 
[Tr. 2627, 10/16/92] stated ``We feel the American workers would 
receive more benefit by implementation of an exposure level of 100 
parts per million, which is achievable, and the subsequent enforcement 
of that level.'' ChemDesign Corporation [Ex. 19-24] believes that the 
``sharp reduction in the exposure limit is unjustified based on lack of 
credible data that this chemical has the potential to cause cancer in 
humans.'' This commenter therefore suggested that the PEL be ``lowered 
by a factor of five to 100 parts per million'' [Ex. 19-24].
    Other commenters supported a variety of PEL values. One suggested 
that a lower PEL be phased in over time, with 75 ppm for two years, 
then 50 ppm for two years, and finally 30 ppm [Ex. 19-20]. The 
reasoning behind this suggestion was that, during this period, 
alternative options to best fit specific operations could be evaluated 
and implemented and sufficient time provided to gather the funds 
necessary to implement the entire system [Ex. 19-20]. OSHA holds, 
however, that the types of engineering controls required under this 
standard are relatively simple and that engineering to 75 ppm, then 50 
ppm, then 30 ppm is likely to be more costly in time and money than 
engineering to or below 25 ppm initially. The suggested phase-in would 
also be administratively burdensome for employers, who would be subject 
to changing OSHA requirements over the years, with no clear advantage 
in reducing the costs of compliance. In addition, if OSHA allowed such 
a phase-in period, workers would be exposed to MC at higher levels than 
would occur if OSHA required no phase-in period. Therefore, the Agency 
sees no advantage to using the phased-in approach described. Moreover, 
the Agency notes that the time-frames for compliance with the 
provisions of the standard, including implementation of engineering 
controls, have been tailored to the size of the establishments, in 
order to give all employers a reasonable amount of time to gather 
resources and information necessary to comply with this regulation. See 
the discussion of start-up dates later in this document.
    Smith Fiberglass Products, Inc. suggested that the PEL should 
remain at 500 ppm because there is no evidence of human harm at the 
present PEL and STEL, since ``studies with rats and mice show that only 
a serious overdose far above the present STEL can cause carcinogenic 
effects'' [Ex. 19-82]. Another commenter [Ex. 19-86] stated that ``The 
present PEL of 500 parts per million (ppm) is not protective enough of 
employees based on toxicological data developed since the PEL was 
established.'' This commenter therefore suggested that the PEL should 
be lower than 500 ppm but higher than 25 ppm (no specific value 
identified). As discussed above, however, OSHA has determined that 
exposure to MC above 25 ppm poses significant cancer risks and that it 
is feasible to protect affected employees from those risks (see the 
Significance of Risk section of the preamble).
    A number of commenters addressed the availability of suitable 
substitutes for MC in their concerns about feasibility [see, e.g., Exs. 
19-6, 19-8, 19-37, 19-43, 19-55, 19-74, 19-79, 19-84, 115-3; Tr. 433, 
9/17/92; Tr. 1591, 9/23/92; Tr. 1712-13, 9/24/92; Tr. 2636-38, 10/16/
92]. Substitution is often a valid means of controlling exposures to a 
particular hazardous chemical when a less hazardous substitute is 
available that can be used to perform a similar function. In 
particular, some commenters stated that there are no viable substitutes 
for MC products used to perform particular tasks. These participants 
argued that companies would go out of business because they would be 
unable to comply with the final standard in a feasible way [Exs. 19-6 
and 19-8]. In addition, one commenter [Ex. 19-8] expressed concern that 
substitute products would pose fire hazards. The National Tank Truck 
Carriers, Inc. testified [Tr. 1712, 9/24/92]:

    One company which discontinued the use of methylene chloride 
found it necessary to supplement the methylene chloride substitute 
with even more hazardous acetone and toluene in order to remove the 
residues from the trailers and containers and properly service the 
industry by providing clean trailers.

    OSHA has determined that for all application groups, compliance 
with this regulation can generally be achieved through the use of 
engineering controls and work practices. The Agency's Final Economic 
Analysis estimated the cost of compliance assuming that almost all 
firms would continue using MC and that only a small fraction of firms 
would substitute away from MC. OSHA agrees that, in an individual 
establishment, the potential use of substitution as a means of control 
must be evaluated carefully to ensure that the magnitude of the hazard 
posed is not the same or increased as a result of the substitution. For 
some applications described in this regulation, many substitutes for MC 
are available for specific applications that do not pose increased 
health or safety hazards. In general, however, OSHA has based it 
findings of feasibility not on the ability of companies in the affected 
sectors to substitute away from MC but on their ability to implement 
conventional engineering and work practice controls.
    In addition to the 8-hour TWA PEL, OSHA is promulgating a short-
term exposure limit (STEL) of 125 ppm, measured over a 15-minute 
period, to protect employees from the acute toxicity of MC and its 
metabolites. The acute toxicity of MC is characterized primarily by CNS 
effects, such as decreased alertness and coordination, headaches, and 
dizziness, which may lead, in turn, to accidents on the job as well as 
material impairment of health. Absence of a STEL would mean that 
employees could be exposed to up to 800 ppm for 15 minutes. Such levels 
are clearly associated with central nervous system effects.
    MC is also metabolized to carbon monoxide (CO). CO produced from MC 
exposure has the same toxic effects in the body as direct exposure to 
CO does. The primary toxic effect of CO is reduction of the ability of 
the blood to carry oxygen to the tissues of the body.
    In the body, carbon monoxide is converted to carboxyhemoglobin. 
Background levels of carboxyhemoglobin in the non-smoking U.S. 
population vary from approximately 0.5% to 2.0%. Carboxyhemoglobin in 
smokers ranges from approximately 3% to 10%. Additional body burden of 
CO (carboxyhemoglobin) due to MC or direct CO exposure can have adverse 
health effects on affected individuals. For example, exposure to 
relatively low levels of carbon monoxide (for example, levels which 
increase carboxyhemoglobin by 2%) reduced time to angina in patients 
with pre-existing heart disease exposed to occupational levels of CO 
[Ex. 21-93]. Exposure of pregnant women to CO has been shown to produce 
adverse health effects on the developing fetus. Workers with anemia or 
other blood abnormalities may be at increased risk of material 
impairment to health because of an already decreased oxygen-carrying 
capacity.
    The carbon monoxide-mediated cardiac effects of MC exposure are of 
particular concern in the occupational setting because a significant 
fraction of the U.S. working population (some investigators estimate 
30% of the U.S. population) has silent or symptomatic heart disease. 
NIOSH has expressed concern that the STEL proposed by OSHA is not low 
enough to protect

[[Page 1577]]

workers from the adverse central nervous system and cardiac effects of 
MC.
    In addition to reducing risks of cardiac and CNS effects, the STEL 
will also enhance employee protection from MC-induced carcinogenesis by 
reducing total exposure to MC and by limiting the metabolism of MC by 
the GST pathway (the putative carcinogenic metabolic process). 
Metabolic evidence suggests that the GST pathway produces more than 
proportionately greater quantities of the putative carcinogenic 
metabolite when MC concentrations reach levels of about 100 ppm. For 
this reason, it is important to limit high concentration, short 
duration exposures to MC. Thus the STEL will reduce the exposure- 
related risks of acute CNS effects, episodes of carboxyhemoglobinemia, 
and cancer.
    Another advantage in requiring a STEL is that it focuses attention 
on sources of MC exposure in the workplace. General industrial hygiene 
principles state that a well-controlled process should have peaks no 
higher than five times the 8-hour TWA. Measurement of STEL exposures 
can indicate point sources which have unacceptably high MC emissions 
and help the employer target those processes for abatement. This can be 
an efficient mechanism to concentrate industrial hygiene resources on 
those emission sources which, when controlled, will reduce total 
employee MC exposure.
    In addition, it has been established that ``[i]f in fact a STEL 
would further reduce a significant health risk and is feasible to 
implement, then the OSH Act [section 6(b)(5)] compels the agency to 
adopt it barring alternative avenues to the same result.'' (emphasis in 
the original) Public Citizen Health Research Group v. Tyson, 796 F.2d 
1479, 1505 (D.C. Cir. 1986) (Ethylene oxide). See also Building and 
Construction Trades Department, AFL-CIO v. Brock, 838 F.2d 1258, 1271 
(D.C. Cir. 1988) (Asbestos).
    In summary, many commenters questioned the need for a reduced PEL, 
for a PEL of 25 ppm, and for the particular 8-hour TWA PEL-STEL 
combination proposed by OSHA, citing concerns about the feasibility of 
these limits and the ability of companies to identify controls and/or 
substitutes to comply with them. However, as discussed in the final 
economic analysis, OSHA has determined that it is both technologically 
and economically feasible for facilities in all affected sectors to 
comply with the final rule. In almost every case, companies will be 
able to use conventional engineering controls and work practices to 
reduce their employees'' exposures to these levels. In addition, many 
employers will find that substitution is a viable approach to 
eliminating the significant risk posed to workers by MC. As the 
economic analysis points out, many firms in many of the covered 
industries have already substituted away from MC, and have enjoyed 
considerable cost savings in the process. Finally, it is important not 
to lose sight of the reasons for regulating MC in the first place: this 
substance poses a significant risk of cancer, central nervous system 
and cardiac effects, and sensory irritation to the quarter of a million 
workers who manufacture, formulate, use, or transport this substance in 
the workplace.
    As the Quantitative Risk Assessment and Significance of Risk 
sections of the preamble demonstrate, the cancer risk remaining at an 
8-hour TWA PEL of 25 ppm is clearly of great concern, in that it 
exceeds the 1/1000 level indicated by the Supreme Court to be clearly 
significant. OSHA therefore encourages employers to further reduce the 
MC exposures of their employees wherever it is feasible to do so. 
Because the residual risk remaining at 25 ppm is great, the Agency 
intends to gather data and information on the feasibility of reducing 
the 8-hour TWA PEL to reduce remaining significant risk in a future 
rulemaking action. The priority assigned to any future rulemaking 
activity will depend in large measure on the prevailing exposure 
levels, feasibility, scientific advances and other information, at the 
time OSHA considers further proposals; to the extent prevailing levels 
are significantly below 25 ppm, the need for subsequent proposals will 
diminish.

Paragraph (d) Exposure Monitoring

    Paragraph (d) addresses the employee exposure monitoring 
requirements for workplaces where employees are exposed to MC. As 
discussed in the preamble to the proposed rule (57 FR 57118-20), OSHA 
requires employee monitoring to facilitate compliance with the PELs. As 
a general matter, exposure monitoring of employee exposure to toxic 
substances is a well-recognized and accepted risk management tool. The 
monitoring provisions of this final MC standard are consistent with the 
monitoring provisions of other OSHA standards. Section 6(b)(7) of the 
OSH Act, which addresses rulemaking requirements for hazardous 
chemicals, requires health standards to include provisions for 
monitoring employee exposures. In the final rule, the exposure 
monitoring provisions have been reorganized and rewritten to improve 
their clarity and readability. The substance of the requirements is 
essentially the same, with the few exceptions noted below.
    The provisions of proposed paragraph (d) elicited a considerable 
amount of comment and testimony. Several rulemaking participants [Ex. 
19-57; Tr. 249, 9/17/92; Tr. 458, 9/17/92; Tr. 1711, 9/24/92] stated 
that the proposed requirements for exposure monitoring would impose 
excessive economic burdens on some employers (e.g., paint strippers, 
tank cleaners). However, in the final rule OSHA has structured the 
exposure monitoring requirements to minimize the burden for employers 
whose employees have lower exposures and for workplaces where groups of 
employees have similar exposures. In addition, the Agency has included 
some alternatives to the initial monitoring provisions that will reduce 
the amount of monitoring required for some workplaces. Ultimately, 
however, the Agency has determined that it is essential to the 
protection of exposed employees that exposure levels be quantified in 
order to select and implement the proper measures to reduce employee 
exposures to MC.
    The overall rulemaking record supports the need for exposure 
monitoring to ascertain exposure levels for the purpose of designing 
appropriate protective measures for employees. In addition, evidence in 
the record indicates that the exposure monitoring requirements are 
economically and technologically feasible for firms in all of the 
affected industry sectors. (See the discussion in the Final Economic 
Analysis [Ex. 129].)
    Paragraph (d)(1) sets forth the general requirements that apply to 
all monitoring provisions. Paragraph (d)(1)(i) states that employers 
must characterize the MC exposure of each employee. Employers may chose 
one of two ways to determine an employee's MC exposure level. First, 
the employer can take a personal air sample in the breathing zone of 
each affected employee. This approach is the most precise method of 
exposure monitoring because it allows each employee's exposure to be 
individually ascertained. However, OSHA recognizes that this approach 
may be burdensome for employers with many employees. Therefore, 
paragraph (d)(1)(ii) permits employers to establish a representative 
monitoring scheme.
    Under this option, a personal breathing zone air sample may be 
considered representative of another employee's 8-hour TWA or STEL 
exposure if the following conditions are met. First, the sampled 
employee must

[[Page 1578]]

be that employee who is likely to have the highest MC exposure among 
the employees included in the group that is to be represented by the 
sample. Second, if the employer wishes a sample taken on an employee in 
a given job on one work shift to represent the exposure of another 
employee in the same job classification on another shift, the employer 
must sample at least one employee in each job classification in each 
work area during every work shift. Paragraph (d)(1)(ii) also contains 
an exception under which a personal breathing zone sample taken on one 
employee in one job classification in a given work area and on a 
particular shift will be considered representative of the exposure of 
employees on other shifts, where the employer documents that the tasks 
performed and conditions in the workplace are similar for all employees 
whose exposures are represented.
    The provision for representative sampling, which is very similar to 
the corresponding provision of the proposed rule, eliminates 
unnecessary monitoring and thus further improves the cost-effectiveness 
of the standard. In a change from the proposal, the final standard also 
allows employers to use representative monitoring to comply with the 
standard's requirement for initial monitoring. OSHA believes that 
representative initial monitoring is appropriate in those cases where 
the employer can accurately determine which employees are likely to 
have similar exposures.
    The accuracy of the methods used to perform exposure monitoring is 
addressed under paragraph (d)(1)(iii). For monitoring of airborne 
concentrations above the 8-hour TWA PEL or the STEL, the results must 
be accurate within plus or minus 25 percent at a confidence level of 95 
percent. Where concentrations are above the action level but at or 
below the PEL, the accuracy must be within plus or minus 35 percent at 
a confidence level of 95 percent.
    Methods of measurement are presently available that can detect MC 
within these limits. One such method is OSHA method 80, which has a 
limit of detection of 0.201 ppm. Copies of this method are available 
from OSHA and can be downloaded from OSHA's World Wide Web site on the 
Internet at ``http.www.osha.gov/.'' Sampling and analysis may also be 
performed by portable direct reading instruments, real-time continuous 
monitoring systems, passive dosimeters or other methods that meet the 
accuracy and precision requirements of the standard under the 
particular conditions which exist at the employer's worksite.
    Paragraph (d)(2) requires employers to make an initial 
determination of affected employees' exposure to MC. OSHA anticipates 
that most employers will need to perform monitoring in order to 
characterize employee exposure and has framed the rule accordingly. The 
standard allows employers to characterize their employee exposures 
using other means, providing that they can meet the requirements for 
such other means presented in the standard. For example, as discussed 
above, some employers may have objective data that establishes that 
employees will not be exposed above the action level or the STEL under 
reasonably foreseeable circumstances. Some employers generate such data 
themselves, while others rely on information provided by the 
manufacturer or supplier. Accordingly, paragraph (d)(2)(i) provides 
that employers can rely on objective data in certain circumstances in 
lieu of performing initial monitoring. The objective data must 
represent the highest MC exposures likely to occur under reasonably 
foreseeable conditions of proccessing, use, or handling in the 
workplace, and the employer must document the objective data relied on 
(see paragraph (m)). This provision corresponds to proposed paragraph 
(a)(2), which was the subject of several comments [Exs. 19-14. 19-31, 
19-57].
    Occidental Chemical testified [Tr. 2010 and 2023, 10/14/92] that 
OSHA should expand the proposed objective data exemption so that 
mixtures with less than one percent MC would be excluded from the scope 
of the MC standard. The Hazard Communication Standard (HCS) addresses 
mixture composition for the purpose of identifying those constituents 
and concentrations that impart their hazardous characteristics to the 
mixture as a whole. According to the HCS, carcinogenic substances such 
as MC are considered to impart their carcinogenic characteristics to 
the mixture if they are present in concentrations of more than one-
tenth of one percent or can be released in concentrations that exceed 
an existing PEL. This is a much more protective requirement than that 
suggested by Occidental, and the Agency believes it would be 
inappropriate to lessen the protections provided to employees under the 
HCS in this substance-specific MC standard. Therefore, OSHA has not 
made the suggested change.
    In addition, OSHA recognizes that it would be unreasonable to 
require initial monitoring under this standard where employers have 
already performed the monitoring needed to characterize employee 
exposure. Paragraph (d)(2)(ii) allows employers who have monitored 
their employees' exposures to MC within one year prior to April 10, 
1997 and that monitoring complies with the accuracy and other 
requirements for monitoring contained in the final rule, to designate 
such monitoring results as sufficient in lieu of performing the initial 
monitoring.
    Dow Chemical Co. [Ex. 19-31] commented that OSHA should allow 
monitoring data collected as much as two years prior to the effective 
date of the final rule to qualify as initial monitoring data. The 
Agency believes that data more than a year old would be unlikely to 
provide a reliable basis for characterizing employee exposure, because 
workplace conditions may well have changed since such data were 
collected. Accordingly, the Agency has not made the suggested change.
    Addressing this point, Scott Schneider of the International Union 
of Electronic, Electrical, Salaried, Machine and Furniture Workers 
(IUE) testified [Tr. 531, 9/18/92] as follows:

    While we support the requirements for exposure monitoring that 
were proposed, we have reservations about section (d)(2)(ii) 
regarding the use of ``earlier monitoring results'' to satisfy the 
initial monitoring requirements. OSHA must specify exactly which 
requirements the data must meet, in terms of both quality and 
quantity. Otherwise, it will be an enormous loophole for companies 
to avoid monitoring.

    The International Brotherhood of Painters & Allied Trades (IBPAT) 
agreed with Mr. Schneider; the union stated that the use of 
``historical monitoring data to characterize exposures for similar 
processes * * * may lead to erroneous estimates of actual exposures'' 
[Ex. 19-23]. OSHA believes that the concerns of these commenters have 
been addressed in the final rule because, to be acceptable under the 
standard, any previously gathered exposure data must meet the 
analytical, sampling, and other requirements specified for initial 
monitoring.
    A number of commenters addressed the application of monitoring 
requirements in construction [Ex. 19-23; Tr. 544-45, 9/18/92; Tr. 814-
17, 9/21/92; and Tr. 1377-80, 9/23/92]. OSHA agrees that conditions on 
construction sites often present special industrial hygiene and 
monitoring problems, particularly since the job may be completed before 
sampling results taken by conventional personal monitoring methods have 
been returned from the laboratory. For example, IBPAT [Ex. 19-23] 
pointed to the exposure variability that typifies construction sites, 
noting that weather, a highly transient workforce, and other factors 
often

[[Page 1579]]

complicate accurate characterization of construction worker exposures. 
OSHA's Advisory Committee for Construction Safety and Health (ACCSH) 
and other participants suggested that OSHA allow the use of direct-
reading instruments to address this problem [ACCSH Tr. 100-103, 7/28/
92; Workgroup report, pp. 3-4; Tr. 814-818, 9/21/92; Tr. 1377-1382, 9/
23/92].
    In response to these comments, the final rule has been revised to 
allow the use of such instruments where employees are exposed to MC on 
fewer than 30 days within a given year. This means that construction 
employers who are involved in short-term construction projects will be 
able to use these instruments to characterize the MC exposures of their 
employees. Paragraph (d)(2)(iii), which addresses transient workplaces 
or work operations where employees are exposed on fewer than 30 days a 
year, permits employers to use direct reading instruments such as 
detector tubes to estimate exposure and determine what protective 
measures to provide to their MC-exposed employees. Although these 
simple measurement tools often do not meet the accuracy requirements 
that other types of monitoring methods do, they have the advantage of 
immediate results and thus allow employers to provide protection 
immediately. OSHA believes that this provision is responsive to the 
comments discussed above and represents an effective solution to a 
difficult worker protection problem.
    Paragraph (d)(3) addresses periodic monitoring. Table X-1, below, 
which corresponds to Table 1 of paragraph (d)(3), displays the various 
monitoring scenarios possible under the final rule's periodic 
monitoring requirements. When the initial determination shows employee 
exposures to be at or above the action level or above the STEL, the 
employer is required to establish a periodic monitoring program. The 8-
hour TWA monitoring is to be done every six months if exposures are at 
or above the action level but at or below the 8-hour TWA PEL and the 
STEL. The 8-hour TWA or STEL monitoring must be done every three months 
if the initial determination or subsequent monitoring shows results 
that are above the 8-hour TWA PEL or the STEL, respectively. If two 
consecutive subsequent monitoring results taken at least seven days 
apart show that exposures have decreased to or below the 8-hour TWA 
PEL, but above the action level, the frequency may be decreased to 
every six months. Eight-hour TWA monitoring may be terminated when two 
consecutive monitoring results taken at least seven days apart show 
that exposures are below the action level. STEL monitoring may be 
terminated when two consecutive monitoring results taken at least seven 
days apart show that exposures are at or below the STEL (See note to 
paragraph (d)(3)).
    There are six possible initial determination exposure scenarios, or 
combinations of 8-hour TWA and short-term exposures, that determine the 
frequency of required monitoring. Table X-1 below lists these six 
exposure scenarios, along with their monitoring frequencies. As shown 
by Table X-1, the action level trigger largely determines whether 
employers must monitor employee exposure to MC. The only exception is 
the scenario in which 8-hour TWA exposures are below the action level 
and short-term exposures are above the STEL. In this case, exceeding 
the STEL obligates employers to monitor short-term exposures four times 
per year at those job locations where the STEL was exceeded, but 
employers are not required to monitor 8-hour TWA exposures at those job 
locations.

   Table X-1.--Six Initial Determination Exposure Scenarios and Their   
                    Associated Monitoring Frequencies                   
------------------------------------------------------------------------
           Exposure Scenario               Required Monitoring Activity 
------------------------------------------------------------------------
Below the action level and at or below   No 8-hour TWA or STEL          
 the STEL.                                monitoring required.          
Below the action level and above the     No 8-hour TWA monitoring       
 STEL.                                    required; monitor STEL        
                                          exposures every three months. 
At or above the action level, at or      Monitor 8-hour TWA exposures   
 below the TWA, and at or below the       every six months.             
 STEL.                                                                  
At or above the action level, at or      Monitor 8-hour TWA exposures   
 below the TWA, and above the STEL.       every six months and monitor  
                                          STEL exposures every three    
                                          months.                       
Above the TWA and at or below the STEL.  Monitor 8-hour TWA exposures   
                                          every three months.           
Above the TWA and above the STEL.......  Monitor 8-hour TWA exposures   
                                          and STEL exposures every three
                                          months.                       
------------------------------------------------------------------------

    Several commenters stated that the proposal required unnecessarily 
frequent monitoring [Exs. 19-25, 19-26, 19-28, 19-30, 19-31, and 19-
57]. Some commenters [Exs. 19-30, 19-31] said that the frequency of 
monitoring should be the same as that in the benzene standard (29 CFR 
1910.1028 (e)(3)), since frequent monitoring does nothing to reduce or 
control exposures. The benzene standard requires monitoring at least 
every six months if employee exposure exceeds the 8-hour TWA, at least 
every year if exposure is at or above the action level but at or below 
the 8-hour TWA, and ``as necessary'' to evaluate short-term exposures. 
OSHA believes that MC exposure is highly variable due to the 
substance's volatility (vapor pressure = 350 mmHg at 20 C, compared 
with a vapor pressure for benzene of 75 mmHg at the same temperature) 
and the way that it is commonly used (e.g., in manual applications), 
and that reducing the frequency of exposure monitoring could therefore 
result in inadequate employee protection. The frequency of monitoring 
required by this MC standard is similar to that in other OSHA standards 
such as Ethylene Oxide (29 CFR 1910.1047), and is sufficient to 
characterize employee exposure and to evaluate the effectiveness of 
exposure control strategies.
    The Advisory Committee on Construction Safety and Health suggested 
that OSHA trigger exposure monitoring by frequency of use as well as 
the exposure level. OSHA believes, however, that the magnitude of an 
employee's exposure is the appropriate determinant of monitoring 
frequency (and the selection of protective measures based on the 
results of that monitoring) because it is cumulative MC dose, not 
frequency of use, that determines the significance of the risk to which 
employees are exposed. Therefore, the Agency has not made the suggested 
change.
    The Polyurethane Foam Association (PFA) [Ex. 19-39] questioned the 
necessity of requiring exposure monitoring at the action level. 
According to the PFA [Ex. 19-39], ``An action level of 12.5 ppm would 
require

[[Page 1580]]

that workers be monitored at a level that has only a remote health risk 
associated with it. The costs of such monitoring, however, would be 
significant.'' OSHA disagrees strongly with the PFA's analysis of the 
significance of the risk remaining at the action level. As discussed in 
the Significance of Risk and Economic Analysis sections of this 
preamble, only feasibility has constrained the Agency from reducing the 
8-hour TWA PEL in the final rule to levels below the action level, 
because even at 10 ppm, the risk remaining is significant. That is, an 
employee exposed to an MC concentration of 10 ppm as an 8-hour TWA over 
a working lifetime would still be at significant risk of dying of MC-
induced cancer.
    Under paragraph (d)(4)(i), employers are required to perform 
additional monitoring when workplace conditions change or there is an 
indication that employee exposures may have increased. Paragraph 
(d)(4)(ii) requires that, where exposure monitoring is performed due to 
a spill, leak, rupture or equipment breakdown, the employer must clean 
up the MC and perform repairs and then monitor MC levels. The changes 
referred to in these provisions would include deliberate changes, such 
as a process or production change, or unexpected changes, such as a 
leak, rupture, or other breakdown. In the case of the latter, the 
employer is to perform the monitoring after taking whatever immediate 
action is required to clean-up or repair the equipment or source of 
exposure. OSHA recognizes that such occurrences can result in very high 
exposures. Several rulemaking participants [Exs. 19-31, 19-57, Tr. 
2035, 10/14/92] stated that remonitoring is not necessary after a spill 
or leak since MC has a high vapor pressure, there would be no visible 
residual MC and no opportunity for significant exposure. However, OSHA 
believes that such remonitoring is an appropriate way to ascertain if 
proper corrective methods have been instituted and if the magnitude of 
an employee's exposure has changed significantly as a result of the 
leak or spill.
    Employees are to be notified in writing of the results of exposure 
monitoring under paragraph (d)(5). This is to be done within 15 working 
days of the time the employer receives the monitoring results, and can 
be done either individually or by posting. When the results show that 
the 8-hour TWA PEL or the STEL has been exceeded, the employer must 
also notify employees of the corrective action being taken, and the 
schedule for completion of the action. This provision is effectively 
identical to the corresponding provision of the proposed rule.
    One commenter [Ex. 19-49] argued that 15 working days is not enough 
time to develop corrective actions, especially where engineering 
controls are involved. OSHA believes that this comment misunderstands 
the requirement, which merely states that employers are required to 
``describe the corrective action being taken * * * and the schedule for 
completion of this action.'' The Agency believes that 15 working days 
is adequate time for the employer to make a preliminary assessment that 
includes the immediate steps being taken to reduce employee exposure, 
such as utilization of air-supplied respirators, and the employer's 
plan for implementing permanent controls and/or work practices. This 
requirement is necessary to assure employees that the employer is 
making efforts to furnish them with a safe and healthful work 
environment, in accordance with section 8(c)(3) of the Act. OSHA would 
expect employers to update the notification when plans for permanent 
controls are made.
    Employees or their designated representatives are provided by 
paragraph (d)(6) with the opportunity to observe any required 
monitoring of employee exposure to MC. This provision is required by 
section 8(c)(3) of the Act (29 U.S.C. 657(c)(3)). It was relocated to 
paragraph (d)(6) of the final rule from proposed paragraph (l) to 
consolidate all of the exposure monitoring requirements in one place. 
The observer, whether an employee or a designated representative, must 
be provided (at no cost to the observer) with any personal protective 
clothing or equipment required to be worn by employees working in the 
area that is being monitored, and must additionally comply with all 
other applicable safety and health procedures. These provisions of the 
final rule are identical to those of the proposed rule.
    As noted above, OSHA received a number of comments on the 
monitoring provisions proposed in the NPRM. For example, Occidental 
Chemical Corporation requested that OSHA consider using what they 
termed ``exposure assessment'' rather than monitoring, testifying [Tr. 
2012-2013, 10/14/92] as follows:
    [I]nstead of just looking at monitoring, which is in the middle 
of the process, exposure assessment looks at a basic * * * 
characterization: What is the characterization of the work force? 
What is the characterization of the workplace? What is the 
characterization of the contaminants in the workplace? All of that 
is weighed together; it's a collection of information.
    The next step, then, is to interpret that information and 
determine what are the actual exposure levels, what category would 
they fit into * * *. If, at that point, and this is still just a 
paper exercise based on that information, you * * * conclude that 
exposures [are] unacceptable * * * you act. You may conclude that 
you have insufficient data and you'd like to monitor. Or you may 
conclude the data are acceptable; in this case, you would act and * 
* * change something and go through the process again. Or, in the 
case they [employee exposures] are acceptable, * * * you would 
document that it is acceptable and then reevaluate at some regular 
frequency, say annually or something like that.

