1494 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

DEPARTMENT OF LABOR

Occupational Safety and Health

Administration

29 CFR Parts 1910, 1915 and 1926

RIN 1218–AA98

Occupational Exposure to Methylene

Chloride

AGENCY: Occupational Safety and Health

Administration (OSHA), Department of

Labor.

ACTION: Final rule.

SUMMARY: The Occupational Safety and

Health Administration (OSHA) hereby

amends its existing regulations for

employee exposure to methylene

chloride (MC), (also known as

methylene dichloride, dichloromethane

or DCM). OSHA has determined, based

on animal and human data, that the

current permissible exposure limits

(PELs) allow employee exposure to a

significant risk of material impairment

of health. OSHA is reducing the existing

8-hour time-weighted average (TWA)

exposure from 500 parts MC per million

parts (ppm) of air to 25 ppm. Also,

OSHA is deleting the existing ceiling

limit concentration of 1,000 ppm and is

reducing the existing short-term

exposure limit from 2,000 ppm

(measured over five minutes in any 2

hour period) to 125 ppm, measured as

a 15-minute TWA. In addition, the

Agency is setting an ‘‘action level’’ of

12.5 ppm, measured as an 8-hour TWA.

The final rule also contains provisions

for exposure control, personal protective

equipment, employee exposure

monitoring, training, medical

surveillance, hazard communication,

regulated areas, and recordkeeping.

Together, these provisions will

substantially reduce significant risk to

the extent feasible. This standard

applies to all employment in general

industry, shipyards and construction.

Small employers, for purposes of the

Regulatory Flexibility Act, 5 U.S.C. 601,

are defined as firms with fewer than

twenty employees. The final standard

will prevent an estimated 31 cancer

deaths per year and an estimated three

deaths per year from acute central

nervous system and

carboxyhemoglobinemic effects, and

will also reduce cardiovascular disease

and material impairment of the central

nervous system. The estimated cost, on

an annualized basis, is $101 million per

year.

DATES: This final rule becomes effective

April 10, 1997.

Compliance: Start-up dates for

specific provisions are set in

§ 1910.1052(n) of the regulatory text.

However, affected parties do not have to

comply with the information collection

requirements in § 1910.1052(d)

exposure monitoring, § 1910.1052(e)

regulated areas, § 1910.1052(j) medical

surveillance, § 1910.1052(l) employee

information and training; and

§ 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
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1495

Chloride Notice of Proposed

Rulemaking Information Collection

Requests: Shipyards, 1218–0177;

Construction, 1218–0178; and General

Industry, 1218–0179. Since the

information requirements are identical

for each industry, the Agency has

combined these three packages into one

entitled Methylene Chloride

§ 1910.1052, OMB number 1218–0179.

Type of Review: Revision of a

currently approved collection.

Agency: Occupational Safety and

Health Administration.

Title: Methylene Chloride

§ 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 forprofit, 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, performanceoriented 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
1496 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

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. § 651(b). To

achieve this goal, Congress authorized

the Secretary of Labor to promulgate

and enforce occupational safety and

health standards. U.S.C. §§ 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. § 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. § 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. § 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 WalshHealey 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
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1497

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 abovedescribed 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
1498 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

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, thenPresident 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,
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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 ozonedepleting 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
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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
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boiling point of 39.8°C (104°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°C (68°F).

Concentration of MC in saturated air at

25°C reaches 550,000 ppm. MC has low

water solubility (1.3 gm per 100 gm of

water at 20°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 glutathioneS-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 Schloromethylglutathione 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 Schloromethylglutathione 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 glutathionedeficient 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 tumorbearing 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.
1504 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

TABLE V–1.—METHYLENE CHLORIDE LIFETIME BIOASSAYS

Reference Species/strain Route and dosing schedule Dosage (No. of animals) Comments

NTP (1985) ....... B6C3F1 mouse ............... Inhalation 6 hr/day, 5

days/week.

0, 2000, 4000 ppm (50 mice/ sex/

dose).

Lung and liver tumors both

sexes, both doses.

Serota (NCA)

(1986).

B6C3F1 mouse ............... Daily in water ................. 0 (125M, 100F), 60 (200M,

100F), 125 (100M, 50F), 185

(100M, 50F), and 250 (125M,

50F) mg/kg/d.

No tumors observed.

NTP (1985) ....... Fischer 344 rat ............... Inhalation 6 hr/day, 5

days/week.

0, 1000, 2000 and 4000 ppm (50

rats/sex/dose).

Mammary and integumentary

fibromas and fibrosarcomas in

both sexes.

Burek (DOW)

(1980).

Sprague-Dawley rat ....... Inhalation 6 hr/day, 5

days/week.

0, 500, 1500 and 3500 ppm (95

rats/sex/dose).

Malignant salivary gland tumors

at 3500 ppm, dose-related increase in mammary tumors.

Nitschke (DOW)

(1982).

Sprague-Dawley rat ....... Inhalation 6 hr/day, 5

days/week.

0, 50, 200 and 500 ppm (70 rats/

sex/dose.

No tumors observed.

Serota (NCA)

(1986).

Fischer 344 rat ............... Daily in water ................. 0, 5, 50, 125 and 250 mg/kg/d

(135/sex at 0, 85/sex/dose).

No tumors observed.

Burek (DOW)

(1980).

Syrian Golden hamster .. Inhalation 6 hr/day, 5

days/week.

0, 500, 1500, 3500 ppm (90 hamsters/sex/ dose).No tumors observed.

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 statisticallysignificant 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 SpragueDawley 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-
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1505

based pharmacokinetic models for MC.

Specifically, these studies helped to

determine that the lack of tumor

development was consistent with model

predictions of the amount of GST

metabolites in lung and liver of mice

and that the MFO pathway was most

likely not primarily responsible for the

mouse tumor response.

The Agency believes that the NTP

studies show the clearest evidence of a

carcinogenic effect of MC and has used

these studies as the basis of its risk

assessment for the following reasons: (1)

The studies were well conducted and

underwent extensive peer review. (2)

The inhalation route of exposure was

used, which is the most appropriate

route for extrapolation to occupational

exposures. (3) Dose-related, statistically

significant increases in tumor incidence

were observed in both sexes in mice and

in female rats. OSHA believes that

because of the clear tumor response, and

quality of the studies, the NTP studies

provide the best data for quantitative

cancer risk assessment. OSHA

concludes from these studies that MC

causes cancer in two species of test

animals by the inhalation route, and

that a clear dose-response has been

demonstrated.

3. Epidemiological Studies

Epidemiological studies of

occupational exposure to MC have been

conducted in the manufacturing of

triacetate fibers, photographic film

production, and the manufacturing of

paint and varnish. Those studies were

reviewed by OSHA in the preamble to

the proposed rule [56 FR 57075] and are

summarized and updated in this

document. In addition, an

epidemiological study of MC exposure

and astrocytic brain cancer is reviewed

in this text.

a. Studies of triacetate fiber

production workers. Ott et al. [Ex. 7–76]

performed a retrospective cohort study

using a cellulose diacetate and triacetate

plant in Rock Hill, South Carolina to

examine the effects of MC on a working

population. In particular, Ott et al.

evaluated the effects that were possibly

mediated through the metabolism of MC

to carboxyhemoglobin. Employees at

this plant had MC exposures close to

OSHA’s time weighted average (TWA)

permissible exposure limit (PEL) of 500

ppm. Ott et al. used workers in a plant

in Narrows, Virginia as a comparison

population because it had operations

similar to those at the Rock Hill plant,

but did not use MC. In this study, Ott

et al. compared the number of deaths

within the exposed cohort with the

United States population and the

Narrows, Virginia referent group. Ott et

al. observed that the overall mortality of

the cohort was comparable to that of the

age, sex, and race-matched U.S.

population. Comparing exposed and

referent cohorts, statistical differences

in risk were observed in white men for

‘‘all causes’’ (risk ratio=2.2, p<0.01),

‘‘diseases of the circulatory system’’

(risk ratio=2.2, p<0.5), and ‘‘ischemic

heart disease’’ (risk ratio=3.1, p<0.05).

In interpreting the results of this

study, Ott noted that there may have

been differences in hiring practices in

the two plants which could have

contributed to the observed differences

in mortality. In their conclusion, Ott et

al. stated that a healthy worker effect

(HWE) and the low power of their study

did not permit them to dismiss the

possibility of increased health risks

within the working population exposed

to MC.

Dr. Mirer of UAW testified [Tr. 1896–

6, 9/24/92] that there is some evidence

that there is excess work-related heart

disease mortality in epidemiological

studies that have observed SMRs greater

than 80% for ischemic heart disease or

any other cardiovascular disease.

Furthermore, when the MC

epidemiological studies are looked at

together, there is evidence, although

limited, that MC exposure has an effect

on cardiovascular mortality.

On the other hand, Kodak [Ex. 91D]

questioned the appropriateness of the

referent population in the Rock Hill

study, alleging that the SMR for

ischemic heart disease in the referent

population was unusually low, and that

this fact, rather than an effect of MC

exposure, caused the observed

differences in ischemic heart disease

rates.

In contrast, NIOSH considered the

Rock Hill study to be suggestive of an

effect of MC on risk of cardiac disease.

According to NIOSH [Tr. 879, 9/21/92]

the Ott study did not use appropriate

analytic techniques that would allow

the acute effects of MC on cardiac

disease risk to be examined.

Furthermore, NIOSH suggested [Tr. 969,

9/21/92] that future epidemiological

studies should examine risks from MC

exposure during the period when

employees are actively working.

In an update to the Rock Hill study,

Lanes et al. followed the Ott et al. cohort

through September 1986 [Ex. 7–260]

and December 1990 [Ex. 106]. Lanes et

al. used the population of York County,

South Carolina as the comparison

group. Statistically significant excess

mortality was observed for cancer of the

liver and biliary passages (SMR=5.75,

CI:1.82–13.78) in the study group.

Excess mortality was also observed for

buccal cavity and pharynx cancer

(SMR=2.31, 95% CI:0.39–7.60) and

melanoma (SMR=2.28, CI:0.38–7.51),

although mortality from these causes

did not reach statistical significance. No

excess mortality was observed for

ischemic heart disease (SMR=0.90,

CI:0.62–1.27).

Examination of the liver and biliary

cancers indicated that the workers had

ten or more years of employment and at

least 20 years since first employment (4

observed v. 0.35 expected). Three of the

four employees who died from liver/

biliary cancer had tumor sites in the

intrahepatic and common bile duct,

common bile duct, and ampulla of

Vater. Approximate durations of

employment for these three cases were

28 years, 20 years, and less than one

year. No medical record for the third

case could be obtained. However, an

autopsy report indicated

adenocarcinoma of the liver for this

case. To estimate the expected number

of biliary cancer deaths, Lanes et al.

used Surveillance, Epidemiology, and

End Results (SEER) mortality rates of

the continental United States. The

computed risk estimate, based on 0.15

cases expected, was SMR=20 (95%

CI:5.2–56.0).

The authors hypothesized that the

biliary duct cancer cases may have been

due to factors such as oral contraceptive

use, gallstones, or ulcerative colitis.

However, it appeared that medical

records showed no indication of

gallstones or ulcerative colitis in

workers who died of biliary cancer.

Moreover, although these factors were

not specifically controlled for, there is

no reason to believe the rates of these

factors would be different in the

exposed cohort compared to the general

U.S. population.

Lanes et al. updated their study

through December 31, 1990 [Ex. 106]

using the National Death Index and

focused on mortality from pancreatic

cancer, biliary and liver cancer, and

ischemic heart disease. Lanes et al.

ascertained fifty more death certificates

from the end of the last follow-up

period on September 1, 1986. As before,

York County, South Carolina was used

as the comparison population.

The overall SMR from all causes of

death was 0.90, and for malignant

neoplasms, the SMR was 0.82. In this

follow-up, the SMR for liver and biliary

cancer dropped from 5.75 to 2.98 (95%

CI:0.81–7.63). No additional deaths from

biliary or liver cancer were observed. In

the original and updated studies

combined, four deaths from biliary/liver

cancer were observed and 0.64 were

expected. Using a Poisson distribution,

Lanes et al. calculated the probability of

failing to observe any liver/biliary
1506 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

cancer deaths in this update if the

‘‘true’’ value of the SMR for liver/biliary

cancer was 5.75 (from the previous

study) and then expecting 3.68 deaths in

this follow-up (0.64×5.75). They

estimated the probability that this

update would have no observed biliary/

liver cancer deaths if the true SMR were

5.75, as e¥3.68=0.025. On the other hand,

if MC had no effect on liver and biliary

cancer mortality, Lanes et al. estimated

that the probability of observing zero

deaths would have been 0.527 (e¥0.64).

Lanes et al. used the likelihood ratio

(0.527/0.025=21.08) to compare these

two hypotheses. The authors concluded

that the null hypothesis that the

SMR=1.0 was 21 times more probable

than the hypothesis that the SMR=5.75.

Because of the small number of cases

involved and the instability of the

numbers generated in this type of

statistical analysis, OSHA believes that

this study, overall, is suggestive (but not

definitive) of an association between

occupational exposure to MC and

elevation of human cancer risk.

Furthermore, the Agency has

determined that the study results are not

inconsistent with the results of the NTP

cancer bioassay.

Hoechst-Celanese [Ex. 19–65, pp. 6–8;

Ex. 19–19] was concerned that OSHA

considered the incidence of biliary

cancer as evidence of a positive effect.

They argued that the reported excess in

biliary tract cancer did not support the

conclusion that MC exposure is

associated with an increased risk of

cancer. Specifically, they noted that,

(1) Biliary cancers have not been reported

in any of the animal cancer studies of MC;

(2) no statistically significant increase in

biliary cancers was seen in the Cumberland

study (described below); (3) no statistically

significant excess in biliary cancers was

reported in the Kodak studies (described

below); (4) It was unlikely that MC could

have been responsible for the biliary tract

cancer observed in one employee who had

been exposed to MC for less than one year;

and (5) the Rock Hill study did not control

for other chemical exposures.

Comments by the Halogenated Solvents

Industry Alliance (HSIA) [Ex. 19–45, p.

47] were in accord with those of

Hoechst-Celanese.

Dr. Shy, on behalf of Kodak, asserted

[Tr. 1303, 9/22/92; Ex. 91F] that MC

exposure failed to meet Bradford Hill’s

criteria for causality (e.g., biological

plausibility, dose-response, and

consistency) for producing biliary tract

cancer. Dr. Shy acknowledged that

animal bioassays have demonstrated

liver tumors from MC exposure, but he

noted that there is no evidence in

humans that liver and biliary tract

cancers have the same etiology.

Furthermore, Dr. Shy argued that,

(1) the results from the Lanes study is

not supported by in vitro or

pharmacokinetic studies.

(2) a dose-response relationship could

not be determined from the Lanes study

because there were no direct

measurements of worker exposure to

MC.

(3) the observed association between

MC exposure and liver/biliary cancer

was an isolated finding and the

existence of a causal relationship could

not be concluded.

(4) the excess biliary tract cancer in

the Lanes study was not consistent with

the other three epidemiological studies

(Hearne, 1987, 1990, 1992; Hearne,

1992; Gibbs, 1992).

Dr. Shy did recognize that there was

a strong association between MC

exposure and biliary tract cancer in the

Lanes study (SMR=20). Moreover, the

20 year time interval between first

exposure and death from biliary tract

cancer provided evidence that

‘‘exposure preceded cancer with an

appropriate interval for induction of the

tumor [Ex. 91F].’’

OSHA disagrees with the conclusions

reached by Dr. Shy. The Agency

believes that the risks of biliary cancer

observed in these studies is consistent

with risks derived from its

pharmacokinetic analysis (see the

Quantitative Risk Assessment, Section

VI). Since the occupational exposures in

these studies are likely to have been

among the highest in any of the

epidemiologic cohorts, there is no

evidence that the increased biliary/liver

cancer result is inconsistent with other

reported epidemiological findings.

Regarding the biological plausibility, the

Agency notes that human biliary cells

appear to contain high concentrations of

the mRNA for GST (the enzyme many

investigators believe to be responsible

for MC-induced carcinogenesis) [Exs.

124 and 124A]. Although this requires

more investigation to determine if there

is a direct relationship, OSHA believes

there is a plausible mechanistic

argument for MC causality in human

biliary tract cancers. The Agency agrees

with Dr. Shy, however, that the lack of

dose-response data and the small

number of cases in this cohort limit the

strength of conclusions that can be

drawn from this study. After weighing

these considerations, the Agency has

determined that there is suggestive

evidence of a causal role for MC in these

cases of biliary cancer.

Gibbs et al. conducted a study of

another cellulose acetate and triacetate

fibers plant in Cumberland, Maryland

[Ex. 54] to evaluate the possible

relationship between MC exposure and

biliary/liver cancer. This plant, which

ceased to operate in 1982, had

operations similar to the plant in Rock

Hill, and it was assumed to have had

similar MC exposure levels as well.

However, exposure measurements were

not submitted for the Cumberland plant

and it is unknown whether the

Cumberland employees experienced the

same exposures as their Rock Hill

counterparts.

The Gibbs study investigated the

mortality of 3,211 workers who were

employed at this plant on or after

January 1970. There were 2,187 men

and 1,024 women in the cohort. Most of

the workers in the cohort were hired

prior to 1979 (2,566 total). The study

population was divided into three

subcohorts based on their estimated

exposure to MC: 1) 834 men and 146

women in the ‘‘high exposure’’ group

(estimated to be 350–700 ppm), 2) 1095

men and 832 women in the ‘‘low but

never high exposure’’ group (estimated

to be 50–100 ppm), and 3) 256 men and

46 women in the ‘‘no exposure’’ group.

This cohort was followed through

December 1989. The observed mortality

was compared to expected death rates

for Allegany County, Maryland (where

the plant was located and where most

of the cohort deaths occurred), the State

of Maryland, and the United States.

The author of this study believed that

the county rates were the most

appropriate to use because the city of

Cumberland is located in a rural area of

Maryland and the state rates may have

been influenced by rates in large urban

areas such as Baltimore. In addition,

local rates tend to adjust for social,

economic, ethnic, and cultural factors

which may be related to disease risk,

access to medical care, etc. However, if

the fiber plant was the major employer

in this rural area, then county rates may

reflect the cohort’s mortality rather than

the background risk, in which case, state

rates or U.S. population rates would be

more appropriate. The overall mortality

rate for the high MC-exposed group was

below the expected rates for Allegany

County, Maryland, and the U.S.

population.

As in the Rock Hill study, mortality

from biliary tract cancer was observed

in the Cumberland study, although no

statistically significant elevated

incidence of biliary cancer was found

(two cases of biliary tract cancer were

observed). In the high exposure group,

there was one death (1.24 expected with

Allegany rates (SMR=80.5) and 1.42

expected with Maryland rates

(SMR=70.4)). In the low MC-exposed

group, there was also one death from

biliary/liver cancer. For the high MC-
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 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 MCexposed 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 nonoccupational). In support of this

hypothesis, no other epidemiological or

animal studies of MC exposure have

suggested a relationship between

prostate cancer and MC. HoechstCelanese [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 MCexposed 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 observedexpected 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, doseresponse 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
1508 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

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 casecontrol study to examine the potential

association between brain cancer and

exposure to organic solvents as a group

and six chlorinated aliphatic

hydrocarbons (CAHs) including MC.

Cases were defined as white males who

died from brain or other central nervous

system tumors in southern Louisiana,

northern New Jersey, and Philadelphia,

Pennsylvania. Controls were randomly

selected from death certificates and

included white males who died of

causes other than brain tumors,

cerebrovascular diseases, epilepsy,

suicide, and homicide. Controls were

frequency-matched to cases by age, year

of death, and geographic area.

Four-digit Standard Industrial

Classification (SIC) and 4-digit Standard

Occupational Classification (SOC) codes

were employed to code occupational

histories of study subjects. These codes

linked work histories to job-exposure

matrices which ‘‘characterized likely

exposure to the six CAHs and to organic

solvents’’ [Ex. 112]. Gomez et al. [Ex.

112] used an algorithm to assign

estimates of probability and intensity of

exposure to each industry/occupation

combination in subjects’ work histories.

As noted by Gomez et al., these

estimates were based on ‘‘occupation

alone, industry alone, or both

occupation and industry, depending on

the specificity of the exposure

environment that could be inferred from

the occupational (SOC) code.’’

The following surrogate measures of

dose, for each substance, were used to

summarize ‘‘likely’’ exposure histories

for each study subject: duration of

employment in occupation/industry

combinations considered exposed, a

cumulative exposure score, and

‘‘average’’ intensity of exposure. Odds

ratios were calculated for exposure

intensity categories to refrain from using

weights. These categories did not

include duration in jobs with lower

intensity for subjects with high or

medium intensity jobs. In their

statistical analyses, Heineman et al.

controlled for age, geographic area, and

employment in electronics-related

occupations/industries.

Astrocytic brain cancer was not found

to be associated with ‘‘ever’’ being

exposed to organic solvents as a group

or to any of the six CAHs examined in

this study. However, as probability of

exposure to organic solvents as a group,

and MC in particular, increased, the risk

of brain cancer increased (chi-squared

statistics for trend for organic solvents

and MC were 1.93 and 2.29 (p<0.05),

respectively). For MC there was a 2.4-

fold increase in risk for subjects with a

high probability of exposure (confidence

interval=1.0–5.9).

Risk of brain cancer significantly

increased with duration of exposure for

subjects with high probabilities of MC

exposure (OR=6.1; CI=1.1–43.8).

Heineman et al. found that, in the high

probability of MC exposure category,

risk significantly increased with

duration (chi for trend=2.58, p<0.01).

Similar results were seen for organic

solvents and methyl chloroform for all

probabilities combined (chi-squared

statistics for trend were 2.35 (p<0.01)

and 1.87 (p<0.05), respectively).

Lagging exposure by 10 years

produced findings analogous to those

noted above. Higher risks and a sharper

increase with duration was observed for

organic solvents when exposure was

lagged by 20 years (all probabilities: 2–

20 years, OR=1.3 (95% CI=0.9–2.0); 21+

years, OR=2.8 (1.1–3.7); p for

trend=0.006; high probability: 2–20

years, OR=1.2 (95% CI=0.7–1.9); 21+

years, OR=3.1 (1.3–7.4), p=0.009).

Subjects with a high probability of

MC exposure experienced a statistically

significant increased risk as the

cumulative exposure score increased

(chi-squared statistics for trend=2.18,

p<0.05). However, risk did not increase

monotonically with cumulative

exposure.

Lagging exposure 20 years supported

the odds ratios and the trends for

organic solvents, particularly in men

with a high probability of exposure (low

cumulative score: OR=1.1 (95% CI=0.5–

2.3); medium: OR=1.4 (0.8–2.5); high:

OR=2.2 (1.0–4.5); p for trend=0.02). Few

individuals had high cumulative scores

when exposure was lagged 20 years for

the individual CAHs.

Compared with jobs with medium or

low intensity exposures to organic

solvents and all six CAHs, risk of brain

cancer was higher for subjects who
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1509

worked in jobs with high intensity

exposures. Brain cancer was associated

most strongly, and increased with

probability of exposure, among subjects

who worked 20 or more years with high

intensity exposure to MC (all

probabilities: OR=6.7, CI=1.3–47.4; high

probability: OR=8.8, CI=1.0–200.0).

Since many subjects were determined

to have been exposed to more than one

of the CAHs, sometimes even in the

same job, Heineman et al. used logistic

regression to examine, simultaneously,

the effects of MC, carbon tetrachloride,

tetrachloroethylene, and

trichloroethylene, controlling for age,

geographic area, and employment in

electronics-related occupations/

industries. MC was the only substance

to show a statistically significant

increase in risk as the probability of

exposure increased (low: OR=0.9,

CI=0.5–1.6); medium: OR=1.4, CI=0.6–

3.1; high: OR=2.4, CI=0.9–6.4; chisquared statistics for trend=2.08,

p<0.05). Risks associated with MC

increased when adjustments for

exposure to the other agents were made.

In addition, subjects employed for 20

years or more in jobs with high average

intensity MC exposure showed an eightfold excess of brain cancer (OR=8.5,

CI=1.3–55.5), taking all probabilities

into consideration.

Among the six CAHs examined in this

study Heineman et al. found the

strongest association between brain

cancer and MC-exposure, for which

relative risks rose with probability,

duration, and average intensity of

exposure, though not with the

cumulative exposure index.

According to Heineman et al., the

major weakness of this study was not

having direct information on exposure

to solvents. Next-of-kin data, poor

specificity of some work histories for

specific solvents, and the

interchangeability of solvents may have

resulted in misclassification of

individuals with respect to any of the

exposure measurements used in this

study. However, Heineman et al.

pointed out that the potential sources of

error probably did not significantly bias

risk estimates away from the null or

generate the observed trends.

Another limitation of this study,

pointed out by Heineman et al., was that

over one-third of the next-of-kin of

eligible cases and controls were not

interviewed. According to Heineman et

al., this could have artificially created

the associations seen in this study ‘‘only

by underrepresenting cases who were

unexposed, and/or controls who were

exposed, to solvents in general, and MC

in particular’’ [Ex. 113]. Heineman

further remarked that differential

misclassification was probably not a

problem in this study because

occupational histories came from nextof-kin of both cases and controls.

In light of the limitations of this

study, however, Heineman et al.

commented that the consistency of

exposure-response trends for MC was

surprising and suggestive. Moreover,

Heineman et al. believed that the trends

and consistency of the associations

between brain cancer and MC could not

be explained by chance alone.

Several commenters [Exs. 115–1, 115–

31, 115–32, 115–36] indicated that

Heineman et al. relied too heavily on

next-of-kin information. Information

provided by next-of-kin concerning jobs

held, job descriptions, dates of

employment, and hours worked per

week may be flawed with recall bias.

Next-of-kin may not be able to

accurately recall job-related

information, especially for jobs held

early in life. If next-of-kin for cases or

controls had better recall than the other

group, differential misclassification

could occur. HSIA [Ex. 115–36] stated

that even small differences in error rates

between cases and controls could

produce false associations. Both HSIA

and NIOSH [Ex.115–31] agreed that this

indirect source of exposure information

was likely to produce some degree of

misclassification. However, NIOSH

noted that misclassification ‘‘is a typical

problem in population based casecontrol studies of this type [Ex. 115–

31]’’ and that this misclassification

could also explain the fact that no

associations were found between brain

cancer and the cumulative exposure

score.

Organization Resources Counselors

(ORC) [Ex. 115–2] and Abbott

Laboratories [Ex. 115–30] were

concerned that the lack of exposure

verification made this NCI study

unreliable for setting MC exposure

limits. ORC stated that exposure values

were assigned to all SIC and SOC codes,

and not developed based on job history

information, which would have given

the study more validity. Kodak also

expressed some concern regarding this

study due to lack of accurate records of

past exposures, reliance on expert

judgement to a large degree, use of nextof-kin to determine potential exposure,

and undocumented qualifications of

those making judgements concerning

the different occupations and industries

involved. In addition, Kodak felt that

the exposure data were ‘‘at best,

unsubstantiated semi-qualitative

judgements of likelihood and intensity

of exposure [Ex. 115–1].’’ Organization

Resources Counselors [Ex. 115–2] and

Abbott Laboratories [Ex. 115–30]

asserted that it was impossible to tell if

those who died of cancer had been

exposed to MC because there was no

exposure verification. Vulcan Chemicals

[Ex. 115–32] criticized the investigators

for not going to work sites and

determining the actual magnitude of

exposure to the CAHs. HSIA [Ex. 115–

36] argued that ‘‘concordance of proxy

reports with actual work histories may

range from 0–50% for decedents’ first

jobs and from 50–70% for last jobs.’’

OSHA believes that exposure

verification would have increased the

validity of the findings of this study.

However, lack of exposure verification

does not nullify the results of the study.

The Agency believes that the

associations observed are suggestive of a

human carcinogenic effect of MC.

Another issue that Kodak [Ex. 115–1]

and Vulcan [Ex. 115–32] emphasized

was the possible exposure to other

chemicals or sources of potential human

carcinogens, such as ionizing radiation,

electromagnetic fields, smoking history,

and place of residence. Vulcan [Ex. 115–

32] noted that there may have been

selection bias in this study because of

the large ratio of astrocytic brain cancer

tumors to the total number of brain

tumors. Although they offered no

explanation of how this selection bias

would operate, Vulcan did suggest that

this issue should be investigated further.

Vulcan was also concerned that the

matching of controls and cases with

respect to occupations and

socioeconomic status may be

inadequate. In particular, Vulcan

criticized the Heineman study for not

presenting the occupations of the

control group and for not matching the

socioeconomic status of the two groups.

Similarly, Kodak [Ex. 115–1] stated that

some adjustment should have been

made in order to match across

educational levels.

Kodak [Ex. 115–1] also believed that

the estimates of trends observed in this

study could have been affected, if

workers in the longest duration or the

higher probability of exposure

categories had longer dates of

employment, worked in more stable

industries, and had better health

benefits, better access to medical care,

and more sophisticated diagnostic

procedures. OSHA believes that there is

no evidence that this is the case in this

study.

HSIA [Ex. 115–36] criticized the

methodology for assessing the number

of industries with exposures to CAHs.

HSIA argued that Gomez et al. did not

fully explain how they determined that

workplaces in the specific SICs would

have CAH exposures. According to

HSIA, Gomez et al. reported inaccurate
1510 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

information regarding industry use of

MC. HSIA cited EPA’s ‘‘Toxic Air

Pollutant/Source Crosswalk, A

Screening Tool for Locating Possible

Sources Emitting Toxic Air Pollutants

(EPA–450/4–87–023A, Dec. 1987)’’

which revealed a higher number of SIC

codes using MC. In conclusion, HSIA

asserted that Gomez et al.’s ‘‘exposure

scenario’’ was incorrect.

Several commenters [Exs. 115–1, 115–

31, 115–36] argued that the Heineman et

al. study should only be considered a

hypothesis-generating study and should

not be used to adjust the PEL.

OSHA agrees with NIOSH that the

Heineman et al. study was wellconducted because there was a

systematic attempt to estimate exposure

by work experience. Furthermore, there

was a remarkably high correlation

between exposure to MC and brain

tumors. OSHA concludes that the

results from this study strongly suggest

a possible association between MC and

brain cancer. However, in the absence of

quantified exposure data for these

workers, it remains relatively

speculative to attempt to estimate a

quantitative dose-response relationship.

Therefore, OSHA concludes that the risk

estimate based on the animal data is the

best available and accordingly it retains

that estimate for its significant risk

analysis.

e. Summary of epidemiological

studies. Considered as a whole, the

available epidemiologic evidence did

not demonstrate a strong, statistically

significant cancer risk associated with

occupational exposures to MC.

However, the positive trend for biliary

tract/liver cancer deaths, the association

between occupational MC exposure and

astrocytic brain cancer and the

statistically significant excess prostate

cancer results are suggestive of an

association between MC exposure and

cancer risk. In addition, the nonpositive epidemiological studies

summarized here are not of sufficient

power to rule out the positive results

from the animal studies. This issue is

addressed further in the Quantitative

Risk Assessment section of this

document.

In summary, the epidemiological

results are suggestive of an association

between occupational exposure to MC

and elevated cancer risk which offers

supporting evidence to the positive

animal bioassay results.

4. Conclusion

OSHA concludes from the

mutagenicity, animal bioassay and

human epidemiology data that MC

causes cancer in test animals and that it

is a potential occupational carcinogen.

The Agency has determined that,

because of the quality of the studies, the

clear dose-response relationship and the

appropriateness of the route of

administration, the NTP rodent bioassay

data are the best available for

quantitative cancer risk assessment.

OSHA also concludes that the

epidemiology data, in some cases,

suggest a positive association between

human MC exposure and cancer

incidence, but the dose-response

relationships are not clear. The Agency

has determined that the remaining

epidemiology data (the non-positive

studies) are not of sufficient power to

rule out the results obtained in the

animal bioassay data and that the

animal data provide the best available

data for quantitative risk assessment.

E. Other Toxic Responses

1. Central Nervous System Toxicity

MC acts on the central nervous system

(CNS) as a CNS depressant. CNS

depression has been described in

humans exposed to MC concentrations

as low as 175 ppm (8-hour TWA). This

depression in CNS activity was

manifested as increased tiredness,

decreased alertness and decreased

vigilance. These effects could

compromise worker safety by leading to

an increased likelihood of accidents

following MC exposure.

a. Animal studies. In the NPRM,

OSHA reviewed two animal studies of

MC CNS toxicity (briefly summarized

below) and concluded that the CNS was

potentially susceptible to reversible and

irreversible effects due to MC exposure.

Savolainen et al. [Ex. 7–178] studied

biochemical changes in the brains of

rats exposed to MC. Rats were exposed

to 500 ppm MC for 6 hr/d. On the fifth

day, after 3 and 4 hours of exposure to

MC, levels of acid proteinase in rat

brains were significantly increased, but

no change in brain RNA levels was

reported. The authors suggested that the

increase in acid proteinase may have

been the result of increased levels of CO

from metabolism of MC. OSHA believes

that this study shows that MC can cause

specific changes in the neurological

system at a biochemical level. The

Agency intends to monitor the scientific

literature for additional developments

on these effects, but has not used this

information in setting the MC exposure

limits because it is presently unclear

how changes in acid proteinase are

related to the observed CNS depressive

effects of MC in humans.

Rosengren et al. [Ex. 7–56] looked at

the effects of MC on glial cell marker

proteins and DNA concentrations in

gerbil brains after continuous exposure

to 210, 350 or 700 ppm MC. Because of

high mortality in the 2 higher doses, no

data were collected at 700 ppm and

exposure was terminated after 10 weeks

at 350 ppm. Exposure to 210 ppm was

continued for three months. Exposure to

MC was followed by four months of no

exposure before animals were examined

for irreversible CNS effects. The authors

found increased levels of glial cell

marker proteins in the frontal cerebral

cortex and sensory motor cortex after

exposure to 350 ppm MC. These

findings are consistent with glial cell

hypertrophy or glial cell proliferation.

Levels of DNA were decreased in the

hippocampus of gerbils exposed to both

210 and 350 ppm and in the cerebellar

hemispheres after 350 ppm MC.

Decreased DNA concentrations indicate

decreased cell density resulting from

cell death or inhibition of DNA

synthesis.

The neurotoxic mechanism of action

of MC in gerbil brains is not understood.

However, since the metabolism of MC to

CO was determined to be saturated at

both 210 and 350 ppm (COHb levels

were equivalent at both exposure

concentrations), the changes in glial cell

proteins and DNA concentrations was

attributed to either a direct effect of MC

or an effect of a metabolite of the GST

pathway. Although this study describes

biochemical changes in the CNS

subsequent to MC exposure, the high

mortality of the experimental animals

and the lack of MC toxicity data in the

gerbil make it difficult to determine the

significance of this study for

extrapolation to other species. It is also

unclear how these effects would relate

to CNS depression observed in humans

after MC exposure. In addition,

continuous exposure to MC has been

shown in other experimental situations

[Exs. 7–14 and 7–130] to elicit more

severe health effects than exposure to

similar or higher concentrations when

the animals are allowed a recovery

period (for example, 6 hours’ exposure

per day). Exposure on a 6 or 8-hour per

day schedule is also more like

occupational exposure scenarios and

therefore those experiments are

generally easier to interpret when

assessing risk to workers.

In summary, OSHA believes that the

rat and gerbil data described above

shows that MC can cause specific

changes in the neurological system at a

biochemical level. The Agency intends

to monitor the scientific literature for

additional developments on these

effects to determine if these types of

effects have implications for human

CNS risks.
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1511

b. Human studies. The CNS

depressant effects of MC have been well

described in the literature [Exs. 7–4, 7–

153, 7–154, 7–160, 7–175, 7–182, 7–183,

7–184]. MC causes CNS depression

which is characterized by tiredness,

difficulty in maintaining concentration,

decreased task vigilance, dizziness,

headaches, and, at high concentrations,

loss of consciousness and death.

Accidental human overexposures to MC

[Exs. 7–18, 7–19] (for example, at

concentrations greater than 10,000 ppm)

have resulted in narcosis and death.

CNS depression has been described after

humans were exposed to experimental

MC concentrations as low as 200 ppm

[Ex. 7–175] and occupational

concentrations as low as 175 ppm [Ex.

7–153].

i. Experimental studies. CNS

depression was detected in human

subjects exposed to MC at

concentrations as low as 200 ppm for 4

hours or 300 ppm for 1.5 hours [Exs. 7–

4, 7–160, 7–175, 7–182 and 7–184]. In

these experiments, which measured

subtle CNS depression (such as dual

task performance and visual evoked

response), it was not possible to

determine a no observed effect level

(NOEL), because the lowest

experimental concentration used (200

ppm) elicited CNS effects. Since a NOEL

was not determined for the CNS effects

of MC, those effects may occur at lower

exposures or after exposure for shorter

durations.

The HSIA questioned whether bias

was introduced into the results of these

studies by inadequate procedures to

establish a ‘‘double blind.’’ This

criticism raises a legitimate concern

about the validity of the study.

However, since Putz et al. did not

describe the blinding procedures used

in their experiments, the Agency

concludes that there is not enough

evidence publicly available to make the

conclusion that the study is biased.

OSHA believes that these studies were

well conducted and is relying on the

quality of the studies overall as

evidence of the validity of the results.

Absent evidence demonstrating the

inadequacy of the blinding procedures,

OSHA has determined that these studies

show that MC can cause mild CNS

depression in humans exposed at

concentrations as low as 200 ppm.

NIOSH expressed concern regarding

the potential for neurobehavioral

impairment (expressed as CNS

depression) at lower exposures and

shorter durations, particularly in

relation to the setting of a STEL for MC

[Exs. 23–18 and 94]. In order to assess

the potential impact of the CNS effects

of MC, NIOSH looked at data gathered

from several studies and compared

breath concentrations of MC (as a

surrogate for brain tissue MC

concentrations) at different ambient

exposure levels with the CNS

depression described by Putz et al. [Ex.

7–175]. NIOSH concluded that:

At the proposed STEL of 125 ppm,

increased uptake of MC in active workers

may place them in the breath concentration

range associated with mild neurobehavioral

impairment. Although there are insufficient

data to draw firm conclusions, extrapolation

from existing studies suggests that the

proposed STEL of 125 ppm may not fully

protect physically active workers from CNS

impairment. Therefore, a lower STEL should

be considered, if feasible.

In response to concerns raised by

NIOSH, the HSIA [Ex. 105] noted that

NIOSH’s analysis of breath MC

concentration versus neurobehavioral

impairment ‘‘seemed highly

speculative.’’ HSIA emphasized that the

exposures which produced the reported

neurobehavioral effects were observed

only after 2 to 4 hours of exposure and

that the effects were observed only

when difficult tasks were measured.

To support their position, the HSIA

asked Mr. Richard Reitz to use a PBPK

model to estimate the concentration of

MC in brain tissue. This analysis [Ex.

105] indicated that at exposures of 200

ppm for 15 minutes with persons

exercising at 50 watts, the brain

concentration of MC would be predicted

to be similar to that observed in the Putz

et al. study for subjects engaged in

‘‘light activity’’ for 2 hours at 200 ppm

MC, which did not produce measurable

CNS depression. (Putz et al. did not

detect CNS depression in subjects

exposed to 200 ppm for 2 hours). The

model also predicted that 15-minute

exposures to 125 ppm while the subject

was exercising at 50 watts would

produce brain MC concentrations

substantially less than that predicted for

the 4 hour exposure to 200 ppm MC.

OSHA considered the PBPK analysis

presented by the HSIA, but was

concerned that there has been no

experimental validation of the predicted

brain MC concentrations or any

evidence as to what MC concentration

would produce detectable CNS

depression. OSHA believes the primary

value of both the NIOSH and HSIA

analyses is in demonstrating the relative

effect that exercise and duration of

exposure is likely to have on brain (or

breath) concentrations of MC. The PBPK

analysis clearly demonstrates that

increasing exercise level increases brain

concentration of MC, which is

consistent with the detected CNS

depression. Workers engaged in

strenuous activity while exposed to MC

should take special precautions, such as

frequent breaks in fresh air, especially if

dizziness or lightheadedness occurs.

Although OSHA found the PBPK

model to be useful for demonstrating the

interaction between exercise and brain

concentration of MC, the Agency did

not use the model quantitatively (for

example, in determining the STEL).

OSHA believes that the data suggest that

there may be CNS effects at levels below

those tested. There are no studies which

directly address whether there are CNS

effects after exposure to STEL

concentrations of MC. To the extent that

these effects occur, the STEL would not

be protective. Mild and reversible CNS

depression was detected at 200 ppm for

4 hours and 300 ppm for 1.5 hours. The

Agency shares NIOSH’s concern, based

on extrapolation of breath MC

concentrations, that the proposed STEL

may not be adequately protective for

physically-active workers.

OSHA concludes that there are clearly

sufficient data to determine that a 125

ppm 15-minute STEL is needed to

prevent a significant risk of material

impairment to the CNS. Impairment of

the CNS would also increase the risk

from accidents. Measured data show

risks at 200 ppm for four hours of

exposure. A lower level at shorter

duration is needed to avoid that risk.

NIOSH’s calculations show that for

active workers a level lower than 125

ppm may be needed. However, because

of feasibility concerns, which would be

greater at lower levels and the

suggestion that short duration of

exposure (i.e., 15-minutes) may mitigate

the effects, OSHA is retaining the

proposed level, but will carefully

monitor and follow up data to

determine if this level eliminates

significant risk.

ii. Occupational exposure studies. In

the NPRM, OSHA summarized studies

which it believed described a

neuropathy associated with chronic

occupational exposure to solvents.

Weiss [Ex. 7–196] described the case of

a 39-year old chemist who worked for

5 years with airborne concentrations of

MC as high as 660 ppm to 3600 ppm in

a room with poor ventilation. After 3

years of exposure, the worker developed

neurological symptoms, characterized

by restlessness, palpitations,

forgetfulness, poor concentration, sleep

disorders, and finally, acoustical

delusions and optical hallucinations. No

hepatic damage or cardiac toxicity was

found. At the first appearance of

symptoms, cessation of exposure

produced an immediate cessation of

symptoms. Later, longer and longer

periods were required after termination

of exposure in order to alleviate the
1512 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

symptoms. The increasing persistence of

symptoms is consistent with a diagnosis

of toxic encephalosis.

Hanke et al. [Ex. 7–195] examined 32

floor tile setters who were exposed

primarily to MC at concentrations from

400 to 5300 ppm for an average tenure

of 7.7 years. Clinical examination of 14

of the workers who had neurological

symptoms (headache, vertigo, sleep

disturbance, digestive complaints and

lapses in concentration and memory)

revealed changes in the EEG patterns of

the exposed workers which persisted

over a weekend pause in exposure.

These EEG changes were characteristic

of a toxic encephalosis produced by

chronic intoxication with a halogenated

solvent (MC). The persistence of the

EEG changes over the weekend break

indicated a prolonged effect of MC

exposure on EEG patterns. (Additional

changes in the EEG found during

exposure could be attributed to an acute

effect of MC). Although these studies

represent a small number of cases with

very high chronic exposures, the

evidence is suggestive of a relationship

between chronic MC exposure and toxic

encephalosis.

In a case study report, Barrowcliff et

al. [Ex. 7–123] attributed cerebral

damage in a case study to CO poisoning

caused by exposure to MC. Axelson [Ex.

7–150] has described an increased

number of neuropsychiatric disorders

among occupations with high solvent

exposures.

In the NPRM, OSHA expressed the

opinion that these studies, taken

together, ‘‘provide suggestive evidence

of a permanent toxicity [different from

the observed reversible CNS depression]

which may be the result of chronic

exposure to MC.’’ NIOSH stated that this

assessment was too speculative and

stated,

in the Hanke study, MC was apparently only

one component of a solvent mixture and may

not have been the only neurotoxic

agent* * * In addition, the observation

interval of 2.5 days was not long enough to

provide convincing evidence of irreversible

effect, regardless of the active agent.

Upon reexamination of these studies,

OSHA agrees with NIOSH [Ex. 19–46]

that although a prolonged effect (over a

weekend break in exposure) of MC on

EEG patterns has been demonstrated,

these studies do not support a

determination that MC exposure is

associated with irreversible brain

damage in humans.

OSHA reviewed several other studies

of occupational exposure to MC for

evidence of CNS effects of MC. The first

study was provided as an English

translation of a Czechoslovakian paper

by Kuzelova et al. [Ex. 7–26]. These

investigators examined workers in a

film production plant who were

exposed to MC concentrations from 29

to 4899 ppm. Several workers suffered

frank MC intoxication and many

workers showed signs of MC-induced

CNS depression. Toxicity associated

with chronic MC exposure was observed

in workers exposed to MC for up to two

years, but the authors recommended

continuing studies of the long-term

health effects.

OSHA believes that this study shows

CNS depression in workers exposed to

MC. The Agency agrees with the authors

that this study was not sufficient to

adequately characterize the long-term

CNS health effects that may be induced

by MC exposure.

Cherry et al. [Ex. 7–154] studied the

effects of occupational exposure to MC

at 28 to 175 ppm in two exposed

populations. In a 1981 study, the

authors found a marginal increase in

self-reported neurological symptoms

among exposed workers. This increase

disappeared when an appropriate

reference group was used for

comparison. However, in a 1983

investigation, Cherry [Ex. 7–153]

showed statistically significant

increases in tiredness and deficits in

reaction time and digit symbol

substitution which correlated with MC

in blood. Ambient MC exposures for

this population ranged from 28 to 175

ppm for the full shift. This study

demonstrated CNS effects due to

occupational MC exposures below 200

ppm (the lowest dose which was

administered in the experimental

studies).

The HSIA [Ex. 105, p. 34] commented

as follows:

Decades of experience with worker

populations exposed even at levels up to the

current 500 ppm TWA have provided no

evidence that such workers have higher rates

of accidents or other signs of significant

neurobehavioral impairment.

To the contrary, OSHA believes that

the occupational studies discussed

above demonstrate that MC has an effect

on the CNS at occupational exposure

levels as low as 175 ppm.

The Agency believes that the 1983

study by Cherry shows that

occupational exposure to MC

concentrations below the former 8-hour

TWA PEL of 500 ppm can produce

detectable CNS effects. Although the

1981 study, which relied on self-report

of neurological symptoms, did not

demonstrate a CNS effect, the 1983

study examined more objective

measures of CNS depression and

correlated the observed effects with a

direct measure of MC exposure. OSHA

believes that this study demonstrates

that, although the CNS depression may

be mild, it is demonstrable in

occupational settings and at

concentrations in the range of the STEL

(although the exposures in this study

were over an 8-hour work day). As

described above, OSHA is sufficiently

concerned about the potential for health

effects at concentrations below the STEL

of 125 ppm that it will continue to

gather information and revisit this issue,

if warranted.

2. Cardiac Toxicity

As described in the section on the

metabolism of MC, MC is metabolized in

vivo (in animals and humans) to CO and

CO2. Cardiovascular stress has been

observed after exposure to CO, so it is

reasonable to suspect that similar health

effects would be observed after exposure

to MC (and metabolism to CO) [Ex. 7–

73, 4–33]. Carbon monoxide

successfully competes with oxygen and

blocks the oxygen binding site on

hemoglobin, producing

carboxyhemoglobin (COHb) and

reducing delivery of oxygen to the

tissues. This reduces the oxygen supply

to the heart itself, which can result in

myocardial infarction (heart attack) [Ex.

4–33].

Generally, humans have a baseline

level of COHb of less than 1% COHb

due to the endogenous production of CO

from normal metabolic processes. The

measured level of COHb in the general

non-smoking population is from 1% to

3% because of direct exposure to CO

from combustion sources such as

automobiles, etc. In smokers, COHb

generally ranges from 2% to 10%

because of the additional CO exposure

during smoking. CO generated from

exposure to MC would be additive to

the COHb burden already experienced

by an individual from direct exposure to

CO. The cardiac health effects

anticipated from exposure to MC itself

or CO as the result of metabolism of MC

are described below.

a. Animal studies. There is no

evidence from animal studies in the MC

rulemaking record that MC has a direct

toxic effect on cardiac tissue. After

lethal doses of MC, death has been

primarily attributed to CNS and

respiratory depression [Exs. 7–27, 7–28].

Also, chronic studies (in which COHb

levels have been maintained at 10% and

higher) [Exs. 7–3, 7–8, 7–14, 7–130, 7–

151] have not shown direct

cardiotoxicity.

Chlorinated solvents have been

shown to sensitize the cardiac tissue to

epinephrine- induced fatal cardiac

arrhythmias [Ex. 7–226]. However, MC

is less effective in sensitizing cardiac
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 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 COinduced 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.
1514 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

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 crosssectional 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 MCassociated hepatotoxic effect. One case

of hepatitis of unknown etiology was

identified. The case physician believed
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 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 nearfatal 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 doserelated 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 MCassociated 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 LongEvans 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
1516 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

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 doserelated 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 wellestablished risk assessment models

based on substantial biologically-based

evidence and theories: there were two

multi-site positive bioassays with doseresponse 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
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 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 PBPKbased 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 nonindependent Monte Carlo simulation—

Monte Carlo simulation is a welldeveloped 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 independentlycollected 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
1518 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

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, highquality 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. Thirtyseven 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 Stransferase 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 chlorideinduced 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.
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 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 interand 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
1520 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

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
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 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. Substancespecific 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. Substancespecific 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 MCinduced mutations were associated with

an increase in DNA ss breaks. They

remarked, ‘‘The results suggest that MCinduced DNA ss breaks seen in other

cell types are associated with DNA

damage which can lead to mutation.’’

In a follow-on to the CHO/HPRT

study, Graves et al. [Ex. 123] conducted

a sequence analysis of HPRT mutations

in CHO cells, comparing the spectrum

of MC-induced mutations with those

induced by 1,2-dibromoethane or

formaldehyde. The investigators

analyzed 28 HPRT mutations: 13 from

1,2-dibromoethane experiments, 6 from

formaldehyde experiments, and 11 from

MC experiments. The authors

characterized their results as follows,

All three compounds induced primarily

point mutations, with a small number of

insertions and deletions. * * * The mutation

sequence results for MC suggest that

formaldehyde may also play a role in MC

mutagenesis, although the majority of

mutations arise from other types of DNA

damage, probably DNA adducts formed by

reaction of S-chloromethyl glutathione with

DNA.

Dr. Douglas A. Bell of NIEHS [Ex.

126–26] had specific comments

regarding the study on the mutation

spectra [Ex. 123]. He stated,

This experiment is extremely weak

scientifically and not of publication quality.

It is unlikely that such a naive experiment

could detect differences in spectra between

the different chemicals tested. To test the

hypothesis that there are chemical specific

mutation spectra requires analysis of

hundreds of mutants at several different

doses. This exhibit contains no useful

information for risk assessment.

OSHA agrees with Dr. Bell that there

are serious methodological problems

with the paper. The Agency also agrees

with Dr. Bell that the important

information in these two studies is that

MC increases the mutation frequency,

showing a clear genotoxic effect.

(ii) Single strand DNA breaks. In a

1995 study, Graves et al. [Ex. 120]

investigated the role of MC exposure in

development of single strand (ss) DNA

breaks in the lung and liver of mice and

rats and in hamsters and human cell

cultures. The authors observed a

transient, dose-related increase in DNA

ss breaks in mouse hepatocytes after

inhalation exposure to MC. No

increased amount of ss breaks was

observed in rat liver cells exposed to

MC as compared to control cells. The

authors also reported a decrease in the

amount of ss DNA breaks in liver and

lung when a glutathione depletor was

administered to mice immediately

before MC exposure.

In mouse and rat hepatocytes

incubated with MC, the authors found

increases in ss breaks, but no increases

in ss breaks in hamster or human

hepatocytes exposed in vitro were

observed. No increase in DNA damage

was observed in CHO cells exposed to

MC plus mouse liver microsomes, while

MC plus mouse liver cytosol induced

detectable ss DNA breaks.

The authors characterized their

findings in the lung as follows:

Here we show that Clara cells are also

sensitive to MC-induced DNA ss breaks and

that the DNA-damaging metabolites are

derived from the GST pathway. * * *

Overall, these findings support the proposal

that Clara cells are the cell of origin of MCinduced mouse lung tumors.

For liver cancer, the investigators

concluded:

These studies suggest that humans (and

rats and hamsters) are insensitive to MCinduced liver cancer.

Commenters raised issues about the

relevance and utility of ss DNA breaks

in assessing the genotoxicity of MC. Dr.

Karl T. Kelsey [Ex. 126–34] and Dr.

Miriam Poirier [Ex. 126–37] raised

concerns about the sensitivity of the

DNA ss break assay for detecting

genotoxic effects.

Specifically, Dr. Kelsey stated,

Reviewing the literature, considerable

weight seems to fall upon the measure of

DNA single strand breaks. I have serious

concerns about this assay. It is well known

that the assay is extraordinarily difficult to

standardize and is sensitive only to very high

doses of genotoxic compounds. This data,
1522 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

therefore, is certainly not compelling;

persuading any competent independent

scientist of its relevance to humans would be

difficult.

Dr. Poirier was concerned with the

sensitivity of the DNA single strand

break assay and the relevance of DNA ss

breaks to carcinogenesis. She remarked

that ss DNA breaks and mutagenicity are

secondary indicators of DNA damage.

She indicated that a better measure of

genotoxicity would be formation of

DNA adducts. Dr. Errol Zeiger [Ex. 126–

28] of NIEHS agreed, stating,

If the mechanism of carcinogenicity is

through an alkylating S-chloromethyl GSH

complex, there should be evidence of DNA

adducts in vitro and in vivo.

OSHA agrees that DNA adducts are

strong evidence of genotoxicity and that

ss DNA breaks and mutagenicity are not

as specific or relevant as indications of

a genotoxic mechanism of action.

However, the Agency has determined

that, even in the absence of identified

MC-specific DNA adducts, the

accumulated evidence suggests that MC

interacts with DNA via a genotoxic

mechanism of action and that the GST

pathway is a plausible carcinogenic

pathway.

Dr. Melnick [Ex. 126–33] stated,

‘‘* * * it has not been demonstrated

that the carcinogenicity of MC in mice

is dependent solely on the induction of

DNA single strand breaks.’’ Dr. Andrew

G. Salmon concurred with this analysis

and also raised a serious concern about

the ability of the assay even to detect

increases in ss breaks, regardless of their

relevance:

Green’s account states that ‘‘mouse

hepatocytes were * * * 20-fold * * * more

sensitive to the effects of methylene chloride

[i.e., DNA strand breaks] than rat hepatocytes

* * * ’’ and no breaks were detected in

hamster or human liver cells. This is

translated in the discussion to an assertion

that not only humans and hamsters but also

rats are completely immune to the

carcinogenic effect of methylene chloride.

However, the data simply do not support the

assertion of a categorical difference as

proposed by the HSIA. This particular work

also raises a number of other issues, such as

whether the liver is an appropriate model

tissue, and whether single-strand breaks are

an appropriate indicator of the type of

genetic damage produced by the putative

genotoxic metabolites of methylene chloride.

OSHA agrees that the ss DNA break

assay is not as sensitive as other

methodologies for assessing the

genotoxic potential of MC in different

systems and therefore data from the ss

DNA break study must be interpreted in

a quantitative, not qualitative context,

with allowance for uncertainty in assay

sensitivity. It is also unclear whether ss

DNA breaks are the appropriate

surrogate measure for carcinogenic

potential. In light of the issues raised by

commenters, the Agency believes that

the ss DNA break data should be

interpreted with caution.

(iii) DNA-protein cross-linking.

Casanova and Heck [Ex. 21–16]

observed DNA-protein crosslinks in

mouse liver, but not mouse lung, after

exposure to 500, 1500 and 4000 ppm.

This study indicated that metabolites of

MC have the ability to interact with

DNA. However, the quantity of DNAprotein crosslinks did not show a strong

correlation with tumor incidence, and

so the DNA-protein crosslinks were not

used as a dose-surrogate for MC

exposure in OSHA’s risk assessment.

The Chemical Industry Institute of

Toxicology (CIIT) [Ex. 126–25]

submitted further evidence that MC

exposure causes DNA-protein crosslinks in mouse liver but not mouse lung,

hamster liver or hamster lung. These

investigators also observed RNA

adducts in mouse, rat and human cells

after incubation with MC, but DNAprotein cross links were only observed

in the mice. In addition, they submitted

a pharmacokinetic model which

modeled the DNA-protein cross-links as

the dose surrogate for MC exposure.

Finally, they made extensive

comparisons of their model with the

PBPK model submitted by Clewell [Ex.

96] and EPA’s risk assessment for MC.

Dr. Roger McClellan summarized the

conclusions they reached as follows,

The pharmacokinetic results suggest that at

very low concentrations of DCM [methylene

chloride], the yield of DPX [DNA-protein

cross-links] is almost linearly proportional to

DCM concentration * * *

DPX cannot be used directly as a surrogate

for the internal dose in humans, however,

because human hepatocytes, unlike mouse

hepatocytes, do not appear to form DPX in

measurable amounts in vitro. * * * These

results suggest that the mouse may not be an

appropriate animal model for human risk

assessment due to its unusual susceptibility

to DPX formation and to the fact that cell

proliferation is a uniquely high-dose

phenomenon that may occur only in this

species.

OSHA believes that this work

provides more evidence for the

formation of genotoxic metabolites in

mouse liver after MC exposure.

However, OSHA is not convinced that

the DNA-protein cross-linking is the

appropriate dose-surrogate for

pharmacokinetic modeling. One of the

strengths of Reitz’s and subsequent

PBPK models was that the dose

surrogate used in the modeling was

linearly related to tumor incidence. That

is one reason that many investigators

have focused on the GST pathway,

instead of the MFO pathway of

metabolism as the carcinogenic

pathway. As explained by Dr. Lorenz

Rhomberg [Ex. 126–16],

* * * if this proportionality in the case of

GST is broken by a deeper analysis, the

rationale for focusing only on GST must be

reevaluated.

Dr. Rhomberg was referring to results

presented by HSIA on the distribution

of GST theta isozymes within and

among cells, but the same sentiment

applies here; if OSHA were to abandon

PBPK modeling using GST metabolites,

all of the HSIA and other studies would

have to be re-evaluated and

considerable more research might need

to be done. Finally, in the CIIT study,

RNA adducts, a more direct measure of

genotoxicity than DNA ss breaks, were

observed in human hepatocytes after

incubation with MC. The amount of

RNA adducts in human cells was only

about 3-fold lower than the amount in

mouse hepatocytes. It is therefore clear

that human hepatocytes in this system

are forming genotoxic metabolites after

exposure to MC.

OSHA notes that, in mouse lung, the

DNA-protein cross-links were not

observed, even though a clear doseresponse relationship for tumors has

been established at this site. OSHA is

not convinced that the explanation for

carcinogenesis in mice is DNA-protein

cross-links in liver. Overall, it is unclear

whether the interspecies difference in

DNA-protein cross-linking is related in

any way to the carcinogenic mechanism

of action.

OSHA concludes that there continue

to be strong reasons for using the mouse

data as the basis for its quantitative risk

assessment because there is a clear doseresponse relationship in the mouse liver

and lung tumor incidence data; the

mouse metabolizes MC by the same

pathways as humans; PBPK models

have been developed which account for

inter-species differences in MC

metabolism; statistical techniques have

been developed to quantify the

uncertainty and variability in the

parameters used in the PBPK models;

and there are no data that demonstrate

that the mouse is an inappropriate

model for assessing human cancer risks.

In fact, OSHA finds further evidence in

the studies described above which

suggest that MC acts via a genotoxic

mechanism in human cells as well as in

mice and rats, which further supports

OSHA’s use of the mouse tumor

incidence as the basis for quantitative

risk.

(iv) Interpreting the genotoxicity

studies. Several other issues were raised

regarding interpretation of the results of
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1523

these studies on the genotoxic

mechanism of action of MC. NIOSH and

others [Exs. 126–30, 126–11, 126–32]

commented that, in general, the data

presented by HSIA supported the

hypothesis that the carcinogenic

metabolite(s) of MC were derived from

the GST pathway. They agreed with

HSIA’s interpretation of the data that

the studies presented here helped to

confirm that the mechanism of MC

carcinogenesis is through one or more

genotoxic metabolites of the GST

pathway.

Interpretation of short-term effects in

explaining chronic mechanisms of

action.

Concerns were raised about the

generalizability of the results of shortterm genotoxicity assays to tumor

incidence, especially when the observed

effect is transient, as in the vacuolation

of Clara cells, the appearance of ss DNA

breaks in mouse liver and lung cells,

etc. Dr. Mirer of the UAW [Ex. 126–31]

commented,

1. The evidence cited concerns acute

effects which appear after a few hours of high

level exposure of the animal to methylene

chloride vapor, or the glassware (in vitro)

mixing of homogenized animal or human

tissue with the solvent. In a number of

studies the effect in the whole animal is

transient.

2. There is no evidence to connect the

acute toxic effect, or single strand breaks of

DNA after acute exposure, to the chronic

effect of lung or liver injury, or cancer. * * *

Dr. Maronpot [Ex. 126–22] was

concerned that the vacuolation observed

in Clara cells was not reproduced in the

NIEHS mechanistic studies. HSIA

responded to this concern by remarking

that the vacuolation could only be

found after single exposures to MC, and

that the vacuolation of Clara cells was

also associated with increased DNA

synthesis in these cells. The fact that

this response was only observed after

single exposures to MC again raises the

issue of the transience of this response

and its relevance to MC carcinogenesis.

Increased cell turnover.

In these studies on genotoxicity, the

authors remarked that increased cell

turnover was observed in the lung

(transient increase in DNA synthesis

after single exposures to MC). Dr. Daniel

Byrd [Ex. 126–32] also commented on

the DNA synthesis issue. Citing an HSIA

study, he contended that there appeared

to be a common mechanism of action

between the lung and the liver since

increased DNA synthesis was observed

in both tissues. Dr. Maronpot of the

NIEHS [Ex. 126–22] disagreed, stating,

The purported ‘‘liver growth’’ in

methylene chloride-exposed mice is

actually an increase in liver weight

attributable to accumulation of glycogen

within hepatocytes. There is no

evidence of replicative DNA synthesis

(cell proliferation) in the liver of

methylene chloride-treated mice, and,

hence, actual increases in the numbers

of hepatocytes did not occur. * * * It is

noteworthy that recovery to normal liver

weight occurs within two weeks after

cessation of exposure to methylene

chloride.

OSHA agrees with Dr. Maronpot that no

data in the rulemaking record show

increases in liver cell proliferation as

the result of MC exposure, although

increased DNA synthesis was actively

searched for in the NIEHS mechanistic

and other studies. The increased DNA

synthesis observed in mouse Clara cells

is a transient phenomenon that has not

been clearly linked to carcinogenesis in

the mouse. In any event, cell

proliferation is not necessarily related in

any way to carcinogenesis and is often

uncorrelated with the doses used in

bioassays and the tumor rates

themselves. Many substances that cause

prolonged cell proliferation do not

cause tumor formation and vice versa

[Ex. 126–22], and many experts believe

that transient increases in cell

proliferation, such as seen with MC,

cannot account for the carcinogenic

effect. Further discussion of cell

turnover as a mechanism of

carcinogenicity is discussed below

under ‘‘Non-genotoxic mechanisms.’’

Clara cell as the mouse lung tumor

cell of origin.

Another issue raised by commenters

concerned the cell of origin of the

mouse lung tumors. The mouse lung has

a higher proportion of Clara cells than

the human lung. The investigators

hypothesized that if the Clara cell were

the mouse lung tumor cell of origin, the

risk estimated from the mouse lung

tumor data may overstate human risk

because humans have fewer Clara cells,

and therefore fewer potential target

cells.

Green et al. have focused much of

their research efforts into determining

the mechanism of action of MC in

mouse lung and liver. In lung tissue, as

described above, they concentrated on

experiments addressing the hypothesis

that the mouse Clara cell is the cell of

origin of the mouse lung tumors

observed in the NTP bioassay. Dr.

Daniel Byrd [Ex. 126–32] indicated that

he believed that the data presented

supported this conclusion. He stated,

‘‘Mouse lung tumors most likely arise

from damaged Clara cells, although a

few pathologists continue to speculate

that mouse lung tumors arise from other

lung cells, such as Type II

pneumocytes.’’

In contrast, Dr. Maronpot of the

NIEHS [Ex. 126–22] disagreed with that

statement, indicating that ‘‘* * *

current belief among researchers is that

mouse lung tumors arise from Type II

pneumocytes rather than Clara cells.’’

Dr. Melnick [Ex. 126–33] suggested that

the HSIA data are not consistent with

the hypothesis that the Clara cell is the

tumor cell of origin. He stated,

DNA damage was detected in lungs of mice

exposed to 2000 ppm methylene chloride;

however, no significant increase in DNA

single strand breaks was observed in Clara

cells isolated from mice exposed to 4000

ppm methylene chloride. This observation

does not support the conclusion that Clara

cells were the cells of origin of methylene

chloride-induced mouse lung tumors.

In their paper, Graves et al. [Ex. 120]

explain their results as follows,

Attempts to measure DNA damage in Clara

cells isolated from mice which had been

exposed to MC in vivo were unsuccessful.

* * * [I]t is possible that cells extensively

damaged by MC do not survive the isolation

procedure. The observation that the in vivo

vacuolation of Clara cells observed after MC

treatment is not seen in vitro when the cells

are isolated from the damaged lungs supports

this proposal.

This means that the authors could

induce ss breaks in the DNA of Clara

cells in vitro, but in mice exposed to MC

in vivo, it is not clear that the DNA ss

breaks observed in lung tissue were

concentrated in the Clara cells. In fact,

the authors state,

Since Clara cells represent only 5% of the

total lung cell population, the DNA ss breaks

observed in vivo may not exclusively result

from damage to this cell population.

OSHA believes that these issues raise

serious doubts as to whether current

evidence supports the determination

that the Clara cell is the cell of origin

of the mouse lung tumors. Although the

absence of increased ss breaks is not

necessarily an indication of lack of

genotoxicity, the presence of ss breaks

in lung tissue (and apparently not

concentrated in Clara cells) reveals an

inconsistency in HSIA’s argument:

either the ss breaks are irrelevant or

Clara cells are not the cells of origin, or

both. Further discussion of the issues

surrounding identification of the Clara

cell as cell of origin for mouse lung

tumors is contained below under ‘‘Nongenotoxic mechanisms of

carcinogenesis.’’

Ability of MC reactive metabolites to

cross membranes.

Although no data were presented by

the HSIA to address this issue directly,

several of the HSIA papers and the

accompanying letters postulate that the
1524 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

reactive metabolites of the GST pathway

are too short-lived to cross membranes.

This argument is used in combination

with the claim of high concentrations of

the mRNA for the GST T1–1* in the

nuclei of mouse cells (but not those of

rats and humans) to support the

contention that humans are not at risk

of developing cancer after exposure to

MC. The reasoning is as follows: (1)

Mice are the only species to have high

concentrations of GST T1–1* in the

nucleus of lung and liver cells. (2) The

reactive metabolites of the GST pathway

are too short-lived to cross the nuclear

membrane. (3) In order to produce a

carcinogenic effect, reactive metabolites

must be produced inside the nucleus in

proximity to the DNA. (4) Because the

mouse has high concentrations of these

enzymes in the nucleus (and rats and

humans do not), the mouse is uniquely

susceptible to lung and liver cancer after

exposure to MC. (5) Therefore, there is

no risk of humans developing cancer

after exposure to MC.

