Occupational Exposure to Methylene Chloride

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

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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

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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.

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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-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 (p2.

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

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