    In response to this comment, OSHA notes that nothing in the 
standard prevents employers from conducting exposure assessments. 
Indeed, the fact that the final standard allows employers to use 
objective data and recent (within the past year) exposure data are both 
examples of the kinds of evaluation made by industrial hygienists 
performing exposure assessments. An employer unable to avail himself or 
herself of the exclusions to initial monitoring offered by the standard 
would logically move to the next step in the exposure assessment 
process: the direct monitoring of employees' exposures to MC. Thus the 
final rule, far from interfering with exposure assessment, actually 
both reflects this process and encourages employers to engage in such 
assessments themselves.

Paragraph (e) Regulated Areas

    Paragraph (e)(1) requires employers to establish a regulated area 
wherever an employee's exposure to airborne concentrations of MC 
exceeds or can be reasonably expected to exceed either the 8-hour TWA 
PEL or the STEL. This paragraph was changed slightly from the proposal 
to clarify that OSHA is concerned with employee exposures that can 
reasonably be anticipated to exceed one of the PELs, rather than 
excessive exposures that ``may'' occur. Regulated areas can be either 
temporary or permanent, depending on the characteristics of a given 
workplace. Such areas are required by the standard to reduce employee 
exposures and to alert employees to those areas in the workplace that 
present the greatest danger of MC overexposures.
    Paragraph (e)(2) limits access to regulated areas to authorized 
persons (a term which is defined in the definitions paragraph (b)). 
This provision applies when either the TWA PEL or STEL is exceeded or 
can reasonably be expected to be exceeded. OSHA believes that the 
establishment of a regulated area will help to ensure that employees 
are aware of areas in the workplace where MC

[[Page 1581]]

levels are above the 8-hour TWA PEL or STEL. OSHA believes that 
regulated areas are an effective means of limiting the risks of high 
exposures to substances suspected of being carcinogenic to humans to as 
few employees as possible.
    Comments from Bristol-Myers Squibb [Ex. 19-14] suggested that OSHA 
delete the regulated area concept from the standard and replace it with 
a ``regulated job classification'' for jobs exceeding the PEL and a 
``regulated procedure'' for procedures exceeding the STEL. This 
commenter's rationale was that since airborne concentrations are 
measured by personal monitoring and by job classification, it does not 
make sense to define an ``area'' of exposure. OSHA does not agree, for 
a number of reasons. First, in many workplaces, specific areas, such as 
quality control monitoring stations, mixing tanks, cutoff saw stations, 
spray booths, etc., are known to be associated with high levels of MC 
on a routine basis, and demarcating these areas protects employees by 
making them aware of the potential for these exposures in these 
locations. Second, it is standard industrial hygiene practice to use 
area monitoring to identify areas of exceptionally high exposures so 
that all non-authorized employees can be protected from overexposure. 
Finally, OSHA does not believe that the approach suggested by Bristol-
Myers has the same potential to alert employees to the presence of high 
airborne concentrations that a demarcated area does, and therefore 
believes that the suggested change would not provide equivalent 
protection from overexposure.
    The Laborers' Safety and Health Fund of North America [Tr. 1378-79, 
9/23/92] testified that, in construction, a regulated area should be 
established wherever MC is used. Although there are many uses of MC on 
construction sites that may warrant establishing regulated areas, there 
are also engineering controls available (for example, portable 
ventilation) which may reduce employee exposures so that a regulated 
area would be unneccessary. OSHA believes that employers should not be 
required to establish regulated areas unless potential exposure levels 
warrant them. The Agency also believes that the employer is in the best 
position to determine whether the exposures from a particular MC 
application will warrant establishing regulated areas at a particular 
work site. The Advisory Committee on Construction Safety and Health 
also suggested that the establishment of regulated areas could replace 
some of the standard's monitoring requirements [Ex. 21-69]. As 
discussed previously, however, OSHA believes that both employers and 
employees benefit from knowing what exposures to MC are in a given 
workplace or on a specific job assignment. OSHA has therefore not 
revised the final rule's requirement for regulated areas in locations 
where exposures exceed or can reasonably be expected to exceed either 
or both of the PELs.
    The proposal would have required that employers supply employees 
entering regulated areas with appropriate respiratory protection and 
ensure its use in such areas at all times. Several commenters [Exs. 19-
25, 19-31 and 19-49] argued that respirator use in such areas should be 
required only if occupational exposures in such areas either exceeded 
the 8-hour TWA PEL or the STEL or could reasonably be expected to 
exceed one or both of these limits. OSHA agrees with these commenters 
and has revised the final rule accordingly. Paragraph (e)(3) states 
that employers must supply a respirator to each person who enters a 
regulated area, but shall require each affected employee to use that 
respirator only if MC exposures are likely to exceed the 8- hour TWA 
PEL or STEL. Thus, not all workers in regulated areas will be required 
to wear respirators in regulated areas at all times.
    For example, under the final rule, an employer would be required to 
demarcate the area around a cutoff saw operator's work station in a 
foam blowing plant as a regulated area and to train the operator to 
recognize the area as regulated; however, the operator would only be 
required to wear a respirator in the area at times when the foam 
``bun'' was coming out of the tunnel for cutting. The employer would 
demarcate the area because he or she recognizes, based on monitoring 
results for the cutoff saw operator, that this work station is one 
where the 8-hour TWA PEL is regularly exceeded during foam blowing 
operations. Because of the intermittent nature of many foam blowing 
operations, however, respirators would need to be worn by the operator 
(or other workers assisting the operator) only when foam was actually 
being blown. This example assumes that foam blowing operations are 
intermittent and that exposures at the cutoff saw would exceed the PELs 
only during foam blowing, although this may not be the case in all 
plants or at all times. In facilities where foam is blown continually 
and the saw operator is stationed at the end of the tunnel over the 
full shift, respiratory protection would likely be required to be worn 
in the regulated area at all times because exposures would routinely 
exceed the PEL in that area.
    Under paragraph (e)(4), which has been added to the final rule, the 
employer shall ensure that, within a regulated area, employees do not 
engage in non-work activities which may increase dermal or oral MC 
exposure. This provision indicates that such non-work activities as 
eating, drinking, smoking, taking medication, applying lotions or 
cosmetics or storing such products in regulated areas are prohibited. 
Proposed paragraph (e)(4) has been promulgated as final rule paragraph 
(e)(6), as discussed below.
    In addition, under paragraph (e)(5), which has been added to the 
final rule, the employer shall ensure that employees who are wearing 
respirators do not engage in activities (such as taking medication or 
chewing gum or tobacco) which interfere with respirator seal or 
performance. Proposed paragraph (e)(5) has been promulgated as final 
rule paragraph (e)(7), as discussed below.
    Final rule paragraphs (e)(4) and (e)(5) are based on the response 
to NPRM Issue 41 (56 FR 57043) which indicated that OSHA was 
considering a provision to prohibit activities such as eating, 
drinking, smoking, etc. in regulated areas and asked for comments on 
this subject. This prohibition was supported by some rulemaking 
participants [Ex. 19-36, Tr. 1379, 9/23/92]. OSHA notes that it is 
standard industrial hygiene practice to limit such activities in 
regulated areas, both because employees should be aware at all times 
that they are working in a high- exposure area and because of health 
concerns. Among other things, since respirators are generally (although 
not always) required to be worn in regulated areas, engaging in the 
prohibited activities while wearing respirators might interfere with 
the respirator seal, placement or performance, thus reducing the 
effectiveness of the respirator. Furthermore, in the case of MC, 
smoking while being exposed to high MC concentrations (such as those 
prevailing in regulated areas) is particularly hazardous because MC is 
metabolized to CO in the body and leads to carboxyhemoglobinemia, a 
potentially life-threatening condition for some individuals, e.g., 
those with silent or symptomatic heart disease. Other OSHA health 
standards (e.g., asbestos, cadmium, ethylene oxide) have included 
similar prohibitions, and OSHA has concluded, based on the reasons 
discussed above and the Agency's experience with other standards, that 
including these

[[Page 1582]]

provisions in the final MC standard is appropriate.
    OSHA has broadened the language and separated it into two 
provisions (paragraphs (e)(4) and (e)(5)) to differentiate the types of 
activities which would generally not be allowed in a regulated area and 
those which would interfere with the effective use of respiratory 
protection. This is consistent with OSHA's intent in this rule to allow 
establishment of regulated areas, but require respirator use only when 
the 8-hour TWA PEL or STEL is likely to be exceeded.
    Paragraph (e)(6), which is essentially unchanged from the proposed 
provision, requires employers to demarcate their regulated areas, but 
it does not specify how this is to be done as long as employees are 
aware of the location of the area and access to it is thus minimized. 
Factors that the Agency believes are appropriate for employers to 
consider in determining how to demarcate their areas include the 
configuration of the area, whether the regulated area is permanent, the 
airborne MC concentration present in the area, the number of employees 
in adjacent areas, and the period of time the area is expected to have 
exposure levels above the PEL or STEL. Permitting employers to choose 
how to identify and limit access to regulated areas is consistent with 
OSHA's belief that employers are in the best position to make such 
determinations, based on the specific conditions of their workplaces. 
This performance-oriented approach gives employers compliance 
flexibility without compromising employee health.
    Paragraph (e)(7), proposed as paragraph (e)(5), requires employers 
at multi-employer worksites who establish a regulated area to 
communicate information to other potentially affected employers at the 
worksite about the location and access restrictions pertaining to the 
regulated area. OSHA believes that such communication will reduce the 
likelihood that unauthorized persons will enter the area or that 
workers not involved in MC-related operations will be exposed 
inadvertently. Those employers whose employees are exposed to MC at 
concentrations above either or both of the PELs must coordinate their 
operations with other employers whose employees could suffer excessive 
exposure because of their proximity to a regulated area where MC is 
being used. Compliance with this provision will ensure that only those 
employees at multi-employer worksites who are properly authorized, 
trained, and equipped enter regulated areas. This provision also 
recognizes OSHA's awareness that, although multi- employer worksites 
are common in construction, they are also increasingly found in other 
industry sectors.

Paragraph (f) Methods of Compliance

    Paragraph (f) addresses the means by which employers are to reduce 
employee exposures to or below the 8-hour time-weighted average (TWA) 
PEL or the STEL. Under paragraph (f)(1), employers are required to 
institute and maintain the effectiveness of engineering controls and 
work practices to reduce employee exposure to or below the PEL and 
STEL, except to the extent the employer can demonstrate such controls 
are not feasible. Where these measures cannot reduce the concentration 
of airborne MC to or below the TWA PEL and STEL, the employer is 
nevertheless required to implement them to achieve the lowest feasible 
level. The employer is required to supplement these controls with 
respirators where necessary to ensure that employees are not exposed to 
MC at levels above either the 8-hour TWA PEL or the 15-minute STEL. 
Section 1910.134(a)(1) of the respiratory protection standard requires 
respirators to be used where effective engineering controls are not 
feasible.
    One commenter [Ex. 19-57] indicated that it should be left to 
professional judgment to determine whether engineering controls or 
respirators are the best method for protecting employees. OSHA does not 
agree with this comment because it fails to acknowledge the industrial 
hygiene hierarchy of controls, which places engineering controls ahead 
of administrative or personal protective equipment as methods of 
protecting employees from hazardous exposures. The hierarchy of 
controls has been established industrial hygiene practice since the 
1950s and is based on the fact that engineering controls are the most 
effective method of protecting employees because they remove the hazard 
from the workplace. In contrast, respirators merely prevent employees 
from breathing the contaminant--it remains in the workplace air. 
Effective respirator use also requires constant supervision, extensive 
employee training and fit testing, and regular (often daily) care and 
maintenance of the respirator. Consequently, respirators should only be 
used as a means of achieving the PELs where feasible engineering 
controls are not available (such as in some vessel cleaning and non-
stationary maintenance operations) or are not sufficient to control 
exposures to required levels. All OSHA substance-specific health 
standards have recognized and required employers to observe the 
hierarchy of controls, and OSHA's enforcement experience with these 
standards has reinforced the importance of this concept to the 
protection of employee health.
    In the Final Economic Analysis, OSHA has described feasible control 
technologies for each industry affected by the final MC standard. Many 
employers have already implemented such controls in their workplaces 
and are currently achieving the MC levels required by the final rule. 
Examples of such feasible control strategies include dilution and local 
exhaust ventilation, chilling coils, magnetic pumps and magnetic 
floating gauges, exhausted lances for drum filling, and inline quality 
control sampling equipment.
    OSHA acknowledges that there may be a few operations where the use 
of engineering and work practice controls to control exposure to MC is 
infeasible because exposures are highly intermittent in nature and 
limited in duration. In particular, OSHA is aware that the use of 
engineering and work practice controls to comply with the PELs is 
infeasible for some maintenance and repair operations and during 
emergency situations. Where it is infeasible to reduce workplace MC 
levels below the PELs through engineering and work practice controls, 
the employer is required to protect employees from excess exposure by 
providing and requiring the proper use of personal protective 
equipment, in this case supplied-air respirators.
    As discussed in the NPRM (56 FR 57120-21), OSHA asked for comments 
on whether employers should be allowed to place increased reliance on 
the use of respirators to protect employees exposed to MC. The 
International Brotherhood of Painters and Allied Trades [Ex. 19-23] 
commented that ``[w]ith the exception of emergencies that require use 
of a SCBA respirator, engineering and work practice controls should be 
the sole method of compliance.''
    In addition, the IUE [Tr. 530, 9/18/92] testified as follows:

    [R]equirements to control those exposures using engineering 
controls are particularly important because of the lack of adequate 
chemical cartridge respirators for methylene chloride. For that 
reason, we reject the question posed by OSHA regarding the 
provisions to allow greater use of respirators which came from 
earlier proceedings on revisions to 1910.1000.
Also, NIOSH [Tr. 884, 9/21/92] testified as follows:

    NIOSH supports the existing OSHA policy on methods of 
compliance, that is the

[[Page 1583]]

hierarchy of controls for controlling exposures to hazardous agents. 
Generally, this policy states that whenever feasible, engineering 
controls and work practices should be used to prevent exposures, and 
that personal protective equipment, including respiratory 
protection, should be used only when engineering controls are not 
feasible.

    As discussed above, OSHA agrees with these comments. The Agency 
considers the use of respirators to be the least satisfactory approach 
to exposure control because respirators provide adequate protection 
only if employers ensure, on a constant basis, that they are properly 
fitted and worn. Also, unlike engineering and work practice controls, 
respirators protect only the employees who are wearing them from a 
hazard, rather than reducing or eliminating the hazard from the 
workplace as a whole. Moreover, respirators are uncomfortable to wear, 
cumbersome to use, and interfere with communication in the workplace, 
which can often be critical to maintaining safety and health. As 
mentioned above, OSHA has reached similar conclusions for other 
standards promulgated to protect employees from exposure to toxic 
substances. Paragraph (g) of the final standard discusses respiratory 
protection requirements.
    The NPRM also proposed requirements for a written compliance 
program that would have required employers to detail their plans for 
implementing engineering and other controls. However, OSHA has decided 
to eliminate these provisions from the final rule for MC to reduce the 
amount of paperwork employers would be required to complete. The 
Paperwork Reduction Act of 1995 (PRA 95), (44 U.S.C. 3501 et seq.), 
requires agencies to minimize the paperwork burdens on the public. 
Preparation of written compliance plans would be classified as 
paperwork under the new Act. OSHA believes that the lack of a written 
compliance plan will not substantially reduce the effectiveness of the 
standard; the Agency solicits comment on this point. One of the primary 
benefits of a written plan is that it encourages employers to consider 
remedial actions soon after the standard is promulgated. For MC, 
however, this may not be an issue because the necessary control 
measures are not complex and, except for the very smallest employers, 
the period for compliance allowed by the standard is relatively short. 
Nevertheless, OSHA believes that many employers will voluntarily 
develop these plans because they make it easier for employers and 
employees to monitor progress toward compliance. OSHA will be 
considering including compliance plans in its standards on a case-by-
case basis in future rulemakings when they are appropriate. The Agency 
believes that employers benefit from having a plan to meet the start-up 
dates, and has included examples of how this might be done in Appendix 
B. There were very few comments about the written compliance plan 
requirements, other than one stating that a written plan is reasonable 
but annual review and update of it is not [Ex. 19-26].
    Paragraph (f)(2), proposed as paragraph (f)(1)(iv), precludes use 
of a schedule of employee rotation as a means of compliance with the 
PELs. Employee rotation reduces the extent of exposure to individual 
employees, but increases the number of employees exposed. OSHA is 
regulating MC as an occupational carcinogen, and the Agency therefore 
prohibits practices that would place more employees at risk. No 
threshold has been demonstrated for the carcinogenic action of MC, and 
it is therefore prudent public health policy to limit the number of 
workers exposed. In addition, since the dose-response relationship for 
MC is convex, exposure to higher concentrations for shorter periods of 
time is riskier than exposure to the equivalent ppm-hour concentration 
spread over 8 hours (when rotation is used as a method of employee 
exposure control, employees tend to be exposed to higher concentrations 
for shorter durations).
    Paragraph (f)(3) requires employers to address leak and spill 
detection in the workplace. Employers must implement procedures to 
detect leaks and contain spills as well as follow appropriate methods 
to dispose of contaminated materials and clean-up or repair the spill 
or leak. These requirements were addressed in proposed paragraph 
(f)(1)(iii), but in the final rule have been separated out and 
clarified to emphasize their importance. Appendix A provides examples 
of procedures that would meet these requirements. Liquid MC has a high 
vapor pressure (350 mm Hg at 20 C). Accordingly, leaks and spills of 
MC-containing products could generate high airborne MC levels. The leak 
and spill detection program reduces the possibility of worker 
overexposure to MC.
    Bristol-Myers Squibb (BMS) [Ex. 19-14] and Dow [Ex. 19-31] 
supported OSHA's performance-oriented requirement for a program to 
detect leaks and spills. For example, BMS stated:

    [T]here are many ways in which this can be done (e.g. monitoring 
of tank levels, walks through areas where leaks may occur). In some 
cases, continuous monitoring can be done to detect leaks, however, 
this is not always feasible. Monitoring equipment may be very 
difficult and expensive to maintain and may not provide the 
sensitivity needed for early detection. We recommend that OSHA leave 
this section as it is and not specify the system or the equipment 
which should be used for the detection program.

    Proposed paragraph (h) required employers to develop emergency 
plans, implement those plans when necessary, equip employees correcting 
emergency situations with appropriate PPE, and alert and evacuate 
employees potentially affected by emergencies, as necessary. In 
reviewing the proposed rule, OSHA concluded that the proposed 
requirements duplicated provisions of the Hazardous Waste Operations 
and Emergency Response (HAZWOPER) standard (Section 1910.120). The 
Agency has therefore deleted the separate MC requirement for an 
emergency plan, and has added a note to final rule paragraph (f)(3)(ii) 
which refers employers to the HAZWOPER standard for the applicable 
requirements.

Paragraph (g) Respiratory Protection

    Paragraph (g) of the final rule addresses requirements for 
respiratory protection allowed to be used to comply with the MC 
standard. Paragraph (g)(1) requires that employers provide respirators 
at no cost to each affected employee, and to ensure that each affected 
employee uses a respirator under the following conditions:
    (1) Whenever an employee's exposure to MC exceeds or can reasonably 
be expected to exceed the 8-hour TWA PEL or the STEL;
    (2) During the time interval necessary to install or implement 
feasible engineering and work practice controls;
    (3) In a few work operations, such as some maintenance operations 
and repair activities, for which the employer demonstrates that 
engineering and work practice controls are infeasible;
    (4) Where feasible engineering and work practice controls are not 
sufficient to reduce exposures to or below the PELs; or
    (5) In emergencies.
    These limitations on the required use of respirators are consistent 
with OSHA's longstanding position on the hierarchy of controls in the 
workplace, as reflected in the respiratory protection requirements in 
other OSHA health standards (e.g., asbestos, Sec. 1910.1001; ethylene 
oxide, Sec. 1910.1047; benzene, Sec. 1910.1028; cadmium, 
Sec. 1910.1027) and with good industrial hygiene practice. They reflect 
OSHA's determination that respirators are inherently less reliable in 
providing protection to exposed

[[Page 1584]]

employees than engineering and work practice controls.
    However, to reflect the changes made to the final rule's regulated 
area provision (paragraph (e)(1)), the final rule's respiratory 
protection requirements differ somewhat from those in proposed 
paragraph (g). In the NPRM, OSHA proposed to require that employers 
provide respirators in the following circumstances: (1) During the time 
interval necessary to install or implement feasible engineering and 
work practice controls; (2) in work operations, such as maintenance and 
repair activities, vessel cleaning, or other activities for which 
engineering and work practice controls are demonstrated to be 
infeasible, and when exposures are intermittent in nature and limited 
in duration; (3) in work situations where feasible engineering controls 
are not yet sufficient to reduce exposure to or below the PELs; and (4) 
in emergencies. In the final rule, another situation where respirator 
use is appropriate is acknowledged: whenever an employee's exposure to 
MC exceeds or can reasonably be expected to exceed either or both of 
the PELs.
    The Building and Construction Trades Department, AFL-CIO, testified 
[Tr. 816-17, 9/21/92] that proposed paragraph (g)(1)(ii) could be 
interpreted by construction contractors ``as an exemption from the 
requirement for adopting a control strategy that places engineering and 
work practice controls above that of the PPE.'' In response, OSHA has 
revised final rule paragraph (g)(1)(ii) to clarify OSHA's intent. OSHA 
recognizes that it may be infeasible to control MC exposure with 
engineering and work practice controls during certain maintenance and 
repair operations, although OSHA is also aware that portable local 
exhaust, ``elephant trunks,'' and other means of providing ventilation 
to, and removing contaminated air from, process vessels and other 
difficult-to-reach work spaces are widely used in construction and 
elsewhere. The Agency also recognizes that there may be other MC-
related activities where an employer could establish the infeasibility 
of controls, particularly where employee exposure is highly 
intermittent or of short duration. Accordingly, OSHA has revised 
proposed paragraph (g)(1)(ii) as described above. This change also 
addresses comments made by the Pharmaceutical Manufacturers Association 
(PMA) [Ex. 19-25; Tr. 1430, 9/23/92], which stated that it was 
infeasible for employers to protect employees during manual unloading 
of batch operated centrifuges and manual loading of dryers from MC 
exposure with engineering and work practice controls. The PMA suggested 
that OSHA revise proposed paragraph (g)(1)(ii) to include those loading 
and unloading activities in the list of operations allowed to protect 
affected employees through the use of air-supplied respirators. 
However, OSHA included examples in the proposal only to provide a 
general indication of the situations where the Agency would accept the 
use of air-supplied respirators in lieu of engineering and work 
practice controls. OSHA believes that the examples suggested by the PMA 
are too narrowly focused for inclusion in such a list. It would not be 
possible for OSHA to enumerate in the final rule all of the workplace-
specific operations where engineering and work practice controls may be 
infeasible. Therefore, in accordance with longstanding OSHA practice, 
employers claiming that engineering and work practice controls are 
infeasible must establish infeasibility on an objective basis.
    Other commenters were concerned about requiring respirators during 
emergency escape situations, noting the time involved in donning a 
respirator in an emergency. The Dow Chemical Company stated ``Dow 
believes the respiratory protection requirements for emergency escape 
are excessive. For the short period of time it takes to escape a 
release of MC, considering the minor acute effects of the material, it 
is excessive to require, as a minimum, a gas mask with an organic vapor 
canister'' [Ex. 19-86].
    Similarly, comparing escaping right away or first finding a 
respirator and then escaping during an emergency situation, Occidental 
Chemical testified [Tr. 2041, 10/14/92]:

    Methylene chloride is not incapacitating so the goal should be 
to escape as fast as possible not trying to find a device--and it 
may be close, it may be further--and then put it on, which could 
take a minute or so, 30 seconds or a minute, and then decide about 
escape. That whole process becomes much longer. So I'm not 
advocating we don't have escape respirators, just that the process 
should be, escape should be the number one priority.