Some commenters [Exs. 126–12, 126–

30, 126–33] maintained that HSIA’s

submitted studies do not support this

argument. As discussed subsequently,

the probe used in these experiments

measured GST T1–1* mRNA, not the

isozyme itself. There is not necessarily

a correlation between the intracellular

concentration of mRNA and the

concentration of enzyme at a specific

locus. In addition, one would expect

there to be higher mRNA outside the

nucleus (since that is where the enzyme

is transcribed from the mRNA), even if

the enzyme were subsequently

concentrated inside the nucleus.

Additionally, as discussed previously,

some of the evidence presented by HSIA

suggests that the metabolites can be

generated outside the cell (not simply

outside the nuclear membrane) and

interact with the DNA. Specifically, Dr.

Dale Hattis [Ex. 126–12] has remarked

that,

* * * as long as these reaction and

detoxification processes are not infinitely fast

(and in principle they cannot be infinitely

fast), a finite fraction of the activated

metabolite molecules must reach the DNA

and react. Even though this chain of events

is required by our basic understanding of the

relevant kinetic processes, in this case we

also have direct empirical evidence that

active metabolites need not be generated in

a cell’s nucleus in order to reach DNA and

do damage. The DNA sequence mutations of

Graves and Green [Ex. 122] and Graves et al.

[Ex. 123], and the DNA single strand breaks

reported by Graves et al. [Ex. 120] for CHO

cells were all produced by exposing

mammalian cells to a tissue culture medium

that had been supplemented with mouse

metabolizing enzymes and methylene

chloride. The active metabolites in those

cases were necessarily generated from

outside of the cells, not just in the cytoplasm

of the cells that manifested the DNA damage.

Therefore, the claim that the active

glutathione transferase metabolite(s) must be

generated in the nucleus and would be

ineffective if generated in the cytoplasm is

flatly contradicted by HSIA’s own evidence.

HSIA [Ex. 126–29] strongly disagreed

that their results should be interpreted

in this way and countered as follows:

The investigators had to use a suspension

assay to maximize the concentration ratio of

methylene chloride to cells to about 1014,

and to optimize the GST activity from mouse

liver preparation. Only under these extreme

nonphysiological conditions with a

transformed cell line could any increase in

mutation frequency be observed. There is

absolutely no justification for assuming

similar conditions in humans, where GST

activity is absent or at very low levels in the

cytoplasm and absent in the nucleus.

OSHA disagrees with HSIA, however,

and finds Dr. Hattis’ and the other

commenters’ reasoning more sound. The

results of these experiments indicate

that the metabolites of MC are stable

enough to cross the cellular and the

nuclear membrane to interact with

DNA. The Agency recognizes that these

are not physiological conditions, but the

conditions of the experiment do support

the common-sense assumption that

enzymatic metabolism takes place in the

cytoplasm of mouse cells and show that

some fraction of the GST metabolite(s)

is stable enough to cross membranes in

the cell. Thus, the Agency believes that

the observed tumorigenesis in the

mouse is not the exclusive result of

nuclear MC metabolism.

Other issues pertaining to

genotoxicity.

The remaining comments on these

studies focused on more general issues

such as the genotoxicity of MC and

other factors related to the GST

metabolic pathway and MC-induced

carcinogenesis. Dr. Melnick [Ex. 126–

33] remarked:

Some fundamental questions related to this

mechanism and its uniqueness to mouse liver

and mouse lung carcinogenesis are also not

addressed by the present research. For

example, why do tumors not develop in other

organs in mice that also have high levels of

GST theta (e.g., kidney)?

OSHA believes this is an important

question that reduces the strength of

HSIA’s contention that the mouse

responds in a unique way to MC. The

investigators have attempted to explain

differences in potency of MC with

respect to liver and lung carcinogenesis

by invoking differences in DNA repair

rates and GST metabolism within the

nuclei of critical cells. However, there

are other tissues which, based on the

HSIA hypothesis, ought to be prime

candidates for carcinogenesis. The

kidney, besides having high levels of

GST theta, also has a slower rate of DNA

repair than the liver. It would appear to

be a logical site of carcinogenesis if

HSIA’s hypothesis is correct. OSHA

believes that the lack of tumor response

in this organ (and perhaps other logical

sites) indicates that the hypothesis

proposed by HSIA fails to account for

all relevant observations.

(2) Non-genotoxic mechanisms of

carcinogenesis. Non-genotoxic

mechanisms of action have also been

hypothesized for MC. Increased cell

turnover, due to cell death caused by

MC toxicity, could theoretically increase

the available number of sites for

mutation and subsequent tumor

formation. However, there is only

limited evidence of increased cell

turnover after MC exposure. Casanova

and Heck [Ex. 21–16] observed

increased DNA synthesis in lung tissue

of mice exposed to MC. Green et al. [Ex.

105] observed Clara cell vacuolation,

and both studies measured increased

DNA synthesis on the first day of

exposure to MC, but not on subsequent

days of exposure. Clara cells may be

targets of MC-induced toxicity because

they contain higher levels of MCmetabolizing enzymes and are therefore

more likely to generate toxic MC

metabolites (for example, carbon

monoxide is known to poison MFO

enzymes). Green et al. suggested that the

Clara cell was the cell of origin of the

lung tumors observed in the NTP mouse

study, because of the metabolic

properties of these cells and the

increased cell turnover observed within

a day of MC exposure (in addition to the

DNA damage described above under the

section entitled, ‘‘Genotoxic

mechanisms of carcinogenesis’’).

Green et al. further suggested that if

the cell of origin of the mouse lung

tumors was the Clara cell, humans

would be at substantially less risk of

lung cancer, because humans have

proportionally fewer Clara cells than

mice do. However, OSHA believes that

there is no clear evidence confirming

that Clara cells were the cell of origin of

the mouse lung tumors (see discussion

above). Other cell types in the lung,

such as the Type II lung cell, also have

relatively high metabolic activity and

could be the site of origin of lung

tumors. These cells have not been

studied separately. Further studies are

needed to clarify the role of the Clara

cell and other lung cell types and cells

in other tissues in MC carcinogenesis.

(i) Increased cell division. In 1994,

Foster et al. [Ex. 119] investigated

increased cell division as the
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1525

mechanism of action of MC in mouse

lung cells. Specifically, they examined

the mechanism of MC action on the

transient vacuolation of bronchiolar

cells observed following single

exposures to MC. In mice exposed to

2000 and 4000 ppm MC, they observed

increased numbers of vacuolated cells

in the bronchiolar epithelium.

Pretreatment of mice with a cytochrome

P450 inhibitor decreased the number of

vacuolated cells, while pretreatment

with a glutathione depletor did not. In

a replication of the observation made by

Green et al. and described above, the

authors found increased cell division

(measured as incorporation of [3H]-

thymidine) in Clara cells isolated from

mice exposed to 4000 ppm MC. They

concluded:

We believe that these results strongly

support the supposition that the vacuolation

of the Clara cells is due to a toxic metabolite

produced by the CYP [cytochrome P–450]

pathway of metabolism. Furthermore the

most likely candidate for inducing the

change is thought to be formyl chloride.

OSHA agrees that these observations

indicate that increased cell turnover

occurs in Clara cells of mice. This may

possibly be a partial explanation of the

mechanism, but only a partial one. In

cases where cytotoxicity has been

considered to be an explanation for risk

occurring only at ‘‘high’’ doses, this

argument is confined to chemicals

believed to act non-genotoxically. MC is

likely to be a genotoxic carcinogen, so

even if cell proliferation is a factor, the

genotoxic mechanism would be the

primary mechanism of concern.

Genotoxic carcinogens are not generally

believed to have a threshold and the

dose-response function is believed to be

approximately linear at low doses. In

addition, the study focused on one type

of cell, which may not be the cell of

origin for lung tumors. Carcinogenicity

in humans (as well as in mice and rats)

seems to originate from various cell

types in various tissues.

(3) Metabolism of MC. As described

above, the mechanism of carcinogenesis

for MC is not known. Numerous studies

over many years have explored

numerous possible mechanisms and

have provided substantial information

regarding the metabolism and the

probable metabolite responsible for the

carcinogenic effect. As discussed in the

Health Effects section, MC is

metabolized by two pathways: the

mixed function oxidase pathway (MFO)

and the glutathione S-transferase (GST)

pathway. Both pathways produce

reactive intermediates which potentially

could contribute to a genotoxic

mechanism of carcinogenicity. During

development of the PBPK model for MC,

Reitz et al. found that tumor incidence

correlated with the estimated amount of

GST metabolite, as well as with the

amount of parent compound

administered, but not with the amount

of MFO metabolite [Ex. 7–225]. The

parent MC is not likely to act as a

genotoxic carcinogen because it is a

fairly non-reactive compound. In

addition, MC blood levels in mice were

lower than in rats, so if MC was the

carcinogenic moiety, one would expect

the risk of cancer in rats to be higher

than mice, whereas the opposite was

observed. Consideration of these factors

has led many investigators to conclude

that the GST pathway is responsible for

carcinogenesis and that it is likely to

produce a genotoxic carcinogenic

moiety. OSHA has reviewed the data

available on mechanism of action and

has concluded that the most plausible

assumption is that the GST pathway is

responsible for the carcinogenic action

of MC and that this should be taken into

account in the quantitative risk

assessment. This represents a casespecific departure from the default

assumption that the administered dose

of the parent compound is the relevant

metric for exposure.

(i) Specific GST isozyme(s)

responsible for MC metabolism to the

carcinogenic metabolite. Recent work

sponsored by the HSIA was directed at

further characterization of the

metabolism of MC by the GST pathway

[Exs. 121, 124, 124A]. Specifically, the

HSIA work on MC metabolism has

focused on the isolation and description

of isozymes in the GST theta class of

enzymes, which HSIA believes are

responsible for the metabolism of MC to

the carcinogenic metabolite in mice.

Mainwaring et al. have shown that the

GST isomer with the greatest specific

activity for MC is a member of the theta

class of GST. [Ex. 121] In rats, three

members of the theta class have been

identified, GST 5–5, GST 12–12 and

GST 13–13. In humans, two theta class

enzymes have been identified, GST T1–

1 and GST T2–2 and in mice, two theta

enzymes have been described, GST T1–

1* and GST T2–2* (also known as GST

MT–1 and GST MT–2). According to

Mainwaring et al. [Ex. 121], rat GST 5–

5 and mouse GST T1–1* have similar

specific activity toward MC and

sequencing studies have shown

‘‘* * *that rat 5–5, mouse T1–1* and

human T1–1 are orthologous proteins as

are rat 12–12 and mouse T2–2* and

human T2–2’’ [Ex. 124A].

The hypothesis under investigation in

this work was that the enzyme similar

to rat GST 5–5 (mouse T1–1* and

human T1–1) was the critical enzyme

responsible for metabolism of MC to the

carcinogenic metabolite, and that

differences in the interspecies intra- and

inter-cellular distributions of this

isozyme and differences in genotoxicity

would be important for characterizing

the risk of carcinogenesis after exposure

to MC.

In order to examine the distribution of

the GST isozymes of interest, the

investigators used DNA oligonucleotide

anti-sense probes complementary to

three regions of the protein nucleotide

sequences of rat GST 5–5, mouse GST

T1–1* and human GST T1–1 to localize

specific mRNA sequences in mouse, rat

and human liver and lung tissue. They

also used an antibody raised against rat

GST 12–12 to localize the protein itself

[Exs. 124, 124A]. In the full paper

describing these experiments [Ex.

124A], Mainwaring characterized the

results of this study, as follows:

The mouse enzymes [T1–1* and T2–2*]

were present in significantly higher

concentrations in both liver and lung than

the equivalent enzymes in rat and human

tissues. In mouse liver, both enzymes were

localized in limiting plate hepatocytes

surrounding the central vein, in bile duct

epithelial cells and in the nuclei of

hepatocytes. In rat liver the distribution of

GST 12–12 was comparable to that seen for

T2–2* in the mouse. GST 5–5 was not

localized in limiting plate hepatocytes or in

nuclei of rat liver. The levels of human

transferase T1–1 in the liver were very low,

with an even distribution throughout the

lobule. The GST 12–12 antibody did reveal

high concentrations of this enzyme in human

bile ducts. The relative amounts of the theta

enzymes in the lungs of the three species

followed the pattern seen in the liver, with

very high concentrations in Clara cells and

ciliated cells of the mouse lung and much

lower levels in the Clara cells only of rat

lung. Low levels of human transferase T1–1

were detected in Clara cells and ciliated cells

found at the alveolar/bronchiolar junction of

one human lung sample. The enzyme was

entirely absent from the large bronchioles.

Mainwaring et al. concluded that:

This study has demonstrated a highly

specific distribution of the theta class GSTs

5–5 and 12–12 in liver and lung tissue from

mice, rats and humans. * * *it was apparent

from these studies that both the distribution

and concentration of theses enzymes differed

markedly between the three species. Whilst

neither mRNA levels nor protein

concentrations necessarily correspond to

active enzyme, the distribution shown by the

mRNA for GST 12–12 was quantitatively

reflected by the antibody to the protein of

this enzyme, suggesting that these techniques

do, in this case, reflect the distribution of

active enzyme. Although an antibody to GST

5–5 is not available, it is reasonable to

assume that mRNA levels for this enzyme are

similarly representative of the distribution of

active enzyme.

An understanding of the cellular and subcellular distribution of GST 5–5 has provided
1526 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

an explanation for the species specificity of

the mouse lung and liver carcinogen

methylene chloride, and has provided

reassurance that humans are not at risk from

exposure to this chemical.

(ii) Issues raised pertaining to

metabolic studies. Many commenters

commended the HSIA for providing

new information on the mechanism of

action of MC and for confirming

previous quantitative studies of the

interspecies differences in MC

metabolism. However, commenters also

raised several specific issues regarding

the conduct and interpretation of these

experiments.

Correlation of mRNA concentrations

with enzyme concentrations.

Mainwaring et al. [Ex. 124A]

correlated the inter- and intra-cellular

distribution of the mRNA for GST 12–

12 in the rat with the distribution of the

antibody for GST 12–12. They stated

that it is reasonable to assume that since

the protein and mRNA for the 12–12

isomer have similar distributions, the

protein for the 5–5 isomer would

distribute in the same manner as the

mRNA for the 5–5 isomer. In support of

their assumption, they noted that there

is 80% homology between the 5–5 and

12–12 isomer. Some commenters

believed that this was not a reasonable

assumption and that there was no

reason to believe that the distribution of

the GST 5–5 isomer protein would

correlate with the distribution of the

GST 5–5 mRNA simply because there

seemed to be a correlation in the 12–12

isomer protein and mRNA distributions

[Exs. 126–7, 126–16]. OSHA concurs

with these commenters, and until there

is actual measurement of the GST 5–5

protein, OSHA does not believe that the

question of the actual distribution of

GST 5–5 isozyme will have been settled.

More importantly, several

commenters stressed that it was mRNA

that was actually observed in these

studies, and mRNA levels do not

necessarily correspond to either protein

levels or protein activity within a cell

[Exs. 126–7, 126–16, 126–28, 126–30,

126–32]. Although Mainwaring et al.

acknowledge this fact [Ex. 124A], the

conclusions reached by the authors still

suggest that measurement of mRNA is

equivalent to measurement of enzyme

activity. Referring to the conclusions

drawn by Mainwaring et al., Dr. Lorenz

Rhomberg [Ex. 126–16] commented:

This interpretation of mRNA distribution is

profoundly in error and contradicts some of

the most well established and fundamental

principles of molecular biology.* * *

Finding mRNA in the nucleus is

unsurprising and uninformative about the

eventual location of the protein products.

Detecting mRNA only reveals that the cell

may be presumed to be manufacturing the

corresponding protein.

Dr. Rhomberg was also concerned that

the concentration of GST T1–1* in the

nucleus of mice may be an artifact of the

experimental conditions, resulting,

perhaps, from a burst of mRNA

synthesis. The concern that the apparent

nuclear concentration of GST may be an

artifact was echoed by Dr. Douglas A.

Bell of the National Institute for

Environmental Health Sciences [Ex.

126–26]. He stated:

Why the [intracellular] distribution should

be different among species is unclear and

unusual. Differences in processing of the

nuclear RNA transcript from full length premRNA may be the underlying cause of this

phenomenon (or perhaps there is a

transcribed pseudogene that is complicating

the process).

Because of the specific cellular

mechanisms that would be required to

concentrate a protein in the nucleus, Dr.

Rhomberg [Ex. 126–16] indicated that

translocation of the GST 5–5 protein to

the nucleus only in mice seemed

unlikely. He stated:

It seems implausible * * * that for a series

of orthologous proteins, such localization

would be found in a particular species and

not in other species.

OSHA agrees with the comments made

by Dr. Rhomberg and Dr. Bell on this

issue, and concludes that the

concentration of mRNA at a particular

cellular site does not necessarily

correlate with concentration of the

enzyme itself. OSHA believes that

caution should be used when

interpreting the results of these

experiments.

Attribution of GST metabolizing

activity to a single GST isozyme.

Concern was also raised about the

validity of attributing all of the

glutathione S-transferase metabolism of

MC to one isomer of the theta class [Exs.

126–7, 126–12]. In particular, Dr. Dale

Hattis noted that there was less enzyme

activity eluting coincident with the peak

identified as the 5–5 form than that

eluting at pH 8, which was not believed

to correspond to the 5–5 form. Dr.

Ronald Brown described results from a

paper by Blocki (1994) [Ex. 127–22]

which showed that ‘‘expression of the

[5–5] isozyme contributes 50% of the

total GST activity toward this

substrate.’’ This leaves the question

open as to whether isozymes which may

have lower specific activity for MC but

which may be expressed in much

greater abundance (particularly μ 4–4),

could contribute as much as the

remaining 50% of the total GST

metabolism (see Table VI–1, reproduced

below from Dr. Brown’s comment [Ex.

126–7], original source Blocki et al.

(1994) [Ex. 127–22]).

TABLE VI–1.—RELATIVE CONTRIBUTION OF DIFFERENT RAT LIVER GLUTATHIONE S-TRANSFERASES IN DICHLOROMETHANE

METABOLISM TO FORMALDEHYDE

Glutathione S-transferases

α Class μ Class θ Class

Comparative parameter (units) ........................ 1–1+1–2+2–2 3–3 3–4 4–4 b 5–5 b 13k

Specific activity (nmol/min/mg of protein) ........ <0.1 7 11 23 11,000 9

% Cytosolic protein (% of total in liver) ........... 6.4 0.7 0.3 0.6 0.002 0.005

Total activity (nmol/min/g of liver protein) ........ <10 49 33 138 22 0.45

% Total activityc ............................................... <1.5 11 7 32 50 0.1

a Data from Meyers et al., 1991.

b Data for 13,000 molecular weight glutathione transferase from Blocki et al., 1992.

cAssuming Vmax conditions for each.

In addition, Mainwaring et al. [Ex.

124A] noted that the ‘‘substrate

specificity of GST 12–12 is currently

poorly characterized,’’ although the

purified enzyme has no activity toward

MC. As described above, these enzymes

appear to be very labile upon

purification. Therefore, it is unclear

how much the 12–12 isomer itself may

contribute to MC metabolism. As Dr.

Kenneth T. Bogen stated, ‘‘* * * while

the substrate specificity of GST 12–12

may currently be poorly characterized,

current data do not appear to rule out

GST 12–12 specificity toward MC.’’
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1527

Limited human samples and human

polymorphism in the GST theta genes.

Several commenters expressed

concern for the limited number of

human samples (one pooled lung

sample and less than 40 human liver

samples have been assayed) and the

potential effect of a known human

polymorphism for the glutathione Stransferase theta class genes on risk

estimations [Exs. 126–7, 126–16, 126–

26, 126–35]. Specifically, commenters

raised concerns that there may be a large

subpopulation of GST conjugators who

may be at increased risk from MC

exposure that has not been adequately

characterized in the limited number of

human samples (especially lung

samples) that have been tested. HSIA

objected to these comments, stating,

The human tissue data base for the

metabolism of methylene chloride by the

GST pathway is one of the largest, if not the

largest, available for this type of risk

assessment. To discount it based on

arguments concerning hypothetical

polymorphisms, as these commenters urge

OSHA to do, would be contrary to the

message consistently put forward by the

National Academy of Sciences and regulatory

authorities for the past decade. * * *’’

In fact, the National Academy of

Sciences report cited by HSIA, ‘‘Science

and Judgement in Risk Assessment’’

does encourage agencies to make use of

biologically-based models, but cautions

that using them without adequately

considering human variability would be

a step backwards:

EPA has not sufficiently accounted for

interindividual variability in biologic

characteristics when it has used various

physiologic or biologically based riskassessment models. The validity of many of

these models and assumptions depends

crucially on the accuracy and precision of the

human biological characteristics that drive

them. In a wide variety of cases,

interindividual variation can swamp the

simple measurement uncertainty or the

uncertainty in modeling that is inherent in

deriving estimates for the ‘‘average’’ person.

The Academy goes on to recommend

specifically that making ‘‘reasonable

inferences’’ about interindividual

variation is required, rather than

assuming that no such variation exists:

Even when the alternative to the default

model hinges on a qualitative, rather than a

quantitative, distinction, such as the possible

irrelevance to humans of the alpha-2uglobulin mechanism involved in the

initiation of some male rat kidney tumors,

the new model must be checked against the

possibility that some humans are

qualitatively different from the norm. Any

alternative assumption might be flawed, if it

turns out to be biologically inappropriate for

some fraction of the human population.

When EPA proposes to adopt an alternative

risk-assessment assumption * * * it should

consider human interindividual variability in

estimating the model parameters or verifying

the assumption of ‘‘irrelevance.’’ If the data

are not available that would enable EPA to

take account of human variability, EPA

should be free to make any reasonable

inferences about its extent and impact (rather

than having to collect or await such data), but

should encourage interested parties to collect

and provide the necessary data.

OSHA believes HSIA has

misinterpreted the NAS

recommendations, and further disagrees

with HSIA that the polymorphism is

‘‘hypothetical.’’ Investigators have

demonstrated this polymorphism in

human GST and have shown how the

polymorphism varies across races [Exs.

127–7, 127–9, 127–17, 127–21, 127–23,

127–24, 127–25]. OSHA agrees with the

commenters that a human

polymorphism in the GST theta genes

may increase concern for individuals

that may be at higher risk from exposure

to MC due to their genetic make-up. The

Agency has considered sensitive

subpopulations in the development of

health standards, including this

rulemaking. For example, the

subpopulation of workers with silent or

symptomatic heart disease was

considered in assessing the cardiac risks

of MC (due to its metabolism to carbon

monoxide). The variation in enzyme

activity raises additional uncertainty in

the use of human data to support the

hypothesis that mice are uniquely

sensitive to MC carcinogenicity.

However, for purposes of quantitative

analysis, the Agency has not attempted

to systematically adjust the risk

estimates based on a ‘‘high GST

metabolizing’’ individual because the

frequency and impact of such

polymorphisms have not been clearly

worked out.

Target site of MC carcinogenesis in

mice versus humans.

Drs. Brown and Melnick [Exs. 126–7,

126–33] also raised the possibility that

the target site for MC carcinogenesis

may be different in humans than in

mice or rats. Specifically, research on

the occurrence of theta isomers of GST

in human blood was described. The

characterization of GST metabolism in

human erythrocytes [Exs. 127–11, 127–

12] suggests the possibility of the bone

marrow as a potential target of MC

carcinogenesis and also the potential for

metabolism in the blood and

translocation of the metabolites to a

variety of potential targets. The HSIA

discounted human blood metabolism of

MC, stating,

The ‘very high capacity to conjugate

methylene chloride’ mentioned by Brown is

in fact very low, approximately 40-fold lower

than the highest activity detected in human

liver.

OSHA believes that although the

specific activity in the blood may be

lower than the human liver activity, the

total activity of the GST enzymes in

blood and marrow may be significant

when one also considers the volume of

these compartments. OSHA also notes

that interspecies tumor site concordance

is not necessarily expected, and it is

prudent to consider any human tissues

which have the potential to metabolize

MC to the putative carcinogen.

Concentration of protein

complementary to rat GST 12–12 in

human bile ducts.

Dr. Bogen [Ex. 126–15] commented

specifically on the human liver protein

complementary to the antibody to rat

GST 12–12 protein. In particular he was

concerned that high concentrations of

this enzyme were reported in bile ducts

of the human liver. He noted,

With regard to potential human

carcinogenicity of MC relative to its known

carcinogenic potential in mice, it seems to

me that these particular data ought not to

reduce regulatory concern, but rather ought

to increase regulatory concern, in view of the

fact that bile duct epithelium cells are the

most likely stem cells for hepatocytes. * * *

Thus hepatocellular bile-duct epithelial cells

are likely to play an important role in liver

carcinogenesis in both mice and humans.

OSHA agrees with Dr. Bogen’s

concerns and also notes that in the

cohort study of textile workers

conducted by Hoescht-Celanese [Ex. 7–

260], an excess of biliary cancers was

observed in those workers exposed to

the highest concentrations of MC and

those with the longest latency period

between exposure and disease. If the

HSIA theory is correct (i.e., a single

isozyme is the culprit), then finding

high levels of this isozyme in human

bile duct is strong evidence implicating

MC in human carcinogenesis.

Interpretation of data as qualitative

versus quantitative differences.

Perhaps most importantly for the

purposes of MC risk assessment, several

commenters remarked that OSHA

should use caution when interpreting

the data from the HSIA submissions,

because any interspecies differences are

rightly considered first as quantitative

rather than qualitative ones. In part, the

commenters cautioned that one should

pay special attention to the threshold of

detection in all assays. As Dr. Andrew

Salmon stated,

Green and co-workers have consistently

confused their inability to measure a result

or parameter value due to its magnitude or

frequency of occurrence being below their

threshold for practical detection, with a true
1528 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

zero value for the parameter or zero risk of

an occurrence [Ex. 126–36].

OSHA agrees that caution should be

used when attempting to characterize a

difference between species as an

absolute qualitative difference. A much

higher burden of proof is required to

support a claim of zero risk than of

diminished risk. (This higher burden is

due to the need to consider assay

sensitivity and other factors; the fact

that the consequences of incorrectly

concluding that humans are at zero risk

are particularly dire only adds to the

already high threshold of scientific

evidence needed to successfully make

such a claim). In the case of MC,

humans clearly have the ability to

metabolize MC via the GST pathway

[Exs. 21–53, 127–16]. Even if the

enzyme concentration of GST T1–1*

itself actually occurs only in the nuclei

of mouse lung or liver (as opposed to

the concentration of mRNA, which may

or may not be localized differently

within mouse cells), it is still unclear

what impact (if any) this fact would

have on the characterization of human

cancer risks for MC. OSHA believes that

the statement that there are absolute

species differences in the activity and

intracellular distribution of GST 5–5 is

highly speculative and is not supported

by the data presented to date, because

the data presented refers to the

distribution of mRNA for GST 5–5, not

the enzyme concentrations or activity

levels of the enzyme; there is no

quantification of the intracellular levels

of the mRNA or enzyme levels, only

photographic representations; and there

is no evidence that any potential

difference in enzyme activity (when

those experiments are completed)

would be greater than the difference

already predicted from allometric

scaling considerations.

Conclusions reached by the HSIA.

HSIA concluded from these studies

that because of a qualitative interspecies difference in the distribution of

the GST theta enzyme responsible for

MC carcinogenesis, humans would not

be at risk of developing cancer under

‘‘foreseeable conditions of exposure.’’

Although some commenters agreed with

the conclusions reached by the HSIA

[e.g., Exs. 126–10, 126–13, 126–20],

many commenters strongly disagreed

with this interpretation of these data

pertaining to the risk assessment for

MC. These commenters [e.g., Exs. 126–

7, 126–11, 126–12, 126–15, 126–16,

126–22, 126–26, 126–30, 126–36] were

concerned that the question was in

reality an issue of quantitation of

enzyme, not a qualitative difference in

metabolism. Dr. Lorenz Rhomberg

commented:

The question is, is there any basis for

believing that the species difference in

activity suggested by the mRNA data is

greater than has been previously supposed?

It should be emphasized that some degree

of species difference in metabolic activity is

expected even under the default crossspecies extrapolation methods. That is, in

keeping with the general pattern of scaling of

physiological processes across species,

general metabolic rates are presumed to be

lower on a per unit of tissue basis in larger

animals. As a default, this pattern can be

presumed to apply to individual metabolic

pathways as well, although data on speciesspecies activities can be used in place of such

defaults if available.

If species-species activities are discovered

by experiment to be less in humans than in

mice to the degree already anticipated by

allometry, then the experiments are simply

confirming the default and no change in the

human risk estimates is warranted. If humans

have a metabolic activity different than the

allometric prediction, the incorporation of

such estimates into PBPK models can show

different human risks from those predicted

under the default. The allometric prediction

is that, on a per unit of tissue basis, humans

should have about 7-fold lower activity than

mice and about 4-fold lower activity than

rats.

Given the limit of detection of the assay

methods, human metabolic activity (or

mRNA levels) only a bit less than the

allometric expectation of 7-fold less than

mice are often difficult to distinguish from

zero. That is, claims that humans have no

activity (or no mRNA production) in certain

tissues must be judged in the light of the fact

that only a small change from the already

acknowledged allometric difference can often

make the human activity undetectable. A 20-

fold mouse-human difference, for example,

really only represents a 3-fold exaggeration of

the 7-fold allometric pattern, yet many assays

may fail to reliably characterize a 20-fold

difference as a quantitative difference rather

than a qualitative difference.

For the above reasons, claims that human

metabolic activity in activating methylene

chloride are so low as to be essentially

qualitatively different than mice should be

interpreted with great caution. In fact,

existing assays have great difficulty in

detecting species differences in metabolic

activity great enough to markedly challenge

existing risk assessments.

Another commenter discussed the fact

that cellular levels of the GST 5–5

isoenzyme would be expected to be

distributed unevenly across cells,

putting some cells at greater or lesser

risk. This would tend to average out

over a tissue and would be best

described by tissue metabolism data.

Other commenters remarked that there

was no need to adjust the risk estimates

based on these studies because current

pharmacokinetic models already

account for interspecies differences in

metabolism. Although OSHA has

incorporated data from these studies,

especially in its ‘‘alternative analysis,’’

OSHA agrees with Dr. Rhomberg and

the other commenters who have taken

exception to the HSIA conclusions.

The Agency does not accept the HSIA

characterization of the results of the

summarized studies. OSHA has

determined that no evidence has yet

been presented that demonstrates that

humans are not at risk of developing

cancer after exposure to MC. At most,

the presented studies suggest a

quantitative inter-species difference in

MC metabolism, which was established

in previous scientific reports and is

already accounted for by PBPK

modeling. As discussed extensively in

this document, OSHA has concluded

that HSIA has undervalued certain

strong evidence and has

overemphasized some more speculative

hypotheses. However, as is clear from

this discussion OSHA has carefully

considered all of the evidence.

Substantial evidence in the record

clearly supports OSHA’s conclusions.

Consequently, OSHA’s approach of

relying on the NTP mouse tumor data as

the basis of its quantitative risk

assessment continues to be the best

approach to risk estimation.

c. Conclusions regarding the

carcinogenesis of MC. The HSIA

submitted these documents to OSHA

with a request that the Agency consider

the mouse tumor data in light of these

additional studies and reject use of the

mouse tumor response data as the basis

of the Agency’s quantitative risk

assessment. OSHA believes it has given

proper weight to all the evidence, giving

greater weight to that which is of the

highest scientific quality. However, in

light of HSIA’s request, the Agency

reopened the rulemaking record and

reviewed all the new data. After

submitting these documents for review,

the HSIA [Ex. 126–29] remarked on

comments submitted to the docket by

other scientists,

In general, the comments submitted by R.

Maronpot, R. Brown, L. Rhomberg, K. Bogen

and D. Hattis exhibit a reluctance to use the

large body of mechanistic data now available

in assessing the potential carcinogenic risk

posed by methylene chloride, even though

most other commenters agree that the

pathway responsible for its observed

carcinogenicity in mouse liver and lung, as

well as species variations in activity of this

critical pathway, have now been identified.

Much of the comment addressed here

appears to be motivated by a desire to

maintain the ‘‘status quo’’ for assessing

carcinogenic risk based on default principles

that were developed twenty years ago.

The HSIA goes on to say,
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1529

Many of the conclusions reached by the

commenters * * * are based, often

erroneously, on single aspects of one or the

other of these publications, rather than on the

entire data base, as a ‘‘weight of evidence’’

approach would demand and as is necessary

to understand the results.

OSHA finds it difficult to understand

why HSIA believes that the scientists

they listed are primarily interested in

preserving the ‘‘status quo.’’ Dr.

Maronpot conducted the mechanistic

studies on MC at NIEHS, which have

generated mechanistic information

useful to the risk assessment process.

Dr. Rhomberg was instrumental in

developing the pharmacokinetic

approach used by the Environmental

Protection Agency in its risk assessment

of MC (an approach never used by the

Agency previously). Dr. Hattis, Dr.

Bogen and Dr. Brown are all experts in

the application of pharmacokinetic

modeling to risk assessment and have

repeatedly called for incorporating more

mechanistic and physiological data into

pharmacokinetic models. These highly

respected scientists, among others,

reviewed the HSIA submissions

critically and independently and

reached conclusions different from

those of the HSIA, conclusions which

themselves depart significantly from the

‘‘status quo.’’ This does not suggest to

OSHA that they are trying to preserve

some status quo in risk assessment, and

OSHA finds nothing in the comments of

these experts to suggest that this is the

case.

In order to respond to HSIA’s desire

to have OSHA further review all of the

data, the Agency has reviewed each

submitted study carefully and critically

on its own merits to determine how

each piece of data fits into the overall

picture of the mechanism of action for

MC. OSHA believes that in this process

the critical issues raised by the HSIA

have received a full airing and the

hazard identification and the risk

assessment for MC have been improved

because of it. OSHA believes, however,

that looking only at the new studies

submitted by HSIA, and examining

them uncritically, would contradict

every principle of scientific analysis.

In summary, in order to accept the

HSIA’s supposition that MC is not

carcinogenic in humans, one must

believe the following:

1. GST 5–5 is the only isozyme which

can metabolize MC to the carcinogenic

metabolite.

2. DNA single strand breaks are

relevant and a sufficient measure of the

tumorigenicity of a compound.

3. The absence of detectable increases

in DNA ss breaks in a single experiment

means that there are in fact no

additional ss breaks.

4. The limited number of human

samples (one sample of pooled lung

tissues being the absolute extreme of

‘‘limited’’ data) used to determine

metabolic parameters are truly

representative of the range of human

variability.

5. An apparent correlation in the

distribution of the GST 12–12 protein

and GST 12–12 mRNA means that the

distribution of GST 5–5 protein will

correlate similarly with the distribution

of GST 5–5 mRNA.

6. Visual interpretation of

photomicrographs staining for GST

mRNA gives a true and accurate

measure of GST activity in the cell.

And one must also ignore the

following contradictory observations

and conclusions about the mechanism

of action (in addition to ignoring the

suggestive epidemiologic evidence):

1. Metabolites of GST can cross cell

and nuclear membranes and interact

with DNA to induce DNA ss breaks and

mutations.

2. GST mRNA and protein stain

heavily in human bile duct cells

(believed to be precursors of

hepatocytes).

3. Human lung tissue has been shown

to stain for GST mRNA.

4. Only 50% of the GST metabolism

of MC can be accounted for by the GST

5–5 isozyme.

5. The metabolic capacity of GST 12–

12 for MC has not been characterized.

OSHA concludes that these studies,

even putting aside all technical

objections to the methodology and

interpretation of individual studies, do

not change the conclusion that

substantial evidence supports the

carcinogenicity of MC. The bioassay

results in mice are still qualitatively and

quantitatively relevant to humans. Once

the HSIA studies have been replicated

and key components quantified (like the

intracellular enzyme activity (instead of

mRNA levels) of GST towards MC), the

HSIA data may be useful in

characterizing quantitative interspecies

differences in MC GST metabolism. In

particular, it would be useful to

determine whether all of the evidence

that HSIA submitted is consistent with

an allometric difference (a difference

expected based on the size of the

animal) in sensitivity to MC or with a

greater interspecies difference in

sensitivity. (The specific activity of GST

toward MC in mice is estimated to be

about 7-fold that of humans, based on

allometric considerations.) OSHA

believes that its final risk assessment,

which relies on an analysis of all

available PBPK data, addresses both

possible interpretations.

B. Selection of Database for

Quantitative Risk Assessment

1. Animal Bioassays

The first step in performing a

quantitative assessment of carcinogenic

risk based on animal data is to choose

a data set or sets from which to define

the dose-response relationship. In its

NPRM, OSHA had chosen the NTP

female mouse lung and liver tumors to

determine its estimates of risk. OSHA

chose these responses because they

provided clear dose-response

relationships, had low background

tumor rates and were more sensitive

measures of dose-response than

corresponding male mouse tumor sites.

The EPA, the CPSC and the FDA

chose to use the combined incidence of

adenomas and carcinomas of the lung

and liver as the basis for their risk

assessments. Specifically, the EPA [Exs.

25–D, 28] placed emphasis on the

experimental species and sex group

showing the highest risk: the number of

female mice showing either adenoma or

carcinoma in either lung or liver (or

both). The CPSC [Ex. 25–I] pooled

benign and malignant tumors of either

the mammary gland, lung or liver and

averaged male and female estimates to

derive an overall risk estimate. The FDA

[Ex. 6–1] used benign and malignant

responses of female mice. The Crump

report [Ex. 12] noted that it may be

reasonable to combine lung and liver

responses to give an indication of the

potency of MC, due to the fact that

metabolism of MC occurs by the same

pathway in both lung and liver and thus

results in the same ultimate metabolites.

However, the report added that since

both tissues have different background

responses, combining responses may

tend to complicate the interpretation of

risk estimates.

In OSHA’s final rule, the NTP study

(rat and mouse, inhalation) was chosen

for quantitative risk assessment because

it provided the best toxicological and

statistical information on the

carcinogenicity of MC [Exs. 12, 7–127]

and because the study was of the

highest data quality. In the NTP study,

MC induced significant increases both

in the incidence and multiplicity of

alveolar/bronchiolar and hepatocellular

neoplasms in male and female mice. In

rats, dose-related, statistically

significant increases in mammary

tumors were also observed. OSHA chose

the female mouse tumor response as the

basis of its quantitative risk assessment,

because of the high quality of data, the

clear dose response of liver and lung
1530 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

tumors and the low background tumor

incidence. Although the female rat

mammary tumor response was also

dose-related, the data of high quality

and amenable to quantitative risk

assessment, the mouse data set had a

clearer dose-response in both liver and

lung tumors than the rat mammary

tumor response and the mouse

background tumor incidence was lower

than in the rat. Therefore the mouse

data set was chosen for quantitative

analysis.

OSHA included the lung adenomas in

the quantitative analysis. The evidence

suggests that the presence of benign

tumors with the potential to progress to

malignancies should be interpreted as

representing a potentially carcinogenic

response. This belief is supported by the

OSTP’s views on chemical

carcinogenesis (50 FR 10371). OSTP

stated that at certain tissue sites, such as

the lung, most tumors diagnosed as

benign really represent a stage in the

progression to malignancy.

Additionally, NIOSH, the EPA, the

CPSC and the FDA have also included

benign responses in their assessments.

Therefore, it is appropriate and

sometimes necessary to combine certain

benign tumors with malignant ones

occurring in the same tissue and the

same organ site. In particular, OSTP also

stated that ‘‘the judgement of the

pathologist as to whether the lesion is

an adenoma or an adenocarcinoma is so

subjective that it is essential they be

combined for statistical purposes.’’ (50

FR 10371).

OSHA chose female mouse lung

tumors as the specific tumor site for its

final quantitative risk assessment. There

is no a priori reason to prefer the mouse

lung tumor response over the liver

tumor response, because both data sets

were of high quality, showed a clear

dose-response relationship and had low

background tumor incidence. In fact, in

the NPRM, the Agency reported

estimates of risk generated using both

sites. However, to reduce the

complexity of the final PBPK analysis,

which required highly intensive

computations, OSHA chose one site (the

female mouse lung tumor response) for

its final risk estimates. The risks

calculated using the female mouse liver

response would likely be slightly lower

than those calculated using the lung

tumor response. On the other hand,

pooling the total number of tumorbearing animals having either a lung or

liver tumor (or both) (which is the

procedure EPA advocates [see its 1986

Guidelines for Cancer Risk Assessment])

would have yielded risk estimates

higher than OSHA’s final values.

The NTP study has been described in

the Health Effects section and, above, in

the discussion regarding hazard

identification.

2. Epidemiologic Data

The epidemiology data are not as

useful for quantitative risk assessment

as the animal data because the animal

data provide a clear dose-response, with

fairly precise indices of exposure, which

cannot be derived from the

epidemiology data. All other things

being equal, risk assessors would prefer

to use epidemiologic data to assess

cancer risk in humans over data from

animal studies whenever good data on

human risk exist. However, the

uncertainty inherent in epidemiologic

studies must be accounted for; in

particular, ‘‘positive’’ studies often have

lower confidence limits that do not rule

out the no-effect hypothesis, while

ostensibly ‘‘negative’’ studies often have

UCLs that would support a substantial

positive effect. OSHA believes (see

discussion below) that the latter

circumstance applies to some of the MC

studies. Other factors, such as duration

and intensity of a chemical exposure

(which can rarely be controlled and

accurately measured in an

epidemiological study), difficulty in

accurately defining the exposed

population, and other confounding

factors diffuse a study’s predictive

power of true risks.

Frequently, animal studies indicate a

positive response to a particular

chemical when epidemiologic studies of

exposures to the same chemical fail to

exhibit a statistically significant

increase in risk. When animal studies

show a substance to be a carcinogen but

epidemiologic studies are non-positive,

the minimum risk which could be

detected by the human study should be

estimated to assess the strength of the

epidemiologic study and justify its

importance in the risk assessment

process. Similarly, the animal-based

potency estimate can be used to predict

the number of human deaths

investigators would likely have seen in

an epidemiologic study if the animalbased estimate was correct; if the

observed number of human deaths is

markedly inconsistent with this

predicted number, the relevance of the

animal-based estimate might well be

called into question. If the human data

are equivocal, or the epidemiologic

study is not sufficiently sensitive to

identify an increased risk predicted by

a well-conducted animal bioassay, it is

necessary to consider the animal data to

protect workers from significant risk.

OSHA concludes that the MC

epidemiology studies do not have

adequate information upon which to

base a quantitative risk assessment.

OSHA has, however, used the analyzed

epidemiological data to determine

whether the results are consistent with

those estimated using the rodent

models. This is discussed later in the

document.

3. Conclusions

After reviewing the animal data and

the quantifiable epidemiology data,

OSHA has determined that the NTP

female mouse lung tumor response is

the appropriate data set on which to

base its quantitative risk assessment,

and has determined that the most

scientifically-appropriate way to use

these data involves constructing a PBPK

model to extrapolate from animals to

humans. OSHA believes that the nonpositive epidemiology data, in

particular those from Kodak, are of in

sufficient power to rule out the risk

estimates derived from the animal data.

C. Choice of Dose-Response Model

Several approaches have been used to

estimate cancer risk from exposure to

toxic agents. A standard approach uses

mathematical models to describe the

relationship between dose (airborne

concentration or target tissue dose

surrogate) and response (cancer).

Generally, mathematical functions are

fit to the data points observed at

different exposure levels and these

functions are used to estimate the risk

that would occur at exposure levels

below those observed. The shapes of

these curves vary, ranging from linear

extrapolations from the observed points

through the origin (zero exposure and

zero risk) to curves which may deviate

far from linearity at the very highest or

lowest doses. The use of a particular

model or curve can be justified in part

by statistical measures of ‘‘goodness-offit’’ to observed data points. That is,

there are various statistical tests which

measure how closely a predicted doseresponse curve fits the observed data.

The most commonly used model for

low-dose extrapolation is the multistage

model of carcinogenesis. This model,

derived from a theory proposed by

Armitage and Doll in 1961, is based on

the biological assumption that cancer is

induced by carcinogens through a series

of independent stages. The Agency

believes that this model conforms most

closely to what we know about the

etiology of cancer. There is no evidence

that the multistage model is biologically

inappropriate, especially for genotoxic

carcinogens, which MC most likely is.

The most recent data submitted by the

HSIA [Exs. 117–124A] clearly add

substantial support to the previous body
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1531

of evidence indicating that one or more

metabolites of MC is a genotoxic

carcinogen. The low-dose linearity

feature of this model is scientifically

required for any exposure that confers

additional risk upon a pre-existing

background level of risk produced by a

similar or equivalent mechanism. Given

the underlying connection between

DNA mutations and cancer and the

obvious background incidence of cancer

in the human population, the

overwhelming scientific consensus is

that genotoxins follow low-dose linear

functions.

The multistage model is generally

considered to be a conservative model

because it is approximately linear at low

doses and because it assumes no

threshold for carcinogenesis, although

there are other plausible models of

carcinogenesis which are more

conservative at low doses. ‘‘No

threshold’’ means that any incremental

amount of exposure to a carcinogen is

associated with some amount of

increased risk. ‘‘Approximately linear at

low doses’’ means that one unit of

change in dose will result in one unit of

change in risk at low doses.

The most common approach for

setting the parameters in the multistage

model is to assume that the doseresponse curve is described by a

polynomial of k-1 degrees, where k is

the number of dose groups tested. The

multistage model thus takes the form

P(Cancer) = 1—exp(-f(dose)),

with f(dose) given by:

f(dose) = a + b1(dose) + b2(dose)2 + ...+

bk-1(dose)k-1.

The number of stages is specified by

k-1, and the parameters a (the

background risk) and bi are estimated

from the observed data.

Alternatives to the multistage model

include the tolerance distribution

models such as the probit model, the

logit model and the Weibull model. The

tolerance distribution models generally

predict dose-response relationships

which are sigmoid in shape. Thus, these

models will approach zero more rapidly

than a linear multistage model. This

means that at low doses, these models

will predict lower risks than will a

linear multistage model.

In the MC rulemaking, most of the

risk assessments submitted to the

Agency used the linearized multistage

model to predict risk. The differences in

risk estimates were not generally due to

the dose-response model used, but to

whether the risk assessor used

pharmacokinetic modeling to estimate

target tissue doses, and what

assumptions were used in the

pharmacokinetic modeling.

D. Selection of Dose Measure

1. Estimation of Occupational Dose

The purpose of low dose

extrapolation is to estimate risk of

cancer at a variety of occupational

exposures. This requires that the doses

be converted into units comparable to

those in which the experimental dose is

measured.

In its NPRM, OSHA first converted

the experimental dose, measured in

ppm, to an inhaled dose, measured in

mg/kg/day. The female mouse body

weight used in these calculations was

0.0308 kg. The breathing rate for mice

was 0.05 m3/day. The Agency then

assumed that equivalent doses in mg/

kg/day would lead to equivalent risk.

Once the experimental dose (in mice)

had been converted to mg/kg/day, it was

then converted to ppm using the human

breathing rate of 9.6 m3/workday and

human body weight of 70 kg in order to

estimate risks at various potential

exposure levels. To determine the dose

to humans corresponding to the risk

estimated from the mouse data, OSHA

used the following equations:

Dose mg m Dose ppm g mol

g m

Dose mg kg d Dose mg m m d

M

M

M

M

( / ) ( )( . / )

.45 ( )( )

( / / ) ( / )( . / )

( .

3

3

3 3

84 9

24

0 05

0 0308

=

=

 (1000 mg)(1000 L)

 L/mol

 (6hr/24hr)(5d/7d)

 kg BW)

OSHA assumed that risk estimates

derived for mice at a given mg/kg/d

would be equivalent to risks

experienced by humans at that mg/kg/

d. Doses in mg/kg/d in humans were

converted to ppm to determine risk at

various potential workplace exposures

using the following equations:

Dose mg m Dose mg kg d

m workday d yr yr

Dose ppm Dose mg m L mol

H

H

H H

( / ) ( / / )

( . / )( / )( / )

( ) ( / )( .45 / )

3

3

3

9 6 5 7d 45 70

24

=

=

 (70kg)

/(84.9 g/mol)

This process was used by K.S. Crump et

al. in their risk assessment submitted to

OSHA [Ex. 12]. Use of mg/kg/d as a

measure of dose has been criticized by

Mr. Harvey Clewell, representing the

U.S. Navy [Ex. 19–59]. He stated,

Strictly speaking, the concept of a mg/kg/

day dose applies only to exposures for which

the term ‘‘administered dose’’ is well

defined, which does not include inhalation

exposure to a volatile, lipophilic chemical

such as MC....If a non-pharmacokinetic dose

surrogate is desired, the choice should be

time-weighted average concentration (ppm)

as used by the FDA.

Mr. Clewell preferred use of dose

surrogates calculated in the PBPK

models to estimate human risk. OSHA

has given careful consideration to the

issues raised by Mr. Clewell and, in the

risk assessment presented here,

considered dose surrogates estimated in

PBPK models and time-weighted

average concentration in addition to the

mg/kg/d dose presented in the NPRM.

For all dose measures used to estimate

human risk, the assumptions used by

OSHA for body weights and exposure

times and rates were those described

above. In OSHA’s final risk assessment,

a Bayesian analysis was used and the

prior distribution for breathing rate was

centered on OSHA’s preferred value of

9.6 m3/d.
1532 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

2. mg/kg/d Versus Other Measures of

Exposure

Quantitative risk assessments based

on animal data are conducted under the

assumption that animals and humans

have equal risks from lifetime exposures

to a chemical when exposure is

measured in the same unit for both

species. Opinions vary, however, on

what is the correct measure of exposure.

For site-of-contact tumors, a ppm-toppm conversion is a generally accepted

measure of dose. For systemic tumors,

commonly used dose conversions

include mg/kg/day (as used by OSHA in

its MC NPRM), mg/surface area/day

(with surface area approximated by

BW2/3), mg/BW3/4/day, and mg/kg/

lifetime. When adequate and

appropriate pharmacokinetic or

metabolic data are available, these data

are sometimes used to estimate internal

dose. In the case of MC, metabolic data

have been gathered and

pharmacokinetic models have been used

by various investigators to estimate

target tissue doses for MC.

Some commenters [Exs. 19–28, 19–57]

had expressed concern that OSHA used

a surface area correction factor in its risk

assessment in the NPRM. In fact, in the

NPRM, OSHA extrapolated from mice to

humans based on body weight rather

than surface area. However, the Agency

requested comment on which species

conversion factor would be appropriate

to use in OSHA’s final risk assessment

and whether incorporation of

pharmacokinetic information should

influence the choice of the conversion

factor. Two commenters [Exs. 19–83,

23–21] referred to the interagency

document on interspecies scaling which

ultimately recommends BW3/4 as the

appropriate extrapolation factor in the

absence of appropriate pharmacokinetic

information, although the document

also indicates that extrapolation factors

based on BW or BW2/3 would also be

consistent with the available data (EPA

Draft Report: ‘‘A cross-species scaling

factor for carcinogen risk assessment

based on equivalence of mg/kg3/4/day.’’

57 FR 24152, June 5, 1992).

There was also considerable

discussion as to whether it was

appropriate to apply an extrapolation

factor such as BW3/4 or BW2/3 in

addition to PBPK modeling of dose, to

account for pharmacodynamic

differences between species (such as

differences in DNA repair rates and

other non-metabolic differences in

interspecies susceptibility to an agent).

The EPA applied the BW2/3

extrapolation factor after incorporation

of the PBPK data for MC in their 1987

draft update of the MC risk assessment.

In their previous risk assessment, which

did not incorporate PBPK data, EPA also

used BW2/3 as the extrapolation factor.

Since OSHA has preferred the BW

extrapolation in other chemical-specific

risk assessments and has used BW as

the extrapolation factor in its best

estimate of risk in the NPRM for MC,

OSHA agrees with Dr. Lorenz

Rhomberg’s assessment [Ex. 28] that

OSHA should continue to use body

weight as its extrapolation factor in its

final MC risk assessment. Thus, OSHA’s

risk estimate does not make any

allowance for possible

pharmacodynamic differences between

rodents and humans, or within the

diverse human population.

3. Pharmacokinetic Modeling of Dose

OSHA discussed issues relating to the

use of pharmacokinetic data in its

NPRM. These issues were further

explored during the hearings and in prehearing and post-hearing comments. In

response to the ANPR [51 FR 42257],

Dow Chemical submitted

documentation of a physiologicallybased pharmacokinetic model (PBPK)

[Exs. 8–14d and 10–6a], developed for

MC by Reitz and Anderson, which

described the rates of metabolism of the

MFO and GST pathways and the levels

of MC and its metabolites in various

tissues of rats, mice, hamsters and

humans. This model was presented as a

basis for converting an applied

(external) dose of MC to an internal dose

of active metabolite in the lung and liver

in various species under various MC

exposure scenarios. Since publication of

the NPRM, several parties have

submitted pharmacokinetic models or

comments on modeling to the

rulemaking record. These are discussed

in detail below.

a. General issues in PBPK modeling.

Physiologically-based pharmacokinetic

modeling can be a useful tool for

describing the distribution, metabolism

and elimination of a compound of

interest under conditions of actual

exposure and, if data are adequate, can

allow extrapolation across dose levels,

across routes of exposure and across

species. One limitation of using PBPK

modeling is a widespread lack of

adequate and appropriate physiological

and metabolic data to define the model.

In particular, difficulties arise in

attempting to define a model for which

the mechanism of carcinogenesis has

not been established, when it is unclear

whether there would be tumor site

concordance across species, and when

the metabolic pathway(s) responsible for

carcinogenesis has not been determined.

The concentration of a chemical in air

or the total inhaled dose (mg/kg/d) may

not be the most biologically relevant

dose to use in comparing toxicity across

doses or across species. The dose

measure that would be most useful in

risk assessment is the dose to the target

tissue of the chemical or metabolite that

is known to directly cause the toxic

effect. Generally, this quantity is

unknown in almost every case because

the proximate carcinogenic moiety is

usually highly reactive, and therefore

very difficult to measure in biological

systems. Since the proximate toxic agent

is unlikely to be a quantity readily

measured in the laboratory, it is

sometimes desirable to use dose

surrogate concentrations, calculated by

methods such as PBPK modeling, to

obtain a more direct estimate of a doseresponse relationship. Examples of dose

surrogates that may be relevant to the

toxic mechanism of action of a chemical

are peak concentrations of a particular

metabolite at a target tissue site, area

under the concentration-time curve of a

metabolite at a target site, and blood

concentration of the parent chemical or

a relevant metabolite.

If the dose surrogate chosen is directly

relevant to the mechanism of action of

a chemical, there is greater confidence

in the risk estimates generated using the

dose surrogate than those generated

using total inhaled concentration. If the

mechanism of action of a chemical is

uncertain, and therefore the relevance of

the dose surrogate to carcinogenicity is

in question, there is proportionally less

confidence in the predicted risks

estimated using that dose surrogate.

Risk estimates from PBPK modeling can

also be limited by the quality and

quantity of available metabolic data.

Since risk estimates are directly

dependent upon the dose or dose

surrogate chosen, reliable measures of

all relevant physiological parameters

and all relevant metabolic pathways in

all target tissues from all species under

investigation are critical. In addition,

measures of the uncertainty and interindividual variability of these

parameters must be generated.

In its NPRM, OSHA solicited

information on the appropriateness of

physiologically- based pharmacokinetic

modeling for the MC risk assessment.

Specifically, OSHA asked the following

questions:

(a) How can pharmacokinetics be best

applied to the risk assessment of MC

and what are the current limitations of

this approach in the quantitation of

health risks? What weight should OSHA

give to pharmacokinetic data in its risk

assessments and why?

(b) Given that five separate risk

assessments have utilized the

pharmacokinetic models for MC in five
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1533

different ways (resulting in from 0 to

170 fold reduction in the final risk when

compared with assessments not

utilizing pharmacokinetic data), how

can OSHA best utilize the existing

pharmacokinetic data and still be

certain of protecting worker health?

(c) Which parameters in the

pharmacokinetic models are most

sensitive to errors in measurement or

estimation? Can an increased database

reduce the uncertainties in these

parameters?

(d) How much confidence can be

placed in the human in vitro MC

metabolism data, especially that for lung

tissue? How will human variability in

these parameters affect the extrapolation

of risk from rodent species?

(e) Are there any studies in progress

which attempt to verify the predictive

ability of the model in vivo, (e.g., by

giving doses in a lifetime bioassay

which will produce cancer in a species

other than the B6C3F1 mouse and the

F344 and Sprague-Dawley rats)?

(f) OSHA recognizes the large areas of

uncertainty which exist in applied dose

risk assessment procedures. If

pharmacokinetic modeling reduces

these uncertainties, can the reduction in

uncertainty be quantified? Are

additional uncertainties introduced into

the risk assessment process by the use

of pharmacokinetic models?

(g) By using the pharmacokinetic

models in the risk assessment process,

one is making an assumption about the

carcinogenic mechanism of action of

methylene chloride. Are there any new

studies on the carcinogenic mechanism

of action of MC which would support or

refute this assumption?

(h) If the carcinogenic process is, in

fact, not the result of the metabolite(s)

from the GST pathway alone, but is due

to a combination of metabolites or a

combination of the parent compound

plus the metabolites, how would the

pharmacokinetic model and the

subsequent risk assessments be affected?

Can these effects be quantified?

(i) One of the assumptions made in

the pharmacokinetic model is that the

target tissues for MC are liver and lung.

Can this model predict cancer

incidences at other sites? If not, is there

a way to factor in consideration of

possible MC-induced human cancers at

other sites than liver and lung?

(j) OSHA solicits information

supporting or refuting interspecies

allometric scaling based on body weight

or body surface area.

OSHA reviewed comments and

testimony on these issues from an

expert witness [Ex. 25–E];

representatives of other U.S.

government agencies, including NIOSH

[Exs. 19–46, 41], EPA [Exs. 25–D, 28],

CPSC [Ex. 25–I] and U.S. Navy [Exs. 19–

59, 96]; the State of California [Ex. 19–

17]; the Halogenated Solvents Industry

Alliance (HSIA) [Exs. 19–45, 19–83,

105]; and the UAW [Exs. 19–22, 23–13,

61]. Comments and testimony from the

expert witness, the other government

agencies and the Halogenated Solvents

Industry Alliance generally reflected the

opinion that the pharmacokinetic

information was sufficiently developed

in the case of MC to justify its use in

estimating human cancer risks. The

predominant view among these

commenters and hearing participants

was that the data collected for MC and

the pharmacokinetic model developed

by Reitz and Andersen adequately

represented the metabolism of MC in

mice. Many commenters also believed

that it was reasonable to conclude that

the lung and liver tumor incidence in

the B6C3F1 mice was the result of the

GST metabolite. As described in further

detail below, OSHA generally agrees

that the PBPK approach is reasonable to

assess cancer risks of MC. In fact, the

Agency has evaluated the submitted

PBPK models, determined that there

were several deficiences in each of those

models, and improved upon those in its

final quantification of risks.

One rulemaking participant was

strongly opposed to using

pharmacokinetic data in the MC risk

assessment. Dr. Franklin Mirer [Ex. 61],

representing the UAW, stated:

The pharmacokinetic model advanced for

methylene chloride carcinogenesis is

incorrect and should not be used for

quantitative risk assessment.

Dr. Mirer was particularly concerned

that the PBPK model ignored the rat

cancer bioassay data and that the model

was based on a ‘‘mechanistic

hypothesis.’’

Dr. Mirer reiterated his concerns in

response to the October 24, 1995

reopening of the rulemaking record [Ex.

126–31], stating,

The simple message is that OSHA should

give no additional weight to the

pharmacokinetic argument. For OSHA to give

the argument any additional weight would

mean that OSHA was ignoring a substantial

body of evidence regarding carcinogenicity of

methylene chloride in additional animal

species.

Dr. Mirer continued,

The pharmacokinetic hypothesis is

unconvincing even as an explanation of the

differences in lung and liver tumors in mice

and rats.

OSHA shares Dr. Mirer’s concerns

that the mechanism of carcinogenicity

for MC has not been clearly established

and that using pharmacokinetic

modeling may lead to risk estimates

which ignore the rat tumor data. The

Agency notes that it has used the NTP

rat data in its hazard identification for

MC. OSHA has also determined,

however, that the mouse data represent

the strongest data set on which to base

a quantitative risk assessment, and notes

that risk estimates based on the rat data

(without PBPK-based adjustment of

dose) are similar to OSHA’s final risk

estimates using mouse data and a PBPK

analysis.

The determination that the mouse

data set was the strongest on which to

base a quantitative risk assessment was

made without regard to the availability

of information on pharmacokinetics.

Incorporating pharmacokinetic

modeling into the risk assessment for

MC is a logical extension of OSHA’s risk

assessment decisionmaking process and

reflects the Agency’s review of the

totality of data on tumor incidence,

metabolism and mechanism of action.

The extensive data base on MC

metabolism and mechanism of action,

although by no means complete, was the

determining factor in the decision to

incorporate pharmacokinetics into its

final risk assessment. The Agency is

aware of very few chemicals of

regulatory interest for which the

available data could match this body of

information. The specific criteria

utilized by the Agency in making this

determination are enumerated below.

Comments on the specific issues

enumerated above are discussed under

the appropriate topics in the sections

that follow.

b. Criteria for using PBPK in

quantitative risk assessment. OSHA

evaluated several criteria before

deciding to use PBPK analysis in its

final quantitative risk assessment for

MC. In future rulemakings in which the

use of pharmacokinetic information in

risk assessment is at issue, it will be

necessary to evaluate at least the criteria

described below before reaching

conclusions, in order to avoid adopting

an alternative hypothesis that is less

(rather than more) reflective of the true

situation than the more generic applieddose assumption. Further, it may be

appropriate to evaluate additional

criteria in some cases, depending on the

metabolism and mechanism of action of

the chemical. The criteria which OSHA

considered before incorporation of

PBPK in the final risk estimate for MC

were:

(1) The predominant and all relevant

minor metabolic pathways must be well

described in several species, including

humans. (Two metabolic pathways are

responsible for the metabolism of MC in

humans, mice, rats and hamsters).
1534 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

(2) The metabolism must be

adequately modeled (Only two

pathways are responsible for the

metabolism of MC as compared to

several potential routes of metabolism

for other compounds, such as benzene

and the dioxins. This simplified the

resulting PBPK models).

(3) There must be strong empirical

support for the putative mechanism of

carcinogenesis (e.g., genotoxicity) and

the proposed mechanism must be

plausible.

(4) The kinetics for the putative

carcinogenic metabolic pathway must

have been measured in test animals in

vivo and in vitro and in corresponding

human tissues (lung and liver) at least

in vitro, although in vivo human data

would be the most definitive.

(5) The putative carcinogenic

metabolic pathway must contain

metabolites which are plausible

proximate carcinogens (for example,

reactive compounds such as

formaldehyde or Schloromethylglutathione).

(6) The contribution to carcinogenesis

via other pathways must be adequately

modeled or ruled out as a factor. For

example, there must be a reasonable

analysis of why reactive metabolites

formed in a second pathway would not

contribute to carcinogenesis (e.g., formyl

chloride produced via the MFO

pathway is likely to be too short-lived

to be important in MC carcinogenesis).

(7) The dose surrogate in target tissues

(lung and liver in the case of MC) used

in PBPK modeling must correlate with

tumor responses experienced by test

animals (mice, rats and hamsters).

(8) All biochemical parameters

specific to the compound, such as

blood:air partition coefficients, must

have been experimentally and

reproducibly measured. This must be

true especially for those parameters to

which the PBPK model is most

sensitive.

(9) The model must adequately

describe experimentally measured

physiological and biochemical

phenomena.

(10) The PBPK models must have

been validated with data (including

human data) which were not used to

construct the models.

(11) There must be sufficient data,

especially data from a broadly

representative sample of humans, to

assess uncertainty and variability in the

PBPK modeling.

In the case of MC, to a large extent

these criteria were met. This made

evaluation of existing PBPK models and

further development of the modeling

strategy a viable option. Therefore, the

Agency evaluated existing PBPK models

and then contracted with Drs. Andrew

Smith, Frederic Bois, and Dale Hattis to

help OSHA improve on the MC PBPK

model in the record, which would

extend the application of modeling

techniques beyond those models which

had been submitted to the Agency and

incorporate all of the data available and

appropriate for quantitative analysis in

the record. OSHA’s evaluation of

existing PBPK models, the development

of a modified MC PBPK analysis, and

OSHA’s final risk assessment are

described later in this document.

c. Choice of GST metabolic pathway

as dose surrogate. The choice of ‘‘dose

surrogate’’ for the MC PBPK model is a

critical factor in estimating PBPK-based

risks. The dose or ‘‘dose surrogate’’ used

in a risk assessment should be a

biologically-important quantity, should

have a plausible mechanism of action at

the target tissue and should correlate

with the response of interest. The

simplest choice of dose is the applied

dose or ambient concentration of the

contaminant measured as ppm or as the

inhaled quantity in mg/kg/day (as used

in the Preliminary Quantitative Risk

Assessment in the NPRM). Such

quantities have the advantage of being

easily and directly measurable during

the bioassay. Other meaningful dose

surrogates could include the

concentration of parent compound in

the target organ, the concentration of

specific metabolites in the target organ,

the area under the time-concentration

curve (integrated dose) of each

metabolite and the parent compound, or

peak blood or target organ levels of each

metabolite and parent compound. These

quantities are not as easily measured.

Often only indirect measurements or

computer modeling of these dose

surrogates are available.

In the PBPK model developed by

Reitz et al. [Ex. 7–225], the dose

surrogates that correlated with the

tumor response were the parent

compound (MC) concentration and the

amount of GST metabolites formed in

the lung and liver. Reitz et al.

discounted the parent compound as the

dose surrogate because MC is not a

chemically reactive compound and

direct-acting carcinogens (and

metabolites of carcinogenic compounds)

are generally hypothesized to be

reactive (usually, electrophilic). They

also discounted the parent compound as

a relevant dose surrogate because parent

MC concentration was higher in the rat

blood than in the mouse for any dose of

MC, while the cancer response of the

mouse was greater than the rat. If parent

MC were the critical compound for MC

carcinogenesis, one would expect the

cancer response across species to

correlate with blood levels of the

compound.

(1) Metabolism via GST versus MFO

pathway. Human metabolism of MC has

been well studied. One clear finding

from the human metabolic studies is

that humans metabolize MC by both the

MFO and GST pathways, as do mice,

rats, and hamsters. Although human

metabolism via the MFO pathway has

been measured in vivo as well as in

vitro, human MC metabolism via the

GST pathway has been measured only

in vitro. Metabolic data on the human

GST pathway have been collected from

several liver samples and one pooled

lung sample (combined samples from

four human subjects). However, it has

not been possible to measure human

GST metabolism of MC in vivo.

Reitz et al. measured the metabolic

constants (Km and Vmax) in vitro for the

GST and the MFO metabolic pathways.

Enzyme activities were determined by

measuring the conversion of 36Cllabeled MC to water-soluble products.

Metabolic constants were then

compared across species (mouse, rat,

hamster and human). In the liver, the

MFO activity was highest in the

hamster, followed by the mouse, human

and rat. Human values were much more

variable than those of the rodent

species. Human Vmax for the liver MFO

pathway ranged approximately an order

of magnitude and human Km varied

approximately three-fold. GST activity

in the liver was determined for mouse

and human tissues only. Mouse liver

had approximately 18-fold greater

activity (Vmax) than human liver, but the

human tissue had about a three-fold

greater affinity constant (Km) for MC

than the mouse.