    OSHA agrees that escape is the first priority for employees exposed 
to MC in an emergency situation. Furthermore, the Agency has 
determined, in general, that the ready availability of escape 
respirators is essential to ensure that employees are able to escape 
safely. To that end, emergency plans must provide for fast access to 
escape respirators where the potential for emergency exposure 
situations has been identified by the employer. In addition, employees 
must be trained to don those respirators properly and quickly and to 
recognize any foreseeable situations where taking the time to obtain 
and put on their respirators would significantly reduce their ability 
to escape or where they can safely escape an emergency situation 
without using respirators. OSHA recognizes that immediate escape is not 
always possible, so respirators are needed to protect those employees 
while they are still in the exposure area.
    Paragraph (g)(2), proposed as paragraph (i)(1)(ii), requires 
employers to determine that any employee required by this standard to 
wear a supplied-air respirator in the negative pressure mode or a 
negative-pressure respirator for escape purposes is medically fit to 
use such a respirator. This provision has been changed from the 
proposal to recognize that medical fitness for respirator users under 
this standard is appropriate only for negative-pressure respirators or 
those operated in that mode. This change will assist employers to 
direct their medical surveillance resources effectively. In addition, 
in keeping with the greater flexibility provided by this standard to 
employers in selecting an appropriate health care professional, 
paragraph (g)(2) uses the final rule's language, ``Physician or other 
licensed health care professional,'' in lieu of the proposal's 
exclusive use of ``physician.''
    Paragraph (g)(3), proposed as paragraph (g)(2), requires employers 
to select appropriate atmosphere-supplying respirators from among those 
listed in Table 2 (Table 1 in the proposed rule), which sets forth the 
minimum requirements for respiratory protection and is unchanged from 
the proposal. Employers may use respirators approved for a higher level 
of protection in lower concentrations of MC. Employers are required to 
select atmosphere-supplying respirators that have been approved by 
NIOSH under the provisions of 42 CFR Part 84. Also, employers must 
select vapor canisters which have been approved by NIOSH when they 
provide gas masks with organic vapor canisters for use in emergency 
escape. The final rule differs from proposed paragraph (g)(2) in that 
it does not require employers to give employees who cannot wear 
negative pressure air-supplied respirators or who cannot wear a 
negative pressure (organic vapor canister) during an emergency escape 
the option of wearing a respirator with less breathing resistance. OSHA 
believes that the respirators required by the final rule will not 
strain an employee's respiratory system during such use.
    Issue 30 (56 FR 57042) asked if the proposed respirator selection 
table

[[Page 1585]]

(Table 1 in the proposal) appropriately regulated the choice of 
respirators. Several commenters suggested changes. For example, Abbott 
Laboratories [Ex. 19-29] suggested that OSHA allow the use of a 
continuous flow air-supplied hood or helmet for exposures up to 5,000 
ppm instead of 625 ppm of MC. On the other hand, the Laborers' Health & 
Safety Fund of North America [Ex. 19-36] suggested that OSHA require 
employers to provide positive pressure SCBAs or airline positive- 
pressure full facepieces with auxiliary escape for all exposures over 
25 ppm, instead of allowing any flexibility, in keeping with NIOSH 
recommendations for respiratory protection against carcinogens. The 
Advisory Committee on Construction Safety and Health [Ex. 21-69] 
recommended that respirators, when used, be pressure-demand, supplied 
air respirators with an auxiliary self-contained breathing apparatus, 
because of MC's fast cartridge/canister breakthrough and the lack of 
effective end-of-service-life indicators.
    OSHA is currently in the process of developing a final standard to 
revise its general respiratory protection provisions in 29 CFR 
1910.134. Until that rulemaking is completed the Agency will continue 
to rely on NIOSH's Assigned Protection Factors (APF) for determining 
the types of respirators required for protection to airborne 
concentrations of MC. The APF for continuous flow hoods/helmets is 25 
in the NIOSH Respirator Decision Logic. The maximum specified use 
concentration for a respirator is generally determined by multiplying 
the exposure limit, in this case 25 ppm, by the protection factor, 
which is 25; therefore, these hood/helmets could be used only up to 625 
ppm of MC. Using the same decision logic, OSHA believes that adequate 
protection can be provided by the respirators described in Table 2 when 
they are used under appropriate exposure conditions.
    Some commenters questioned the reliability of atmosphere-supplying 
respirators. For example, in the furniture stripping industry 
commenters noted that MC could cause damage or potential damage to the 
hoses, the plastic lens, and the gasket of the facepiece of air line 
respirators or other kind of respirators, resulting in inadequate 
protection. [Ex. 19-11; Tr. 348-9, 9/17/92; Tr. 2146-7, 10/14/92; Tr. 
2505-2506, 10/15/92]. In addition, the Occidental Chemical Corporation 
[Tr. 2115, 10/14/92] noted that none of the manufacturers contacted had 
hoses resistant to MC-induced corrosion. The Agency acknowledges that 
MC may damage respirator components, if the MC is left on them for 
extended periods of time. However, existing Sec. 1910.134 (f) already 
requires employers to inspect respirators frequently and to maintain 
respirators at their original effectiveness. In addition, MC does not 
damage rubber components which are available. Most importantly, if 
feasible engineering controls and work practices are not available, 
properly utilized air-supplied respirators are the only way to protect 
employee health from significant risk.
    Issue 30 also requested information on the circumstances under 
which air-purifying respirators may be used. Dr. Morton Corn of Johns 
Hopkins University testified [Tr. 2352, 10/15/92] that ``* * * with the 
current state of knowledge and the breakthroughs I indicated, [allowing 
gas masks with organic canisters for emergency escape only] is a 
prudent restriction at this time.''
    Several commenters disagreed with Dr. Corn and remarked that there 
are some situations where air-purifying respirators may be appropriate 
in addition to emergency situations, and recommended that OSHA expand 
the provision to allow the use of air-purifying (filter) respirators. 
For example, Occidental Chemical testified [Tr. 2113-4, 10/14/92] as 
follows:

    Transportation workers who make deliveries in trucks can have 
intermittent exposure to methylene chloride inside the truck and, if 
you set the PEL too low, and in that emergency situation * * * you 
can't have engineering controls on some types of trucks, especially 
if they are rented. You ought to allow the use of respirators in 
that case; it's a very short type exposure, goes in, takes the drum 
out, and then gets back in the truck. Now it may be possible to 
schedule operations in certain industries where the PEL is exceeded 
for short periods of time. Filter cartridge respirators could be 
used to protect the worker during the short periods of time without 
the use of cumbersome supplied-air respirators. Of course, you have 
to have changes in the regulated areas in the rules also if you're 
going to allow the use of respirators where you have intermittent 
exposures above the PEL.
    And a short breakthrough time does not mean a respirator is 
useless. If you use the NIOSH calculations, at 200 parts per million 
which might be typical of paint stripping, you ought to have about 
118 minutes worth of time before you get breakthrough; and that may 
be enough in paint stripping operations.

    Similarly, Bristol-Myers Squibb stated that air-purifying 
respirators may be appropriate in certain circumstances [Ex. 19-14]:

    Based upon the scientific information now in the record, BMS 
requested that OSHA consider allowing chemical cartridge air-
purifying respirators for specific types of activities (lower MC 
concentrations, shorter durations).
    Organic vapor cartridges can be used for protecting employees 
against exposures to MC where using an air-supplied respirator would 
not be feasible due to costs or process (e.g. multiple working 
areas). Only air-supplied respirators should be used for operations 
involving the need for extended wear (e.g. greater than several 
hours).

    The Eastman Kodak Company [Ex. 102] also requested that OSHA allow 
air-purifying respirators ``in circumstances where their effectiveness 
can be adequately demonstrated, engineering controls are not feasible 
and supplied-air respirators are impractical or potentially unsafe. 
OSHA also should permit the use of half mask respirators'' [Tr. 1196-7, 
9/22/92]. In addition, Kodak described specific situations where it 
believed the use of air-purifying respirators was appropriate:

    The use of air-supplied respirators must be an essential 
component of the exposure-control strategies for both the Roll 
Coating Division and the Dope Department. Moreover, the evidence 
demonstrates that air-purifying canister or cartridge-type 
respirators may appropriately be used in some operations, such as 
certain dope maintenance tasks. The use of air-purifying respirators 
is appropriate where: (1) air-supplied respirators or other controls 
are impractical or potentially unsafe, (2) personal monitoring of 
employees is conducted regularly, (3) the extremes and conditions of 
the exposure potential are well characterized, and (4) used 
cartridges are tested after use to verify the absence of 
unacceptable breakthrough. It is essential that OSHA permit the use 
of air-purifying respirators under these circumstances so that Kodak 
can control employee exposure when engineering and work practice 
controls and air-supplied respirators are infeasible, ineffective or 
potentially unsafe.

    OSHA considered including a provision in the final rule to allow 
exceptions for the use of air-purifying respirators in limited 
circumstances where very tight control of the respirator program is 
implemented. However, the Agency has rejected this alternative for 
several reasons. First, the record strongly supports the inadequacy of 
such respirators for employee protection. Consequently, the use of air-
purifying respirators should only be considered when the use of air- 
supplied respirators presents major disadvantages. Second, a program to 
use air-purifying respirators would have to be very detailed and be 
tailored to a specific workplace. It would be difficult, if not 
impossible, to list all of the relevant factors and criteria for such a 
program in the regulatory text, which must necessarily be appropriate 
to apply to many workplaces. (Below, OSHA discusses the Agency's 
variance procedures, which employers wishing to use air-purifying 
respirators may use to apply for a variance.)

[[Page 1586]]

    While there may be circumstances when the use of filter respirators 
may seem preferable to the use of atmosphere-supplied respirators, OSHA 
has concluded, as a general matter, that air- purifying respirators do 
not provide sufficient, consistent, and reliable protection to 
employees exposed to MC. In support of this conclusion, NIOSH testified 
as follows [Tr. 887-89, 9/21/92]:

    At the request of OSHA, NIOSH has completed an in-depth study of 
the breakthrough characteristics of MC for organic vapor respirator 
cartridges and canisters under a variety of test conditions. This 
work was undertaken to determine MC breakthrough time for 
commercially available, organic vapor respirator cartridges and 
canisters. Several MC challenge concentrations were studied, ranging 
from 50 ppm to 1,000 ppm. As received cartridges and canisters were 
tested at equivalent flow rates of 64 Lpm through the respirator and 
at both 50% and 80% relative humidities (RHs). Breakthrough times 
were determined for individual cartridges and canisters, as well as 
stacked cartridges. The results of this study show rapid 
breakthrough of MC for organic vapor cartridges even for low 
concentrations of MC (e.g., 5 ppm breakthrough at approximately 30 
minutes for 50 ppm challenge concentration and 80% RH). Appendix D 
is a detailed report of this study. At 125 ppm challenge 
concentration, 5 ppm breakthrough, and 80% RH, one brand of 
cartridge showed breakthrough times of approximately 40 minutes. The 
same brand of chin-style canister, that contains approximately 2 and 
\1/2\ to 3 times more sorbent than two cartridges (i.e., two 
cartridges per respirator) showed breakthrough times of 
approximately 100 minutes when tested at the same conditions. The 
same brand of front- or back-mounted canister, that contains 
approximately 10 times more sorbent than two cartridges, showed 
breakthrough times of approximately 600 minutes. Based on the 
results of this study, NIOSH supports the OSHA proposal to require 
the use of air-supplied respirators in lieu of air-purifying 
respirators. However, because of the potential carcinogenicity of 
MC, NIOSH continues to recommend only the most protective positive-
pressure respirators as noted previously.

    The NIOSH study indicated that MC quickly penetrates organic vapor 
cartridges (in a fraction of a typical work shift), contrary to the 
assertions of Occidental Chemical and the other commenters mentioned 
above. Larger canisters, which contain greater amounts of absorbent, 
last longer, but are still effective for less than a work shift (except 
for very large canisters). Another problem with organic vapor 
cartridges and canisters is that MC migrates through the absorbent even 
when the respirator is not being used. This further decreases the 
breakthrough time and raises the possibility that the employee will be 
exposed to significant concentrations of MC. Also, humidity decreases 
the amount of MC collected by the absorbent.
    Another problem with air-purifying respirators in the case of MC is 
this substance's poor warning properties, which mean that workers will 
not be able to smell or sense the presence of MC when breakthrough 
occurs. OSHA believes that employees wearing air-purifying respirators 
could easily have a false sense of security and be lulled into 
believing that they were being protected against MC when it could 
already have broken through the absorbent. Accordingly, OSHA has 
concluded that it would be inappropriate to allow broad-scale use of 
air-purifying respirators because of MC's quick breakthrough time and 
its carcinogenic health effects.
    Employers who believe that the use of filter respirators is 
appropriate for their operations may apply for a permanent variance 
from the requirements of paragraph (g)(3) of this section, pursuant to 
the authority granted by Sec. 6(d) of the Occupational Safety and 
Health Act and the procedures set out in 29 CFR part 1905. In 
particular, an applicant would need to establish that the use of filter 
respirators in a specific workplace would provide employee protection 
equivalent to that which would be provided through compliance with 
final rule paragraph (g)(3). As discussed below, the respirator 
program, procedures, and data needed to support the use of such 
respirators under a variance are extensive.
    A successful variance application for an exception that would allow 
air-purifying respirators would have to address a number of the 
characteristics that employers such as Eastman-Kodak [Ex. 102] indicate 
they have undertaken with regard to the use of such equipment. For 
example, extensive exposure monitoring would have to be done to 
accurately characterize employee MC exposure levels. Furthermore, the 
breakthrough time for MC when used in the airborne concentrations 
expected in the workplace would have to be known, and cartridges would 
have to be changed before employees are unacceptably exposed. The 
program would have to be carefully monitored by a trained and 
experienced individual such as a certified industrial hygienist or the 
equivalent. Finally, the respirators would have to be appropriately fit 
tested for each affected employee. For all of the reasons stated above, 
OSHA has determined that the interests of employee protection will be 
best served by requiring all employers, except those whose respiratory 
program, procedures, and exposure data can support a variance request, 
to provide their employees with the respirators shown in Table 2.
    Paragraph (g)(4), which is identical to the proposed (g)(3), 
requires employers to implement a respiratory protection program in 
accordance with 29 CFR 1910.134 whenever respirator use is required by 
this standard. The respiratory protection program must include basic 
requirements for proper selection, fit, use, training of employees, 
cleaning, and maintenance of respirators. For employers to ensure that 
employees use respirators properly, OSHA has found that the employees 
need to understand the respirator's limits and the hazard against which 
it is providing protection in order to appreciate why specific 
requirements must be followed.
    Paragraph (g)(5) (effectively identical to proposed paragraph 
(g)(4)) requires that employers allow employees wearing respirators to 
leave the regulated area to readjust the respirator facepiece to their 
faces for proper fit. In addition, employers must permit employees who 
wear respirators to leave the regulated area to wash their faces as 
necessary to prevent skin irritation associated with respirator use. 
These requirements encourage the proper use of respirators by 
authorizing employees to take specific actions that ensure the 
effective functioning of respirators and reduce the likelihood that 
employees will experience adverse side effects from wearing 
respirators.
    Paragraph (g)(6), which is essentially the same as the 
corresponding proposed paragraph, addresses situations where employers 
provide gas masks with organic vapor cartridges for purposes of 
emergency escape. If gas masks are used, the canisters are to be 
replaced before the gas masks are returned to service. This requirement 
is necessary because actual MC exposures during emergencies are 
generally not known, so the expected service life of the canister 
cannot be determined. In addition, the migration of MC within the 
canister after emergency exposure further reduces the amount of useful 
life remaining, posing exposure risks for subsequent users.
    Paragraph (g)(7) addresses respirator fit and is essentially 
identical to the corresponding provision of the proposal. It requires 
the employer to ensure that each respirator issued is properly fitted 
and has the least possible facepiece leakage.
    Under paragraph (g)(7)(ii), the employer must perform qualitative 
or quantitative fit testing initially and at

[[Page 1587]]

least annually thereafter for each employee wearing a negative pressure 
respirator, including those employees for whom emergency escape 
respirators of this type are provided. A note has been added to this 
provision to indicate clearly that the only supplied-air respirators to 
which this provision would apply are SCBAs operated in the negative 
pressure mode and full facepiece supplied-air respirators operated in 
negative pressure mode. Quantitative fit testing relies on objective 
data generated by measurements of facepiece seal leakage, in contrast 
to qualitative fit testing, which is based on subjective observations 
made by the respirator wearer. Many commenters expressed a preference 
for quantitative fit testing over qualitative fit testing. For example, 
Newport News Shipbuilding (NNS) [Ex. 19-37, p. 2] stated: 
``Quantitative respirator fit testing is the method of choice. At NNS 
we use quantitative fit testing exclusively, as this method is more 
definitive than qualitative fit testing and provides a record of the 
fit test.'' The Shipbuilders Council of America [Ex. 19-56, p. 11] took 
the same view.
    Several commenters noted the importance of proper selection and fit 
testing of respirators [Exs. 19-12, p. 3; 19-31, pp. 15-17; 19-71, p. 
4]. Dr. David Newcombe of the Department of Environmental and Health 
Sciences at The Johns Hopkins University testified as follows:

    I think that's [quantitative fit testing] a very important 
parameter because, first of all, respiratory protection when it's 
required takes a reasonable amount of time to ensure that the 
individual is properly fitted so that the mask fits if that's the 
piece that's going to be used and is protective against the 
substance that you're protecting against and, in addition, I think 
it's important to note that some people may have deformities that 
cause a poor fit and, therefore, don't protect and so I would think 
that you have to have a careful assessment of the type of 
respiratory protection you're going to use, its fit in a single 
individual as well [Tr. 800, 9/18/92].

    In most cases, OSHA has determined that positive pressure 
respirators are the respirators of choice for MC exposure, especially 
loose-fitting models such as hoods or helmets; for these respirators, 
fit testing is generally not needed. However, for those situations 
where negative pressure respirators are used, fit testing is needed. 
Qualitative or quantitative fit testing allows the employer to test 
various respirators on the employee until the appropriate fit is 
identified and selected for the employee.

Paragraph (h) Protective Work Clothing and Equipment

    Paragraph (h) requires that, where needed, employers provide and 
ensure the use of the appropriate protective clothing and equipment. 
The requirements for protective work clothing and equipment were 
separated from proposed paragraph (g) (respiratory protection and 
personal protective equipment) and moved to paragraph (h) to facilitate 
compliance. Proposed paragraph (g)(6) was effectively identical to this 
paragraph.
    Protective clothing used during exposure to MC, such as gloves or 
aprons, must be resistant to MC. The Building and Construction Trades 
Department, AFL-CIO [Tr. 832, 9/21/92] suggested that OSHA codify 
NIOSH's recommendations for protective clothing materials suitable for 
use with MC. MC is a constituent of so many different products that a 
codification of guidance regarding appropriate protective clothing 
would be unwieldy and unlikely to be complete. Further, the continual 
formulation and reformulation of MC products virtually ensures the 
early obsolescence of any protective clothing guidelines.
    Therefore, OSHA believes that it is appropriate for paragraph (h) 
to set general criteria and for the Agency to adopt the NIOSH 
recommendations in a nonmandatory appendix so employers will have more 
detailed guidance and so OSHA can update that guidance, without 
rulemaking, as advances in PPE technology cause existing guidance to 
become outdated. As discussed above, this performance-oriented approach 
reflects OSHA's belief that employers are in the best position to 
select protective measures that are tailored specifically to the needs 
of their workplaces.
    Paragraph (h) requires the employer to provide all necessary 
protective clothing and equipment at no cost to the employee and to 
launder, repair, replace and safely dispose of that clothing and 
equipment. The final rule is performance-oriented so the employer has 
the flexibility to provide only the protective clothing and equipment 
necessary to protect employees in each particular work operation from 
MC exposure. The generic requirements for PPE in the general industry, 
construction, and shipyard standards also apply to PPE for MC, except 
where a specific provision of the MC standard applies.

Paragraph (i) Hygiene Facilities

    Paragraph (i) of the final rule establishes requirements for 
hygiene facilities in establishments where it is reasonably foreseeable 
that an employee's eyes or skin may contact solutions containing 0.1 
percent or greater MC. Although such provisions were not part of the 
proposed rule, OSHA requested comment on the appropriateness of 
including such requirements in Issue 38 (56 FR 57122). Specifically, 
the Agency requested comment on the appropriateness of including 
requirements for quick-drench showers and eye-wash facilities in the 
final rule. OSHA described quick-drench showers as,'' * * * showers 
that could drench an employee with piped-in water applied with force,'' 
and eyewash facilities as devices ``that could flush the eyes 
repeatedly with a great amount of water.'' In response to comments, 
described below, the Agency has decided that it is not necessary to 
specify in the final rule when showers and eyewash facilities are 
required to protect employees from skin or eye contact with MC, because 
employers are in the best position to determine whether the MC used in 
their establishments meets the 0.1 percent cutoff specified in this 
provision and whether contact of the eyes or skin with MC can 
reasonably be foreseen.
    Paragraph (i)(1) requires employers to provide conveniently located 
washing facilities appropriate to removing MC if it is reasonably 
foreseeable that the employee's skin may contact a solution containing 
0.1 percent or greater MC through splashes or spills. MC can be 
absorbed into the body through skin contact (percutaneous absorption), 
which would add to the dose employees receive via inhalation and thus 
increase the risk of cancer and other adverse health effects. However, 
MC is not a corrosive chemical, and, if left on the skin for short 
periods, is not likely to cause long-term or irreversible damage. 
Therefore, it is important that employers make provisions to remove MC 
from the skin of employees quickly, although immediate drenching is not 
usually required. This requirement has been stated in performance-
oriented language in the final rule to allow employers to determine 
what type of washing facilities are needed and at what distance from 
affected employees. This provision thus recognizes that employers in 
some facilities, such as furniture stripping shops where a thick MC gel 
is used that may burn the skin on contact, employers need to position 
washing facilities in closer proximity to affected employees than is 
the case where less hazardous solutions of MC are used. OSHA believes 
that this requirement of the final rule strikes the

[[Page 1588]]

right balance between employee protection and employer flexibility by 
ensuring that washing facilities for the skin will be available and 
appropriately placed in workplaces where such contact is likely.
    MC splashed into the eyes will cause irritation if the MC is not 
promptly washed out, and immediate flushing is therefore required. 
Paragraph (i)(2) requires employers to provide appropriate eyewash 
facilities within the immediate work area for emergency use if it is 
reasonably foreseeable that an employee's eyes will contact solutions 
containing 0.1 percent or greater MC through splashes or spills.
    Existing OSHA requirements at Sec. 1910.141 and Sec. 1926.51 
establish generic provisions for hygiene facilities but do not focus on 
MC-specific situations. Existing Sec. 1910.151(c) and Sec. 1926.50 (g) 
require employers to provide suitable facilities for quick-drenching or 
flushing of body and eyes within the immediate work area for immediate 
emergency use, when the body or eyes may be exposed to injurious 
corrosive materials. However, because MC is not classified as a 
corrosive material, these existing requirements would not apply. Thus 
the final rule's performance-oriented requirements will provide 
guidance to employers about what facilities and access distances are 
appropriate for conditions in their workplaces. In addition, Appendix A 
provides examples of both washing facilities and eyewash facilities 
that would satisfy this requirement.
    The response to Issue 38 emphasized the need for eyewash and shower 
facilities [Exs. 19-37, 19-56; Tr. 2644-2645, 10/16/92; Tr. 1942-1943, 
9/24/92]. For example, PRMA testified [Tr. 348, 9/17/92] that MC 
splashes happen ``almost every day'' in furniture stripping workplaces.
    Commenters also addressed the health effects associated with such 
accidental exposures. The Amalgamated Clothing and Textile Workers 
Union testified [Tr. 1825, 9/24/92]:

    I would advocate including it [the provisions for showers and 
eyewash facilities]. It [methylene chloride] has skin effects. 
Anyone who's ever stripped paint can tell you about what it's like 
to get it on their skin or their eyes. So it's very important to be 
able to irrigate an affected area promptly.
    One means to provide protection from prolonged skin or eye exposure 
to MC from accidents is to specifically require quick-drench showers 
and eyewashes. The NPRM sought comments on whether or not the final 
rule should require employers to provide quick-drench showers and 
eyewash facilities. Many commenters recommended that the final rule 
contain such provisions [Exs. 19-15; 19-36; Tr. 532, 9/18/92; Tr. 1380, 
9/23/92; Tr. 2352-53, 10/15/92]. For example, PRMA [Ex. 19-11] favored 
a requirement for eyewash/ quick drench facilities, stating as follows:

    An eyewash station is a safety device that should be required in 
any work environment where there is the possibility of splashing 
chemicals into ones eyes. Quick drench showers are also a safety 
device that should be standard equipment in every facility. MC paint 
removers are one of the few paint removers that are easily rinsed 
from one's eyes.

The Dow Chemical Company commented [Ex. 19-31]:

    Washing facilities are always a good idea when working with any 
material, however, it is not always necessary to have quick-drench 
showers, etc. Incidentally, quick-drench showers do not deliver 
water ``applied with force.'' They work on a deluge system 
delivering a large amount of water to wash off the material, not 
force it off. Installing showers and eyewash fountains in all 
workplaces may not be economically feasible. There are other systems 
such as water hoses, portable eye-washes, etc. that work effectively 
for MC. MC is a material that, in some cases, may be painful if held 
against the skin for a period of time, but is not eye nor skin nor 
life threatening. Therefore, an immediate shower is not required.

    OSHA agrees that quick drench and eyewash facilities are effective 
means for treating employees who have been accidentally exposed to MC 
by spills or splashes. However, the Agency agrees with Dow Chemical 
that quick drench showers are not the only means to ensure proper first 
aid treatment for MC exposure due to accidental splashes or spills and 
believes that other types of washing facilities can also provide 
effective treatment for accidental exposure.
    In some cases, the availability of a hose attached to a potable 
water supply would enable employers to provide effective first aid 
treatment. This could be an especially effective means of protection at 
a construction worksite. Several commenters [Ex. 19-23, 19-38; Tr. 859, 
9/21/92] agreed that construction employers should have potable water 
at the worksite in case of accidental exposure. For example, the 
Building and Construction Trades Department, AFL-CIO, testified [Tr. 
817, 9/21/92]:

    The standard does not address the need for available hygiene 
facilities. Since methylene chloride can damage the skin and eyes 
and potable water is often in limited supply on construction sites, 
the requirement for potable washing areas must be clearly stated in 
the standard. Potable water supplies should be of sufficient volume 
to provide at least 15 minutes of continuous flushing.

    The Occupational Health Foundation testified that the MC standard 
should require that hygiene facilities be provided within a reasonable 
distance at construction worksites [Tr. 858-859, 9/21/92]:

    Unlike in a lot of other work sites where at least there's a 
sink nearby, in construction you really need to specifically mandate 
that provision to be sure that there's going to be water anywhere 
remote, you know, within a reasonable distance to the work site.

    Issue 38 also requested information on the extent to which MC-
exposed employees are already provided with quick drench showers and 
eye wash facilities. Several commenters described workplaces that have 
emergency shower or eyewash facilities in place. The United Automobile, 
Aerospace and Agricultural Implement Workers of America (UAW) testified 
[Tr. 1942-1943, 9/24/92] ``[t]here are a lot of showers and eye washes 
in areas where you have open-top chemicals or use of chemicals.'' In 
addition, the Occidental Chemical Corporation testified [Tr. 2159, 10/
14/92]:

    . . . we conducted a survey of our customers that were not CMA 
and not NACCD members recently and asked them questions like that. 
We have some information on that. It doesn't necessarily mean that 
we hit a large percentage of our methylene chloride customers, 
though.
    . . . we have safety shower[s] and eyewash[es] [in our plants], 
certainly. We have . . . recommendations on it and we certainly 
follow the ANSI standards on it.

    Newport News Shipbuilding (NNS) and the Shipbuilders Council for 
America both commented [Exs. 19-37 and 19-56] that ``[p]rocedures at 
NNS now require eyewash units. For the most part we use portable (5 
gallon) units. Plumbed combination units would be better.'' The 
National Tank Truck Carriers, Inc. also indicated that their facilities 
are already equipped with emergency showers [Tr. 1750-51, 9/24/92].
    With regard to the proximity of employees to emergency showers and 
eye washes, commenters and testimony indicated that, depending on the 
work operation, shower facilities have been installed as close as eight 
feet or as far away as 100 feet. For example, the J. M. Murray Center, 
testified [Tr. 1047-48, 9/21/92] that they have both eye washes and 
showers that are ten to twelve feet from the employees.
    The Polyurethane Foam Association (PFA) testified [Tr. 1630, 9/23/
92] that the proximity of shower facilities and eye washes depends on 
the plant and

[[Page 1589]]

operation within the plant, stating as follows:

    We've got methylene chloride in bulk storage area and we also 
use it at the foam machine. The total range from those things that 
you might be would be anywhere from eight feet to may be 60 feet. 
And I'm guessing at the 60 feet. That, again, is specific for those 
plants that I am responsible for. There are 80-some-odd plants out 
there, and I can't speak for that particular physical setup in each 
one of those plants.

    The PFA further stated in its post hearing comment:

    Eye wash and drench showers are available in the production 
areas. These are located within 10 to 15 feet of the work stations, 
such as near bulk storage tanks and the mixing head, where a higher 
risk of employee exposure exists. Hygiene facilities may be 50 to 75 
feet away from other work areas [Ex. L-100A].

    The Eastman Kodak Company testified [Tr. 1259, 9/22/92] that 
emergency eye-wash and quick-drench showers are available in their 
workplaces, and that such stations are between 50 and 100 feet from all 
work areas where exposure to chemicals may occur.
    Striptech International, which advocated requirements for pressure 
showers and eyewash facilities where workers are exposed to MC [Ex. 19-
15], also testified that hygiene facilities are not readily accessible 
in the aircraft paint stripping industry [Tr. 1834-35, 9/24/92]:

    I've heard people ask about deluge in eye wash. Does it exist in 
aircraft maintenance hangars? Yes, it surely does; but you also have 
to look at where they normally are. They're normally on the walls. 
When a man or a lady is on top of an aircraft, on the tail of an 
aircraft, they may be nine stories in the air. If they get methylene 
chloride in their eyes or really a bad shot of it, they've got to 
come down nine stories and may be cross a 400 to 600-foot-long 
hangar to get to it. Deluge showers, yes; all aircraft people have 
them. Are they readily accessible? No.

    It is important for the employer to evaluate the potential hazard 
posed by the particular use of MC and to provide appropriate washing 
facilities within a reasonable distance and eyewash facilities within 
immediate reach. In addition, employers are required to provide 
employees who are at risk of skin and/or eye contact with MC with 
appropriate protective clothing and eye protection. Portable eyewash 
units, which would significantly reduce any delay in irrigating the 
eyes, are available and can be located within easy access distance of 
affected employees. As described above, access to washing facilities 
should be quick, but immediate showering is not generally necessary to 
address the MC skin hazard. Therefore, an employee stripping an 
airplane would likely have time to get to the showers located along the 
walls of the hangar to wash MC from the skin. (Note: Some paint 
stripping compounds do contain corrosives, and immediate access to 
quick-drench facilities is essential in such cases.) Based on a review 
of the rulemaking record, the Agency has determined that performance-
oriented provisions for hygiene facilities are reasonably necessary to 
supplement the other requirements of the final rule and has promulgated 
paragraph (i) accordingly.

Paragraph (j) Medical Surveillance

    Section 6(b)(7) of the OSH Act requires that, where appropriate, 
occupational health standards shall prescribe the type and frequency of 
medical exams or other tests to be made available, by the employer or 
at the employer's cost, to exposed employees in order to determine if 
the employee's health is being adversely affected by exposure to 
workplace hazards.
    A medical surveillance program that complies with paragraph (j) 
enables the employer to:
    (1) Determine if an employee has an underlying health condition 
that places the employee at increased risk from the effects of exposure 
to MC;
    (2) detect, insofar as possible, early or mild clinical conditions 
arising as a result of MC exposure, so that appropriate preventive 
measures can be taken;
    (3) identify any occupational diseases that occur as a result of MC 
exposure; and
    (4) help to evaluate possible trends in the incidence of these 
diseases.
    The most serious health effect that may result from MC exposure is 
cancer. Although a medical surveillance program cannot detect MC-
induced cancer at a preneoplastic stage, OSHA anticipates that, as in 
the past, methods for early detection and treatments leading to 
increased survival rates will continue to evolve. Moreover, the 
cardiovascular disease, central nervous sytem and dermal irritation 
effects caused by MC exposure can already be detected at early or mild 
stages by medical surveillance provisions such as a medical history and 
a medical exam. MC has not been tested adequately for the full range of 
possible health effects that may result from exposure, so it is also 
not presently possible to identify all diseases that may be associated 
with exposure to MC. The specific level of protection afforded the 
worker by the final standard cannot be predicted with certainty, 
although the risk of exposure for those effects that have been 
identified are significant, and the record shows that reducing the 
exposure of employees will significantly reduce that risk. An important 
goal of the medical surveillance program is to provide information 
related to the adequacy of the PELs for MC by documenting the health 
condition of exposed employees, particularly in the area of 
carcinogenicity.
    Several rulemaking participants [Exs. 19-31, 19-83, Tr. 1802-3, 9/
24/92] stated that the proposed medical surveillance provision should 
be deleted from the final rule because it would not detect employee 
exposure to harmful levels of MC. In addition participants contended 
[Ex. 19-83, Tr. 458, 9/17/92] that the medical surveillance provision 
is too expensive and burdensome. OSHA has determined that the medical 
surveillance program required by the final rule is reasonably necessary 
for the protection of workers. In particular, medical surveillance will 
directly benefit workers with cardiovascular disease, central nervous 
system effects, and dermal irritation. These conditions can be detected 
by the medical surveillance program required by this paragraph of the 
final rule, and the detection of such conditions can, in turn, alert 
the employer to potential overexposures to MC in the workplace and to 
the need to limit MC exposures for certain employees with underlying 
heart disease or other conditions.
    In addition, by increasing the performance orientation of the rule, 
OSHA has minimized the costs of medical surveillance while maintaining 
its effectiveness. For example, the final rule leaves the content of 
laboratory surveillance for individual employees to the discretion of 
the physician or other licensed health care professional. Also, the 
requirement for a physical examination has been tailored to the age of 
the employee, so that employees younger than 45 generally receive an 
exam only every three years, instead of annually. The medical 
surveillance program also will aid in the evaluation of cancer 
incidence in the workplace and temporal trends therein.
    Paragraph (j)(1) specifies the circumstances under which employers 
must provide medical surveillance for employees who are or may be 
exposed to MC. Under paragraph (j)(1)(i), employers must make medical 
surveillance available to all employees who are exposed to MC at or 
above the action level for 30 days or more in any year or above either 
of the PELs for at least 10 days in any year. This provision is 
effectively identical to the corresponding provision of the

[[Page 1590]]

proposed rule. Also, this requirement is consistent with the approach 
taken by OSHA in the benzene standard (29 CFR 1910.1028). OSHA 
recognizes that the health effects associated with MC exposure are, in 
general, the result of chronic exposures to MC. Accordingly, employees 
exposed only for a few days in any year will be at relatively low risk 
of developing MC-induced disease. The exposure duration thresholds in 
the final rule will thus enable employers to focus valuable medical 
resources on high-risk employees.
    Some commenters were concerned about the use of the PELs and action 
level as triggers for medical surveillance. The Building and 
Construction Trades Department, AFL-CIO [Tr. 817, 9/21/92] was 
concerned that this provision would preclude medical surveillance for 
some employees with MC exposures that exceeded the PELs on fewer than 
10 days in a given year but who might nonetheless be at risk of adverse 
health effects. OSHA has determined that employees who have been 
identified by a physician or other licensed health care professional as 
being at risk for cardiac disease or some other serious MC-related 
health condition and who are exposed to MC at levels that exceed the 
PELs on fewer than 10 days in any year should have the option of 
participating in a medical surveillance program. Accordingly, paragraph 
(j)(1)(ii) has been added to the final rule. This provision states that 
medical surveillance must be provided to any employee (1) who is 
exposed above the 8-hour TWA PEL or STEL for any time period, and (2) 
who has been identified by a physician or other licensed health care 
professional as being at risk from cardiac disease or from some other 
serious MC-related health condition, and (3) who requests inclusion in 
the medical surveillance program. As noted in the Health Effects 
section, above, OSHA is concerned that any MC exposure above either of 
the PELs could exacerbate cardiac problems. This paragraph enables such 
high-risk employees to participate in a medical surveillance program.
    Under paragraph (j)(1)(iii), appropriate surveillance is required 
to be made available to employees exposed in an emergency regardless of 
the airborne concentrations of MC normally present in the workplace. 
Where very large amounts of materials are kept in a sealed system, 
routine exposure may be very low. However, rupture of the container 
might result in extremely high MC exposures. Thus, it is appropriate 
for employers who have identified operations where there is a potential 
for an emergency involving MC to plan ahead so that emergency medical 
surveillance would be available if needed. This provision is 
effectively identical to proposed paragraph (i)(1)(iii).
    Proposed paragraph (i)(1)(ii) would have required that the employer 
have the examining physician or other licensed health care professional 
determine if affected employees are physically fit to wear respirators. 
OSHA has placed this requirement with the other respiratory protection 
provisions in paragraph (g) of this final rule.
    Paragraph (j)(2) requires that employers offer examinations without 
cost to employees, at a reasonable time and place, and without loss of 
pay. OSHA believes that this provision is necessary to encourage 
employees to participate in the medical surveillance program. Final 
rule paragraph (j)(2), which is essentially identical to proposed 
paragraph (i)(2), is also consistent with other OSHA health standards 
and with provisions contained in the OSH Act.
    Paragraph (j)(3) requires that all medical procedures be performed 
by or under the supervision of a physician or other licensed health 
care professional, defined as ``an individual whose legally permitted 
scope of practice (i.e., license, registration, or certification) 
allows him or her to independently provide or be delegated the 
responsibility to provide some or all of the health care services 
required by paragraph (j) of the standard.'' The proposal required that 
all medical procedures be performed only by or under the supervision of 
a physician. Only one commenter [Ex. 19-31] specifically supported this 
provision.
    OSHA has long considered the issue of whether and how to identify 
the particular professionals who are to perform the medical 
surveillance required by its health standards. The Agency has 
determined that other professionals who are licensed under state laws 
to provide medical surveillance services would also be appropriate 
providers of such services for the purposes of the MC standard. The 
Agency recognizes that the personnel able to provide the required 
medical surveillance may vary from state to state, depending on state 
licensing laws. Under the final rule, an employer has the flexibility 
to retain the services of a range of qualified licensed health care 
professionals, thus potentially reducing costs, increasing flexibility, 
and allowing employers to identify those professionals, who may not 
necessarily be physicians, with the greatest expertise in diagnosing 
and treating occupational diseases. In future rulemakings, OSHA may 
attempt, with the cooperation of interested stakeholders, to specify 
which licensed health care professionals are the most appropriate to 
perform each of the diagnostic, therapeutic, medical management and 
other services required by the Agency's standards.
    Paragraph (j)(4) of the final standard addresses when medical 
examinations and consultations are to be provided.
    Initial surveillance. Under paragraph (j)(4)(i), initial medical 
surveillance must be provided before an employee's initial assignment 
to work in an area where they would be exposed to MC or by the start-up 
dates described in paragraph (n)(2)(iii) of the final MC standard, 
whichever is later. The employer need not repeat equivalent medical 
surveillance if it has already been provided within the past 12 months. 
OSHA's requirement for a preplacement examination is intended to 
determine if an individual is at increased risk of adverse effects from 
exposure to MC. It also establishes a general baseline for future 
reference. The provisions of final rule paragraph (j)(4) are 
effectively identical to those in proposed paragraph (i)(3), except 
that the proposed rule did not take into account medical surveillance 
provided prior to the effective date of this section. In the preamble 
to the NPRM (56 FR 57124), OSHA stated that it was considering a 
provision that would give employers credit for medical examinations 
provided within one year of the standard's effective date. The Agency 
requested comment on the usefulness of such a provision. Commenters 
[Exs. 19-31, 19-55b, 19-83] supported such a provision. In particular, 
Dow Chemical [Ex. 19-31] stated ``[i]f this is not done this section 
will be unfair to those employers who have on-going health surveillance 
programs.'' OSHA agrees with these commenters and has promulgated the 
final rule accordingly.
    Periodic surveillance. Paragraph (j)(4)(ii) addresses periodic 
medical surveillance. OSHA proposed to require annual medical 
surveillance for all affected employees. In the final rule, this has 
been changed so that the employer is required to update the medical and 
work history for each affected employee every year but must only 
provide physical examinations on a schedule that varies with the age of 
the employee. For affected employees 45 years of age or older, the 
physical examination must be conducted every year. For employees less 
than 45 years of age, the examination need only be done every three 
years.

[[Page 1591]]

    OSHA differentiated these groups of employees in an effort to 
target surveillance resources effectively. The probability of 
developing heart disease (which can be exacerbated by MC exposure) 
increases as employees age. Age 45 is a rough approximation of the 
point at which medical professionals would have heightened concern for 
cardiac effects. In other words, it is generally more likely that 
employees 45 years and older would experience the adverse cardiac 
effects of MC exposure. Three-year intervals between physical 
examinations for workers younger than 45 seemed the proper interval to 
balance the conservation of valuable medical resources and the 
provision of a medical surveillance program that is useful for 
detecting adverse MC health effects. The annual updates on medical and 
work history will enable the physician or other licensed health care 
professional to identify those individuals for whom more frequent 
examinations would be appropriate.
    To a lesser extent, this would be true for the detection of MC-
induced cancer as well. Although MC-induced cancer cannot currently be 
detected at the pre-neoplastic stage, early detection of cancer 
generally increases the survival rate, so it is important to include 
employees exposed to MC in a medical surveillance program that may 
detect tumors. Since any cancers caused by MC are more likely to be 
found in older employees and employees exposed to MC for longer 
durations, it is reasonable to concentrate medical surveillance 
resources on older employees.
    The main goal of periodic medical surveillance for workers is to 
detect adverse health effects at an early, and potentially still 
reversible, stage. The intervals chosen based on the age of the 
employee are consistent with this purpose and with other OSHA health 
standards. The Agency believes that these periodic surveillance 
requirements strike a proper balance between the need to diagnose 
health effects, such as cancer, at an early stage, thus increasing the 
effectiveness of medical intervention, and the expectation that a 
limited number of cases will be identified through the surveillance 
program. This approach decreases the cost burden of surveillance by 
lengthening the period of time between examinations for younger 
employees who have fewer years of exposure and thus have a lower risk 
of adverse health effects.
    Termination of employment or reassignment. Paragraph (j)(4)(iii) 
requires the employer to provide medical surveillance when an employee 
terminates employment or is reassigned to an area where exposure is 
consistently at or below the action level and the STEL. The termination 
examination need not be conducted if medical surveillance has been 
performed within the past six months. This requirement reduces the 
likelihood that an employee who terminates employment has an active, 
but undiagnosed, disease related to his or her MC exposure. In the 
NPRM, OSHA had proposed that the termination examination be performed 
unless medical surveillance had been conducted on that employee within 
the past three months. The Motor Vehicle Manufacturers Association [Ex. 
19-42] requested that the exam should only be required if the employee 
has not had a medical exam within six months of termination or 
reassignment, instead of three months as had been proposed. The MVMA 
stated that ``six months is adequate and consistent with other OSHA 
health standards (Cadmium, Sec. 1910.1027(l)(8)). We see no 
contribution to reducing employee risk from examining such employees at 
an earlier date, especially since the exposure to methylene chloride 
has been removed.'' Upon reconsideration of the issue, OSHA has adopted 
this suggestion in the final rule.
    The Agency requested public comment on whether continued annual 
surveillance should be offered to employees who have left employment, 
retired, or transferred to other areas within the employer's 
operations. Such an approach would be consistent with the requirement 
in the Benzene standard (29 CFR 1910.1028), which makes medical 
surveillance available to certain employees who have been exposed to 
benzene during their employment with their current employer. Several 
commenters [Exs. 19-31, 19-38, 19-42, 19-48, 19-55b, 19-58] stated that 
there should be no medical surveillance after an employee leaves a job 
in an exposure area or for employees previously exposed to MC. In 
particular, Dow Chemical [Ex. 19-31] stated: ``[W]e do not believe that 
the employer should be responsible for continued medical surveillance 
for employees who leave MC exposure areas * * *. [T]he continued 
surveillance does nothing more than divert occupational medical 
resources from more important work.'' Taking a different view, the IUE 
[Tr. 533, 9/18/92] testified that formerly exposed retirees should be 
included in the medical surveillance program. They also stated that 
retirees, presently employed workers formerly exposed to MC in previous 
jobs, and workers relocated to nonexposed areas should be included in 
the medical surveillance program. The ACTWU agreed, testifying [Tr. 
1763-1764, 9/24/92] that employees who continue to work for the same 
employer after their exposure to MC is terminated should be entitled to 
participate in the medical surveillance program.
    OSHA has decided that it would be inappropriate to include retirees 
and other formerly exposed employees in the medical surveillance 
program. A major value of medical surveillance is to detect the acute 
heart disease and CNS effects associated with MC exposure. Workers no 
longer exposed to MC, or retirees, would be at much less risk of 
experiencing these effects.
    Additional surveillance. Paragraph (j)(4)(iv) requires employers to 
provide additional surveillance when the physician or other licensed 
health care professional recommends that it be provided. This may be 
warranted, for example, for an employee who is under 45 years of age 
but has a health condition that requires surveillance more frequently 
than every 3 years. Inclusion of this provision in the final rule will 
ensure that all employees receive the most appropriate level of 
surveillance for their particular health situation. The proposed 
provision was essentially identical.
    Paragraph (j)(5) of the final rule, like paragraph (i)(4) of the 
proposal, establishes the requirements for the content of medical 
exams. This provision requires a comprehensive medical and work 
history, a physical examination, laboratory surveillance, and any 
additional information determined to be necessary by the physician or 
other licensed health care professional. The language in the proposed 
rule, which was similar, has been revised for clarity and to provide 
guidance about what constitutes adequate medical surveillance. For 
example, the final rule addresses medical and work history in greater 
detail than the proposal because, in some cases, three years may elapse 
before a subsequent physical examination is provided. On the other 
hand, the specific content of the physical examination and laboratory 
surveillance has been left largely to the discretion of the physician 
or other licensed health care professional.
    Paragraph (j)(5)(i) requires that a comprehensive medical and work 
history be obtained from each participating employee. This paragraph 
requires a medical evaluation that includes a comprehensive medical and 
work history with special emphasis on neurological symptoms, skin 
conditions, history of hematologic or liver disease,

[[Page 1592]]

signs or symptoms suggestive of heart disease (angina, coronary artery 
disease), risk factors for heart disease, MC exposures, and the work 
practices and personal protective equipment used to control exposures. 
OSHA has included an example of a medical and work history format that 
would satisfy this requirement in non- mandatory Appendix B of the 
standard. The proposed provision required a comprehensive or interim 
medical and work history with emphasis on neurological symptoms, mental 
status, and cardiac health. Final rule paragraph (j)(5)(i) has been 
revised to indicate clearly what is required.
    The medical and work history component of the initial medical 
evaluation will assist the physician or licensed health care 
professional in identifying pre-existing conditions that might place 
the employee at increased risk when exposed to MC. It also establishes 
a health baseline for future monitoring. The subsequent annual updates 
will identify changes in neurological symptoms, skin conditions or 
cardiac health, and, in combination with laboratory analyses and 
information on exposure history, may provide early warnings of MC 
toxicity. The information derived from a medical evaluation assists the 
physician or other licensed health care professional in distinguishing 
between MC-related effects and those effects that are unrelated to MC 
exposure. This information is particularly important because the health 
effects associated with MC exposure are not unique to such exposure. 
For example, the proposed requirement to assess mental health status 
has been eliminated from the final rule because no specific correlation 
has been demonstrated between mental health status and MC exposure.
    Paragraph (j)(5)(ii) requires that the extent and nature of the 
required physical examinations be determined by the physician or 
licensed health care professional based on the health status of the 
employee and analysis of the medical and work history for that 
employee. The standard also requires that the examiner give particular 
attention to the lungs, cardiovascular system (including blood pressure 
and pulse), liver, nervous system and skin. Proposed paragraph 
(i)(4)(ii) specifically would have required that the examination 
address the lungs, liver, nervous system and breast. OSHA has 
determined that, in order to indicate clearly that the physician or 
licensed health care professional should assess the potential cardiac 
health impacts of MC, the medical exam should give attention to the 
cardiovascular system, blood pressure and pulse. In addition, the 
Agency has decided that, because of the skin irritation effects of MC, 
it is necessary to include evaluation of the skin in the medical exam.
    Two hearing participants [Tr. 803, 9/18/92; Tr. 2434-35, 10/15/92] 
testified that men over 40 years old should be given electrocardiograms 
(ECGs), which should be repeated every 1 to 3 years. OSHA is not 
requiring ECGs because there is no evidence in the record that 
associates specific changes in ECGs with MC exposures. However, the 
physician or licensed health care professional has the discretion to 
order an ECG for any employee where it is deemed appropriate.
    Proposed paragraph (i)(4)(iv) also required the physician to make a 
determination of any reproductive difficulties of the employee. Vulcan 
Chemicals [Ex. 19-48] and Organization Resources Counselors (ORC) [Ex. 
19-51] commented that the evidence for a relationship between 
reproductive effects and MC exposure did not warrant inclusion of such 
a provision in the final rule. OSHA agrees with these commenters that 
the evidence associating MC exposure and specific reproductive health 
effects is sparse. Therefore, the Agency has not included reproductive 
effects in the list of effects the physician or other licensed health 
care professional should focus on. However, the Agency will continue to 
monitor the literature to determine if future evidence indicates that 
inclusion of this provision is warranted.
    Two commenters [Exs. 19-28, 19-42] stated that the breast 
examination requirement should be eliminated from the final rule 
because breast exams would be highly unlikely to identify effects 
related to exposure to MC. In the proposal OSHA placed attention on the 
breast because of concern raised by the increased number of breast 
tumors in the rat bioassay. Upon further consideration, OSHA has 
dropped the requirement for breast exams. The Agency notes that rats 
are particularly sensitive to mammary tumors and it is unclear that 
humans have similar risks of developing breast cancer after exposure to 
MC. The Agency remains concerned about the potential for MC 
carcinogenicity evidenced by the rat mammary tumors, however, and has 
relied, in part, on mammary tumor data in identifying MC as a cancer 
hazard.
    In final rule paragraph (j)(5)(iii), laboratory surveillance of 
employees is to be conducted as the examining physician or licensed 
health care professional determines to be necessary and appropriate, 
based on the employee's health status and the medical and work history. 
This is a more performance-oriented provision than the corresponding 
provision of the proposed rule. The proposal would have required 
several specific laboratory tests, while the final rule leaves 
laboratory test requirements to the discretion of the physician or 
other licensed health care professional. Non-mandatory Appendix B 
includes guidance regarding the types of tests that may be appropriate.
    Some commenters [Exs. 19-28, 19-42, 19-48, 19-49] stated that COHb 
levels, which had been included among the tests in the NPRM, are not a 
good measure of toxic exposure to MC. In particular, the MVMA [Ex. 19-
42] stated that it is difficult to determine the COHb level 
attributable to MC exposure for employees who are smokers or who may 
have other exposures to CO. Several other participants [Exs. 19-25, 19-
57, 19-83 and Tr. 1438, 9/23/92] suggested that COHb testing should be 
done only after over-exposure to MC, such as after an emergency. The 
Laborers Health and Safety Fund [Tr. 1386, 9/23/92] testified,

    [W]e're not convinced that that's [COHb monitoring] an 
appropriate and accurate measure of exposures, given other sources 
of carbon monoxide on construction sites as well as the issue of 
smokers versus non-smokers.
    However, the Department of the Army [Ex. 19-55b] suggested that 
COHb levels are a more cost-effective measurement of the oxygen-
carrying capacity of blood than a complete blood count. Similarly, the 
California Department of Health Services [Ex. 19-17] requested that 
references to COHb testing be moved from the appendix to the regulatory 
text.

    COHb levels greater than 3% can exacerbate angina symptoms, 
decrease exercise tolerance and increase risks for myocardial 
infarctions (heart attacks) in susceptible individuals. COHb 
concentrations can also be used as a rough estimate of worker exposure 
to MC (taking into consideration smoking behavior, time since exposure, 
and exposure to other CO sources) to calibrate personal MC monitoring 
measurements. Before- and after-shift COHb determinations can be useful 
in correlating recent MC exposures with COHb levels. The Agency is not 
requiring COHb testing, however, because confounding factors, such as 
smoking or exposure to a CO source, can reduce the usefulness of the 
results of the tests and, in addition, COHb does not measure a health 
effect per se but is instead a surrogate measure of MC exposure. 
However, COHb testing may

[[Page 1593]]

be clinically important in the evaluation of a symptomatic worker and 
therefore remains an option for the physician or other licensed health 
care professional to pursue. Exposure monitoring (see paragraph (d) of 
the final rule) must be performed to quantify an employee's exposure to 
MC.
    In the comments received subsequent to publication of the ANPR for 
MC [Exs. 10-3, 10-10, 10-28], several industry commenters indicated 
that urine analysis, liver function tests and chest X-rays are commonly 
performed as part of the medical surveillance programs of these 
companies. OSHA believes that annual urine analysis or chest X-ray 
would not be relevant to detection of MC-related health effects. Liver 
function tests have also been evaluated for inclusion as a requirement 
in the medical surveillance provision. As discussed above in the Health 
Effects section, animal studies and human clinical studies show an 
association between chronic MC exposure and some changes in liver 
enzymes, particularly after high exposures or doses of MC for prolonged 
periods of time. The changes in liver enzyme levels after MC exposure 
are not consistent in the human clinical studies, however, and in 
general, changes in liver enzymes are not specific or unique to MC 
exposure. Therefore, the Agency believes that it should be left to the 
physician's or other licensed health care professional's discretion to 
determine if laboratory analysis of liver enzymes is warranted.
    Several commenters [Exs. 19-11, 19-26, 19-42, 19-48, 19-55b] agreed 
that routine use of all of the tests included in the proposal would not 
be appropriate or necessary for the detection of MC-related health 
effects. The Agency also sought comments on the inclusion of other 
medical tests in the final MC rule. Two commenters [Exs. 19-31, 19-48] 
stated that a complete blood count was not necessary because the 
results of this test may not correlate with MC overexposure. In 
particular, the Dow Chemical Co. [Ex. 19-31] commented that a complete 
blood count is not necessary because blood cell volume and hemoglobin 
findings would suffice. OSHA has reevaluated the utility of the 
proposed tests and has decided that leaving laboratory surveillance to 
the discretion of the physician or licensed health care professional is 
more cost-effective than the approach taken in the proposal and will 
not negatively impact worker health.
    In paragraph (j)(5)(iv), the final rule requires the medical 
surveillance program of the employer to include any other information 
or reports the physician or other licensed health care professional 
determines are necessary. This is to ensure that a complete medical 
profile is available to the physician or licensed health care 
professional to make decisions regarding the employee's health and 
exposure status. This provision is essentially identical to that 
proposed.
    Paragraph (j)(6) of the final rule describes the required contents 
of emergency medical surveillance. The proposed rule did not specify 
what elements should be included in an emergency medical exam. The 
final rule clarifies that emergency medical surveillance should include 
any appropriate emergency treatment and decontamination of the exposed 
employee, a comprehensive physical exam, an updated medical and work 
history, and laboratory surveillance, if needed.
    The Dow Chemical Company [Ex. 19-31] commented that employees 
exposed to MC during an emergency should not automatically be included 
in the regular medical surveillance program. Instead, this commenter 
argued that only those components of a medical examination that are 
appropriate in a given situation should be conducted. OSHA believes 
that it is important for an employer to provide medical examinations 
and appropriate follow-up to employees exposed to MC during an 
emergency. After considering the issue and comments raised during the 
rulemaking, the Agency agrees with Dow that employees exposed to MC 
during an emergency should not necessarily be enrolled in the 
continuing medical surveillance program provided to employees routinely 
exposed to MC. To that end, OSHA has added language to the final rule 
that clearly indicates what emergency medical surveillance is required. 
OSHA believes that final rule paragraph (j)(6) allows the employer 
appropriate flexibility, while at the same time ensuring that those 
employees exposed to MC during an emergency receive appropriate medical 
surveillance.
    Paragraph (j)(7) requires the employer to provide medical 
surveillance services, in addition to those specified in final rule 
paragraphs (j)(5) and (j)(6), when the physician or other licensed 
health care professional determines that they are necessary. Compliance 
with this requirement will ensure that the information needed to 
evaluate the effects of MC exposure on employees is available. This 
provision is essentially the same as proposed paragraph (i)(5).
    Paragraph (j)(8) requires that the employer provide the physician 
or other licensed health care professional with (1) a copy of the 
standard, including the relevant appendices; (2) a description of the 
affected employee's past, current, and anticipated future duties as 
they relate to the employee's MC exposure; (3) a description of former, 
current or anticipated exposure levels (including the frequency and 
exposure levels anticipated to be associated with emergencies), as 
applicable; (4) a description of any PPE that the employee must use or 
will use, such as respirators; and (5) information from any previous 
medical examinations that would not otherwise be available to the 
examining physician or other licensed health care professional. OSHA 
has determined that the physician or other licensed health care 
professional needs the above-listed background information in order to 
place the information derived from medical surveillance in the proper 
context. For example, a well-documented exposure history assists the 
physician or other licensed health care professional in determining 
whether an observed health condition may be related to MC exposure. It 
also helps this individual to determine if the results of medical 
surveillance indicate a need to limit an employee's occupational 
exposure to MC. This paragraph is essentially the same as proposed 
paragraph (i)(6).
    Paragraph (j)(9) of the final rule requires employers to ensure 
that the examining physician or other licensed health care professional 
provides the employer and the affected employee with a written opinion 
that addresses (1) the physician's or other licensed health care 
professional's opinion as to whether the employee has any detected 
medical condition that would place the employee at increased risk of 
material health impairment as a result of exposure to MC; (2) any 
recommended limitations on the employee's exposure or use of personal 
protective clothing or equipment and respirators; (3) a statement that 
the employee has been informed of the potential carcinogenicity of MC, 
the risk factors for heart disease, and the potential for exacerbation 
of underlying heart disease associated with exposure to MC; and (4) a 
statement that the employee has been informed of the results of the 
medical examination and any medical conditions related to MC exposure 
that require further explanation or treatment.
    The physician or other licensed health care professional must 
provide copies of the written medical opinion to the employee and the 
employer within 15 days after completion of the evaluation of medical 
and laboratory findings, but no later than 30 days after the medical 
examination. This