In the lung, the activity of the MFO

and GST enzymes was determined for a

single substrate concentration. For the

MFO pathway, mouse tissue had the

highest activity, followed by hamster

and rat. No MFO activity specific for

MC was detected in the human lung

tissue, although other MFO isozymes

were demonstrated to be active in the

tissue. For the GST pathway in lung,

mouse tissue was the most active,

followed by rat and human. No GST

activity was detected in the hamster

lung.

In humans, the MFO pathway has

been measured in vivo as well as in vitro

[Ex. 7–225]. Human in vivo

experimentation was conducted by

several investigators. Metabolism via the

MFO pathway is relatively easy to

measure because the end product is

carbon monoxide [Ex. 7–24]. The

metabolic rates measured in vitro were

not similar to those measured in vivo

after exposure to known concentrations
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1535

of MC, which means that in vitro

measurements in human tissue (in

particular for the GST pathway for

which there are no human in vivo data)

could not be used directly as a measure

of metabolism. Human in vivo and in

vitro MFO metabolism data were

important in developing the

pharmacokinetic models because they

provided human data for MC-specific

metabolism which could be used to help

validate the models. Unfortunately, the

modeling of the putative critical

pathway for carcinogenesis (the GST

pathway) could not be validated for

humans. This is a weakness in the PBPK

modeling for MC shared by all of the

models, including OSHA’s final PBPK

analysis.

In the PBPK models submitted to

OSHA, the human rate of metabolism of

MC, particularly via the GST pathway,

was based on data gathered from four

liver samples and one pooled lung

sample. Although the liver metabolic

data were of the same magnitude as

those collected by Green et al., Green’s

data were not considered in Reitz’s

model and the variability of those data

was not assessed. Therefore, the

estimates of the dose surrogates in

Reitz’s model were based on the average

of four liver samples. Four liver samples

are not nearly enough data to

confidently estimate and account for

human variability. Considerations of the

variability and uncertainty of these data

are discussed in more detail later in this

document.

The human lung data were even more

limited. Four human lung samples were

pooled to provide a single data point.

This lack of lung tissue data is

particularly critical in PBPK modeling

when calculating the ratios of A1 and

A2 (the distribution of metabolism

between liver and lung tissue in

humans). Errors in calculating these

ratios will significantly affect the final

risk estimates, as discussed by Mr.

Harvey Clewell for the U.S. Navy [Ex.

96].

HSIA submitted additional data on

the human metabolism of MC in the

form of a study of GST metabolism in

human liver samples conducted by

Bogaards et al. [Ex. 127–16]. The human

GST liver metabolism data collected in

this study were not directly comparable

to the data collected by Reitz or Green,

becausethe Bogaards data were

measured using a colorimetric method

which was not as sensitive as the 36Cl

method. Under contract to OSHA, Dr.

Andrew Smith and Dr. Frederic Bois

compared the data from different

laboratories and collected under

different methodologies and developed

a correction factor across methodologies

so that they could use all of the human

metabolic data available in OSHA’s final

PBPK model [Ex. 128]. There are now

over 30 data points for human liver in

vitro metabolism by the GST pathway

and 5 human lung data points (the

additional lung data points were

reported in Green et al., Ex. 124A).

OSHA determined that it was important

to use as much of the available human

data in its PBPK model for MC as

scientifically justifiable. These data

were used to estimate the variability and

uncertainty surrounding the measures of

human GST metabolism. Although the

methodologies differed across studies,

OSHA has adjusted and incorporated all

of the available human data in its PBPK

model.

(2) Parallelogram approach. When the

metabolic rates for the MFO pathway

measured in vivo and in vitro within

each species were compared, it was

determined that those rates were not

equivalent. This meant that, unlike the

case for some other chemical

compounds, the in vitro GST data could

not substitute directly for an in vivo

measurement of metabolism. Reitz and

Andersen [Ex. 7–225] suggested a

‘‘parallelogram’’ approach to the

problem of non-comparability of in vitro

and in vivo rates. This approach makes

the assumption that the ratio of in vivo

to in vitro measurements is roughly

comparable across species (including

humans). They measured metabolic

rates of both pathways in vitro and in

vivo in rodents and then used the

average ratio of the in vitro to in vivo

metabolic rate in three rodent species to

extrapolate from in vitro rates in

humans [Ex. 7–225] to an estimated in

vivo value.

BILLING CODE 4510–26–P

BILLING CODE 4510–26–C

Assumption

or

human (in 

:

,

rodent (in vitro)

rodent (in vivo)

human (in vitro)

human (in vivo)

 human (in vivo) = rodent (in vivo) vitro) 

rodent (in vitro)

=

×
1536 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

Ron Brown [Ex. 25–E], an expert

witness for OSHA, was concerned that

‘‘...the methodology used to extrapolate

the in vitro data to the in vivo state is

problematic and the accuracy of the

human in vitro measurement of GST

activity toward MC is uncertain.’’ This

may be due to the small sample size,

variability in the laboratory analysis or

inadequacy of the in vitro model. OSHA

believes that this is a critical point of

uncertainty in using the PBPK model for

risk assessment. The Agency also notes

that in the risk assessments using PBPK

models submitted during the MC

rulemaking, none used the

parallelogram approach as the basis of

determining human in vivo metabolic

rates. Instead, allometric scaling was

used to estimate human values. OSHA

has conducted risk assessments using

both the allometric approach (OSHA’s

final risk estimates) and the

parallelogram approach (OSHA’s

alternative analysis). The Agency did

this in order to determine what the risk

estimates would be if all possible

quantitative data were used to the

fullest extent, regardless of the

uncertainties in the data.

OSHA agrees that evidence presented

in the record generally supports the GST

pathway as a plausible carcinogenic

mechanism of action of MC. The Agency

remains concerned, however, that sole

reliance on the GST pathway may show

insufficient consideration for potential

contributions of the parent compound

and/or metabolites of the MFO pathway

to the carcinogenesis of MC. It is clear

that ambient MC concentration is doserelated to tumor response. It has not

been shown with any certainty that MC

GST metabolites are related to tumor

response across species. Thus, there is

greater confidence that the lifetime

bioassays predict MC carcinogenicity in

humans than there is that cancer

occurred through a specific mechanism,

and even less confidence that the

metabolic rates measured in vitro

accurately measure differences in

species that correlate to tumor

development. This is particularly true

for lung metabolism where only one

pooled and five individual human

samples were analyzed.

Notwithstanding the uncertainties

described above, the Agency believes

that the hypothesis that GST is the

carcinogenic pathway presents a

plausible mechanism of action for MC

and is sufficiently well-developed to

warrant the use of PBPK modeling of the

GST pathway as the dose surrogate of

choice in the quantitative risk

assessment for MC.

d. Structure of the MC PBPK model.

The PBPK models described below are

based on the model originally submitted

by Dr. Reitz on behalf of HSIA in 1992

[Ex. 7–225]. Over the years since the

first submission of a MC PBPK model to

OSHA, significant improvements have

been made in model structure and in the

data collected for PBPK modeling,

especially in how the uncertainty and

variability in the data are treated. The

general structure of the models

submitted to OSHA are described

below, followed by a description of the

parameters used in the various models.

Next follows a description of how the

variability, uncertainty, and sensitivity

of the models to uncertainty have been

assessed, noting the improvements that

have been made in developing methods

to handle these issues. This is followed

by a comparison of the risk estimates

generated by these models. Finally,

OSHA’s final risk assessment is

described. This risk assessment

incorporates lessons learned from

previous models and uses all of the

available, appropriate, quantifiable data

in a Bayesian approach to modeling the

dose metric for MC.

In the PBPK model submitted by Dr.

Reitz of HSIA [Ex. 7–225], a series of

differential equations was used to model

the mass balance of MC and its

metabolites in five physiologicallydefined compartments, including the

lung, liver, richly perfused tissue,

slowly perfused tissue, and fat.

Metabolism via the MFO pathway was

described by saturable MichaelisMenten kinetic equations and GST

metabolism was modeled using firstorder nonsaturable kinetics. With the

exception of the PBPK model sumitted

by ICI [Ex. 14A], all of the PBPK models

submitted to the Agency followed these

assumptions regarding the metabolism

of MC. The rate constants for the

metabolic equations were estimated

based on measurements of the partition

coefficients, allometric approximations

of the physiological constants (e.g., lung

weight), and estimations (i.e., allometric

scaling of rodent data, estimations made

using the parallelogram approach, etc.)

of the biochemical constants (e.g.,

Michaelis-Menten constants).

NIOSH presented a PBPK model in

1993 [Ex. 94], also structurally based on

the Reitz-Andersen model, but with

modifications to the human breathing

rate and cardiac output to account for

uptake of MC in physically active

workers, rather than at-rest humans or

humans involved in light activity, and

including an analysis of the variability

of the human metabolic parameters.

Specifically, NIOSH compared estimates

derived from the arithmetic average of

the human GST metabolism data with

the individual human liver data points

to estimate the uncertainty in an

individual’s risk of cancer from

occupational MC exposure. This

approach began to incorporate some

necessary features, such as a special

focus on physically active workers and

the variability of human metabolic

parameters, but did not attempt to

quantify the uncertainty and variability

of the individual parameters and their

contribution to the uncertainty

associated with the PBPK model.

Mr. Harvey Clewell, representing the

U.S. Navy, also submitted several PBPK

models to OSHA. In his initial

submission (1992), Mr. Clewell

modified an existing PBPK model [Ex.

7–125] to include more recent data on

the mouse blood/air partition coefficient

[Ex. 19–59]. In a second PBPK model, he

‘‘started from scratch’’ to construct a

model based on data derived from

sources independent of the previous

work of Reitz and Andersen [Ex. 23–14],

which was described in Mr. Clewell’s

testimony [Tr. 2361,10/15/92]. This

model was structurally similar to the

model presented by HSIA with the

following exceptions: it featured three

lumped compartments (slowly perfused,

moderately perfused and rapidly

perfused) based on tissue kinetic

constants rather than the earlier two

lumped compartment models based on

tissue blood volumes; and the mouse

blood/air partition coefficient was

corrected to 19.4 instead of the earlier

8.29 on the basis of more recent data. A

third model submitted by Mr. Clewell

was identical in structure to the Reitz/

Andersen model, but incorporated the

more recent experimental data on the

partition coefficients and the more

recent mouse metabolism data [Ex. 96].

OSHA used Mr. Clewell’s third model

in its comparison of PBPK-derived risk

estimates because of its similarity in

structure to the original Reitz model and

its incorporation of the most recent

experimental data.

In his third model, Clewell either

derived probability distributions for

each parameter from the literature or

estimated distributions for those

parameters for which data were not

available, and conducted Monte Carlo

simulations to derive output

distributions for the dose surrogates.

These distributions of dose surrogates

were then used to derive four risk

estimates: the doses input into the

multistage dose-response analysis of the

tumor bioassay were derived either from

the mean or from the 95th percentile of

the output distribution of PBPK

parameters, and these in turn were

coupled with the either the MLE or the

UCL of the distribution of possible

values of the multistage model
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1537

parameters. This analysis was an

advance over that of previous models

because it took into account some of the

uncertainty and variability known to be

associated with the data used in the

PBPK model.

After evaluating these submitted

models, OSHA determined that

Clewell’s model provided the best

prototype on which to base its final

PBPK modeling approach for MC.

Therefore, the Agency worked with Drs.

Smith and Bois to review Clewell’s

model and with the assistance of Dr.

Hattis, to develop a refined PBPK

modeling approach with a more

sophisticated analysis of variability and

uncertainty (and other refinements as

described below). In this way the

Agency developed an approach which

would incorporate what was learned in

the development of earlier PBPK models

and make use of as much of the

available physiological and metabolic

data in the record as possible. Clewell’s

model was chosen for comparison,

because this was the only model to

provide a systematic analysis of the

uncertainty, variability and sensitivity

of the model using Monte Carlo

techniques. OSHA’s final risk

assessment approach is described in

greater detail below.

e. Choice of parameters for PBPK

modeling. The definitions of the

parameters used in the models

described above are contained in Table

VI–2. Note that not all parameters were

used in each model and slightly

different variable names were used by

different investigators. For example,

OSHA’s final analysis contains a bone

marrow compartment, while Clewell’s

model did not. OSHA refers to the blood

flow for poorly (or slowly) perfused

tissues as ‘‘QppC,’’ while Clewell used

‘‘QSC.’’

TABLE VI–2.—DEFINITIONS OF PHARMACOKINETIC PARAMETERS

Parameter (units) Definition

BW (kg) ............................................................... Body weight in kg. Human body weights were assumed to be 70-kg (Reference Man). Mouse

body weights were the average weight of mice in the NTP bioassay.

QPC unscaled (1/hr, 1 kg BW) ........................... Breathing rate. QPC = QP(1/hr)/BW.75 where QP = alveolar ventilation rate. Human QP was

based on rate of 9.6 m3/8-hr (converted 1/hr and adjusted to alveolar ventilation (= 0.70 total

ventilation) except in NIOSH and OSHA-modified models. Mouse QP = (24.3 1/hr)(0.70 alveolar/total).

QCC unscaled (1/hr, 1 kg BW) ........................... Cardiac output. QCC = QC(1/hr)/BW.75 where QC = cardiac output in 1/hr. Reitz set QC = QP.

Clewell and NIOSH based human QC on Astrand et al. [Ex. 7–120] data on cardiac output

and breathing rate vs. workload.

VPR (ratio, unitless) ............................................ Alveolar ventilation/perfusion ratio.

Blood flows to tissues

QGC or QgiC (fraction of cardiac output) ........... Blood flow to gastrointestinal tract as a fraction of cardiac output. QGC = QG/QC.

QLC or QliC (fraction of cardiac output) ............. Blood flow to liver as a fraction of cardiac output. QLC = QL/QC.

QFC or QfatC (fraction of cardiac output) .......... Blood flow to fat as a fraction of cardiac output. QFC = QF/QC.

QSC or QppC (fraction of cardiac output) .......... Blood flow to slowly (or poorly) perfused tissues as a fraction of cardiac output. QSC = QS/

QC.

QRC or QwpC (fraction of cardiac output) ......... Blood flow to rapidly (or well) perfused tissues as a fraction of cardiac output. QRC = QR/QC.

QmarC (fraction of cardiac output) ..................... Blood flow to bone marrow as a fraction of cardiac output.

Tissue volumes

VGC or VgiC (fraction of body weight) ............... Volume of GI tract as a fraction of body weight. VGC = VG/BW.

VLC or VliC (fraction of body weight) ................. Volume of liver as a fraction of body weight. VLC = VL/BW.

VFC or VfatC (fraction of body weight) .............. Volume of fat as a fraction of body weight. VFC = VF/BW.

VSC or VppC (fraction of body weight) .............. Volume of slowly (or poorly) perfused tissues as a fraction of body weight. VSC = VS/BW.

VRC or VwpP (fraction of body weight) ............. Volume of rapidly (or well) perfused tissues as a fraction of body weight. VRC = VR/BW.

VluC (fraction of body weight) ............................ Volume of lung as a fraction of body weight.

VmarC (fraction of body weight) ......................... Volume of bone marrow as a fraction of body weight.

Partition coefficients

PB or Pblo ........................................................... Blood/air partition coefficient.

PG or Pgi ............................................................ GI tract/blood partition coefficient (GI tract/air divided by PB).

PL or Pli .............................................................. Liver/blood partition coefficient (Liver/air divided by PB).

PF or Pfat ............................................................ Fat/blood partition coefficient (Fat/air divided by PB).

PS or Ppp ........................................................... Slowly (or poorly) perfused tissue/blood partition coefficient (Slowly perfused tissue/air divided

by PB).

PR or Pwp ........................................................... Rapidly (or well) perfused tissue/blood partition coefficient (Rapidly perfused tissue/air divided

by PB).

PLU or Plu .......................................................... Lung/blood partition coefficient (Lung/air divided by PB).

Pmar .................................................................... Bone marrow:air partition coefficient.

Metabolic parameters

VMAXC unscaled (mg/hr, 1 kg animal) .............. MFO pathway Michaelis-Menten maximum velocity for MC metabolism. VMAXC = VMAX (mg/

hr)/BW.75.

KM (mg/l) ............................................................ MFO pathway Michaelis-Menten affinity constant for MC metabolism.
1538 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

TABLE VI–2.—DEFINITIONS OF PHARMACOKINETIC PARAMETERS—Continued

Parameter (units) Definition

KFC, unscaled, (/hr, 1 kg animal) ....................... GST pathway 1st order kinetic rate constant for MC metabolism. KFC = KF (/hr)(BW.25).

A1 (ratio) ............................................................. Ratio of distribution of MFO pathway MC metabolism between lung and liver. A1 =

VMAXC(lung)/VMAXC(liver).

A2 (ratio) ............................................................. Ratio of distribution of GST pathway MC metabolism between lung and liver. A2 = KFC(lung)/

KFC(liver).

B1 (ratio) ............................................................. Ratio of lung and liver tissue content of microsomal protein.

B2 (ratio) ............................................................. Ratio of lung and liver tissue content of cytosolic protein.

Sp—Kf ................................................................. Allometric scaling power for body weight scaling of KFC from mice to humans.

The MC physiologically-based

pharmacokinetic (PBPK) models

discussed here contain the following

types of parameters as defined above:

body weight, breathing rate, cardiac

output, blood flows to tissue

compartments (as a fraction of the

cardiac output), volumes of tissue

compartments (as a fraction of body

weight), partition coefficients, the

metabolic parameters (the MichaelisMenten parameters, Vmax and Km, for

the MFO pathway and the 1st-order rate

constant, Kf, for the GST pathway) and

the ratio of the pathway-specific

metabolic capacity between the major

metabolic sites (lung and liver).

Differences in model structure (such as

choice of lumped tissue compartments)

and differences in sources of data for

individual parameters lead to

differences in the parameter values used

in different models.

The parameter values (point

estimates) used in the PBPK models

reviewed by OSHA are presented in

Table VI–3. The parameter distributions

used by OSHA in its analysis are

presented later.

As far as OSHA could determine, the

parameters chosen by HSIA were those

presented in Reitz’s 1989 paper [Ex. 21–

53] except that OSHA’s preferred values

for breathing rates (based on 9.6 m3/

workday) and 8-hour human exposures

were used. The model submitted by

NIOSH used the parameters and

computer code from the Reitz model,

except for the human breathing rate,

human cardiac output and human

metabolic parameters. The parameters

used by Clewell were summarized in his

post-hearing submission [Ex. 96], which

included more recent experimental data

for the partition coefficients and mouse

metabolic parameters and a different

scaling for human cardiac output.

TABLE VI–3.—PARAMETERS USED IN PBPK MODELS REVIEWED BY OSHA

Model Clewell [Ex. 96] NIOSH [Ex. 23–18] HSIA [Ex. 19–45]

Parameter Mouse Human Mouse Human Mouse Human

BW (kg) ................................................................. 0.0345 70 0.0345 70 0.0345 70

QPC, unscaled alveolar ventilation (1/hr, 1 kg

animal) ............................................................... 29.0 35 29.0 43.1 29.0 35.0

QCC, unscaled cardiac output (1/hr, 1 kg animal) 16.5 18 29.0 20.9 29.0 35.0

QGC a, flow to GI tract (fraction of cardiac output) 0.165 0.195 0.0 0.0 0.0 0.0

QLC a, flow to liver (fraction of cardiac output) ..... 0.035 0.07 0.24 0.2093 0.24 0.24

QFC a, flow to fat (fraction of cardiac output) ....... 0.03 0.05 0.05 0.040 0.05 0.05

QSC a, flow to slowly perfused tissues (fraction of

cardiac output) ................................................... 0.25 0.24 0.19 0.4319 0.19 0.19

QRC a, flow to rapidly perfused tissues (fraction

of cardiac output) .............................................. 0.52 0.445 0.52 0.3188 0.52 0.52

VGC, GI volume (fraction of BW) ......................... 0.031 0.045 0.0 0.0 0.0 0.0

VLC, liver volume (fraction of BW) ....................... 0.046 0.023 0.04 0.0314 0.04 0.0314

VFC, fat volume (fraction of BW) ......................... 0.100 0.16 0.07 0.231 0.07 0.231

VSC, slowly perfused tissue volume (fraction of

BW) .................................................................... 0.513 0.48 0.75 0.621 0.75 0.621

VRC, rapidly perfused tissue volume (fraction of

BW) .................................................................... 0.041 0.033 0.05 0.0371 0.05 0.0371

VLUC, lung volume (fraction of BW) .................... 0.008 0.006 0.012 0.011 0.012 0.011

PB, blood/air part. coeff ........................................ 23.0 12.9 8.29 9.7 8.29 9.7

PG, GI tract/air part. coeff .................................... 0.52 0.93 NA NA NA NA

PL, liver/blood part. coeff ...................................... 1.6 2.9 1.71 1.46 1.71 1.46

PF, fat/blood part. coeff ........................................ 5.1 9.1 14.5 12.4 14.5 12.4

PS, slowly perf./blood part. coeff .......................... 0.44 0.78 0.96 0.82 0.96 0.82

PR, rapidly perf./blood part. coeff ......................... 0.52 0.93 1.71 1.46 1.71 1.46

PLU, lung/blood part. coeff ................................... 0.46 0.82 1.71 1.46 1.71 1.46

VMAXC mg/hr, 1 kg animal (unscaled) ................ 13.4 5.0 13.2 3.98

1.15

9.81

4.71

13.2 4.9

KM (mg/L) ............................................................. 1.35 0.4 0.396 0.72

0.55

0.26

0.79

0.396 0.580
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1539

TABLE VI–3.—PARAMETERS USED IN PBPK MODELS REVIEWED BY OSHA—Continued

Model Clewell [Ex. 96] NIOSH [Ex. 23–18] HSIA [Ex. 19–45]

Parameter Mouse Human Mouse Human Mouse Human

KFC /hr, 1 kg animal (unscaled) ........................... 1.5 1.5 1.73 1.56

0.00

1.62

1.79

1.73 1.24

A1 (Vmaxc(lung)/Vmaxc(liver)) ............................. 0.41 0.015 0.416 0.00143 0.416 0.00143

A2 (KFC(lung)/KFC(liver)) ..................................... 0.28 0.18 0.137 0.18 0.137 0.18

aQGC + QLC + QFC + QSC + QRC MUST = 1.00.

f. Assessment of the sensitivity and

uncertainty of the PBPK model. In the

NPRM, OSHA expressed concern that, if

PBPK models were used to adjust risk

assessments, the uncertainty in PBPK

modeling should be adequately

addressed. Specifically, OSHA was

concerned that the uncertainty in the

mechanism of action and the lack of

human lung metabolism data were the

greatest obstacles to incorporation of

pharmacokinetic data into the MC final

risk assessment. Many of the

uncertainties in model parameters have

been quantified by various hearing

participants and are summarized below.

The quantification of these

uncertainties, however, did not address

OSHA’s primary concerns regarding the

mechanism of action and the

distribution of metabolism between lung

and liver. OSHA’s analyses of the

uncertainty and variability of

parameters in the PBPK model are

presented with its risk assessment later

in this document.

The concepts of uncertainty,

variability and sensitivity in PBPK

modeling were defined in comments

submitted by the U.S. Navy [Ex. 19–59]:

As it relates to the issue of using PBPK

modeling in risk assessment, uncertainty can

be defined as the possible error in estimating

the ‘‘true’’ value of a parameter for a

representative (‘‘average’’) animal.

Variability, on the other hand, should only be

considered to represent true interindividual

differences.

The normalized sensitivity coefficient

gives the percentage change in a model

output due to a percentage change in the

parameter value and represents the relative

importance of the parameter to the model

output under the conditions of the

simulation.

Each of these quantities is of concern for

risk assessment and PBPK modeling.

For example, we know that there is

variability or inter-individual

heterogeneity in the body weights of

humans (and mice), yet we estimate

risks for an average member of the

population (70 kg in humans, average

bioassay weight in mice). For many

parameters, the interindividual

variability may not be known and must

be estimated.

Uncertainty in estimation of the value

of a parameter representing an average

member of a population is primarily due

to laboratory measurement and related

errors. Measurement errors, in many

cases, can be quantified or estimated so

that the potential impact of this

uncertainty on the outcome of the PBPK

modeling can be assessed.

The sensitivity of the model to

particular parameters is useful for

determining which experiments should

be conducted to confirm parameters and

to determine the amount of confidence

that PBPK model outputs merit. For

example, when a sensitivity analysis is

conducted and it is determined that the

model outcomes are not very sensitive

to changes in the definitions of the

lumped tissue volumes, it suggests that

there is little need to conduct

experiments to describe those

relationships more precisely. Similarly,

even though the lumped tissue volume

does not represent a ‘‘true’’ biological

quantity, there is confidence that its

precise definition is not critically

important in PBPK model outcomes.

Therefore, if the only large (quantifiable)

uncertainty resides in this

measurement, one would have greater

confidence that the model predictions

were reasonably accurate. Therefore, it

is instructive to understand which

parameters influence the model

outcomes to the greatest degree.

Conversely, if the PBPK model outputs

are sensitive to a parameter which has

not been precisely described (such as

the distribution of GST metabolism

between lung and liver), the confidence

in model outputs is correspondingly

reduced.

Various investigators have attempted

to determine the sensitivity of the PBPK

models to parameter values and to

characterize the uncertainty and

variability within parameters in the

models. The first attempt to describe the

sensitivity of the Reitz’s original PBPK

model was performed by the Consumer

Product Safety Commission (CPSC).

The CPSC conducted a sensitivity

analysis of the metabolic parameters,

Km, Vmax and Kf, in the ‘‘Updated Risk

Assessment for Methylene Chloride’’

[Ex. 7–126]. They analyzed the

sensitivity of the model by selecting

alternative point estimates for the

metabolic parameters and determining

what the resulting ratio of GST

metabolite at 4000 ppm vs. 1 ppm

would be. This analysis shows how this

ratio would vary if the metabolic

parameters used in the model were

higher or lower than the measured

values as selected by CPSC. The results

showed that the ratio of the GST

metabolite in the liver at 4000 ppm to

the GST metabolite at 1 ppm (or the

ratio of the GST metabolite in the lung

at 4000 ppm to the GST metabolite at 1

ppm) was relatively insensitive to the

value of Kf (when CPSC varied Kf from

0.01 to 5.3, while Km and Vmax were

held constant at Reitz-Andersen values).

HSIA presented a sensitivity analysis

of the PBPK parameters from the Reitz

(HSIA) model in the testimony of Dr.

Reitz [Ex. 23–21A]. Results were

presented for mice at 4000 ppm, mice at

1 ppm, humans at 1000 ppm and

humans at 1 ppm. In the first analysis

(mice at 4000 ppm), the most sensitive

parameters were determined to be PB

(blood:air partition coefficient) and Kf

(metabolic parameter for the GST

pathway). The authors observed that at

high MC exposure levels the model

output was at least an order of

magnitude less sensitive to changes in

the other sixteen parameters

investigated.

When mice were exposed to lower

concentrations of MC (1 ppm) Vmax and

Km for the MFO pathway were the most

sensitive parameters (sensitivity

coefficient was over 120% for each of

these parameters). In addition, several

other parameters were found to exert a

significant influence on model outputs:

QP, QL, PB, VLu, and KF.

In humans, at high concentrations (>

1000 ppm) the results were similar to

those observed in mice: the model was

most sensitive to PB and KF, with
1540 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

sensitivity coefficients of 87% and 97%,

respectively. In addition, the human

model was also sensitive to the value

chosen for the QP (sensitivity coefficient

= 43%).

In humans, at 1 ppm MC, Km and

Vmax for the MFO pathway were the

most sensitive parameters out of the six

parameters which had a significant

effect upon model outputs: QP, QL, PB,

Vmax, Km, and KF.

This type of sensitivity analysis

improves on that conducted by the

CPSC, because it looks at more of the

parameters. It is still deficient, however,

because it examines the effect of each

parameter individually, and because it

does not examine the effect of

uncertainty in two key parameters, A1

and A2 (the ratios of distribution of the

MFO and GST pathways between lung

and liver), on the outcomes of the

modeling.

Mr. Clewell [Ex. 19–59] also

conducted a sensitivity analysis to

determine the impact of uncertainty in

PBPK parameters on the model

outcomes. In contrast to the HSIA

analysis, he examined the sensitivity of

the outcomes to the ratios A1 and A2,

and he chose a more realistic

occupational exposure level (100 ppm).

He found that for mice at 4000 ppm, the

most sensitive parameters for estimation

of lung tumors were KF, A2, and PB. In

the liver, the most sensitive parameters

were KF and PB, which agrees with the

results of the HSIA analysis. For

humans at 100 ppm, the most sensitive

parameters for estimating lung tumors

were KF and A2. Other parameters with

significant effects on model outcomes

were PB, QPC, BW, KM, QCC, and QLC.

The most sensitive parameters for

estimating liver tumors were VMAX,

KF, QPC and BW, while PB, KM, QCC

and QLC also produced significant

effects on model outcomes.

In all of these analyses, the PBPK

models were clearly sensitive to the

values chosen for the metabolic

parameters, especially the GST

metabolic parameter (KF). Other

parameters with consistently significant

impact on the outcomes of the model

included breathing rate (QP) and

distribution of GST metabolism between

lung and liver (A2). These analyses

suggest that additional studies to

quantify the metabolic parameters (KF,

KM and VMAX), breathing rates (QP)

and distribution of GST metabolism

between lung and liver (A2) would

increase confidence in the model

outcomes. Characterization of the

distribution of metabolism between lung

and liver is particularly critical because

estimates for human lung metabolism

were initially based on one pooled

sample of lung tissue, and the

variability and uncertainty of the value

of this parameter has not been

quantified.

Some analysts [Ex. 21–52] have

suggested that the uncertainty is

increased in risk assessments based on

PBPK as compared to applied-dose risk

assessments, because some methods of

quantifying the uncertainty result in

rather broad distributions of

uncertainties. OSHA, in contrast, agrees

with most commenters that quantifying

uncertainty in a PBPK model or risk

assessment does not increase the

uncertainty. The Agency stresses that

the appearance of increasing uncertainty

with the identification of sources of

uncertainty almost certainly means that

the original uncertainty was

underestimated. (In fact, since many

assessors have not attempted even to

quantify the uncertainty in applied-dose

risk assessments, the uncertainty has

often been infinitely underestimated.)

When conducting a risk assessment

using PBPK that appears to increase the

uncertainty over delivered-dose

methodologies, the investigator should

go back and recalibrate what the

uncertainty in the original analysis

likely was, in light of the sources of

uncertainty identified using PBPK. This

would tend to broaden the confidence

limits of the traditional risk

assessments, almost certainly beyond

the limits generated in a thoughtful

PBPK-based assessment. For example,

many analyses using delivered dose

assume that in the interspecies scaling

factor, BWx, x is known with perfect

certainty (e.g., it is known to equal 2/3

or 1.0). An analysis that uses an

empirically-derived probability

distribution for x, which might

reasonably extend from approximately

0.6 to approximately 1.0, would yield a

rather broad distribution of uncertainty

in the resulting estimate of risk.

The Agency also agrees that the

primary uncertainties lie in the choice

of the dose surrogate and assumptions

regarding cross-species scaling. Clewell

[Ex. 23–14] investigated the uncertainty

of the PBPK parameters using Monte

Carlo analyses of the assumed

distributions of uncertainty of each

parameter. The resulting estimates of

dose surrogate values were

characterized by a mean of the

distribution and an upper 95th

percentile estimate. Mr. Clewell stated

[Ex. 19–59]:

[T]he use of the 95th percentile of the

distribution of estimates accounts for

additional uncertainty concerning the true

values of the PBPK parameters for the

bioassay animals and humans.

Mr. Clewell recommended that OSHA

use the upper 95th percentile of the

Monte Carlo distribution of GST

metabolites (from PBPK modeling) as an

input to the multistage model to

generate risk estimates, and then use of

the MLE from the multistage model in

those risk estimates, in accordance with

previous OSHA risk assessments. He

remarked that use of the upper 95th

percentile of the PBPK output would be

a reasonable mechanism to account for

the uncertainty quantified in these

analyses. Using the upper 95th

percentile of the distribution of GST

metabolites, Mr. Clewell’s risk estimate

for lifetime occupational exposure to 25

ppm MC was 0.9 deaths per 1000 using

the MLE of the multistage model, and

1.1 per 1000 using the 95th percentile

upper confidence limit (UCL) from the

multistage model. Using the mean of the

distribtution of GST metabolites, his

MLE risk estimate was 0.28 deaths per

1000 at the same exposure level, with an

UCL of 0.35/1000.

The HSIA disagreed with using the

upper 95th percentile for estimating

risks, and stated [Ex. 105]:

[T]he analyses conducted by Clewell et al.

indicate that consideration of model

parameter variability does not contribute

orders of magnitude to the uncertainty

associated with PB–PK risk assessments.

Further, the uncertainty associated with PB–

PK risk assessments is significantly less than

that associated with risk assessments that fail

to consider pharmacokinetics. The

uncertainty in PB–PK based procedures is

simply more readily available for calculation.

OSHA disagrees with the HSIA that

the uncertainty and variability

associated with PBPK risk assessments

is significantly less than that associated

with risk assessments that fail to

consider pharmacokinetics.

Quantification of uncertainty does not

equate with reducing uncertainty in an

analysis. In fact, at a different level, the

assumptions made regarding

mechanism of action of MC and

extrapolation of lung metabolic rates

from one human in vitro sample may

serve to underestimate the uncertainty

inherent in the PBPK-based risk

assessment if the underlying

assumptions are wrong. Also, as stated

above, identification of uncertainty may

lead us to recalibrate the uncertainty

associated with traditional risk

assessment methods. In any event, the

possibility that using PBPK significantly

reduces uncertainty does not affect the

need to account for whatever

uncertainty remains.

In addition, OSHA agrees with

Clewell that using the upper 95th

percentile of the Monte Carlo

distribution of GST metabolites as input
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1541

to the multistage model is a reasonable

way to incorporate the quantifiable

uncertainty and variability into a risk

assessment. In its final risk estimates,

OSHA has used the upper 95th

percentile on the distribution of GST

metabolites from the Bayesian analysis

as the input to the multistage model, as

described later in this document.

E. Other Risk Estimates Based on PBPK

Models Prior to OSHA’s Final Analysis.

A PBPK model can produce estimates

of target tissue doses (or dose

surrogates) for different hypotheses of

action of a chemical. The appropriate

choice of target tissue dose can greatly

influence risk estimates based on that

dose. For MC, the dose surrogate that

has been used most frequently to

estimate cancer risks is the amount of

GST metabolite produced. The amount

of GST metabolite can then be used to

extrapolate from a high bioassay dose of

MC to a low occupational (or

environmental) dose of MC and from

mouse MC metabolic rates to human

metabolic rates.

In the NPRM, OSHA reviewed

available risk assessments for MC that

used PBPK modeling in a variety of

ways. The Food and Drug

Administration risk assessment [Ex. 6–

1] was not adjusted to account for

pharmacokinetic information. The

Consumer Product Safety Commission,

in its ‘‘Updated risk assessment for

methylene chloride’’ [Ex. 7–126], used

pharmacokinetic data to adjust for

differences in metabolism in

extrapolating from high dose (4000 ppm

mouse bioassay) to low dose (1 ppm)

exposures, but did not adjust for

interspecies differences in the

metabolism of MC. The resulting risk

estimate was approximately 2-fold

lower than a risk estimate using applied

dose.

The U.S. EPA analyzed the MC

pharmacokinetic data in its documents,

‘‘Technical analysis of new methods

and data regarding dichloromethane

hazard assessment’’ [Ex. 7–129] and

‘‘Update to the Health Assessment

Document and Addendum for

dichloromethane (methylene chloride):

pharmacokinetics, mechanism of action,

and epidemiology’’ [Ex. 7–128]. The

EPA used the PBPK data to adjust its

risk estimates in its Integrated Risk

Information System (IRIS) database.

Adjustments were made for high-to-low

dose and cross-species extrapolation.

EPA’s risk estimates for low human

exposures to MC were decreased by

approximately a factor of 9 from its risk

estimates made without consideration of

PBPK data.

The HSIA [Ex. 105] and ECETOC [Ex.

14] also submitted risk assessments

based on PBPK data. The primary

difference between the HSIA and the

EPA risk estimates was that the HSIA

did not use a surface area correction to

account for interspecies differences

other than pharmacokinetics (e.g.,

pharmacodynamic differences) while

the EPA did. Also, HSIA’s risk estimates

used OSHA’s preferred breathing rates

and an occupational exposure scenario.

ECETOC based its risk estimates on

different measures of human MC

metabolism. In a pre-hearing

submission, ‘‘Using PB–PK Models for

Risk Assessment with Methylene

Chloride (Comparison of U.S. and U.K.

procedures)’’ [Ex. 19–83A], scientists

from the U.S. and the U.K. compared

methodologies for using PBPK data in

the MC risk assessment and presented a

consensus opinion that OSHA should

use the methodology developed by Dr.

Richard Reitz [Ex. 7–225] for the U.S.

For this reason, OSHA evaluated Dr.

Reitz’s analysis, as presented by the

HSIA, and did not separately consider

the ECETOC risk assessment.

As described previously, Clewell [Ex.

96] and NIOSH [Ex. 94] have submitted

analyses of the PBPK data and risk

assessments based on those analyses.

Both of these analyses used PBPK

modeling of the amount of GST

metabolites produced in their estimates

of carcinogenic risks.

OSHA has evaluated the data in the

rulemaking record and has concluded

that, if PBPK modeling is used to adjust

estimates of risk, the weight of evidence

supports using the amount of GST

metabolites as the preferred surrogate

for target tissue dose. The amount of

GST metabolites predicted by the PBPK

model varies depending upon the values

or distributions chosen for the

parameters in the model.

Of the risk assessments described

above, OSHA has chosen to compare

risks estimated using PBPK models

submitted by Reitz et al., Clewell et al.

and NIOSH with applied dose

methodology using either of two scaling

assumptions: the inhaled dose in mg/kg/

day (the estimates of risk presented in

the NPRM) and ppm-to-ppm

extrapolation. OSHA evaluated the

methodologies used in developing these

risk estimates before developing its final

risk estimates, which are presented in

the next section.

The risk estimates derived from using

PBPK with the multistage dose-response

model submitted to the Agency by Reitz

et al., Clewell et al., and NIOSH, and the

risk estimates derived from applied dose

methodologies, are shown in Table VI–

4.

TABLE VI–4.—LIFETIME EXCESS RISK ESTIMATES (PER 1000) FROM OCCUPATIONAL EXPOSURE BASED ON FEMALE

MOUSE LUNG TUMOR DATA

Model

MLE (UCL)**

25 ppm 50 ppm 500 ppm

OSHA NPRM Risk Assessment (mg/kg/d, BW extrapolation) without PBPK Adjustment ...... 2.32 (2.97) ........ 4.64 (5.92) ........ 45.5 (57.7)

PPM to PPM extrapolation without PBPK Adjustment ............................................................. 11.3 (14.4) ........ 22.4 (28.5) ........ 203 (251)

PBPK Reitz female mouse lung—Reitz human (HSIA assumptions) ...................................... 0.43 (0.53) ........ 0.93 (1.17) ........ 14.3 (17.9)

PBPK Reitz female mouse lung—Dankovic average human (NIOSH assumptions) .............. 0.81 (1.02) ........ 1.69 (2.12) ........ 15.0 (18.7)

PBPK Clewell female mouse lung—Clewell human (Navy assumptions)* .............................. 0.91 (1.14) ........ 1.88 (2.36) ........ 27.5 (34.2)

OSHA Final Risk Assessment (female mouse lung with PBPK) ............................................. 3.62 .................. 7.47 .................. 125.8

* Upper 95th percentile of the GST metabolites distribution was used as input in the multistage model.

** Maximum likelihood estimates and 95th percentile upper confidence limit (in parentheses) of the multistage dose-response function.

Of those risk estimates considered by

OSHA prior to its final risk assessment,

the risk estimates for lifetime

occupational exposure to the 8-hour

TWA PEL of 25 ppm ranged from 0.43

per 1000 to 11.3 per 1000. The risk

assessment presented in the NPRM was

based on a body weight extrapolation

from mice to humans of a mg/kg/day

dose of MC. Mr. Harvey Clewell [Ex. 19–

59] stated that this dose was not a useful

dose for estimating risks from volatile

solvents such as MC. He suggested that,

if PBPK modeling was not used to

estimate target tissue dose (his preferred
1542 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

method of estimating risk), then a ppmto-ppm extrapolation would be more

appropriate. The ppm-to-ppm

extrapolation resulted in an estimated

risk of 11.3 deaths per 1000 after

lifetime occupational exposure to 25

ppm. However, the ppm-to-ppm

extrapolation is generally preferred for

site-of-contact tumors. Although it is

possible that the MC lung tumors were

the result of a site-of-contact mechanism

of action, the data are more supportive

of a systemic, genotoxic mechanism

mediated through metabolites of MC. In

addition, the liver tumors are clearly not

the result of a site-of-contact carcinogen

because the liver is not a site of contact

during inhalation bioassays.

Several commenters [Exs. 19–26, 19–

28, 19–29, 19–45, 19–48, 19–57, 19–59,

25–E, 25–I] suggested using PBPK

modeling to estimate target tissue dose

and to account for differences in

metabolism at high and low doses and

differences in metabolism of MC across

species. OSHA compared three sets of

parameters in the PBPK models

submitted by interested parties to adjust

the dose across species and across

doses. The risk estimates for those

models (using the MLE of the multistage

model parameters) ranged from 0.43 to

0.91 deaths per 1000 after lifetime

occupational exposure to 25 ppm. Mr.

Clewell’s risk estimate (0.91/1000 MLE),

unlike the other PBPK analyses,

represent the upper 95th percentile of

the Monte Carlo distribution of GST

metabolites as input into the multistage

model. The Monte Carlo simulation

takes into account the assumed

distribution of values for each

parameter, including the parameters

used to estimate human metabolism of

MC. The other PBPK models used point

estimates instead of distributions for the

PBPK parameters, and therefore it is not

known whether these are central

estimates or upper bounds. OSHA

agrees that the distributional approach

used by Clewell is a reasonable way to

account for the uncertainty and

variability inherent in PBPK modeling,

and that uncertainty and variability

must be considered in any useful risk

assessment. The Agency has used the

upper 95th percentile on the

distribution of GST metabolites from the

Bayesian modeling, coupled with the

MLEs of the multistage model

parameters, for its final estimates of MC

risk.

OSHA has concluded that all the risk

estimates presented above support an 8-

hour TWA PEL of 25 ppm or lower. The

risks estimated from the PBPK models

were less than an order of magnitude

different from estimates of risk based on

applied dose methodology. Either with

or without PBPK modeling , the

estimates of risk at 25 ppm clearly

indicate a significant risk.

The risks estimated from these PBPK

models and ppm-to-ppm extrapolation

offer a range of risks which might be

expected after lifetime occupational

exposure to MC. OSHA has assessed

these models and has decided to modify

and expand on the submitted PBPK and

uncertainty analyses in its final

estimates of cancer risk, in order to give

full consideration to all of the available

data. This analysis is presented in the

next section.

F. OSHA’s PBPK Analysis and Final

Risk Estimates

In developing an approach to PBPK

modeling for MC, OSHA wished to use

all of the available, appropriate and

quantifiable biochemical and

physiological data in its PBPK modeling

and in assessing the uncertainty and

variability in model parameters. The

Agency determined that this approach

would provide the best characterization

of the variability and uncertainty in the

data and the model. In addition,

incorporation of as much of the

available data as possible should give

the most realistic PBPK model, and in

turn, the most realistic risk estimate.

Before development of OSHA’s PBPK

model, Clewell’s approach (described

above) was the most comprehensive

pharmacokinetic approach submitted to

the Agency. It addressed many of the

issues of concern to the Agency, and

OSHA believes that Clewell’s approach

was a reasonable template for using

PBPK in risk assessment. However,

since Clewell’s work was done, PBPK

modeling has continued to advance.

Therefore OSHA modified Clewell’s

model to accommodate these advances

and to allow incorporation of additional

biochemical and physiological data that

had been added to the rulemaking

record. The following is a summary of

OSHA’s final (revised) PBPK analysis. A

more detailed discussion can be found

in the reports submitted to the Agency,

reflecting OSHA’s analysis in which the

Agency was assisted by contractors [Ex.

128].

1. Review of Clewell’s PBPK Analysis

a. Clewell’s analytical approach.

Clewell et al. [Ex. 96] employed

Monte Carlo techniques to investigate

imprecision in estimates of human

health risk from occupational exposure

to MC, as a function of imprecision in

parameter values of the PBPK and doseresponse models. (As described below,

OSHA and its contractors believe that

Clewell et al. did not correctly parse out

uncertainty and variability, so their

analysis is described as accounting for

‘‘imprecision’’ rather than uncertainty

or variability). In the Clewell et al.

analysis, probability distributions were

specified for each PBPK model

parameter in an attempt to characterize

imprecision. Computer-based

techniques were used to obtain pseudorandom samples from these statistical

distributions, generating multiple sets of

model parameter values. These sets of

parameter values were then used to

obtain a corresponding distribution of

PBPK model predictions of various

measures of internal dose for a

simulated animal bioassay (e.g., GST

metabolism in lungs of mice exposed to

2000 ppm and 4000 ppm for 6 hrs/day,

5 days/wk). The mean of the mouse

internal dose distribution was used as

the dose input to obtain the MLE and

UCL on the multistage model

parameters, using the tumor incidence

data from the NTP bioassay. The

multistage model was run a second time

using the upper 95th percentile of the

mouse internal dose distribution as the

dose input to obtain the MLE and UCL

on the multistage model parameters.

This yielded a total of four estimates of

the parameters (qo, q1, and q2) of the

mouse dose-response function: 1) Mean

of internal dose distribution/MLE of

multistage model parameters; 2) Mean

of internal dose distribution/UCL of

multistage model parameters; 3) Upper

95th percentile of internal dose

distribution/MLE of multistage model

parameters; and 4) Upper 95th

percentile of internal dose distribution/

UCL of multistage model parameters.

Each set of dose-response parameters

obtained from the analysis of the mouse

data was then used to calculate human

risk estimates. The upper 95th

percentile of the human internal dose

distribution was used to calculate the

dose surrogate at 25 ppm, 8 hr/d

exposure and then substituted into the

MLE and UCL of the multistage

parameters to obtain the MLE and UCL

estimates of risk. Similarly the mean of

the human internal dose distribution

was used in conjunction with the MLE

and UCL of the multistage model

parameters. Therefore, four human risk

estimates were generated, based on the

distribution of human internal doses

and the dose- response function derived

from the multistage analysis of the NTP

mouse bioassay. The four human risk

estimates are: 1) upper 95th percentile

of the human internal dose distribution/

MLE of the multistage model

parameters; 2) mean of human internal

dose distribution/MLE of the multistage

model parameters; 3) upper 95th

percentile of the human internal dose
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1543

distribution/UCL of the multistage

model parameters; and 4) mean of the

human internal dose distribution/UCL

of the multistage model parameters.

A major finding of that analysis was

that the mean estimate of added cancer

risk for occupational exposure at the

proposed PEL of 25 ppm based on the

PBPK-derived GST-lung dose surrogate

(PBPK(mean) / potency(MLE) = 0.39 x

10 -3) was 6-fold lower than the

corresponding OSHA estimate (MLE =

2.32 x 10 -3) based on administered dose

scaled to body weight. The 95 percentile

upper bound estimate of risk using the

same PBPK distributions and the

distribution of 95%UCLs on

carcinogenic potency (PBPK(95%)/

potency(95%) = 1.56 x 10 ¥3), was

nearly 2-fold less than OSHA’s 95%UCL

on risk (2.97 x 10 ¥3).

b. Clewell’s PBPK model. The PBPK

model used by Clewell et al. in

performing their Monte Carlo analysis

was slightly modified from the PBPK

model developed by Andersen et al. and

submitted to OSHA by HSIA [Ex. 328].

The primary modification was the

addition of a separate compartment for

the GI-tract. The general structure of this

model has received considerable use by

PBPK modelers. Nevertheless, there

were several deficiencies in this model

and in the subsequent statistical

analysis that the Agency believed

warranted major modification. These are

described in the following section.

c. Prior distributions for model

parameters.Truncated normals were

used as the form for all probability

distributions except for metabolic

constants, which were described by

truncated lognormals. All distributions

were truncated to prevent sampling of

nonsensical values (e.g., negative

values). Truncation in some instances

was 2 standard deviations (SDs) from

mean values, in others more than 4 SDs.

A variety of sources of information

were used as a basis for the probability

distributions of the PBPK parameters in

Clewell’s model: literature summaries

for most physiologic and anatomic

parameters, direct laboratory

measurement of partition coefficients

based on vial equilibration studies, and

statistical regression analyses of

experimental data for fitted metabolic

constants.

Clewell et al. stated that the focus of

their analysis was on characterizing the

effect of ‘‘uncertainty’’ in parameter

values on uncertainty in PBPK model

predictions, uncertainty being defined

as the possible error in estimating the

‘‘true’’ value of a parameter for a

representative ‘‘average’’ animal. To

maintain consistency with a focus on

investigating effects of parameter

uncertainty, a logical choice would have

been to center their probability

distributions using estimates of mean

values for all model parameters and to

use the standard error of the mean

(SEM) to characterize dispersion. It it

unclear whether this was done for blood

flows, tissue volumes, inhalation rates

or cardiac output, since Clewell et al.

appear to have relied extensively on an

unpublished review of scientific

literature performed by S. Lindstedt for

the ILSI Risk Science Institute

Physiological Parameter Working

Group.

Based on Clewell’s comments

accompanying his PBPK model, it

appears that standard errors were not

used to characterize variability among

individual replicates of measured

equilibrium partition coefficients;

instead, standard deviations were used.

Nor does it appear that Clewell et al.

consistently made use of standard errors

in characterizing imprecision in their

fitted metabolic constants. Inspection of

the joint confidence region for their

fitted estimates of mouse VmaxC and

Km (for the MFO pathway), shown in

Figure 6 of Ex. 399, suggest coefficients

of variation (%CVs) for VmaxC of about

2%. Similarly, for KfC, the %CV in the

fitted MLE appears to be about 3%.

These %CVs are considerably smaller

than the assumed values of 20% and

30%, respectively, used by Clewell et al.

in their Monte Carlo analysis. On the

other hand, their %CV for Km does

coincide with that indicated by the joint

confidence regions. One should also

note the high degree of correlation

among the fitted values for VmaxC and

Km.

In assessing variability in the ratio of

in vitro MFO and GST metabolism in

lung versus liver tissue (i.e., the A1 and

A2 parameters), Clewell et al. used the

in vitro MC metabolism data of Reitz et

al. (1989). Yet it appears that the %CV

for these data is 24% when one uses

SDs among replicates for MFO

metabolism in lung and liver of mice.

This is substantially less than the 50%

assumed by Clewell. One obtains a %CV

of 9% when using SEMs.

It appears then, that some of the

probability distributions used by

Clewell et al. reflect variability beyond

that readily identifiable as uncertainty

in estimates of sample means. It may be

that Clewell made a subjective inflation

of variances. Though ad hoc, inflating

variances would not be unreasonable

given the sparse data on certain model

parameters. Another possibility is that

the distributions reflect variability due

to both uncertainty and intersubject

heterogeneity—another reason to inflate

variances, or alternately, use SDs rather

than SEMs to describe the distributions

of the parameters. If so, then it might be

more appropriate to view the proportion

of simulated estimates of risk that fall

within a specified interval as the

probability that the true risk for a

randomly selected individual is in that

interval. Yet strictly speaking this

would require that the probability

distributions reflect both the full range

of uncertainty and heterogeneity in the

population of interest, with the latter

being unlikely based on inspection. If

the analysis only considered

imprecision due to uncertainty, as

suggested in Clewell et al., then the

resulting distribution should instead be

viewed as describing the uncertainty in

risk for a hypothetical ‘‘average’’

individual.

2. OSHA’s Modifications to PBPK

Analysis

a. Basis for modifying approach of

Clewell et al. In addition to the

likelihood that Clewell et al. used

broader distributions than those

necessary to model uncertainty in the

PBPK analysis (as opposed to modeling

some hybrid of uncertainty and

variability), the analytical approach they

used (1992 and 1993) also has two wellknown methodological limitations.

Their representation of imprecision in

fitted parameters (e.g., VmaxC, Km, KfC)

is problematic because they estimated

the variability in these parameters by

optimizing the model fit to in vivo data,

while assuming nominal values for all

other model parameters. However, the

organ volumes, blood flows, and

partition coefficients for the mice used

in the gas uptake studies and the

humans used in the open chamber

studies are clearly not known with exact

precision, and are not, therefore,

accurately represented by nominal

values. Consequently, the variances of

the fitted parameters will be

underestimated with this approach,

since full acknowledgment of variability

in other model parameters will have

been ignored. Furthermore, it is quite

likely that the joint parameter space for

fitted PBPK model parameters will

exhibit a considerable degree of

correlation. Importantly, failure to

account for such covariances when

performing Monte Carlo sampling may

overstate variance in some model

predictions by assuming independence

where it does not exist. The

implications of these methodological

limitations on predicted risk are

unclear, since they would seem to exert

countervailing effects on estimating

uncertainty. Thus, OSHA decided that it

was important to perform an analysis

that addressed these limitations. The
1544 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

use of a Bayesian statistical framework

provided a means of overcoming the

above limitations.

b. Bayesian Approach. A Bayesian

analysis allows the logical combination

of two forms of information: ‘‘prior

knowledge’’ about parameter values

drawn from the scientific literature, and

data from experimental studies (e.g., the

mouse gas uptake studies, or, for

humans, the open chamber experiments

performed by Dow Chemical company),

all within the context of a PBPK model.

Clearly, neither prior information about

parameter values nor experimental data

alone are capable of precisely

determining all parameter values in the

PBPK model. If prior information were

sufficient, the additional experiments

performed by Clewell et al. and Dow

Chemical Co. would not have had to be

done. But the available experimental

data alone are insufficient to pin down

all parameters of the model to

reasonable values (which is why no

attempt was made to simultaneously

optimize all PBPK parameters to data).

Fitting only two or three parameters

while holding others constant so as to

reduce dimensionality leads to the

biases and underestimation of variance

mentioned above.

A second feature of this Bayesian

approach is that it yields distributions

for all of the PBPK model parameters

together with information about their

entire joint covariance structure. Thus,

the Bayesian analysis outputs

distributions of parameter values that

are consistent with both all the available

data as well as the prior information. It

is then possible to use samples from the

joint posterior distribution of the

parameters to simulate formation of GST

metabolites in lung tissue from different

species and cancer risk, therefore

producing posterior distributions for

these endpoints. It should be noted that

if no data are available (or if the data are

not informative as to the likely value of

the parameter), the posterior

distribution is equivalent to the prior

distribution and this approach is then

equivalent to the standard Monte Carlo

sampling from the prior distribution, as

in Clewell et al. Alternately, Bayesian

updating with a uniform prior

distribution (i.e., complete ignorance

about plausible values) used in

conjunction with data leads to a

posterior distribution proportional to

the distribution of the data. The most

important applications of the Bayesian

approach arise when informative (e.g.,

physiological, anatomical) prior

distributions exist, in parallel with

experimental metabolic data. This is

now the case with PBPK modeling of

MC. In this case, Bayesian modeling

results in all the information content of

both prior distributions of parameter

values and metabolic data being

incorporated in the posterior

distribution of parameter values, which

will have reduced variance compared to

the prior distribution. Distributions of

parameter values for both human and

mouse PBPK models, and the multistage

cancer model, were determined with

this technique.

c. PBPK Model Modifications. OSHA’s

final risk estimates were based on the

Bayesian analysis described here. The

Clewell model formed the structural

core of the analysis, although five

additional structural modifications were

made as described below. These

modifications were necessary to make

the PBPK model more physiologically

realistic:

(1) Bone marrow was treated as a

separate compartment. In the Clewell

model (as in many PBPK models), bone

marrow tissue was combined with other

tissues into a (presumably) kinetically

homologous compartment. Based on

blood perfusion rates, a reasonable

choice would be to place marrow in the

well-perfused tissue compartment.

However, if the physicochemical

affinity of the compartment is

considered, it makes more sense to

place marrow in the adipose tissue

compartment, since red marrow (at least

in humans) has a fat content of about

40% and yellow marrow has a fat

content of 80%. In comparison, liver,

brain, kidney and heart all have fat

contents (in humans) well under 20% .

In addition, bone marrow accounts for

a significant percentage of body weight

and receives a substantial fraction of

cardiac output. Therefore, a strong

argument can be made for treating bone

marrow as a separate compartment, as

OSHA has done here.

(2) Partitioning MFO and GST

metabolism between the lung and liver.

Clewell made the MFO and GST

metabolic constants for lung dependent

on the fitted constants for the liver, so

as to reduce the number of fitted

parameters to be simultaneously

estimated from rodent and human in

vivo data. For example, A1 is defined as

the ratio of lung to liver in vitro MFO

enzymatic activity, normalized to

microsomal protein,

A nmol DCM o

nmol DCM o

1 = xidized/min/mg lung microsomal protein

xidized/min/mg liver microsomal protein

Similarly, A2 is the ratio of lung to liver

in vitro GST enzymatic activity,

normalized to cytosolic protein,

A nmol DCM c

nmol DCM c

2 = onjugated/min/mg lung cytosolic protein

onjugated/min/mg liver cytosolic protein

This assumes that lung and liver have

equivalent mg protein per mg tissue

contents. Yet the data of Litterst et al.

(1973) argue against such an

assumption. Litterst et al. measured

microsomal protein and soluble protein

in lung and liver tissues of mice, rats,

hamsters, guinea pigs and rabbits. These

data indicated ratios of mg microsomal

protein content of lung versus liver

tissue of less than 0.3, and a similar

ratio for soluble protein of about 0.7.

Thus, some adjustment of the constants

A1 and A2 are required.

The equations used to compute a lung

Vmax for the MFO pathway and a lung

Kf for the GST pathway from a liver

Vmax and Kf were thus modified to

include an additional proportionality

factor to account for differences in

microsomal and cytosolic protein

content of lung and liver tissue.

Specifically,
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1545

V V V V A B max max [ / ] lung MFO liver MFO lung liver . . = × × ×1 1

where B1 is the ratio of [mg microsomal

protein per mg of lung tissue] to the

same measure for liver tissue. A

geometric mean and geometric standard

deviation for B1 were derived from the

data of Litterst et al. (1973) to use as

input in the Bayesian prior distribution

for this parameter. Notably, accounting

for this difference in protein content

leads to a proportionality factor

approximately four-fold less than that

used by the Clewell et al. (i.e., A1 x B1

= 0.41 × 0.27 = 0.11).

Similarly, for Kflung.GST,

Kf Kf A B lung GST liver GST . . = × ×2 2

Here too, the data of Litterst et al. (1973)

were used to compute a ratio of mg

soluble protein per mg lung to the same

measure for liver, yielding a mean value

of 0.68 for B2. For a human B2, the

average of the ratios computed for mice,

rats, hamsters, guinea pigs, and rabbits

as per Litterst et al. (1973) was used.

(3) Linkage of alveolar ventilation to

cardiac output. In recognition of

OSHA’s interest in occupational

exposures, Clewell used values of

cardiac output and alveolar ventilation

rates consistent with the performance of

light work. However, they did not

account for the altered distribution of

regional blood flows known to occur in

response to increases in work intensity

[Exs. 7–115, 7–120, 21–81], as was done

in subsequent MC PBPK work by

Dankovic and Bailer [Ex. 23–18] (1994).

In the latter analysis, alveolar

ventilation (QP) was made dependent

on cardiac output (QC) by making QP =

QC × VPR, where VPR is the ventilationperfusion ratio. VPR was treated as a

random variable with an assigned prior

probability distribution.

(4) Linkage of work intensity to

changes in physiology. Cardiac output,

ventilation perfusion ratio, and percent

of cardiac output delivered to tissues

were made dependent on work

intensity. Using the data of A ̊ strand

(1983) [Ex. 21–81]—and similar to what

was done by Dankovic and Bailer (1994)

[Ex. 23–18]—slope factors were derived

to describe change in flows per change

in work intensity as measured in watts.

These slope factors were then used to

modify resting flows for varying levels

of work intensity. This approach was

taken so that the influence of variability

in work load (i.e, work load was treated

as a random variable)—with

concomitant adjustments to regional

blood flows and ventilation rate—on

delivered dose could be modeled.

(5) Maintaining mass balance in

sampling of fractional blood flows and

compartment volumes. Monte Carlo

sampling of fractional quantities such as

the proportion of cardiac output

delivered to different compartments, or

the proportion of body weight

represented by a given compartment,

requires the imposition of some type of

constraint to prevent random sampling

leading to summed proportions greater

than the whole (and thus causing

nonsensical departures from mass

balance). The following constraint was

imposed: VppC = 0.82—∑ViC ’s (0.82 is

a nominal value for the fraction of body

weight absent bone, blood, and stomach

and intestinal contents), QwpC = 1—

∑QiC ’s (in the mouse model), and

QppC = 1—∑QiC ’s (in the human

model). The use of either QwpC or

QppC as the quantity to be made

dependent on the other fractional flows

has biological appeal—one expects that

higher fractional blood flow to the

poorly-perfused compartment (i.e.,

muscle and skin) should be

accompanied by a lower fractional flow

to the well-perfused compartment, and

vice versa. The choice of QwpC versus

QppC as the one to be made dependent

on others appeared to be unimportant in

work with the mouse model. The choice

was important in work with the human

model. Here it was necessary to choose

QppC, because of its large variance

relative to QwpC (i.e., since QppC

cannot be estimated precisely, it makes

sense to let our greater knowledge of the

other fractional flows inform us about

plausible values of QppC).

The above approach modifies the

approach taken by Clewell et al. [Ex.

96]. Their approach was to randomly

draw from the distributions for cardiac

output and all fractional flows, use the

random draws to compute the absolute

flows to the individual compartments,

and then to sum the individual flows to

make a new cardiac output value for use

in the simulation. On the other hand,

OSHA’s final analysis avoided

arbitrarily modifying the prior

distribution for cardiac output (which

happens to be one of the relatively wellknown parameters). Furthermore,

Clewell did not make the fractional

flows dependent on one another.

d. Prior Probability Distributions. A

skewed, lognormal-like distribution is

generally observed for biological

parameters. However, most, if not all,

parameters are also positive and have

physiological bounds. Thus, truncated

lognormal distributions of the parameter

values were used in this analysis. They

do not differ appreciably from normal

distributions for small values of the

variance.

In specifying prior distributions an

attempt was made to characterize the

variability of the mean parameter values

for small groups of rodents and humans.

This focus was adopted to make the

prior distribution congruent with the

data sets available for Bayesian analysis.

For example, the rodent gas uptake data

represent the aggregate pharmacokinetic

behavior of groups of 5 mice. Prior

distributions were therefore constructed

to reflect the degree of variability in

mean physiological and anatomical

PBPK parameters for small groups of

mice. A similar approach was taken in

defining prior distributions for human

physiologic and anatomic parameters,

since the available experimental data

reflected the averaged pharmacokinetic

behavior of 6 subjects. In practice, this

meant amassing studies reporting mean

values for certain PBPK parameters (e.g.,

tissue weights, blood flows, cardiac

output, minute ventilation), and then

using these means as data for computing

a geometric mean (GM) and geometric

standard deviation (GSD) with which to

estimate the parameter values for the

truncated lognormal distributions.

Sampling of all lognormal distributions

was truncated at 2 GSDs, with one

exception. Truncation of the blood:air

partition coefficient was extended to 3

GSDs based on results from preliminary

runs.

Table VI–5 presents a summary of the

prior probability distributions used in

the Bayesian fitting of the mouse and

human data sets. The prior distributions

for metabolic constants to be estimated

from in vivo data were made very broad

(i.e., assigned a GSD of 10) to reflect our

ignorance of these values before

examining the data. Similarly, the prior

distributions for parameters of the

multistage cancer model were broad

uniform distributions, constrained to be

positive, as required by the standard

model.
1546 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

TABLE VI–5.—PRIOR DISTRIBUTIONS USED IN BAYESIAN ANALYSIS OF MOUSE AND HUMAN IN-VIVO DATA

Parameter

Mouse priors Human priors

GM GSD GM GSD

Flows:

QCC Cardiac Output (l/hr/kg—BW) ......................................... a 34.8 1.14 4.2 .................... 1.10

VPR Alveolar Ventilation Perfusion Rate ................................ b 1.22 1.95 1.35 .................. 1.15

Tissue Blood

Flows (fraction

of cardiac output):

QgiC GI Tract ........................................................................... 0.165 1.30 0.191 ................ 1.25

QliC Liver ................................................................................ 0.017 1.20 0.067 ................ 1.20

QfatC Fat ................................................................................... 0.047 1.60 0.057 ................ 1.45

QppC Poorly Perfused Tissues ................................................. 0.276 1.25 0.198 c .............. 1.55

QwpC Well Perfused Tissues .................................................... c 0.369 1.10 0.443 ................ 1.25

QmarC Bone Marrow ................................................................... 0.089 1.60 0.044 ................ 1.70

Tissue Volumes

(fraction of

body weight):

VgiC GI Tract ........................................................................... 0.035 1.30 0.017 ................ 1.10

VliC Liver ................................................................................ 0.045 1.20 0.026 ................ 1.10

VfatC Fat ................................................................................... 0.077 1.40 0.204 ................ 1.20

VppC Poorly Perfused Tissues ................................................. c 0.556 1.10 0.470 c .............. 1.15

VwpC Well Perfused Tissues .................................................... 0.065 1.15 0.044 ................ 1.10

VluC Lung ................................................................................ 0.008 1.30 0.008 ................ 1.15

VmarC Bone Marrow ................................................................... 0.033 1.50 0.050 ................ 1.10

Equilibrium Partition Coefficients:

Pblo Blood:Air .......................................................................... 13.7 1.80 8.4 .................... 1.30

Pgi GI Tract:Air ...................................................................... 10.5 1.20 8.1 .................... 1.60

Pli Liver:Air ........................................................................... 22.9 2.00 9.9 .................... 1.60

Pfat Fat:Air .............................................................................. 98.2 1.40 97.6 .................. 1.25

Ppp Poorly Perfused Tissues:Air ........................................... 9.5 1.30 6.8 .................... 1.60

Pwp Well Perfused Tissues:Air ............................................... 10.2 1.20 7.6 .................... 1.40

Plu Lung:Air ........................................................................... 10.0 1.30 7.6 .................... 1.50

Pmar Bone Marrow:Air ............................................................. 62.0 1.60 48.8 .................. 1.60

Metabolic Parameters:

VmaxC Maximum metabolic velocity of MFO saturable pathway

(mg/hr/kg—liver).

750 10.00 75 ..................... 10.00

KM Affinity of MFO saturable pathway (mg/l) ....................... 1.35 10.00 0.6 .................... 10.00

KFC First order rate constant for GST pathway (l/hr/

kg¥0.25).

1.5 10.00 Mouse post. d ... Mouse post. d

A1 Ratio of lung to liver in-vitro MFO metabolic velocities

(nmol/min/gm—lung—micros.Prot)/ (nmol/min/gm—

liver—micros.Prot).

0.405 1.67 0.0045 .............. 4.50

A2 Ratio of lung to liver in-vitro GST metabolic velocities

(nmol/min/gm—lung—cytos.Prot)/ (nmol/min/gm—

liver—cytos.Prot).

0.282 1.67 0.122 ................ 3.60

B1 Ratio of lung and liver tissue content of microsomal

protein.

0.271 1.25 0.297 ................ 1.10

B2 Ratio of lung and liver tissue content of cytosolic protein.0.721 1.25 0.807 ................ 1.20

Sp—Kf Allometric scaling power for body weight scaling of

KFC from mice to humans.

...................... ...................... ¥0.272 e .......... 0.08 e

Notes: (a) value computed for 0.025 kg mouse, 70 kg human; (b) unitless; (c) prior distribution not used, fractional flow made functionally dependent on others (see text); (d) human prior set equal to mouse posterior; (e) mean and standard deviation of a truncated normal distribution.

While it is desirable to separate

variability into components reflecting

pure uncertainty (e.g., measurement

error) versus interindividual

heterogeneity and to propagate them

separately, it is necessary to build from

the start an adequate statistical model.

The problem here is complicated by the

fact that both the rodent and human in

vivo data used for estimating metabolic

constants reflected either aggregated or

averaged pharmacokinetic behavior.

Thus the prior distributions and the

statistical model used here aggregate

variability due to both finite precision

in measured values and heterogeneity

among average values for small groups

of rodents or humans; they do not, it

must be emphasized, reflect

heterogeneity among the individual

humans in a large, representative

population.

e. In Vivo Rodent and Human data.

Bayesian updating of the distributions

was performed using the same data sets

used by Clewell et al. to obtain fitted

estimates of mouse and human

metabolic constants; namely, gas uptake

studies with mice with or without

pretreatment with a MFO inhibitor and

the human open chamber inhalation

studies. All mouse gas uptake studies

were conducted with 5 female mice in
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1547

a single chamber. Thus, measured

observations of decline in chamber

concentration of MC represent the

aggregate pharmacokinetic behavior of

groups of 5 animals.

The human in vivo data were obtained

from Tables 2 and 3 in Andersen et al.

(1991) [Ex. 21–94]. Briefly, these data

represent exhaled breath and venous

blood concentrations of MC for 6 male

human volunteers exposed to MC

concentrations of 100 or 350 ppm for a

period of 6 hours. These data have only

been reported as means and standard

deviations of the six subjects, which is

unfortunate. Thus, the available data

reflect the average pharmacokinetic

behavior of the 6 subjects. When

simulating the human data reported in

Andersen et al. (1991), the work load

was assumed to be zero watts (rest) and

the averaged body weight of the 6

subjects was assumed to be known

without error (86 kg).

f. Simulating the Rodent Bioassay and

Human Occupational Exposure.

Distributions for GST metabolism in the

lungs of mice exposed to 2000 ppm or

4000 ppm exposures, for 6 hrs/day and

5 days/week, were obtained by

simulating these two exposures (the

ones used in the NTP bioassay) with

5000 realizations drawn from the joint

posterior distribution of the mouse

PBPK parameters.

The quantity of metabolites formed

during the 4th week (dynamic

equilibrium reached) was divided by 7

to give an average measure per day. For

use as an input dose to the multistage

model, these posterior distributions

were approximated by truncated

lognormals.

The same set of 5000 parameter

vectors was used to simulate both 2000

and 4000 ppm MC exposures. The

control dose was always assumed to be

0. Thus, a 5000-by-3 matrix of doses was

generated, where the three column

vectors represent different realizations

of a particular dose group (0, 2000 and

4000 ppm MC) and the row vectors

represent different realizations of

bioassay doses.

This method of using the joint

posterior distributions for the two doses

in the mouse bioassay implies certain

assumptions about the uncertainties.

Most importantly, this approach

(referred to in this document as the

‘‘dependence case’’) assumes that the

posterior distributions primarily reflect

uncertainty about a single average value

equally applicable to all groups of

approximately 50 mice (i.e., it assumes

groups of 50 mice will have the same

‘‘average’’ physiological, anatomical,

physicochemical and metabolic

attributes, and that these average values

are simply known to us with

uncertainty). An alternative would be to

model the ‘‘independence case’’ by

using a different random draw from the

vector of PBPK parameters for one dose

group than for the other. This approach

assumes that the posterior distributions

primarily reflect heterogeneity in the

average attributes of groups of 50

rodents. Under the dependence case,

estimates of metabolized dose for the

two exposures would tend to move in

tandem for a given simulation (i.e.,

when one dose is estimated to be low

relative to its average, so is the other;

likewise, when one is high, so is the

other), and in principle would therefore

exhibit less variability in dose-response

shape (e.g., linear, sublinear,

supralinear).

It appears that the dependence case is

more reasonable than the independence

case, by appealing to biological theory

and by examining the results of the

sensitivity analysis conducted as part of

this risk assessment. The sensitivity

analysis showed that predicted mouse

GST metabolism at 2000 ppm was most

sensitive to variation in the model

parameter A2. Variability in A2 was

primarily a consequence of uncertainty

in using an in vitro ratio of enzymatic

activity to make inferences about an in

vivo ratio. Therefore, uncertainty rather

than heterogeneity seems to dominate

the distribution of mouse GST

metabolism estimates. Besides,

laboratory rodents have a carefully

controlled genetic makeup, primarily so

that they will differ little from each

other physiologically; thus, groups of 50

rodents should have extremely similar

average characteristics (the variance of

the mean of a characteristic within a

group of 50 rodents will be

approximately 50 times smaller than the

(already small) inter-individual

variance). OSHA has determined that

this reasoning supports use of the

dependence case in this analysis. (Note

that the excess risk estimates using the

dependence case are only about a factor

of 1.5 higher than those using the

independence case).

Five human occupational exposures

were simulated: constant exposure to

10, 25, 50, 100 or 500 ppm MC for 8-

hrs per day and 5 days per week.

Simulations were made up to 4 weeks

of work, at which a dynamic

equilibrium was reached, and as with

mice, were performed using 5000

parameter human vectors drawn from

their joint posterior distribution,

augmented by allowing for additional

variability in human body weight and

work intensity (the latter linked to

changes in cardiac, ventilationperfusion and regional blood flow as

described above).

g. Sensitivity Analysis. The influence

of variability in mouse and human

PBPK model parameters on variability

in predicted mouse and human GST

lung metabolism was assessed by

computing pairwise correlation

coefficients using each parameter vector

(i.e., the marginal posterior distribution)

and the corresponding vector of model

predictions. For mice, the sensitivity to

predicted GST—lung metabolism in the

simulated 2000 ppm bioassay dose

group was evaluated. For humans,

predicted GST—lung metabolism for an

occupational exposure to 25 ppm was

considered. Pairwise correlation

coefficients were computed using 5000

parameter vectors drawn from the joint

posterior distribution and the associated

model output vector.

Table VI–6 presents the results from

the sensitivity analysis. The strongest

pairwise correlation between predicted

lung GST metabolism and any input

parameter, for either mouse or human

simulations, was A2. For the mouse

simulation of a 2000 ppm exposure, B2

gave the next strongest pairwise

correlation. The mouse parameters

QlivC, VlivC, VmaxC, Pfat and QppC all

exhibited more moderate (though not

negligible) correlations. For the human

occupational simulation, the parameters

KfC, VmaxC, SplKf, and B2 all

exhibited moderate pairwise

correlations with human lung GST

metabolism. For both mice and human

sensitivity analyses, there were a halfdozen or more parameters exhibiting

weak (r between 0.1 and 0.2)

correlations. It is important to note that

all parameters are further correlated via

their posterior joint distribution

function. This explains why the sum of

the regression coefficients (i.e., squares

of the correlation coefficients) is greater

than 1. Thus considerable care should

be exercised in quantitatively estimating

the ability of variability in any input

parameter to explain variability in

predicted GST metabolism, especially

among parameters with similar pairwise

correlation coefficients.
1548 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

TABLE VI–6.—CORRELATION COEFFICIENTS FOR TOTAL GST LUNG METABOLISM FROM MONTE CARLO ANALYSIS USING

MOUSE AND HUMAN POSTERIOR DISTRIBUTIONS

Mouse 2000 PPM Human 25 PPM

Parameter

Correlation

coefficient

(r)

Parameter

Correlation

coefficient

(r)

A2 ................................................................................................................................................. 0.860 A2 0.850

B2 ................................................................................................................................................. 0.530 KfC 0.315

QliC .............................................................................................................................................. 0.335 VmaxC ¥0.291

VliC ............................................................................................................................................... ¥0.248 Sp—Kf 0.232

VmaxC ......................................................................................................................................... ¥0.229 B2 0.221

Pfat ............................................................................................................................................... ¥0.203 Pmar ¥0.183

QppC ............................................................................................................................................ ¥0.202 QfatC 0.180

VPR .............................................................................................................................................. 0.193 B1 0.179

Pli ................................................................................................................................................. ¥0.173 VliC 0.161

A1 ................................................................................................................................................. ¥0.149 VmarC 0.146

QgiC ............................................................................................................................................. ¥0.145 Work 0.142

Pmar ............................................................................................................................................. 0.144 QwpC 0.141

VwpC ............................................................................................................................................ ¥0.121 VfatC 0.136

KfC ............................................................................................................................................... 0.120 QmarC 0.136

Pwp .............................................................................................................................................. ¥0.106 Km ¥0.095

VluC ............................................................................................................................................. ¥0.120 QC ¥0.083

B1 ................................................................................................................................................. ¥0.093 QliC ¥0.083

QmarC .......................................................................................................................................... ¥0.083 A1 ¥0.071

Ppp ............................................................................................................................................... ¥0.076 QgiC ¥0.065

VgiC ............................................................................................................................................. 0.074 Pfat ¥0.061

Pgi ................................................................................................................................................ 0.054 Pwp ¥0.058

QC ................................................................................................................................................ ¥0.049 VluC ¥0.052

BW ............................................................................................................................................... ¥0.042 Pgi ¥0.050

Plu ................................................................................................................................................ 0.039 VwpC 0.041

Km ................................................................................................................................................ ¥0.035 Pblood 0.039

tVmaxC ........................................................................................................................................ 0.024 dVPR/dW 0.039

QfatC ............................................................................................................................................ 0.020 BW ¥0.038

Pblood .......................................................................................................................................... 0.019 dQli/dW ¥0.033

VfatC ............................................................................................................................................ ¥0.013 Plu 0.023

Vmar ............................................................................................................................................. ¥0.007 Ppp 0.021

dQfat/dW 0.016

VgiC ¥0.012

Pli ¥0.010

dQgi/dW ¥0.010

dQmar/dW ¥0.009

VPR 0.006

dQC/dW ¥0.000

dQwp/dW ¥0.000

h. Posterior PBPK Parameter

Distributions. Table VI–7 lists the

posterior distributions for mouse PBPK

parameters obtained by Bayesian

updating of the prior distributions using

the available gas uptake data.

Comparison of the prior and posterior

probability distributions reveals that the

gas uptake data retain considerable

influence on the distributions of many

of the important PBPK model

parameters. Medians of the posterior

distributions for VPR, Qfat, Pblood,

Pmar, Km, A1, and A2 were all

appreciably different than the medians

for their corresponding prior

distributions. Percent CVs for nearly all

posterior distributions were

considerably smaller than those of their

prior distributions. As expected, the

marginal variances for the metabolic

constants were considerably greater

than what was obtained under nonlinear

maximum likelihood regression analysis

with all other model parameters fixed at

nominal values.

TABLE VI–7. PRIOR AND POSTERIOR (FITTED) DISTRIBUTIONS OF THE MOUSE MODEL PARAMETERS

Parameter

Central tendency

Maximum

posterior

Variability

Prior median Posterior

median Prior %CV Posterior%CV

Flows:

QCC Cardiac Output (l/hr/kglBW) .......................... 34.8 34.4 37.6 18 9

VPR Alveolar Ventilation Perfusion Ratio ................ 1.22 1.59 1.49 75 14

Tissue Blood

Flows (fraction

of cardiac output):

QgiC GI Tract ............................................................ 0.165 0.140 0.175 26 16
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1549

TABLE VI–7. PRIOR AND POSTERIOR (FITTED) DISTRIBUTIONS OF THE MOUSE MODEL PARAMETERS—Continued

Parameter

Central tendency

Maximum

posterior

Variability

Prior median Posterior

median Prior %CV Posterior%CV

QliC Liver ................................................................. 0.017 0.020 0.017 19 16

QfatC Fat .................................................................... 0.047 0.090 0.098 43 19

QppC Poorly Perfused Tissues .................................. 0.276 0.290 0.243 22 18

QwpC Well Perfused Tissues ..................................... 0.369 a 0.360 0.378 a

QmarC Bone Marrow ................................................... 0.089 0.100 0.090 51 27

Tissue Volumes

(fraction of

body weight):

VgiC GI Tract ............................................................ 0.035 0.040 0.038 26 22

VliC Liver ................................................................. 0.045 0.050 0.050 18 12

VfatC Fat .................................................................... 0.077 0.070 0.055 35 24

VppC Poorly Perfused Tissues .................................. 0.556 b 0.540 0.569 b

VwpC Well Perfused Tissues ..................................... 0.065 0.070 0.065 14 12

VluC Lung ................................................................. 0.008 0.010 0.007 27 22

VmarC Bone Marrow ................................................... 0.033 0.040 0.037 42 29

Equilibrium Partition Coefficients:

Pblo Blood:Air .......................................................... 13.7 18.5 13.1 66 18

Pgi GI Tract:Air ...................................................... 10.5 11.3 9.5 19 17

Pli Liver:Air ............................................................ 22.9 28.2 23.9 79 32

Pfat Fat:Air .............................................................. 98.2 100.5 106.7 35 21

Ppp Poorly Perfused Tissues:Air ............................ 9.5 12.1 13.1 27 17

Pwp Well Perfused Tissues:Air ............................... 10.2 10.4 10.3 19 16

Plu Lung:Air ............................................................ 10.0 11.3 12.5 27 22

Pmar Bone Marrow:Ait .............................................. 62.0 70.4 89.2 50 25

Metabolic Parameters:

VmaxC Maximum metabolic velocity of MFO saturable pathway (mg/hr/kglliver).750 718 661 1413 12

tVmaxC Maximum metabolic velocity of MFO saturable pathway in t-DCE pretreated mice.8.4 7.2 11.3 58 50

Km Affinity of MFO saturable pathway (mg/l) ........ 1.35 0.04 0.03 1413 97

KfC First order rate constant for GST pathway (l/

hr/kg∧0.25).

1.5 1.77 2.47 1413 24

A1 Ratio of lung to liver in-vitro MFO metabolic

velocities (nmol/min/

gmllunglmicros.Prot)/(nmol/min/

gmlliverlmicros.Prot).

0.405 0.28 0.30 54 31

A2 Ratio of lung to liver in-vitro GST metabolic

velocities (nmol/min/gmllunglcytos.Prot)/

(nmol/min/gmlliverlcytos.Prot).

0.282 0.37 0.30 55 41

B1 Ratio of lung and liver tissue content of

microsomal protein.

0.271 0.26 0.29 23 18

B2 Ratio of lung and liver tissue content of

cytosolic protein.

0.721 0.70 0.84 22 17

Notes: (a) functionally defined as 1lsum (other fractional flows); (b) functionally defined as 0.82lsum (other fractional volumes).

Table VI–8 presents the

corresponding set of results for human

PBPK parameters. The human in vivo

data also appeared to contain

considerable information about many of

the model parameters, as evidenced by

shifts in medians and tightening of

posterior distributions relative to priors.

Fitted estimates of the metabolic

constants were fairly precise, even for

Km (Table VI–8); indeed, the fits were

markedly superior to those shown in

Andersen et al. [Ex. 21–94] and Clewell

et al. [Ex. 96].

TABLE VI–8.—Prior and Posterior (Fitted) Distributions of the Human Model Parameters

Parameter

Prior distribution Posterior distribution

GM GSD %CV

Posteriors for Bayesian fit Modified by exercise

Median %CV Median %CV

Flows:

QCC Cardiac Ouput (1/

hr/kglBW).

4.2 1.10 10 4.0 6 6.2 17
1550 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

TABLE VI–8.—Prior and Posterior (Fitted) Distributions of the Human Model Parameters—Continued

Parameter

Prior distribution Posterior distribution

GM GSD %CV

Posteriors for Bayesian fit Modified by exercise

Median %CV Median %CV

VPR Alveolar Ventilation Perfusion

Ratio.

1.35 1.15 15 1.03 1 1.37 9

Tissue Blood

Flows (fraction of cardiac

output):

............................. ...................... ...................... .................... ...................... .................... ...................... ....................

QgiC GI Tract .............. 0.191 1.25 23 0.149 12 0.122 14

QliC Liver .................... 0.067 1.20 19 0.063 15 0.041 24

QfatC Fat ...................... .057 1.45 38 0.045 10 0.052 11

QppC Poorly Perfused

Tissues.

0.198 1.55 a 0.378 a 9 a 0.453 10

Qwpc Well Perfused

Tissues.

0.443 1.25 23 0.294 3 0.258 7

QmarC Bone Marrow ...... 0.044 1.70 57 0.071 38 0.072 38

Tissue Volumes

(fraction of

body weight):

............................. ...................... ...................... .................... ...................... .................... ...................... ....................

VgiC GI Tract .............. 0.017 1.10 10 0.018 8 0.018 8

VliC Liver .................... 0.026 1.10 10 0.026 8 0.026 8

VfatC Fat ...................... 0.204 1.20 18 0.183 11 0.183 11

VppC Poorly Perfused

Tissues.

0.470 1.15 b 0.489 b 5 b 0.489 5

VwpC Well Perfused

Tissues.

0.044 1.10 9 0.47 7 0.047 7

VluC Lung .................... 0.008 1.15 14 0.008 11 0.008 11

VmarC Bone Marrow ...... 0.050 1.10 10 0.049 8 0.049 8

Equilibrium Partition Coefficients:............................. ...................... ...................... .................... ...................... .................... ...................... ....................

PC.blood Blood:Air ............. 8.4 1.30 26 16.5 2 16.5 2

PC.gi GI Tract:Air ......... 8.1 1.60 50 10.7 36 10.7 36

PC.li Liver:Air .............. 9.9 1.60 50 13.7 33 13.7 33

PC.fat Fat:Air ................. 97.6 1.25 22 84.4 12 84.4 12

PC.pp Poorly Perfuse

Tissue:Air.

6.8 1.60 48 13.3 13 13.3 13

PC.wp Well Perfused

Tissue:Air.

7.6 1.40 35 13.1 14 13.1 14

PC.lu Lung:Air .............. 7.6 1.50 43 9.4 33 9.4 33

PC.mar Bone Marrow:Air 48.8 1.60 49 47.8 27 47.8 27

Metabolic Parameters:............................. ...................... ...................... .................... ...................... .................... ...................... ....................

VmaxC Maximum MFO

metabolic rate

(mg/mg/hr/kg–

liver).

75.0 10.00 1413 97.2 11 97.2 11

Km MFO Michaelis

Menton constant (mg/1).

0.60 10.00 1413 0.52 39 0.52 39

Kf 1st order rate

constant for

GST pathway

(1/hr).

0.12 2.07 81 0.23 63 0.23 63

A1 [V/S]–lung/[V/S–

MFO–liver.

0.0045 4.50 226 0.024 77 0.024 77

A2 [V/S]–lung/[V/S]–

GST–liver.

0.236 2.04 83 0.364 49 0.364 49

B1 [mg micr.Prot/gm

lung]/[mg

micr.Prot/gm

liver].

0.297 1.10 10 0.300 8 0.300 8

B2 [mg cyt. Prot/gm

lung]/[mg

cyt.Prot/gm

liver].

0.807 1.20 18 0.845 15 0.845 15

Notes (a) operationally defined as 1—sum (other fractional flows); (b) functionally defined as 0.82—sum (other fractional volumes).
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1551

Tables VI–9 and VI–10 compare the posterior distributions for mice and human PBPK parameters with the distributions

used by Clewell. For mice, there were appreciable differences in the median values for QCC, VPR, QfatC, QwpC,

VwpC, VmaxC, Km, KfC, and the apparent A1 (i.e., A1 × B1). With the exception of VliC, Pblood, Pliv, Ppp and

Km, the posterior distributions for all other parameters were tighter than the distributions used by Clewell. The human

posterior distributions in Table VI–10 are somewhat different than those in Table VI–8, in that they reflect the influence

of modeling variable work intensity on QC, VPR, and all regional blood flows. In comparing these modified posterior

distributions to the distributions used by Clewell, one finds appreciable differences in median values for VPR, many

of the fractional blood flows (QgiC, QliC, QppC, QwpC), VgiC, PCblood, PCliv, PCfat, VmaxC, KfC, and the apparent

A2 (i.e., A2 × B2). All human posterior distributions except for VliC, Pli, and SplKf, had appreciably tighter distributions

than those used by Clewell et al. [Ex. 96].

TABLE VI–9.—COMPARISON OF MOUSE PROBABILITY DISTRIBUTIONS USED BY CLEWELL ET AL. WITH OSHA’S POSTERIOR

PROBABILITY DISTRIBUTIONS

Parameter

Central tendency Variability

Clewell et al.

median

OSHA medianClewell et

al. %CV OSHA %CV

Flows:

QCC Cardiac Output (1/hr/kglBW) ............................................. a 41.5 34.4 9 9

VPR Alveolar Ventilation Perfusion Ratio ..................................... b 1.76 1.59 58 14

Tissue Blood Flows

(fraction of cardiac

output):

QgiC GI Tract ................................................................................ 0.165 0.14 25 16

QliC Liver ...................................................................................... 0.035 0.02 96 16

QfatC Fat ........................................................................................ 0.030 0.09 60 19

QppC Poorly Perfused Tissues ...................................................... 0.250 0.29 40 18

QwpC Well Perfused Tissues ......................................................... 0.520 c 0.36 50 c

QmarC Bone Marrow ........................................................................ NA 0.10 NA 27

Tissue Volumes (fraction of body weight):

VgiC GI Tract ................................................................................ 0.031 0.04 30 22

VliC Liver ...................................................................................... 0.046 0.05 6 12

VfatC Fat ........................................................................................ 0.100 0.07 30 24

VppC Poorly Perfused Tissues ...................................................... 0.513 d 0.54 30 d

VwpC Well Perfused Tissues ......................................................... 0.041 0.07 30 12

VluC Lung ...................................................................................... 0.008 0.01 30 22

VmarC Bone Marrow ........................................................................ NA 0.04 NA 29

Equilibrium Partition

Coefficients:

Pblo Blood:Air ............................................................................... 23.0 18.5 15 18

Pgi GI Tract:Air ........................................................................... 11.4 11.3 30 17

Pli Liver:Air ................................................................................ 38.7 28.2 20 32

Pfat Fat:Air ................................................................................... 107.0 100.5 30 21

Ppp Poorly Perfused Tissues:Air ................................................. 8.5 12.1 10 17

Pwp Well Perfused Tissues:Air .................................................... 11.4 10.4 20 16

Plu Lung:Air ................................................................................ 10.0 11.3 30 22

Pmar Bone Marrow:Air ................................................................... NA 70.4 NA 25

Metabolic Parameters:

VmaxC Maximum metabolic velocity of MFO saturable pathway

(mg/hr/kglliver).

970 718 20 12

Km Affinity of MFO saturable pathway (mg/l) ............................. 1.35 0.04 30 97

KfC First order rate constant for GST pathway (l/hr/kgl0.25) .. 1.5 1.77 30 24

A1 Ratio of lung to liver in-vitor MFO metabolic velocities

(nmol/min/gmllunglmicros.Prot)/(nmol/min/

gmlliverlmicros.Prot).

0.405 0.28 50 31

A2 Ratio of lung to liver in-vitro GST metabolic velocities

(nmol/min/gmllunglcytos.Prot)/(nmol/min/

gmlliverlcytos.Prot).

0.282 0.37 50 41

B1 Ratio of lung and liver tissue content of microsomal protein 1 0.25 0 18

B2 Ratio of lung and liver tissue content of cytosolic protein ... 1 0.69 0 17

Notes: (a) value computed for 0.025 kg mouse; (b) unitless; (c) functionally defined as 1—sum (other fractional flows); (d) functionally defined

as 0.82—sum(other fractional volumes); (na) not applicable.

TABLE VI–10. COMPARISON OF HUMAN PROBABILITY DISTRIBUTIONS USED BY CLEWELL ET AL. WITH OSHA’S POSTERIOR

PROBABILITY DISTRIBUTIONS

Parameter

Central tendency Variability

Clewell et al.

median

OSHA medianClewell et

al. %CV OSHA %CV

Flows:
1552 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

TABLE VI–10. COMPARISON OF HUMAN PROBABILITY DISTRIBUTIONS USED BY CLEWELL ET AL. WITH OSHA’S POSTERIOR

PROBABILITY DISTRIBUTIONS—Continued

Parameter

Central tendency Variability

Clewell et al.

median

OSHA medianClewell et

al. %CV OSHA %CV

QCC Cardiac Output (l/hr/kglBW) ....................................................... a 6.2 c 6.3 9 c 17

VPR Alveolar Ventilation Perfusion Ratio .............................................. b 1.95 c 1.36 18 c 9

Tissue Blood

Flows (fraction

of cardiac output):

QgiC GI Tract ......................................................................................... 0.195 c 0.12 10 c 13

QliC Liver ............................................................................................... 0.070 c 0.04 35 c 23

QfatC Fat ................................................................................................. 0.050 c 0.05 30 c 15

QppC Poorly Perfused Tissues ............................................................... 0.240 c 0.46 15 c 10

QwpC Well Perfused Tissues .................................................................. 0.445 c, d 0.26 20 c, d 7

QmarC Bone Marrow ................................................................................. NA c 0.07 NA c 45

Tissue Volumes

(fraction of

body weight):

VgiC GI Tract ......................................................................................... 0.045 0.017 10 8

VliC Liver ............................................................................................... 0.023 0.026 5 8

VfatC Fat ................................................................................................. 0.160 0.187 30 12

VppC Poorly Perfused Tissues ............................................................... 0.480 e 0.483 30 e 5

VwpC Well Perfused Tissues .................................................................. 0.033 0.047 10 7

VluC Lung ............................................................................................... 0.006 0.008 10 12

VmarC Bone Marrow ................................................................................. NA 0.050 NA 8

Equilibrium Partition Coefficients:

Pblo Blood:Air ........................................................................................ 12.9 16.5 15 2

Pgi GI Tract:Air .................................................................................... 12.0 13.5 30 31

Pli Liver:Air ......................................................................................... 37.4 13.6 20 34

Pfat Fat:Air ............................................................................................ 117.0 81.2 30 13

Ppp Poorly Perfused Tissues:Air .......................................................... 10.0 13.3 10 14

Pwp Well Perfused Tissues:Air ............................................................. 12.0 13.0 20 14

Plu Lung:Air ......................................................................................... 10.6 9.1 30 32

Pmar Bone Marrow:Air ............................................................................ NA 51.2 NA 35

Metabolic Parameters:

VmaxC Maximum metabolic velocity of MFO saturable pathway (mg/hr/

kglliver).

75.2 94.2 30 12

Km Affinity of MFO saturable pathway (mg/l) ..................................... 0.4 0.49 50 35

KfC First order rate constant for GST pathway (l/hr/kg¥0.25) ........... 1.5 1.82 50 24

A1 Ratio of lung to liver in-vitro MFO metabolic velocities (nmol/min/

gmllunglmicros. Prot)/(nmol/min/gmlliverlmicros.Prot).

0.015 0.03 70 69

A2 Ratio of lung to liver in-vitro GST metabolic velocities (nmol/min/

gmllunglcytos.Prot)/ (nmol/min/gmlliverlcytos.Prot).

0.18 0.45 70 71

B1 Ratio of lung and liver tissue content of microsomal protein ........ 1.0 0.31 0 8

B2 Ratio of lung and liver tissue content of cytosolic protein ............ 1.0 0.84 0 14

SplKf Allometric scaling power for body weight scaling of KFC from

mice to humans.

¥0.25 ¥0.267 0 22

Notes: (a) value computed for 70 kg human; (b) unitless; (c) posterior distributions adjusted for effects of light activity; (d) functionally defined

as 1—sum(other fractional flows); (d) functionally defined as 0.82—sum(other fractional volumes); (NA) not applicable.

i. Alternative analysis using the

‘‘parallelogram’’ approach. Andersen et

al. [Ex. 21–94] estimated a human first

order rate constant (Kf) for glutathione

(GST) metabolism of MC in the liver by

allometric scaling of a fitted estimate of

an in vivo mouse rate constant

(KfCmouse). Specifically,

Kf KfC human mouse = X BWspKf

where spKf was the allometric scaling

power with value ¥0.25. In their Monte

Carlo analysis, Clewell et al. followed

the approach of Andersen et al., treating

KfCmouse as a lognormally distributed

random variable and spKf as a known

constant. The Bayesian analysis

summarized above also made use of the

allometric scaling given by the equation

above, but prior probability

distributions were specified for both

KfCmouse and spKf.

Reitz et al. (1988, 1989) [Exs. 7–225

and 21–53] proposed an alternative

approach for estimating an apparent in

vivo human Kf. The approach, referred

to as the ‘‘parallelogram method,’’

assumes there is a constant

proportionality across species between

in vitro and apparent in vivo metabolic

rates when normalized for substrate

concentration ([S]). For example, the

equation modeling the apparent in vivo

rate of GSH conjugation (dMGST/dt) is

given by:

dM

dt

Kf S Vol GST = × × liver [ ]

The constant proportionality between

apparent in vivo rates of metabolism and

in vitro rates implies
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1553

dM dt

S

k V S Kf Vol GST

p GST liver

/

[ ]

= × = × [ / ]

where [V/S]GST denotes an in vitro

enzymatic rate normalized to [S] and kp

the in vivo—in vitro proportionality

constant. This approach assumes a

common value of kp across species, such

that knowledge of a [V/S]GST-rodent and

Kfrodent (sufficient to estimate a value for

kp as the ratio of Kfrodent to [V/S]GST-rodent)

and knowledge of [V/S]GST-human

is sufficient to estimate the remaining

corner of a parallelogram, namely

Kfhuman. Therefore, this approach

assumes,

[ / ]

[ / ]

V S

V S

Kf

Kf

GST

GST

human

rodent

human

rodent

=

or:

Kf V S Kf

V S human GST

rodent

GST human

rodent

= × [ / ] [ / ]

Reitz et al. [Ex. 21–53] obtained an

estimate for Kfhuman using the

parallelogram method that was very

similar to the estimate obtained by

Andersen et al. [Ex. 21–94] using

allometric scaling. However, Reitz and

coworkers estimated a mean [V/

S]GST-human based on liver samples from

only four human subjects—three of

which had appreciable enzymatic

activity and one with no detectable

activity. More recent publications

(Bogaards et al., 1993 [Ex. 127–16];

Graves et al., 1995 [Ex. 122]) and

unpublished data (Green et al., 1987

[Ex. 14]) provide measured values of [V/

S]GST on another 35 human subjects.

These additional data demonstrate

considerable variation in rates of GST

metabolism among human subjects,

consistent with a known human

polymorphism for GST, described

earlier in this Quantitative Risk

Assessment. Moreover, these data

indicated that, putting aside questions

of interlaboratory comparability of

measurements, three of the four human

samples used by Reitz et al. had GST

metabolic rates among the highest

reported to date. Consequently, the

mean [V/S]GST-human used by Reitz and

coworkers was greater than the mean

estimable from the full complement of

data on human GST activity.

Since OSHA was interested in

assessing the effect of accounting for the

full complement of data on human GST

activity on estimates of cancer risk, this

additional analysis was performed,

despite the Agency’s reservations

concerning the appropriateness of using

the parallelogram approach in the MC

risk assessment. Although this approach

allows the use of all of the available

data, the uncertainties in the ratio of in

vitro to in vivo metabolic constants raise

serious questions for the utility of this

analysis. OSHA is presenting this

analysis for purposes of comparison and

notes that HSIA and Clewell used

allometric adjustments in their final

PBPK models.

The use of a Kfhuman derived by the

parallelogram method required: (1)

modification of the human PBPK model;

(2) specification of a prior probability

distribution for Kfhuman; (3) replication of

the Bayesian analysis of the human in

vivo open chamber data using the new

prior for Kfhuman; (4) simulation of the

occupational exposure scenario using

the joint posterior distributions from the

new Bayesian analysis to obtain a

posterior distribution for human GST

lung metabolism; and (5) re-estimation

of the extra cancer risk.

(1) PBPK Model Modifications. The

only structural modification to the

PBPK models was to replace the

parameter for allometric scaling of

Kfmouse with a direct insert of a model

parameter Kfhuman, having its own prior

probability distribution.

(2) Prior Probability Distributions.

Mouse prior probability distributions

were unchanged. Prior probability

distributions for human model

parameters were also unchanged, with

the exception of prior distributions for

KfC, spKf and A2. Prior probability

distributions for KfC and spKf were

replaced with a prior probability

distribution for Kfhuman. The prior

probability distribution for A2 was

modified to account for additional data

on human lung GST activity submitted

to OSHA by HSIA [Ex. 122].

The prior probability distribution for

Kfhuman was derived using the equation:

Kf Kf

V S

V S

err human rodent

GST

GST

k human

rodent

p = × ×

[ / ]

[ / ]

where errkp is an error term added to

account for uncertainty in estimating

the proportionality constant kp, as

kmouse. Thus, to derive a prior

probability distribution for Kfhuman, it

was necessary to derive prior

distributions for Kfrodent, [V/S]GST-rodent,

[V/S]GST-human and errkp, which in turn

were propagated using Monte Carlo

techniques in accordance with the

relationships specified by the equation

above.

(i) Prior distribution for rodent Kf. The

posterior probability distribution used

in the main analysis for the apparent in

vivo rodent KfC parameter was used as

the basis for a prior probability

distribution for Kfrodent. The posterior

distribution was well described by a

truncated lognormal distribution with a

mean and standard deviation of 1.8 and

0.43 l/hr/bw /¥0.25, and lower and upper

truncations at 0.84 and 3.07 l/hr/bw / ¥0.25, respectively. The posterior

distribution was converted to units of

(hour) ¥1 by using Monte Carlo

techniques to multiply the truncated

lognormal by the scalar, (rodent body

weight) ¥0.25.

(ii) Prior for rodent liver GST [V/S]. A

prior probability distribution for a low

dose mouse [V/S]GST was obtained as

the ratio of the fitted estimates of in

vitro Vmax and Km reported by Reitz et

al. for liver glutathione conjugation of

MC. The fitted estimates of Vmax and Km

and their associated standard errors

were used to set the parameters for

normal distributions. Monte Carlo

techniques were used to obtain the ratio

of these two distributions (i.e., Vmax/Km),

under the assumption that the joint

sample space for Vmax and Km was

correlated with a π = 0.9. Correlation

was induced because a reanalysis of the

mouse in vitro reported in Reitz et al.

showed that the joint parameter space

for these two fitted parameters was

highly correlated.

(iii) Prior distribution for human GST

[V/S]. There were four data sets

reporting measured values of in vitro

GST activity in liver samples from 39

human subjects. These data reflect work

from different laboratories using (in

some cases) different assay methods and

different substrate concentrations. In

order to make use of all the data to

estimate central tendencies and

population variability, it was necessary

that all measurements be placed on a

common scale.

With respect to assay methods, two of

the studies [Exs. 21–53 and 122]

reported measured values of [V/S]GST

based on detection of [36]Cl from

labelled MC. The other two studies [Exs.

14 and 127–16] reported values of [V/

S]GST based on detection of

formaldehyde, a known decomposition

product from GSH conjugation with MC.

In a comparison of these two methods,

Green et al. [Ex. 14] reported results

indicating a systematic difference in

measured values of [V/S]GST, with the

[36]Cl detection method appearing to

give estimates approximately 1.7-fold

higher than the formaldehyde detection

method. In this analysis, the [36]Cl

method was chosen as the common

scale, since the mouse [V/S]GST data

used above were based on this method.

Thus, the formaldehyde assay results

were multiplied by 1.7 to put them on

the [36]Cl scale.

Adjustments for both substrate

concentration and nonlinear metabolism

were made by converting all the
1554 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

1Since the single observation of [V]GST-lung

reported by Reitz et al. (1988) was from a pooled

sample of lung tissue from two human subjects, the

data point was treated as two observations with the

same value.

reported in vitro velocity data, [V]GST, to

Vmax/Km ratios (i.e., low dose metabolic

velocity), by the equation:

V

K

V K S S

m K

GST m

m

max ([ ] ( [ ]))/[ ] = × +

The above equation follows from

assuming in vitro kinetics can be

reasonably modeled as a single-substrate

Michaelis-Menton process (i.e., [V]GST =

{Vmax x [S]}/{Km + [S]}). In making

adjustments, assay specific substrate

concentrations were used (i.e., [S],

which ranged from 35 to 94 mM) along

with the average estimate of an in vitro

Km reported by Reitz et al. [Ex. 21–53]

in analysis of data from two human

subjects ( 44 mM). It is noteworthy that

none of the human in vitro [V/S]gst data

reported in Reitz et al. were truly

reflective of linear kinetics, whereas the

mice data were.

After the two above adjustments were

made, a lognormal distribution was fit

to the transformed data yielding a GM

of 0.031 l/min/mg protein, and a GSD of

2.72. This distribution models

intersubject variability in in vitro

metabolic activity. However, the prior

probability distribution for [V/S]gst-human

should reflect variation in means of six

subjects, because the in vivo human data

from Dow Chemical Company reflect

the averaged pharmacokinetic behavior

of tissue from six subjects. Thus,

dispersion in the above distribution was

adjusted to give the corresponding

sampling distribution for means of n =

6.

(iv) Prior distribution for error term.

The in vivo and in vitro metabolic

data on the MFO metabolic pathway,

reported by Reitz et al. [Ex. 21–53], were

used to estimate the uncertainty in

assuming a constant kp across species.

These were the only data for which both

in vivo and in vitro information was

available on several species and which

was directly relevant to MC. To avoid

artifacts due to the very imprecise fitted

estimates of apparent in vivo Km’s, in

vivo / in vitro comparisons were

constructed based on estimates of Vmax

alone. These estimates were then

normalized by the ratio obtained for

mice, providing a measure of the error

in using a mouse ratio to estimate ratios

in three other species: rats (1.42),

hamsters (0.64), and humans (0.41). The

GM (0.72) and GSD (1.89) of these three

values were used to set parameters for

a lognormal distribution used as the

prior probability distribution for errkp.

Note that the human value of 0.41

reflected an average of separate

estimates on four human subjects, with

ratios ranging from 0.1 to 1.0.

(v) Monte Carlo simulation to obtain

a prior for human Kf. The above prior

probability distributions for Kfmouse, [V/

S]gst-mouse, [V/S]GST and errkp were

independently sampled by Monte Carlo

techniques (n = 5000) and combined to

give a prior distribution for Kfhuman for

use in Bayesian analysis of the human

open chamber data.

(vi) Revised prior distribution for A2.

A2 is the ratio of in vitro GST

enzymatic activity in lung tissue to the

same activity in liver tissue. In the main

analysis, the prior probability

distribution for A2 was derived

according to the equation:

A

V S

V S

err

GST

GST

vivo vitro

lung

liver

2 = ×

[ / ]

[ / ] /

where errvivo/vitro is an error term to

account for uncertainty in using a ratio

of in vitro activity to make inferences

about in vivo activity, and the data of

Reitz et al. [Ex. 21–53] were used to

estimate prior distributions for [V/

S]GST-lung and [V/S]GST-liver. This prior

distribution was revised to account for

additional human [V/S]GST-lung and [V/

S]GST-liver data.

(vii) Prior for human lung GST [V/S].

Previously, only a single measured

value for [V]GST-lung from a pooled lung

sample from two human subjects was

available for estimating A2. Mainwaring

et al. [Ex. 124] recently submitted

additional [V]GST-lung data to OSHA,

consisting of measured values on three

additional human subjects (0.00, 0.06

and 0.21 nmol/min/mg protein). The

value reported as 0.00 was assumed

equal to one-half the detection limit for

the assay. Since these new [V]GST-lung

data were obtained using the

formaldehyde detection assay, it was

necessary to transform the values to the

[36]Cl scale. Lacking direct information,

it was assumed that the same HCOOH

‰ [36]Cl correction factor derived for

the liver data held for the lung data. A

correction for substrate concentration

was also made, under the assumption of

equivalency in lung and liver in vitro

Km’s. The resulting transformed

[V]GST-lung data were used to construct a

prior probability distribution describing

uncertainty in the mean of five 1

observations (GM = 0.00082, GSD =

1.61). Note that, in this case, an attempt

was made to model pure uncertainty in

a low dose [V/S]GST-lung, without

information indicating appreciable

heterogeneity in the ratio of lung and

liver enzymatic activity within an

individual.

(viii) Prior probability distribution for

uncertainty in human liver GST [V/S].

Because of the focus on uncertainty in

A2, the prior probability distribution for

[V/S]GST-liver derived above was

modified to describe uncertainty about

the mean, given a sample size of 39

subjects.

(ix) Uncertainty in using an in vitro

ratio of lung and liver GST activity to

make an inference about the

corresponding ratio for apparent in vivo

GST activity. A prior probability

distribution for errvivo/vitro was derived

using data on in vivo and in vitro ratios

of liver MFO enzymatic activity for

different species, as a surrogate for intraspecies lung versus liver GST enzymatic

activity. Thus, two key assumptions are

made: (i) That relative enzymatic

activity for liver tissue from two species

is a reasonable surrogate for relative

activities of lung versus liver tissue

within a single species, and (ii) that the

degree of consistency in ratios of in vivo

versus in vitro enzymatic activity will be

the same for either MFO or GST

mediated processes.

If the apparent in vivo Vmax for the

MFO pathway in the lung was modeled

as:

V V

V S

V S

Vol

Vol MFOlung MFOliver

lung

liver

MFO

MFO

lung

liver

max max

[ / ]

[ / ] = × ×

it follows that, V A

V A

V S

V S

MFO

MFO

MFO

MFO

lung

liver

lung

liver

max

max

[ / ]

[ / ] = where VmaxA denotes normalization

of Vmax to unit tissue volume.

Although there were insufficient data to
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1555

allow for a direct evaluation of the

above equation, the data tabulated by

Reitz et al. [Ex. 7–225] for MFO

enzymatic activity in mice, rats and

hamsters did allow an evaluation of the

equality,

V A

V A

V S

V S

MFO

MFO

MFO

MFO

liversp

liversp

liversp

liversp

max

max

[ / ]

[ / ]

1

2

1

2

=

where the subscripts sp1 and sp2

denote species 1 and 2 (e.g., mouse and

rat). Using the apparent in vivo Vmax

and in vitro [V/S] data reported in Reitz

et al. [Exs. 7–225 and 21–53], it was

possible to compute mouse:rat,

hamster:mouse and rat:hamster ratios

for in vivo Vmax and in vitro [V/S] as

shown in table VI–11, below.

TABLE VI–11.—Interspecies

Comparison of MFO Activity

Species ratio

Ratios of MFO enzymatic

activity

in vivo

Vmax

in vitro

[V/S]

FoldDifference *

Rat: mouse ........ 0.49 0.36 1.36

Mouse: hamster 1.20 0.79 1.53

Hamster: rat ...... 0.59 0.28 2.06

* Ratio of values in in vivo Vmax column to

values in in vitro [V/S] column.

The assumption was made that the

use of an in vitro ratio as a surrogate for

an in vivo ratio is unbiased (i.e.,

errvivo/vitro should be centered on a value

of 1). The mean of the three estimates

of fold-difference (1.65) is our best

estimate of a GSD for errvivo/vitro. Thus,

the prior probability distribution for

errvivo/vitro was modeled as a lognormal

variate with expected value 1.0 and GSD

of 1.65.

(x) Monte Carlo simulation to obtain

a prior probability distribution for A2.

The above prior probability

distributions for [V/S]GST-lung, [V/

S]GST-liver and errvivo/vitro were

independently sampled by Monte Carlo

techniques (n = 5000) and combined to

give a prior probability distribution for

A2 for use in Bayesian analysis with the

human open chamber data. The

resulting distribution was well

described as a lognormal variate with a

GM of 0.236 and a GSD of 2.0.

(3) Human in vivo data and

simulating occupational exposure.

Bayesian updating was performed with

the same human in vivo data used in the

main analysis. These data consisted of

time serial measurements of exhaled

breath and venous blood concentrations

of MC for 6 human volunteers exposed

to 100 and 350 ppm MC for 6 hours.

Unfortunately, the data have only been

reported as averages of the 6 subjectspecific observations at each time point.

When simulating the human data,

subjects were assumed to be at rest (i.e.,

work load set equal to 0), and the

reported average body weight for the six

subjects (86 kg) was assumed to be

known without error.

A single human occupational

exposure was simulated: constant

exposure to 25 ppm MC for 8-hours per

day and 5 days per week.

(4) Distribution of human metabolized

dose and sensitivity analysis. The

distribution for GST metabolism in the

human lung resulting from simulated

occupational exposure to 25 ppm MC

had a median and mean of 0.139 and

0.192 mg/day/liter lung, about 3-fold

less than values obtained using the

allometrically scaled Kf.

From the sensitivity analysis, Kf and

A2′ exhibited the strongest pairwise

correlations with predicted lung GST

metabolism, with all other parameters

having considerably smaller correlation

coefficients. Indeed, other than PC.mar

(partition coefficient air:marrow), all

other parameters were only weakly

correlated with GST lung metabolism.

These results differ somewhat from

those obtained when using an

allometrically scaled Kf, and reflect the

effect of greater variability in a Kf based

on the parallelogram method.

(5) Posterior distributions in the

‘‘parallelogram method’’ analysis. The

posterior distributions for many model

parameters were considerably tighter

than their corresponding prior

distributions, most notably for fractional

blood flow and partition coefficient

parameters. Similar results were

obtained in the main analysis. In

general, medians and %CVs of the

posterior distributions were similar to

those in the main analysis, with the

exception of Kf, which was expected,

given its revised prior distribution.

However, differences among the

posterior distributions for Kf were less

than expected due to an appreciable

shift toward larger values (and some

tightening) in the posterior distribution

for the parallelogram-based Kf relative

to its prior distribution. Thus, it would

appear that the data had some

information about plausible values of

Kf.

The results of the covariance analysis

indicated that the covariance structure

was fairly similar to the results from the

main analysis, with moderate to high

pairwise correlations among 15 pairs of

parameters.

G. Results of OSHA’s PBPK Risk

Assessments; Discussion

Summary statistics for OSHA’s main

analysis modifying the other analysis

and the alternative (parallelogram)

analysis are reported in Table VI–12.

From the main analysis, the MLE of

excess cancer risk obtained using the

upper 95th percentile of the human

internal dose distribution was 3.62/

1000, for an occupational lifetime

exposure to 25 ppm MC. The MLE of

cancer risk obtained using the mean of

the human internal dose distribution

was 1.24/1000. The alternative

(parallelogram) analysis yielded slightly

lower estimates of risk. In that analysis,

the MLE of cancer risk using the upper

95th percentile of the human internal

dose distribution was 1.23/1000. The

MLE of cancer risk for the alternative

analysis using the mean of the human

internal dose distribution was 0.40/

1000. After evaluating the

methodologies and uncertainties in the

two analyses, OSHA determined that

the main analysis was most appropriate

for the Agency’s final risk assessment

and the MLE of cancer risk using the

upper 95th percentile of the human

internal dose distribution was best

supported as OSHA’s final MC risk

estimate. Therefore, OSHA’s final risk

estimate for occupational lifetime

exposure to MC at 25 ppm is 3.62/1000.

TABLE VI–12.—Summary Statistics on Estimates of Extra Cancer Risk From Occupational Exposure to 25 ppm MC

FOR 8 HRS/DAY, 5 DAYS/WK FOR 45 YEARS

Computational approach

Summary statistics for distributions of extra risk

95% ** Mean %CV * Skewness Kurtosis

Maximum likelihood fitting: Dependence

case.

3.62 *** per 1000 ............... 1.24 per 1000 ..................... 103 2.2 10.2
1556 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

TABLE VI–12.—Summary Statistics on Estimates of Extra Cancer Risk From Occupational Exposure to 25 ppm MC

FOR 8 HRS/DAY, 5 DAYS/WK FOR 45 YEARS—Continued

Computational approach

Summary statistics for distributions of extra risk

95% ** Mean %CV * Skewness Kurtosis

Maximum likelihood fitting: Independence case..2.43 per 1000 ..................... 0.79 per 1000 ..................... 113 2.3 11.3

* %CV denotes coefficient of variation ([standard deviation/mean] x 100).

** 95% denotes the 95th percentile value of the distribution of GST matabolites for extra cancer risk.

*** OSHA’s final risk estimate.

Figure VI–1 shows the end result of

the main PBPK analysis: the cumulative

distribution function of excess lifetime

cancer risk (log10 scale) from exposure

to 25 ppm MC, 8 hours per day, 5 days

per week for 45 years, when estimated

using the MLE of the dose-response

parameters, GST lung metabolism as the

dose surrogate, and a human Kf based

on allometric scaling and Bayesian prior

information. As described in the main

analysis, the ‘‘dependence case’’ was

used. Several summary statistics can be

discerned from this cumulative

distribution function: (1) the 95th

percentile of this hybrid distribution of

uncertainty and heterogeneity gives a

risk estimate of 3.62 x 10¥3 (point ‘‘A’’

in the figure); (2) the mean value of the

distribution (point ‘‘B’’ in the figure)

gives a risk estimate of 1.24 x 10¥3.

BILLING CODE 4510–26–P
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1557

BILLING CODE 4510–26–C
1558 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

OSHA conducted the alternative

analysis in order to determine the

impact of basing the human GST

metabolite distribution on allometry

(human GST metabolic rates estimated

based on the relative size of animals and

humans) versus the parallelogram

approach (human GST metabolic rates

based on ratio of various rodent in vitro:

in vivo metabolic rates applied to

human in vitro rates) on risk estimates.

As discussed in greater detail above,

allometry predicts that one would

expect that humans have approximately

seven-fold less GST activity than mice.

The parallelogram approach, on the

other hand, predicts approximately 18-

fold less GST activity in humans than in

mice. After analyzing the available data,

OSHA has determined that the

allometric assumptions are best

supported by the scientific literature,

primarily because of the lack of human

in vivo GST data and the lack of

validation of the parallelogram

approach. The Agency has therefore

used that approach in its final (main)

estimate of risk, but has also presented

an alternative analysis using the

parallelogram methodology.

During the rulemaking, studies were

submitted to the Agency by HSIA

challenging the relevance of the mouse

data for estimating human cancer risks.

However, as described in detail

previously, if one examines the HSIA

data critically, it is clear that the studies

most likely could not detect differences

in metabolic activity (and hence in risk)

between mice and humans of the

magnitude predicted by allometry. For

example, the lack of detection of an

increase in DNA ss breaks in human

cells compared to mouse cells could be

explained because the methodology

used could not detect an increase in ss

breaks 7-fold smaller than that observed

in mice. Clearly, an 18-fold difference,

as predicted by the parallelogram

method, would be even harder to detect.

Moreover, if the human in vitro data

are examined more closely, it becomes

apparent that the in vitro: in vivo ratios

calculated for the 35 individual humans

who have been studied were as low as

4.6 (the median value in this series was

24). Therefore, the use of allometry

(ratio = 7) or the parallelogram approach

(ratio = 18) would lead to risk estimates

that clearly underestimate the risks for

some individuals. In addition, RNA

adduct data [Ex. 126–25] indicate that

exposure of human cells to MC results

in only a 3-fold lower amount of RNA

adducts than formed in mouse cells.

This ratio may not be a close surrogate

for the GST ratio, but it does heighten

concern that both PBPK approaches may

be underestimating cancer risks from

occupational exposure to MC, because

humans may be appreciably less

sensitive than mice.

The distribution of risk presented in

either the main or the alternative

analysis most closely reflects

uncertainty about risk for some

randomly chosen worker (with respect

to work intensity and body weight),

chosen among the population of

workers with physiologic, anatomic,

and metabolic attributes similar to those

of the average subject from the Dow

human study group. The Dow

pharmacokinetic data did not contain

individual data on the 6 subjects, so the

results obtained and the predictions

made are conditioned by the use of

averages. This means that the model is

truly only applicable to people who

physiologically and biochemically

resemble the Dow group of six subjects.

Although six subjects do not represent

a large data base from which to draw a

representative PBPK sample, this is

much more human data than is usually

available to base a risk assessment on.

In fact, in OSHA’s preliminary

quantitative risk assessment, point

estimates were used for body weight,

breathing rates, etc. to represent the

entire working population with a single

‘‘average’’ number. Therefore, this

sample, although small, represents a

significant improvement over the point

estimates of human parameter values for

PBPK modeling. Although these are the

best data available, the small number of

individuals upon which the human

parameter values are based increases

concern that the Agency may be

underestimating risks for a significant

portion of the working population by

relying upon these values and using

PBPK modeling to estimate human

internal doses. OSHA considered

making an ad hoc inflation of the

variance of the distributions of human

GST enzyme kinetics parameters in

order to account for some of this

unmeasured heterogeneity (as

recommended by the NAS Committee

report discussed above), but decided not

to make this ‘‘conservative’’ choice but

instead to rely on the unadjusted

analyses.

OSHA has chosen for its final risk

estimate to couple one measure of

central tendency (the MLE of the doseresponse parameters) with a somewhat

‘‘conservative’’ measure (the 95th

percentile of the distribution of human

GST metabolites (internal dose)).

Congress and the courts have

permitted—indeed, encouraged—OSHA

to consider ‘‘conservative’’ responses to

both uncertainty and human variability.

The OSH Act addresses the latter when

it refers, for example, to OSHA’s

responsibility to set standards such that

‘‘no employee shall suffer material

impairment of health* * *;’’ a standard

that only considered risk to the average

employee clearly would not be

responsive to the statute. Similarly, the

1980 ‘‘Benzene decision’’ affirmed that

‘‘the Agency is free to use conservative

assumptions in interpreting the data

with respect to carcinogens, risking

error on the side of over-protection

rather than under-protection.’’

In past rulemakings, OSHA has

frequently estimated carcinogenic

potency via the MLE of the multistage

model parameters. The Agency has

recently received comments,

particularly in a public meeting in

February 1996 on risk assessment issues

surrounding the first phase of its ‘‘PEL

Update’’ process, critical of the MLE on

the grounds that this estimator can be

highly unstable with respect to small

fluctuations in the observed bioassay

response rates. Although OSHA may in

the future move to a different estimator,

such as the mean value of the likelihood

function of the multistage model

parameters, such a change would have

neglible practical impact in the case of

MC. The observed data in the NTP

mouse bioassay follow a nearly

precisely linear trend, so the MLE, mean

and UCL estimates are all very nearly

equivalent to each other.

However, OSHA needs to take

particular care not to underestimate risk

when it departs from a relatively simple

methodology (in this case, the

assumption that administered dose is

the most relevant measure of exposure)

in favor of a relatively more complex

and computationally- intensive

methodology (in this case, that the

human lung GST metabolite, calculated

via a PBPK model, is the most relevant

measure of exposure). This is even more

important in this particular PBPK

analysis, because the variance of the

output distributions represents an

unknown hybrid of uncertainty in the

various parameters and true

heterogeneity among the humans

exposed to MC. As Clewell stated with

respect to his own PBPK analysis (see

discussion above), the 95th percentile

estimator provides a modicum of

assurance that the risk to the average

human—and hence the population

risk—is not underestimated.

Moreover, it is critical to use an

estimator other than the central

tendency here so that it will not be

inevitable that the risk to a human of

above-average susceptibility (due to

enzyme kinetics that produce relatively

more reactive metabolite per unit of

administered dose, or due to other

attributes related to body weight, organ
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1559

volumes, partition coefficients, etc.) is

not underestimated, potentially by a

substantial amount. Any

‘‘conservatism’’ introduced by using the

95th percentile of the PBPK output

distribution is further attenuated by the

unmeasured model uncertainty inherent

in this more complex model structure.

Several aspects of the model itself are

known to be oversimplifications (e.g.,

assuming the lung is the only tissue at

risk); therefore, the resulting risk

distributions could be biased

downward.

Finally, it is important to note that

there is no risk of ‘‘cascading

conservatism’’ with this 95th percentile

estimator; the individual model

parameters are permitted to vary over

their entire ranges, and the selected

percentile is only applied to the

distribution resulting from the

combined influence of all parameters.

Furthermore, the newest refinements to

the model ensure that the 95th

percentile is not affected by any

probability assigned to impossible

combinations of parameters. The

attention paid to issues of mass balance,

covariance structure and truncation

ensures that this percentile represents a

fully plausible set of input parameters.

In sum, the combination of the MLE of

the multistage parameters and the 95th

percentile of the PBPK output

distribution represents a reasonable

attempt to account for uncertainty and

variability without unduly exacerbating

the magnitude or the probability of

underestimation of errors.

H. Comparison of Animal-Based Risk

Estimates With ‘‘Non-Positive’’

Epidemiology Data

Direct comparisons between animal

bioassays and human epidemiological

studies are difficult to make because

experimental protocols between animal

and human studies differ substantially.

Animals are generally exposed to a fixed

dose of a chemical, for several hours per

day, from approximately 6–8 weeks of

age until study termination, which is

usually at 2 years. This would be

chronologically equivalent to a human

exposure that starts when a human is

approximately 4–5 years old and

continuing until the human is

approximately 74 years old (assuming a

74 year average life-span for humans)

[Ex. 89]. This clearly differs from the

typical pattern of occupational exposure

encountered in epidemiological studies

of worker populations. For example, in

the Kodak cohort, the workers were

never exposed to a constant level of MC;

exposure to MC for these workers did

not start until their adult life; and most

of them were exposed to the chemical

for less than one third of their life-span.

Exposure to MC has been found to

induce lung and liver cancer in mice

and mammary tumors in rats. As

discussed above, there are positive

epidemiology studies which suggest an

association between MC exposure and

cancer risk. Because exposure data are

inadequate or unavailable, it is not

possible to quantify the risks in these

studies. OSHA acknowledges that there

are also non-positive epidemiology

studies.

In 1986, Crump analyzed the

preliminary results from the 1964–70

Kodak cohort followed through 1984

and compared them to the rodent

bioassay results. The results from the

Kodak epidemiological study have also

been used by Tollefson et al. [Ex. 7–

249], Hearne [Ex. 91–D], and NIOSH to

compare the predictions of excess

cancer risk from the animal risk

assessment models. In addition, Hearne

used data from the cellulose triacetate

fiber study in Cumberland, Maryland,

and a different analytical approach, to

validate the excess cancer risk predicted

by the animal data [Ex. 91–D]. The

details of these analyses can be found in

the cited exhibits. OSHA has analyzed

the different approaches to assessing the

mouse bioassay in light of the

epidemiology data and has determined

that the approach taken by NIOSH

(summarized below) represents the most

comprehensive and clearest way to

examine those data. OSHA also agrees

with the conclusions reached by

NIOSH, that the epidemiology results

and the mouse bioassay data are not

inconsistent with each other.

NIOSH compared the confidence

intervals for the standardized mortality

ratios (SMRs) from the Kodak study

with the predicted confidence intervals

derived from OSHA’s risk assessment

models from the NPRM [Ex. 89]. To

estimate predicted SMRs using the

multistage model, NIOSH used the

following approach:

1. The expected excess number of deaths

in each of the exposure groups was derived

by multiplying the number of workers in

each exposure group by the excess risk as

determined by the multistage model (after

correcting for dose equivalence between

animals and humans, and differences in

length of follow-up).

2. This number of expected deaths, derived

from the animal data, was then added to the

expected (denoted Ep) number of deaths

which were derived from the Kodak study,

after correcting for the HWE, (this can be

viewed as the background risk) to estimate

the number of ‘‘observed’’ deaths that would

have been predicted by the multistage model

assuming it was valid for humans (denoted

Op).

3. Op was then divided by Ep to calculate

predicted SMRs and 95% confidence

intervals, where calculated.

NIOSH’s results indicated that the

non-positive findings from the Kodak

study were not inconsistent with the

predicted risk estimates in OSHA’s risk

assessment. The predicted confidence

intervals from the animal multistage

model were completely nested within

the observed confidence intervals from

the Kodak study. This is not to suggest

that results from this non-positive

epidemiology study are equivalent to

the positive results from the animal

inhalation study. Rather, based on these

findings, one can conclude that the nonpositive results from the Kodak

epidemiologic study were not of

sufficient power to contradict risk

predictions of the multistage model

developed from the animal bioassay

data (when appropriate adjustments for

differences in study protocol were taken

into account).

Basically, the Kodak study examined

approximately 1000 workers whose

average MC exposure was 26 ppm.

Therefore, the animal-based potency

estimates would predict only about 3

excess cancer deaths in that cohort (the

risk at 26 ppm is approximately 3 per

1000), even if they were followed for

many decades after exposure ceased.

This small predicted excess is clearly

too small an increment to be observable

with statistical confidence, considering

the much larger background of cancer

present in the human population. The

differences between the NIOSH and

Hearne analyses essentially represent

different ways to estimate the ‘‘signal-tonoise’’ ratio for the Kodak study; OSHA

believes that any reasonable method of

estimating this ratio would conclude

that the Kodak study has insufficient

power to rule out a ‘‘signal’’ of

significant human risk.

NIOSH’s approach for adjusting for

the healthy worker effect (HWE) was

criticized in the comments to the record

submitted by Hearne. Hearne stated that

the HWE is unlikely to be present in

long term cancer studies and therefore

an adjustment for the HWE is not

necessary [Ex. 91–D]. Hearne argued

that since the HWE diminishes with

time, the healthy worker effect would

have been minimal in the 1946–70

Kodak cohort because the median

follow-up period was 32 years and that

only 20% of the cohort members were

still actively employed [Tr. 10/15/92].

There is evidence in the literature

showing that the HWE can be weaker for

some types of cancer than for other

causes of death; however, in this case

NIOSH believed and OSHA agreed that

the difference between control and
1560 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

exposed populations reflected an HWE

for cancer. In addition, results from a

similar analysis done by NIOSH without

the HWE adjustment did not contradict

the results including the HWE

adjustment. NIOSH testified [Tr. 985–6,

9/21/92] that there would be a

difference in the results obtained when

adjusting for HWE and the unadjusted

results. However, the conclusions

reached would not be different. In other

words, the analysis still supported the

conclusion that the epidemiologic and

mouse bioassay results were not

inconsistent with each other. OSHA

supports NIOSH’s position on the use of

an adjustment factor for HWE in this

cohort. Other criticisms of NIOSH’s

approach can be found in the hearing

transcripts and post-hearing comments.

OSHA has evaluated these

methodological criticisms and has

determined that NIOSH used the best

available methodology in analyzing this

issue and that their conclusions are

supported by those arrived at

independently by Crump and by

Tollefson et al.

Specifically, NIOSH predicted 23.25

deaths from cancers (at all sites) in the

full cohort, after adjusting for the HWE.

This value is closer to the observed

number (22) than is the unadjusted

expected number of deaths (29.61).

Looking at lung cancer deaths

separately, NIOSH predicted 22.36

deaths for the entire cohort (adjusted for

HWE) compared with 22 observed and

28.67 expected by Hearne. Hearne

observed no deaths from liver cancer in

the entire cohort (1.14 deaths were

expected). NIOSH predicted 0.88 deaths

from liver cancer when they adjusted for

the HWE.

OSHA believes that NIOSH’s

approach in comparing results from an

animal bioassay to those of an

epidemiological study is the most

reasonable comparison between data

sets because it is more accurate and

better addresses computational and

experimental issues inherent in the data

sets. The Agency has evaluated the

extent to which the cancer risk

calculated using the human data is

consistent with the cancer risk

calculated using animal data. Based on

its review of those studies, OSHA

concluded that the human epidemiology

results are not inconsistent with the

animal bioassays and has determined

that the bioassays are the appropriate

basis for its quantitative risk assessment.

I. Conclusions

OSHA has determined that MC is a

potential occupational carcinogen and

has conducted a quantitative risk

assessment in order to estimate human

risks of cancer after occupational

exposure to MC. The Agency reviewed

all of the human and animal data on MC

and determined that MC is carcinogenic

in mice and in rats, causing tumors at

multiple sites, in both species, and in

both sexes of animals. Some

epidemiologic data also indicate an

association between MC exposure and

excess cancer in exposed workers

(statistically significant increases in

biliary cancers in textile workers and

astrocytic brain cancer in workers

exposed to MC in solvent applications).

Mechanistic data indicate that MC is

likely to be metabolized to a genotoxic

carcinogen. MC has been clearly shown

to be metabolized by similar enzymatic

pathways in rodents and humans,

indicating that the metabolic processes

which produce cancer in mice and rats

are also present in humans. Finally, no

data have been presented which

demonstrate that the mouse is an

inappropriate model for humans

because of a physiological or

biochemical component or process.

Therefore, the Agency has determined

that it is appropriate to assess the

carcinogenic risks of MC using the NTP

mouse bioassay dose-response.

The NTP mouse MC bioassays

demonstrated a clear dose-tumor

response relationship. OSHA

determined that the NTP female mouse

lung tumor response was the best data

set on which to base a quantitative

analysis because there was a clear doseresponse, low background tumor

incidence and it represented the most

sensitive tumor site/sex combination.

After examining the PBPK models

submitted to the Agency, OSHA

concluded that PBPK modeling

estimates of the amount of GST

metabolites produced are reasonable

dose surrogates for MC and are

supported by substantial scientific

evidence in the record. For that reason,

OSHA has used PBPK modeling in its

final risk assessment. OSHA reviewed

methodologies used in PBPK models

submitted to the Agency and decided to

modify and expand an existing model.

Specifically, a Bayesian analysis was

conducted as described above. Use of

the Bayesian model analysis was a

logical next step in development and

use of pharmacokinetic models for MC.

It has great advantages in accounting for

the covariance of the PBPK parameters

and incorporating distributions of

physiological parameters obtained from

the scientific literature. OSHA’s final

estimates of risk use the PBPK analysis

described above and are based on the

MLE of the dose-response parameters

using the upper 95th percentile of the

human internal dose distribution. For

an occupational lifetime exposure to 25

ppm MC, OSHA estimates an excess risk

of 3.6 MC-induced cancer deaths per

1000 workers.

VII. Significance of Risk

A. Introduction.

In the 1980 Benzene decision, the

Supreme Court, in its discussion of the

level of risk that Congress authorized

OSHA to regulate, indicated its view of

the boundaries of acceptable and

unacceptable risk. The Court stated:

It is the Agency’s responsibility to

determine in the first instance what it

considers to be a ‘‘significant’’ risk. Some

risks are plainly acceptable and others are

plainly unacceptable. If for example, the

odds are one in a billion that a person will

die from cancer by taking a drink of

chlorinated water, the risk clearly could not

be considered significant. On the other hand,

if the odds are one in a thousand that regular

inhalation of gasoline vapors that are 2

percent benzene will be fatal, a reasonable

person might well consider the risk

significant and take the appropriate steps to

decrease or eliminate it. (I.U.D. v. A.P.I., 448

U.S. 607, 655).

So a risk of 1/1000 (10¥3) is clearly

significant. It represents the uppermost

end of a million-fold range suggested by

the Court, somewhere below which the

boundary of acceptable versus

unacceptable risk must fall.