[[Page 1594]]

requirement was included to ensure that the employee and the employer 
have been informed of the above-mentioned results of the medical 
examination in a timely manner. This requirement differs slightly from 
that in proposed paragraph (i)(7)(i). Instead of the physician 
providing a copy of the written medical opinion to the employer, who 
then provides a copy to the employee, the final rule requires the 
physician or other licensed health care professional to supply a copy 
of the written medical opinion directly to both the employer and the 
employee. In addition, the time allowed for providing the opinion has 
been changed to recognize that time may be needed to receive and 
evaluate laboratory or other medical findings. The Agency believes that 
notifying both the employer and affected employees of the MC-related 
results of the medical surveillance at the same time is an efficient 
approach to disseminating this information to the appropriate parties. 
Providing copies of the same written opinion both to the employer and 
the employee ensures that the employer is aware of any factors that may 
influence work assignments or choice of personal protective equipment.
    OSHA has added a requirement to the final rule that the physician 
or other licensed health care professional inform the employee of the 
carcinogenic and cardiac effects of MC to reinforce the information on 
MC's serious health effects that was transmitted during training. The 
Agency believes that this reinforcement will help to ensure that 
employees are aware of the potential effects of MC and take appropriate 
precautions when using this toxic substance.
    OSHA received several comments on different aspects of paragraph 
(j)(9). For example, the UAW [Tr. 1884, 9/24/92] testified that the 
written opinion transmitted to the employer by the physician or other 
licensed health care professional should only state the limitations on 
the employee's exposure or use of respiratory or other personal 
protective equipment recommended by the physician or other health care 
professional, and should not include the medical or other reasons 
behind the recommended limitations.
    OSHA agrees with the UAW that it is important to protect the 
privacy of employees enrolled in medical surveillance programs. 
Consequently, OSHA health standards have traditionally included a 
statement to the effect that no findings or diagnoses should be 
included in the physician's written opinion that are unrelated to 
occupational exposure. This requirement is intended both to protect the 
employee's privacy and to encourage employees to participate in the 
employer's medical surveillance program. The restriction on what may be 
revealed in the written opinion appears in the final rule as paragraph 
(j)(9)(ii), and is intended to apply to all of the information provided 
in the physician's or other licensed health care professional's written 
opinion, including that related to recommended limitations.
    The MVMA [Ex. 19-42] and ORC [Ex. 19-57] stated that the proposed 
15-day requirement for providing the employer with a copy of the 
written opinion should be 15 days from the physician's or other 
licensed health care professional's receipt of the test results rather 
than 15 days from the date of the examination. The Agency agrees and, 
as described above, has changed the requirement so that the written 
opinion must be provided within 15 days of completion of evaluation of 
medical findings, but not more than 30 days after the examination. OSHA 
believes that this strikes the proper balance between allowing 
sufficient time for the physician or other licensed health care 
professional to evaluate any laboratory findings while still providing 
the information to the employer and the employee in a timely manner.
    Newport News Shipbuilding [Ex. 19-37] and the Shipbuilders Council 
of America [Ex. 19-56] stated that the written opinion should require 
only that employees be notified of abnormal test results, not normal 
results. In response to these comments, OSHA notes that such a 
provision would actually require many physicians and other licensed 
health care professionals to change their current practice because it 
would require them specifically to delete normal results from printouts 
of laboratory and other findings. Such reports routinely display all 
results, both normal and abnormal, for a given individual. In addition, 
OSHA believes that employees benefit from knowing which of their blood 
parameters and other test results are normal and which are abnormal. 
OSHA does not believe that requiring medical personnel to increase the 
amount of paperwork they perform is a good use of medical resources, 
and has therefore not revised the final rule to respond to these 
comments.
    Under paragraph (j)(9)(ii) of the final rule, the physician or 
other licensed health care professional must exclude findings or 
diagnoses that are unrelated to MC exposure from the written opinion 
provided to the employer. As discussed above, OSHA has included this 
provision in the final rule to reassure employees participating in 
medical surveillance that they will not be penalized or embarrassed by 
the employer's obtaining information about them that is not directly 
pertinent to MC exposure. The above provisions are identical to those 
in proposed paragraph (i)(7)(ii). A note has been added to the final 
rule that states that the written opinion developed to comply with the 
MC standard may also contain information related to other OSHA 
standards. For example, an employer whose employees are enrolled in 
medical surveillance due to their exposure to benzene, formaldehyde and 
MC could receive a single, consolidated written opinion that addressed 
findings related to all three substances. This performance-oriented 
provision could result in reduced paperwork burdens for employers.
    NPRM Issue 3 solicited input regarding whether the Agency should 
add a provision for Medical Removal Protection (MRP). Medical removal 
protection encourages employee participation in (and therefore 
increases the effectiveness of) the medical surveillance program by 
ensuring that reporting symptoms or health conditions to the physician 
or licensed health care professional will not result in loss of job or 
pay. Several rulemaking participants expressed support for the 
inclusion of MRP in the final rule [Exs. 19-23, 19-38; Tr. 1787, 9/24/
92; Tr. 1802, 9/24/92; Tr. 1869, 9/24/92; and Tr. 1883, 9/24/92]. For 
example, the Amalgamated Clothing and Textile Workers (ACTWU) [Tr. 
1793, 9/24/92] testified that OSHA should require MRP based on clinical 
judgment, as OSHA allowed in the final rule for formaldehyde (29 CFR 
1910.1048). They also stated that they believed it was critical to have 
a medical removal protection provision in the MC standard in order to 
ensure worker participation. Mr. Frumin of the ACTWU testified as 
follows [Tr. 1792-1793, 9/24/92]:

    As I say, the problems that employers, physicians and, for that 
matter, OSHA confront in trying to assure the integrity of medical 
surveillance programs are not limited to a particular substance. 
They deal with the general perception--these problems arise from the 
general perception of workers, which is widespread through industry, 
that if they submit to a medical examination and it's not 
confidential, and employers could get the results of the medical 
findings, that health problems may result in some negative action.
    You have a symptom-based medical surveillance program, at least 
for the non-cancer effects. And if workers are supposed to report 
the types of symptoms, for instance, that Dr. Soden was looking for, 
shortness of breath, things of that nature--and they're

[[Page 1595]]

concerned that reporting that might involve some negative action 
against them: either their job security or their pay. You know, they 
will be discouraged from participating in medical surveillance, and 
the whole structure of the program is undermined. So the fact that 
these health effects are symptom-based rather than, say, based on 
laboratory tests alone, makes it all the more important to include 
medical removal protection and multiple physician review in the 
final rule.

    Two commenters [Exs. 19-23, 19-38] suggested that MRP should be 
based on COHb levels. However, Dr. Mirer of the UAW [Tr. 1940, 9/24/92] 
disagreed with this idea and concurred with Mr. Frumin's remarks that 
medical removal protection should be based on symptoms and professional 
discretion. He stated,

    * * * the guidance for the physicians, once the physician 
decides this employee is at increased risk, if they continue in this 
exposure and I want to remove him or her from the job, that's the 
trigger. At this moment, I would leave it that way. Increased 
carboxyhemoglobin is more an index of exposure than an adverse 
clinical effect, so I don't have any particular guidance. If the 
doctor wants to pull that man or woman out of a job, that's where I 
am now.

    He continued,

    * * * the other benefit of protecting the disclosure of symptoms 
is that it's going to identify sources of exposure, because one of 
the ways of determining exposure is by the presentation of symptoms. 
So the benefit of having them disclose symptoms is it will lead to 
lower exposure.
    I can't think of anything much else that you would need to get 
out of MRP than improved participation, although at least our 
experience in lead is that MRP has been the driving force to reduce 
exposures independent of that.

    OSHA considered the issues raised during the MC rulemaking and in 
general agrees with these worker representatives that MRP increases 
employee participation in medical surveillance. OSHA remains concerned 
about several issues, however. The Agency recognizes that employees may 
hesitate to participate in medical surveillance if they have reason to 
expect that the results may adversely affect them economically. 
However, OSHA has determined that there is no substantive guidance that 
it could give a physician or other licensed health care professional to 
indicate when it might be appropriate to remove an employee temporarily 
from the workplace, or what an appropriate trigger for return to work 
might be. Accordingly, OSHA has decided to promulgate the final rule 
for MC without including MRP provisions. The Agency will continue to 
monitor compliance with the medical surveillance and PPE provisions of 
this standard and the experience in industries subject to standards 
with medical removal protection provisions to determine whether any 
further action is warranted.

Paragraph (k) Hazard Communication

    The requirements for hazard communication have been changed from 
proposed paragraph (j) (Communication of MC hazards to employees) and 
promulgated in paragraph (k) of the final rule. The paragraph 
addressing hazard communication in the final MC rule is consistent with 
the requirements of OSHA's Hazard Communication Standard (HCS). The HCS 
requires all chemical manufacturers and importers to assess the hazards 
of the chemicals they produce or import. It also requires all employers 
to provide information concerning the hazards of such chemicals to 
their employees. The transmittal of hazard information to employees is 
to be accomplished by such means as container labeling and other forms 
of warning, material safety data sheets and employee training.
    Since the HCS ``is intended to address comprehensively the issue of 
evaluating the potential hazard of chemicals and communicating 
information concerning hazards and appropriate protective measures to 
employees'' (52 FR 31877), OSHA is including paragraph (k) in the final 
rule only to reference the HCS requirements for labels and material 
safety data sheets, and to indicate specifically the MC health effects 
that are required to be addressed under that rule. This additional 
guidance to employers simply reiterates the requirements of the HCS to 
convey information to affected employees about all health hazards to 
which they are potentially exposed. The health effects addressed by the 
final MC rule are cancer, cardiac effects (including elevation of 
carboxyhemoglobin), central nervous system effects, and skin and eye 
irritation. There may also be other health hazards or physical hazards 
associated with MC that meet the definitions of coverage under the HCS. 
These should be addressed appropriately on the label and MSDS as well.
    Employers who have already met their longstanding requirements to 
comply with the HCS will have no additional duties with regard to 
labels and MSDSs under the MC final rule. This is consistent with the 
suggestions of some commenters that no requirements should be mandated 
beyond those listed in the HCS [Exs. 19-25, 19-31, 19-42]. OSHA agrees 
that the HCS addresses the issue comprehensively, and additional 
requirements are not necessary to protect MC-exposed employees 
specifically. As a result, the Agency has deleted the proposed 
requirement for warning signs. Such signs are not required under the 
HCS, although they may be useful in some situations and employers may 
choose to use them. The Organization Resources Counselors [Ex. 19-57] 
commented that the required signs should say ``warning'' and not 
``danger'' as proposed, and suggested consistency with the benzene and 
ethylene oxide standards. It should be noted that the terms ``warning'' 
and ``danger'' have specific meaning in the context of labels, and 
there are criteria for their application under voluntary consensus 
standards such as the ANSI Z129.1 standard for precautionary labeling. 
ORC's comment is otherwise moot at this point since the relevant 
requirement has been deleted.

Paragraph (l) Employee Information and Training

    The requirements for employee information and training, which were 
part of proposed paragraph (j) (Communication of MC hazards to 
employees), have been separated from the hazard communication 
requirements for labels and data sheets described above, and 
promulgated as paragraph (l) in the final MC rule. Some of the training 
provisions that were proposed duplicated requirements of the HCS. These 
have been removed, and a reference to the information and training 
required under the HCS has been added to simply remind employers of 
their longstanding obligations under that rule to ensure that employees 
are apprised of the hazards of the chemicals in their workplaces, as 
well as appropriate protective measures. The information and training 
requirements in the final MC rule build upon those requirements with 
additional information specific to MC that will help employees 
understand the risks of exposure and the means to prevent adverse 
health effects from occurring in their particular workplaces.
    It should be noted that the information and training requirements 
in the final rule have been separated from each other rather than being 
addressed together, because they deal with different ways of conveying 
information. ``Information'' transmittal is simply that--a passive 
process of making information available to employees should they choose 
to use it. In some cases, this may be done in writing or some other 
simple manner of information transfer. ``Training,'' on the other hand, 
is not a passive process. The

[[Page 1596]]

information provided to employees in training requires them to 
comprehend it and subsequently to use it in the performance of their 
duties in the workplace. There are many different ways to accomplish 
training effectively, but it cannot be a simple transfer of information 
such as handing someone a written document. OSHA's voluntary training 
guidelines, which are found in OSHA Publication No. 2252, are available 
to provide employers additional guidance in setting up and implementing 
an appropriate employee training program. An effective training program 
is a critical component of any safety and health program in the 
workplace. Workers who are fully informed and engaged in the protective 
measures established by the employer will play a significant role in 
the prevention of adverse health effects. Ineffective training will not 
serve the purpose of making workers full participants in the program, 
and the likelihood of a successful program for safety and health in the 
absence of an effectively trained workforce is remote.
    Paragraph (l)(1) requires employers to provide all employees who 
are potentially exposed to MC with information and training on MC prior 
to or at the time of initial assignment to a job involving MC exposure. 
Thus employees will have the information they need to protect 
themselves before they are actually subject to exposure. The final rule 
further indicates in paragraph (l)(2) that employers shall ensure that 
the information and training is presented in a manner that is 
understandable to employees and that employees have received the 
information and training required under the HCS.
    Paragraph (l)(3) addresses the information to be provided to 
affected employees. This includes the requirements of the final MC 
standard and information available in its appendices, as well as how 
the employee can access or obtain a copy of it in the workplace. This 
will ensure that MC-exposed employees are aware that specific 
requirements have been established to protect them from adverse health 
effects, and give them an opportunity to review those requirements 
themselves if they so desire. Wherever employee exposures exceed or can 
reasonably be expected to exceed the action level, the employer is 
required to inform employees about the location of MC in the workplace, 
what operations may be affected, particularly noting where in the 
workplace there may be exposures above the permissible exposure limits.
    Paragraph (l)(4) requires each employer to train each affected 
employee as required under the Hazard Communication Standard (29 CFR 
1910.1200, 29 CFR 1915.1200 or 29 CFR 1926.59, as appropiate). This 
provision simply reminds employers of their obligation to train 
employees regarding the hazards of MC under the Hazard Communication 
Standard.
    The final rule does not provide a specific time period for updating 
the training, whereas the proposed standard included a requirement for 
annual retraining. Instead, the final rule indicates in paragraph 
(l)(5) that the employer shall re-train each affected employee as 
necessary to ensure that employees exposed above the action level or 
the STEL maintain a good understanding of the principles of safe use 
and handling of MC in the workplace. Employers can assess whether this 
understanding is generally present in exposed employees in various 
ways, such as by observing their actions in the workplace. For example, 
if an employee is not using appropriate protective equipment or 
following safe work practices routinely, this may be an indication that 
additional training is required. This provision of the final rule is a 
performance-oriented requirement that allows each employer to determine 
how much or how often training is needed.
    Paragraph (l)(6) requires that the employer do additional training 
when the workplace is modified or changed in such a way that employees 
are subject to greater exposures and those exposures exceed or can 
reasonably be expected to exceed the action level and those employees 
need information and training to understand how to implement the 
modifications or training successfully. This provision was not in the 
proposal, but the Agency considers it necessary to further protect 
employees from the hazards of MC when significant changes in workplace 
conditions occur.
    Paragraph (l)(7) requires the employer whose employees are exposed 
to MC at a multi-employer worksite to notify the other employers with 
work operations at that site regarding the use of MC-containing 
materials, the hazards associated with the use of those materials and 
the control measures implemented to protect affected employees from MC 
exposure, in accordance with the requirements of the Hazard 
Communication Standard (HCS). The HCS addresses sharing information at 
multi-employer worksites, and since this final rule covers construction 
where most of the sites are multi-employer, this provision was added to 
remind such employers of these requirements. OSHA is also aware that an 
increasing number of manufacturing worksites involve more than one 
employer.
    In paragraph (l)(8) of the final rule, OSHA has indicated that the 
Assistant Secretary or the Director may access all materials relating 
to employee information and training in the workplace. This would be 
done in conjunction with an inspection to ascertain compliance with the 
rule, or in the event of a NIOSH health hazard evaluation. Review of 
the available materials regarding information and training will help 
assess whether the program has been properly conducted, as well as 
evaluate what could be improved if employees do not appear to be 
effectively trained.
    The information and training provisions of this standard are 
performance-oriented, because employees are exposed to MC in a wide 
variety of circumstances and the best method of conveying the necessary 
data may vary from site-to-site. The standard lists the categories of 
information to be transmitted to employees but does not specify the 
ways in which it is to be transmitted.
    Some commenters [Tr. 531-32, 9/18/92; Tr. 545-49, 9/18/92; Tr. 828-
32, 9/21/92; Tr. 1380, 1384-85, 9/23/92] suggested that OSHA make the 
proposed training provisions more specific, such as by including 
requirements for length of training, qualifications of instructors, or 
requirements for interactive training. In addition, hearing 
participants and commenters suggested that OSHA require employers to 
monitor the effectiveness of training [Ex. 19-38, Tr. 531-32, 9/18/92]. 
These participants suggested that provisions be made, as well, for 
training of workers in languages other than English and for training of 
workers with limited literacy [Ex. 19-38, Tr. 531-32, 9/18/92; Tr. 831-
32, 9/21/92].
    The International Brotherhood of Painters and Allied Trades, AFL-
CIO, testified [Tr. 830-831, 9/21/92]:

    We urge OSHA to promulgate a standard that requires that workers 
receive a minimum of 16 hours training. Such training would include 
at the minimum information on the hazards of methylene chloride and 
how it harms the body. Engineering controls that can be implemented 
in the field should be described and demonstrated. We will submit 
information on one such control to the record. Training should also 
include information on work practices associated with specific job 
assignments, methods by which workers can protect themselves, the 
limits of respirators use, appropriate procedures for work in 
confined spaces, employee rights under the standard, the

[[Page 1597]]

purpose of medical surveillance and other elements of training as 
enumerated in Section (j)(4).

    OSHA does not agree that specifying a time frame for training 
ensures that it will be complete, appropriate, or effective. The amount 
of training required will depend to a large extent on the conditions of 
use in a given workplace. It will also be related to the extent of 
training on MC that has already been done by the employer under the 
HCS. Therefore, the final rule provisions remain performance-oriented 
with regard to the time needed to convey the information and training.
    With regard to the issues of literacy and language, these remain a 
significant consideration in the proper design and implementation of 
any training program. Because working safely with MC is such a 
significant concern, the employer must make every effort to ensure that 
the training is presented in such a way that employees can understand 
and act on the information.
    OSHA expects that employers will ensure that the information and 
training is effective. Any good training program should include an 
evaluation component to help ensure effectiveness. The voluntary 
training guidelines previously recommended can provide additional 
guidance in this respect.
    OSHA received comments that indicated that the MC standard should 
simply refer to the HCS rather than having separate requirements [Exs. 
19-25; 19-49]. While the Agency agrees with these comments in reference 
to the label and MSDS requirements, it does not appear that this is the 
appropriate approach to training. While the HCS addresses training 
about the hazards of a chemical and appropriate precautionary measures, 
there are other items of training that are specific to the MC standard 
requirements and the determinations made in this rulemaking regarding 
MC. As such, it is important to ensure that the already-required HCS 
training is supplemented with information and training specific to MC.

Paragraph (m) Recordkeeping

    Paragraph (m) of the final rule addresses requirements for 
employers to create and maintain records of their compliance with some 
of the provisions of this section. Section 8(c)(1) of the OSH Act 
authorizes the Agency to promulgate regulations requiring employers to 
keep necessary and appropriate records regarding activities to permit 
the enforcement of the Act or to develop information regarding the 
causes and prevention of occupational accidents and illnesses. Section 
8(c)(3) of the Act specifically addresses the promulgation of 
``regulations requiring employers to maintain accurate records of 
employee exposures to potentially toxic materials or harmful physical 
agents which are required to be monitored or measured under section 
6.''
    Paragraph (m)(1) requires that employers who rely on objective data 
to characterize potential exposures to MC, rather than conducting 
initial monitoring under paragraph (d) of this section, maintain 
records that show the information and methodology used in reaching 
their conclusion that exposures are at or below the action level and no 
additional monitoring is required. The record must include the MC-
containing material evaluated; the source of the objective data; the 
testing protocol, and the results or analysis of the testing; a 
description of the operation(s) exempted from monitoring, and how the 
data support the exemption; and other relevant data.
    Since the use of objective data exempts the employer from 
conducting monitoring, as well as establishing that most of the other 
provisions need not be complied with due to the low level of potential 
exposure, it is critical that this determination be carefully 
documented. Compliance with the requirement to maintain a record of 
objective data protects the employer at later dates from the contention 
that initial monitoring was improperly omitted. The record will also be 
available to employees so that they can examine the determination made 
by the employer. The employer is required to maintain the record for 
the duration of the employer's reliance upon objective data. This 
provision is effectively identical to proposed paragraph (k)(1).
    Paragraph (m)(2) requires that employers establish and keep an 
accurate record of all measurements taken to monitor employee exposure 
to MC. For employers with 20 or more employees, the record must include 
at least: the date of measurement for each sample taken; the operation 
involving exposure to MC which is being monitored; sampling and 
analytical methods used and evidence of their accuracy; number, 
duration and results of samples taken; the type of personal protective 
equipment, such as respiratory protective devices worn (if any); and 
name, social security number, and job classification and exposure of 
all the employees deemed to be represented by such monitoring, 
indicating which employees were actually monitored. For employers with 
fewer than 20 employees, the record shall include, at a minimum: the 
date of measurement for each sample; the number, duration and results 
of samples taken; and name, social security number, job classification 
and exposure of all the employees deemed to be represented by such 
monitoring, indicating which employees were actually monitored. OSHA 
believes it is necessary to maintain these records so that employers, 
employees and OSHA can determine the extent to which MC exposure has 
been identified and subsequently controlled. Over time, the exposure 
records can help determine if additional measures are needed for 
employee protection. OSHA has reduced the amount of information 
required for small businesses in recognition of the more limited 
variety of operations and exposure levels there. This should ease these 
employers' recordkeeping burden without compromising employee safety 
and health in these types of facilities.
    Two commenters [Exs. 19-25, 19-49] suggested that such 
documentation should only be required for each person actually 
monitored (paragraph (d)(1) provides for representative monitoring). 
However, OSHA believes that it is necessary for records to be kept for 
each employee represented by the exposure monitoring so that individual 
employees can access information that characterizes their own exposures 
to MC. If records were kept only for those actually monitored, it would 
be unreasonably difficult for an employee to identify the exposure 
measurement that is intended to represent his or her experience. 
Accordingly, OSHA has not made the suggested change.
    Paragraph (m)(3) requires that the employer keep accurate medical 
records for each employee subject to medical surveillance. The 
information to be included in the record addresses identification of 
the employee; the physician's or other licensed health care 
professional's written opinions; and documentation of any employee 
medical conditions that are found to be related to MC exposure. 
Maintenance of employee medical records is necessary for the proper 
evaluation of the employee's health, as well as for appropriate 
followup.
    Proposed paragraph (k)(3)(ii)(D) required that a copy of the 
information provided to the physician or other licensed health care 
professional be included in the employee record. The Dow Chemical 
Company [Ex. 19-31] requested that, because many larger companies have 
company medical facilities, some provision be made so that records do 
not have to be maintained in medical department records and duplicated 
in the personnel record of every employee potentially

[[Page 1598]]

exposed to MC. The information required under paragraph (j)(8) of this 
section includes a copy of this section including its appendices, a 
description of duties involving MC exposure, exposure levels, personal 
protective equipment, and previous medical surveillance information. 
Since this information is available to the employee through other 
means, OSHA believes that the requirements under proposed paragraph 
(k)(3)(ii)(D) were unnecessarily burdensome, and OSHA has therefore 
deleted this paragraph from the final rule. OSHA has also deleted 
proposed requirements for maintaining records of employee fit testing 
as being unnecessarily burdensome. Dow also suggested that an employee 
identification number be permitted in lieu of social security number 
[Ex. 19-31]. OSHA does not agree with this suggestion. Social security 
numbers have much wider application, and are correlated to employee 
identity in other types of records. These numbers are a more useful 
differentiation among employees since each number is unique to an 
individual for a lifetime and does not change as an employee changes 
employers.
    Paragraph (m)(4) of the final rule specifies that access to 
exposure and medical records by employees, employees'' designated 
representatives, NIOSH and OSHA shall be provided in accordance with 29 
CFR 1910.1020. OSHA promulgated 29 CFR 1910.1020 as the generic rule 
for access to employee exposure and medical records on May 23, 1980 (45 
FR 35212). It applies to records created under specific OSHA standards 
and to records that are voluntarily created by employers. OSHA retains 
unrestricted access to medical and exposure records but its access to 
personally identifiable records is subject to the Agency's rules of 
practice and procedure concerning OSHA access to employee medical 
records, which have been published at 29 CFR 1913.10.
    The time periods required for retention of exposure records and 
medical records is thirty years and the period of employment plus 
thirty years, respectively. These retention requirements are consistent 
with those in the OSHA records access standard and with pertinent 
sections of the Toxic Substances Control Act. It is necessary to keep 
records for extended periods of time because of the long latency 
periods commonly observed for the induction of cancer caused by 
exposures to carcinogens. Cancer often cannot be detected until 20 or 
more years after onset of exposure. The extended record retention 
period is therefore needed for two purposes. First, possession of past 
and present exposure data and medical records furthers the diagnosis of 
workers' ailments. In addition, retaining records for extended periods 
makes possible a review at some future date of the effectiveness and 
adequacy of the standard.
    Paragraph (m)(5) requires employers to comply with the requirements 
of 29 CFR 1910.1020(h). That provision requires the employer to notify 
the Director of NIOSH in writing at least 90 days prior to the disposal 
of records and to transfer those records to NIOSH unless told not to do 
so by NIOSH. The employer is required to comply with any other 
applicable requirements set forth in the records retention standard.