The Court further stated that ‘‘while

the Agency must support its findings

that a certain level of risk exists with

substantial evidence, we recognize that

its determination that a particular level

of risk is significant will be based

largely on policy considerations.’’ The

Court added that the significant risk

determination required by the OSH Act

is ‘‘not a mathematical straitjacket,’’ and

that ‘‘OSHA is not required to support

its findings with anything approaching

scientific certainty.’’ The Court ruled

that ‘‘a reviewing court [is] to give

OSHA some leeway where its findings

must be made on the frontiers of

scientific knowledge [and that] . . . the

Agency is free to use conservative

assumptions in interpreting the data

with respect to carcinogens, risking

error on the side of overprotection

rather than underprotection’’ (448 U.S.

at 655, 656).

Nonetheless, OSHA has taken various

steps that make it fairly confident its

risk assessment methodology is not

‘‘conservative’’ (in the sense of erring on

the side of overprotection). For example,

there are several options for

extrapolating human risks from animal

data via interspecies scaling factors. The

plausible factors range from body

weight extrapolation (risks equivalent at

equivalent body weights) to (body
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1561

weight)2/3 (risks equivalent at equivalent

surface areas). Intermediate values have

also been used, and the value of (body

weight)3/4, which is supported by

physiological theory and empirical

evidence, is generally considered to be

the midpoint of the plausible values.

(Body weight)2/3 is the most

conservative value in this series. Body

weight extrapolation is the least

conservative. OSHA has generally used

body weight extrapolation in assessing

risks from animal data, our approach

which tends to be significantly less

conservative than the other

methodologies and most likely is less

conservative even than the central

tendency of the plausible values.

Other examples in OSHA’s risk

assessment methodology where the

Agency does not use a conservative

approach are selection of the maximum

likelihood estimator to parameterize the

dose-response function rather than the

upper 95% confidence limit, and the

use of site-specific tumor incidence

rather than pooled tumor response in

determining the dose-response function

for a chemical agent.

OSHA’s overall analytic approach to

regulating occupational exposure to

particular substances is a four-step

process consistent with recent court

interpretations of the OSH Act, such as

the Benzene decision, and rational,

objective policy formulation. In the first

step, OSHA quantifies the pertinent

health risks, to the extent possible,

performing quantitative risk

assessments. The Agency considers a

number of factors to determine whether

the substance to be regulated poses a

significant risk to workers. These factors

include the type of risk posed, the

quality of the underlying data, the

plausibility and precision of the risk

assessment, the statistical significance

of the findings and the magnitude of

risk [48 FR 1864, January 14, 1983]. In

the second step, OSHA considers

which, if any, of the regulatory options

being considered will substantially

reduce the identified risks. In the third

step, OSHA looks at the best available

data to set permissible exposure limits

that, to the extent possible, both protect

employees from significant risks and are

also technologically and economically

feasible. In the fourth and final step,

OSHA considers the most cost-effective

way to fulfill its statutory mandate by

crafting regulations that allow

employers to reach the feasible PEL as

efficiently as possible.

B. Review of Data Quality and

Statistical Significance

The former OSHA standard for MC

was designed to prevent irritation and

injury to the neurological system of the

employees exposed to MC. In 1985, the

National Toxicology Program (NTP)

released the results of their MC rodent

lifetime bioassays. Those results

indicated that MC is carcinogenic to rats

and mice. As discussed in the Events

Leading to the Final Standard section,

based on the NTP findings, EPA now

considers MC a probable human

carcinogen, and NIOSH regards MC as a

potential occupational carcinogen and

recommends controlling the exposure to

MC to the lowest feasible level. In 1988,

ACGIH classified MC as an industrial

substance suspected of carcinogenic

potential for humans.

As discussed in the Health Effects

section, OSHA has determined, based

on the NTP data, that MC is a potential

occupational carcinogen. This

conclusion is supported by high-quality

data in both rodent species. Having

determined, as discussed in the

Quantitative Risk Assessment section,

that the NTP study provided suitable

data for quantitative analysis, OSHA

performed quantitative risk assessments

to determine if MC exposure at the

current PEL presents a significant risk.

As discussed in the Health Effects and

Quantitative Risk Assessment sections,

OSHA evaluated four MC rodent

bioassays [Exs. 4–35, 4–25, 7–29, 7–30,

7–31] to select the most appropriate

bioassay as the basis for a quantitative

risk assessment. These bioassays were

conducted in three rodent species (rat,

mouse, and hamster) using two routes of

administration (oral and inhalation).

The NTP study (rat and mouse,

inhalation) was chosen for a

quantitative risk assessment because it

provides the clearest toxicological and

statistical evidence of the

carcinogenicity of MC [Exs. 12, 7–127]

and because the studies were of the

highest data quality. In the NTP study,

MC induced significant increases both

in the incidence and multiplicity of

alveolar/bronchiolar and hepatocellular

neoplasms in male and female mice. In

rats, dose-related, statistically

significant increases in mammary

tumors were also observed. OSHA chose

the female mouse tumor response as the

basis of its quantitative risk assessment,

because of the high quality of data, the

clear dose response of liver and lung

tumors and the low background tumor

incidence. OSHA chose female mouse

lung tumors as the specific tumor site

for its final quantitative risk assessment.

There is no a priori reason to prefer the

mouse lung tumor response over the

liver tumor response because both data

sets were of high quality, showed a clear

dose-response relationship and had low

background tumor incidence. In fact, in

the NPRM, the Agency reported

estimates of risk generated using both

sites. However, to reduce the

complexity of the final PBPK analysis,

which required highly intensive

computations, OSHA chose one site (the

female mouse lung tumor response) for

its final risk estimates. The risks

calculated using the female mouse liver

response would likely be only slightly

lower than those calculated using the

lung tumor response. On the other hand,

pooling the total number of tumorbearing animals having either a lung or

liver tumor (or both) would have

yielded risk estimates higher than

OSHA’s final values.

Once the alveolar/bronchiolar

neoplasms in female mice were chosen

as the most appropriate data set, the

multistage model of carcinogenesis was

used to predict a lifetime excess risk of

cancer from occupational exposure to

MC at several concentration levels. The

multistage model is a mechanistic

model based on the biological

assumption that cancer is induced by

carcinogens through a series of stages.

The model may be conservative, in the

sense that it risks error on the side of

overprotection rather than

underprotection, because it assumes no

threshold for carcinogenesis and

because it is approximately linear at low

doses, although there are other plausible

models of carcinogenesis which are

more conservative. The Agency believes

that this model conforms most closely to

what we know of the etiology of cancer.

There is no evidence that the multistage

model is biologically incorrect,

especially for genotoxic carcinogens,

which MC most likely is. OSHA’s

preference is consistent with the

position of the Office of Science and

Technology Policy which recommends

that ‘‘when data and information are

limited, and when much uncertainty

exists regarding the mechanisms of

carcinogenic action, models or

procedures that incorporate low-dose

linearity are preferred when compatible

with limited information’’ [Ex. 7–227].

In the NPRM, OSHA solicited

comment and testimony on the

application of physiologically-based

pharmacokinetic (PBPK) modeling to

refine the MC risk assessment. There

was an intensive discussion of

pharmacokinetic issues during the

hearings and in comments and briefs

submitted to OSHA. PBPK modeling is

used to account for metabolic and

pharmacokinetic differences between

rodents and humans and when

extrapolating from high experimental

doses to lower occupational exposures.

OSHA has evaluated several risk

assessments produced using
1562 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

pharmacokinetic models. Discussion of

the major issues surrounding the use of

PBPK in risk assessment can be found

in the Quantitative Risk Assessment

section. Although serious questions

remain concerning the application of

these models in the MC risk assessment,

the Agency has used the estimates

generated via PBPK modeling as its final

estimate of the carcinogenic risk of MC

exposure.

In accepting PBPK analysis, the

Agency wanted to be able to utilize all

of the data available and appropriate for

the analysis. OSHA was also concerned

that the uncertainties and interindividual variabilities in PBPK models

were insufficiently quantified to allow

analysis of the impact of those

uncertainties on the risk. Several

rulemaking participants have conducted

sensitivity and uncertainty analyses, the

most extensive of which was that

submitted by Mr. Harvey Clewell on

behalf of the U.S. Navy. These analyses

show the impact of the variability and

uncertainty of the parameters which are

used in the PBPK model and suggest

methods of quantifying the impact of

that uncertainty on the risk estimates.

OSHA has determined that the PBPK

data are of sufficient weight to warrant

reliance on PBPK modeling to develop

a risk estimate in the specific case of

MC, a chemical with more extensive

information on metabolism than exists

for most other substances. To that end,

OSHA adopted a Bayesian approach in

which all of the physiological and MCspecific data could be used to generate

a distribution of estimates of the

carcinogenic risks of MC. OSHA used

the mean and the upper 95th percentile

estimator of the distribution of human

PBPK parameters, coupled with the

maximum likelihood estimator of cancer

potency, to generate its final estimates

of risks.

As discussed in more detail in the

Health Effects Section above, human

data concerning the carcinogenicity of

MC were presented in several

epidemiology studies. In a study of

cellulose triacetate fiber production (MC

used as solvent) workers, an increased

incidence of liver/biliary cancer [Ex. 7–

260] was noted. Although the case

numbers were small and the exposure

information limited, this

epidemiological evidence is consistent

with findings from animal studies and

indicates that there may be an

association between human cancer risk

and MC exposure. A study of workers in

photographic film production was nonpositive [7–163]. However, the

exposures experienced by these workers

were likely to have been much less than

those in the cellulose triacetate fiber

plant and, as discussed in the

quantitative risk assessment section, the

study lacked the power to detect the

magnitude of the increase in cancer

deaths that would have been predicted

given only the bioassay results. A casecontrol study conducted by the National

Cancer Institute showed a statistically

significant association between

occupational MC exposure and

development of astrocytic brain cancer.

Exposure levels could not be

determined in this study. The results of

the epidemiological studies summarized

here were not inconsistent with the

results of the animal-based cancer

potency estimate.

C. Material Impairment of Health

MC is a potential occupational

carcinogen. Cancer is a material

impairment of health. OSHA has set the

8-hour TWA PEL primarily to reduce

the risk to employees of developing

cancer.

The STEL of 125 ppm averaged over

15 minutes is primarily designed to

protect against MC’s non-cancer risks.

As discussed in the Health Effects

section, there are substantial risks of

CNS effects and cardiac toxicity

resulting from acute exposure to MC

and its metabolites. CNS effects have

been demonstrated in workers at

concentrations as low as 175 ppm [Ex.

7–153] and a STEL of 125 ppm for 15

minutes would thus be protective

against the CNS effects described.

Metabolism of MC to CO increases the

body burden of COHb in exposed

workers. Levels of COHb above 3%

COHb may exacerbate angina symptoms

and reduce exercise tolerance in

workers with silent or symptomatic

heart disease. Smokers are at higher risk

for these effects because of the already

increased COHb associated with

smoking (COHb ranges from 2 to 10% in

most smokers). Limiting short term

exposure to 125 ppm for 15 minutes

will keep COHb levels due to MC

exposure below the 3% level, protecting

the sub-population of workers with

silent or symptomatic heart disease and

also limiting the additional COHb

burden in smokers.

In addition to protecting against CNS

and cardiac effects, there is evidence

that reducing the GST metabolite

production by reducing short term

exposure to high concentrations of MC

may also lower the cancer risk. This is

because metabolism by the MFO

pathway (not generally believed to be

associated with carcinogenesis) appears

to saturate beginning around 100 ppm.

This means that exposure to higher

concentrations of MC would lead to

increased metabolism by the GST

pathway (the putative carcinogenic

pathway) and therefore, greater than

proportionally increased risk.

All of the health effects averted by

reducing MC exposure are potentially or

likely to be fatal, and this clearly

represents ‘‘material impairment of

health’’ as defined by the OSH Act and

case law.

D. Risk Estimates

OSHA’s final estimate of excess

cancer risks at the current PEL of 500

ppm (8-hour TWA) is 126 per 1000. The

risk at the new PEL of 25 ppm is 3.62

per 1000. The risk at 25 ppm is similar

to the risk estimated in OSHA’s

preliminary quantitative risk assessment

based on applied dose of MC on a mg/

kg/day basis (2.3 per 1000 workers) and

clearly supports a PEL of 25 ppm. Risks

greater than or equal to 10¥3 are clearly

significant and the Agency deems them

unacceptably high. However, OSHA did

not collect the data necessary to

document the feasibility of a PEL below

25 ppm across all affected industry

sectors, and so the Agency has set the

PEL at 25 ppm in the final rule. OSHA

intends in the future to gather more

information pertaining to the feasibility

of lower PELs.

E. ‘‘Significant Risk’’ Policy Issues

Further guidance for the Agency in

evaluating significant risk and

narrowing the million-fold range

provided in the ‘‘Benzene decision’’ is

provided by an examination of

occupational risk rates, legislative

intent, and the academic literature on

‘‘acceptable risk’’ issues. For example,

in the high risk occupations of mining

and quarrying, the average risk of death

from an occupational injury or an acute

occupationally-related illness over a

lifetime of employment (45 years) is

15.1 per 1,000 workers. The typical

occupational risk of deaths for all

manufacturing industries is 1.98 per

1,000. Typical lifetime occupational risk

of death in an occupation of relatively

low risk, like retail trade, is 0.82 per

1,000. (These rates are averages derived

from 1984–1986 Bureau of Labor

Statistics data for employers with 11 or

more employees, adjusted to 45 years of

employment, for 50 weeks per year).

Congress passed the Occupational

Safety and Health Act of 1970 because

of a determination that occupational

safety and health risks were too high.

Congress therefore gave OSHA authority

to reduce significant risks when it is

feasible to do so. Within this context,

OSHA’s final estimate of risk from

occupational exposure to MC at the

current 8-hour TWA PEL (126 per 1000)

is substantially higher than other risks
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1563

2OSHA also conducted an alternative PBPK

analysis that uses all of the available human data

on MC metabolism, despite the very limited

quantity of data available and the additional bias

introduced by adopting the ‘‘parallelogram’’

assumptions for interspecies scaling (see

Quantitative Risk Assessment for a discussion of

this analysis and the uncertainties and biases

therein). The risk estimate using this alternative

method, 1.2 per 1000, is also unambiguously

significant.

that OSHA has concluded are

significant, is substantially higher than

the risk of fatality in some high-risk

occupations, and is substantially higher

than the example presented by the

Supreme Court. Moreover, a risk of 3.62

per 1000 at 25 ppm is also clearly

significant; therefore, the PEL must be

set at least as low as the level of 25 ppm

documented as feasible across all

industries.

Further, applying the rationale of the

Benzene decision, the other risk

assessments presented by OSHA and the

risk estimates presented by rulemaking

participants, including the HSIA (see

Table VII–1, below), all support OSHA’s

conclusion that the human cancer risk

for employees exposed to MC above 25

ppm as an 8-hour TWA is significant.

TABLE VII–1.—LIFETIME EXCESS RISK ESTIMATES (PER 1000) FROM OCCUPATIONAL EXPOSURE BASED ON FEMALE

MOUSE LUNG TUMOR DATA

Model

MLE (UCL)**

25 ppm 50 ppm 500 ppm

OSHA NPRM Risk Assessment (mg/kg/d, BW extrapolation) without PBPK Adjustment ...... 2.32 (2.97) ........ 4.64 (5.92) ........ 45.5 (57.7)

PPM to PPM extrapolation without PBPK Adjustment ............................................................. 11.3 (14.4) ........ 22.4 (28.5) ........ 203 (251)

PBPK Reitz female mouse lung—Reitz human (HSIA assumptions) ...................................... 0.43 (0.53) ........ 0.93 (1.17) ........ 14.3 (17.9)

PBPK Reitz female mouse lung—Dankovic average human (NIOSH assumptions) .............. 0.81 (1.02) ........ 1.69 (2.12) ........ 15.0 (18.7)

PBPK Clewell female mouse lung—Clewell human (Navy assumptions)* .............................. 0.91 (1.14) ........ 1.88 (2.36) ........ 27.5 (34.2)

OSHA Final Risk Assessment (female mouse lung with PBPK) ............................................. 3.62 .................. 7.47 .................. 125.8

*Upper 95th percentile of the GST metabolites distribution was used as input in the multistage model.

**Maximum likelihood estimates are 95th percentile upper confidence limit (in parentheses) of the multistage dose-response function.

In addition to being 100 to 1000 times

higher than the risk levels generally

regarded by other Federal Agencies as

on the boundary between significant

and insignificant risk (see, e.g., Travis et

al., 1987), and 1000 times higher than

the ‘‘acceptable risk’’ level Congress set

in the 1990 Clean Air Act Amendments,

the level of 10¥3 is within the range

where economic studies document a

marked nonlinearity. In other words,

individuals regard risks this high as

qualitatively different from ‘‘smaller’’

risks. Although risks below 10¥3 are not

unambiguously significant, depending

on the size of the affected population,

the benefits associated with the risky

activity, and other factors, this policy

determination is not relevant to this

regulation, since OSHA’s final risk

estimate is substantially greater than 1

per 1000. Risks at or above 10¥3 are

always significant by any empirical,

legal or economic argument available.2

Because of the lack of documented

feasibility data for potential PELs of less

than 25 ppm, OSHA has concluded that

there is not enough information

available to support lowering the 8-hour

TWA PEL or STEL further at this time.

However, OSHA has integrated other

protective provisions into the final

standard to further reduce the risk of

developing cancer among employees

exposed to MC. Employees exposed to

MC at the 8-hour TWA PEL limit

without the supplementary provisions

would remain at risk of developing

adverse health effects, so that inclusion

of other protective provisions, such as

medical surveillance and employee

training, is both necessary and

appropriate. The action level will

encourage those employers for whom it

is feasible to do so to lower exposures

below 12.5 ppm to further reduce

significant risk. Consequently, the

programs triggered by the action level

will further decrease the incidence of

disease beyond the predicted reductions

attributable merely to a lower PEL. As

a result, OSHA concludes that its 8-hour

TWA PEL of 25 ppm and associated

action level (12.5 ppm) and STEL (125

ppm) will reduce significant risk and

that employers who comply with the

provisions of the standard will be taking

reasonable steps to protect their

employees from the hazards of MC.

The Agency notes that even at the

final PELs, the risks to workers remain

clearly significant. OSHA will be

gathering information on the risks of,

and feasibility of compliance with, PELs

less than 25 ppm, to determine whether

future rulemaking is appropriate in

order to further reduce the MC risks to

employees.

VIII. Summary of the Final Economic

Analysis

In its Final Economic and Regulatory

Flexibility Analysis document, OSHA

addresses the significant issues related

to technological and economic

feasibility and small business impacts

raised in the rulemaking process. The

Final Economic Analysis is also OSHA’s

most comprehensive explanation of the

standard’s practical impact on the

regulated community; in the Final

Economic Analysis, OSHA explains in

detail the Agency’s findings and

conclusions concerning pre-standard

(baseline) conditions, such as exposure

levels, in establishments in the

regulated community, and discusses

how and why the requirements of the

standard are expected to eliminate

significant risk to the extent feasible.

This document also sets forth OSHA’s

Final Regulatory Flexibility Analysis

and the analyses required by Executive

Order 12866. This Federal Register

preamble and the Final Economic

Analysis are integrally related and

together present the fullest statement of

OSHA’s reasoning concerning this

standard. The Final Economic and

Regulatory Flexibility Analysis, together

with supporting appendix material, has

been placed in the rulemaking docket

for methylene chloride (Ex. 129).

The purpose of the Final Economic

Analysis is to:

• Describe the need for a standard

governing occupational exposure to

methylene chloride;

• Identify the establishments and

industries potentially affected by the

standard;

• Evaluate the costs, benefits,

economic impacts and small business

impacts of the standard on affected

firms;

• Assess the technological and

economic feasibility of the standard for

affected establishments, industries, and

small businesses;

• Evaluate the availability of effective

non-regulatory approaches to the

problem of occupational exposure to

methylene chloride; and

• Present changes designed to reduce

the impact of the standard on small
1564 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

firms while meeting the objectives of the

OSH Act.

Need for the Standard

OSHA’s final methylene chloride

(MC) standard covers occupational

exposures to this substance, one of the

most widely used of all organic

solvents, in general industry,

construction, and shipyard

employment. In all, about 237,000

employees are estimated to be exposed

to MC. These workers are exposed to

MC in many different ways, including

the manufacturing, formulation,

distribution, and use of MC-containing

products. The most common uses of MC

are in paint stripping, metal cleaning,

and furniture stripping.

Workers exposed to MC are at

significant risk of developing cancer,

heart and liver effects, and central

nervous system impairments, as well as

eye, skin, and mucous membrane

irritation. Animal bioassays have shown

MC to be carcinogenic in mice and rats

of both sexes, and epidemiologic studies

in workers have produced suggestive

evidence of its carcinogenicity in

humans. Acute overexposure to the

vapors of MC can lead to central

nervous system depression, respiratory

paralysis, and death: OSHA receives

fatality reports every year involving

workers who have died using MC to

perform such tasks as stripping floors

and removing paint. To protect all MCexposed workers from these adverse

health effects, the final standard lowers

the airborne concentration of MC to

which workers may be exposed from the

current permissible exposure limit (PEL)

of 500 ppm as an 8-hour time-weighted

average (8-hour TWA) to 25 ppm, and

from the Agency’s current short-term

limit of 1000 ppm as an acceptable

ceiling, or 2000 ppm as an acceptable

peak above the acceptable ceiling for 5

minutes in any 2-hour period, to a shortterm exposure limit (STEL) of 125 ppm,

averaged over 15 minutes. (For a

detailed discussion of the risks posed to

workers by exposure to MC, see the

Quantitative Risk Assessment and

Significance of Risk sections of the

preamble, above.)

OSHA’s final MC standard is similar

in format and content to other health

standards issued under Section (6)(b)(5)

of the Act. In addition to setting PELs,

the standard requires employers to

monitor the exposures of workers;

establish regulated areas when

exposures may reasonably be expected

to exceed one of these PELs; implement

engineering and work practice controls

to reduce employee exposures to MC;

provide respiratory protection to

supplement engineering controls where

these are not feasible, are insufficient to

meet the PELs, or in emergencies;

provide other protective clothing and

equipment as necessary for employee

protection; make industrial hygiene

facilities (such as eyewash and

emergency showers) available in certain

circumstances; provide medical

surveillance; train workers about the

hazards of MC (as required by OSHA’s

Hazard Communication Standard); and

keep records relating to the standard.

The contents of the standard are

explained briefly in Chapter I of the

Final Economic Analysis and in detail

in the Summary and Explanation

(Section X of the preamble, below).

Chapter II of the economic analysis

describes the uses of methylene chloride

and the industries in which such use

occurs. Employee exposures to MC are

analyzed on the basis of ‘‘application

groups,’’ i.e., groups of firms that use

MC to perform a particular function,

such as metal cleaning or industrial

paint stripping, regardless of the

particular industry in which the use

takes place. The methodology used by

OSHA in the analysis is appropriate

when a ubiquitous chemical like MC is

used to perform the same function in

many kinds of firms in many industries,

because the processes used, employee

exposures generated, and controls in

place or needed to achieve compliance

are the same, whether the process takes

place in a machine shop, on board ship,

or on a construction site. For example,

because the process of using MC to strip

paint or coatings from an object is

essentially the same whether the object

being stripped is a spray paint booth,

boat, church pew, or automobile, and

the exposures generated during the

process are similar in important

respects, it is appropriate to analyze

such activities as a group. However,

OSHA’s technological feasibility and

cost analyses reflect the fact that job

classifications and work processes may

differ within a given application group.

Table VIII–1 shows the application

groups analyzed in the economic

analysis, and the numbers of MC-using

establishments, MC-exposed workers,

and estimated volume of MC handled

annually by establishments in each

application group.

TABLE VIII–1.—METHYLENE CHLORIDE APPLICATION GROUPS

Application group

Estimated

number of

MC-using

establishments *

Estimated total

employment*

Estimated

number of

exposed

workers *

Estimated

MC handled

(millions of

lbs)

Methylene Chloride Manufacturing ............................................................................... 4 1,664 84 469.20

Distribution/Formulation of Solvents ............................................................................. 320 84,004 1,701 189.65

Metal Cleaning:

Cold Degreasing and Other Cold Cleaning: 23,717 901,232 94,537 32.56

Open-Top Vapor Degreasing ......................................................................... 278 27,105 608 14.87

Conveyorized Vapor Degreasing ................................................................... 45 2,920 75 1.13

Semiconductors .............................................................................................. 239 217,960 1,392 0.40

Printed Circuit Boards .................................................................................... 141 77,795 298 13.98

Aerosol Packaging ........................................................................................................ 52 4,142 520 25.21

Paint Remover Manufacturing ...................................................................................... 80 6,134 200 136.85

Paint Manufacturing ...................................................................................................... 49 8,909 229 3.54

Paint Stripping:

Aircraft Stripping .................................................................................................... 300 266,826 2,470 13.17

Furniture Stripping ................................................................................................. 6,152 23,592 7,872 23.26

Other Industrial Paint Stripping ............................................................................. 35,041 2,312,721 46,605 59.36

Flexible Polyurethane Foam Manufacturing ................................................................. 100 9,800 600 50.32

Plastics and Adhesives Manufacturing and Use .......................................................... 3,487 1,186,040 10,481 41.90

Adhesive Production ............................................................................................. 165 56,254 497 ....................

Adhesive Use ........................................................................................................ 1,753 596,291 5,269 ....................

Injection Molding ................................................................................................... 80 27,211 240 ....................
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1565

TABLE VIII–1.—METHYLENE CHLORIDE APPLICATION GROUPS—Continued

Application group

Estimated

number of

MC-using

establishments *

Estimated total

employment*

Estimated

number of

exposed

workers *

Estimated

MC handled

(millions of

lbs)

Lamination ............................................................................................................. 1,323 450,031 4,070 ....................

Mold Release ........................................................................................................ 165 56,254 497 ....................

Ink Use:

Ink and Ink Solvent Manufacturing ....................................................................... 15 2,010 58 3.68

Ink Solvent Use in Printing .................................................................................... 11,869 197,619 39,481 3.68

Pesticide Manufacturing and Formulation .................................................................... 60 1,440 120 9.58

Pharmaceutical Manufacturing ..................................................................................... 108 70,223 1,431 39.53

Solvent Recovery ......................................................................................................... 34 932 137 32.10

Film Base Manufacturing .............................................................................................. 1 45,000 500 8.90

Polycarbonate Manufacturing ....................................................................................... 4 1,898 67 6.70

Construction .................................................................................................................. 9,504 63,115 24,896 2.44

Shipyards ...................................................................................................................... 25 85,212 3,040 0.47

Total, all application groups ............................................................................... 91,624 5,598,293 237,496 **

*In most cases, the estimated number of establishments in each application group was based on the volume flow of MC in 1990 divided by

the estimated MC use per facility. The estimated number of establishments was multiplied by the total number of employees per establishment

and exposed employees per establishment as reported in CONSAD’s survey.

** Netting out rehandling, estimated total consumption equals 469.2 million pounds manufactured, minus 129.1 million pounds exported, + 19.3

million pounds imported, + 32.10 million pounds recovered from used solvent. The column does not sum to 391.5 million pounds because nonconsumptive uses such as production, distribution and formulation, and solvent recovery are included.

Sources: CONSAD, HSIA, PRMA, Office of Regulatory Analysis.

In all, OSHA analyzed 28 application

groups. These application groups

include, among others, methylene

chloride manufacturing, paint

manufacturing, metal cleaning,

polyurethane foam manufacturing,

plastics and adhesives manufacturing,

ink use, pharmaceuticals, and

construction and shipyards. A total of

91,624 establishments are estimated to

be potentially affected by the standard.

These establishments employ a total of

5.6 million employees, of whom

237,496 are estimated to be exposed to

MC in the course of their work. The

application groups with the largest

numbers of directly exposed employees

are the Metal Cleaning, All Other

Industrial Paint Stripping, and Ink

Solvent Use groups. In many facilities,

MC is used only by a small number of

employees; the average number of MCexposed employees per establishment

covered by the final rule is only 2.6

employees.

Chapter III of the analysis assesses the

technological feasibility of the final

standard’s requirements, and

particularly its PELs, for firms in the 28

application groups identified in the

Industry Profile. OSHA finds, based on

an analysis of exposure data taken on

workers performing the MC-related

tasks identified for each application

group, that compliance with the

standard is technologically feasible for

establishments in every application

group studied. With few exceptions,

employers will be able to achieve

compliance with both PELs through the

use of engineering controls and work

practices. The few exceptions are

certain maintenance activities, such as

vessel cleaning, which have

traditionally involved the use of

respiratory protection, and operations in

two applications where the

supplemental use of respirators may be

necessary. These operations are

centrifuge unloading and dryer loading

at one bulk pharmaceutical

manufacturing facility operated by

Abbott Laboratories, and operations

involving access to and entering of the

roll coating machine used by the

Eastman Kodak Company to make film

base.

The exposure data relied on by OSHA

in making its technological feasibility

determinations have been compiled in a

database that contains thousands of MC

exposure results (see Appendix B of this

analysis) taken by OSHA compliance

officers, consultation program

consultants, MC-using companies, and

interested parties. These data show that

many facilities in many of the affected

application groups have already

achieved the reductions in employee

exposures required by the final rule. In

addition, the exposures of many

employees in many job categories in a

number of the application groups have

been reduced to levels that are close to

those required by the standard. OSHA’s

analysis of technological feasibility

analyzes employee exposures at the

operation or task level to the extent that

such data are available. In other words,

the analysis identifies relevant exposure

data on a job-category-by-job category

basis to permit the Agency to pinpoint

those MC-exposed workers and job

operations that are not yet under good

process control and will thus need

additional controls (including improved

housekeeping, maintenance procedures,

and employee work practices) to

achieve compliance. Costs are then

developed (see Chapter V of the

economic analysis) for the improved

controls needed to reach the new levels.

The benefits that will accrue to MCexposed employees and their employers

are substantial and take a number of

forms. Chapter IV of the analysis

describes these benefits, both in

quantitative and qualitative form. First,

based on a physiologically-based

pharmacokinetic (PBPK) model, OSHA

estimated that, if all 237,000 employees

were exposed at the existing 8-hour

TWA exposure limit of 500 ppm for an

occupational lifetime of 45 years, a total

of 29,862 excess cancer deaths would

occur, or 126 excess cancer deaths per

1,000 workers. If, however, the 237,000

employees were exposed to the final

standard’s PEL of 25 ppm for 45 years,

8533 excess cancer deaths would be

expected (3.6 per thousand workers).

However, few workers are currently

being exposed to 500 ppm of MC as an

8-hour TWA. The actual exposure levels

of most affected workers are

considerably lower, and, when these

exposure levels, rather than 500 ppm,

are used as the baseline, the PBPK

model estimates that 1405 cancer deaths

will be averted over a 45-year period. By

reducing the total number of MC-related

cancer deaths from 1,804 deaths to 399

deaths over 45 years, the standard will
1566 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

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

estimates.

TABLE VIII–2.—LUNG CANCER RISK OVER 45 YEARS FOR WORKERS EXPOSED AT CURRENT EXPOSURE LEVELS AND

AT THE LEVELS EXPECTED AFTER IMPLEMENTATION OF THE FINAL STANDARD

0–12.5 12.5–25 25 25–50 50–100 100–200 200–350 350–500 500+*** Total

Lifetime

Excess

Cancer

Risk

(per

thousand

workers)* ... 0.91 2.71 3.60 5.53 11.98 28.45 61.75 104.44 125.78 ................................

Baseline

Number of

Workers Exposed 141,323 26,464 162 22,839 23,903 14,803 3,281 1,297 3,422 237,495

Estimated

Excess

Deaths

in

Baseline

(Existing

PEL)** 129 72 1 126 286 421 203 135 430 1,804

Predicted

Number of

Workers Exposed

at New

PEL .... 159,825 28,441 49,229 0 0 0 0 0 0 237,495

Predicted

Excess

Deaths

at New

PEL** 146 77 176 0 0 0 0 0 0 399

*Based on OSHA’s final estimate using the PBPK model, as presented in the Quantitative Risk Assessment section of the Preamble.

**Computed as level of lifetime risk times the number of exposed workers.

***For workers exposed to levels of greater than the current PEL of 500 ppm, the risk estimate is that associated with a lifetime exposure to

500 ppm.

Source: Office of Regulatory Analysis; OSHA; Department of Labor.

In addition to cancer deaths, the

standard is estimated to prevent 3

deaths per year from MC’s acute central

nervous system and

carboxyhemoglobinemic effects.

(Carboxy-hemoglobinemia is the

inability of the blood to carry sufficient

oxygen to supply the heart muscle;

because methylene chloride interferes

with the blood’s ability to carry oxygen,

exposure to it places susceptible

individuals, such as those with silent

cardiovascular disease, pregnant

women, and smokers, at greater risk.)

OSHA receives reports every year of

workers who have succumbed to MC’s

acute CNS toxicity while they were

engaged in such tasks as floor stripping.

For example, the Agency recently

received a fatality report on two young

workers who died after pouring 14

gallons of MC on a squash court they

were refinishing. Both of these

employees lost consciousness,

collapsed, and subsequently died of

respiratory failure. In addition, MC

exposures above the level at which the

final rule’s STEL is set—125 ppm—are

also associated with acute central

nervous system effects, such as

dizziness, staggered gait, and

diminished alertness, all effects that can

lead to workplace accidents. OSHA

estimates that as many as 30,000 to

54,000 workers will be protected by the

final rule’s STEL from experiencing

CNS effects and episodes of

carboxyhemoglobinemia every year.

Moreover, exposure to the liquid or

vapor forms of MC can lead to eye, skin,

and mucous membrane irritation, and

these material impairments will also be

averted by compliance with the final

rule. Finally, contact of the skin with

MC can lead to percutaneous absorption

and systemic toxicity and thus lead to

additional cases of cancer that have not

been taken into account in the benefits

assessment presented in Chapter IV of

the Final Economic Analysis.

The costs employers in the affected

application groups are estimated to

incur to comply with the standard total

$101 million in 1994 dollars. These

costs, which are presented in Chapter V

of the full economic analysis, are

annualized over a 10-year horizon at a

discount rate of 7 percent. Table VIII–

3 shows annualized costs by provision

of the standard; the most costly
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1567

provisions are those requiring

engineering controls, protective clothing

and eye protection, and medical

surveillance for MC-exposed workers.

These three provisions together account

for approximately 75 percent of the

standard’s compliance costs.

TABLE VIII–3.—ANNUALIZED COSTS BY

PROVISION

Provision Annualized

Costs

Engineering Controls .............. $38,773,642

Respirators .............................. 6,374,083

Monitoring ............................... 9,849,577

Protective Clothing and Eye

Protection ............................ 29,578,340

Emergency Eyewash and

Shower ................................ 3,183,486

Medical Surveillance ............... 7,986,493

Leak and Spill Detection Program .................................... 3,703,286

Regulated Areas ..................... 150,884

Recordkeeping ........................ 652,121

Training ................................... 196,656

Understanding Regulation and

Developing Training ............ 777,132

Subtotal ........................ 101,225,701

Costs of Substitution ............... 237,336

Total ............................. 101,463,037

Source: Office of Regulatory Analysis;

OSHA; Department of Labor.

Table VIII–4 analyzes compliance

costs by application group and shows

that the Cold Cleaning application

group, which is in the larger Metal

Cleaning grouping, and the Furniture

Stripping application group, which is in

the larger Paint Stripping category, will

incur the largest costs of compliance

(though not necessarily the largest

economic impacts). These costs reflect

the high exposures and relative lack of

control measures currently existing in

many establishments in these two

application groups. In other words,

because MC exposures are poorly

controlled in so many cold cleaning and

furniture stripping facilities, employers

in these industries will be required by

the standard to implement control

measures to protect their employees

from the significant risk of MC

exposure.

TABLE VIII–4.—ANNUALIZED COSTS BY

METHYLENE CHLORIDE APPLICATION

GROUPS

Application group Annualized

costs

Methylene Chloride Manufacturing ................................... 8,150

Distribution/Formulation of

Solvents ............................... 794,099

Metal Cleaning:

Cold Degreasing and Other

Cold Cleaning .................. 26,950,869

Open-Top Vapor

Degreasing ...................... 371,096

Conveyorized Vapor

Degreasing ...................... 97,253

Semiconductors ................... 247,666

Printed Circuit Boards ......... 217,479

Aerosol Packaging .................. 297,999

Paint Remover Manufacturing 229,724

Paint Manufacturing ................ 89,697

Paint Stripping:

Aircraft Stripping .................. 8,148,754

Furniture Stripping ............... 10,689,840

All Other Industrial Paint

Stripping ........................... 24,413,924

Flexible Polyurethane Foam

Manufacturing ...................... 4,252,861

Plastics and Adhesives Manufacturing and use ................ 5,417,950

Adhesive Production

Adhesive Use

Injection Molding

Lamination

Mold Release

Ink and Ink Solvent Manufacturing ................................... 23,518

TABLE VIII–4.—ANNUALIZED COSTS BY

METHYLENE CHLORIDE APPLICATION

GROUPS—Continued

Application group Annualized

costs

Ink Solvent Use ...................... 3,360,723

Pesticide Manufacturing and

Formulation ......................... 106,060

Pharmaceutical Manufacturing 311,708

Solvent Recovery .................... 49,829

Film Base Manufacturing ........ 47,454

Polycarbonate Manufacturing 4,651

Construction ............................ 14,922,000

Shipyards ................................ 518,544

Total, all application

groups ....................... 101,463,037

Source: Office of Regulatory Analysis;

OSHA; Department of Labor.

Chapter VI of the economic analysis

analyzes the impacts of compliance

costs on firms in affected application

groups. The standard is clearly

economically feasible: on average,

annualized compliance costs amount

only to 0.18 percent of estimated sales

and 3.79 percent of profits. For all but

three application groups—polyurethane

foam blowing, furniture stripping, and

construction—compliance costs are less

than 3 percent of profits, and for all but

one application group—furniture

stripping—annualized compliance costs

are less than 0.5 percent of the value of

sales. Table VIII–5 shows average

compliance cost impacts across the

many Standard Industrial Classification

(SIC) codes potentially involved in the

application groups studied.

TABLE VIII–5.—SCREENING ANALYSIS TO IDENTIFY POSSIBLE ECONOMIC IMPACT OF THE FINAL MC STANDARD

Application group

Number of

establishments complying

Annualized costs of compliance

As percent

of sales

As percent

of profit

Manufacture of MC ................................................................................................................................... 4 (*) 0.04

Distribution/Formulation of Solvents ........................................................................................................ 320 0.04 0.55

Metal Cleaning:

Cold Degreasing and Other

Cold Cleaning .................................................................................................................................... 23,717 0.01 0.18

Open-Top Vapor Degreasing ............................................................................................................ 278 0.01 0.22

Conveyorized Vapor Degreasing ...................................................................................................... 45 0.02 0.35

Semiconductors ................................................................................................................................. 239 (*) 0.05

Printed Circuit Boards ....................................................................................................................... 141 0.02 0.41

Aerosol Packaging ................................................................................................................................... 50 0.01 0.13

Paint Remover Manufacturing .................................................................................................................. 80 0.02 0.06

Paint Manufacturing ................................................................................................................................. 49 0.01 0.04

Paint Remover Use (Paint Stripping):

Aircraft Stripping (Large Firms) ......................................................................................................... 75 0.07 1.34

Aircraft Stripping ( Small Firms) ........................................................................................................ 225 0.08 2.12

Furniture Stripping ............................................................................................................................. 6,152 2.04 **39.40
1568 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

TABLE VIII–5.—SCREENING ANALYSIS TO IDENTIFY POSSIBLE ECONOMIC IMPACT OF THE FINAL MC STANDARD—

Continued

Application group

Number of

establishments complying

Annualized costs of compliance

As percent

of sales

As percent

of profit

All Other Industrial Paint Stripping .................................................................................................... 35,041 0.01 0.11

Flexible Polyurethane Foam Manufacturing ............................................................................................ 100 0.32 **9.23

Plastics and Adhesives Manufacturing and Use ..................................................................................... 3,487 0.03 0.52

Ink and Ink Solvent Manufacturing .......................................................................................................... 15 (*) 0.03

Ink Solvent Use ........................................................................................................................................ 11,869 0.03 0.05

Pesticide Manufacturing and Formulation ................................................................................................ 60 0.01 0.35

Pharmaceutical Manufacturing ................................................................................................................. 108 (*) 0.03

Solvent Recovery ..................................................................................................................................... 37 0.05 0.85

Film Base ................................................................................................................................................. 1 (*) 0.01

Polycarbonates ......................................................................................................................................... 4 (*) (*)

Construction ............................................................................................................................................. 9,504 0.35 **9.67

Shipyards .................................................................................................................................................. 25 0.07 1.72

All Application groups ............................................................................................................................... 91,625 0.18 3.79

* = less than .005%.

** These relatively high impacts on profits assume that no price increase is possible. In all three cases, price increases of 2.1 percent or less

would fully restore profits. In all of these application groups, most firms will be able to increase prices to offset their regulatory costs. In furniture

stripping, a substantial portion of the market is for antique refinishing that involves MC use, a service which is relatively price insenstive. Soft

flexible foam of the kind MC is used to make is an essential material in the construction of cushions of all types. In the construction sector, MC

based paint stripping and foam blowing are essential operations of many of the jobs in which they are used.

SOURCES: CONSAD; Dun & Bradstreet; Office of Regulatory Analysis, OSHA, Department of Labor.

It is important to understand that

OSHA’s methodology tends to

overestimate the economic impacts of

the standard, for a number of reasons.

For example, OSHA’s cost methodology

does not take into account the many

simple and virtually cost-less

improvements in employee work

practices and housekeeping procedures

that would enable many employers to

achieve compliance with the final rule’s

PELs. In flexible polyurethane foam

manufacturing, for example, OSHA’s

costs may be overestimated because it

was assumed that no firms would

substitute away from MC entirely, even

though some firms have already done so

(as described in Chapter III,

Technological Feasibility). Despite the

fact that OSHA’s cost estimates are

likely to be overestimates, OSHA

decided to examine in greater detail the

three application groups shown by the

economic analysis to have the highest

costs as a percentage of profits, i.e.,

furniture stripping, polyurethane foam

manufacturing, and construction.

In the furniture refinishing

application group, compliance costs are

2.0 percent of the value of revenues and

39 percent of the value of before-tax

profits. Approximately half of all

furniture refinishing sales derive from

antique refinishing, a market niche that

is unlikely to be sensitive to a 2.0

percent change in price. Even in the

area of used furniture refinishing, which

constitutes the remaining half of the

furniture refinishing market, a 2.0

percent price increase would be

unlikely to significantly alter the

amount of furniture being refinished. In

general, price increases of this

magnitude would be expected to result

only in a very small drop in the demand

for furniture refinishing. If this were not

the case, normal business fluctuations,

such as drops in the relative cost of new

furniture or a major increase in the price

of methylene chloride (such as has

occurred in recent years) would also

have had major impacts on the industry.

In construction and polyurethane

foam manufacturing, compliance costs

for the average firm are 9.2 and 9.7

percent of profits, respectively.

However, to offset these costs,

construction firms would need only to

increase their revenues by 0.35 percent

and foam blowing operations would

need only to increase the price of their

products by 0.32 percent. In

construction, such price increases are

unlikely to present a problem, since the

use of MC is essential on many larger

construction projects. For example, it is

difficult to believe that demand for

remodeling or renovation projects

would be seriously altered by a 0.35

percent increase in the cost of the paint

stripping portion of the job. In flexible

polyurethane foam manufacturing,

either MC or an appropriate substitute is

essential to the production of low

density, or soft, foam, and foam, in turn,

is essential to the production of many

kinds of furniture. Demand for such

products is unlikely to change as a

result of an 0.32 percent increase in the

price of flexible foam. OSHA therefore

concludes that even marginal firms in

these three sectors—furniture stripping,

construction, and flexible foam

blowing— are unlikely to close as a

result of the compliance costs of this

standard.

To ensure that the analysis of average

impacts presented in the economic

analysis did not obscure potentially

significant economic impacts at the 4-

digit SIC level, OSHA performed an indepth analysis of the 4-digit SICs

potentially involved in the Cold

Cleaning and All Other Industrial Paint

Stripping application groups. The

results of this in-depth analysis are

presented in Appendix D of the full

economic analysis. In all, a total of 162

4-digit SICs potentially impacted by the

standard in the Cold Cleaning group and

more than 200 4-digit SICs in the Other

Industrial Paint Stripping group were

analyzed. Across all of the Cold

Cleaning SICs, the average impact of the

costs of compliance is 0.06 percent of

revenues and 1.12 percent of profits.

The largest impacts on profits occur in

SIC 3412, Metal Barrels, Drums, and

Pails, and SIC 3494, Valves and Pipe

Fittings not elsewhere classified; in

these cases, impacts on profits are 13.3

and 15.1 percent, respectively. In both

of these cases, however, these impacts

are explained by extremely low profit

margins (less than .02 percent of sales,

i.e., less than $2 per $10,000 in sales, in

1994). As a result, a price increase of

less than one cent per $100 of revenue

would leave profits unchanged. Such a

price increase is feasible because an
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1569

3As a result of data and information received

from commenters and other information in the

record, the Final Economic Analysis does not

identify significant impacts or technologic or

economic feasibility problems for aircraft stripping

operations of any size.

increase of this magnitude is unlikely to

lead to significant changes in the

demand for metal barrels or valves and

pipe fittings. In no other 4-digit Cold

Cleaning SIC did impacts reach even 5

percent of profits.

Across all 200-plus Industrial Paint

Stripping SICs, the average impact of

the costs of compliance on revenues is

0.03 percent. The largest impact of costs

on sales is 0.33 percent and occurs in

SIC 7532, Auto Top, Body Repair, and

Paint Shops (discussed further below).

The average impacts of costs on profits

across these SICs is 0.17 percent. The

largest impacts on profits occur in SIC

3412, SIC 3494 (both discussed above),

and in SIC 7532, Auto Tops, Body

Repair and Paint Shops; in all three of

these SICs, cost impacts are between 6

and 8 percent of profits. Again, the

explanation for these impacts in SICs

3412 and 3494 is that their profit margin

in 1994 was vanishingly low. The

resulting price increases required to

maintain profits are also extremely

small, and OSHA concludes that such

an increase is likely to take place in

these cases. In SIC 7532, the other

relatively high impact SIC, profit

margins are relatively high

(approximately 4.4 percent), and thus a

small decline of this magnitude would

have relatively little impact.

Summary of the Regulatory Flexibility

Analysis

In its 1991 proposal, OSHA requested

comments and information that would

assist the Agency in identifying smallbusiness users of MC and in structuring

the final standard so that these users

would be able to achieve the standard’s

worker protection goals in ways that

would be technologically and

economically feasible for them (56 FR

57041 to 57043). OSHA anticipated that,

as stated in the proposal, the standard

might have a significant economic

impact on small entities in at least two

application groups: firms with fewer

than 20 employees that engage in

stripping of paint from aircraft, and

firms with fewer than 20 employees that

engage in furniture stripping.3 OSHA

also requested comment concerning the

standard’s impact on small employers in

light of the Regulatory Flexibility Act’s

mandate to consider and minimize

impacts on small businesses, consistent

with the purposes and criteria of the

standard’s enabling legislation (56 FR

57115 to 57121).

Many commenters identified

additional application groups that

include small establishments likely to

have difficulty achieving all of the

standard’s protective goals if the

requirements of the standard were

structured in a one-size-fits-all manner.

These commenters provided

considerable data and identified many

possible modifications and alternatives

to the proposed standard that they

believed would facilitate compliance

and mitigate the standard’s impact on

MC-using establishments with fewer

than 20 employees.

None of the comments concerning

small employer issues, whether in the

context of economic or technological

feasibility or the Regulatory Flexibility

Act, disagreed with OSHA’s basic

premise that the fewer-than-20-

employee cut-off was appropriate to

distinguish between large and small

MC-using businesses, was a useful way

of characterizing the compliance

abilities and limitations of affected

employers and is an appropriate

definition for purposes of the Regulatory

Flexibility Act. Use of this numerical

cut-off point captures 61 percent of all

establishments potentially affected by

the final rule. MC-users with fewer than

20 workers tend to have the

characteristics of ‘‘mom-and-pop’’

businesses, whereas establishments

with 20 or more workers are generally

more sophisticated in terms of the

technology they use and their

management resources. The 20-

employee threshold has also proved to

be an agreed-on and useful cut-off point

in past OSHA rulemakings (see, for

example, the permit-required confined

spaces standard (58 FR 4547) and the

process safety management standard (57

FR 6402)).

During Executive Order 12866 review,

the Office of Advocacy of the Small

Business Administration expressed its

views concerning OSHA’s small

business definition. In a letter to OMB,

the SBA’s Chief Counsel for Advocacy

stated in a letter dated August 16, 1996,

that ‘‘[t]he regulatory alternatives

developed, using OSHA’s size standard

of less than 20 employees, were

somewhat beneficial to two of the three

industries [furniture stripping,

polyurethane foam blowing, and

construction]. These industries, i.e.,

furniture stripping and construction, are

predominantly micro businesses that

fall into OSHA’s definition of small’’

(Ex. 130). The Office of Advocacy was

concerned, however, that the 20-

employee cut-off did not adequately

deal with the MC-using polyurethane

foam manufacturing sector. (In this

application group, the majority of

establishments likely to experience

significant economic impacts fall into

the 20 to 99- employee size category.)

‘‘[T]he characteristics of the

manufacturing sector indicate that the

[20 employee] size standard was not

appropriate in that industry for the

purposes of regulatory flexibility.’’ Id.

The SBA concluded that OSHA should

consider taking additional steps to

address implementation burdens and

the needs of the polyurethane foam

manufacturing sector.

Working with OMB and the SBA’s

Office of Advocacy to resolve this

concern, OSHA reexamined the

potential impacts of the standard on

polyurethane foam manufacturing

establishments in the 20 to 99 employee

size category in the context of economic

impact issues. As explained more fully

in the Final Economic and Regulatory

Flexibility Analysis, OSHA concluded

that, even though members of this group

were not small employers, some

accommodation would be necessary to

assure that employees working in

establishments of this size in this

industry would not receive less

protection than all other MC-exposed

employees. Accordingly, OSHA

extended the engineering control

implementation date for this group of

establishments by one year. This

extended phase-in is designed to enable

this group of employers to plan for and

accumulate the capital to finance

needed controls, install them, and

ensure their effective and consistent

operation before the compliance

deadline.

OSHA’s extensive feasibility studies

and focus on small business issues

resulted in a number of modifications

that have made the standard more costeffective for business while maintaining

protection for workers. In addition,

OSHA conducted an alternative

screening analysis to measure the final

rule’s potential impacts on

establishments in the regulated

community using the SBA’s size

standards. For most application groups,

this meant that OSHA examined the

standard’s economic impacts on firms at

the 500 employee level. (Financial data

are not available for cut-off points

higher than 500 employees; thus, OSHA

used that cut-off for all application

groups.) In some cases, the SBA size

standards are defined in terms of annual

revenues, and for SICs so defined,

OSHA translated these revenue figures

into the appropriate employee size

category. This SBA-based alternative

screening analysis enabled the Agency

to determine whether, by failing to look
1570 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

at potential impacts among firms in

other size classes, significant impacts

had been overlooked. The analysis

conducted using the SBA size standards

confirmed that any potentially

significant economic impacts associated

with the final rule occur among firms in

the fewer-than-20-employee category,

with one exception, i.e., firms in the 20–

99 employee size category in the

polyurethane foam manufacturing

industry. (See the full Final Economic

Analysis for additional detail.)

For the final rule, OSHA has analyzed

the costs of compliance as a percentage

of profits, and costs as a percentage of

revenues, for firms with fewer than 20

employees in every application group.

This analysis identified significant

economic impacts on a substantial

number of small entities, and the

Agency has accordingly conducted a

full Final Regulatory Flexibility

Analysis in accordance with the

Regulatory Flexibility Act, as amended

in 1996. The three application groups

for which such impacts were identified

were Furniture Stripping, Polyurethane

Foam Blowing, and Construction. Table

VIII–6 shows the results of this analysis

in detail.

The full regulatory flexibility analysis

is presented in Chapter VI of the Final

Economic and Regulatory Flexibility

Analysis. The remainder of this section

briefly summarizes that analysis.

This rule is needed to prevent cancer

deaths and other illnesses, as discussed

in greater detail in the Health Effects

Section (Section V of this Preamble).

Section III of this preamble, Events

Leading to the Final Standard,

summarizes OSHA’s efforts to assure

input to this rulemaking by affected

small firms. Table VIII–6 identifies the

affected small firms by sector. OSHA

estimates that a total of 56,000 small

firms will be affected by this standard.

TABLE VIII–6.—SCEENING ANALYSIS OF POTENTIAL ECONOMIC IMPACTS ON SMALL FIRMS

Application group

Number of

small establishments

affected

Costs as a

percentage

of profits for

small firms

Costs as a

percentage

of sales for

small firms

Manufacture of MC ................................................................................................................................... 0 NA NA

Distribution/Formulation of Solvents ........................................................................................................ 139 3.0% 0.2

Metal Cleaning:

Cold Degreasing and Other Cold Cleaning ...................................................................................... 9,223 0.9 0.0

Open-Top Vapor Degreasing ............................................................................................................ 0 NA NA

Conveyorized Vapor Degreasing ...................................................................................................... 11 2.4 0.1

Semiconductors ................................................................................................................................. 0 NA NA

Printed Circuit Boards ....................................................................................................................... 20 2.0 0.1

Aerosol Packaging ................................................................................................................................... 10 0.7 0.1

Paint Remover Manufacturing .................................................................................................................. 34 0.3 0.1

Paint Manufacturing ................................................................................................................................. 7 0.1 0.0

Paint Remover Use (Paint Stripping):

Aircraft Stripping (Large Firms) ......................................................................................................... 0 NA NA

Aircraft Stripping ( Small Firms) ........................................................................................................ 75 4.5 0.1

Furniture Stripping ............................................................................................................................. 5,901 41.5* 2.2

All Other Industrial Paint Stripping .................................................................................................... 25,441 0.8 0.0

Flexible Polyurethane Foam Manufacturing ............................................................................................ 8 60.3* 1.7

Plastics and Adhesives Manufacturing and Use ..................................................................................... 498 1.8 0.1

Ink and Ink Solvent Manufacturing .......................................................................................................... 3 NA NA

Ink Solvent Use ........................................................................................................................................ 5,395 0.1 0.1

Pesticide Manufacturing and Formulation ................................................................................................ 40 6.6 0.2

Pharmaceutical Manufacturing ................................................................................................................. 0 NA NA

Solvent Recovery ..................................................................................................................................... 17 2.7 0.1

Film Base ................................................................................................................................................. 0 NA NA

Polycarbonates ......................................................................................................................................... 0 NA NA

Construction ............................................................................................................................................. 9,085 19.9* 0.5

Shipyards .................................................................................................................................................. 0 NA NA

All Application groups ............................................................................................................................... 55,908 8.2 0.3

NA=No small firms in this application group.

* These relatively high impacts on profits assume that no price increase is possible. In all three cases, price increases of 2.1 percent or less

would fully restore profits. In all of these application groups, most firms will be able to increase prices to offset their regulatory costs. In furniture

stripping, a susbtantial portion of the market is for antique refinishing that involves MC use, a service which is relatively price insensitive. Soft

flexible foam of the kind MC is used to make is an essential material in the construction of cushions of all types. In the construction sector, MC

based paint stripping and foam blowing are essential operations of many of the jobs in which they are used.

Sources: CONSAD; Dun & Bradstreet; Office of Regulatory Analysis, OSHA, Department of Labor.

The Summary and Explanation

section of this preamble provides a

description of the compliance

requirements associated with this rule,

and a paperwork burden analysis of the

record keeping requirements is provided

in the Collection of Information Request

for Comment section at the beginning of

this preamble. Based on comments

regarding anticipated effects on small

businesses, OSHA has reduced the final

rule’s overall paperwork requirements

from those proposed and has refined

some paperwork requirements to

simplify compliance for small entities.

OSHA considered numerous

regulatory alternatives and

modifications to the requirements of the

proposed standard (ranging from higher

PELs, to 40-hour rather than 8-hour time

weighted average exposure limits, to

delayed implementation dates) that

commenters believed might minimize

significant economic impacts on small

businesses. OSHA rejected those

alternatives that clearly decreased the

safety of workers in small

establishments, but the Agency also

adopted many regulatory changes that

will improve small employers’ ability to

provide their employees with the same

level of protection as that afforded

workers in larger establishments. As
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1571

explained more fully in the Final

Economic Analysis and summarized in

Table VIII–7, the final standard contains

delayed implementation dates, reduced

paperwork requirements, streamlined

medical surveillance provisions and

other accommodations that, in the

Agency’s judgment, will minimize any

significant economic impacts of the

standard on small employers to the

extent necessary to enable them to meet

the standard’s protective goals.

TABLE VIII–7. CHANGES MADE SINCE THE PROPOSED REGULATION TO REDUCE THE FINAL STANDARD’S IMPACTS ON

SMALL BUSINESSES

Change to proposed regulation Impact on small businesses

Firms with fewer than 20 employees given 3 years (rather than 1) to

achieve PEL using engineering controls.

More performance oriented and flexible, reduces costs to small businesses in first two years by 30 to 40 %, allows small businesses

time to plan major expenditures.

Allows the use of licensed health care professionals in addition to physicians for medical surveillance.Provides greater flexibility.

Laboratory tests are at the discretion of physician rather than automatically required.Reduces costs of medical surveillance by more than 14 percent, more

performance oriented.

Employees under 45 are required to have a physical every three years

rather than annually.

Reduces costs of medical surveillance by 30 percent.

Respirators required in regulated areas only when PEL is likely to be

exceeded.

Decreases respirator use and costs for small business.

If MC is used less than 30 days per year, monitoring may be conducted with direct reading instruments.Significantly reduces costs of monitoring for establishments making

limited use of MC; this provision will be especially helpful in construction.

Written compliance plans are no longer required .................................... Reduces paperwork.

Hazard communication requirements do not go beyond what is already

required by hazard communication standard.

Reduces paperwork and costs.

Employee re-training only as needed rather than annually ..................... More performance oriented, reduces costs of training 80 percent.

Simplified recordkeeping for small businesses for exposure monitoring

data.

Reduces paperwork.

IX. Environmental Impact

This section analyzes the impact on

the environment of changing the

standard for methylene chloride (MC) to

an eight-hour time weighted average

(TWA8) permissible exposure limit

(PEL) of 25 parts per million (ppm),

with a 125 ppm 15-minute short-term

exposure limit (STEL) and ancillary

requirements. It is based principally on

information collected for OSHA by

CONSAD Research Corporation and its

subcontractor, PEI Associates Inc., and

reported in Economic Analysis of Draft

Regulatory Standard for Methylene

Chloride, 1990, OSHA Docket, Ex. 15,

and also draws upon other materials in

the OSHA docket.

Current uses of methylene chloride

involve releases to the air through

venting of storage tanks or drums and

through evaporation of MC during the

performance of various activities such

as paint stripping and cold cleaning

indoors or outdoors. The volume of MC

emitted as a percentage of MC used

varies greatly among industries. Some

processes, such as polyurethane foam

manufacturing and paint stripping,

typically release 100 percent of the MC

to the atmosphere (Ex. 15). Other uses,

such as solvent recovery and the

manufacture of methylene chloride,

involve less than 1 percent of the MC

used being emitted to the atmosphere

(Ex. 15). In addition, air, water, or solid

waste pollution may occur as a result of

the disposal of waste residues

containing MC. Additional details by

application group are presented in

CONSAD’s report [Ex. 15].

Future environmental releases of

methylene chloride resulting from the

final standard will largely be a function

of how it affects the demand for

methylene chloride and for its

substitutes. The demand for methylene

chloride has been declining (e.g.,

generally, it is no longer being used in

formulating hairsprays). Any regulatory

action by OSHA is expected to further

reduce the demand for MC and thus the

extent of its environmental releases.

Although it is technically possible to

substitute chlorofluorocarbons (CFCs)

for methylene chloride in electronics

and foam blowing, OSHA does not

expect the revision of the MC standard

to have any such effect. CFC products

are significantly more expensive than

MC products and are themselves being

phased out or banned because of their

effects on the environment.

To the extent that firms might have to

use greater quantities of substitute

chemicals to get the same effects

formerly obtained with MC, waste

residues and disposal costs would

increase. On the other hand, increases

in MC leak prevention and recycling

would improve the environment.

The Paint Remover Manufacturers

Association (PRMA) has charged that

the standard would cause ‘‘massive

amounts’’ of methylene chloride to be

emitted into the atmosphere (Ex. 19–11).

In Chapter III, OSHA noted that it could

find no convincing argument by PRMA

as to why the total amount emitted after

installation of exhaust ventilation

would differ significantly from the

amount now simply leaking into the

atmosphere.

At informal public hearings, PRMA

stated that ‘‘an exposure level of 25 PPM

is so low that it brings into the issue the

formation of vapor clouds with levels of

greater than 25 PPM that could move in

and around the neighborhood,’’

allegedly through decomposition of the

MC [Tr. 245, 9/17/92]. There is no

evidence that this hypothetical situation

has ever occurred. PRMA may have

confused decomposition with diffusion

[Tr. 940–941, 9/21/92]. At Eastman

Kodak Company, which currently emits

more methylene chloride into the

atmosphere than any furniture stripper

possibly could, the chemical has

diffused so rapidly that no clouds of MC

have been formed [Tr. 1237–1238, 9/22/

92].

Generally, it is not expected that any

significant environmental impact will

result from revision of the methylene

chloride standard.

X. Summary and Explanation of the

Final Standard

Introduction

The final standard for occupational

exposure to methylene chloride (MC) is

different in several important respects

from the proposed MC standard
1572 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

published in the Federal Register in

1991 (56 FR 57036). For example, the

standard has been written in plain

language, is more performance-oriented

than the proposal, and substantially

reduces the amount of paperwork

employers will have to complete.

Employers will thus find compliance

with the standard easier, their

paperwork less extensive, and their

obligations clearer and less burdensome.

These changes are discussed in greater

detail in the appropriate sections of this

Summary and Explanation. OSHA seeks

input from users of the standard on

whether these changes are helpful and

what other changes could be made to

future standards to increase their userfriendliness. OSHA will also be

conducting a number of compliance

assistance and outreach projects in

connection with this standard to assist

employers and employees to comply.

As part of the Agency’s new approach

to standards writing, OSHA has

included an introductory paragraph in

the standard to provide readers with

information on MC, its health effects

and principal uses, and the reasons

OSHA is regulating this toxic substance.

This introductory language is nonmandatory and is intended only to

provide information and enhance

compliance.

This final rule is an occupational

health standard that establishes

requirements to control employee

exposure to MC, a chemical compound

found in many different types of

industries. OSHA has determined that

this standard is necessary because

exposure to MC places employees at

significant risk of developing exposurerelated adverse health effects. These

effects include cancer, effects on the

heart and central nervous system, and

skin and eye irritation. Employee

exposure to MC can occur through

inhalation or through skin absorption or

contact with the skin. This substance is

frequently used as a solvent in many

different kinds of jobs, including

furniture stripping, foam blowing, film

manufacturing and metal degreasing.

Although the final rule covers many

different types of workplaces where MC

is used, the extent of coverage depends

on the magnitude of employee exposure.

Although all covered employers, i.e.,

those with MC in the workplace, must

determine initially the extent to which

their employees are exposed to MC,

those with exposures at or below the

action level will only have to document

the results of this initial determination,

provide employee information and

training, and provide means of

protecting employees from contact with

liquid MC. The standard’s other

requirements, such as those for

engineering controls, medical

surveillance, etc. apply only to

workplaces where employee exposures

to MC exceed the action level.

Paragraph (a) Scope and application

This standard applies to all

occupational exposures in workplaces

covered by OSHA in general industry,

construction and shipyards where MC is

produced, released, stored, handled, or

used.

As discussed in the Health Effects and

Significance of Risk sections of this

preamble, OSHA has determined that

exposure to MC at the former PEL

creates a significant risk that employees’

health will be materially impaired.

Possible adverse health effects include

cancer, cardiac effects, central nervous

system effects, and skin or eye irritation.

Exposures to MC are found in various

general industry, construction, and

shipyard facilities, and OSHA has

determined that there are feasible

measures to control them in each of

these types of employment.

In the proposal’s Authority section,

OSHA preliminarily determined, under

Section 4(b)(2) of the OSH Act, that it

would be appropriate for the MC

standard to supersede any

corresponding longshoring standards in

§ 1910.16 and 29 CFR part 1918. The

Agency therefore proposed to add a new

paragraph (m) to § 1910.19. In addition,

in questions raised by the Agency in its

Notice of Public Hearing, OSHA

requested input regarding the use of MC

in longshoring. However, OSHA has

subsequently proposed (59 FR 28594,

June 2, 1994) to revise its marine

terminal (part 1917) and longshoring

(part 1918) standards. Those proposed

standards (proposed §§ 1910.16(b)(2),

1917.1(b)(2)(xiv), and 1918.1(b)(1))

would apply OSHA’s toxic substance

standards (part 1910, subpart Z) only

when the packaging in which a

substance is being transported in the

maritime environment has broken open.

This language, based on the existing

marine terminal standard

(§ 1910.16(b)(2)(ii)), reflects the view

that hazardous substances, when

properly packaged, do not pose

significant exposure risks for the

shipyard employees transporting them

in closed packages.

Therefore, as revised, final rule

§1910.19(m) states that §1910.1052 will

address MC exposure in marine

terminal and longshore employment

only where leaking or broken packages

allow MC exposure that is not addressed

through compliance with 29 CFR parts

1917 and 1918. Given the promulgation

of § 1910.19(m), the Agency has

determined that it is unnecessary to

mention marine terminals and

longshoring in final rule § 1910.1052(a),

Scope and application.

OSHA has not learned of any

circumstances in which marine terminal

or longshore employees have been

exposed to MC because of damage to

packaging. The Agency, accordingly,

anticipates that the MC final rule will

have little or no impact on the marine

terminal and longshoring industries.

In developing this rule, OSHA has

consulted with its Shipyard

Employment Standards Advisory

Committee (SESAC) to obtain

information on MC use and exposure in

shipyards and has taken the

Committee’s input into consideration in

developing the standard. In particular,

OSHA has relied on data provided by

SESAC in assessing the technological

feasibility and costs of compliance of

the standard for shipyards covered by

the rule.

Since the construction industry is also

included in the scope of the final rule,

OSHA is required to consult the

Advisory Committee on Construction

Safety and Health (ACCSH) in

accordance with section 107 of the

Contract Work Hours and Safety

Standards Act (40 U.S.C. 333) (the

Construction Safety Act) and 29 CFR

1911.10. On July 28, 1992, OSHA

formally consulted with ACCSH

regarding the construction-specific

aspects of occupational exposure to MC.

The Agency solicited comment and

testimony regarding ACCSH’s

recommendations through a Federal

Register notice (57 FR 36964, August

17, 1992). One of ACCSH’s suggestions

was that the rule specifically require

originators of contract bids to stipulate

a requirement for compliance with the

MC standard in their bids. OSHA has

not adopted this suggestion in the final

rule because construction contracts

already require compliance with all

relevant Federal regulations. The

specific suggestions made by ACCSH

and OSHA’s responses to ACCSH’s

input are discussed below in the

relevant paragraphs of the Summary and

Explanation.

In the proposal, the scope and

application paragraph included an

exemption for employers with

workplaces where MC products were

present but objective data were available

to demonstrate that the product could

not release MC above the action level or

STEL under those foreseeable

conditions of processing, use, and

handling that would cause the greatest

possible release. This concept remains

in the final standard, although the

provision has been moved to the
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1573

exposure monitoring section (paragraph

(d)), because this provision constitutes,

in effect, an exception to the standard’s

requirement for initial monitoring.