Paragraph (n) Dates

    This paragraph establishes the effective date for the MC final 
rule, and the start-up dates for the various provisions of the 
standard. The start-up dates allow employers additional time to comply 
with some of the provisions of the standard that require more effort to 
accomplish. It is expected that such work will commence by the 
effective date, and be completed as soon as possible but in no case 
later than the compliance deadline established by the effective date. 
All other obligations imposed by the standard become effective on the 
effective date unless otherwise indicated.
    Paragraph (n)(1) of the final rule provides that this standard will 
become effective on April 10, 1997. This date is 90 days from the date 
of publication in the Federal Register. Proposed paragraph (m)(1) had 
provided that the final rule would become effective 60 days after 
publication in the Federal Register. OSHA stated in the preamble to the 
proposed rule [56 FR 57128] that the proposed effective date, in 
conjunction with the proposed start-up dates, would allow sufficient 
time for employers to achieve compliance with the substantive 
requirements of the proposed rule.
    Although no commenters directly addressed the 60-day period 
proposed in paragraph (m)(1), several commenters addressed the 
reasonableness of the start-up dates in proposed paragraph (m)(2). 
Those comments, discussed below, indicated that some employers would 
need more time to comply than the proposed rule would have allowed.
    The Agency sets the effective date to allow sufficient time for 
employers to obtain the standard, read and understand its requirements, 
and undertake the necessary planning and preparation for compliance. 
Section 6(b)(4) of the OSHA Act provides that the effective date of an 
OSHA standard may be delayed for up to 90 days from the date of 
publication in the Federal Register. Given the concerns expressed by 
commenters, OSHA's interest in having employers implement effective 
compliance efforts, and the minimal effect of the additional 30 day 
delay, the Agency has decided that it is appropriate to set the 
effective date at 90 days from publication, rather than at 60 days.
    Paragraph (n)(2) of the final rule establishes the start-up dates 
for compliance with the provisions of the MC standard. The start-up 
dates are based on information in the record about the state of the art 
with regard to the types of provisions employers are expected to 
implement, such as available control measures, their complexity, and 
the time that is reasonably necessary to complete their installation 
and implementation. In the case of MC, the types of provisions included 
in the rule, such as requirements that will require conventional 
controls, are identical to the elements included in all OSHA health 
standards.
    Proposed paragraphs (m)(2)(i), (ii) and (iii) required that initial 
monitoring be completed by all employers within 120 days of the 
effective date of the MC standard, engineering controls within one year 
of the effective date and all other requirements within 180 days of the 
effective date. As described below, OSHA received numerous comments on 
the appropriateness of the start-up dates, especially for small 
businesses. Given the large number of small employers covered by the 
requirements, and the special problems of many of those employers in 
identifying and implementing appropriate control measures, OSHA has 
decided to phase-in compliance and to permit these employers a longer 
time period in which to comply with the requirements of the standard. 
The schedule for compliance with the provisions of the standard are 
described below.
    OSHA received a number of comments on the proposed periods for 
compliance with the control requirements. In 1992, Kodak [Exs. 19-18 
and 19-102] described circumstances at its film base production 
facility that would prevent compliance with the PELs through 
engineering controls before mid-1995. Kodak stated ``[it] is essential 
that OSHA be responsive to these considerations in promulgating the 
final rule. OSHA should permit adequate time for Kodak to implement 
feasible engineering controls in an orderly and minimally disruptive 
schedule.'' Considering the effective

[[Page 1599]]

date and start-up dates in this regulation, OSHA has determined that 
affected parties will have sufficient time to comply with the standard.
    Similar requests for longer time periods for compliance were also 
received from a variety of other commenters [Exs. 19-55, 19-57, 19-67, 
19-72, 19-75, 115-3, 115-28, 115-33, 115-37, Tr. 1422, 1427-29, 9/23/
92, Tr. 2103, 10/14/92, Tr. 2291-92, 2300, 10/15/92]. However, OSHA's 
Final Economic Analysis for this rulemaking indicates that readily 
available control measures can be used to control exposure in many of 
the operations where MC is present. In general, compliance will not 
require the development of new or novel control technology. 
Accordingly, OSHA believes that more extended time periods for 
compliance are not necessary for all affected industries. However, as 
discussed below, small businesses (for example, those with fewer than 
20 employees and polyurethane foam manufacturers with 20 to 99 
employees) have been granted additional time to comply.
    As discussed above in Section VIII, several commenters [Exs. 19-14, 
19-25, 19-28 and 19-29] stated that engineering controls to achieve 
compliance were not available. These commenters further stated that the 
development and implementation of the process changes and engineering 
controls needed to achieve compliance would take four years from the 
effective date, not the single year proposed. For example, the 
Pharmaceutical Manufacturers Association and Abbott Laboratories [Exs. 
19-25 and 19-29] stated as follows:

    [I]f the agency should rule that the exposure level to MC be 
reduced to 25 ppm for an 8-hour TWA and a 125 ppm STEL, a minimum of 
1 year from the effective date must be allowed for identification of 
the engineering controls. A minimum of 3 years from the effective 
date must be allowed for compliance with paragraph (f)(1) of the 
proposed rule.

    Those commenters and the HSIA [Ex. 19-45] also indicated that FDA 
approval is needed in the pharmaceutical industry for any alteration of 
manufacturing processes, substitution for MC, or modification of work 
practices to achieve compliance with OSHA's MC standard, and requested 
that OSHA consider the FDA's regulatory requirements when establishing 
start-up dates. In particular, Abbott Laboratories described how it 
took three years to obtain FDA approval for the substitution of 
hydroalcoholic or aqueous solutions for MC in tablet coating 
operations, stating ``[p]resently, completion of required testing and 
obtaining FDA approval for production of a single product can take 3 
months to three years, depending upon the extent of the change.''
    Abbott also commented as follows [Ex. 19-29]:

    As stated previously, feasible engineering controls do not exist 
for the present bulk pharmaceutical centrifugal separation and 
drying equipment. Implementation of engineering controls would 
therefore require the use of a different process or a different 
production method. Changes of that degree require Abbott 
Laboratories to complete development work on an alternative process 
and/or identify new production equipment; erect a building to house 
the equipment; purchase, receive and install the equipment; train 
employees; and validate the process. This cannot be accomplished in 
one year.

    OSHA is aware that pharmaceutical manufacturers must comply with 
other regulatory requirements, including those set by the FDA. The 
Agency has considered how affected employers, in general, need to 
coordinate their OSHA compliance efforts with their other regulatory 
compliance activities, that this regulation does not require 
implementation of particularly complicated or novel control 
technologies, and that the compliance time frames are in keeping with 
those in other OSHA standards. OSHA views the coordination of OSHA 
compliance with other regulatory compliance activities as an ongoing 
employer effort, not just an ad hoc response to a particular OSHA 
action (such as the revision of a PEL). For example, a pharmaceutical 
manufacturer would need to consider the implications for OSHA 
compliance of process changes undertaken due to FDA requirements or for 
other reasons, whether those changes were to be made during the MC 
standard's ``start-up'' period or subsequently.
    Accordingly, the Agency has determined that the commenters have not 
established a need for the requested extension of the start-up dates. 
OSHA believes that the proposed one-year period in which to implement 
controls will, in general, be adequate and, therefore, has not made the 
suggested change. However, as discussed elsewhere, OSHA has tailored 
the compliance schedule to the size of the establishment and 
anticipated impact of the standard on those businesses.
    Dow [Ex. 19-31] also expressed concern that many employers would be 
unable to meet the start-up dates, focusing on the time and resources 
that would be required to conduct initial monitoring. In addition, Dow 
stated as follows ``OSHA should require that certain actions be 
completed within the stated time periods and that if the actions can 
not be completed, the employer should have a written plan and 
corresponding actions to show a good faith effort to meet the 
requirements.'' OSHA agrees that there may be circumstances where, 
despite good faith efforts, employers cannot achieve compliance within 
the time periods specified by paragraph (n)(2). OSHA further agrees 
that developing a written plan and taking other ``good faith'' actions 
towards compliance would be appropriate measures to mitigate any 
circumstances of non-compliance with the regulation. Indeed, the 
suggested procedure closely resembles the temporary variance process 
already established by OSHA.
    Under section 6(b)(6) of the OSH Act, an employer can obtain a 
temporary variance from compliance with an OSHA standard if it shows 
that it cannot achieve compliance by the effective date; is taking all 
available steps to safeguard its employees from the pertinent hazard; 
and has an effective program for coming into compliance with the 
standard. The implementing regulations for the temporary variance 
process appear at 29 CFR part 1905. Employers who experience 
difficulties in meeting the start-up dates should contact OSHA and 
apply for a temporary variance.
    The HSIA [Ex. 19-45] recommended that OSHA ``provide a compliance 
schedule similar to that provided in the generic PEL update * * * 
[which] in some circumstances allows employers until December 31, 1993 
to comply (a total of 4 years and 10 months).'' In addition to 
mentioning the lengthy FDA approval process, the HSIA noted that ``DCM 
users, particularly many of the smaller companies, will find compliance 
technologically and economically difficult at best.''
    As stated above, OSHA believes that the sort of extended compliance 
schedule set through the generic PEL update is unnecessary for the MC 
standard. Based on its review of the rulemaking record, the Agency has 
reached the general conclusion that employers will be able to achieve 
compliance within the time frames established in paragraph (n).
    However, OSHA is concerned that some small facilities affected by 
this rulemaking, such as many of those in the furniture refinishing 
industry and the polyurethane foam manufacturing industry, may have 
difficulties determining the appropriate control measures to use and 
also may not be able to absorb the costs of compliance, particularly 
those associated with implementing the appropriate

[[Page 1600]]

engineering controls within the time frames initially proposed. The 
Agency has estimated (see Section VIII, Summary of the Final Economic 
Analysis) that allowing a variable schedule of compliance, based upon 
size of establishment, will enable firms in all impacted sectors to 
absorb many of the compliance costs without endangering their financial 
health.
    Based on these considerations, OSHA has determined that the 
following implementation schedule is reasonable and appropriate for 
businesses of all sizes:

----------------------------------------------------------------------------------------------------------------
                                                             Implementation of                                  
                                      Initial monitoring   engineering controls    All other provisions must be 
        Establishment size            provisions must be     must be completed         complied with within     
                                     complied with within         within                                        
----------------------------------------------------------------------------------------------------------------
Fewer than 20 employees...........  300 days of the        3 years of the        1 year of the effective date.  
                                     effective date.        effective date.                                     
Polyurethane foam manufacturers     210 days of the        2 years of the        270 days of the effective date.
 with 20 to 99 employees.            effective date.        effective date.                                     
All other employers...............  120 days of the        1 year of the         180 days of the effective date.
                                     effective date.        effective date.                                     
----------------------------------------------------------------------------------------------------------------

    The Agency is promulgating paragraph (n) accordingly.
    The schedule of intermediate start-up dates (210 d, 270 d and 2 
years) for polyurethane foam manufacturers with 20 to 99 employees was 
limited to this application group because this group has the highest 
potential economic impacts except for the furniture stripping and 
construction groups. In both of the latter groups, most firms have 
fewer than 20 employees, and thus would already be allowed additional 
time to comply with the final rule's start-up dates. In contrast, in 
the flexible polyurethane foam manufacturing group, even firms with 
fewer than 100 employees will need to install several types of 
engineering controls and are likely to have unusually high capital 
expenditures in order to meet the requirements of the regulation. This 
extension of compliance deadlines will allow those firms that need 
extensive engineering controls time to adequately plan for and 
implement their system of controls. This modification will thus also 
help to ensure adequate protection for workers.

Paragraph (o) Appendices

    The final paragraph of the standard simply states that the 
appendices which follow are not intended to create any additional 
obligations beyond those already specified in the standard. They are 
basically intended as non-mandatory guidance documents to supplement 
and complement the regulatory requirements in the standard, and to 
provide additional information about MC and its safe handling and use 
to exposed employees, employers, and health care professionals.
    A few comments were received by OSHA regarding the text of the 
appendices as proposed. These addressed the need for additional 
information [Ex. 57, Tr. 832, 9/21/92, Tr. 1380 and 1384-85, 9/23/92], 
or whether information should appear in an appendix or in the 
regulatory text itself [see, e.g., Tr. 2435-36 and 2448-49, 10/15/92]. 
OSHA has reviewed and updated the text in the appendices to address 
these comments and ensure that they are consistent with the new 
regulatory text in the final standard.
    Also, proposed Non-mandatory Appendix C, which addressed respirator 
fit testing, has not been included in the final rule, because OSHA has 
determined that very few of the respirators used to comply with this 
standard will require fit testing. In addition, OSHA's revision of the 
generic respirator standard (29 CFR 1910.134) will contain an up-to-
date appendix that addresses fit testing for all respirators.

XI. Authority and Signature

    This document was prepared under the direction of Joseph A. Dear, 
Assistant Secretary of Labor for Occupational Safety and Health, U.S. 
Department of Labor, 200 Constitution Avenue, NW., Washington, DC 
20210.
    Pursuant to sections 4, 6(b), 8(c) and 8(g) of the Occupational 
Safety and Health Act (29 U.S.C. 653, 655, 657), section 107 of the 
Contract Work Hours and Safety Standards Act (the Construction Safety 
Act) (40 U.S.C. 333); the Longshore and Harbor Workers' Compensation 
Act (33 U.S.C. 941); the Secretary of Labor's Order No. 1-90 (55 FR 
9033); and 29 CFR part 1911; 29 CFR parts 1910, 1915 and 1926 are 
amended as set forth below.

List of Subjects in 29 CFR Part 1910, 1915 and 1926

    Chemicals, Cancer, Health risk-assessment, Methylene chloride, 
Occupational safety and health.
    Signed at Washington, D.C., this 31st day of December 1996.
Joseph A. Dear,
Assistant Secretary of Labor.

XII. Final Standard Regulatory Text

    Parts 1910, 1915, and 1926 of Title 29 of the Code of Federal 
Regulations are amended as follows:

PART 1910--[AMENDED]

Subpart B--[Amended]

    1. The authority citation for subpart B of part 1910 continues to 
read as follows:

    Authority: Secs. 4, 6 and 8 of the Occupational Safety and 
Health Act, 29 U.S.C. 653, 655, 657; Walsh-Healey Act, 29 U.S.C. 35 
et seq; Service Contract Act of 1965, 41 U.S.C. 351 et seq; Contract 
Work Hours and Safety Standards Act (Construction Safety Act), 40 
U.S.C. 333; Sec 41 Longshore and Harbor Worker's Compensation Act, 
33 U.S.C. 941; National Foundation on Arts and Humanities, 20 U.S.C. 
951 et seq; Secretary of Labor's Order No, 12-71 (36 FR 8754); 8-76 
(41 FR 25059); 9-83 (48 FR 35736); 1-90 (55 FR 9033); and 29 CFR 
part 1911.

    2. By adding a new paragraph (m) to Sec. 1910.19 to read as 
follows:


Sec. 1910.19  Special provisions for air contaminants.

* * * * *
    (m) Methylene Chloride (MC): Section 1910.1052 shall apply to the 
exposure of every employee to MC in every employment and place of 
employment covered by Sec. 1910.16 in lieu of any different standard on 
exposure to MC which would otherwise be applicable by virtue of that 
section when it is not present in sealed, intact containers.

Subpart Z--[Amended]

    3. The authority citation for subpart Z of 29 CFR part 1910 
continues to read, in part, as follows:

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


Sec. 1910.1000  [Amended]

    4. By removing the entire entry for Methylene Chloride (Z37.23-
1969) in Table Z-2 of Sec. 1910.1000 and adding the

[[Page 1601]]

following entry in its place in the substance column: ``Methylene 
chloride: see Sec. 1910.1052''.
    5. By adding a new Sec. 1910.1052 to read as follows:


Sec. 1910.1052  Methylene Chloride.

    This occupational health standard establishes requirements for 
employers to control occupational exposure to methylene chloride (MC). 
Employees exposed to MC are at increased risk of developing cancer, 
adverse effects on the heart, central nervous system and liver, and 
skin or eye irritation. Exposure may occur through inhalation, by 
absorption through the skin, or through contact with the skin. MC is a 
solvent which is used in many different types of work activities, such 
as paint stripping, polyurethane foam manufacturing, and cleaning and 
degreasing. Under the requirements of paragraph (d) of this section, 
each covered employer must make an initial determination of each 
employee's exposure to MC. If the employer determines that employees 
are exposed below the action level, the only other provisions of this 
section that apply are that a record must be made of the determination, 
the employees must receive information and training under paragraph (l) 
of this section and, where appropriate, employees must be protected 
from contact with liquid MC under paragraph (h) of this section. The 
provisions of the MC standard are as follows:
    (a) Scope and application. This section applies to all occupational 
exposures to methylene chloride (MC), Chemical Abstracts Service 
Registry Number 75-09-2, in general industry, construction and shipyard 
employment.
    (b) Definitions. For the purposes of this section, the following 
definitions shall apply:
    Action level means a concentration of airborne MC of 12.5 parts per 
million (ppm) calculated as an eight (8)-hour time-weighted average 
(TWA).
    Assistant Secretary means the Assistant Secretary of Labor for 
Occupational Safety and Health, U.S. Department of Labor, or designee.
    Authorized person means any person specifically authorized by the 
employer and required by work duties to be present in regulated areas, 
or any person entering such an area as a designated representative of 
employees for the purpose of exercising the right to observe monitoring 
and measuring procedures under paragraph (d) of this section, or any 
other person authorized by the OSH Act or regulations issued under the 
Act.
    Director means the Director of the National Institute for 
Occupational Safety and Health, U.S. Department of Health and Human 
Services, or designee.
    Emergency means any occurrence, such as, but not limited to, 
equipment failure, rupture of containers, or failure of control 
equipment, which results, or is likely to result in an uncontrolled 
release of MC. If an incidental release of MC can be controlled by 
employees such as maintenance personnel at the time of release and in 
accordance with the leak/spill provisions required by paragraph (f) of 
this section, it is not considered an emergency as defined by this 
standard.
    Employee exposure means exposure to airborne MC which occurs or 
would occur if the employee were not using respiratory protection.
    Methylene chloride (MC) means an organic compound with chemical 
formula, CH2Cl2. Its Chemical Abstracts Service Registry 
Number is 75-09-2. Its molecular weight is 84.9 g/mole.
    Physician or other licensed health care professional is an 
individual whose legally permitted scope of practice (i.e., license, 
registration, or certification) allows him or her to independently 
provide or be delegated the responsibility to provide some or all of 
the health care services required by paragraph (j) of this section.
    Regulated area means an area, demarcated by the employer, where an 
employee's exposure to airborne concentrations of MC exceeds or can 
reasonably be expected to exceed either the 8-hour TWA PEL or the STEL.
    Symptom means central nervous system effects such as headaches, 
disorientation, dizziness, fatigue, and decreased attention span; skin 
effects such as chapping, erythema, cracked skin, or skin burns; and 
cardiac effects such as chest pain or shortness of breath.
    This section means this methylene chloride standard.
    (c) Permissible exposure limits (PELs). (1) Eight-hour time-
weighted average (TWA) PEL. The employer shall ensure that no employee 
is exposed to an airborne concentration of MC in excess of twenty-five 
parts of MC per million parts of air (25 ppm) as an 8-hour TWA.
    (2) Short-term exposure limit (STEL). The employer shall ensure 
that no employee is exposed to an airborne concentration of MC in 
excess of one hundred and twenty-five parts of MC per million parts of 
air (125 ppm) as determined over a sampling period of fifteen minutes.
    (d) Exposure monitoring. (1) Characterization of employee exposure. 
(i) Where MC is present in the workplace, the employer shall determine 
each employee's exposure by either:
    (A) Taking a personal breathing zone air sample of each employee's 
exposure; or
    (B) Taking personal breathing zone air samples that are 
representative of each employee's exposure.
    (ii) Representative samples. The employer may consider personal 
breathing zone air samples to be representative of employee exposures 
when they are taken as follows:
    (A) 8-hour TWA PEL. The employer has taken one or more personal 
breathing zone air samples for at least one employee in each job 
classification in a work area during every work shift, and the employee 
sampled is expected to have the highest MC exposure.
    (B) Short-term exposure limits. The employer has taken one or more 
personal breathing zone air samples which indicate the highest likely 
15-minute exposures during such operations for at least one employee in 
each job classification in the work area during every work shift, and 
the employee sampled is expected to have the highest MC exposure.
    (C) Exception. Personal breathing zone air samples taken during one 
work shift may be used to represent employee exposures on other work 
shifts where the employer can document that the tasks performed and 
conditions in the workplace are similar across shifts.
    (iii) Accuracy of monitoring. The employer shall ensure that the 
methods used to perform exposure monitoring produce results that are 
accurate to a confidence level of 95 percent, and are:
    (A) Within plus or minus 25 percent for airborne concentrations of 
MC above the 8-hour TWA PEL or the STEL; or
    (B) Within plus or minus 35 percent for airborne concentrations of 
MC at or above the action level but at or below the 8-hour TWA PEL.
    (2) Initial determination. Each employer whose employees are 
exposed to MC shall perform initial exposure monitoring to determine 
each affected employee's exposure, except under the following 
conditions:
    (i) Where objective data demonstrate that MC cannot be released in 
the workplace in airborne concentrations at or above the action level 
or above the STEL. The objective data shall represent the highest MC 
exposures likely to occur under reasonably foreseeable conditions of 
processing, use, or handling. The employer shall document the objective 
data exemption as specified in paragraph (m) of this section;

[[Page 1602]]

    (ii) Where the employer has performed exposure monitoring within 12 
months prior to April 10, 1997 and that exposure monitoring meets all 
other requirements of this section, and was conducted under conditions 
substantially equivalent to existing conditions; or
    (iii) Where employees are exposed to MC on fewer than 30 days per 
year (e.g., on a construction site), and the employer has measurements 
by direct-reading instruments which give immediate results (such as a 
detector tube) and which provide sufficient information regarding 
employee exposures to determine what control measures are necessary to 
reduce exposures to acceptable levels.
    (3) Periodic monitoring. Where the initial determination shows 
employee exposures at or above the action level or above the STEL, the 
employer shall establish an exposure monitoring program for periodic 
monitoring of employee exposure to MC in accordance with Table 1:

    Table 1.--Six Initial Determination Exposure Scenarios and Their    
                    Associated Monitoring Frequencies                   
------------------------------------------------------------------------
           Exposure scenario               Required monitoring activity 
------------------------------------------------------------------------
Below the action level and at or below   No 8-hour TWA or STEL          
 the STEL.                                monitoring required.          
Below the action level and above the     No 8-hour TWA monitoring       
 STEL.                                    required; monitor STEL        
                                          exposures every three months. 
At or above the action level, at or      Monitor 8-hour TWA exposures   
 below the TWA, and at or below the       every six months.             
 STEL.                                                                  
At or above the action level, at or      Monitor 8-hour TWA exposures   
 below the TWA, and above the STEL.       every six months and monitor  
                                          STEL exposures every three    
                                          months.                       
Above the TWA and at or below the STEL.  Monitor 8-hour TWA exposures   
                                          every three months.           
Above the TWA and above the STEL.......  Monitor 8-hour TWA exposures   
                                          and STEL exposures every three
                                          months.                       
------------------------------------------------------------------------

    [Note to paragraph (d)(3): The employer may decrease the 
frequency of exposure monitoring to every six months when at least 2 
consecutive measurements taken at least 7 days apart show exposures 
to be at or below the 8-hour TWA PEL. The employer may discontinue 
the periodic 8-hour TWA monitoring for employees where at least two 
consecutive measurements taken at least 7 days apart are below the 
action level. The employer may discontinue the periodic STEL 
monitoring for employees where at least two consecutive measurements 
taken at least 7 days apart are at or below the STEL.]
    (4) Additional monitoring. (i) The employer shall perform exposure 
monitoring when a change in workplace conditions indicates that 
employee exposure may have increased. Examples of situations that may 
require additional monitoring include changes in production, process, 
control equipment, or work practices, or a leak, rupture, or other 
breakdown.
    (ii) Where exposure monitoring is performed due to a spill, leak, 
rupture or equipment breakdown, the employer shall clean-up the MC and 
perform the appropriate repairs before monitoring.
    (5) Employee notification of monitoring results. (i) The employer 
shall, within 15 working days after the receipt of the results of any 
monitoring performed under this section, notify each affected employee 
of these results in writing, either individually or by posting of 
results in an appropriate location that is accessible to affected 
employees.
    (ii) Whenever monitoring results indicate that employee exposure is 
above the 8-hour TWA PEL or the STEL, the employer shall describe in 
the written notification the corrective action being taken to reduce 
employee exposure to or below the 8-hour TWA PEL or STEL and the 
schedule for completion of this action.
    (6) Observation of monitoring. (i) Employee observation. The 
employer shall provide affected employees or their designated 
representatives an opportunity to observe any monitoring of employee 
exposure to MC conducted in accordance with this section.
    (ii) Observation procedures. When observation of the monitoring of 
employee exposure to MC requires entry into an area where the use of 
protective clothing or equipment is required, the employer shall 
provide, at no cost to the observer(s), and the observer(s) shall be 
required to use such clothing and equipment and shall comply with all 
other applicable safety and health procedures.
    (e) Regulated areas. (1) The employer shall establish a regulated 
area wherever an employee's exposure to airborne concentrations of MC 
exceeds or can reasonably be expected to exceed either the 8-hour TWA 
PEL or the STEL.
    (2) The employer shall limit access to regulated areas to 
authorized persons.
    (3) The employer shall supply a respirator, selected in accordance 
with paragraph (h)(3) of this section, to each person who enters a 
regulated area and shall require each affected employee to use that 
respirator whenever MC exposures are likely to exceed the 8-hour TWA 
PEL or STEL.
    [Note to paragraph (e)(3): An employer who has implemented all 
feasible engineering, work practice and administrative controls (as 
required in paragraph (f) of this section), and who has established 
a regulated area (as required by paragraph (e)(1) of this section) 
where MC exposure can be reliably predicted to exceed the 8-hour TWA 
PEL or the STEL only on certain days (for example, because of work 
or process schedule) would need to have affected employees use 
respirators in that regulated area only on those days.]
    (4) The employer shall ensure that, within a regulated area, 
employees do not engage in non-work activities which may increase 
dermal or oral MC exposure.
    (5) The employer shall ensure that while employees are wearing 
respirators, they do not engage in activities (such as taking 
medication or chewing gum or tobacco) which interfere with respirator 
seal or performance.
    (6) The employer shall demarcate regulated areas from the rest of 
the workplace in any manner that adequately establishes and alerts 
employees to the boundaries of the area and minimizes the number of 
authorized employees exposed to MC within the regulated area.
    (7) An employer at a multi-employer worksite who establishes a 
regulated area shall communicate the access restrictions and locations 
of these areas to all other employers with work operations at that 
worksite.
    (f) Methods of compliance. (1) Engineering and work practice 
controls. The employer shall institute and

[[Page 1603]]

maintain the effectiveness of engineering controls and work practices 
to reduce employee exposure to or below the PELs except to the extent 
that the employer can demonstrate that such controls are not feasible. 
Wherever the feasible engineering controls and work practices which can 
be instituted are not sufficient to reduce employee exposure to or 
below the 8-TWA PEL or STEL, the employer shall use them to reduce 
employee exposure to the lowest levels achievable by these controls and 
shall supplement them by the use of respiratory protection that 
complies with the requirements of paragraph (g) of this section.
    (2) Prohibition of rotation. The employer shall not implement a 
schedule of employee rotation as a means of compliance with the PELs.
    (3) Leak and spill detection. (i) The employer shall implement 
procedures to detect leaks of MC in the workplace. In work areas where 
spills may occur, the employer shall make provisions to contain any 
spills and to safely dispose of any MC-contaminated waste materials.
    (ii) The employer shall ensure that all incidental leaks are 
repaired and that incidental spills are cleaned promptly by employees 
who use the appropriate personal protective equipment and are trained 
in proper methods of cleanup. [Note to paragraph (f)(3)(ii): See 
Appendix A of this section for examples of procedures that satisfy this 
requirement. Employers covered by this standard may also be subject to 
the hazardous waste and emergency response provisions contained in 29 
CFR 1910.120 (q).]
    (g) Respiratory protection. (1) General requirements. The employer 
shall provide a respirator which complies with the requirement of this 
paragraph, at no cost to each affected employee, and ensure that each 
affected employee uses such respirator where appropriate. Respirators 
shall be used in the following circumstances:
    (i) Whenever an employee's exposure to MC exceeds or can reasonably 
be expected to exceed the 8-hour TWA PEL or the STEL (such as where an 
employee is using MC in a regulated area);
    (ii) During the time interval necessary to install or implement 
feasible engineering and work practice controls;
    (iii) In a few work operations, such as some maintenance operations 
and repair activities, for which the employer demonstrates that 
engineering and work practice controls are infeasible;
    (iv) Where feasible engineering and work practice controls are not 
sufficient to reduce exposures to or below the PELs; or
    (v) In emergencies.
    (2) Medical Evaluation. Before having any employee use a supplied-
air respirator in the negative pressure mode, or a gas mask with 
organic vapor canister for emergency escape, the employer shall have a 
physician or other licensed health care professional ascertain each 
affected employee's ability to use such respiratory protection. The 
physician or other licensed health care professional shall provide his 
or her findings to the affected employee and the employer in a written 
opinion.
    (3) Respirator selection. The appropriate atmosphere-supplying 
respirators, as specified in Table 2, shall be selected from those 
approved by the National Institute for Occupational Safety and Health 
(NIOSH) under the provisions of 42 CFR Part 84, ``Respiratory 
Protective Devices.'' When employers elect to provide gas masks with 
organic vapor canisters for use in emergency escape, the organic vapor 
canisters shall bear the approval of NIOSH.