The Air Transport Association [Ex.

19–75] requested that airlines be

excluded from the general industry

standard, and that a separate standard

covering MC use in the airline industry

be developed. OSHA has specifically

determined that the exposures, work

operations, and means of compliance for

aircraft-related MC uses are similar to

those in many other establishments and

thus that there is no substantive basis

for the requested exemption.

Consequently, OSHA has concluded

that no industry-specific standard for

airlines is warranted. MC uses in the

airline industry are discussed in the

section of the final economic analysis

entitled ‘‘Aircraft Stripping.’’

Paragraph (b) Definitions

This paragraph includes definitions of

a number of terms used in the regulatory

text of the final standard. Although

some of these terms are in common use,

OSHA believes that these definitions

will help to ensure that their meaning

in the context of the standard is clear.

Action level means an airborne

concentration of MC of 12.5 ppm,

measured as an 8-hour time-weighted

average. One purpose of the action level

is to relieve the burden on employers by

providing a cut-off point below which

many of the compliance activities in the

standard are not required. In addition,

due to the variable nature of employee

exposures to airborne concentrations of

MC, compliance with an action level

provides employers with greater

assurance that their employees will not

be exposed to MC concentrations above

the permissible exposure limits.

The action level also increases the

cost-effectiveness and performance

orientation of the standard while

improving employee protection. The

standard will encourage employers who

can, in a cost-effective manner, identify

approaches or innovative methodologies

to reduce their employees’ exposures to

levels below the action level, because

this will eliminate the costs associated

with exposure monitoring and medical

surveillance, two provisions of the

standard that are triggered by exposure

exceeding the action level. At the same

time, the employees of such employers

will be protected because their MC

exposures will be less than half of those

permitted by the permissible exposure

limit. Employees of those employers

who are not able to lower exposures

below the action level will have the

additional protection provided by

medical surveillance, exposure

monitoring, and the other provisions of

the standard that are triggered by the

action level.

The statistical basis for using an

‘‘action level’’ has been discussed in

connection with several other OSHA

health standards [see, for example,

acrylonitrile (29 CFR 1910.1045) and

ethylene oxide (29 CFR 1910.1047)]. In

brief, although all employee exposure

measurements on a given day may fall

below the permissible exposure limit,

some probability exists that on

unmeasured days the employee’s actual

exposure may exceed the permissible

exposure limit. Where exposure

measurements are above the action

level, the employer cannot reasonably

be confident that the employee may not

be overexposed on a given day.

Therefore, requiring periodic employee

exposure measurements to begin at the

action level provides the employer with

a reasonable degree of confidence in the

results of his or her exposure

measurement program [Ex. 7–248].

OSHA’s decision to set the action level

at one-half the PEL is based on its

successful experience using this fraction

as the action level in many standards,

such as arsenic, ethylene oxide, vinyl

chloride and benzene.

OSHA received comments from a

number of rulemaking participants [Exs.

19–16, 19–20, 19–22, 19–31, 19–47, 19–

75] suggesting that the proposed PELs

and, by association, the action level, be

revised. For instance, Hukill Chemical

Corporation [Ex. 19–47] argued that the

action level should be set at 100 ppm

because it believes that: 1) CNS effects

from MC are not observed in humans

until 300 ppm; and 2) there is no

evidence of excess cancer mortality in

humans up to a level of 475 ppm. As

explained in the Health Effects and

Quantitative Risk Assessment sections

of this preamble, OSHA disagrees with

this commenter because the Agency has

determined that significant risks exist at

levels substantially below those referred

to by the commenter and therefore that

the suggested levels would not be

adequately protective.

The Pharmaceutical Manufacturers

Association (PMA) [Ex. 19–25]

commented that the action level of 12.5

ppm is appropriate, but requested an

exemption from ‘‘various requirements

of the standard’’ if exposure occurs on

fewer than 30 days a year. In particular,

PMA suggested that periodic monitoring

be required only when there is exposure

above the PEL or STEL for at least 10

days a year or at or above the action

level for at least 30 days a year. OSHA

has considered this issue, along with

similar concerns raised by ACCSH, and

agreed that in cases where exposure

occurs only on a few days per year, it

was appropriate to alter the exposure

monitoring requirements. Specifically,

paragraph (d)(2)(iii) would permit

employers whose employees are

exposed to MC on fewer than 30 days

per year to forego the initial monitoring

required by paragraph (d)(2), provided

that the employer has taken

measurements that give immediate

results (such as those taken by detector

tube) and that provide sufficient

information about exposures to

determine what (if any) control

measures are necessary. In addition, the

medical surveillance requirement

(paragraph (j)), with the exceptions

described in the final rule, applies only

where employees are exposed above the

action level on at least 30 days within

a year or above the PELs on at least 10

days within a year.

Newport News Shipbuilding [Ex. 19–

37] suggested that the action level be set

at 15 ppm. However, adopting this

suggestion would not be consistent with

the statistical basis for establishing the

action level at one-half the PEL, as

described above. In addition, Markey

Restoration Company [Tr. 2671–72,

10/16/92] recommended that the action

level be eliminated based on the costs

of medical surveillance triggered by that

level. As noted above, an action level is

based on the probability of exceeding

the PEL and is designed to enhance both

employee protection and the standard’s

cost-effectiveness, and OSHA does not

believe it would serve either employers

or employees to eliminate this concept

from the final rule.

The UAW [Tr. 1885–86, 9/24/92]

questioned the statistical arguments

underpinning the action level that

OSHA has used for some years.

According to the UAW’s calculations,

the action level should actually be set at

one-tenth the PEL to accomplish the

purpose OSHA intended. Accordingly,

the UAW argued that: ‘‘[I]f you leave it

[the action level] at 1/2, [there is] almost

the virtual certainty that workers are

overexposed on that job.’’ In response,

OSHA notes that its experience with

action levels set at one-half the 8-hour

TWA PEL has been favorable and that

employers and employees have

benefitted from the use of the action

level concept. In particular, it is OSHA’s

experience that, for most workplaces,

variability is normally such that an

action level set at one-half the TWA PEL

is appropriate. The final standard thus

continues this practice.

Emergency means any occurrence,

such as but not limited to, equipment

failure, rupture of containers, or failure

of control equipment, which results, or

is likely to result in an uncontrolled
1574 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

release of MC. The word ‘‘uncontrolled’’

was changed from ‘‘unexpected’’ in the

proposal to be more descriptive and to

be consistent with the Hazard

Communication Standard (29 CFR

1910.1200) and the Hazardous Waste

Operations and Emergency Response

Standard (29 CFR 1910.120). Incidental

releases of MC—i.e., those where the

substance can be absorbed, neutralized,

or otherwise controlled at the time of

release by maintenance personnel or

other employees working in the

immediate release area—are not

considered to be emergencies within the

scope of this standard. Dow Chemical

Company [Ex. 19–31] indicated that the

examples of emergencies provided in

the proposal (purging lines and cleaning

sludge from tanks) should not be

included in the final rule. Other

commenters [Exs. 19–25, 19–28, 19–57]

agreed with Dow that the examples

provided with the definition in the

proposal were inappropriate. In

particular, Eli Lilly and Company [Ex.

19–28, p. 7] stated

Lilly agrees with the concept that an

emergency should be tied to unexpected

releases. It is therefore curious and illogical

that the examples given—purging of lines

and cleaning tanks—are not unexpected

events. To the contrary, in the

pharmaceutical industry these are planned

events which could even occur daily.

On the other hand, the Upjohn

Company [Ex. 19–49] commented as

follows:

The language ‘‘unexpected significant

release’’ is very vague and will not result in

any consistent interpretation as to what type

of a release meets this definition. We would

recommend that the language be changed to

‘‘* * * which may lead to employee

exposure at or above the eight hour, timedweighted average (TWA) or at or above the

short-term exposure limit (STEL).’’

OSHA acknowledges that the

language in question could be

misunderstood and has deleted the

parenthetical listing of some examples

of emergency situations. Furthermore,

the Agency recognizes that emergency

situations, by their very nature, are

difficult to anticipate and describe.

Therefore, OSHA has not provided

examples of emergency situations in the

final rule. Instead, the final rule lists

situations that OSHA does not consider

emergencies, because these will help

employers to identify situations in their

workplaces that do constitute

emergencies. OSHA recognizes that

emergencies have certain aspects in

common but that other aspects are

specific to a given workplace. For

example, employee exposure must be

uncontrolled for an emergency to exist.

Provisions of the standard that include

requirements that employers must meet

in case of an emergency include

Methods of Compliance, Respiratory

Protection, Medical Surveillance, and

Employee Information and Training.

Employee exposure is defined as that

exposure to airborne MC which occurs

or which would occur if the employee

were not using respiratory protective

equipment. This definition is consistent

with OSHA’s previous use of the term

‘‘employee exposure’’ in other health

standards.

Methylene chloride (MC), or

dichloromethane, means an organic

compound with the chemical formula,

CH2Cl2. Its Chemical Abstracts Registry

Number is 75–09–2. Its molecular

weight is 84.9 g/mole. Other

information regarding the characteristics

of MC may be found in the appendices

to the final standard. MC is a colorless,

volatile, liquid with a chloroform-like

odor and is not flammable by standard

tests in air, but will burn under extreme

conditions. It has a boiling point of

39.85 C (104 F) at standard atmospheric

pressure, a lower explosive limit of 12%

and an upper explosive limit of 19.5%

in air. It is completely miscible with

most organic solvents but is sparingly

soluble in water (1.3% by weight at

room temperature). It has an extensive

oil and fat solubility. Decomposition

products during combustion or fire

include phosgene, hydrochloric acid

and carbon monoxide.

Physician or other licensed health

care professional is defined as a person

whose legally permitted scope of

practice allows him or her to

independently provide or be delegated

the responsibility to provide some or all

of the health care services required by

final rule paragraph (j), Medical

Surveillance. Use of this phrase is

designed to increase the flexibility of

the standard; the proposal used the

more restrictive term ‘‘physician.’’

OSHA intends that employers should

consider the opinion of the applicable

state licensing board, which defines the

scope of practice for licensed health

care professionals, when they are

determining the appropriate provider to

supply some or all of the medical

services required by the standard. The

new terminology recognizes that there

are many services that non-physicians

can provide, that some non-physicians

have particular expertise in diagnosing

and treating occupationally related

diseases, and that the use of these

providers is often a cost-effective and

protective approach to the provision of

medical care.

Regulated area means an area,

demarcated by the employer, where an

employee’s exposure to airborne

concentrations of MC exceeds or can

reasonably be expected to exceed either

the eight (8)-hour time-weighted average

limit or the short-term exposure limit.

The wording of this definition has been

changed slightly from that in the

proposal for clarity. The requirements

for regulated areas are discussed below

in relation to paragraph (e).

OSHA has added a definition for

symptom to the final rule to clarify what

is meant by that term when it is referred

to in the regulatory text. MC has a wide

range of possible adverse health effects.

This definition clarifies what portion of

that range would be considered a

symptom for purposes of the standard.

The covered symptoms would include

indications of central nervous system

effects, such as headaches,

disorientation, dizziness, fatigue, and

decreased attention span; cardiac

effects, such as chest pain and shortness

of breath; and skin effects, such as

chapping, erythema, or skin burns.

The definitions of ‘‘Assistant

Secretary,’’ ‘‘Authorized Person,’’

‘‘Director’’ and ‘‘This section’’ are

consistent with OSHA’s previous uses

of these terms in other health standards.

The Boeing Company [Ex. 19–26]

suggested that a definition be added for

‘‘work area’’ to preclude unnecessary

monitoring in areas that do not contain

MC. OSHA does not believe that this is

necessary. If there is no MC present in

an area, no monitoring needs to be

performed for MC. In addition, the focus

of this standard is employee exposure,

as measured by personal monitoring,

and not particular locations.

Paragraph (c) Permissible Exposure

Limits

OSHA is promulgating an 8-hour

time-weighted average (TWA)

permissible exposure limit (PEL) of 25

ppm, and a short-term exposure limit

(STEL) of 125 ppm averaged over 15

minutes, as proposed. OSHA has

determined, based on evidence in the

record, that occupational exposure to

MC at the current 500 ppm 8-hour TWA

PEL presents a significant risk of

material health impairment, and

particularly of cancer, to exposed

employees and that compliance with the

new standard will substantially reduce

that risk. In combination with the STEL,

the 8-hour TWA PEL and the other

industrial hygiene provisions of the

standard will also protect exposed

employees from the other health effects

caused by exposure to MC.

The basis for the 8-hour permissible

exposure limit is discussed above in the

sections on Health Effects and

Significance of Risk, as well as in the

economic analysis. OSHA believes that
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1575

compliance with the new 25 ppm 8-

hour TWA PEL is feasible and necessary

to protect exposed employees from this

significant risk of material health

impairment.

OSHA received comments from a

number of rulemaking participants

suggesting that the proposed PELs and,

by association, the action level be

revised. The arguments for revising the

proposed PELs were based on

interpretations of the scientific support

for given PELs and the feasibility of

particular PELs in certain situations.

Some commenters felt that the current

level of 500 ppm does not provide

adequate protection for employees and

agreed that the PEL should be set at 25

ppm [Exs. 19–15, 19–49]. Specifically,

Striptech International, Inc. [Ex. 19–15]

stated:

The OSHA proposed 25 ppm standard for

MC does substantially eliminate significant

risk and it is feasible and definitely

appropriate. The technology exists to enable

the industries using MC to comply or to use

an alternate method.

However, a number of rulemaking

participants [Exs. 19–22, 19–23, 19–36,

19–38, Tr. 530, 9/18/92, Tr. 1776, 9/24/

92, Tr. 1869, 9/24/92] suggested that

OSHA set the 8-hour TWA PEL below

25 ppm, because they believe that the

proposed 25 ppm limit would not

adequately protect workers. For

example, the UAW stated that setting a

PEL at 25 ppm ‘‘will permit too much

exposure to methylene chloride,

therefore placing workers at great risk,

contrary to the requirements of the

OSHA Act’’ [Tr. 1869, 9/24/92]. The

UAW stated that the proposed limit

‘‘would permit 2 deaths per thousand

workers,’’ and therefore suggested

setting a PEL of 10 ppm, which the

union felt would be feasible through

specified engineering and work practice

controls [Ex. 19–22, Tr. 1869, 9/24/92].

Scott Schneider, representing the IUE,

also suggested that ‘‘because of the

evidence of health effects from low level

exposures’’ to MC, the PEL should be

lowered below 25 ppm [Ex. 19–38]. The

IUE and the ACTWU both supported the

UAW recommendation of 10 ppm [Tr.

530, 9/18/92, Tr. 1776, 9/24/92].

The Laborers’ Safety and Health Fund

of North America [Ex. 19–36] suggested

that worker exposure should be

controlled to the lowest feasible level,

which is consistent with NIOSH’s

position. NIOSH recommended ‘‘that

occupational exposure to methylene

chloride, which is a potential

occupational carcinogen and may

induce ischemic heart disease, be

reduced below the proposed PEL to the

lowest feasible level’’ [Tr. 868, 9/21/94].

OSHA agrees with these commenters

that a significant risk remains at 25

ppm, but believes that this level is the

lowest level for which OSHA can

currently document feasibility across

the affected application groups and

industries.

OSHA’s primary justification for the

new standard is the risk of cancer

associated with exposure to MC. Some

commenters stated that the

carcinogenicity of MC has not been

proven and therefore that

carcinogenicity should not be the basis

for setting the PEL [Exs. 19–18, 19–29,

19–31, 19–45]. In particular, Kodak [Ex.

19–18] stated that it ‘‘does not believe

that the human or animal data

demonstrate a need to establish

methylene chloride exposure limits at

the levels proposed by OSHA in order

to adequately protect employee health.’’

Mr. Bixenman, representing Benco

Sales, testified [Tr. 2638, 10/16/92]

‘‘And surely with our current level of

technology, if methylene chloride were

a human carcinogen, it could be

established without question with

actual diagnosed cases.’’ Also, the Air

Transport Association stated [Ex. 19–

75]:

[T]he limited findings regarding cancer in

mice at high MC dosage is weak justification

for the proposed regulatory action. None of

our members have found permanent health

symptoms related to the use of MC, while

usage at some facilities goes back at least 30

years. We have no data or experience

connecting heart disease with MC use.

As discussed more extensively in the

Quantitative Risk Assessment section,

above, OSHA has based its assessment

of MC cancer risk on the determination

(supported by the NTP, EPA, and other

agencies) that there is clear evidence of

MC carcinogenicity in mice and rats.

Although there are a few substances for

which clear evidence of carcinogenicity

in rodents has been deemed to be

irrelevant to humans due to compelling

evidence of mechanisms of action

unique to the species tested, no such

evidence exists for MC. In fact, as

discussed in the Risk Assessment

section, mechanistic evidence adds to

the weight-of-the-evidence suggesting

that MC is also carcinogenic in humans.

OSHA’s final risk estimate indicates a

risk of 7.5 deaths per 1000 workers

exposed to MC at 50 ppm over a

working lifetime and a risk of 3.6 deaths

per thousand workers exposed to MC at

25 ppm over a working lifetime. OSHA

has determined, using quantitative risk

assessment, that the estimated risk of

developing cancer warrants setting the

8-hour TWA PEL at 25 ppm and a 15-

minute STEL at 125 ppm; in fact, at the

25 ppm PEL the residual risk still

greatly exceeds any significant risk

threshold, and only the lack of

documentation of the feasibility of

lower PELs across the affected

industries has convinced the Agency

not to reduce the PEL even further at

this time.

OSHA disputes the contention of Mr.

Bixenman that ‘‘actual diagnosed cases’’

are a precondition for establishing that

a particular substance is carcinogenic to

humans. Due to the natural background

rate of all cancers, epidemiologic

studies of groups are the only way to

analyze human cause-effect

relationships. As discussed in the

Quantitative Risk Assessment section,

OSHA has concluded that some of the

available epidemiologic studies suggest

a positive association between MC

exposure and human cancer and that no

epidemiologic studies of sufficient

power exist to cast serious doubt on

such conclusions.

Several commenters preferred a PEL

of 50 ppm, which is the current ACGIH

threshold limit value for MC, because

they felt that a 25 ppm PEL would be

either too costly to implement or the

technology to achieve such a level of

control was not available [Exs. 19–2,

19–3, 19–12, 19–14, 19–15, 19–29, 19–

31, 19–35, 19–37, 19–39, 19–48, 19–50,

19–56, 19–57]. For example, Abbott

Laboratories [Ex. 19–29] commented

that specific processes in the

pharmaceutical industry ‘‘cannot be

controlled through existing

conventional engineering controls.’’

Also, AMETEK [Ex. 19–12] stated that

‘‘It will be hard for many industries to

reach the 50 ppm level and extremely

difficult, if not, impossible, for most to

reach the 25 ppm level.’’ Therefore, this

commenter proposed ‘‘that OSHA set

the PEL for methylene chloride at 50

ppm (8-hour TWA) with no AL [action

level] and leave the STEL at 125 ppm

(15-minute average) as originally

written.’’ AMETEK contended that this

approach ‘‘combines aspects of both

ACGIH guidelines and OSHA’s

proposed standard into a regulation

which would be both protective of

worker health and economically feasible

for industry’’ [Ex 19–12].

Many other commenters argued for a

PEL of at least 100 ppm [Exs. 19–1, 19–

4, 19–10, 19–11, 19–16, 19–24, 19–47,

19–51, 19–52, 19–53, 19–54, 19–67, 19–

75, 19–79, 98, 115–3, Tr. 397, 9/17/92,

Tr. 2216, 10/14/92, Tr. 2627, 10/16/92,

Tr. 2671, 10/16/92, Tr. 2702, 10/16/92].

For example, Besway Systems, Inc.,

testified [Tr. 397, 9/17/92]: ‘‘We would

like to see a PEL for these companies of

200 ppm, which we’ve been able to

show is safe and economically

attainable in our real life experience. We
1576 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

believe that the absolute maximum PEL

for our industry should be set at 100

ppm eight hour time weighted

average. . . .’’ Also, Benco Sales [Tr.

2627, 10/16/92] stated ‘‘We feel the

American workers would receive more

benefit by implementation of an

exposure level of 100 parts per million,

which is achievable, and the subsequent

enforcement of that level.’’ ChemDesign

Corporation [Ex. 19–24] believes that

the ‘‘sharp reduction in the exposure

limit is unjustified based on lack of

credible data that this chemical has the

potential to cause cancer in humans.’’

This commenter therefore suggested that

the PEL be ‘‘lowered by a factor of five

to 100 parts per million’’ [Ex. 19–24].

Other commenters supported a variety

of PEL values. One suggested that a

lower PEL be phased in over time, with

75 ppm for two years, then 50 ppm for

two years, and finally 30 ppm [Ex. 19–

20]. The reasoning behind this

suggestion was that, during this period,

alternative options to best fit specific

operations could be evaluated and

implemented and sufficient time

provided to gather the funds necessary

to implement the entire system [Ex. 19–

20]. OSHA holds, however, that the

types of engineering controls required

under this standard are relatively simple

and that engineering to 75 ppm, then 50

ppm, then 30 ppm is likely to be more

costly in time and money than

engineering to or below 25 ppm

initially. The suggested phase-in would

also be administratively burdensome for

employers, who would be subject to

changing OSHA requirements over the

years, with no clear advantage in

reducing the costs of compliance. In

addition, if OSHA allowed such a

phase-in period, workers would be

exposed to MC at higher levels than

would occur if OSHA required no

phase-in period. Therefore, the Agency

sees no advantage to using the phasedin approach described. Moreover, the

Agency notes that the time-frames for

compliance with the provisions of the

standard, including implementation of

engineering controls, have been tailored

to the size of the establishments, in

order to give all employers a reasonable

amount of time to gather resources and

information necessary to comply with

this regulation. See the discussion of

start-up dates later in this document.

Smith Fiberglass Products, Inc.

suggested that the PEL should remain at

500 ppm because there is no evidence

of human harm at the present PEL and

STEL, since ‘‘studies with rats and mice

show that only a serious overdose far

above the present STEL can cause

carcinogenic effects’’ [Ex. 19–82].

Another commenter [Ex. 19–86] stated

that ‘‘The present PEL of 500 parts per

million (ppm) is not protective enough

of employees based on toxicological

data developed since the PEL was

established.’’ This commenter therefore

suggested that the PEL should be lower

than 500 ppm but higher than 25 ppm

(no specific value identified). As

discussed above, however, OSHA has

determined that exposure to MC above

25 ppm poses significant cancer risks

and that it is feasible to protect affected

employees from those risks (see the

Significance of Risk section of the

preamble).

A number of commenters addressed

the availability of suitable substitutes

for MC in their concerns about

feasibility [see, e.g., Exs. 19–6, 19–8, 19–

37, 19–43, 19–55, 19–74, 19–79, 19–84,

115–3; Tr. 433, 9/17/92; Tr. 1591, 9/23/

92; Tr. 1712–13, 9/24/92; Tr. 2636–38,

10/16/92]. Substitution is often a valid

means of controlling exposures to a

particular hazardous chemical when a

less hazardous substitute is available

that can be used to perform a similar

function. In particular, some

commenters stated that there are no

viable substitutes for MC products used

to perform particular tasks. These

participants argued that companies

would go out of business because they

would be unable to comply with the

final standard in a feasible way [Exs.

19–6 and 19–8]. In addition, one

commenter [Ex. 19–8] expressed

concern that substitute products would

pose fire hazards. The National Tank

Truck Carriers, Inc. testified [Tr. 1712,

9/24/92]:

One company which discontinued the use

of methylene chloride found it necessary to

supplement the methylene chloride

substitute with even more hazardous acetone

and toluene in order to remove the residues

from the trailers and containers and properly

service the industry by providing clean

trailers.

OSHA has determined that for all

application groups, compliance with

this regulation can generally be

achieved through the use of engineering

controls and work practices. The

Agency’s Final Economic Analysis

estimated the cost of compliance

assuming that almost all firms would

continue using MC and that only a small

fraction of firms would substitute away

from MC. OSHA agrees that, in an

individual establishment, the potential

use of substitution as a means of control

must be evaluated carefully to ensure

that the magnitude of the hazard posed

is not the same or increased as a result

of the substitution. For some

applications described in this

regulation, many substitutes for MC are

available for specific applications that

do not pose increased health or safety

hazards. In general, however, OSHA has

based it findings of feasibility not on the

ability of companies in the affected

sectors to substitute away from MC but

on their ability to implement

conventional engineering and work

practice controls.

In addition to the 8-hour TWA PEL,

OSHA is promulgating a short-term

exposure limit (STEL) of 125 ppm,

measured over a 15-minute period, to

protect employees from the acute

toxicity of MC and its metabolites. The

acute toxicity of MC is characterized

primarily by CNS effects, such as

decreased alertness and coordination,

headaches, and dizziness, which may

lead, in turn, to accidents on the job as

well as material impairment of health.

Absence of a STEL would mean that

employees could be exposed to up to

800 ppm for 15 minutes. Such levels are

clearly associated with central nervous

system effects.

MC is also metabolized to carbon

monoxide (CO). CO produced from MC

exposure has the same toxic effects in

the body as direct exposure to CO does.

The primary toxic effect of CO is

reduction of the ability of the blood to

carry oxygen to the tissues of the body.

In the body, carbon monoxide is

converted to carboxyhemoglobin.

Background levels of

carboxyhemoglobin in the non-smoking

U.S. population vary from

approximately 0.5% to 2.0%.

Carboxyhemoglobin in smokers ranges

from approximately 3% to 10%.

Additional body burden of CO

(carboxyhemoglobin) due to MC or

direct CO exposure can have adverse

health effects on affected individuals.

For example, exposure to relatively low

levels of carbon monoxide (for example,

levels which increase

carboxyhemoglobin by 2%) reduced

time to angina in patients with preexisting heart disease exposed to

occupational levels of CO [Ex. 21–93].

Exposure of pregnant women to CO has

been shown to produce adverse health

effects on the developing fetus. Workers

with anemia or other blood

abnormalities may be at increased risk

of material impairment to health

because of an already decreased oxygencarrying capacity.

The carbon monoxide-mediated

cardiac effects of MC exposure are of

particular concern in the occupational

setting because a significant fraction of

the U.S. working population (some

investigators estimate 30% of the U.S.

population) has silent or symptomatic

heart disease. NIOSH has expressed

concern that the STEL proposed by

OSHA is not low enough to protect
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1577

workers from the adverse central

nervous system and cardiac effects of

MC.

In addition to reducing risks of

cardiac and CNS effects, the STEL will

also enhance employee protection from

MC-induced carcinogenesis by reducing

total exposure to MC and by limiting the

metabolism of MC by the GST pathway

(the putative carcinogenic metabolic

process). Metabolic evidence suggests

that the GST pathway produces more

than proportionately greater quantities

of the putative carcinogenic metabolite

when MC concentrations reach levels of

about 100 ppm. For this reason, it is

important to limit high concentration,

short duration exposures to MC. Thus

the STEL will reduce the exposurerelated risks of acute CNS effects,

episodes of carboxyhemoglobinemia,

and cancer.

Another advantage in requiring a

STEL is that it focuses attention on

sources of MC exposure in the

workplace. General industrial hygiene

principles state that a well-controlled

process should have peaks no higher

than five times the 8-hour TWA.

Measurement of STEL exposures can

indicate point sources which have

unacceptably high MC emissions and

help the employer target those processes

for abatement. This can be an efficient

mechanism to concentrate industrial

hygiene resources on those emission

sources which, when controlled, will

reduce total employee MC exposure.

In addition, it has been established

that ‘‘[i]f in fact a STEL would further

reduce a significant health risk and is

feasible to implement, then the OSH Act

[section 6(b)(5)] compels the agency to

adopt it barring alternative avenues to

the same result.’’ (emphasis in the

original) Public Citizen Health Research

Group v. Tyson, 796 F.2d 1479, 1505

(D.C. Cir. 1986) (Ethylene oxide). See

also Building and Construction Trades

Department, AFL–CIO v. Brock, 838

F.2d 1258, 1271 (D.C. Cir. 1988)

(Asbestos).

In summary, many commenters

questioned the need for a reduced PEL,

for a PEL of 25 ppm, and for the

particular 8-hour TWA PEL-STEL

combination proposed by OSHA, citing

concerns about the feasibility of these

limits and the ability of companies to

identify controls and/or substitutes to

comply with them. However, as

discussed in the final economic

analysis, OSHA has determined that it

is both technologically and

economically feasible for facilities in all

affected sectors to comply with the final

rule. In almost every case, companies

will be able to use conventional

engineering controls and work practices

to reduce their employees’’ exposures to

these levels. In addition, many

employers will find that substitution is

a viable approach to eliminating the

significant risk posed to workers by MC.

As the economic analysis points out,

many firms in many of the covered

industries have already substituted

away from MC, and have enjoyed

considerable cost savings in the process.

Finally, it is important not to lose sight

of the reasons for regulating MC in the

first place: this substance poses a

significant risk of cancer, central

nervous system and cardiac effects, and

sensory irritation to the quarter of a

million workers who manufacture,

formulate, use, or transport this

substance in the workplace.

As the Quantitative Risk Assessment

and Significance of Risk sections of the

preamble demonstrate, the cancer risk

remaining at an 8-hour TWA PEL of 25

ppm is clearly of great concern, in that

it exceeds the 1/1000 level indicated by

the Supreme Court to be clearly

significant. OSHA therefore encourages

employers to further reduce the MC

exposures of their employees wherever

it is feasible to do so. Because the

residual risk remaining at 25 ppm is

great, the Agency intends to gather data

and information on the feasibility of

reducing the 8-hour TWA PEL to reduce

remaining significant risk in a future

rulemaking action. The priority assigned

to any future rulemaking activity will

depend in large measure on the

prevailing exposure levels, feasibility,

scientific advances and other

information, at the time OSHA

considers further proposals; to the

extent prevailing levels are significantly

below 25 ppm, the need for subsequent

proposals will diminish.

Paragraph (d) Exposure Monitoring

Paragraph (d) addresses the employee

exposure monitoring requirements for

workplaces where employees are

exposed to MC. As discussed in the

preamble to the proposed rule (57 FR

57118–20), OSHA requires employee

monitoring to facilitate compliance with

the PELs. As a general matter, exposure

monitoring of employee exposure to

toxic substances is a well-recognized

and accepted risk management tool. The

monitoring provisions of this final MC

standard are consistent with the

monitoring provisions of other OSHA

standards. Section 6(b)(7) of the OSH

Act, which addresses rulemaking

requirements for hazardous chemicals,

requires health standards to include

provisions for monitoring employee

exposures. In the final rule, the

exposure monitoring provisions have

been reorganized and rewritten to

improve their clarity and readability.

The substance of the requirements is

essentially the same, with the few

exceptions noted below.

The provisions of proposed paragraph

(d) elicited a considerable amount of

comment and testimony. Several

rulemaking participants [Ex. 19–57; Tr.

249, 9/17/92; Tr. 458, 9/17/92; Tr. 1711,

9/24/92] stated that the proposed

requirements for exposure monitoring

would impose excessive economic

burdens on some employers (e.g., paint

strippers, tank cleaners). However, in

the final rule OSHA has structured the

exposure monitoring requirements to

minimize the burden for employers

whose employees have lower exposures

and for workplaces where groups of

employees have similar exposures. In

addition, the Agency has included some

alternatives to the initial monitoring

provisions that will reduce the amount

of monitoring required for some

workplaces. Ultimately, however, the

Agency has determined that it is

essential to the protection of exposed

employees that exposure levels be

quantified in order to select and

implement the proper measures to

reduce employee exposures to MC.

The overall rulemaking record

supports the need for exposure

monitoring to ascertain exposure levels

for the purpose of designing appropriate

protective measures for employees. In

addition, evidence in the record

indicates that the exposure monitoring

requirements are economically and

technologically feasible for firms in all

of the affected industry sectors. (See the

discussion in the Final Economic

Analysis [Ex. 129].)

Paragraph (d)(1) sets forth the general

requirements that apply to all

monitoring provisions. Paragraph

(d)(1)(i) states that employers must

characterize the MC exposure of each

employee. Employers may chose one of

two ways to determine an employee’s

MC exposure level. First, the employer

can take a personal air sample in the

breathing zone of each affected

employee. This approach is the most

precise method of exposure monitoring

because it allows each employee’s

exposure to be individually ascertained.

However, OSHA recognizes that this

approach may be burdensome for

employers with many employees.

Therefore, paragraph (d)(1)(ii) permits

employers to establish a representative

monitoring scheme.

Under this option, a personal

breathing zone air sample may be

considered representative of another

employee’s 8-hour TWA or STEL

exposure if the following conditions are

met. First, the sampled employee must
1578 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

be that employee who is likely to have

the highest MC exposure among the

employees included in the group that is

to be represented by the sample.

Second, if the employer wishes a

sample taken on an employee in a given

job on one work shift to represent the

exposure of another employee in the

same job classification on another shift,

the employer must sample at least one

employee in each job classification in

each work area during every work shift.

Paragraph (d)(1)(ii) also contains an

exception under which a personal

breathing zone sample taken on one

employee in one job classification in a

given work area and on a particular shift

will be considered representative of the

exposure of employees on other shifts,

where the employer documents that the

tasks performed and conditions in the

workplace are similar for all employees

whose exposures are represented.

The provision for representative

sampling, which is very similar to the

corresponding provision of the

proposed rule, eliminates unnecessary

monitoring and thus further improves

the cost-effectiveness of the standard. In

a change from the proposal, the final

standard also allows employers to use

representative monitoring to comply

with the standard’s requirement for

initial monitoring. OSHA believes that

representative initial monitoring is

appropriate in those cases where the

employer can accurately determine

which employees are likely to have

similar exposures.

The accuracy of the methods used to

perform exposure monitoring is

addressed under paragraph (d)(1)(iii).

For monitoring of airborne

concentrations above the 8-hour TWA

PEL or the STEL, the results must be

accurate within plus or minus 25

percent at a confidence level of 95

percent. Where concentrations are above

the action level but at or below the PEL,

the accuracy must be within plus or

minus 35 percent at a confidence level

of 95 percent.

Methods of measurement are

presently available that can detect MC

within these limits. One such method is

OSHA method 80, which has a limit of

detection of 0.201 ppm. Copies of this

method are available from OSHA and

can be downloaded from OSHA’s World

Wide Web site on the Internet at

‘‘http.www.osha.gov/.’’ Sampling and

analysis may also be performed by

portable direct reading instruments,

real-time continuous monitoring

systems, passive dosimeters or other

methods that meet the accuracy and

precision requirements of the standard

under the particular conditions which

exist at the employer’s worksite.

Paragraph (d)(2) requires employers to

make an initial determination of

affected employees’ exposure to MC.

OSHA anticipates that most employers

will need to perform monitoring in

order to characterize employee exposure

and has framed the rule accordingly.

The standard allows employers to

characterize their employee exposures

using other means, providing that they

can meet the requirements for such

other means presented in the standard.

For example, as discussed above, some

employers may have objective data that

establishes that employees will not be

exposed above the action level or the

STEL under reasonably foreseeable

circumstances. Some employers

generate such data themselves, while

others rely on information provided by

the manufacturer or supplier.

Accordingly, paragraph (d)(2)(i)

provides that employers can rely on

objective data in certain circumstances

in lieu of performing initial monitoring.

The objective data must represent the

highest MC exposures likely to occur

under reasonably foreseeable conditions

of proccessing, use, or handling in the

workplace, and the employer must

document the objective data relied on

(see paragraph (m)). This provision

corresponds to proposed paragraph

(a)(2), which was the subject of several

comments [Exs. 19–14. 19–31, 19–57].

Occidental Chemical testified [Tr.

2010 and 2023, 10/14/92] that OSHA

should expand the proposed objective

data exemption so that mixtures with

less than one percent MC would be

excluded from the scope of the MC

standard. The Hazard Communication

Standard (HCS) addresses mixture

composition for the purpose of

identifying those constituents and

concentrations that impart their

hazardous characteristics to the mixture

as a whole. According to the HCS,

carcinogenic substances such as MC are

considered to impart their carcinogenic

characteristics to the mixture if they are

present in concentrations of more than

one-tenth of one percent or can be

released in concentrations that exceed

an existing PEL. This is a much more

protective requirement than that

suggested by Occidental, and the

Agency believes it would be

inappropriate to lessen the protections

provided to employees under the HCS

in this substance-specific MC standard.

Therefore, OSHA has not made the

suggested change.

In addition, OSHA recognizes that it

would be unreasonable to require initial

monitoring under this standard where

employers have already performed the

monitoring needed to characterize

employee exposure. Paragraph (d)(2)(ii)

allows employers who have monitored

their employees’ exposures to MC

within one year prior to April 10, 1997

and that monitoring complies with the

accuracy and other requirements for

monitoring contained in the final rule,

to designate such monitoring results as

sufficient in lieu of performing the

initial monitoring.

Dow Chemical Co. [Ex. 19–31]

commented that OSHA should allow

monitoring data collected as much as

two years prior to the effective date of

the final rule to qualify as initial

monitoring data. The Agency believes

that data more than a year old would be

unlikely to provide a reliable basis for

characterizing employee exposure,

because workplace conditions may well

have changed since such data were

collected. Accordingly, the Agency has

not made the suggested change.

Addressing this point, Scott

Schneider of the International Union of

Electronic, Electrical, Salaried, Machine

and Furniture Workers (IUE) testified

[Tr. 531, 9/18/92] as follows:

While we support the requirements for

exposure monitoring that were proposed, we

have reservations about section (d)(2)(ii)

regarding the use of ‘‘earlier monitoring

results’’ to satisfy the initial monitoring

requirements. OSHA must specify exactly

which requirements the data must meet, in

terms of both quality and quantity.

Otherwise, it will be an enormous loophole

for companies to avoid monitoring.

The International Brotherhood of

Painters & Allied Trades (IBPAT) agreed

with Mr. Schneider; the union stated

that the use of ‘‘historical monitoring

data to characterize exposures for

similar processes * * * may lead to

erroneous estimates of actual

exposures’’ [Ex. 19–23]. OSHA believes

that the concerns of these commenters

have been addressed in the final rule

because, to be acceptable under the

standard, any previously gathered

exposure data must meet the analytical,

sampling, and other requirements

specified for initial monitoring.

A number of commenters addressed

the application of monitoring

requirements in construction [Ex. 19–

23; Tr. 544–45, 9/18/92; Tr. 814–17, 9/

21/92; and Tr. 1377–80, 9/23/92]. OSHA

agrees that conditions on construction

sites often present special industrial

hygiene and monitoring problems,

particularly since the job may be

completed before sampling results taken

by conventional personal monitoring

methods have been returned from the

laboratory. For example, IBPAT [Ex. 19–

23] pointed to the exposure variability

that typifies construction sites, noting

that weather, a highly transient

workforce, and other factors often
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1579

complicate accurate characterization of

construction worker exposures. OSHA’s

Advisory Committee for Construction

Safety and Health (ACCSH) and other

participants suggested that OSHA allow

the use of direct-reading instruments to

address this problem [ACCSH Tr. 100–

103, 7/28/92; Workgroup report, pp. 3–

4; Tr. 814–818, 9/21/92; Tr. 1377–1382,

9/23/92].

In response to these comments, the

final rule has been revised to allow the

use of such instruments where

employees are exposed to MC on fewer

than 30 days within a given year. This

means that construction employers who

are involved in short-term construction

projects will be able to use these

instruments to characterize the MC

exposures of their employees. Paragraph

(d)(2)(iii), which addresses transient

workplaces or work operations where

employees are exposed on fewer than 30

days a year, permits employers to use

direct reading instruments such as

detector tubes to estimate exposure and

determine what protective measures to

provide to their MC-exposed employees.

Although these simple measurement

tools often do not meet the accuracy

requirements that other types of

monitoring methods do, they have the

advantage of immediate results and thus

allow employers to provide protection

immediately. OSHA believes that this

provision is responsive to the comments

discussed above and represents an

effective solution to a difficult worker

protection problem.

Paragraph (d)(3) addresses periodic

monitoring. Table X–1, below, which

corresponds to Table 1 of paragraph

(d)(3), displays the various monitoring

scenarios possible under the final rule’s

periodic monitoring requirements.

When the initial determination shows

employee exposures to be at or above

the action level or above the STEL, the

employer is required to establish a

periodic monitoring program. The 8-

hour TWA monitoring is to be done

every six months if exposures are at or

above the action level but at or below

the 8-hour TWA PEL and the STEL. The

8-hour TWA or STEL monitoring must

be done every three months if the initial

determination or subsequent monitoring

shows results that are above the 8-hour

TWA PEL or the STEL, respectively. If

two consecutive subsequent monitoring

results taken at least seven days apart

show that exposures have decreased to

or below the 8-hour TWA PEL, but

above the action level, the frequency

may be decreased to every six months.

Eight-hour TWA monitoring may be

terminated when two consecutive

monitoring results taken at least seven

days apart show that exposures are

below the action level. STEL monitoring

may be terminated when two

consecutive monitoring results taken at

least seven days apart show that

exposures are at or below the STEL (See

note to paragraph (d)(3)).

There are six possible initial

determination exposure scenarios, or

combinations of 8-hour TWA and shortterm exposures, that determine the

frequency of required monitoring. Table

X–1 below lists these six exposure

scenarios, along with their monitoring

frequencies. As shown by Table X–1,

the action level trigger largely

determines whether employers must

monitor employee exposure to MC. The

only exception is the scenario in which

8-hour TWA exposures are below the

action level and short-term exposures

are above the STEL. In this case,

exceeding the STEL obligates employers

to monitor short-term exposures four

times per year at those job locations

where the STEL was exceeded, but

employers are not required to monitor 8-

hour TWA exposures at those job

locations.

TABLE X–1.—SIX INITIAL DETERMINATION EXPOSURE SCENARIOS AND THEIR ASSOCIATED MONITORING FREQUENCIES

Exposure Scenario Required Monitoring Activity

Below the action level and at or below the STEL .................................... No 8-hour TWA or STEL monitoring required.

Below the action level and above the STEL ............................................ No 8-hour TWA monitoring required; monitor STEL exposures every

three months.

At or above the action level, at or below the TWA, and at or below the

STEL.

Monitor 8-hour TWA exposures every six months.

At or above the action level, at or below the TWA, and above the STEL Monitor 8-hour TWA exposures every six months and monitor STEL

exposures every three months.

Above the TWA and at or below the STEL .............................................. Monitor 8-hour TWA exposures every three months.

Above the TWA and above the STEL ...................................................... Monitor 8-hour TWA exposures and STEL exposures every three

months.

Several commenters stated that the

proposal required unnecessarily

frequent monitoring [Exs. 19–25, 19–26,

19–28, 19–30, 19–31, and 19–57]. Some

commenters [Exs. 19–30, 19–31] said

that the frequency of monitoring should

be the same as that in the benzene

standard (29 CFR 1910.1028 (e)(3)),

since frequent monitoring does nothing

to reduce or control exposures. The

benzene standard requires monitoring at

least every six months if employee

exposure exceeds the 8-hour TWA, at

least every year if exposure is at or

above the action level but at or below

the 8-hour TWA, and ‘‘as necessary’’ to

evaluate short-term exposures. OSHA

believes that MC exposure is highly

variable due to the substance’s volatility

(vapor pressure = 350 mmHg at 20 C,

compared with a vapor pressure for

benzene of 75 mmHg at the same

temperature) and the way that it is

commonly used (e.g., in manual

applications), and that reducing the

frequency of exposure monitoring could

therefore result in inadequate employee

protection. The frequency of monitoring

required by this MC standard is similar

to that in other OSHA standards such as

Ethylene Oxide (29 CFR 1910.1047), and

is sufficient to characterize employee

exposure and to evaluate the

effectiveness of exposure control

strategies.

The Advisory Committee on

Construction Safety and Health

suggested that OSHA trigger exposure

monitoring by frequency of use as well

as the exposure level. OSHA believes,

however, that the magnitude of an

employee’s exposure is the appropriate

determinant of monitoring frequency

(and the selection of protective

measures based on the results of that

monitoring) because it is cumulative MC

dose, not frequency of use, that

determines the significance of the risk to

which employees are exposed.

Therefore, the Agency has not made the

suggested change.

The Polyurethane Foam Association

(PFA) [Ex. 19–39] questioned the

necessity of requiring exposure

monitoring at the action level.

According to the PFA [Ex. 19–39], ‘‘An

action level of 12.5 ppm would require
1580 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

that workers be monitored at a level that

has only a remote health risk associated

with it. The costs of such monitoring,

however, would be significant.’’ OSHA

disagrees strongly with the PFA’s

analysis of the significance of the risk

remaining at the action level. As

discussed in the Significance of Risk

and Economic Analysis sections of this

preamble, only feasibility has

constrained the Agency from reducing

the 8-hour TWA PEL in the final rule to

levels below the action level, because

even at 10 ppm, the risk remaining is

significant. That is, an employee

exposed to an MC concentration of 10

ppm as an 8-hour TWA over a working

lifetime would still be at significant risk

of dying of MC-induced cancer.

Under paragraph (d)(4)(i), employers

are required to perform additional

monitoring when workplace conditions

change or there is an indication that

employee exposures may have

increased. Paragraph (d)(4)(ii) requires

that, where exposure monitoring is

performed due to a spill, leak, rupture

or equipment breakdown, the employer

must clean up the MC and perform

repairs and then monitor MC levels. The

changes referred to in these provisions

would include deliberate changes, such

as a process or production change, or

unexpected changes, such as a leak,

rupture, or other breakdown. In the case

of the latter, the employer is to perform

the monitoring after taking whatever

immediate action is required to clean-up

or repair the equipment or source of

exposure. OSHA recognizes that such

occurrences can result in very high

exposures. Several rulemaking

participants [Exs. 19–31, 19–57, Tr.

2035, 10/14/92] stated that remonitoring

is not necessary after a spill or leak

since MC has a high vapor pressure,

there would be no visible residual MC

and no opportunity for significant

exposure. However, OSHA believes that

such remonitoring is an appropriate way

to ascertain if proper corrective methods

have been instituted and if the

magnitude of an employee’s exposure

has changed significantly as a result of

the leak or spill.

Employees are to be notified in

writing of the results of exposure

monitoring under paragraph (d)(5). This

is to be done within 15 working days of

the time the employer receives the

monitoring results, and can be done

either individually or by posting. When

the results show that the 8-hour TWA

PEL or the STEL has been exceeded, the

employer must also notify employees of

the corrective action being taken, and

the schedule for completion of the

action. This provision is effectively

identical to the corresponding provision

of the proposed rule.

One commenter [Ex. 19–49] argued

that 15 working days is not enough time

to develop corrective actions, especially

where engineering controls are

involved. OSHA believes that this

comment misunderstands the

requirement, which merely states that

employers are required to ‘‘describe the

corrective action being taken * * * and

the schedule for completion of this

action.’’ The Agency believes that 15

working days is adequate time for the

employer to make a preliminary

assessment that includes the immediate

steps being taken to reduce employee

exposure, such as utilization of airsupplied respirators, and the employer’s

plan for implementing permanent

controls and/or work practices. This

requirement is necessary to assure

employees that the employer is making

efforts to furnish them with a safe and

healthful work environment, in

accordance with section 8(c)(3) of the

Act. OSHA would expect employers to

update the notification when plans for

permanent controls are made.

Employees or their designated

representatives are provided by

paragraph (d)(6) with the opportunity to

observe any required monitoring of

employee exposure to MC. This

provision is required by section 8(c)(3)

of the Act (29 U.S.C. 657(c)(3)). It was

relocated to paragraph (d)(6) of the final

rule from proposed paragraph (l) to

consolidate all of the exposure

monitoring requirements in one place.

The observer, whether an employee or

a designated representative, must be

provided (at no cost to the observer)

with any personal protective clothing or

equipment required to be worn by

employees working in the area that is

being monitored, and must additionally

comply with all other applicable safety

and health procedures. These provisions

of the final rule are identical to those of

the proposed rule.

As noted above, OSHA received a

number of comments on the monitoring

provisions proposed in the NPRM. For

example, Occidental Chemical

Corporation requested that OSHA

consider using what they termed

‘‘exposure assessment’’ rather than

monitoring, testifying [Tr. 2012–2013,

10/14/92] as follows:

[I]nstead of just looking at monitoring,

which is in the middle of the process,

exposure assessment looks at a basic * * *

characterization: What is the characterization

of the work force? What is the

characterization of the workplace? What is

the characterization of the contaminants in

the workplace? All of that is weighed

together; it’s a collection of information.

The next step, then, is to interpret that

information and determine what are the

actual exposure levels, what category would

they fit into * * *. If, at that point, and this

is still just a paper exercise based on that

information, you * * * conclude that

exposures [are] unacceptable * * * you act.

You may conclude that you have insufficient

data and you’d like to monitor. Or you may

conclude the data are acceptable; in this case,

you would act and * * * change something

and go through the process again. Or, in the

case they [employee exposures] are

acceptable, * * * you would document that

it is acceptable and then reevaluate at some

regular frequency, say annually or something

like that.

In response to this comment, OSHA

notes that nothing in the standard

prevents employers from conducting

exposure assessments. Indeed, the fact

that the final standard allows employers

to use objective data and recent (within

the past year) exposure data are both

examples of the kinds of evaluation

made by industrial hygienists

performing exposure assessments. An

employer unable to avail himself or

herself of the exclusions to initial

monitoring offered by the standard

would logically move to the next step in

the exposure assessment process: the

direct monitoring of employees’

exposures to MC. Thus the final rule, far

from interfering with exposure

assessment, actually both reflects this

process and encourages employers to

engage in such assessments themselves.

Paragraph (e) Regulated Areas

Paragraph (e)(1) requires employers to

establish a regulated area wherever an

employee’s exposure to airborne

concentrations of MC exceeds or can be

reasonably expected to exceed either the

8-hour TWA PEL or the STEL. This

paragraph was changed slightly from the

proposal to clarify that OSHA is

concerned with employee exposures

that can reasonably be anticipated to

exceed one of the PELs, rather than

excessive exposures that ‘‘may’’ occur.

Regulated areas can be either temporary

or permanent, depending on the

characteristics of a given workplace.

Such areas are required by the standard

to reduce employee exposures and to

alert employees to those areas in the

workplace that present the greatest

danger of MC overexposures.

Paragraph (e)(2) limits access to

regulated areas to authorized persons (a

term which is defined in the definitions

paragraph (b)). This provision applies

when either the TWA PEL or STEL is

exceeded or can reasonably be expected

to be exceeded. OSHA believes that the

establishment of a regulated area will

help to ensure that employees are aware

of areas in the workplace where MC
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1581

levels are above the 8-hour TWA PEL or

STEL. OSHA believes that regulated

areas are an effective means of limiting

the risks of high exposures to substances

suspected of being carcinogenic to

humans to as few employees as

possible.

Comments from Bristol-Myers Squibb

[Ex. 19–14] suggested that OSHA delete

the regulated area concept from the

standard and replace it with a

‘‘regulated job classification’’ for jobs

exceeding the PEL and a ‘‘regulated

procedure’’ for procedures exceeding

the STEL. This commenter’s rationale

was that since airborne concentrations

are measured by personal monitoring

and by job classification, it does not

make sense to define an ‘‘area’’ of

exposure. OSHA does not agree, for a

number of reasons. First, in many

workplaces, specific areas, such as

quality control monitoring stations,

mixing tanks, cutoff saw stations, spray

booths, etc., are known to be associated

with high levels of MC on a routine

basis, and demarcating these areas

protects employees by making them

aware of the potential for these

exposures in these locations. Second, it

is standard industrial hygiene practice

to use area monitoring to identify areas

of exceptionally high exposures so that

all non-authorized employees can be

protected from overexposure. Finally,

OSHA does not believe that the

approach suggested by Bristol-Myers

has the same potential to alert

employees to the presence of high

airborne concentrations that a

demarcated area does, and therefore

believes that the suggested change

would not provide equivalent protection

from overexposure.

The Laborers’ Safety and Health Fund

of North America [Tr. 1378–79, 9/23/92]

testified that, in construction, a

regulated area should be established

wherever MC is used. Although there

are many uses of MC on construction

sites that may warrant establishing

regulated areas, there are also

engineering controls available (for

example, portable ventilation) which

may reduce employee exposures so that

a regulated area would be unneccessary.

OSHA believes that employers should

not be required to establish regulated

areas unless potential exposure levels

warrant them. The Agency also believes

that the employer is in the best position

to determine whether the exposures

from a particular MC application will

warrant establishing regulated areas at a

particular work site. The Advisory

Committee on Construction Safety and

Health also suggested that the

establishment of regulated areas could

replace some of the standard’s

monitoring requirements [Ex. 21–69]. As

discussed previously, however, OSHA

believes that both employers and

employees benefit from knowing what

exposures to MC are in a given

workplace or on a specific job

assignment. OSHA has therefore not

revised the final rule’s requirement for

regulated areas in locations where

exposures exceed or can reasonably be

expected to exceed either or both of the

PELs.

The proposal would have required

that employers supply employees

entering regulated areas with

appropriate respiratory protection and

ensure its use in such areas at all times.

Several commenters [Exs. 19–25, 19–31

and 19–49] argued that respirator use in

such areas should be required only if

occupational exposures in such areas

either exceeded the 8-hour TWA PEL or

the STEL or could reasonably be

expected to exceed one or both of these

limits. OSHA agrees with these

commenters and has revised the final

rule accordingly. Paragraph (e)(3) states

that employers must supply a respirator

to each person who enters a regulated

area, but shall require each affected

employee to use that respirator only if

MC exposures are likely to exceed the

8- hour TWA PEL or STEL. Thus, not all

workers in regulated areas will be

required to wear respirators in regulated

areas at all times.

For example, under the final rule, an

employer would be required to

demarcate the area around a cutoff saw

operator’s work station in a foam

blowing plant as a regulated area and to

train the operator to recognize the area

as regulated; however, the operator

would only be required to wear a

respirator in the area at times when the

foam ‘‘bun’’ was coming out of the

tunnel for cutting. The employer would

demarcate the area because he or she

recognizes, based on monitoring results

for the cutoff saw operator, that this

work station is one where the 8-hour

TWA PEL is regularly exceeded during

foam blowing operations. Because of the

intermittent nature of many foam

blowing operations, however,

respirators would need to be worn by

the operator (or other workers assisting

the operator) only when foam was

actually being blown. This example

assumes that foam blowing operations

are intermittent and that exposures at

the cutoff saw would exceed the PELs

only during foam blowing, although this

may not be the case in all plants or at

all times. In facilities where foam is

blown continually and the saw operator

is stationed at the end of the tunnel over

the full shift, respiratory protection

would likely be required to be worn in

the regulated area at all times because

exposures would routinely exceed the

PEL in that area.

Under paragraph (e)(4), which has

been added to the final rule, the

employer shall ensure that, within a

regulated area, employees do not engage

in non-work activities which may

increase dermal or oral MC exposure.

This provision indicates that such nonwork activities as eating, drinking,

smoking, taking medication, applying

lotions or cosmetics or storing such

products in regulated areas are

prohibited. Proposed paragraph (e)(4)

has been promulgated as final rule

paragraph (e)(6), as discussed below.

In addition, under paragraph (e)(5),

which has been added to the final rule,

the employer shall ensure that

employees who are wearing respirators

do not engage in activities (such as

taking medication or chewing gum or

tobacco) which interfere with respirator

seal or performance. Proposed

paragraph (e)(5) has been promulgated

as final rule paragraph (e)(7), as

discussed below.

Final rule paragraphs (e)(4) and (e)(5)

are based on the response to NPRM

Issue 41 (56 FR 57043) which indicated

that OSHA was considering a provision

to prohibit activities such as eating,

drinking, smoking, etc. in regulated

areas and asked for comments on this

subject. This prohibition was supported

by some rulemaking participants [Ex.

19–36, Tr. 1379, 9/23/92]. OSHA notes

that it is standard industrial hygiene

practice to limit such activities in

regulated areas, both because employees

should be aware at all times that they

are working in a high- exposure area

and because of health concerns. Among

other things, since respirators are

generally (although not always) required

to be worn in regulated areas, engaging

in the prohibited activities while

wearing respirators might interfere with

the respirator seal, placement or

performance, thus reducing the

effectiveness of the respirator.

Furthermore, in the case of MC,

smoking while being exposed to high

MC concentrations (such as those

prevailing in regulated areas) is

particularly hazardous because MC is

metabolized to CO in the body and leads

to carboxyhemoglobinemia, a

potentially life-threatening condition for

some individuals, e.g., those with silent

or symptomatic heart disease. Other

OSHA health standards (e.g., asbestos,

cadmium, ethylene oxide) have

included similar prohibitions, and

OSHA has concluded, based on the

reasons discussed above and the

Agency’s experience with other

standards, that including these
1582 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

provisions in the final MC standard is

appropriate.

OSHA has broadened the language

and separated it into two provisions

(paragraphs (e)(4) and (e)(5)) to

differentiate the types of activities

which would generally not be allowed

in a regulated area and those which

would interfere with the effective use of

respiratory protection. This is consistent

with OSHA’s intent in this rule to allow

establishment of regulated areas, but

require respirator use only when the 8-

hour TWA PEL or STEL is likely to be

exceeded.

Paragraph (e)(6), which is essentially

unchanged from the proposed

provision, requires employers to

demarcate their regulated areas, but it

does not specify how this is to be done

as long as employees are aware of the

location of the area and access to it is

thus minimized. Factors that the Agency

believes are appropriate for employers

to consider in determining how to

demarcate their areas include the

configuration of the area, whether the

regulated area is permanent, the

airborne MC concentration present in

the area, the number of employees in

adjacent areas, and the period of time

the area is expected to have exposure

levels above the PEL or STEL.

Permitting employers to choose how to

identify and limit access to regulated

areas is consistent with OSHA’s belief

that employers are in the best position

to make such determinations, based on

the specific conditions of their

workplaces. This performance-oriented

approach gives employers compliance

flexibility without compromising

employee health.

Paragraph (e)(7), proposed as

paragraph (e)(5), requires employers at

multi-employer worksites who establish

a regulated area to communicate

information to other potentially affected

employers at the worksite about the

location and access restrictions

pertaining to the regulated area. OSHA

believes that such communication will

reduce the likelihood that unauthorized

persons will enter the area or that

workers not involved in MC-related

operations will be exposed

inadvertently. Those employers whose

employees are exposed to MC at

concentrations above either or both of

the PELs must coordinate their

operations with other employers whose

employees could suffer excessive

exposure because of their proximity to

a regulated area where MC is being

used. Compliance with this provision

will ensure that only those employees at

multi-employer worksites who are

properly authorized, trained, and

equipped enter regulated areas. This

provision also recognizes OSHA’s

awareness that, although multiemployer worksites are common in

construction, they are also increasingly

found in other industry sectors.

Paragraph (f) Methods of Compliance

Paragraph (f) addresses the means by

which employers are to reduce

employee exposures to or below the 8-

hour time-weighted average (TWA) PEL

or the STEL. Under paragraph (f)(1),

employers are required to institute and

maintain the effectiveness of

engineering controls and work practices

to reduce employee exposure to or

below the PEL and STEL, except to the

extent the employer can demonstrate

such controls are not feasible. Where

these measures cannot reduce the

concentration of airborne MC to or

below the TWA PEL and STEL, the

employer is nevertheless required to

implement them to achieve the lowest

feasible level. The employer is required

to supplement these controls with

respirators where necessary to ensure

that employees are not exposed to MC

at levels above either the 8-hour TWA

PEL or the 15-minute STEL. Section

1910.134(a)(1) of the respiratory

protection standard requires respirators

to be used where effective engineering

controls are not feasible.

One commenter [Ex. 19–57] indicated

that it should be left to professional

judgment to determine whether

engineering controls or respirators are

the best method for protecting

employees. OSHA does not agree with

this comment because it fails to

acknowledge the industrial hygiene

hierarchy of controls, which places

engineering controls ahead of

administrative or personal protective

equipment as methods of protecting

employees from hazardous exposures.

The hierarchy of controls has been

established industrial hygiene practice

since the 1950s and is based on the fact

that engineering controls are the most

effective method of protecting

employees because they remove the

hazard from the workplace. In contrast,

respirators merely prevent employees

from breathing the contaminant—it

remains in the workplace air. Effective

respirator use also requires constant

supervision, extensive employee

training and fit testing, and regular

(often daily) care and maintenance of

the respirator. Consequently, respirators

should only be used as a means of

achieving the PELs where feasible

engineering controls are not available

(such as in some vessel cleaning and

non-stationary maintenance operations)

or are not sufficient to control exposures

to required levels. All OSHA substancespecific health standards have

recognized and required employers to

observe the hierarchy of controls, and

OSHA’s enforcement experience with

these standards has reinforced the

importance of this concept to the

protection of employee health.

In the Final Economic Analysis,

OSHA has described feasible control

technologies for each industry affected

by the final MC standard. Many

employers have already implemented

such controls in their workplaces and

are currently achieving the MC levels

required by the final rule. Examples of

such feasible control strategies include

dilution and local exhaust ventilation,

chilling coils, magnetic pumps and

magnetic floating gauges, exhausted

lances for drum filling, and inline

quality control sampling equipment.

OSHA acknowledges that there may

be a few operations where the use of

engineering and work practice controls

to control exposure to MC is infeasible

because exposures are highly

intermittent in nature and limited in

duration. In particular, OSHA is aware

that the use of engineering and work

practice controls to comply with the

PELs is infeasible for some maintenance

and repair operations and during

emergency situations. Where it is

infeasible to reduce workplace MC

levels below the PELs through

engineering and work practice controls,

the employer is required to protect

employees from excess exposure by

providing and requiring the proper use

of personal protective equipment, in

this case supplied-air respirators.

As discussed in the NPRM (56 FR

57120–21), OSHA asked for comments

on whether employers should be

allowed to place increased reliance on

the use of respirators to protect

employees exposed to MC. The

International Brotherhood of Painters

and Allied Trades [Ex. 19–23]

commented that ‘‘[w]ith the exception

of emergencies that require use of a

SCBA respirator, engineering and work

practice controls should be the sole

method of compliance.’’

In addition, the IUE [Tr. 530, 9/18/92]

testified as follows:

[R]equirements to control those exposures

using engineering controls are particularly

important because of the lack of adequate

chemical cartridge respirators for methylene

chloride. For that reason, we reject the

question posed by OSHA regarding the

provisions to allow greater use of respirators

which came from earlier proceedings on

revisions to 1910.1000.

Also, NIOSH [Tr. 884, 9/21/92] testified

as follows:

NIOSH supports the existing OSHA policy

on methods of compliance, that is the
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1583

hierarchy of controls for controlling

exposures to hazardous agents. Generally,

this policy states that whenever feasible,

engineering controls and work practices

should be used to prevent exposures, and

that personal protective equipment,

including respiratory protection, should be

used only when engineering controls are not

feasible.

As discussed above, OSHA agrees

with these comments. The Agency

considers the use of respirators to be the

least satisfactory approach to exposure

control because respirators provide

adequate protection only if employers

ensure, on a constant basis, that they are

properly fitted and worn. Also, unlike

engineering and work practice controls,

respirators protect only the employees

who are wearing them from a hazard,

rather than reducing or eliminating the

hazard from the workplace as a whole.

Moreover, respirators are uncomfortable

to wear, cumbersome to use, and

interfere with communication in the

workplace, which can often be critical

to maintaining safety and health. As

mentioned above, OSHA has reached

similar conclusions for other standards

promulgated to protect employees from

exposure to toxic substances. Paragraph

(g) of the final standard discusses

respiratory protection requirements.

The NPRM also proposed

requirements for a written compliance

program that would have required

employers to detail their plans for

implementing engineering and other

controls. However, OSHA has decided

to eliminate these provisions from the

final rule for MC to reduce the amount

of paperwork employers would be

required to complete. The Paperwork

Reduction Act of 1995 (PRA 95), (44

U.S.C. 3501 et seq.), requires agencies to

minimize the paperwork burdens on the

public. Preparation of written

compliance plans would be classified as

paperwork under the new Act. OSHA

believes that the lack of a written

compliance plan will not substantially

reduce the effectiveness of the standard;

the Agency solicits comment on this

point. One of the primary benefits of a

written plan is that it encourages

employers to consider remedial actions

soon after the standard is promulgated.

For MC, however, this may not be an

issue because the necessary control

measures are not complex and, except

for the very smallest employers, the

period for compliance allowed by the

standard is relatively short.

Nevertheless, OSHA believes that many

employers will voluntarily develop

these plans because they make it easier

for employers and employees to monitor

progress toward compliance. OSHA will

be considering including compliance

plans in its standards on a case-by-case

basis in future rulemakings when they

are appropriate. The Agency believes

that employers benefit from having a

plan to meet the start-up dates, and has

included examples of how this might be

done in Appendix B. There were very

few comments about the written

compliance plan requirements, other

than one stating that a written plan is

reasonable but annual review and

update of it is not [Ex. 19–26].

Paragraph (f)(2), proposed as

paragraph (f)(1)(iv), precludes use of a

schedule of employee rotation as a

means of compliance with the PELs.

Employee rotation reduces the extent of

exposure to individual employees, but

increases the number of employees

exposed. OSHA is regulating MC as an

occupational carcinogen, and the

Agency therefore prohibits practices

that would place more employees at

risk. No threshold has been

demonstrated for the carcinogenic

action of MC, and it is therefore prudent

public health policy to limit the number

of workers exposed. In addition, since

the dose-response relationship for MC is

convex, exposure to higher

concentrations for shorter periods of

time is riskier than exposure to the

equivalent ppm-hour concentration

spread over 8 hours (when rotation is

used as a method of employee exposure

control, employees tend to be exposed

to higher concentrations for shorter

durations).

Paragraph (f)(3) requires employers to

address leak and spill detection in the

workplace. Employers must implement

procedures to detect leaks and contain

spills as well as follow appropriate

methods to dispose of contaminated

materials and clean-up or repair the

spill or leak. These requirements were

addressed in proposed paragraph

(f)(1)(iii), but in the final rule have been

separated out and clarified to emphasize

their importance. Appendix A provides

examples of procedures that would meet

these requirements. Liquid MC has a

high vapor pressure (350 mm Hg at 20

C). Accordingly, leaks and spills of MCcontaining products could generate high

airborne MC levels. The leak and spill

detection program reduces the

possibility of worker overexposure to

MC.

Bristol-Myers Squibb (BMS) [Ex. 19–

14] and Dow [Ex. 19–31] supported

OSHA’s performance-oriented

requirement for a program to detect

leaks and spills. For example, BMS

stated:

[T]here are many ways in which this can

be done (e.g. monitoring of tank levels, walks

through areas where leaks may occur). In

some cases, continuous monitoring can be

done to detect leaks, however, this is not

always feasible. Monitoring equipment may

be very difficult and expensive to maintain

and may not provide the sensitivity needed

for early detection. We recommend that

OSHA leave this section as it is and not

specify the system or the equipment which

should be used for the detection program.

Proposed paragraph (h) required

employers to develop emergency plans,

implement those plans when necessary,

equip employees correcting emergency

situations with appropriate PPE, and

alert and evacuate employees

potentially affected by emergencies, as

necessary. In reviewing the proposed

rule, OSHA concluded that the

proposed requirements duplicated

provisions of the Hazardous Waste

Operations and Emergency Response

(HAZWOPER) standard (Section

1910.120). The Agency has therefore

deleted the separate MC requirement for

an emergency plan, and has added a

note to final rule paragraph (f)(3)(ii)

which refers employers to the

HAZWOPER standard for the applicable

requirements.