 Table 2.--Minimum Requirements for Respiratory Protection for Airborne 
                           Methylene Chloride                           
------------------------------------------------------------------------
      Methylene chloride airborne                                       
concentration (ppm) or condition of use  Minimum respirator required \1\
------------------------------------------------------------------------
Up to 625 ppm (25 X PEL)...............  (1) Continuous flow supplied-  
                                          air respirator, hood or       
                                          helmet.                       
Up to 1250 ppm (50 X 8-TWA PEL)........  (1) Full facepiece supplied-air
                                          respirator operated in        
                                          negative pressure (demand)    
                                          mode.                         
                                         (2) Full facepiece self-       
                                          contained breathing apparatus 
                                          (SCBA) operated in negative   
                                          pressure (demand) mode.       
Up to 5000 ppm (200 X 8-TWA PEL).......  (1) Continuous flow supplied-  
                                          air respirator, full          
                                          facepiece.                    
                                         (2) Pressure demand supplied-  
                                          air respirator, full          
                                          facepiece.                    
                                         (3) Positive pressure full     
                                          facepiece SCBA.               
Unknown concentration, or above 5000     (1) Positive pressure full     
 ppm (Greater than 200 X 8-TWA PEL).      facepiece SCBA.               
                                         (2) Full facepiece pressure    
                                          demand supplied-air respirator
                                          with an auxiliary self-       
                                          contained air supply.         
Fire fighting..........................  Positive pressure full         
                                          facepiece SCBA.               
Emergency escape.......................  (1) Any continuous flow or     
                                          pressure demand SCBA.         
                                         (2) Gas mask with organic vapor
                                          canister.                     
------------------------------------------------------------------------
\1\ Respirators assigned for higher airborne concentrations may be used 
  at lower concentrations.                                              

    (4) Respirator program. Where respiratory protection is required by 
this section, the employer shall institute a respirator program in 
accordance with 29 CFR 1910.134.
    (5) Permission to leave area. The employer shall permit employees 
who wear respirators to leave the regulated area to readjust the 
facepieces to their faces to achieve a proper fit, and to wash their 
faces and respirator facepieces as necessary in order to prevent skin 
irritation associated with respirator use.
    (6) Filter respirators. Employers who provide gas masks with 
organic vapor canisters for the purpose of emergency escape shall 
replace those canisters after any emergency use before those gas masks 
are returned to service.
    (7) Respirator fit testing. (i) The employer shall ensure that each 
respirator issued to the employee is properly fitted and exhibits the 
least possible facepiece leakage from among the facepieces tested.
    (ii) The employer shall perform qualitative or quantitative fit 
tests at the time of initial fitting and at least annually thereafter 
for each employee wearing a negative pressure respirator, including 
those employees for whom emergency escape respirators are provided.
    [Note to paragraph (g)(7)(ii): The only supplied-air respirators 
to which this provision would apply are SCBA in negative pressure 
mode and full facepiece supplied-air respirators operated in 
negative pressure mode. The small business compliance guides will 
contain examples of protocols for qualitative and quantitative fit 
testing.]
    (h) Protective Work Clothing and Equipment. (1) Where needed to 
prevent

[[Page 1604]]

MC-induced skin or eye irritation, the employer shall provide clean 
protective clothing and equipment which is resistant to MC, at no cost 
to the employee, and shall ensure that each affected employee uses it. 
Eye and face protection shall meet the requirements of 29 CFR 1910.133 
or 29 CFR 1915.153, as applicable.
    (2) The employer shall clean, launder, repair and replace all 
protective clothing and equipment required by this paragraph as needed 
to maintain their effectiveness.
    (3) The employer shall be responsible for the safe disposal of such 
clothing and equipment. [Note to paragraph (h)(4): See Appendix A for 
examples of disposal procedures that will satisfy this requirement.]
    (i) Hygiene facilities. (1) If it is reasonably foreseeable that 
employees' skin may contact solutions containing 0.1 percent or greater 
MC (for example, through splashes, spills or improper work practices), 
the employer shall provide conveniently located washing facilities 
capable of removing the MC, and shall ensure that affected employees 
use these facilities as needed.
    (2) If it is reasonably foreseeable that an employee's eyes may 
contact solutions containing 0.1 percent or greater MC (for example 
through splashes, spills or improper work practices), the employer 
shall provide appropriate eyewash facilities within the immediate work 
area for emergency use, and shall ensure that affected employees use 
those facilities when necessary.
    (j) Medical surveillance. (1) Affected employees. The employer 
shall make medical surveillance available for employees who are or may 
be exposed to MC as follows:
    (i) At or above the action level on 30 or more days per year, or 
above the 8- hour TWA PEL or the STEL on 10 or more days per year;
    (ii) Above the 8-TWA PEL or STEL for any time period where an 
employee has been identified by a physician or other licensed health 
care professional as being at risk from cardiac disease or from some 
other serious MC-related health condition and such employee requests 
inclusion in the medical surveillance program;
    (iii) During an emergency.
    (2) Costs. The employer shall provide all required medical 
surveillance at no cost to affected employees, without loss of pay and 
at a reasonable time and place.
    (3) Medical personnel. The employer shall ensure that all medical 
surveillance procedures are performed by a physician or other licensed 
health care professional, as defined in paragraph (b) of this section.
    (4) Frequency of medical surveillance. The employer shall make 
medical surveillance available to each affected employee as follows:
    (i) Initial surveillance. The employer shall provide initial 
medical surveillance under the schedule provided by paragraph 
(n)(2)(iii) of this section, or before the time of initial assignment 
of the employee, whichever is later. The employer need not provide the 
initial surveillance if medical records show that an affected employee 
has been provided with medical surveillance that complies with this 
section within 12 months before April 10, 1997.
    (ii) Periodic medical surveillance. The employer shall update the 
medical and work history for each affected employee annually. The 
employer shall provide periodic physical examinations, including 
appropriate laboratory surveillance, as follows:
    (A) For employees 45 years of age or older, within 12 months of the 
initial surveillance or any subsequent medical surveillance; and
    (B) For employees younger than 45 years of age, within 36 months of 
the initial surveillance or any subsequent medical surveillance.
    (iii) Termination of employment or reassignment. When an employee 
leaves the employer's workplace, or is reassigned to an area where 
exposure to MC is consistently at or below the action level and STEL, 
medical surveillance shall be made available if six months or more have 
elapsed since the last medical surveillance.
    (iv) Additional surveillance. The employer shall provide additional 
medical surveillance at frequencies other than those listed above when 
recommended in the written medical opinion. (For example, the physician 
or other licensed health care professional may determine an examination 
is warranted in less than 36 months for employees younger than 45 years 
of age based upon evaluation of the results of the annual medical and 
work history.)
    (5) Content of medical surveillance. (i) Medical and work history. 
The comprehensive medical and work history shall emphasize neurological 
symptoms, skin conditions, history of hematologic or liver disease, 
signs or symptoms suggestive of heart disease (angina, coronary artery 
disease), risk factors for cardiac disease, MC exposures, and work 
practices and personal protective equipment used during such exposures. 
[Note to paragraph (j)(5)(i): See Appendix B of this section for an 
example of a medical and work history format that would satisfy this 
requirement.]
    (ii) Physical examination. Where physical examinations are provided 
as required above, the physician or other licensed health care 
professional shall accord particular attention to the lungs, 
cardiovascular system (including blood pressure and pulse), liver, 
nervous system, and skin. The physician or other licensed health care 
professional shall determine the extent and nature of the physical 
examination based on the health status of the employee and analysis of 
the medical and work history.
    (iii) Laboratory surveillance. The physician or other licensed 
health care professional shall determine the extent of any required 
laboratory surveillance based on the employee's observed health status 
and the medical and work history. [Note to paragraph (j)(5)(iii): See 
Appendix B of this section for information regarding medical tests. 
Laboratory surveillance may include before- and after-shift 
carboxyhemoglobin determinations, resting ECG, hematocrit, liver 
function tests and cholesterol levels.]
    (iv) Other information or reports. The medical surveillance shall 
also include any other information or reports the physician or other 
licensed health care professional determines are necessary to assess 
the employee's health in relation to MC exposure.
    (6) Content of emergency medical surveillance. The employer shall 
ensure that medical surveillance made available when an employee has 
been exposed to MC in emergency situations includes, at a minimum:
    (i) Appropriate emergency treatment and decontamination of the 
exposed employee;
    (ii) Comprehensive physical examination with special emphasis on 
the nervous system, cardiovascular system, lungs, liver and skin, 
including blood pressure and pulse;
    (iii) Updated medical and work history, as appropriate for the 
medical condition of the employee; and
    (iv) Laboratory surveillance, as indicated by the employee's health 
status. [Note to paragraph (j)(6)(iv): See Appendix B for examples of 
tests which may be appropriate.]
    (7) Additional examinations and referrals. Where the physician or 
other licensed health care professional determines it is necessary, the 
scope of the medical examination shall be expanded and the appropriate 
additional medical surveillance, such as referrals for consultation or 
examination, shall be provided.

[[Page 1605]]

    (8) Information provided to the physician or other licensed health 
care professional. The employer shall provide the following information 
to a physician or other licensed health care professional who is 
involved in the diagnosis of MC-induced health effects:
    (i) A copy of this section including its applicable appendices;
    (ii) A description of the affected employee's past, current and 
anticipated future duties as they relate to the employee's MC exposure;
    (iii) The employee's former or current exposure levels or, for 
employees not yet occupationally exposed to MC, the employee's 
anticipated exposure levels and the frequency and exposure levels 
anticipated to be associated with emergencies;
    (iv) A description of any personal protective equipment, such as 
respirators, used or to be used; and
    (v) Information from previous employment-related medical 
surveillance of the affected employee which is not otherwise available 
to the physician or other licensed health care professional.
    (9) Written medical opinions. (i) For each physical examination 
required by this section, the employer shall ensure that the physician 
or other licensed health care professional provides to the employer and 
to the affected employee a written opinion regarding the results of 
that examination within 15 days of completion of the evaluation of 
medical and laboratory findings, but not more than 30 days after the 
examination. The written medical opinion shall be limited to the 
following information:
    (A) The physician's or other licensed health care professional's 
opinion concerning whether the employee has any detected medical 
condition(s) which would place the employee's health at increased risk 
of material impairment from exposure to MC;
    (B) Any recommended limitations upon the employee's exposure to MC 
or upon the employee's use of protective clothing or equipment and 
respirators;
    (C) A statement that the employee has been informed by the 
physician or other licensed health care professional that MC is a 
potential occupational carcinogen, of risk factors for heart disease, 
and the potential for exacerbation of underlying heart disease by 
exposure to MC through its metabolism to carbon monoxide; and
    (D) A statement that the employee has been informed by the 
physician or other licensed health care professional of the results of 
the medical examination and any medical conditions resulting from MC 
exposure which require further explanation or treatment.
    (ii) The employer shall instruct the physician or other licensed 
health care professional not to reveal to the employer, orally or in 
the written opinion, any specific records, findings, and diagnoses that 
have no bearing on occupational exposure to MC. [Note to paragraph 
(j)(9)(ii): The written medical opinion may also include information 
and opinions generated to comply with other OSHA health standards.]
    (k) Hazard communication. The employer shall communicate the 
following hazards associated with MC on labels and in material safety 
data sheets in accordance with the requirements of the Hazard 
Communication Standard, 29 CFR 1910.1200, 29 CFR 1915.1200, or 29 CFR 
1926.59, as appropiate: cancer, cardiac effects (including elevation of 
carboxyhemoglobin), central nervous system effects, liver effects, and 
skin and eye irritation.
    (l) Employee information and training. (1) The employer shall 
provide information and training for each affected employee prior to or 
at the time of initial assignment to a job involving potential exposure 
to MC.
    (2) The employer shall ensure that information and training is 
presented in a manner that is understandable to the employees.
    (3) In addition to the information required under the Hazard 
Communication Standard at 29 CFR 1910.1200, 29 CFR 1915.1200, or 29 CFR 
1926.59, as appropiate:
    (i) The employer shall inform each affected employee of the 
requirements of this section and information available in its 
appendices, as well as how to access or obtain a copy of it in the 
workplace;
    (ii) Wherever an employee's exposure to airborne concentrations of 
MC exceeds or can reasonably be expected to exceed the action level, 
the employer shall inform each affected employee of the quantity, 
location, manner of use, release, and storage of MC and the specific 
operations in the workplace that could result in exposure to MC, 
particularly noting where exposures may be above the 8-hour TWA PEL or 
STEL;
    (4) The employer shall train each affected employee as required 
under the Hazard Communication standard at 29 CFR 1910.1200, 29 CFR 
1915.1200, or 29 CFR 1926.59, as appropiate.
    (5) The employer shall re-train each affected employee as necessary 
to ensure that each employee exposed above the action level or the STEL 
maintains the requisite understanding of the principles of safe use and 
handling of MC in the workplace.
    (6) Whenever there are workplace changes, such as modifications of 
tasks or procedures or the institution of new tasks or procedures, 
which increase employee exposure, and where those exposures exceed or 
can reasonably be expected to exceed the action level, the employer 
shall update the training as necessary to ensure that each affected 
employee has the requisite proficiency.
    (7) An employer whose employees are exposed to MC at a multi-
employer worksite shall notify the other employers with work operations 
at that site in accordance with the requirements of the Hazard 
Communication Standard, 29 CFR 1910.1200, 29 CFR 1915.1200, or 29 CFR 
1926.59, as appropiate.
    (8) The employer shall provide to the Assistant Secretary or the 
Director, upon request, all available materials relating to employee 
information and training.
    (m) Recordkeeping. (1) Objective data. (i) Where an employer seeks 
to demonstrate that initial monitoring is unnecessary through 
reasonable reliance on objective data showing that any materials in the 
workplace containing MC will not release MC at levels which exceed the 
action level or the STEL under foreseeable conditions of exposure, the 
employer shall establish and maintain an accurate record of the 
objective data relied upon in support of the exemption.
    (ii) This record shall include at least the following information:
    (A) The MC-containing material in question;
    (B) The source of the objective data;
    (C) The testing protocol, results of testing, and/or analysis of 
the material for the release of MC;
    (D) A description of the operation exempted under paragraph 
(d)(2)(i) of this section and how the data support the exemption; and
    (E) Other data relevant to the operations, materials, processing, 
or employee exposures covered by the exemption.
    (iii) The employer shall maintain this record for the duration of 
the employer's reliance upon such objective data.
    (2) Exposure measurements. (i) The employer shall establish and 
keep an accurate record of all measurements taken to monitor employee 
exposure to MC as prescribed in paragraph (d) of this section.
    (ii) Where the employer has 20 or more employees, this record shall 
include at least the following information:
    (A) The date of measurement for each sample taken;
    (B) The operation involving exposure to MC which is being 
monitored;

[[Page 1606]]

    (C) Sampling and analytical methods used and evidence of their 
accuracy;
    (D) Number, duration, and results of samples taken;
    (E) Type of personal protective equipment, such as respiratory 
protective devices, worn, if any; and
    (F) Name, social security number, job classification and exposure 
of all of the employees represented by monitoring, indicating which 
employees were actually monitored.
    (iii) Where the employer has fewer than 20 employees, the record 
shall include at least the following information:
    (A) The date of measurement for each sample taken;
    (B) Number, duration, and results of samples taken; and
    (C) Name, social security number, job classification and exposure 
of all of the employees represented by monitoring, indicating which 
employees were actually monitored.
    (iv) The employer shall maintain this record for at least thirty 
(30) years, in accordance with 29 CFR 1910.1020.
    (3) Medical surveillance. (i) The employer shall establish and 
maintain an accurate record for each employee subject to medical 
surveillance under paragraph (j) of this section.
    (ii) The record shall include at least the following information:
    (A) The name, social security number and description of the duties 
of the employee;
    (B) Written medical opinions; and
    (C) Any employee medical conditions related to exposure to MC.
    (iii) The employer shall ensure that this record is maintained for 
the duration of employment plus thirty (30) years, in accordance with 
29 CFR 1910.1020.
    (4) Availability. (i) The employer, upon written request, shall 
make all records required to be maintained by this section available to 
the Assistant Secretary and the Director for examination and copying in 
accordance with 29 CFR 1910.1020. [Note to paragraph (m)(4)(i): All 
records required to be maintained by this section may be kept in the 
most administratively convenient form (for example, electronic or 
computer records would satisfy this requirement).]
    (ii) The employer, upon request, shall make any employee exposure 
and objective data records required by this section available for 
examination and copying by affected employees, former employees, and 
designated representatives in accordance with 29 CFR 1910.1020.
    (iii) The employer, upon request, shall make employee medical 
records required to be kept by this section available for examination 
and copying by the subject employee and by anyone having the specific 
written consent of the subject employee in accordance with 29 CFR 
1910.1020.
    (5) Transfer of records. The employer shall comply with the 
requirements concerning transfer of records set forth in 29 CFR 
1910.1020(h).
    (n) Dates. (1) Effective date. This section shall become effective 
April 10, 1997.
    (2) Start-up dates.
    (i) Initial monitoring required by paragraph (d)(2) of this section 
shall be completed according to the following schedule:
    (A) For employers with fewer than 20 employees, within 300 days 
after the effective date of this section.
    (B) For polyurethane foam manufacturers with 20 to 99 employees, 
within 210 days after the effective date of this section.
    (C) For all other employers, within 120 days after the effective 
date of this section.
    (ii) Engineering controls required under paragraph (f)(1) of this 
section shall be implemented according to the following schedule:
    (A) For employers with fewer than 20 employees, within three (3) 
years after the effective date of this section.
    (B) For polyurethane foam manufacturers with 20 to 99 employees, 
within two (2) years after the effective date of this section.
    (C) For all other employers, within one (1) year after the 
effective date of this section.
    (iii) All other requirements of this section shall be complied with 
according to the following schedule:
    (A) For employers with fewer than 20 employees, within one (1) year 
after the effective date of this section.
    (B) For polyurethane foam manufacturers with 20 to 99 employees, 
within 270 days after the effective date of this section.
    (C) For all other employers, within 180 days after the effective 
date of this section.
    (3) Transitional dates. The exposure limits for MC specified in 29 
CFR 1910.1000 (1996), Table Z-2, shall remain in effect until the 
start-up dates for the exposure limits specified in paragraph (n) of 
this section, or if the exposure limits in this section are stayed or 
vacated.
    (o) Appendices. The information contained in the appendices does 
not, by itself, create any additional obligations not otherwise imposed 
or detract from any existing obligation.

Appendix A to Section 1910.1052: Substance Safety Data Sheet and 
Technical Guidelines for Methylene Chloride

I. Substance Identification

    A. Substance: Methylene chloride (CH2Cl2).
    B. Synonyms: MC, Dichloromethane (DCM); Methylene dichloride; 
Methylene bichloride; Methane dichloride; CAS: 75-09-2; NCI-C50102.
    C. Physical data:
    1. Molecular weight: 84.9.
    2. Boiling point (760 mm Hg): 39.8 deg.C (104 deg.F).
    3. Specific gravity (water=1): 1.3.
    4. Vapor density (air=1 at boiling point): 2.9.
    5. Vapor pressure at 20 deg. C (68 deg. F): 350 mm Hg.
    6. Solubility in water, g/100 g water at 20 deg. C (68 deg. 
F)=1.32.
    7. Appearance and odor: colorless liquid with a chloroform-like 
odor.
    D. Uses:
    MC is used as a solvent, especially where high volatility is 
required. It is a good solvent for oils, fats, waxes, resins, 
bitumen, rubber and cellulose acetate and is a useful paint stripper 
and degreaser. It is used in paint removers, in propellant mixtures 
for aerosol containers, as a solvent for plastics, as a degreasing 
agent, as an extracting agent in the pharmaceutical industry and as 
a blowing agent in polyurethane foams. Its solvent property is 
sometimes increased by mixing with methanol, petroleum naphtha or 
tetrachloroethylene.
    E. Appearance and odor:
    MC is a clear colorless liquid with a chloroform-like odor. It 
is slightly soluble in water and completely miscible with most 
organic solvents.
    F. Permissible exposure:
    Exposure may not exceed 25 parts MC per million parts of air (25 
ppm) as an eight-hour time-weighted average (8-hour TWA PEL) or 125 
parts of MC per million parts of air (125 ppm) averaged over a 15-
minute period (STEL).

II. Health Hazard Data

    A. MC can affect the body if it is inhaled or if the liquid 
comes in contact with the eyes or skin. It can also affect the body 
if it is swallowed.
    B. Effects of overexposure:
    1. Short-term Exposure:
    MC is an anesthetic. Inhaling the vapor may cause mental 
confusion, light-headedness, nausea, vomiting, and headache. 
Continued exposure may cause increased light-headedness, staggering, 
unconsciousness, and even death. High vapor concentrations may also 
cause irritation of the eyes and respiratory tract. Exposure to MC 
may make the symptoms of angina (chest pains) worse. Skin exposure 
to liquid MC may cause irritation. If liquid MC remains on the skin, 
it may cause skin burns. Splashes of the liquid into the eyes may 
cause irritation.
    2. Long-term (chronic) exposure:
    The best evidence that MC causes cancer is from laboratory 
studies in which rats, mice and hamsters inhaled MC 6 hours per day,

[[Page 1607]]

5 days per week for 2 years. MC exposure produced lung and liver 
tumors in mice and mammary tumors in rats. No carcinogenic effects 
of MC were found in hamsters.
    There are also some human epidemiological studies which show an 
association between occupational exposure to MC and increases in 
biliary (bile duct) cancer and a type of brain cancer. Other 
epidemiological studies have not observed a relationship between MC 
exposure and cancer. OSHA interprets these results to mean that 
there is suggestive (but not absolute) evidence that MC is a human 
carcinogen.
    C. Reporting signs and symptoms:
    You should inform your employer if you develop any signs or 
symptoms and suspect that they are caused by exposure to MC.
    D. Warning Properties:
    1. Odor Threshold:
    Different authors have reported varying odor thresholds for MC. 
Kirk-Othmer and Sax both reported 25 to 50 ppm; Summer and May both 
reported 150 ppm; Spector reports 320 ppm. Patty, however, states 
that since one can become adapted to the odor, MC should not be 
considered to have adequate warning properties.
    2. Eye Irritation Level:
    Kirk-Othmer reports that ``MC vapor is seriously damaging to the 
eyes.'' Sax agrees with Kirk-Othmer's statement. The ACGIH 
Documentation of TLVs states that irritation of the eyes has been 
observed in workers exposed to concentrations up to 5000 ppm.
    3. Evaluation of Warning Properties:
    Since a wide range of MC odor thresholds are reported (25-320 
ppm), and human adaptation to the odor occurs, MC is considered to 
be a material with poor warning properties.

III. Emergency First Aid Procedures

    In the event of emergency, institute first aid procedures and 
send for first aid or medical assistance.
    A. Eye and Skin Exposures:
    If there is a potential for liquid MC to come in contact with 
eye or skin, face shields and skin protective equipment must be 
provided and used. If liquid MC comes in contact with the eye, get 
medical attention. Contact lenses should not be worn when working 
with this chemical.
    B. Breathing:
    If a person breathes in large amounts of MC, move the exposed 
person to fresh air at once. If breathing has stopped, perform 
cardiopulmorary resuscitation. Keep the affected person warm and at 
rest. Get medical attention as soon as possible.
    C. Rescue:
    Move the affected person from the hazardous exposure 
immediately. If the exposed person has been overcome, notify someone 
else and put into effect the established emergency rescue 
procedures. Understand the facility's emergency rescue procedures 
and know the locations of rescue equipment before the need arises. 
Do not become a casualty yourself.

IV. Respirators, Protective Clothing, and Eye Protection

    A. Respirators:
    Good industrial hygiene practices recommend that engineering 
controls be used to reduce environmental concentrations to the 
permissible exposure level. However, there are some exceptions where 
respirators may be used to control exposure. Respirators may be used 
when engineering and work practice controls are not feasible, when 
such controls are in the process of being installed, or when these 
controls fail and need to be supplemented. Respirators may also be 
used for operations which require entry into tanks or closed 
vessels, and in emergency situations.
    If the use of respirators is necessary, the only respirators 
permitted are those that have been approved by the Mine Safety and 
Health Administration (MSHA) or the National Institute for 
Occupational Safety and Health (NIOSH). Supplied-air respirators are 
required because air-purifying respirators do not provide adequate 
respiratory protection against MC.
    In addition to respirator selection, a complete written 
respiratory protection program should be instituted which includes 
regular training, maintenance, inspection, cleaning, and evaluation. 
If you can smell MC while wearing a respirator, proceed immediately 
to fresh air. If you experience difficulty in breathing while 
wearing a respirator, tell your employer.
    B. Protective Clothing:
    Employees must be provided with and required to use impervious 
clothing, gloves, face shields (eight-inch minimum), and other 
appropriate protective clothing necessary to prevent repeated or 
prolonged skin contact with liquid MC or contact with vessels 
containing liquid MC. Any clothing which becomes wet with liquid MC 
should be removed immediately and not reworn until the employer has 
ensured that the protective clothing is fit for reuse. Contaminated 
protective clothing should be placed in a regulated area designated 
by the employer for removal of MC before the clothing is laundered 
or disposed of. Clothing and equipment should remain in the 
regulated area until all of the MC contamination has evaporated; 
clothing and equipment should then be laundered or disposed of as 
appropriate.
    C. Eye Protection:
    Employees should be provided with and required to use splash-
proof safety goggles where liquid MC may contact the eyes.

V. Housekeeping and Hygiene Facilities

    For purposes of complying with 29 CFR 1910.141, the following 
items should be emphasized:
    A. The workplace should be kept clean, orderly, and in a 
sanitary condition. The employer should institute a leak and spill 
detection program for operations involving liquid MC in order to 
detect sources of fugitive MC emissions.
    B. Emergency drench showers and eyewash facilities are 
recommended. These should be maintained in a sanitary condition. 
Suitable cleansing agents should also be provided to assure the 
effective removal of MC from the skin.
    C. Because of the hazardous nature of MC, contaminated 
protective clothing should be placed in a regulated area designated 
by the employer for removal of MC before the clothing is laundered 
or disposed of.

VI. Precautions for Safe Use, Handling, and Storage

    A. Fire and Explosion Hazards:
    MC has no flash point in a conventional closed tester, but it 
forms flammable vapor-air mixtures at approximately 100 deg.C 
(212 deg.F), or higher. It has a lower explosion limit of 12%, and 
an upper explosion limit of 19% in air. It has an autoignition 
temperature of 556.1 deg.C (1033 deg.F), and a boiling point of 
39.8 deg.C (104 deg.F). It is heavier than water with a specific 
gravity of 1.3. It is slightly soluble in water.
    B. Reactivity Hazards:
    Conditions contributing to the instability of MC are heat and 
moisture. Contact with strong oxidizers, caustics, and chemically 
active metals such as aluminum or magnesium powder, sodium and 
potassium may cause fires and explosions.
    Special precautions: Liquid MC will attack some forms of 
plastics, rubber, and coatings.
    C. Toxicity:
    Liquid MC is painful and irritating if splashed in the eyes or 
if confined on the skin by gloves, clothing, or shoes. Vapors in 
high concentrations may cause narcosis and death. Prolonged exposure 
to vapors may cause cancer or exacerbate cardiac disease.
    D. Storage:
    Protect against physical damage. Because of its corrosive 
properties, and its high vapor pressure, MC should be stored in 
plain, galvanized or lead lined, mild steel containers in a cool, 
dry, well ventilated area away from direct sunlight, heat source and 
acute fire hazards.
    E. Piping Material:
    All piping and valves at the loading or unloading station should 
be of material that is resistant to MC and should be carefully 
inspected prior to connection to the transport vehicle and 
periodically during the operation.
    F. Usual Shipping Containers:
    Glass bottles, 5- and 55-gallon steel drums, tank cars, and tank 
trucks.

    Note: This section addresses MC exposure in marine terminal and 
longshore employment only where leaking or broken packages allow MC 
exposure that is not addressed through compliance with 29 CFR parts 
1917 and 1918, respectively.

    G. Electrical Equipment:
    Electrical installations in Class I hazardous locations as 
defined in Article 500 of the National Electrical Code, should be 
installed according to Article 501 of the code; and electrical 
equipment should be suitable for use in atmospheres containing MC 
vapors. See Flammable and Combustible Liquids Code (NFPA No. 325M), 
Chemical Safety Data Sheet SD-86 (Manufacturing Chemists' 
Association, Inc.).
    H. Fire Fighting:
    When involved in fire, MC emits highly toxic and irritating 
fumes such as phosgene, hydrogen chloride and carbon monoxide. Wear 
breathing apparatus and use water spray to keep fire-exposed 
containers cool. Water spray may be used to flush spills away from 
exposures. Extinguishing media are dry

[[Page 1608]]

chemical, carbon dioxide, foam. For purposes of compliance with 29 
CFR 1910.307, locations classified as hazardous due to the presence 
of MC shall be Class I.
    I. Spills and Leaks:
    Persons not wearing protective equipment and clothing should be 
restricted from areas of spills or leaks until cleanup has been 
completed. If MC has spilled or leaked, the following steps should 
be taken:
    1. Remove all ignition sources.
    2. Ventilate area of spill or leak.
    3. Collect for reclamation or absorb in vermiculite, dry sand, 
earth, or a similar material.
    J. Methods of Waste Disposal:
    Small spills should be absorbed onto sand and taken to a safe 
area for atmospheric evaporation. Incineration is the preferred 
method for disposal of large quantities by mixing with a combustible 
solvent and spraying into an incinerator equipped with acid 
scrubbers to remove hydrogen chloride gases formed. Complete 
combustion will convert carbon monoxide to carbon dioxide. Care 
should be taken for the presence of phosgene.
    K. You should not keep food, beverage, or smoking materials, or 
eat or smoke in regulated areas where MC concentrations are above 
the permissible exposure limits.
    L. Portable heating units should not be used in confined areas 
where MC is used.
    M. Ask your supervisor where MC is used in your work area and 
for any additional plant safety and health rules.

VII. Medical Requirements

    Your employer is required to offer you the opportunity to 
participate in a medical surveillance program if you are exposed to 
MC at concentrations at or above the action level (12.5 ppm 8-hour 
TWA) for more than 30 days a year or at concentrations exceeding the 
PELs (25 ppm 8-hour TWA or 125 ppm 15-minute STEL) for more than 10 
days a year. If you are exposed to MC at concentrations over either 
of the PELs, your employer will also be required to have a physician 
or other licensed health care professional ensure that you are able 
to wear the respirator that you are assigned. Your employer must 
provide all medical examinations relating to your MC exposure at a 
reasonable time and place and at no cost to you.

VIII. Monitoring and Measurement Procedures

    A. Exposure above the Permissible Exposure Limit:
    1. Eight-hour exposure evaluation: Measurements taken for the 
purpose of determining employee exposure under this section are best 
taken with consecutive samples covering the full shift. Air samples 
must be taken in the employee's breathing zone.
    2. Monitoring techniques: The sampling and analysis under this 
section may be performed by collection of the MC vapor on two 
charcoal adsorption tubes in series or other composition adsorption 
tubes, with subsequent chemical analysis. Sampling and analysis may 
also be performed by instruments such as real-time continuous 
monitoring systems, portable direct reading instruments, or passive 
dosimeters as long as measurements taken using these methods 
accurately evaluate the concentration of MC in employees'' breathing 
zones.
    OSHA method 80 is an example of a validated method of sampling 
and analysis of MC. Copies of this method are available from OSHA or 
can be downloaded from the Internet at http://www.osha.gov. The 
employer has the obligation of selecting a monitoring method which 
meets the accuracy and precision requirements of the standard under 
his or her unique field conditions. The standard requires that the 
method of monitoring must be accurate, to a 95 percent confidence 
level, to plus or minus 25 percent for concentrations of MC at or 
above 25 ppm, and to plus or minus 35 percent for concentrations at 
or below 25 ppm. In addition to OSHA method 80, there are numerous 
other methods available for monitoring for MC in the workplace.
    B. Since many of the duties relating to employee exposure are 
dependent on the results of measurement procedures, employers must 
assure that the evaluation of employee exposure is performed by a 
technically qualified person.

IX. Observation of Monitoring

    Your employer is required to perform measurements that are 
representative of your exposure to MC and you or your designated 
representative are entitled to observe the monitoring procedure. You 
are entitled to observe the steps taken in the measurement 
procedure, and to record the results obtained. When the monitoring 
procedure is taking place in an area where respirators or personal 
protective clothing and equipment are required to be worn, you or 
your representative must also be provided with, and must wear, 
protective clothing and equipment.

X. Access To Information

    A. Your employer is required to inform you of the information 
contained in this Appendix. In addition, your employer must instruct 
you in the proper work practices for using MC, emergency procedures, 
and the correct use of protective equipment.
    B. Your employer is required to determine whether you are being 
exposed to MC. You or your representative has the right to observe 
employee measurements and to record the results obtained. Your 
employer is required to inform you of your exposure. If your 
employer determines that you are being over exposed, he or she is 
required to inform you of the actions which are being taken to 
reduce your exposure to within permissible exposure limits.
    C. Your employer is required to keep records of your exposures 
and medical examinations. These records must be kept by the employer 
for at least thirty (30) years.
    D. Your employer is required to release your exposure and 
medical records to you or your representative upon your request.
    E. Your employee is required to provide labels and material 
safety data sheets (MSDS) for all materials, mixtures or solutions 
composed of greater than 0.1 percent MC. An example of a label that 
would satisfy these requirements would be:

Danger Contains Methylene Chloride Potential Cancer Hazard

    May worsen heart disease because methylene chloride is converted 
to carbon monoxide in the body.
    May cause dizziness, headache, irritation of the throat and 
lungs, loss of consciousness and death at high concentrations (for 
example, if used in a poorly ventilated room).
    Avoid Skin Contact. Contact with liquid causes skin and eye 
irritation.

XI. Common Operations and Controls

    The following list includes some common operations in which 
exposure to MC may occur and control methods which may be effective 
in each case:

------------------------------------------------------------------------
                Operations                            Controls          
------------------------------------------------------------------------
Use as solvent in paint and varnish         General dilution            
 removers; manufacture of aerosols; cold     ventilation; local exhaust 
 cleaning and ultrasonic cleaning; and as    ventilation; personal      
 a solvent in furniture stripping.           protective equipment;      
                                             substitution.              
Use as solvent in vapor degreasing........  Process enclosure; local    
                                             exhaust ventilation;       
                                             chilling coils;            
                                             substitution.              
Use as a secondary refrigerant in air       General dilution            
 conditioning and scientific testing.        ventilation; local exhaust 
                                             ventilation; personal      
                                             protective equipment.      
------------------------------------------------------------------------

Appendix B to Section 1910.1052: Medical Surveillance for Methylene 
Chloride

I. Primary Route of Entry

    Inhalation.

II. Toxicology

    Methylene Chloride (MC) is primarily an inhalation hazard. The 
principal acute hazardous effects are the depressant action on the 
central nervous system, possible cardiac toxicity and possible liver 
toxicity. The range of CNS effects are from decreased eye/hand 
coordination and decreased performance in vigilance tasks to 
narcosis and even death of individuals exposed at very high doses. 
Cardiac toxicity is due to the metabolism of MC to carbon monoxide, 
and the effects of carbon monoxide on heart tissue. Carbon monoxide 
displaces oxygen in the blood, decreases the oxygen available to 
heart tissue, increasing the risk of damage to the heart, which may 
result in heart attacks in susceptible individuals. Susceptible 
individuals include persons with heart disease and those with risk 
factors for heart disease.
    Elevated liver enzymes and irritation to the respiratory 
passages and eyes have also been reported for both humans and 
experimental animals exposed to MC vapors.
    MC is metabolized to carbon monoxide and carbon dioxide via two 
separate pathways. Through the first pathway, MC is metabolized to 
carbon monoxide as an end-product via the P-450 mixed function 
oxidase pathway located in the microsomal

[[Page 1609]]

fraction of the cell. This biotransformation of MC to carbon 
monoxide occurs through the process of microsomal oxidative 
dechlorination which takes place primarily in the liver. The amount 
of conversion to carbon monoxide is significant as measured by the 
concentration of carboxyhemoglobin, up to 12% measured in the blood 
following occupational exposure of up to 610 ppm. Through the second 
pathway, MC is metabolized to carbon dioxide as an end product (with 
formaldehyde and formic acid as metabolic intermediates) via the 
glutathione dependent enzyme found in the cytosolic fraction of the 
liver cell. Metabolites along this pathway are believed to be 
associated with the carcinogenic activity of MC.
    MC has been tested for carcinogenicity in several laboratory 
rodents. These rodent studies indicate that there is clear evidence 
that MC is carcinogenic to male and female mice and female rats. 
Based on epidemiologic studies, OSHA has concluded that there is 
suggestive evidence of increased cancer risk in MC-related worker 
populations. The epidemiological evidence is consistent with the 
finding of excess cancer in the experimental animal studies. NIOSH 
regards MC as a potential occupational carcinogen and the 
International Agency for Research Cancer (IARC) classifies MC as an 
animal carcinogen. OSHA considers MC as a suspected human 
carcinogen.

III. Medical Signs and Symptoms of Acute Exposure

    Skin exposure to liquid MC may cause irritation or skin burns. 
Liquid MC can also be irritating to the eyes. MC is also absorbed 
through the skin and may contribute to the MC exposure by 
inhalation.
    At high concentrations in air, MC may cause nausea, vomiting, 
light-headedness, numbness of the extremities, changes in blood 
enzyme levels, and breathing problems, leading to bronchitis and 
pulmonary edema, unconsciousness and even death.
    At lower concentrations in air, MC may cause irritation to the 
skin, eye, and respiratory tract and occasionally headache and 
nausea. Perhaps the greatest problem from exposure to low 
concentrations of MC is the CNS effects on coordination and 
alertness that may cause unsafe operations of machinery and 
equipment, leading to self-injury or accidents.
    Low levels and short duration exposures do not seem to produce 
permanent disability, but chronic exposures to MC have been 
demonstrated to produce liver toxicity in animals, and therefore, 
the evidence is suggestive for liver toxicity in humans after 
chronic exposure.
    Chronic exposure to MC may also cause cancer.

IV. Surveillance and Preventive Considerations

    As discussed above, MC is classified as a suspect or potential 
human carcinogen. It is a central nervous system (CNS) depressant 
and a skin, eye and respiratory tract irritant. At extremely high 
concentrations, MC has caused liver damage in animals.
    MC principally affects the CNS, where it acts as a narcotic. The 
observation of the symptoms characteristic of CNS depression, along 
with a physical examination, provides the best detection of early 
neurological disorders. Since exposure to MC also increases the 
carboxyhemoglobin level in the blood, ambient carbon monoxide levels 
would have an additive effect on that carboxyhemoglobin level. Based 
on such information, a periodic post-shift carboxyhemoglobin test as 
an index of the presence of carbon monoxide in the blood is 
recommended, but not required, for medical surveillance.
    Based on the animal evidence and three epidemiologic studies 
previously mentioned, OSHA concludes that MC is a suspect human 
carcinogen. The medical surveillance program is designed to observe 
exposed workers on a regular basis. While the medical surveillance 
program cannot detect MC-induced cancer at a preneoplastic stage, 
OSHA anticipates that, as in the past, early detection and 
treatments of cancers leading to enhanced survival rates will 
continue to evolve.
    A. Medical and Occupational History:
    The medical and occupational work history plays an important 
role in the initial evaluation of workers exposed to MC. It is 
therefore extremely important for the examining physician or other 
licensed health care professional to evaluate the MC-exposed worker 
carefully and completely and to focus the examination on MC's 
potentially associated health hazards. The medical evaluation must 
include an annual detailed work and medical history with special 
emphasis on cardiac history and neurological symptoms.
    An important goal of the medical history is to elicit 
information from the worker regarding potential signs or symptoms 
associated with increased levels of carboxyhemoglobin due to the 
presence of carbon monoxide in the blood. Physicians or other 
licensed health care professionals should ensure that the smoking 
history of all MC exposed employees is known. Exposure to MC may 
cause a significant increase in carboxyhemoglobin level in all 
exposed persons. However, smokers as well as workers with anemia or 
heart disease and those concurrently exposed to carbon monoxide are 
at especially high risk of toxic effects because of an already 
reduced oxygen carrying capacity of the blood.
    A comprehensive or interim medical and work history should also 
include occurrence of headache, dizziness, fatigue, chest pain, 
shortness of breath, pain in the limbs, and irritation of the skin 
and eyes.
    In addition, it is important for the physician or other licensed 
health care professional to become familiar with the operating 
conditions in which exposure to MC is likely to occur. The physician 
or other licensed health care professional also must become familiar 
with the signs and symptoms that may indicate that a worker is 
receiving otherwise unrecognized and exceptionally high exposure 
levels of MC.
    An example of a medical and work history that would satisfy the 
requirement for a comprehensive or interim work history is 
represented by the following:
    The following is a list of recommended questions and issues for 
the self-administered questionnaire for methylene chloride exposure.

Questionnaire For Methylene Chloride Exposure

I. Demographic Information

1. Name
2. Social Security Number
3. Date
4. Date of Birth
5. Age
6. Present occupation
7. Sex
8. Race

II. Occupational History

    1. Have you ever worked with methylene chloride, 
dichloromethane, methylene dichloride, or CH2Cl2 (all are 
different names for the same chemical)? Please list which on the 
occupational history form if you have not already.
    2. If you have worked in any of the following industries and 
have not listed them on the occupational history form, please do so.
Furniture stripping
Polyurethane foam manufacturing
Chemical manufacturing or formulation
Pharmaceutical manufacturing
Any industry in which you used solvents to clean and degrease 
equipment or parts
Construction, especially painting and refinishing
Aerosol manufacturing
Any industry in which you used aerosol adhesives

    3. If you have not listed hobbies or household projects on the 
occupational history form, especially furniture refinishing, spray 
painting, or paint stripping, please do so.

III. Medical History

A. General

    1. Do you consider yourself to be in good health? If no, state 
reason(s).
    2. Do you or have you ever had:
    a. Persistent thirst
    b. Frequent urination (three times or more at night)
    c. Dermatitis or irritated skin
    d. Non-healing wounds
    3. What prescription or non-prescription medications do you 
take, and for what reasons?
    4. Are you allergic to any medications, and what type of 
reaction do you have?

B. Respiratory

    1. Do you have or have you ever had any chest illnesses or 
diseases? Explain.
    2. Do you have or have you ever had any of the following:
    a. Asthma
    b. Wheezing
    c. Shortness of breath
    3. Have you ever had an abnormal chest X-ray? If so, when, 
where, and what were the findings?
    4. Have you ever had difficulty using a respirator or breathing 
apparatus? Explain.
    5. Do any chest or lung diseases run in your family? Explain.

[[Page 1610]]

    6. Have you ever smoked cigarettes, cigars, or a pipe? Age 
started:
    7. Do you now smoke?
    8. If you have stopped smoking completely, how old were you when 
you stopped?
    9. On the average of the entire time you smoked, how many packs 
of cigarettes, cigars, or bowls of tobacco did you smoke per day?

C. Cardiovascular

    1. Have you ever been diagnosed with any of the following: Which 
of the following apply to you now or did apply to you at some time 
in the past, even if the problem is controlled by medication? Please 
explain any yes answers (i.e., when problem was diagnosed, length of 
time on medication).

a. High cholesterol or triglyceride level
b. Hypertension (high blood pressure)
c. Diabetes
d. Family history of heart attack, stroke, or blocked arteries

    2. Have you ever had chest pain? If so, answer the next five 
questions.

a. What was the quality of the pain (i.e., crushing, stabbing, 
squeezing)?
b. Did the pain go anywhere (i.e., into jaw, left arm)?
c. What brought the pain out?
d. How long did it last?
e. What made the pain go away?

    3. Have you ever had heart disease, a heart attack, stroke, 
aneurysm, or blocked arteries anywhere in you body? Explain (when, 
treatment).
    4. Have you ever had bypass surgery for blocked arteries in your 
heart or anywhere else? Explain.
    5. Have you ever had any other procedures done to open up a 
blocked artery (balloon angioplasty, carotid endarterectomy, clot-
dissolving drug)?
    6. Do you have or have you ever had (explain each):

a. Heart murmur
b. Irregular heartbeat
c. Shortness of breath while lying flat
d. Congestive heart failure
e. Ankle swelling
f. Recurrent pain anywhere below the waist while walking

    7. Have you ever had an electrocardiogram (EKG)? When?
    8. Have you ever had an abnormal EKG? If so, when, where, and 
what were the findings?
    9. Do any heart diseases, high blood pressure, diabetes, high 
cholesterol, or high triglycerides run in your family? Explain.

D. Hepatobiliary and Pancreas

    1. Do you now or have you ever drunk alcoholic beverages? Age 
started: ________ Age stopped: ________.
    2. Average numbers per week:

a. Beers: ________, ounces in usual container:
b. Glasses of wine: ________, ounces per glass:
c. Drinks: ________, ounces in usual container:

    3. Do you have or have you ever had (explain each):

a. Hepatitis (infectious, autoimmune, drug-induced, or chemical)
b. Jaundice
c. Elevated liver enzymes or elevated bilirubin
d. Liver disease or cancer

E. Central Nervous System

    1. Do you or have you ever had (explain each):

a. Headache
b. Dizziness
c. Fainting
d. Loss of consciousness
e. Garbled speech
f. Lack of balance
g. Mental/psychiatric illness
h. Forgetfulness
F. Hematologic

    1. Do you have, or have you ever had (explain each):

a. Anemia
b. Sickle cell disease or trait
c. Glucose-6-phosphate dehydrogenase deficiency
d. Bleeding tendency disorder

    2. If not already mentioned previously, have you ever had a 
reaction to sulfa drugs or to drugs used to prevent or treat 
malaria? What was the drug? Describe the reaction.

B. Physical Examination

    The complete physical examination, when coupled with the medical 
and occupational history, assists the physician or other licensed 
health care professional in detecting pre-existing conditions that 
might place the employee at increased risk, and establishes a 
baseline for future health monitoring. These examinations should 
include:
    1. Clinical impressions of the nervous system, cardiovascular 
function and pulmonary function, with additional tests conducted 
where indicated or determined by the examining physician or other 
licensed health care professional to be necessary.
    2. An evaluation of the advisability of the worker using a 
respirator, because the use of certain respirators places an 
additional burden on the cardiopulmonary system. It is necessary for 
the attending physician or other licensed health care professional 
to evaluate the cardiopulmonary function of these workers, in order 
to inform the employer in a written medical opinion of the worker's 
ability or fitness to work in an area requiring the use of certain 
types of respiratory protective equipment. The presence of facial 
hair or scars that might interfere with the worker's ability to wear 
certain types of respirators should also be noted during the 
examination and in the written medical opinion.
    Because of the importance of lung function to workers required 
to wear certain types of respirators to protect themselves from MC 
exposure, these workers must receive an assessment of pulmonary 
function before they begin to wear a negative pressure respirator 
and at least annually thereafter. The recommended pulmonary function 
tests include measurement of the employee's forced vital capacity 
(FVC), forced expiratory volume at one second (FEV1), as well as 
calculation of the ratios of FEV1 to FVC, and the ratios of measured 
FVC and measured FEV1 to expected respective values corrected for 
variation due to age, sex, race, and height. Pulmonary function 
evaluation must be conducted by a physician or other licensed health 
care professional experienced in pulmonary function tests.
    The following is a summary of the elements of a physical exam 
which would fulfill the requirements under the MC standard:

Physical Exam

I. Skin and appendages

1. Irritated or broken skin
2. Jaundice
3. Clubbing cyanosis, edema
4. Capillary refill time
5. Pallor

II. Head

1. Facial deformities
2. Scars
3. Hair growth

III. Eyes

1. Scleral icterus
2. Corneal arcus
3. Pupillary size and response
4. Fundoscopic exam

IV. Chest

1. Standard exam

V. Heart

1. Standard exam
2. Jugular vein distension
3. Peripheral pulses

VI. Abdomen

1. Liver span

VII. Nervous System

1. Complete standard neurologic exam

VIII. Laboratory

1. Hemoglobin and hematocrit
2. Alanine aminotransferase (ALT, SGPT)
3. Post-shift carboxyhemoglobin

IX. Studies

1. Pulmonary function testing
2. Electrocardiogram

    An evaluation of the oxygen carrying capacity of the blood of 
employees (for example by measured red blood cell volume) is 
considered useful, especially for workers acutely exposed to MC.
    It is also recommended, but not required, that end of shift 
carboxyhemoglobin levels be determined periodically, and any level 
above 3% for non-smokers and above 10% for smokers should prompt an 
investigation of the worker and his workplace. This test is 
recommended because MC is metabolized to CO, which combines strongly 
with hemoglobin, resulting in a reduced capacity of the blood to 
transport oxygen in the body. This is of particular concern for 
cigarette smokers because they already have a diminished hemoglobin 
capacity due to the presence of CO in cigarette smoke.

C. Additional Examinations and Referrals

1. Examination by a Specialist

    When a worker examination reveals unexplained symptoms or signs 
(i.e. in the physical examination or in the laboratory tests), 
follow-up medical examinations are necessary to assure that MC 
exposure is not

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adversely affecting the worker's health. When the examining 
physician or other licensed health care professional finds it 
necessary, additional tests should be included to determine the 
nature of the medical problem and the underlying cause. Where 
relevant, the worker should be sent to a specialist for further 
testing and treatment as deemed necessary.
    The final rule requires additional investigations to be covered 
and it also permits physicians or other licensed health care 
professionals to add appropriate or necessary tests to improve the 
diagnosis of disease should such tests become available in the 
future.

2. Emergencies

    The examination of workers exposed to MC in an emergency should 
be directed at the organ systems most likely to be affected. If the 
worker has received a severe acute exposure, hospitalization may be 
required to assure proper medical intervention. It is not possible 
to precisely define ``severe,'' but the physician or other licensed 
health care professional's judgement should not merely rest on 
hospitalization. If the worker has suffered significant 
conjunctival, oral, or nasal irritation, respiratory distress, or 
discomfort, the physician or other licensed health care professional 
should instigate appropriate follow-up procedures. These include 
attention to the eyes, lungs and the neurological system. The 
frequency of follow-up examinations should be determined by the 
attending physician or other licensed health care professional. This 
testing permits the early identification essential to proper medical 
management of such workers.

D. Employer Obligations

    The employer is required to provide the responsible physician or 
other licensed health care professional and any specialists involved 
in a diagnosis with the following information: a copy of the MC 
standard including relevant appendices, a description of the 
affected employee's duties as they relate to his or her exposure to 
MC; an estimate of the employee's exposure including duration (e.g., 
15hr/wk, three 8-hour shifts/wk, full time); a description of any 
personal protective equipment used by the employee, including 
respirators; and the results of any previous medical determinations 
for the affected employee related to MC exposure to the extent that 
this information is within the employer's control.

E. Physicians' or Other Licensed Health Care Professionals' Obligations

    The standard requires the employer to ensure that the physician 
or other licensed health care professional provides a written 
statement to the employee and the employer. This statement should 
contain the physician's or licensed health care professional's 
opinion as to whether the employee has any medical condition placing 
him or her at increased risk of impaired health from exposure to MC 
or use of respirators, as appropriate. The physician or other 
licensed health care professional should also state his or her 
opinion regarding any restrictions that should be placed on the 
employee's exposure to MC or upon the use of protective clothing or 
equipment such as respirators. If the employee wears a respirator as 
a result of his or her exposure to MC, the physician or other 
licensed health care professional's opinion should also contain a 
statement regarding the suitability of the employee to wear the type 
of respirator assigned. Furthermore, the employee should be informed 
by the physician or other licensed health care professional about 
the cancer risk of MC and about risk factors for heart disease, and 
the potential for exacerbation of underlying heart disease by 
exposure to MC through its metabolism to carbon monoxide. Finally, 
the physician or other licensed health care professional should 
inform the employer that the employee has been told the results of 
the medical examination and of any medical conditions which require 
further explanation or treatment. This written opinion must not 
contain any information on specific findings or diagnosis unrelated 
to employee's occupational exposures.
    The purpose in requiring the examining physician or other 
licensed health care professional to supply the employer with a 
written opinion is to provide the employer with a medical basis to 
assist the employer in placing employees initially, in assuring that 
their health is not being impaired by exposure to MC, and to assess 
the employee's ability to use any required protective equipment.

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PART 1915--[AMENDED]

    6. The authority citation for 29 CFR part 1915 continues to read as 
follows:

    Authority: Sec. 41, Longshore and Harbor Workers Compensation 
Act (33 U.S.C. 941); secs. 4, 6, 8, Occupational Safety and Health 
Act of 1970 (29 U.S.C. 653, 655, 657); Secretary of Labor's Order 
No. 12-71 (36 FR 8754), 8-76 (41 FR 25059), 9-83 (48 FR 35736) or 1-
90 (55 FR 9033), as applicable; 29 CFR part 1911.

    7. In Table Z of section 1915.1000, Air Contaminants, the entire 
entry for methylene chloride is removed and replaced with the following 
entry added in the substance column: ``Methylene chloride: see 
Sec. 1910.1052''.
    8. Subpart Z of part 1915 is amended by adding Sec. 1915.1052, as 
follows:


Sec. 1915.1052  Methylene chloride.

    Note: The requirements applicable to shipyard employment under 
this section are identical to those set forth at 29 CFR 1910.1052.

PART 1926--[AMENDED]

Subpart D--[Amended]

    9. The authority citation for subpart D of part 1926 continues to 
read as follows:

    Authority: Sec. 107, Contract Work Hours and Safety Standards 
Act (40 U.S.C. 333), secs. 4, 6, and 8, Occupational Safety and 
Health Act of 1970 (29 U.S.C. 653, 655, 657); Secretary of Labor's 
Orders No. 12-71 (36 FR 8754), 8-76 (41 FR 25059), 9-83 (48 FR 
35736), or 1-90 (55 FR 9033), as applicable.

    10. In Appendix A of section 1926.55, Gases, vapors, fumes, dusts 
and mists, the entire entry for methylene chloride is removed and 
replaced by the following entry added in the substance column: 
``Methylene chloride: see Sec. 1910.1052''.

Subpart Z--[Amended]

    11. The authority citation for subpart Z of part 1926 continues to 
read as follows:

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

    12. Subpart Z of part 1926 is amended by adding Sec. 1926.1152, as 
follows:


Sec. 1926.1152  Methylene chloride.

    Note: The requirements applicable to construction employment 
under this section are identical to those set forth at 29 CFR 
1910.1052.

[FR Doc. 97-198 Filed 1-9-97; 8:45 am]
BILLING CODE 4510-26-P`