Paragraph (g) Respiratory Protection

Paragraph (g) of the final rule

addresses requirements for respiratory

protection allowed to be used to comply

with the MC standard. Paragraph (g)(1)

requires that employers provide

respirators at no cost to each affected

employee, and to ensure that each

affected employee uses a respirator

under the following conditions:

(1) Whenever an employee’s exposure

to MC exceeds or can reasonably be

expected to exceed the 8-hour TWA PEL

or the STEL;

(2) During the time interval necessary

to install or implement feasible

engineering and work practice controls;

(3) In a few work operations, such as

some maintenance operations and repair

activities, for which the employer

demonstrates that engineering and work

practice controls are infeasible;

(4) Where feasible engineering and

work practice controls are not sufficient

to reduce exposures to or below the

PELs; or

(5) In emergencies.

These limitations on the required use

of respirators are consistent with

OSHA’s longstanding position on the

hierarchy of controls in the workplace,

as reflected in the respiratory protection

requirements in other OSHA health

standards (e.g., asbestos, §1910.1001;

ethylene oxide, §1910.1047; benzene,

§1910.1028; cadmium, §1910.1027) and

with good industrial hygiene practice.

They reflect OSHA’s determination that

respirators are inherently less reliable in

providing protection to exposed
1584 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

employees than engineering and work

practice controls.

However, to reflect the changes made

to the final rule’s regulated area

provision (paragraph (e)(1)), the final

rule’s respiratory protection

requirements differ somewhat from

those in proposed paragraph (g). In the

NPRM, OSHA proposed to require that

employers provide respirators in the

following circumstances: (1) During the

time interval necessary to install or

implement feasible engineering and

work practice controls; (2) in work

operations, such as maintenance and

repair activities, vessel cleaning, or

other activities for which engineering

and work practice controls are

demonstrated to be infeasible, and when

exposures are intermittent in nature and

limited in duration; (3) in work

situations where feasible engineering

controls are not yet sufficient to reduce

exposure to or below the PELs; and (4)

in emergencies. In the final rule, another

situation where respirator use is

appropriate is acknowledged: whenever

an employee’s exposure to MC exceeds

or can reasonably be expected to exceed

either or both of the PELs.

The Building and Construction Trades

Department, AFL–CIO, testified [Tr.

816–17, 9/21/92] that proposed

paragraph (g)(1)(ii) could be interpreted

by construction contractors ‘‘as an

exemption from the requirement for

adopting a control strategy that places

engineering and work practice controls

above that of the PPE.’’ In response,

OSHA has revised final rule paragraph

(g)(1)(ii) to clarify OSHA’s intent. OSHA

recognizes that it may be infeasible to

control MC exposure with engineering

and work practice controls during

certain maintenance and repair

operations, although OSHA is also

aware that portable local exhaust,

‘‘elephant trunks,’’ and other means of

providing ventilation to, and removing

contaminated air from, process vessels

and other difficult-to-reach work spaces

are widely used in construction and

elsewhere. The Agency also recognizes

that there may be other MC-related

activities where an employer could

establish the infeasibility of controls,

particularly where employee exposure

is highly intermittent or of short

duration. Accordingly, OSHA has

revised proposed paragraph (g)(1)(ii) as

described above. This change also

addresses comments made by the

Pharmaceutical Manufacturers

Association (PMA) [Ex. 19–25; Tr. 1430,

9/23/92], which stated that it was

infeasible for employers to protect

employees during manual unloading of

batch operated centrifuges and manual

loading of dryers from MC exposure

with engineering and work practice

controls. The PMA suggested that OSHA

revise proposed paragraph (g)(1)(ii) to

include those loading and unloading

activities in the list of operations

allowed to protect affected employees

through the use of air-supplied

respirators. However, OSHA included

examples in the proposal only to

provide a general indication of the

situations where the Agency would

accept the use of air-supplied

respirators in lieu of engineering and

work practice controls. OSHA believes

that the examples suggested by the PMA

are too narrowly focused for inclusion

in such a list. It would not be possible

for OSHA to enumerate in the final rule

all of the workplace-specific operations

where engineering and work practice

controls may be infeasible. Therefore, in

accordance with longstanding OSHA

practice, employers claiming that

engineering and work practice controls

are infeasible must establish

infeasibility on an objective basis.

Other commenters were concerned

about requiring respirators during

emergency escape situations, noting the

time involved in donning a respirator in

an emergency. The Dow Chemical

Company stated ‘‘Dow believes the

respiratory protection requirements for

emergency escape are excessive. For the

short period of time it takes to escape a

release of MC, considering the minor

acute effects of the material, it is

excessive to require, as a minimum, a

gas mask with an organic vapor

canister’’ [Ex. 19–86].

Similarly, comparing escaping right

away or first finding a respirator and

then escaping during an emergency

situation, Occidental Chemical testified

[Tr. 2041, 10/14/92]:

Methylene chloride is not incapacitating so

the goal should be to escape as fast as

possible not trying to find a device—and it

may be close, it may be further—and then put

it on, which could take a minute or so, 30

seconds or a minute, and then decide about

escape. That whole process becomes much

longer. So I’m not advocating we don’t have

escape respirators, just that the process

should be, escape should be the number one

priority.

OSHA agrees that escape is the first

priority for employees exposed to MC in

an emergency situation. Furthermore,

the Agency has determined, in general,

that the ready availability of escape

respirators is essential to ensure that

employees are able to escape safely. To

that end, emergency plans must provide

for fast access to escape respirators

where the potential for emergency

exposure situations has been identified

by the employer. In addition, employees

must be trained to don those respirators

properly and quickly and to recognize

any foreseeable situations where taking

the time to obtain and put on their

respirators would significantly reduce

their ability to escape or where they can

safely escape an emergency situation

without using respirators. OSHA

recognizes that immediate escape is not

always possible, so respirators are

needed to protect those employees

while they are still in the exposure area.

Paragraph (g)(2), proposed as

paragraph (i)(1)(ii), requires employers

to determine that any employee

required by this standard to wear a

supplied-air respirator in the negative

pressure mode or a negative-pressure

respirator for escape purposes is

medically fit to use such a respirator.

This provision has been changed from

the proposal to recognize that medical

fitness for respirator users under this

standard is appropriate only for

negative-pressure respirators or those

operated in that mode. This change will

assist employers to direct their medical

surveillance resources effectively. In

addition, in keeping with the greater

flexibility provided by this standard to

employers in selecting an appropriate

health care professional, paragraph

(g)(2) uses the final rule’s language,

‘‘Physician or other licensed health care

professional,’’ in lieu of the proposal’s

exclusive use of ‘‘physician.’’

Paragraph (g)(3), proposed as

paragraph (g)(2), requires employers to

select appropriate atmospheresupplying respirators from among those

listed in Table 2 (Table 1 in the

proposed rule), which sets forth the

minimum requirements for respiratory

protection and is unchanged from the

proposal. Employers may use respirators

approved for a higher level of protection

in lower concentrations of MC.

Employers are required to select

atmosphere-supplying respirators that

have been approved by NIOSH under

the provisions of 42 CFR Part 84. Also,

employers must select vapor canisters

which have been approved by NIOSH

when they provide gas masks with

organic vapor canisters for use in

emergency escape. The final rule differs

from proposed paragraph (g)(2) in that it

does not require employers to give

employees who cannot wear negative

pressure air-supplied respirators or who

cannot wear a negative pressure (organic

vapor canister) during an emergency

escape the option of wearing a respirator

with less breathing resistance. OSHA

believes that the respirators required by

the final rule will not strain an

employee’s respiratory system during

such use.

Issue 30 (56 FR 57042) asked if the

proposed respirator selection table
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1585

(Table 1 in the proposal) appropriately

regulated the choice of respirators.

Several commenters suggested changes.

For example, Abbott Laboratories [Ex.

19–29] suggested that OSHA allow the

use of a continuous flow air-supplied

hood or helmet for exposures up to

5,000 ppm instead of 625 ppm of MC.

On the other hand, the Laborers’ Health

& Safety Fund of North America [Ex.

19–36] suggested that OSHA require

employers to provide positive pressure

SCBAs or airline positive- pressure full

facepieces with auxiliary escape for all

exposures over 25 ppm, instead of

allowing any flexibility, in keeping with

NIOSH recommendations for respiratory

protection against carcinogens. The

Advisory Committee on Construction

Safety and Health [Ex. 21–69]

recommended that respirators, when

used, be pressure-demand, supplied air

respirators with an auxiliary selfcontained breathing apparatus, because

of MC’s fast cartridge/canister

breakthrough and the lack of effective

end-of-service-life indicators.

OSHA is currently in the process of

developing a final standard to revise its

general respiratory protection

provisions in 29 CFR 1910.134. Until

that rulemaking is completed the

Agency will continue to rely on

NIOSH’s Assigned Protection Factors

(APF) for determining the types of

respirators required for protection to

airborne concentrations of MC. The APF

for continuous flow hoods/helmets is 25

in the NIOSH Respirator Decision Logic.

The maximum specified use

concentration for a respirator is

generally determined by multiplying the

exposure limit, in this case 25 ppm, by

the protection factor, which is 25;

therefore, these hood/helmets could be

used only up to 625 ppm of MC. Using

the same decision logic, OSHA believes

that adequate protection can be

provided by the respirators described in

Table 2 when they are used under

appropriate exposure conditions.

Some commenters questioned the

reliability of atmosphere-supplying

respirators. For example, in the

furniture stripping industry commenters

noted that MC could cause damage or

potential damage to the hoses, the

plastic lens, and the gasket of the

facepiece of air line respirators or other

kind of respirators, resulting in

inadequate protection. [Ex. 19–11; Tr.

348–9, 9/17/92; Tr. 2146–7, 10/14/92;

Tr. 2505–2506, 10/15/92]. In addition,

the Occidental Chemical Corporation

[Tr. 2115, 10/14/92] noted that none of

the manufacturers contacted had hoses

resistant to MC-induced corrosion. The

Agency acknowledges that MC may

damage respirator components, if the

MC is left on them for extended periods

of time. However, existing §1910.134 (f)

already requires employers to inspect

respirators frequently and to maintain

respirators at their original

effectiveness. In addition, MC does not

damage rubber components which are

available. Most importantly, if feasible

engineering controls and work practices

are not available, properly utilized airsupplied respirators are the only way to

protect employee health from significant

risk.

Issue 30 also requested information

on the circumstances under which airpurifying respirators may be used. Dr.

Morton Corn of Johns Hopkins

University testified [Tr. 2352, 10/15/92]

that ‘‘* * * with the current state of

knowledge and the breakthroughs I

indicated, [allowing gas masks with

organic canisters for emergency escape

only] is a prudent restriction at this

time.’’

Several commenters disagreed with

Dr. Corn and remarked that there are

some situations where air-purifying

respirators may be appropriate in

addition to emergency situations, and

recommended that OSHA expand the

provision to allow the use of airpurifying (filter) respirators. For

example, Occidental Chemical testified

[Tr. 2113–4, 10/14/92] as follows:

Transportation workers who make

deliveries in trucks can have intermittent

exposure to methylene chloride inside the

truck and, if you set the PEL too low, and in

that emergency situation * * * you can’t

have engineering controls on some types of

trucks, especially if they are rented. You

ought to allow the use of respirators in that

case; it’s a very short type exposure, goes in,

takes the drum out, and then gets back in the

truck. Now it may be possible to schedule

operations in certain industries where the

PEL is exceeded for short periods of time.

Filter cartridge respirators could be used to

protect the worker during the short periods

of time without the use of cumbersome

supplied-air respirators. Of course, you have

to have changes in the regulated areas in the

rules also if you’re going to allow the use of

respirators where you have intermittent

exposures above the PEL.

And a short breakthrough time does not

mean a respirator is useless. If you use the

NIOSH calculations, at 200 parts per million

which might be typical of paint stripping,

you ought to have about 118 minutes worth

of time before you get breakthrough; and that

may be enough in paint stripping operations.

Similarly, Bristol-Myers Squibb stated

that air-purifying respirators may be

appropriate in certain circumstances

[Ex. 19–14]:

Based upon the scientific information now

in the record, BMS requested that OSHA

consider allowing chemical cartridge airpurifying respirators for specific types of

activities (lower MC concentrations, shorter

durations).

Organic vapor cartridges can be used for

protecting employees against exposures to

MC where using an air-supplied respirator

would not be feasible due to costs or process

(e.g. multiple working areas). Only airsupplied respirators should be used for

operations involving the need for extended

wear (e.g. greater than several hours).

The Eastman Kodak Company [Ex.

102] also requested that OSHA allow

air-purifying respirators ‘‘in

circumstances where their effectiveness

can be adequately demonstrated,

engineering controls are not feasible and

supplied-air respirators are impractical

or potentially unsafe. OSHA also should

permit the use of half mask respirators’’

[Tr. 1196–7, 9/22/92]. In addition,

Kodak described specific situations

where it believed the use of airpurifying respirators was appropriate:

The use of air-supplied respirators must be

an essential component of the exposurecontrol strategies for both the Roll Coating

Division and the Dope Department.

Moreover, the evidence demonstrates that

air-purifying canister or cartridge-type

respirators may appropriately be used in

some operations, such as certain dope

maintenance tasks. The use of air-purifying

respirators is appropriate where: (1) airsupplied respirators or other controls are

impractical or potentially unsafe, (2) personal

monitoring of employees is conducted

regularly, (3) the extremes and conditions of

the exposure potential are well characterized,

and (4) used cartridges are tested after use to

verify the absence of unacceptable

breakthrough. It is essential that OSHA

permit the use of air-purifying respirators

under these circumstances so that Kodak can

control employee exposure when engineering

and work practice controls and air-supplied

respirators are infeasible, ineffective or

potentially unsafe.

OSHA considered including a

provision in the final rule to allow

exceptions for the use of air-purifying

respirators in limited circumstances

where very tight control of the respirator

program is implemented. However, the

Agency has rejected this alternative for

several reasons. First, the record

strongly supports the inadequacy of

such respirators for employee

protection. Consequently, the use of airpurifying respirators should only be

considered when the use of airsupplied respirators presents major

disadvantages. Second, a program to use

air-purifying respirators would have to

be very detailed and be tailored to a

specific workplace. It would be difficult,

if not impossible, to list all of the

relevant factors and criteria for such a

program in the regulatory text, which

must necessarily be appropriate to apply

to many workplaces. (Below, OSHA

discusses the Agency’s variance

procedures, which employers wishing

to use air-purifying respirators may use

to apply for a variance.)
1586 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

While there may be circumstances

when the use of filter respirators may

seem preferable to the use of

atmosphere-supplied respirators, OSHA

has concluded, as a general matter, that

air- purifying respirators do not provide

sufficient, consistent, and reliable

protection to employees exposed to MC.

In support of this conclusion, NIOSH

testified as follows [Tr. 887–89, 9/21/

92]:

At the request of OSHA, NIOSH has

completed an in-depth study of the

breakthrough characteristics of MC for

organic vapor respirator cartridges and

canisters under a variety of test conditions.

This work was undertaken to determine MC

breakthrough time for commercially

available, organic vapor respirator cartridges

and canisters. Several MC challenge

concentrations were studied, ranging from 50

ppm to 1,000 ppm. As received cartridges

and canisters were tested at equivalent flow

rates of 64 Lpm through the respirator and at

both 50% and 80% relative humidities (RHs).

Breakthrough times were determined for

individual cartridges and canisters, as well as

stacked cartridges. The results of this study

show rapid breakthrough of MC for organic

vapor cartridges even for low concentrations

of MC (e.g., 5 ppm breakthrough at

approximately 30 minutes for 50 ppm

challenge concentration and 80% RH).

Appendix D is a detailed report of this study.

At 125 ppm challenge concentration, 5 ppm

breakthrough, and 80% RH, one brand of

cartridge showed breakthrough times of

approximately 40 minutes. The same brand

of chin-style canister, that contains

approximately 2 and 1⁄2 to 3 times more

sorbent than two cartridges (i.e., two

cartridges per respirator) showed

breakthrough times of approximately 100

minutes when tested at the same conditions.

The same brand of front- or back-mounted

canister, that contains approximately 10

times more sorbent than two cartridges,

showed breakthrough times of approximately

600 minutes. Based on the results of this

study, NIOSH supports the OSHA proposal

to require the use of air-supplied respirators

in lieu of air-purifying respirators. However,

because of the potential carcinogenicity of

MC, NIOSH continues to recommend only

the most protective positive-pressure

respirators as noted previously.

The NIOSH study indicated that MC

quickly penetrates organic vapor

cartridges (in a fraction of a typical work

shift), contrary to the assertions of

Occidental Chemical and the other

commenters mentioned above. Larger

canisters, which contain greater

amounts of absorbent, last longer, but

are still effective for less than a work

shift (except for very large canisters).

Another problem with organic vapor

cartridges and canisters is that MC

migrates through the absorbent even

when the respirator is not being used.

This further decreases the breakthrough

time and raises the possibility that the

employee will be exposed to significant

concentrations of MC. Also, humidity

decreases the amount of MC collected

by the absorbent.

Another problem with air-purifying

respirators in the case of MC is this

substance’s poor warning properties,

which mean that workers will not be

able to smell or sense the presence of

MC when breakthrough occurs. OSHA

believes that employees wearing airpurifying respirators could easily have a

false sense of security and be lulled into

believing that they were being protected

against MC when it could already have

broken through the absorbent.

Accordingly, OSHA has concluded that

it would be inappropriate to allow

broad-scale use of air-purifying

respirators because of MC’s quick

breakthrough time and its carcinogenic

health effects.

Employers who believe that the use of

filter respirators is appropriate for their

operations may apply for a permanent

variance from the requirements of

paragraph (g)(3) of this section, pursuant

to the authority granted by § 6(d) of the

Occupational Safety and Health Act and

the procedures set out in 29 CFR part

1905. In particular, an applicant would

need to establish that the use of filter

respirators in a specific workplace

would provide employee protection

equivalent to that which would be

provided through compliance with final

rule paragraph (g)(3). As discussed

below, the respirator program,

procedures, and data needed to support

the use of such respirators under a

variance are extensive.

A successful variance application for

an exception that would allow airpurifying respirators would have to

address a number of the characteristics

that employers such as Eastman-Kodak

[Ex. 102] indicate they have undertaken

with regard to the use of such

equipment. For example, extensive

exposure monitoring would have to be

done to accurately characterize

employee MC exposure levels.

Furthermore, the breakthrough time for

MC when used in the airborne

concentrations expected in the

workplace would have to be known, and

cartridges would have to be changed

before employees are unacceptably

exposed. The program would have to be

carefully monitored by a trained and

experienced individual such as a

certified industrial hygienist or the

equivalent. Finally, the respirators

would have to be appropriately fit tested

for each affected employee. For all of

the reasons stated above, OSHA has

determined that the interests of

employee protection will be best served

by requiring all employers, except those

whose respiratory program, procedures,

and exposure data can support a

variance request, to provide their

employees with the respirators shown

in Table 2.

Paragraph (g)(4), which is identical to

the proposed (g)(3), requires employers

to implement a respiratory protection

program in accordance with 29 CFR

1910.134 whenever respirator use is

required by this standard. The

respiratory protection program must

include basic requirements for proper

selection, fit, use, training of employees,

cleaning, and maintenance of

respirators. For employers to ensure that

employees use respirators properly,

OSHA has found that the employees

need to understand the respirator’s

limits and the hazard against which it

is providing protection in order to

appreciate why specific requirements

must be followed.

Paragraph (g)(5) (effectively identical

to proposed paragraph (g)(4)) requires

that employers allow employees

wearing respirators to leave the

regulated area to readjust the respirator

facepiece to their faces for proper fit. In

addition, employers must permit

employees who wear respirators to leave

the regulated area to wash their faces as

necessary to prevent skin irritation

associated with respirator use. These

requirements encourage the proper use

of respirators by authorizing employees

to take specific actions that ensure the

effective functioning of respirators and

reduce the likelihood that employees

will experience adverse side effects

from wearing respirators.

Paragraph (g)(6), which is essentially

the same as the corresponding proposed

paragraph, addresses situations where

employers provide gas masks with

organic vapor cartridges for purposes of

emergency escape. If gas masks are

used, the canisters are to be replaced

before the gas masks are returned to

service. This requirement is necessary

because actual MC exposures during

emergencies are generally not known, so

the expected service life of the canister

cannot be determined. In addition, the

migration of MC within the canister

after emergency exposure further

reduces the amount of useful life

remaining, posing exposure risks for

subsequent users.

Paragraph (g)(7) addresses respirator

fit and is essentially identical to the

corresponding provision of the

proposal. It requires the employer to

ensure that each respirator issued is

properly fitted and has the least possible

facepiece leakage.

Under paragraph (g)(7)(ii), the

employer must perform qualitative or

quantitative fit testing initially and at
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1587

least annually thereafter for each

employee wearing a negative pressure

respirator, including those employees

for whom emergency escape respirators

of this type are provided. A note has

been added to this provision to indicate

clearly that the only supplied-air

respirators to which this provision

would apply are SCBAs operated in the

negative pressure mode and full

facepiece supplied-air respirators

operated in negative pressure mode.

Quantitative fit testing relies on

objective data generated by

measurements of facepiece seal leakage,

in contrast to qualitative fit testing,

which is based on subjective

observations made by the respirator

wearer. Many commenters expressed a

preference for quantitative fit testing

over qualitative fit testing. For example,

Newport News Shipbuilding (NNS) [Ex.

19–37, p. 2] stated: ‘‘Quantitative

respirator fit testing is the method of

choice. At NNS we use quantitative fit

testing exclusively, as this method is

more definitive than qualitative fit

testing and provides a record of the fit

test.’’ The Shipbuilders Council of

America [Ex. 19–56, p. 11] took the

same view.

Several commenters noted the

importance of proper selection and fit

testing of respirators [Exs. 19–12, p. 3;

19–31, pp. 15–17; 19–71, p. 4]. Dr.

David Newcombe of the Department of

Environmental and Health Sciences at

The Johns Hopkins University testified

as follows:

I think that’s [quantitative fit testing] a very

important parameter because, first of all,

respiratory protection when it’s required

takes a reasonable amount of time to ensure

that the individual is properly fitted so that

the mask fits if that’s the piece that’s going

to be used and is protective against the

substance that you’re protecting against and,

in addition, I think it’s important to note that

some people may have deformities that cause

a poor fit and, therefore, don’t protect and so

I would think that you have to have a careful

assessment of the type of respiratory

protection you’re going to use, its fit in a

single individual as well [Tr. 800, 9/18/92].

In most cases, OSHA has determined

that positive pressure respirators are the

respirators of choice for MC exposure,

especially loose-fitting models such as

hoods or helmets; for these respirators,

fit testing is generally not needed.

However, for those situations where

negative pressure respirators are used,

fit testing is needed. Qualitative or

quantitative fit testing allows the

employer to test various respirators on

the employee until the appropriate fit is

identified and selected for the

employee.

Paragraph (h) Protective Work Clothing

and Equipment

Paragraph (h) requires that, where

needed, employers provide and ensure

the use of the appropriate protective

clothing and equipment. The

requirements for protective work

clothing and equipment were separated

from proposed paragraph (g) (respiratory

protection and personal protective

equipment) and moved to paragraph (h)

to facilitate compliance. Proposed

paragraph (g)(6) was effectively

identical to this paragraph.

Protective clothing used during

exposure to MC, such as gloves or

aprons, must be resistant to MC. The

Building and Construction Trades

Department, AFL–CIO [Tr. 832, 9/21/92]

suggested that OSHA codify NIOSH’s

recommendations for protective

clothing materials suitable for use with

MC. MC is a constituent of so many

different products that a codification of

guidance regarding appropriate

protective clothing would be unwieldy

and unlikely to be complete. Further,

the continual formulation and

reformulation of MC products virtually

ensures the early obsolescence of any

protective clothing guidelines.

Therefore, OSHA believes that it is

appropriate for paragraph (h) to set

general criteria and for the Agency to

adopt the NIOSH recommendations in a

nonmandatory appendix so employers

will have more detailed guidance and so

OSHA can update that guidance,

without rulemaking, as advances in PPE

technology cause existing guidance to

become outdated. As discussed above,

this performance-oriented approach

reflects OSHA’s belief that employers

are in the best position to select

protective measures that are tailored

specifically to the needs of their

workplaces.

Paragraph (h) requires the employer to

provide all necessary protective clothing

and equipment at no cost to the

employee and to launder, repair, replace

and safely dispose of that clothing and

equipment. The final rule is

performance-oriented so the employer

has the flexibility to provide only the

protective clothing and equipment

necessary to protect employees in each

particular work operation from MC

exposure. The generic requirements for

PPE in the general industry,

construction, and shipyard standards

also apply to PPE for MC, except where

a specific provision of the MC standard

applies.

Paragraph (i) Hygiene Facilities

Paragraph (i) of the final rule

establishes requirements for hygiene

facilities in establishments where it is

reasonably foreseeable that an

employee’s eyes or skin may contact

solutions containing 0.1 percent or

greater MC. Although such provisions

were not part of the proposed rule,

OSHA requested comment on the

appropriateness of including such

requirements in Issue 38 (56 FR 57122).

Specifically, the Agency requested

comment on the appropriateness of

including requirements for quickdrench showers and eye-wash facilities

in the final rule. OSHA described quickdrench showers as,’’ * * * showers that

could drench an employee with pipedin water applied with force,’’ and

eyewash facilities as devices ‘‘that could

flush the eyes repeatedly with a great

amount of water.’’ In response to

comments, described below, the Agency

has decided that it is not necessary to

specify in the final rule when showers

and eyewash facilities are required to

protect employees from skin or eye

contact with MC, because employers are

in the best position to determine

whether the MC used in their

establishments meets the 0.1 percent

cutoff specified in this provision and

whether contact of the eyes or skin with

MC can reasonably be foreseen.

Paragraph (i)(1) requires employers to

provide conveniently located washing

facilities appropriate to removing MC if

it is reasonably foreseeable that the

employee’s skin may contact a solution

containing 0.1 percent or greater MC

through splashes or spills. MC can be

absorbed into the body through skin

contact (percutaneous absorption),

which would add to the dose employees

receive via inhalation and thus increase

the risk of cancer and other adverse

health effects. However, MC is not a

corrosive chemical, and, if left on the

skin for short periods, is not likely to

cause long-term or irreversible damage.

Therefore, it is important that employers

make provisions to remove MC from the

skin of employees quickly, although

immediate drenching is not usually

required. This requirement has been

stated in performance-oriented language

in the final rule to allow employers to

determine what type of washing

facilities are needed and at what

distance from affected employees. This

provision thus recognizes that

employers in some facilities, such as

furniture stripping shops where a thick

MC gel is used that may burn the skin

on contact, employers need to position

washing facilities in closer proximity to

affected employees than is the case

where less hazardous solutions of MC

are used. OSHA believes that this

requirement of the final rule strikes the
1588 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

right balance between employee

protection and employer flexibility by

ensuring that washing facilities for the

skin will be available and appropriately

placed in workplaces where such

contact is likely.

MC splashed into the eyes will cause

irritation if the MC is not promptly

washed out, and immediate flushing is

therefore required. Paragraph (i)(2)

requires employers to provide

appropriate eyewash facilities within

the immediate work area for emergency

use if it is reasonably foreseeable that an

employee’s eyes will contact solutions

containing 0.1 percent or greater MC

through splashes or spills.

Existing OSHA requirements at

§ 1910.141 and § 1926.51 establish

generic provisions for hygiene facilities

but do not focus on MC-specific

situations. Existing § 1910.151(c) and

§ 1926.50 (g) require employers to

provide suitable facilities for quickdrenching or flushing of body and eyes

within the immediate work area for

immediate emergency use, when the

body or eyes may be exposed to

injurious corrosive materials. However,

because MC is not classified as a

corrosive material, these existing

requirements would not apply. Thus the

final rule’s performance-oriented

requirements will provide guidance to

employers about what facilities and

access distances are appropriate for

conditions in their workplaces. In

addition, Appendix A provides

examples of both washing facilities and

eyewash facilities that would satisfy this

requirement.

The response to Issue 38 emphasized

the need for eyewash and shower

facilities [Exs. 19–37, 19–56; Tr. 2644–

2645, 10/16/92; Tr. 1942–1943, 9/24/

92]. For example, PRMA testified [Tr.

348, 9/17/92] that MC splashes happen

‘‘almost every day’’ in furniture

stripping workplaces.

Commenters also addressed the health

effects associated with such accidental

exposures. The Amalgamated Clothing

and Textile Workers Union testified [Tr.

1825, 9/24/92]:

I would advocate including it [the

provisions for showers and eyewash

facilities]. It [methylene chloride] has skin

effects. Anyone who’s ever stripped paint can

tell you about what it’s like to get it on their

skin or their eyes. So it’s very important to

be able to irrigate an affected area promptly.

One means to provide protection from

prolonged skin or eye exposure to MC

from accidents is to specifically require

quick-drench showers and eyewashes.

The NPRM sought comments on

whether or not the final rule should

require employers to provide quickdrench showers and eyewash facilities.

Many commenters recommended that

the final rule contain such provisions

[Exs. 19–15; 19–36; Tr. 532, 9/18/92; Tr.

1380, 9/23/92; Tr. 2352–53, 10/15/92].

For example, PRMA [Ex. 19–11] favored

a requirement for eyewash/ quick

drench facilities, stating as follows:

An eyewash station is a safety device that

should be required in any work environment

where there is the possibility of splashing

chemicals into ones eyes. Quick drench

showers are also a safety device that should

be standard equipment in every facility. MC

paint removers are one of the few paint

removers that are easily rinsed from one’s

eyes.

The Dow Chemical Company

commented [Ex. 19–31]:

Washing facilities are always a good idea

when working with any material, however, it

is not always necessary to have quick-drench

showers, etc. Incidentally, quick-drench

showers do not deliver water ‘‘applied with

force.’’ They work on a deluge system

delivering a large amount of water to wash

off the material, not force it off. Installing

showers and eyewash fountains in all

workplaces may not be economically

feasible. There are other systems such as

water hoses, portable eye-washes, etc. that

work effectively for MC. MC is a material

that, in some cases, may be painful if held

against the skin for a period of time, but is

not eye nor skin nor life threatening.

Therefore, an immediate shower is not

required.

OSHA agrees that quick drench and

eyewash facilities are effective means

for treating employees who have been

accidentally exposed to MC by spills or

splashes. However, the Agency agrees

with Dow Chemical that quick drench

showers are not the only means to

ensure proper first aid treatment for MC

exposure due to accidental splashes or

spills and believes that other types of

washing facilities can also provide

effective treatment for accidental

exposure.

In some cases, the availability of a

hose attached to a potable water supply

would enable employers to provide

effective first aid treatment. This could

be an especially effective means of

protection at a construction worksite.

Several commenters [Ex. 19–23, 19–38;

Tr. 859, 9/21/92] agreed that

construction employers should have

potable water at the worksite in case of

accidental exposure. For example, the

Building and Construction Trades

Department, AFL–CIO, testified [Tr.

817, 9/21/92]:

The standard does not address the need for

available hygiene facilities. Since methylene

chloride can damage the skin and eyes and

potable water is often in limited supply on

construction sites, the requirement for

potable washing areas must be clearly stated

in the standard. Potable water supplies

should be of sufficient volume to provide at

least 15 minutes of continuous flushing.

The Occupational Health Foundation

testified that the MC standard should

require that hygiene facilities be

provided within a reasonable distance at

construction worksites [Tr. 858–859, 9/

21/92]:

Unlike in a lot of other work sites where

at least there’s a sink nearby, in construction

you really need to specifically mandate that

provision to be sure that there’s going to be

water anywhere remote, you know, within a

reasonable distance to the work site.

Issue 38 also requested information

on the extent to which MC-exposed

employees are already provided with

quick drench showers and eye wash

facilities. Several commenters described

workplaces that have emergency shower

or eyewash facilities in place. The

United Automobile, Aerospace and

Agricultural Implement Workers of

America (UAW) testified [Tr. 1942–

1943, 9/24/92] ‘‘[t]here are a lot of

showers and eye washes in areas where

you have open-top chemicals or use of

chemicals.’’ In addition, the Occidental

Chemical Corporation testified [Tr.

2159, 10/14/92]:

. . . we conducted a survey of our

customers that were not CMA and not

NACCD members recently and asked them

questions like that. We have some

information on that. It doesn’t necessarily

mean that we hit a large percentage of our

methylene chloride customers, though.

. . . we have safety shower[s] and

eyewash[es] [in our plants], certainly. We

have . . . recommendations on it and we

certainly follow the ANSI standards on it.

Newport News Shipbuilding (NNS)

and the Shipbuilders Council for

America both commented [Exs. 19–37

and 19–56] that ‘‘[p]rocedures at NNS

now require eyewash units. For the

most part we use portable (5 gallon)

units. Plumbed combination units

would be better.’’ The National Tank

Truck Carriers, Inc. also indicated that

their facilities are already equipped

with emergency showers [Tr. 1750–51,

9/24/92].

With regard to the proximity of

employees to emergency showers and

eye washes, commenters and testimony

indicated that, depending on the work

operation, shower facilities have been

installed as close as eight feet or as far

away as 100 feet. For example, the J. M.

Murray Center, testified [Tr. 1047–48, 9/

21/92] that they have both eye washes

and showers that are ten to twelve feet

from the employees.

The Polyurethane Foam Association

(PFA) testified [Tr. 1630, 9/23/92] that

the proximity of shower facilities and

eye washes depends on the plant and
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1589

operation within the plant, stating as

follows:

We’ve got methylene chloride in bulk

storage area and we also use it at the foam

machine. The total range from those things

that you might be would be anywhere from

eight feet to may be 60 feet. And I’m guessing

at the 60 feet. That, again, is specific for those

plants that I am responsible for. There are 80-

some-odd plants out there, and I can’t speak

for that particular physical setup in each one

of those plants.

The PFA further stated in its post

hearing comment:

Eye wash and drench showers are available

in the production areas. These are located

within 10 to 15 feet of the work stations, such

as near bulk storage tanks and the mixing

head, where a higher risk of employee

exposure exists. Hygiene facilities may be 50

to 75 feet away from other work areas [Ex.

L–100A].

The Eastman Kodak Company

testified [Tr. 1259, 9/22/92] that

emergency eye-wash and quick-drench

showers are available in their

workplaces, and that such stations are

between 50 and 100 feet from all work

areas where exposure to chemicals may

occur.

Striptech International, which

advocated requirements for pressure

showers and eyewash facilities where

workers are exposed to MC [Ex. 19–15],

also testified that hygiene facilities are

not readily accessible in the aircraft

paint stripping industry [Tr. 1834–35, 9/

24/92]:

I’ve heard people ask about deluge in eye

wash. Does it exist in aircraft maintenance

hangars? Yes, it surely does; but you also

have to look at where they normally are.

They’re normally on the walls. When a man

or a lady is on top of an aircraft, on the tail

of an aircraft, they may be nine stories in the

air. If they get methylene chloride in their

eyes or really a bad shot of it, they’ve got to

come down nine stories and may be cross a

400 to 600-foot-long hangar to get to it.

Deluge showers, yes; all aircraft people have

them. Are they readily accessible? No.

It is important for the employer to

evaluate the potential hazard posed by

the particular use of MC and to provide

appropriate washing facilities within a

reasonable distance and eyewash

facilities within immediate reach. In

addition, employers are required to

provide employees who are at risk of

skin and/or eye contact with MC with

appropriate protective clothing and eye

protection. Portable eyewash units,

which would significantly reduce any

delay in irrigating the eyes, are available

and can be located within easy access

distance of affected employees. As

described above, access to washing

facilities should be quick, but

immediate showering is not generally

necessary to address the MC skin

hazard. Therefore, an employee

stripping an airplane would likely have

time to get to the showers located along

the walls of the hangar to wash MC from

the skin. (Note: Some paint stripping

compounds do contain corrosives, and

immediate access to quick-drench

facilities is essential in such cases.)

Based on a review of the rulemaking

record, the Agency has determined that

performance-oriented provisions for

hygiene facilities are reasonably

necessary to supplement the other

requirements of the final rule and has

promulgated paragraph (i) accordingly.

Paragraph (j) Medical Surveillance

Section 6(b)(7) of the OSH Act

requires that, where appropriate,

occupational health standards shall

prescribe the type and frequency of

medical exams or other tests to be made

available, by the employer or at the

employer’s cost, to exposed employees

in order to determine if the employee’s

health is being adversely affected by

exposure to workplace hazards.

A medical surveillance program that

complies with paragraph (j) enables the

employer to:

(1) Determine if an employee has an

underlying health condition that places

the employee at increased risk from the

effects of exposure to MC;

(2) detect, insofar as possible, early or

mild clinical conditions arising as a

result of MC exposure, so that

appropriate preventive measures can be

taken;

(3) identify any occupational diseases

that occur as a result of MC exposure;

and

(4) help to evaluate possible trends in

the incidence of these diseases.

The most serious health effect that

may result from MC exposure is cancer.

Although a medical surveillance

program cannot detect MC-induced

cancer at a preneoplastic stage, OSHA

anticipates that, as in the past, methods

for early detection and treatments

leading to increased survival rates will

continue to evolve. Moreover, the

cardiovascular disease, central nervous

sytem and dermal irritation effects

caused by MC exposure can already be

detected at early or mild stages by

medical surveillance provisions such as

a medical history and a medical exam.

MC has not been tested adequately for

the full range of possible health effects

that may result from exposure, so it is

also not presently possible to identify

all diseases that may be associated with

exposure to MC. The specific level of

protection afforded the worker by the

final standard cannot be predicted with

certainty, although the risk of exposure

for those effects that have been

identified are significant, and the record

shows that reducing the exposure of

employees will significantly reduce that

risk. An important goal of the medical

surveillance program is to provide

information related to the adequacy of

the PELs for MC by documenting the

health condition of exposed employees,

particularly in the area of

carcinogenicity.

Several rulemaking participants [Exs.

19–31, 19–83, Tr. 1802–3, 9/24/92]

stated that the proposed medical

surveillance provision should be

deleted from the final rule because it

would not detect employee exposure to

harmful levels of MC. In addition

participants contended [Ex. 19–83, Tr.

458, 9/17/92] that the medical

surveillance provision is too expensive

and burdensome. OSHA has determined

that the medical surveillance program

required by the final rule is reasonably

necessary for the protection of workers.

In particular, medical surveillance will

directly benefit workers with

cardiovascular disease, central nervous

system effects, and dermal irritation.

These conditions can be detected by the

medical surveillance program required

by this paragraph of the final rule, and

the detection of such conditions can, in

turn, alert the employer to potential

overexposures to MC in the workplace

and to the need to limit MC exposures

for certain employees with underlying

heart disease or other conditions.

In addition, by increasing the

performance orientation of the rule,

OSHA has minimized the costs of

medical surveillance while maintaining

its effectiveness. For example, the final

rule leaves the content of laboratory

surveillance for individual employees to

the discretion of the physician or other

licensed health care professional. Also,

the requirement for a physical

examination has been tailored to the age

of the employee, so that employees

younger than 45 generally receive an

exam only every three years, instead of

annually. The medical surveillance

program also will aid in the evaluation

of cancer incidence in the workplace

and temporal trends therein.

Paragraph (j)(1) specifies the

circumstances under which employers

must provide medical surveillance for

employees who are or may be exposed

to MC. Under paragraph (j)(1)(i),

employers must make medical

surveillance available to all employees

who are exposed to MC at or above the

action level for 30 days or more in any

year or above either of the PELs for at

least 10 days in any year. This provision

is effectively identical to the

corresponding provision of the
1590 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

proposed rule. Also, this requirement is

consistent with the approach taken by

OSHA in the benzene standard (29 CFR

1910.1028). OSHA recognizes that the

health effects associated with MC

exposure are, in general, the result of

chronic exposures to MC. Accordingly,

employees exposed only for a few days

in any year will be at relatively low risk

of developing MC-induced disease. The

exposure duration thresholds in the

final rule will thus enable employers to

focus valuable medical resources on

high-risk employees.

Some commenters were concerned

about the use of the PELs and action

level as triggers for medical

surveillance. The Building and

Construction Trades Department, AFLCIO [Tr. 817, 9/21/92] was concerned

that this provision would preclude

medical surveillance for some

employees with MC exposures that

exceeded the PELs on fewer than 10

days in a given year but who might

nonetheless be at risk of adverse health

effects. OSHA has determined that

employees who have been identified by

a physician or other licensed health care

professional as being at risk for cardiac

disease or some other serious MCrelated health condition and who are

exposed to MC at levels that exceed the

PELs on fewer than 10 days in any year

should have the option of participating

in a medical surveillance program.

Accordingly, paragraph (j)(1)(ii) has

been added to the final rule. This

provision states that medical

surveillance must be provided to any

employee (1) who is exposed above the

8-hour TWA PEL or STEL for any time

period, and (2) who has been identified

by a physician or other licensed health

care professional as being at risk from

cardiac disease or from some other

serious MC-related health condition,

and (3) who requests inclusion in the

medical surveillance program. As noted

in the Health Effects section, above,

OSHA is concerned that any MC

exposure above either of the PELs could

exacerbate cardiac problems. This

paragraph enables such high-risk

employees to participate in a medical

surveillance program.

Under paragraph (j)(1)(iii),

appropriate surveillance is required to

be made available to employees exposed

in an emergency regardless of the

airborne concentrations of MC normally

present in the workplace. Where very

large amounts of materials are kept in a

sealed system, routine exposure may be

very low. However, rupture of the

container might result in extremely high

MC exposures. Thus, it is appropriate

for employers who have identified

operations where there is a potential for

an emergency involving MC to plan

ahead so that emergency medical

surveillance would be available if

needed. This provision is effectively

identical to proposed paragraph

(i)(1)(iii).

Proposed paragraph (i)(1)(ii) would

have required that the employer have

the examining physician or other

licensed health care professional

determine if affected employees are

physically fit to wear respirators. OSHA

has placed this requirement with the

other respiratory protection provisions

in paragraph (g) of this final rule.

Paragraph (j)(2) requires that

employers offer examinations without

cost to employees, at a reasonable time

and place, and without loss of pay.

OSHA believes that this provision is

necessary to encourage employees to

participate in the medical surveillance

program. Final rule paragraph (j)(2),

which is essentially identical to

proposed paragraph (i)(2), is also

consistent with other OSHA health

standards and with provisions

contained in the OSH Act.

Paragraph (j)(3) requires that all

medical procedures be performed by or

under the supervision of a physician or

other licensed health care professional,

defined as ‘‘an individual whose legally

permitted scope of practice (i.e., license,

registration, or certification) allows him

or her to independently provide or be

delegated the responsibility to provide

some or all of the health care services

required by paragraph (j) of the

standard.’’ The proposal required that

all medical procedures be performed

only by or under the supervision of a

physician. Only one commenter [Ex.

19–31] specifically supported this

provision.

OSHA has long considered the issue

of whether and how to identify the

particular professionals who are to

perform the medical surveillance

required by its health standards. The

Agency has determined that other

professionals who are licensed under

state laws to provide medical

surveillance services would also be

appropriate providers of such services

for the purposes of the MC standard.

The Agency recognizes that the

personnel able to provide the required

medical surveillance may vary from

state to state, depending on state

licensing laws. Under the final rule, an

employer has the flexibility to retain the

services of a range of qualified licensed

health care professionals, thus

potentially reducing costs, increasing

flexibility, and allowing employers to

identify those professionals, who may

not necessarily be physicians, with the

greatest expertise in diagnosing and

treating occupational diseases. In future

rulemakings, OSHA may attempt, with

the cooperation of interested

stakeholders, to specify which licensed

health care professionals are the most

appropriate to perform each of the

diagnostic, therapeutic, medical

management and other services required

by the Agency’s standards.

Paragraph (j)(4) of the final standard

addresses when medical examinations

and consultations are to be provided.

Initial surveillance. Under paragraph

(j)(4)(i), initial medical surveillance

must be provided before an employee’s

initial assignment to work in an area

where they would be exposed to MC or

by the start-up dates described in

paragraph (n)(2)(iii) of the final MC

standard, whichever is later. The

employer need not repeat equivalent

medical surveillance if it has already

been provided within the past 12

months. OSHA’s requirement for a

preplacement examination is intended

to determine if an individual is at

increased risk of adverse effects from

exposure to MC. It also establishes a

general baseline for future reference.

The provisions of final rule paragraph

(j)(4) are effectively identical to those in

proposed paragraph (i)(3), except that

the proposed rule did not take into

account medical surveillance provided

prior to the effective date of this section.

In the preamble to the NPRM (56 FR

57124), OSHA stated that it was

considering a provision that would give

employers credit for medical

examinations provided within one year

of the standard’s effective date. The

Agency requested comment on the

usefulness of such a provision.

Commenters [Exs. 19–31, 19–55b, 19–

83] supported such a provision. In

particular, Dow Chemical [Ex. 19–31]

stated ‘‘[i]f this is not done this section

will be unfair to those employers who

have on-going health surveillance

programs.’’ OSHA agrees with these

commenters and has promulgated the

final rule accordingly.

Periodic surveillance. Paragraph

(j)(4)(ii) addresses periodic medical

surveillance. OSHA proposed to require

annual medical surveillance for all

affected employees. In the final rule,

this has been changed so that the

employer is required to update the

medical and work history for each

affected employee every year but must

only provide physical examinations on

a schedule that varies with the age of

the employee. For affected employees

45 years of age or older, the physical

examination must be conducted every

year. For employees less than 45 years

of age, the examination need only be

done every three years.
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1591

OSHA differentiated these groups of

employees in an effort to target

surveillance resources effectively. The

probability of developing heart disease

(which can be exacerbated by MC

exposure) increases as employees age.

Age 45 is a rough approximation of the

point at which medical professionals

would have heightened concern for

cardiac effects. In other words, it is

generally more likely that employees 45

years and older would experience the

adverse cardiac effects of MC exposure.

Three-year intervals between physical

examinations for workers younger than

45 seemed the proper interval to balance

the conservation of valuable medical

resources and the provision of a medical

surveillance program that is useful for

detecting adverse MC health effects. The

annual updates on medical and work

history will enable the physician or

other licensed health care professional

to identify those individuals for whom

more frequent examinations would be

appropriate.

To a lesser extent, this would be true

for the detection of MC-induced cancer

as well. Although MC-induced cancer

cannot currently be detected at the preneoplastic stage, early detection of

cancer generally increases the survival

rate, so it is important to include

employees exposed to MC in a medical

surveillance program that may detect

tumors. Since any cancers caused by

MC are more likely to be found in older

employees and employees exposed to

MC for longer durations, it is reasonable

to concentrate medical surveillance

resources on older employees.

The main goal of periodic medical

surveillance for workers is to detect

adverse health effects at an early, and

potentially still reversible, stage. The

intervals chosen based on the age of the

employee are consistent with this

purpose and with other OSHA health

standards. The Agency believes that

these periodic surveillance

requirements strike a proper balance

between the need to diagnose health

effects, such as cancer, at an early stage,

thus increasing the effectiveness of

medical intervention, and the

expectation that a limited number of

cases will be identified through the

surveillance program. This approach

decreases the cost burden of

surveillance by lengthening the period

of time between examinations for

younger employees who have fewer

years of exposure and thus have a lower

risk of adverse health effects.

Termination of employment or

reassignment. Paragraph (j)(4)(iii)

requires the employer to provide

medical surveillance when an employee

terminates employment or is reassigned

to an area where exposure is

consistently at or below the action level

and the STEL. The termination

examination need not be conducted if

medical surveillance has been

performed within the past six months.

This requirement reduces the likelihood

that an employee who terminates

employment has an active, but

undiagnosed, disease related to his or

her MC exposure. In the NPRM, OSHA

had proposed that the termination

examination be performed unless

medical surveillance had been

conducted on that employee within the

past three months. The Motor Vehicle

Manufacturers Association [Ex. 19–42]

requested that the exam should only be

required if the employee has not had a

medical exam within six months of

termination or reassignment, instead of

three months as had been proposed. The

MVMA stated that ‘‘six months is

adequate and consistent with other

OSHA health standards (Cadmium, Sec.

1910.1027(l)(8)). We see no contribution

to reducing employee risk from

examining such employees at an earlier

date, especially since the exposure to

methylene chloride has been removed.’’

Upon reconsideration of the issue,

OSHA has adopted this suggestion in

the final rule.

The Agency requested public

comment on whether continued annual

surveillance should be offered to

employees who have left employment,

retired, or transferred to other areas

within the employer’s operations. Such

an approach would be consistent with

the requirement in the Benzene

standard (29 CFR 1910.1028), which

makes medical surveillance available to

certain employees who have been

exposed to benzene during their

employment with their current

employer. Several commenters [Exs. 19–

31, 19–38, 19–42, 19–48, 19–55b, 19–58]

stated that there should be no medical

surveillance after an employee leaves a

job in an exposure area or for employees

previously exposed to MC. In particular,

Dow Chemical [Ex. 19–31] stated: ‘‘[W]e

do not believe that the employer should

be responsible for continued medical

surveillance for employees who leave

MC exposure areas * * *. [T]he

continued surveillance does nothing

more than divert occupational medical

resources from more important work.’’

Taking a different view, the IUE [Tr.

533, 9/18/92] testified that formerly

exposed retirees should be included in

the medical surveillance program. They

also stated that retirees, presently

employed workers formerly exposed to

MC in previous jobs, and workers

relocated to nonexposed areas should be

included in the medical surveillance

program. The ACTWU agreed, testifying

[Tr. 1763–1764, 9/24/92] that employees

who continue to work for the same

employer after their exposure to MC is

terminated should be entitled to

participate in the medical surveillance

program.

OSHA has decided that it would be

inappropriate to include retirees and

other formerly exposed employees in

the medical surveillance program. A

major value of medical surveillance is to

detect the acute heart disease and CNS

effects associated with MC exposure.

Workers no longer exposed to MC, or

retirees, would be at much less risk of

experiencing these effects.

Additional surveillance. Paragraph

(j)(4)(iv) requires employers to provide

additional surveillance when the

physician or other licensed health care

professional recommends that it be

provided. This may be warranted, for

example, for an employee who is under

45 years of age but has a health

condition that requires surveillance

more frequently than every 3 years.

Inclusion of this provision in the final

rule will ensure that all employees

receive the most appropriate level of

surveillance for their particular health

situation. The proposed provision was

essentially identical.

Paragraph (j)(5) of the final rule, like

paragraph (i)(4) of the proposal,

establishes the requirements for the

content of medical exams. This

provision requires a comprehensive

medical and work history, a physical

examination, laboratory surveillance,

and any additional information

determined to be necessary by the

physician or other licensed health care

professional. The language in the

proposed rule, which was similar, has

been revised for clarity and to provide

guidance about what constitutes

adequate medical surveillance. For

example, the final rule addresses

medical and work history in greater

detail than the proposal because, in

some cases, three years may elapse

before a subsequent physical

examination is provided. On the other

hand, the specific content of the

physical examination and laboratory

surveillance has been left largely to the

discretion of the physician or other

licensed health care professional.

Paragraph (j)(5)(i) requires that a

comprehensive medical and work

history be obtained from each

participating employee. This paragraph

requires a medical evaluation that

includes a comprehensive medical and

work history with special emphasis on

neurological symptoms, skin conditions,

history of hematologic or liver disease,
1592 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

signs or symptoms suggestive of heart

disease (angina, coronary artery

disease), risk factors for heart disease,

MC exposures, and the work practices

and personal protective equipment used

to control exposures. OSHA has

included an example of a medical and

work history format that would satisfy

this requirement in non- mandatory

Appendix B of the standard. The

proposed provision required a

comprehensive or interim medical and

work history with emphasis on

neurological symptoms, mental status,

and cardiac health. Final rule paragraph

(j)(5)(i) has been revised to indicate

clearly what is required.

The medical and work history

component of the initial medical

evaluation will assist the physician or

licensed health care professional in

identifying pre-existing conditions that

might place the employee at increased

risk when exposed to MC. It also

establishes a health baseline for future

monitoring. The subsequent annual

updates will identify changes in

neurological symptoms, skin conditions

or cardiac health, and, in combination

with laboratory analyses and

information on exposure history, may

provide early warnings of MC toxicity.

The information derived from a medical

evaluation assists the physician or other

licensed health care professional in

distinguishing between MC-related

effects and those effects that are

unrelated to MC exposure. This

information is particularly important

because the health effects associated

with MC exposure are not unique to

such exposure. For example, the

proposed requirement to assess mental

health status has been eliminated from

the final rule because no specific

correlation has been demonstrated

between mental health status and MC

exposure.

Paragraph (j)(5)(ii) requires that the

extent and nature of the required

physical examinations be determined by

the physician or licensed health care

professional based on the health status

of the employee and analysis of the

medical and work history for that

employee. The standard also requires

that the examiner give particular

attention to the lungs, cardiovascular

system (including blood pressure and

pulse), liver, nervous system and skin.

Proposed paragraph (i)(4)(ii) specifically

would have required that the

examination address the lungs, liver,

nervous system and breast. OSHA has

determined that, in order to indicate

clearly that the physician or licensed

health care professional should assess

the potential cardiac health impacts of

MC, the medical exam should give

attention to the cardiovascular system,

blood pressure and pulse. In addition,

the Agency has decided that, because of

the skin irritation effects of MC, it is

necessary to include evaluation of the

skin in the medical exam.

Two hearing participants [Tr. 803, 9/

18/92; Tr. 2434–35, 10/15/92] testified

that men over 40 years old should be

given electrocardiograms (ECGs), which

should be repeated every 1 to 3 years.

OSHA is not requiring ECGs because

there is no evidence in the record that

associates specific changes in ECGs with

MC exposures. However, the physician

or licensed health care professional has

the discretion to order an ECG for any

employee where it is deemed

appropriate.

Proposed paragraph (i)(4)(iv) also

required the physician to make a

determination of any reproductive

difficulties of the employee. Vulcan

Chemicals [Ex. 19–48] and Organization

Resources Counselors (ORC) [Ex. 19–51]

commented that the evidence for a

relationship between reproductive

effects and MC exposure did not

warrant inclusion of such a provision in

the final rule. OSHA agrees with these

commenters that the evidence

associating MC exposure and specific

reproductive health effects is sparse.

Therefore, the Agency has not included

reproductive effects in the list of effects

the physician or other licensed health

care professional should focus on.

However, the Agency will continue to

monitor the literature to determine if

future evidence indicates that inclusion

of this provision is warranted.

Two commenters [Exs. 19–28, 19–42]

stated that the breast examination

requirement should be eliminated from

the final rule because breast exams

would be highly unlikely to identify

effects related to exposure to MC. In the

proposal OSHA placed attention on the

breast because of concern raised by the

increased number of breast tumors in

the rat bioassay. Upon further

consideration, OSHA has dropped the

requirement for breast exams. The

Agency notes that rats are particularly

sensitive to mammary tumors and it is

unclear that humans have similar risks

of developing breast cancer after

exposure to MC. The Agency remains

concerned about the potential for MC

carcinogenicity evidenced by the rat

mammary tumors, however, and has

relied, in part, on mammary tumor data

in identifying MC as a cancer hazard.

In final rule paragraph (j)(5)(iii),

laboratory surveillance of employees is

to be conducted as the examining

physician or licensed health care

professional determines to be necessary

and appropriate, based on the

employee’s health status and the

medical and work history. This is a

more performance-oriented provision

than the corresponding provision of the

proposed rule. The proposal would have

required several specific laboratory

tests, while the final rule leaves

laboratory test requirements to the

discretion of the physician or other

licensed health care professional. Nonmandatory Appendix B includes

guidance regarding the types of tests

that may be appropriate.

Some commenters [Exs. 19–28, 19–42,

19–48, 19–49] stated that COHb levels,

which had been included among the

tests in the NPRM, are not a good

measure of toxic exposure to MC. In

particular, the MVMA [Ex. 19–42] stated

that it is difficult to determine the COHb

level attributable to MC exposure for

employees who are smokers or who may

have other exposures to CO. Several

other participants [Exs. 19–25, 19–57,

19–83 and Tr. 1438, 9/23/92] suggested

that COHb testing should be done only

after over-exposure to MC, such as after

an emergency. The Laborers Health and

Safety Fund [Tr. 1386, 9/23/92]

testified,

[W]e’re not convinced that that’s [COHb

monitoring] an appropriate and accurate

measure of exposures, given other sources of

carbon monoxide on construction sites as

well as the issue of smokers versus nonsmokers.

However, the Department of the Army

[Ex. 19–55b] suggested that COHb levels

are a more cost-effective measurement

of the oxygen-carrying capacity of blood

than a complete blood count. Similarly,

the California Department of Health

Services [Ex. 19–17] requested that

references to COHb testing be moved

from the appendix to the regulatory text.

COHb levels greater than 3% can

exacerbate angina symptoms, decrease

exercise tolerance and increase risks for

myocardial infarctions (heart attacks) in

susceptible individuals. COHb

concentrations can also be used as a

rough estimate of worker exposure to

MC (taking into consideration smoking

behavior, time since exposure, and

exposure to other CO sources) to

calibrate personal MC monitoring

measurements. Before- and after-shift

COHb determinations can be useful in

correlating recent MC exposures with

COHb levels. The Agency is not

requiring COHb testing, however,

because confounding factors, such as

smoking or exposure to a CO source, can

reduce the usefulness of the results of

the tests and, in addition, COHb does

not measure a health effect per se but is

instead a surrogate measure of MC

exposure. However, COHb testing may
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1593

be clinically important in the evaluation

of a symptomatic worker and therefore

remains an option for the physician or

other licensed health care professional

to pursue. Exposure monitoring (see

paragraph (d) of the final rule) must be

performed to quantify an employee’s

exposure to MC.

In the comments received subsequent

to publication of the ANPR for MC [Exs.

10–3, 10–10, 10–28], several industry

commenters indicated that urine

analysis, liver function tests and chest

X-rays are commonly performed as part

of the medical surveillance programs of

these companies. OSHA believes that

annual urine analysis or chest X-ray

would not be relevant to detection of

MC-related health effects. Liver function

tests have also been evaluated for

inclusion as a requirement in the

medical surveillance provision. As

discussed above in the Health Effects

section, animal studies and human

clinical studies show an association

between chronic MC exposure and some

changes in liver enzymes, particularly

after high exposures or doses of MC for

prolonged periods of time. The changes

in liver enzyme levels after MC

exposure are not consistent in the

human clinical studies, however, and in

general, changes in liver enzymes are

not specific or unique to MC exposure.

Therefore, the Agency believes that it

should be left to the physician’s or other

licensed health care professional’s

discretion to determine if laboratory

analysis of liver enzymes is warranted.

Several commenters [Exs. 19–11, 19–

26, 19–42, 19–48, 19–55b] agreed that

routine use of all of the tests included

in the proposal would not be

appropriate or necessary for the

detection of MC-related health effects.

The Agency also sought comments on

the inclusion of other medical tests in

the final MC rule. Two commenters

[Exs. 19–31, 19–48] stated that a

complete blood count was not necessary

because the results of this test may not

correlate with MC overexposure. In

particular, the Dow Chemical Co. [Ex.

19–31] commented that a complete

blood count is not necessary because

blood cell volume and hemoglobin

findings would suffice. OSHA has

reevaluated the utility of the proposed

tests and has decided that leaving

laboratory surveillance to the discretion

of the physician or licensed health care

professional is more cost-effective than

the approach taken in the proposal and

will not negatively impact worker

health.

In paragraph (j)(5)(iv), the final rule

requires the medical surveillance

program of the employer to include any

other information or reports the

physician or other licensed health care

professional determines are necessary.

This is to ensure that a complete

medical profile is available to the

physician or licensed health care

professional to make decisions

regarding the employee’s health and

exposure status. This provision is

essentially identical to that proposed.

Paragraph (j)(6) of the final rule

describes the required contents of

emergency medical surveillance. The

proposed rule did not specify what

elements should be included in an

emergency medical exam. The final rule

clarifies that emergency medical

surveillance should include any

appropriate emergency treatment and

decontamination of the exposed

employee, a comprehensive physical

exam, an updated medical and work

history, and laboratory surveillance, if

needed.

The Dow Chemical Company [Ex. 19–

31] commented that employees exposed

to MC during an emergency should not

automatically be included in the regular

medical surveillance program. Instead,

this commenter argued that only those

components of a medical examination

that are appropriate in a given situation

should be conducted. OSHA believes

that it is important for an employer to

provide medical examinations and

appropriate follow-up to employees

exposed to MC during an emergency.

After considering the issue and

comments raised during the rulemaking,

the Agency agrees with Dow that

employees exposed to MC during an

emergency should not necessarily be

enrolled in the continuing medical

surveillance program provided to

employees routinely exposed to MC. To

that end, OSHA has added language to

the final rule that clearly indicates what

emergency medical surveillance is

required. OSHA believes that final rule

paragraph (j)(6) allows the employer

appropriate flexibility, while at the

same time ensuring that those

employees exposed to MC during an

emergency receive appropriate medical

surveillance.

Paragraph (j)(7) requires the employer

to provide medical surveillance

services, in addition to those specified

in final rule paragraphs (j)(5) and (j)(6),

when the physician or other licensed

health care professional determines that

they are necessary. Compliance with

this requirement will ensure that the

information needed to evaluate the

effects of MC exposure on employees is

available. This provision is essentially

the same as proposed paragraph (i)(5).

Paragraph (j)(8) requires that the

employer provide the physician or other

licensed health care professional with

(1) a copy of the standard, including the

relevant appendices; (2) a description of

the affected employee’s past, current,

and anticipated future duties as they

relate to the employee’s MC exposure;

(3) a description of former, current or

anticipated exposure levels (including

the frequency and exposure levels

anticipated to be associated with

emergencies), as applicable; (4) a

description of any PPE that the

employee must use or will use, such as

respirators; and (5) information from

any previous medical examinations that

would not otherwise be available to the

examining physician or other licensed

health care professional. OSHA has

determined that the physician or other

licensed health care professional needs

the above-listed background information

in order to place the information

derived from medical surveillance in

the proper context. For example, a welldocumented exposure history assists the

physician or other licensed health care

professional in determining whether an

observed health condition may be

related to MC exposure. It also helps

this individual to determine if the

results of medical surveillance indicate

a need to limit an employee’s

occupational exposure to MC. This

paragraph is essentially the same as

proposed paragraph (i)(6).

Paragraph (j)(9) of the final rule

requires employers to ensure that the

examining physician or other licensed

health care professional provides the

employer and the affected employee

with a written opinion that addresses (1)

the physician’s or other licensed health

care professional’s opinion as to

whether the employee has any detected

medical condition that would place the

employee at increased risk of material

health impairment as a result of

exposure to MC; (2) any recommended

limitations on the employee’s exposure

or use of personal protective clothing or

equipment and respirators; (3) a

statement that the employee has been

informed of the potential

carcinogenicity of MC, the risk factors

for heart disease, and the potential for

exacerbation of underlying heart disease

associated with exposure to MC; and (4)

a statement that the employee has been

informed of the results of the medical

examination and any medical

conditions related to MC exposure that

require further explanation or treatment.

The physician or other licensed

health care professional must provide

copies of the written medical opinion to

the employee and the employer within

15 days after completion of the

evaluation of medical and laboratory

findings, but no later than 30 days after

the medical examination. This
1594 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

requirement was included to ensure that

the employee and the employer have

been informed of the above-mentioned

results of the medical examination in a

timely manner. This requirement differs

slightly from that in proposed paragraph

(i)(7)(i). Instead of the physician

providing a copy of the written medical

opinion to the employer, who then

provides a copy to the employee, the

final rule requires the physician or other

licensed health care professional to

supply a copy of the written medical

opinion directly to both the employer

and the employee. In addition, the time

allowed for providing the opinion has

been changed to recognize that time

may be needed to receive and evaluate

laboratory or other medical findings.

The Agency believes that notifying both

the employer and affected employees of

the MC-related results of the medical

surveillance at the same time is an

efficient approach to disseminating this

information to the appropriate parties.

Providing copies of the same written

opinion both to the employer and the

employee ensures that the employer is

aware of any factors that may influence

work assignments or choice of personal

protective equipment.

OSHA has added a requirement to the

final rule that the physician or other

licensed health care professional inform

the employee of the carcinogenic and

cardiac effects of MC to reinforce the

information on MC’s serious health

effects that was transmitted during

training. The Agency believes that this

reinforcement will help to ensure that

employees are aware of the potential

effects of MC and take appropriate

precautions when using this toxic

substance.

OSHA received several comments on

different aspects of paragraph (j)(9). For

example, the UAW [Tr. 1884, 9/24/92]

testified that the written opinion

transmitted to the employer by the

physician or other licensed health care

professional should only state the

limitations on the employee’s exposure

or use of respiratory or other personal

protective equipment recommended by

the physician or other health care

professional, and should not include the

medical or other reasons behind the

recommended limitations.

OSHA agrees with the UAW that it is

important to protect the privacy of

employees enrolled in medical

surveillance programs. Consequently,

OSHA health standards have

traditionally included a statement to the

effect that no findings or diagnoses

should be included in the physician’s

written opinion that are unrelated to

occupational exposure. This

requirement is intended both to protect

the employee’s privacy and to

encourage employees to participate in

the employer’s medical surveillance

program. The restriction on what may

be revealed in the written opinion

appears in the final rule as paragraph

(j)(9)(ii), and is intended to apply to all

of the information provided in the

physician’s or other licensed health care

professional’s written opinion,

including that related to recommended

limitations.

The MVMA [Ex. 19–42] and ORC [Ex.

19–57] stated that the proposed 15-day

requirement for providing the employer

with a copy of the written opinion

should be 15 days from the physician’s

or other licensed health care

professional’s receipt of the test results

rather than 15 days from the date of the

examination. The Agency agrees and, as

described above, has changed the

requirement so that the written opinion

must be provided within 15 days of

completion of evaluation of medical

findings, but not more than 30 days after

the examination. OSHA believes that

this strikes the proper balance between

allowing sufficient time for the

physician or other licensed health care

professional to evaluate any laboratory

findings while still providing the

information to the employer and the

employee in a timely manner.

Newport News Shipbuilding [Ex. 19–

37] and the Shipbuilders Council of

America [Ex. 19–56] stated that the

written opinion should require only that

employees be notified of abnormal test

results, not normal results. In response

to these comments, OSHA notes that

such a provision would actually require

many physicians and other licensed

health care professionals to change their

current practice because it would

require them specifically to delete

normal results from printouts of

laboratory and other findings. Such

reports routinely display all results,

both normal and abnormal, for a given

individual. In addition, OSHA believes

that employees benefit from knowing

which of their blood parameters and

other test results are normal and which

are abnormal. OSHA does not believe

that requiring medical personnel to

increase the amount of paperwork they

perform is a good use of medical

resources, and has therefore not revised

the final rule to respond to these

comments.

Under paragraph (j)(9)(ii) of the final

rule, the physician or other licensed

health care professional must exclude

findings or diagnoses that are unrelated

to MC exposure from the written

opinion provided to the employer. As

discussed above, OSHA has included

this provision in the final rule to

reassure employees participating in

medical surveillance that they will not

be penalized or embarrassed by the

employer’s obtaining information about

them that is not directly pertinent to MC

exposure. The above provisions are

identical to those in proposed paragraph

(i)(7)(ii). A note has been added to the

final rule that states that the written

opinion developed to comply with the

MC standard may also contain

information related to other OSHA

standards. For example, an employer

whose employees are enrolled in

medical surveillance due to their

exposure to benzene, formaldehyde and

MC could receive a single, consolidated

written opinion that addressed findings

related to all three substances. This

performance-oriented provision could

result in reduced paperwork burdens for

employers.

NPRM Issue 3 solicited input

regarding whether the Agency should

add a provision for Medical Removal

Protection (MRP). Medical removal

protection encourages employee

participation in (and therefore increases

the effectiveness of) the medical

surveillance program by ensuring that

reporting symptoms or health

conditions to the physician or licensed

health care professional will not result

in loss of job or pay. Several rulemaking

participants expressed support for the

inclusion of MRP in the final rule [Exs.

19–23, 19–38; Tr. 1787, 9/24/92; Tr.

1802, 9/24/92; Tr. 1869, 9/24/92; and

Tr. 1883, 9/24/92]. For example, the

Amalgamated Clothing and Textile

Workers (ACTWU) [Tr. 1793, 9/24/92]

testified that OSHA should require MRP

based on clinical judgment, as OSHA

allowed in the final rule for

formaldehyde (29 CFR 1910.1048). They

also stated that they believed it was

critical to have a medical removal

protection provision in the MC standard

in order to ensure worker participation.

Mr. Frumin of the ACTWU testified as

follows [Tr. 1792–1793, 9/24/92]:

As I say, the problems that employers,

physicians and, for that matter, OSHA

confront in trying to assure the integrity of

medical surveillance programs are not

limited to a particular substance. They deal

with the general perception—these problems

arise from the general perception of workers,

which is widespread through industry, that

if they submit to a medical examination and

it’s not confidential, and employers could get

the results of the medical findings, that

health problems may result in some negative

action.

You have a symptom-based medical

surveillance program, at least for the noncancer effects. And if workers are supposed

to report the types of symptoms, for instance,

that Dr. Soden was looking for, shortness of

breath, things of that nature—and they’re
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1595

concerned that reporting that might involve

some negative action against them: either

their job security or their pay. You know,

they will be discouraged from participating

in medical surveillance, and the whole

structure of the program is undermined. So

the fact that these health effects are

symptom-based rather than, say, based on

laboratory tests alone, makes it all the more

important to include medical removal

protection and multiple physician review in

the final rule.

Two commenters [Exs. 19–23, 19–38]

suggested that MRP should be based on

COHb levels. However, Dr. Mirer of the

UAW [Tr. 1940, 9/24/92] disagreed with

this idea and concurred with Mr.

Frumin’s remarks that medical removal

protection should be based on

symptoms and professional discretion.

He stated,

* * * the guidance for the physicians,

once the physician decides this employee is

at increased risk, if they continue in this

exposure and I want to remove him or her

from the job, that’s the trigger. At this

moment, I would leave it that way. Increased

carboxyhemoglobin is more an index of

exposure than an adverse clinical effect, so

I don’t have any particular guidance. If the

doctor wants to pull that man or woman out

of a job, that’s where I am now.

He continued,

* * * the other benefit of protecting the

disclosure of symptoms is that it’s going to

identify sources of exposure, because one of

the ways of determining exposure is by the

presentation of symptoms. So the benefit of

having them disclose symptoms is it will

lead to lower exposure.

I can’t think of anything much else that

you would need to get out of MRP than

improved participation, although at least our

experience in lead is that MRP has been the

driving force to reduce exposures

independent of that.

OSHA considered the issues raised

during the MC rulemaking and in

general agrees with these worker

representatives that MRP increases

employee participation in medical

surveillance. OSHA remains concerned

about several issues, however. The

Agency recognizes that employees may

hesitate to participate in medical

surveillance if they have reason to

expect that the results may adversely

affect them economically. However,

OSHA has determined that there is no

substantive guidance that it could give

a physician or other licensed health care

professional to indicate when it might

be appropriate to remove an employee

temporarily from the workplace, or what

an appropriate trigger for return to work

might be. Accordingly, OSHA has

decided to promulgate the final rule for

MC without including MRP provisions.

The Agency will continue to monitor

compliance with the medical

surveillance and PPE provisions of this

standard and the experience in

industries subject to standards with

medical removal protection provisions

to determine whether any further action

is warranted.

Paragraph (k) Hazard Communication

The requirements for hazard

communication have been changed from

proposed paragraph (j) (Communication

of MC hazards to employees) and

promulgated in paragraph (k) of the

final rule. The paragraph addressing

hazard communication in the final MC

rule is consistent with the requirements

of OSHA’s Hazard Communication

Standard (HCS). The HCS requires all

chemical manufacturers and importers

to assess the hazards of the chemicals

they produce or import. It also requires

all employers to provide information

concerning the hazards of such

chemicals to their employees. The

transmittal of hazard information to

employees is to be accomplished by

such means as container labeling and

other forms of warning, material safety

data sheets and employee training.

Since the HCS ‘‘is intended to address

comprehensively the issue of evaluating

the potential hazard of chemicals and

communicating information concerning

hazards and appropriate protective

measures to employees’’ (52 FR 31877),

OSHA is including paragraph (k) in the

final rule only to reference the HCS

requirements for labels and material

safety data sheets, and to indicate

specifically the MC health effects that

are required to be addressed under that

rule. This additional guidance to

employers simply reiterates the

requirements of the HCS to convey

information to affected employees about

all health hazards to which they are

potentially exposed. The health effects

addressed by the final MC rule are

cancer, cardiac effects (including

elevation of carboxyhemoglobin),

central nervous system effects, and skin

and eye irritation. There may also be

other health hazards or physical hazards

associated with MC that meet the

definitions of coverage under the HCS.

These should be addressed

appropriately on the label and MSDS as

well.

Employers who have already met

their longstanding requirements to

comply with the HCS will have no

additional duties with regard to labels

and MSDSs under the MC final rule.

This is consistent with the suggestions

of some commenters that no

requirements should be mandated

beyond those listed in the HCS [Exs. 19–

25, 19–31, 19–42]. OSHA agrees that the

HCS addresses the issue

comprehensively, and additional

requirements are not necessary to

protect MC-exposed employees

specifically. As a result, the Agency has

deleted the proposed requirement for

warning signs. Such signs are not

required under the HCS, although they

may be useful in some situations and

employers may choose to use them. The

Organization Resources Counselors [Ex.

19–57] commented that the required

signs should say ‘‘warning’’ and not

‘‘danger’’ as proposed, and suggested

consistency with the benzene and

ethylene oxide standards. It should be

noted that the terms ‘‘warning’’ and

‘‘danger’’ have specific meaning in the

context of labels, and there are criteria

for their application under voluntary

consensus standards such as the ANSI

Z129.1 standard for precautionary

labeling. ORC’s comment is otherwise

moot at this point since the relevant

requirement has been deleted.

Paragraph (l) Employee Information and

Training

The requirements for employee

information and training, which were

part of proposed paragraph (j)

(Communication of MC hazards to

employees), have been separated from

the hazard communication requirements

for labels and data sheets described

above, and promulgated as paragraph (l)

in the final MC rule. Some of the

training provisions that were proposed

duplicated requirements of the HCS.

These have been removed, and a

reference to the information and

training required under the HCS has

been added to simply remind employers

of their longstanding obligations under

that rule to ensure that employees are

apprised of the hazards of the chemicals

in their workplaces, as well as

appropriate protective measures. The

information and training requirements

in the final MC rule build upon those

requirements with additional

information specific to MC that will

help employees understand the risks of

exposure and the means to prevent

adverse health effects from occurring in

their particular workplaces.

It should be noted that the

information and training requirements

in the final rule have been separated

from each other rather than being

addressed together, because they deal

with different ways of conveying

information. ‘‘Information’’ transmittal

is simply that—a passive process of

making information available to

employees should they choose to use it.

In some cases, this may be done in

writing or some other simple manner of

information transfer. ‘‘Training,’’ on the

other hand, is not a passive process. The
1596 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

information provided to employees in

training requires them to comprehend it

and subsequently to use it in the

performance of their duties in the

workplace. There are many different

ways to accomplish training effectively,

but it cannot be a simple transfer of

information such as handing someone a

written document. OSHA’s voluntary

training guidelines, which are found in

OSHA Publication No. 2252, are

available to provide employers

additional guidance in setting up and

implementing an appropriate employee

training program. An effective training

program is a critical component of any

safety and health program in the

workplace. Workers who are fully

informed and engaged in the protective

measures established by the employer

will play a significant role in the

prevention of adverse health effects.

Ineffective training will not serve the

purpose of making workers full

participants in the program, and the

likelihood of a successful program for

safety and health in the absence of an

effectively trained workforce is remote.

Paragraph (l)(1) requires employers to

provide all employees who are

potentially exposed to MC with

information and training on MC prior to

or at the time of initial assignment to a

job involving MC exposure. Thus

employees will have the information

they need to protect themselves before

they are actually subject to exposure.

The final rule further indicates in

paragraph (l)(2) that employers shall

ensure that the information and training

is presented in a manner that is

understandable to employees and that

employees have received the

information and training required under

the HCS.

Paragraph (l)(3) addresses the

information to be provided to affected

employees. This includes the

requirements of the final MC standard

and information available in its

appendices, as well as how the

employee can access or obtain a copy of

it in the workplace. This will ensure

that MC-exposed employees are aware

that specific requirements have been

established to protect them from adverse

health effects, and give them an

opportunity to review those

requirements themselves if they so

desire. Wherever employee exposures

exceed or can reasonably be expected to

exceed the action level, the employer is

required to inform employees about the

location of MC in the workplace, what

operations may be affected, particularly

noting where in the workplace there

may be exposures above the permissible

exposure limits.

Paragraph (l)(4) requires each

employer to train each affected

employee as required under the Hazard

Communication Standard (29 CFR

1910.1200, 29 CFR 1915.1200 or 29 CFR

1926.59, as appropiate). This provision

simply reminds employers of their

obligation to train employees regarding

the hazards of MC under the Hazard

Communication Standard.

The final rule does not provide a

specific time period for updating the

training, whereas the proposed standard

included a requirement for annual

retraining. Instead, the final rule

indicates in paragraph (l)(5) that the

employer shall re-train each affected

employee as necessary to ensure that

employees exposed above the action

level or the STEL maintain a good

understanding of the principles of safe

use and handling of MC in the

workplace. Employers can assess

whether this understanding is generally

present in exposed employees in

various ways, such as by observing their

actions in the workplace. For example,

if an employee is not using appropriate

protective equipment or following safe

work practices routinely, this may be an

indication that additional training is

required. This provision of the final rule

is a performance-oriented requirement

that allows each employer to determine

how much or how often training is

needed.

Paragraph (l)(6) requires that the

employer do additional training when

the workplace is modified or changed in

such a way that employees are subject

to greater exposures and those

exposures exceed or can reasonably be

expected to exceed the action level and

those employees need information and

training to understand how to

implement the modifications or training

successfully. This provision was not in

the proposal, but the Agency considers

it necessary to further protect employees

from the hazards of MC when

significant changes in workplace

conditions occur.

Paragraph (l)(7) requires the employer

whose employees are exposed to MC at

a multi-employer worksite to notify the

other employers with work operations at

that site regarding the use of MCcontaining materials, the hazards

associated with the use of those

materials and the control measures

implemented to protect affected

employees from MC exposure, in

accordance with the requirements of the

Hazard Communication Standard (HCS).

The HCS addresses sharing information

at multi-employer worksites, and since

this final rule covers construction where

most of the sites are multi-employer,

this provision was added to remind

such employers of these requirements.

OSHA is also aware that an increasing

number of manufacturing worksites

involve more than one employer.

In paragraph (l)(8) of the final rule,

OSHA has indicated that the Assistant

Secretary or the Director may access all

materials relating to employee

information and training in the

workplace. This would be done in

conjunction with an inspection to

ascertain compliance with the rule, or in

the event of a NIOSH health hazard

evaluation. Review of the available

materials regarding information and

training will help assess whether the

program has been properly conducted,

as well as evaluate what could be

improved if employees do not appear to

be effectively trained.

The information and training

provisions of this standard are

performance-oriented, because

employees are exposed to MC in a wide

variety of circumstances and the best

method of conveying the necessary data

may vary from site-to-site. The standard

lists the categories of information to be

transmitted to employees but does not

specify the ways in which it is to be

transmitted.

Some commenters [Tr. 531–32, 9/18/

92; Tr. 545–49, 9/18/92; Tr. 828–32, 9/

21/92; Tr. 1380, 1384–85, 9/23/92]

suggested that OSHA make the

proposed training provisions more

specific, such as by including

requirements for length of training,

qualifications of instructors, or

requirements for interactive training. In

addition, hearing participants and

commenters suggested that OSHA

require employers to monitor the

effectiveness of training [Ex. 19–38, Tr.

531–32, 9/18/92]. These participants

suggested that provisions be made, as

well, for training of workers in

languages other than English and for

training of workers with limited literacy

[Ex. 19–38, Tr. 531–32, 9/18/92; Tr.

831–32, 9/21/92].

The International Brotherhood of

Painters and Allied Trades, AFL-CIO,

testified [Tr. 830–831, 9/21/92]:

We urge OSHA to promulgate a standard

that requires that workers receive a minimum

of 16 hours training. Such training would

include at the minimum information on the

hazards of methylene chloride and how it

harms the body. Engineering controls that

can be implemented in the field should be

described and demonstrated. We will submit

information on one such control to the

record. Training should also include

information on work practices associated

with specific job assignments, methods by

which workers can protect themselves, the

limits of respirators use, appropriate

procedures for work in confined spaces,

employee rights under the standard, the
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1597

purpose of medical surveillance and other

elements of training as enumerated in

Section (j)(4).

OSHA does not agree that specifying

a time frame for training ensures that it

will be complete, appropriate, or

effective. The amount of training

required will depend to a large extent

on the conditions of use in a given

workplace. It will also be related to the

extent of training on MC that has

already been done by the employer

under the HCS. Therefore, the final rule

provisions remain performance-oriented

with regard to the time needed to

convey the information and training.

With regard to the issues of literacy

and language, these remain a significant

consideration in the proper design and

implementation of any training

program. Because working safely with

MC is such a significant concern, the

employer must make every effort to

ensure that the training is presented in

such a way that employees can

understand and act on the information.

OSHA expects that employers will

ensure that the information and training

is effective. Any good training program

should include an evaluation

component to help ensure effectiveness.

The voluntary training guidelines

previously recommended can provide

additional guidance in this respect.

OSHA received comments that

indicated that the MC standard should

simply refer to the HCS rather than

having separate requirements [Exs. 19–

25; 19–49]. While the Agency agrees

with these comments in reference to the

label and MSDS requirements, it does

not appear that this is the appropriate

approach to training. While the HCS

addresses training about the hazards of

a chemical and appropriate

precautionary measures, there are other

items of training that are specific to the

MC standard requirements and the

determinations made in this rulemaking

regarding MC. As such, it is important

to ensure that the already-required HCS

training is supplemented with

information and training specific to MC.

Paragraph (m) Recordkeeping

Paragraph (m) of the final rule

addresses requirements for employers to

create and maintain records of their

compliance with some of the provisions

of this section. Section 8(c)(1) of the

OSH Act authorizes the Agency to

promulgate regulations requiring

employers to keep necessary and

appropriate records regarding activities

to permit the enforcement of the Act or

to develop information regarding the

causes and prevention of occupational

accidents and illnesses. Section 8(c)(3)

of the Act specifically addresses the

promulgation of ‘‘regulations requiring

employers to maintain accurate records

of employee exposures to potentially

toxic materials or harmful physical

agents which are required to be

monitored or measured under section

6.’’

Paragraph (m)(1) requires that

employers who rely on objective data to

characterize potential exposures to MC,

rather than conducting initial

monitoring under paragraph (d) of this

section, maintain records that show the

information and methodology used in

reaching their conclusion that exposures

are at or below the action level and no

additional monitoring is required. The

record must include the MC-containing

material evaluated; the source of the

objective data; the testing protocol, and

the results or analysis of the testing; a

description of the operation(s) exempted

from monitoring, and how the data

support the exemption; and other

relevant data.

Since the use of objective data

exempts the employer from conducting

monitoring, as well as establishing that

most of the other provisions need not be

complied with due to the low level of

potential exposure, it is critical that this

determination be carefully documented.

Compliance with the requirement to

maintain a record of objective data

protects the employer at later dates from

the contention that initial monitoring

was improperly omitted. The record

will also be available to employees so

that they can examine the determination

made by the employer. The employer is

required to maintain the record for the

duration of the employer’s reliance

upon objective data. This provision is

effectively identical to proposed

paragraph (k)(1).

Paragraph (m)(2) requires that

employers establish and keep an

accurate record of all measurements

taken to monitor employee exposure to

MC. For employers with 20 or more

employees, the record must include at

least: the date of measurement for each

sample taken; the operation involving

exposure to MC which is being

monitored; sampling and analytical

methods used and evidence of their

accuracy; number, duration and results

of samples taken; the type of personal

protective equipment, such as

respiratory protective devices worn (if

any); and name, social security number,

and job classification and exposure of

all the employees deemed to be

represented by such monitoring,

indicating which employees were

actually monitored. For employers with

fewer than 20 employees, the record

shall include, at a minimum: the date of

measurement for each sample; the

number, duration and results of samples

taken; and name, social security

number, job classification and exposure

of all the employees deemed to be

represented by such monitoring,

indicating which employees were

actually monitored. OSHA believes it is

necessary to maintain these records so

that employers, employees and OSHA

can determine the extent to which MC

exposure has been identified and

subsequently controlled. Over time, the

exposure records can help determine if

additional measures are needed for

employee protection. OSHA has

reduced the amount of information

required for small businesses in

recognition of the more limited variety

of operations and exposure levels there.

This should ease these employers’

recordkeeping burden without

compromising employee safety and

health in these types of facilities.

Two commenters [Exs. 19–25, 19–49]

suggested that such documentation

should only be required for each person

actually monitored (paragraph (d)(1)

provides for representative monitoring).

However, OSHA believes that it is

necessary for records to be kept for each

employee represented by the exposure

monitoring so that individual

employees can access information that

characterizes their own exposures to

MC. If records were kept only for those

actually monitored, it would be

unreasonably difficult for an employee

to identify the exposure measurement

that is intended to represent his or her

experience. Accordingly, OSHA has not

made the suggested change.

Paragraph (m)(3) requires that the

employer keep accurate medical records

for each employee subject to medical

surveillance. The information to be

included in the record addresses

identification of the employee; the

physician’s or other licensed health care

professional’s written opinions; and

documentation of any employee

medical conditions that are found to be

related to MC exposure. Maintenance of

employee medical records is necessary

for the proper evaluation of the

employee’s health, as well as for

appropriate followup.

Proposed paragraph (k)(3)(ii)(D)

required that a copy of the information

provided to the physician or other

licensed health care professional be

included in the employee record. The

Dow Chemical Company [Ex. 19–31]

requested that, because many larger

companies have company medical

facilities, some provision be made so

that records do not have to be

maintained in medical department

records and duplicated in the personnel

record of every employee potentially
1598 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

exposed to MC. The information

required under paragraph (j)(8) of this

section includes a copy of this section

including its appendices, a description

of duties involving MC exposure,

exposure levels, personal protective

equipment, and previous medical

surveillance information. Since this

information is available to the employee

through other means, OSHA believes

that the requirements under proposed

paragraph (k)(3)(ii)(D) were

unnecessarily burdensome, and OSHA

has therefore deleted this paragraph

from the final rule. OSHA has also

deleted proposed requirements for

maintaining records of employee fit

testing as being unnecessarily

burdensome. Dow also suggested that an

employee identification number be

permitted in lieu of social security

number [Ex. 19–31]. OSHA does not

agree with this suggestion. Social

security numbers have much wider

application, and are correlated to

employee identity in other types of

records. These numbers are a more

useful differentiation among employees

since each number is unique to an

individual for a lifetime and does not

change as an employee changes

employers.

Paragraph (m)(4) of the final rule

specifies that access to exposure and

medical records by employees,

employees’’ designated representatives,

NIOSH and OSHA shall be provided in

accordance with 29 CFR 1910.1020.

OSHA promulgated 29 CFR 1910.1020

as the generic rule for access to

employee exposure and medical records

on May 23, 1980 (45 FR 35212). It

applies to records created under specific

OSHA standards and to records that are

voluntarily created by employers. OSHA

retains unrestricted access to medical

and exposure records but its access to

personally identifiable records is subject

to the Agency’s rules of practice and

procedure concerning OSHA access to

employee medical records, which have

been published at 29 CFR 1913.10.

The time periods required for

retention of exposure records and

medical records is thirty years and the

period of employment plus thirty years,

respectively. These retention

requirements are consistent with those

in the OSHA records access standard

and with pertinent sections of the Toxic

Substances Control Act. It is necessary

to keep records for extended periods of

time because of the long latency periods

commonly observed for the induction of

cancer caused by exposures to

carcinogens. Cancer often cannot be

detected until 20 or more years after

onset of exposure. The extended record

retention period is therefore needed for

two purposes. First, possession of past

and present exposure data and medical

records furthers the diagnosis of

workers’ ailments. In addition, retaining

records for extended periods makes

possible a review at some future date of

the effectiveness and adequacy of the

standard.

Paragraph (m)(5) requires employers

to comply with the requirements of 29

CFR 1910.1020(h). That provision

requires the employer to notify the

Director of NIOSH in writing at least 90

days prior to the disposal of records and

to transfer those records to NIOSH

unless told not to do so by NIOSH. The

employer is required to comply with

any other applicable requirements set

forth in the records retention standard.

Paragraph (n) Dates

This paragraph establishes the

effective date for the MC final rule, and

the start-up dates for the various

provisions of the standard. The start-up

dates allow employers additional time

to comply with some of the provisions

of the standard that require more effort

to accomplish. It is expected that such

work will commence by the effective

date, and be completed as soon as

possible but in no case later than the

compliance deadline established by the

effective date. All other obligations

imposed by the standard become

effective on the effective date unless

otherwise indicated.

Paragraph (n)(1) of the final rule

provides that this standard will become

effective on April 10, 1997. This date is

90 days from the date of publication in

the Federal Register. Proposed

paragraph (m)(1) had provided that the

final rule would become effective 60

days after publication in the Federal

Register. OSHA stated in the preamble

to the proposed rule [56 FR 57128] that

the proposed effective date, in

conjunction with the proposed start-up

dates, would allow sufficient time for

employers to achieve compliance with

the substantive requirements of the

proposed rule.

Although no commenters directly

addressed the 60-day period proposed

in paragraph (m)(1), several commenters

addressed the reasonableness of the

start-up dates in proposed paragraph

(m)(2). Those comments, discussed

below, indicated that some employers

would need more time to comply than

the proposed rule would have allowed.

The Agency sets the effective date to

allow sufficient time for employers to

obtain the standard, read and

understand its requirements, and

undertake the necessary planning and

preparation for compliance. Section

6(b)(4) of the OSHA Act provides that

the effective date of an OSHA standard

may be delayed for up to 90 days from

the date of publication in the Federal

Register. Given the concerns expressed

by commenters, OSHA’s interest in

having employers implement effective

compliance efforts, and the minimal

effect of the additional 30 day delay, the

Agency has decided that it is

appropriate to set the effective date at 90

days from publication, rather than at 60

days.

Paragraph (n)(2) of the final rule

establishes the start-up dates for

compliance with the provisions of the

MC standard. The start-up dates are

based on information in the record

about the state of the art with regard to

the types of provisions employers are

expected to implement, such as

available control measures, their

complexity, and the time that is

reasonably necessary to complete their

installation and implementation. In the

case of MC, the types of provisions

included in the rule, such as

requirements that will require

conventional controls, are identical to

the elements included in all OSHA

health standards.

Proposed paragraphs (m)(2)(i), (ii) and

(iii) required that initial monitoring be

completed by all employers within 120

days of the effective date of the MC

standard, engineering controls within

one year of the effective date and all

other requirements within 180 days of

the effective date. As described below,

OSHA received numerous comments on

the appropriateness of the start-up

dates, especially for small businesses.

Given the large number of small

employers covered by the requirements,

and the special problems of many of

those employers in identifying and

implementing appropriate control

measures, OSHA has decided to phasein compliance and to permit these

employers a longer time period in

which to comply with the requirements

of the standard. The schedule for

compliance with the provisions of the

standard are described below.

OSHA received a number of

comments on the proposed periods for

compliance with the control

requirements. In 1992, Kodak [Exs. 19–

18 and 19–102] described circumstances

at its film base production facility that

would prevent compliance with the

PELs through engineering controls

before mid-1995. Kodak stated ‘‘[it] is

essential that OSHA be responsive to

these considerations in promulgating

the final rule. OSHA should permit

adequate time for Kodak to implement

feasible engineering controls in an

orderly and minimally disruptive

schedule.’’ Considering the effective
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1599

date and start-up dates in this

regulation, OSHA has determined that

affected parties will have sufficient time

to comply with the standard.

Similar requests for longer time

periods for compliance were also

received from a variety of other

commenters [Exs. 19–55, 19–57, 19–67,

19–72, 19–75, 115–3, 115–28, 115–33,

115–37, Tr. 1422, 1427–29, 9/23/92, Tr.

2103, 10/14/92, Tr. 2291–92, 2300, 10/

15/92]. However, OSHA’s Final

Economic Analysis for this rulemaking

indicates that readily available control

measures can be used to control

exposure in many of the operations

where MC is present. In general,

compliance will not require the

development of new or novel control

technology. Accordingly, OSHA

believes that more extended time

periods for compliance are not

necessary for all affected industries.

However, as discussed below, small

businesses (for example, those with

fewer than 20 employees and

polyurethane foam manufacturers with

20 to 99 employees) have been granted

additional time to comply.

As discussed above in Section VIII,

several commenters [Exs. 19–14, 19–25,

19–28 and 19–29] stated that

engineering controls to achieve

compliance were not available. These

commenters further stated that the

development and implementation of the

process changes and engineering

controls needed to achieve compliance

would take four years from the effective

date, not the single year proposed. For

example, the Pharmaceutical

Manufacturers Association and Abbott

Laboratories [Exs. 19–25 and 19–29]

stated as follows:

[I]f the agency should rule that the

exposure level to MC be reduced to 25 ppm

for an 8-hour TWA and a 125 ppm STEL, a

minimum of 1 year from the effective date

must be allowed for identification of the

engineering controls. A minimum of 3 years

from the effective date must be allowed for

compliance with paragraph (f)(1) of the

proposed rule.

Those commenters and the HSIA [Ex.

19–45] also indicated that FDA approval

is needed in the pharmaceutical

industry for any alteration of

manufacturing processes, substitution

for MC, or modification of work

practices to achieve compliance with

OSHA’s MC standard, and requested

that OSHA consider the FDA’s

regulatory requirements when

establishing start-up dates. In particular,

Abbott Laboratories described how it

took three years to obtain FDA approval

for the substitution of hydroalcoholic or

aqueous solutions for MC in tablet

coating operations, stating ‘‘[p]resently,

completion of required testing and

obtaining FDA approval for production

of a single product can take 3 months

to three years, depending upon the

extent of the change.’’

Abbott also commented as follows

[Ex. 19–29]:

As stated previously, feasible engineering

controls do not exist for the present bulk

pharmaceutical centrifugal separation and

drying equipment. Implementation of

engineering controls would therefore require

the use of a different process or a different

production method. Changes of that degree

require Abbott Laboratories to complete

development work on an alternative process

and/or identify new production equipment;

erect a building to house the equipment;

purchase, receive and install the equipment;

train employees; and validate the process.

This cannot be accomplished in one year.

OSHA is aware that pharmaceutical

manufacturers must comply with other

regulatory requirements, including

those set by the FDA. The Agency has

considered how affected employers, in

general, need to coordinate their OSHA

compliance efforts with their other

regulatory compliance activities, that

this regulation does not require

implementation of particularly

complicated or novel control

technologies, and that the compliance

time frames are in keeping with those in

other OSHA standards. OSHA views the

coordination of OSHA compliance with

other regulatory compliance activities as

an ongoing employer effort, not just an

ad hoc response to a particular OSHA

action (such as the revision of a PEL).

For example, a pharmaceutical

manufacturer would need to consider

the implications for OSHA compliance

of process changes undertaken due to

FDA requirements or for other reasons,

whether those changes were to be made

during the MC standard’s ‘‘start-up’’

period or subsequently.

Accordingly, the Agency has

determined that the commenters have

not established a need for the requested

extension of the start-up dates. OSHA

believes that the proposed one-year

period in which to implement controls

will, in general, be adequate and,

therefore, has not made the suggested

change. However, as discussed

elsewhere, OSHA has tailored the

compliance schedule to the size of the

establishment and anticipated impact of

the standard on those businesses.

Dow [Ex. 19–31] also expressed

concern that many employers would be

unable to meet the start-up dates,

focusing on the time and resources that

would be required to conduct initial

monitoring. In addition, Dow stated as

follows ‘‘OSHA should require that

certain actions be completed within the

stated time periods and that if the

actions can not be completed, the

employer should have a written plan

and corresponding actions to show a

good faith effort to meet the

requirements.’’ OSHA agrees that there

may be circumstances where, despite

good faith efforts, employers cannot

achieve compliance within the time

periods specified by paragraph (n)(2).

OSHA further agrees that developing a

written plan and taking other ‘‘good

faith’’ actions towards compliance

would be appropriate measures to

mitigate any circumstances of noncompliance with the regulation. Indeed,

the suggested procedure closely

resembles the temporary variance

process already established by OSHA.

Under section 6(b)(6) of the OSH Act,

an employer can obtain a temporary

variance from compliance with an

OSHA standard if it shows that it cannot

achieve compliance by the effective

date; is taking all available steps to

safeguard its employees from the

pertinent hazard; and has an effective

program for coming into compliance

with the standard. The implementing

regulations for the temporary variance

process appear at 29 CFR part 1905.

Employers who experience difficulties

in meeting the start-up dates should

contact OSHA and apply for a

temporary variance.

The HSIA [Ex. 19–45] recommended

that OSHA ‘‘provide a compliance

schedule similar to that provided in the

generic PEL update * * * [which] in

some circumstances allows employers

until December 31, 1993 to comply (a

total of 4 years and 10 months).’’ In

addition to mentioning the lengthy FDA

approval process, the HSIA noted that

‘‘DCM users, particularly many of the

smaller companies, will find

compliance technologically and

economically difficult at best.’’

As stated above, OSHA believes that

the sort of extended compliance

schedule set through the generic PEL

update is unnecessary for the MC

standard. Based on its review of the

rulemaking record, the Agency has

reached the general conclusion that

employers will be able to achieve

compliance within the time frames

established in paragraph (n).

However, OSHA is concerned that

some small facilities affected by this

rulemaking, such as many of those in

the furniture refinishing industry and

the polyurethane foam manufacturing

industry, may have difficulties

determining the appropriate control

measures to use and also may not be

able to absorb the costs of compliance,

particularly those associated with

implementing the appropriate
1600 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

engineering controls within the time

frames initially proposed. The Agency

has estimated (see Section VIII,

Summary of the Final Economic

Analysis) that allowing a variable

schedule of compliance, based upon

size of establishment, will enable firms

in all impacted sectors to absorb many

of the compliance costs without

endangering their financial health.

Based on these considerations, OSHA

has determined that the following

implementation schedule is reasonable

and appropriate for businesses of all

sizes:

Establishment size Initial monitoring provisions must be

complied with within

Implementation of engineering controls must be completed within

All other provisions

must be complied

with within

Fewer than 20 employees ................... 300 days of the effective date ............ 3 years of the effective date ............... 1 year of the effective

date.

Polyurethane foam manufacturers with

20 to 99 employees.

210 days of the effective date ............ 2 years of the effective date ............... 270 days of the effective date.

All other employers .............................. 120 days of the effective date ............ 1 year of the effective date ................. 180 days of the effective date.

The Agency is promulgating

paragraph (n) accordingly.

The schedule of intermediate start-up

dates (210 d, 270 d and 2 years) for

polyurethane foam manufacturers with

20 to 99 employees was limited to this

application group because this group

has the highest potential economic

impacts except for the furniture

stripping and construction groups. In

both of the latter groups, most firms

have fewer than 20 employees, and thus

would already be allowed additional

time to comply with the final rule’s

start-up dates. In contrast, in the flexible

polyurethane foam manufacturing

group, even firms with fewer than 100

employees will need to install several

types of engineering controls and are

likely to have unusually high capital

expenditures in order to meet the

requirements of the regulation. This

extension of compliance deadlines will

allow those firms that need extensive

engineering controls time to adequately

plan for and implement their system of

controls. This modification will thus

also help to ensure adequate protection

for workers.

Paragraph (o) Appendices

The final paragraph of the standard

simply states that the appendices which

follow are not intended to create any

additional obligations beyond those

already specified in the standard. They

are basically intended as non-mandatory

guidance documents to supplement and

complement the regulatory

requirements in the standard, and to

provide additional information about

MC and its safe handling and use to

exposed employees, employers, and

health care professionals.

A few comments were received by

OSHA regarding the text of the

appendices as proposed. These

addressed the need for additional

information [Ex. 57, Tr. 832, 9/21/92,

Tr. 1380 and 1384–85, 9/23/92], or

whether information should appear in

an appendix or in the regulatory text

itself [see, e.g., Tr. 2435–36 and 2448–

49, 10/15/92]. OSHA has reviewed and

updated the text in the appendices to

address these comments and ensure that

they are consistent with the new

regulatory text in the final standard.

Also, proposed Non-mandatory

Appendix C, which addressed respirator

fit testing, has not been included in the

final rule, because OSHA has

determined that very few of the

respirators used to comply with this

standard will require fit testing. In

addition, OSHA’s revision of the generic

respirator standard (29 CFR 1910.134)

will contain an up-to-date appendix that

addresses fit testing for all respirators.

XI. Authority and Signature

This document was prepared under

the direction of Joseph A. Dear,

Assistant Secretary of Labor for

Occupational Safety and Health, U.S.

Department of Labor, 200 Constitution

Avenue, NW., Washington, DC 20210.

Pursuant to sections 4, 6(b), 8(c) and

8(g) of the Occupational Safety and

Health Act (29 U.S.C. 653, 655, 657),

section 107 of the Contract Work Hours

and Safety Standards Act (the

Construction Safety Act) (40 U.S.C.

333); the Longshore and Harbor

Workers’ Compensation Act (33 U.S.C.

941); the Secretary of Labor’s Order No.

1–90 (55 FR 9033); and 29 CFR part

1911; 29 CFR parts 1910, 1915 and 1926

are amended as set forth below.

List of Subjects in 29 CFR Part 1910,

1915 and 1926

Chemicals, Cancer, Health riskassessment, Methylene chloride,

Occupational safety and health.

Signed at Washington, D.C., this 31st day

of December 1996.

Joseph A. Dear,

Assistant Secretary of Labor.

XII. Final Standard Regulatory Text

Parts 1910, 1915, and 1926 of Title 29

of the Code of Federal Regulations are

amended as follows:

PART 1910—[AMENDED]

Subpart B—[Amended]

1. The authority citation for subpart B

of part 1910 continues to read as

follows:

Authority: Secs. 4, 6 and 8 of the

Occupational Safety and Health Act, 29

U.S.C. 653, 655, 657; Walsh-Healey Act, 29

U.S.C. 35 et seq; Service Contract Act of

1965, 41 U.S.C. 351 et seq; Contract Work

Hours and Safety Standards Act

(Construction Safety Act), 40 U.S.C. 333; Sec

41 Longshore and Harbor Worker’s

Compensation Act, 33 U.S.C. 941; National

Foundation on Arts and Humanities, 20

U.S.C. 951 et seq; Secretary of Labor’s Order

No, 12–71 (36 FR 8754); 8–76 (41 FR 25059);

9–83 (48 FR 35736); 1–90 (55 FR 9033); and

29 CFR part 1911.

2. By adding a new paragraph (m) to

§1910.19 to read as follows:

§ 1910.19 Special provisions for air

contaminants.

* * * * *

(m) Methylene Chloride (MC): Section

1910.1052 shall apply to the exposure of

every employee to MC in every

employment and place of employment

covered by §1910.16 in lieu of any

different standard on exposure to MC

which would otherwise be applicable by

virtue of that section when it is not

present in sealed, intact containers.

Subpart Z—[Amended]

3. The authority citation for subpart Z

of 29 CFR part 1910 continues to read,

in part, as follows:

Authority: Secs. 6 and 8 Occupational

Safety and Health Act, 29 U.S.C. 655, 657;

Secretary of Labor’s Orders 12–71 (36 FR

8754), 8–76 (41 FR 25059), 9–83 (48 FR

35736) or 1–90 (55 FR 9033), as applicable;

and 29 CFR part 1911.

* * * * *

§ 1910.1000 [Amended]

4. By removing the entire entry for

Methylene Chloride (Z37.23–1969) in

Table Z-2 of § 1910.1000 and adding the
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1601

following entry in its place in the

substance column: ‘‘Methylene chloride:

see § 1910.1052’’.

5. By adding a new § 1910.1052 to

read as follows:

§ 1910.1052 Methylene Chloride.

This occupational health standard

establishes requirements for employers

to control occupational exposure to

methylene chloride (MC). Employees

exposed to MC are at increased risk of

developing cancer, adverse effects on

the heart, central nervous system and

liver, and skin or eye irritation.

Exposure may occur through inhalation,

by absorption through the skin, or

through contact with the skin. MC is a

solvent which is used in many different

types of work activities, such as paint

stripping, polyurethane foam

manufacturing, and cleaning and

degreasing. Under the requirements of

paragraph (d) of this section, each

covered employer must make an initial

determination of each employee’s

exposure to MC. If the employer

determines that employees are exposed

below the action level, the only other

provisions of this section that apply are

that a record must be made of the

determination, the employees must

receive information and training under

paragraph (l) of this section and, where

appropriate, employees must be

protected from contact with liquid MC

under paragraph (h) of this section. The

provisions of the MC standard are as

follows:

(a) Scope and application. This

section applies to all occupational

exposures to methylene chloride (MC),

Chemical Abstracts Service Registry

Number 75–09–2, in general industry,

construction and shipyard employment.

(b) Definitions. For the purposes of

this section, the following definitions

shall apply:

Action level means a concentration of

airborne MC of 12.5 parts per million

(ppm) calculated as an eight (8)-hour

time-weighted average (TWA).

Assistant Secretary means the

Assistant Secretary of Labor for

Occupational Safety and Health, U.S.

Department of Labor, or designee.

Authorized person means any person

specifically authorized by the employer

and required by work duties to be

present in regulated areas, or any person

entering such an area as a designated

representative of employees for the

purpose of exercising the right to

observe monitoring and measuring

procedures under paragraph (d) of this

section, or any other person authorized

by the OSH Act or regulations issued

under the Act.

Director means the Director of the

National Institute for Occupational

Safety and Health, U.S. Department of

Health and Human Services, or

designee.

Emergency means any occurrence,

such as, but not limited to, equipment

failure, rupture of containers, or failure

of control equipment, which results, or

is likely to result in an uncontrolled

release of MC. If an incidental release of

MC can be controlled by employees

such as maintenance personnel at the

time of release and in accordance with

the leak/spill provisions required by

paragraph (f) of this section, it is not

considered an emergency as defined by

this standard.

Employee exposure means exposure

to airborne MC which occurs or would

occur if the employee were not using

respiratory protection.

Methylene chloride (MC) means an

organic compound with chemical

formula, CH2Cl2. Its Chemical Abstracts

Service Registry Number is 75–09–2. Its

molecular weight is 84.9 g/mole.

Physician or other licensed health

care professional is an individual whose

legally permitted scope of practice (i.e.,

license, registration, or certification)

allows him or her to independently

provide or be delegated the

responsibility to provide some or all of

the health care services required by

paragraph (j) of this section.

Regulated area means an area,

demarcated by the employer, where an

employee’s exposure to airborne

concentrations of MC exceeds or can

reasonably be expected to exceed either

the 8-hour TWA PEL or the STEL.

Symptom means central nervous

system effects such as headaches,

disorientation, dizziness, fatigue, and

decreased attention span; skin effects

such as chapping, erythema, cracked

skin, or skin burns; and cardiac effects

such as chest pain or shortness of

breath.

This section means this methylene

chloride standard.

(c) Permissible exposure limits (PELs).

(1) Eight-hour time-weighted average

(TWA) PEL. The employer shall ensure

that no employee is exposed to an

airborne concentration of MC in excess

of twenty-five parts of MC per million

parts of air (25 ppm) as an 8-hour TWA.

(2) Short-term exposure limit (STEL).

The employer shall ensure that no

employee is exposed to an airborne

concentration of MC in excess of one

hundred and twenty-five parts of MC

per million parts of air (125 ppm) as

determined over a sampling period of

fifteen minutes.

(d) Exposure monitoring. (1)

Characterization of employee exposure.

(i) Where MC is present in the

workplace, the employer shall

determine each employee’s exposure by

either:

(A) Taking a personal breathing zone

air sample of each employee’s exposure;

or

(B) Taking personal breathing zone air

samples that are representative of each

employee’s exposure.

(ii) Representative samples. The

employer may consider personal

breathing zone air samples to be

representative of employee exposures

when they are taken as follows:

(A) 8-hour TWA PEL. The employer

has taken one or more personal

breathing zone air samples for at least

one employee in each job classification

in a work area during every work shift,

and the employee sampled is expected

to have the highest MC exposure.

(B) Short-term exposure limits. The

employer has taken one or more

personal breathing zone air samples

which indicate the highest likely 15-

minute exposures during such

operations for at least one employee in

each job classification in the work area

during every work shift, and the

employee sampled is expected to have

the highest MC exposure.

(C) Exception. Personal breathing

zone air samples taken during one work

shift may be used to represent employee

exposures on other work shifts where

the employer can document that the

tasks performed and conditions in the

workplace are similar across shifts.

(iii) Accuracy of monitoring. The

employer shall ensure that the methods

used to perform exposure monitoring

produce results that are accurate to a

confidence level of 95 percent, and are:

(A) Within plus or minus 25 percent

for airborne concentrations of MC above

the 8-hour TWA PEL or the STEL; or

(B) Within plus or minus 35 percent

for airborne concentrations of MC at or

above the action level but at or below

the 8-hour TWA PEL.

(2) Initial determination. Each

employer whose employees are exposed

to MC shall perform initial exposure

monitoring to determine each affected

employee’s exposure, except under the

following conditions:

(i) Where objective data demonstrate

that MC cannot be released in the

workplace in airborne concentrations at

or above the action level or above the

STEL. The objective data shall represent

the highest MC exposures likely to

occur under reasonably foreseeable

conditions of processing, use, or

handling. The employer shall document

the objective data exemption as

specified in paragraph (m) of this

section;
1602 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

(ii) Where the employer has

performed exposure monitoring within

12 months prior to April 10, 1997 and

that exposure monitoring meets all other

requirements of this section, and was

conducted under conditions

substantially equivalent to existing

conditions; or

(iii) Where employees are exposed to

MC on fewer than 30 days per year (e.g.,

on a construction site), and the

employer has measurements by directreading instruments which give

immediate results (such as a detector

tube) and which provide sufficient

information regarding employee

exposures to determine what control

measures are necessary to reduce

exposures to acceptable levels.

(3) Periodic monitoring. Where the

initial determination shows employee

exposures at or above the action level or

above the STEL, the employer shall

establish an exposure monitoring

program for periodic monitoring of

employee exposure to MC in accordance

with Table 1:

Table 1.—SIX INITIAL DETERMINATION EXPOSURE SCENARIOS AND THEIR ASSOCIATED MONITORING FREQUENCIES

Exposure scenario Required monitoring activity

Below the action level and at or below the STEL .................................... No 8-hour TWA or STEL monitoring required.

Below the action level and above the STEL ............................................ No 8-hour TWA monitoring required; monitor STEL exposures every

three months.

At or above the action level, at or below the TWA, and at or below the

STEL.

Monitor 8-hour TWA exposures every six months.

At or above the action level, at or below the TWA, and above the STEL Monitor 8-hour TWA exposures every six months and monitor STEL

exposures every three months.

Above the TWA and at or below the STEL .............................................. Monitor 8-hour TWA exposures every three months.

Above the TWA and above the STEL ...................................................... Monitor 8-hour TWA exposures and STEL exposures every three

months.

[Note to paragraph (d)(3): The employer

may decrease the frequency of exposure

monitoring to every six months when at least

2 consecutive measurements taken at least 7

days apart show exposures to be at or below

the 8-hour TWA PEL. The employer may

discontinue the periodic 8-hour TWA

monitoring for employees where at least two

consecutive measurements taken at least 7

days apart are below the action level. The

employer may discontinue the periodic STEL

monitoring for employees where at least two

consecutive measurements taken at least 7

days apart are at or below the STEL.]

(4) Additional monitoring. (i) The

employer shall perform exposure

monitoring when a change in workplace

conditions indicates that employee

exposure may have increased. Examples

of situations that may require additional

monitoring include changes in

production, process, control equipment,

or work practices, or a leak, rupture, or

other breakdown.

(ii) Where exposure monitoring is

performed due to a spill, leak, rupture

or equipment breakdown, the employer

shall clean-up the MC and perform the

appropriate repairs before monitoring.

(5) Employee notification of

monitoring results. (i) The employer

shall, within 15 working days after the

receipt of the results of any monitoring

performed under this section, notify

each affected employee of these results

in writing, either individually or by

posting of results in an appropriate

location that is accessible to affected

employees.

(ii) Whenever monitoring results

indicate that employee exposure is

above the 8-hour TWA PEL or the STEL,

the employer shall describe in the

written notification the corrective action

being taken to reduce employee

exposure to or below the 8-hour TWA

PEL or STEL and the schedule for

completion of this action.

(6) Observation of monitoring. (i)

Employee observation. The employer

shall provide affected employees or

their designated representatives an

opportunity to observe any monitoring

of employee exposure to MC conducted

in accordance with this section.

(ii) Observation procedures. When

observation of the monitoring of

employee exposure to MC requires entry

into an area where the use of protective

clothing or equipment is required, the

employer shall provide, at no cost to the

observer(s), and the observer(s) shall be

required to use such clothing and

equipment and shall comply with all

other applicable safety and health

procedures.

(e) Regulated areas. (1) The employer

shall establish a regulated area wherever

an employee’s exposure to airborne

concentrations of MC exceeds or can

reasonably be expected to exceed either

the 8-hour TWA PEL or the STEL.

(2) The employer shall limit access to

regulated areas to authorized persons.

(3) The employer shall supply a

respirator, selected in accordance with

paragraph (h)(3) of this section, to each

person who enters a regulated area and

shall require each affected employee to

use that respirator whenever MC

exposures are likely to exceed the 8-

hour TWA PEL or STEL.

[Note to paragraph (e)(3): An employer

who has implemented all feasible

engineering, work practice and

administrative controls (as required in

paragraph (f) of this section), and who has

established a regulated area (as required by

paragraph (e)(1) of this section) where MC

exposure can be reliably predicted to exceed

the 8-hour TWA PEL or the STEL only on

certain days (for example, because of work or

process schedule) would need to have

affected employees use respirators in that

regulated area only on those days.]

(4) The employer shall ensure that,

within a regulated area, employees do

not engage in non-work activities which

may increase dermal or oral MC

exposure.

(5) The employer shall ensure that

while employees are wearing

respirators, they do not engage in

activities (such as taking medication or

chewing gum or tobacco) which

interfere with respirator seal or

performance.

(6) The employer shall demarcate

regulated areas from the rest of the

workplace in any manner that

adequately establishes and alerts

employees to the boundaries of the area

and minimizes the number of

authorized employees exposed to MC

within the regulated area.

(7) An employer at a multi-employer

worksite who establishes a regulated

area shall communicate the access

restrictions and locations of these areas

to all other employers with work

operations at that worksite.

(f) Methods of compliance. (1)

Engineering and work practice controls.

The employer shall institute and
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1603

maintain the effectiveness of

engineering controls and work practices

to reduce employee exposure to or

below the PELs except to the extent that

the employer can demonstrate that such

controls are not feasible. Wherever the

feasible engineering controls and work

practices which can be instituted are not

sufficient to reduce employee exposure

to or below the 8–TWA PEL or STEL,

the employer shall use them to reduce

employee exposure to the lowest levels

achievable by these controls and shall

supplement them by the use of

respiratory protection that complies

with the requirements of paragraph (g)

of this section.

(2) Prohibition of rotation. The

employer shall not implement a

schedule of employee rotation as a

means of compliance with the PELs.

(3) Leak and spill detection. (i) The

employer shall implement procedures to

detect leaks of MC in the workplace. In

work areas where spills may occur, the

employer shall make provisions to

contain any spills and to safely dispose

of any MC-contaminated waste

materials.

(ii) The employer shall ensure that all

incidental leaks are repaired and that

incidental spills are cleaned promptly

by employees who use the appropriate

personal protective equipment and are

trained in proper methods of cleanup.

[Note to paragraph (f)(3)(ii): See

Appendix A of this section for examples

of procedures that satisfy this

requirement. Employers covered by this

standard may also be subject to the

hazardous waste and emergency

response provisions contained in 29

CFR 1910.120 (q).]

(g) Respiratory protection. (1) General

requirements. The employer shall

provide a respirator which complies

with the requirement of this paragraph,

at no cost to each affected employee,

and ensure that each affected employee

uses such respirator where appropriate.

Respirators shall be used in the

following circumstances:

(i) Whenever an employee’s exposure

to MC exceeds or can reasonably be

expected to exceed the 8-hour TWA PEL

or the STEL (such as where an employee

is using MC in a regulated area);

(ii) During the time interval necessary

to install or implement feasible

engineering and work practice controls;

(iii) In a few work operations, such as

some maintenance operations and repair

activities, for which the employer

demonstrates that engineering and work

practice controls are infeasible;

(iv) Where feasible engineering and

work practice controls are not sufficient

to reduce exposures to or below the

PELs; or

(v) In emergencies.

(2) Medical Evaluation. Before having

any employee use a supplied-air

respirator in the negative pressure

mode, or a gas mask with organic vapor

canister for emergency escape, the

employer shall have a physician or

other licensed health care professional

ascertain each affected employee’s

ability to use such respiratory

protection. The physician or other

licensed health care professional shall

provide his or her findings to the

affected employee and the employer in

a written opinion.

(3) Respirator selection. The

appropriate atmosphere-supplying

respirators, as specified in Table 2, shall

be selected from those approved by the

National Institute for Occupational

Safety and Health (NIOSH) under the

provisions of 42 CFR Part 84,

‘‘Respiratory Protective Devices.’’ When

employers elect to provide gas masks

with organic vapor canisters for use in

emergency escape, the organic vapor

canisters shall bear the approval of

NIOSH.

TABLE 2.—MINIMUM REQUIREMENTS FOR RESPIRATORY PROTECTION FOR AIRBORNE METHYLENE CHLORIDE

Methylene chloride airborne concentration (ppm) or condition of use Minimum respirator required 1

Up to 625 ppm (25 X PEL) ....................................................................... (1) Continuous flow supplied-air respirator, hood or helmet.

Up to 1250 ppm (50 X 8–TWA PEL) ....................................................... (1) Full facepiece supplied-air respirator operated in negative pressure

(demand) mode.

(2) Full facepiece self-contained breathing apparatus (SCBA) operated

in negative pressure (demand) mode.

Up to 5000 ppm (200 X 8–TWA PEL) ..................................................... (1) Continuous flow supplied-air respirator, full facepiece.

(2) Pressure demand supplied-air respirator, full facepiece.

(3) Positive pressure full facepiece SCBA.

Unknown concentration, or above 5000 ppm (Greater than 200 X 8–

TWA PEL).

(1) Positive pressure full facepiece SCBA.

(2) Full facepiece pressure demand supplied-air respirator with an auxiliary self-contained air supply.

Fire fighting ............................................................................................... Positive pressure full facepiece SCBA.

Emergency escape ................................................................................... (1) Any continuous flow or pressure demand SCBA.

(2) Gas mask with organic vapor canister.

1 Respirators assigned for higher airborne concentrations may be used at lower concentrations.

(4) Respirator program. Where

respiratory protection is required by this

section, the employer shall institute a

respirator program in accordance with

29 CFR 1910.134.

(5) Permission to leave area. The

employer shall permit employees who

wear respirators to leave the regulated

area to readjust the facepieces to their

faces to achieve a proper fit, and to

wash their faces and respirator

facepieces as necessary in order to

prevent skin irritation associated with

respirator use.

(6) Filter respirators. Employers who

provide gas masks with organic vapor

canisters for the purpose of emergency

escape shall replace those canisters after

any emergency use before those gas

masks are returned to service.

(7) Respirator fit testing. (i) The

employer shall ensure that each

respirator issued to the employee is

properly fitted and exhibits the least

possible facepiece leakage from among

the facepieces tested.

(ii) The employer shall perform

qualitative or quantitative fit tests at the

time of initial fitting and at least

annually thereafter for each employee

wearing a negative pressure respirator,

including those employees for whom

emergency escape respirators are

provided.

[Note to paragraph (g)(7)(ii): The only

supplied-air respirators to which this

provision would apply are SCBA in negative

pressure mode and full facepiece suppliedair respirators operated in negative pressure

mode. The small business compliance guides

will contain examples of protocols for

qualitative and quantitative fit testing.]

(h) Protective Work Clothing and

Equipment. (1) Where needed to prevent
1604 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

MC-induced skin or eye irritation, the

employer shall provide clean protective

clothing and equipment which is

resistant to MC, at no cost to the

employee, and shall ensure that each

affected employee uses it. Eye and face

protection shall meet the requirements

of 29 CFR 1910.133 or 29 CFR 1915.153,

as applicable.

(2) The employer shall clean, launder,

repair and replace all protective

clothing and equipment required by this

paragraph as needed to maintain their

effectiveness.

(3) The employer shall be responsible

for the safe disposal of such clothing

and equipment. [Note to paragraph

(h)(4): See Appendix A for examples of

disposal procedures that will satisfy this

requirement.]

(i) Hygiene facilities. (1) If it is

reasonably foreseeable that employees’

skin may contact solutions containing

0.1 percent or greater MC (for example,

through splashes, spills or improper

work practices), the employer shall

provide conveniently located washing

facilities capable of removing the MC,

and shall ensure that affected employees

use these facilities as needed.

(2) If it is reasonably foreseeable that

an employee’s eyes may contact

solutions containing 0.1 percent or

greater MC (for example through

splashes, spills or improper work

practices), the employer shall provide

appropriate eyewash facilities within

the immediate work area for emergency

use, and shall ensure that affected

employees use those facilities when

necessary.

(j) Medical surveillance. (1) Affected

employees. The employer shall make

medical surveillance available for

employees who are or may be exposed

to MC as follows:

(i) At or above the action level on 30

or more days per year, or above the 8-

hour TWA PEL or the STEL on 10 or

more days per year;

(ii) Above the 8–TWA PEL or STEL

for any time period where an employee

has been identified by a physician or

other licensed health care professional

as being at risk from cardiac disease or

from some other serious MC-related

health condition and such employee

requests inclusion in the medical

surveillance program;

(iii) During an emergency.

(2) Costs. The employer shall provide

all required medical surveillance at no

cost to affected employees, without loss

of pay and at a reasonable time and

place.

(3) Medical personnel. The employer

shall ensure that all medical

surveillance procedures are performed

by a physician or other licensed health

care professional, as defined in

paragraph (b) of this section.

(4) Frequency of medical surveillance.

The employer shall make medical

surveillance available to each affected

employee as follows:

(i) Initial surveillance. The employer

shall provide initial medical

surveillance under the schedule

provided by paragraph (n)(2)(iii) of this

section, or before the time of initial

assignment of the employee, whichever

is later. The employer need not provide

the initial surveillance if medical

records show that an affected employee

has been provided with medical

surveillance that complies with this

section within 12 months before April

10, 1997.

(ii) Periodic medical surveillance. The

employer shall update the medical and

work history for each affected employee

annually. The employer shall provide

periodic physical examinations,

including appropriate laboratory

surveillance, as follows:

(A) For employees 45 years of age or

older, within 12 months of the initial

surveillance or any subsequent medical

surveillance; and

(B) For employees younger than 45

years of age, within 36 months of the

initial surveillance or any subsequent

medical surveillance.

(iii) Termination of employment or

reassignment. When an employee leaves

the employer’s workplace, or is

reassigned to an area where exposure to

MC is consistently at or below the

action level and STEL, medical

surveillance shall be made available if

six months or more have elapsed since

the last medical surveillance.

(iv) Additional surveillance. The

employer shall provide additional

medical surveillance at frequencies

other than those listed above when

recommended in the written medical

opinion. (For example, the physician or

other licensed health care professional

may determine an examination is

warranted in less than 36 months for

employees younger than 45 years of age

based upon evaluation of the results of

the annual medical and work history.)

(5) Content of medical surveillance. (i)

Medical and work history. The

comprehensive medical and work

history shall emphasize neurological

symptoms, skin conditions, history of

hematologic or liver disease, signs or

symptoms suggestive of heart disease

(angina, coronary artery disease), risk

factors for cardiac disease, MC

exposures, and work practices and

personal protective equipment used

during such exposures. [Note to

paragraph (j)(5)(i): See Appendix B of

this section for an example of a medical

and work history format that would

satisfy this requirement.]

(ii) Physical examination. Where

physical examinations are provided as

required above, the physician or other

licensed health care professional shall

accord particular attention to the lungs,

cardiovascular system (including blood

pressure and pulse), liver, nervous

system, and skin. The physician or other

licensed health care professional shall

determine the extent and nature of the

physical examination based on the

health status of the employee and

analysis of the medical and work

history.

(iii) Laboratory surveillance. The

physician or other licensed health care

professional shall determine the extent

of any required laboratory surveillance

based on the employee’s observed

health status and the medical and work

history. [Note to paragraph (j)(5)(iii):

See Appendix B of this section for

information regarding medical tests.

Laboratory surveillance may include

before- and after-shift

carboxyhemoglobin determinations,

resting ECG, hematocrit, liver function

tests and cholesterol levels.]

(iv) Other information or reports. The

medical surveillance shall also include

any other information or reports the

physician or other licensed health care

professional determines are necessary to

assess the employee’s health in relation

to MC exposure.

(6) Content of emergency medical

surveillance. The employer shall ensure

that medical surveillance made

available when an employee has been

exposed to MC in emergency situations

includes, at a minimum:

(i) Appropriate emergency treatment

and decontamination of the exposed

employee;

(ii) Comprehensive physical

examination with special emphasis on

the nervous system, cardiovascular

system, lungs, liver and skin, including

blood pressure and pulse;

(iii) Updated medical and work

history, as appropriate for the medical

condition of the employee; and

(iv) Laboratory surveillance, as

indicated by the employee’s health

status. [Note to paragraph (j)(6)(iv): See

Appendix B for examples of tests which

may be appropriate.]

(7) Additional examinations and

referrals. Where the physician or other

licensed health care professional

determines it is necessary, the scope of

the medical examination shall be

expanded and the appropriate

additional medical surveillance, such as

referrals for consultation or

examination, shall be provided.
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1605

(8) Information provided to the

physician or other licensed health care

professional. The employer shall

provide the following information to a

physician or other licensed health care

professional who is involved in the

diagnosis of MC-induced health effects:

(i) A copy of this section including its

applicable appendices;

(ii) A description of the affected

employee’s past, current and anticipated

future duties as they relate to the

employee’s MC exposure;

(iii) The employee’s former or current

exposure levels or, for employees not

yet occupationally exposed to MC, the

employee’s anticipated exposure levels

and the frequency and exposure levels

anticipated to be associated with

emergencies;

(iv) A description of any personal

protective equipment, such as

respirators, used or to be used; and

(v) Information from previous

employment-related medical

surveillance of the affected employee

which is not otherwise available to the

physician or other licensed health care

professional.

(9) Written medical opinions. (i) For

each physical examination required by

this section, the employer shall ensure

that the physician or other licensed

health care professional provides to the

employer and to the affected employee

a written opinion regarding the results

of that examination within 15 days of

completion of the evaluation of medical

and laboratory findings, but not more

than 30 days after the examination. The

written medical opinion shall be limited

to the following information:

(A) The physician’s or other licensed

health care professional’s opinion

concerning whether the employee has

any detected medical condition(s)

which would place the employee’s

health at increased risk of material

impairment from exposure to MC;

(B) Any recommended limitations

upon the employee’s exposure to MC or

upon the employee’s use of protective

clothing or equipment and respirators;

(C) A statement that the employee has

been informed by the physician or other

licensed health care professional that

MC is a potential occupational

carcinogen, of risk factors for heart

disease, and the potential for

exacerbation of underlying heart disease

by exposure to MC through its

metabolism to carbon monoxide; and

(D) A statement that the employee has

been informed by the physician or other

licensed health care professional of the

results of the medical examination and

any medical conditions resulting from

MC exposure which require further

explanation or treatment.

(ii) The employer shall instruct the

physician or other licensed health care

professional not to reveal to the

employer, orally or in the written

opinion, any specific records, findings,

and diagnoses that have no bearing on

occupational exposure to MC. [Note to

paragraph (j)(9)(ii): The written medical

opinion may also include information

and opinions generated to comply with

other OSHA health standards.]

(k) Hazard communication. The

employer shall communicate the

following hazards associated with MC

on labels and in material safety data

sheets in accordance with the

requirements of the Hazard

Communication Standard, 29 CFR

1910.1200, 29 CFR 1915.1200, or 29

CFR 1926.59, as appropiate: cancer,

cardiac effects (including elevation of

carboxyhemoglobin), central nervous

system effects, liver effects, and skin

and eye irritation.

(l) Employee information and

training. (1) The employer shall provide

information and training for each

affected employee prior to or at the time

of initial assignment to a job involving

potential exposure to MC.

(2) The employer shall ensure that

information and training is presented in

a manner that is understandable to the

employees.

(3) In addition to the information

required under the Hazard

Communication Standard at 29 CFR

1910.1200, 29 CFR 1915.1200, or 29

CFR 1926.59, as appropiate:

(i) The employer shall inform each

affected employee of the requirements

of this section and information available

in its appendices, as well as how to

access or obtain a copy of it in the

workplace;

(ii) Wherever an employee’s exposure

to airborne concentrations of MC

exceeds or can reasonably be expected

to exceed the action level, the employer

shall inform each affected employee of

the quantity, location, manner of use,

release, and storage of MC and the

specific operations in the workplace

that could result in exposure to MC,

particularly noting where exposures

may be above the 8-hour TWA PEL or

STEL;

(4) The employer shall train each

affected employee as required under the

Hazard Communication standard at 29

CFR 1910.1200, 29 CFR 1915.1200, or

29 CFR 1926.59, as appropiate.

(5) The employer shall re-train each

affected employee as necessary to

ensure that each employee exposed

above the action level or the STEL

maintains the requisite understanding of

the principles of safe use and handling

of MC in the workplace.

(6) Whenever there are workplace

changes, such as modifications of tasks

or procedures or the institution of new

tasks or procedures, which increase

employee exposure, and where those

exposures exceed or can reasonably be

expected to exceed the action level, the

employer shall update the training as

necessary to ensure that each affected

employee has the requisite proficiency.

(7) An employer whose employees are

exposed to MC at a multi-employer

worksite shall notify the other

employers with work operations at that

site in accordance with the

requirements of the Hazard

Communication Standard, 29 CFR

1910.1200, 29 CFR 1915.1200, or 29

CFR 1926.59, as appropiate.

(8) The employer shall provide to the

Assistant Secretary or the Director, upon

request, all available materials relating

to employee information and training.

(m) Recordkeeping. (1) Objective data.

(i) Where an employer seeks to

demonstrate that initial monitoring is

unnecessary through reasonable reliance

on objective data showing that any

materials in the workplace containing

MC will not release MC at levels which

exceed the action level or the STEL

under foreseeable conditions of

exposure, the employer shall establish

and maintain an accurate record of the

objective data relied upon in support of

the exemption.

(ii) This record shall include at least

the following information:

(A) The MC-containing material in

question;

(B) The source of the objective data;

(C) The testing protocol, results of

testing, and/or analysis of the material

for the release of MC;

(D) A description of the operation

exempted under paragraph (d)(2)(i) of

this section and how the data support

the exemption; and

(E) Other data relevant to the

operations, materials, processing, or

employee exposures covered by the

exemption.

(iii) The employer shall maintain this

record for the duration of the employer’s

reliance upon such objective data.

(2) Exposure measurements. (i) The

employer shall establish and keep an

accurate record of all measurements

taken to monitor employee exposure to

MC as prescribed in paragraph (d) of

this section.

(ii) Where the employer has 20 or

more employees, this record shall

include at least the following

information:

(A) The date of measurement for each

sample taken;

(B) The operation involving exposure

to MC which is being monitored;
1606 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

(C) Sampling and analytical methods

used and evidence of their accuracy;

(D) Number, duration, and results of

samples taken;

(E) Type of personal protective

equipment, such as respiratory

protective devices, worn, if any; and

(F) Name, social security number, job

classification and exposure of all of the

employees represented by monitoring,

indicating which employees were

actually monitored.

(iii) Where the employer has fewer

than 20 employees, the record shall

include at least the following

information:

(A) The date of measurement for each

sample taken;

(B) Number, duration, and results of

samples taken; and

(C) Name, social security number, job

classification and exposure of all of the

employees represented by monitoring,

indicating which employees were

actually monitored.

(iv) The employer shall maintain this

record for at least thirty (30) years, in

accordance with 29 CFR 1910.1020.

(3) Medical surveillance. (i) The

employer shall establish and maintain

an accurate record for each employee

subject to medical surveillance under

paragraph (j) of this section.

(ii) The record shall include at least

the following information:

(A) The name, social security number

and description of the duties of the

employee;

(B) Written medical opinions; and

(C) Any employee medical conditions

related to exposure to MC.

(iii) The employer shall ensure that

this record is maintained for the

duration of employment plus thirty (30)

years, in accordance with 29 CFR

1910.1020.

(4) Availability. (i) The employer,

upon written request, shall make all

records required to be maintained by

this section available to the Assistant

Secretary and the Director for

examination and copying in accordance

with 29 CFR 1910.1020. [Note to

paragraph (m)(4)(i): All records

required to be maintained by this

section may be kept in the most

administratively convenient form (for

example, electronic or computer records

would satisfy this requirement).]

(ii) The employer, upon request, shall

make any employee exposure and

objective data records required by this

section available for examination and

copying by affected employees, former

employees, and designated

representatives in accordance with 29

CFR 1910.1020.

(iii) The employer, upon request, shall

make employee medical records

required to be kept by this section

available for examination and copying

by the subject employee and by anyone

having the specific written consent of

the subject employee in accordance

with 29 CFR 1910.1020.

(5) Transfer of records. The employer

shall comply with the requirements

concerning transfer of records set forth

in 29 CFR 1910.1020(h).

(n) Dates. (1) Effective date. This

section shall become effective April 10,

1997.

(2) Start-up dates.

(i) Initial monitoring required by

paragraph (d)(2) of this section shall be

completed according to the following

schedule:

(A) For employers with fewer than 20

employees, within 300 days after the

effective date of this section.

(B) For polyurethane foam

manufacturers with 20 to 99 employees,

within 210 days after the effective date

of this section.

(C) For all other employers, within

120 days after the effective date of this

section.

(ii) Engineering controls required

under paragraph (f)(1) of this section

shall be implemented according to the

following schedule:

(A) For employers with fewer than 20

employees, within three (3) years after

the effective date of this section.

(B) For polyurethane foam

manufacturers with 20 to 99 employees,

within two (2) years after the effective

date of this section.

(C) For all other employers, within

one (1) year after the effective date of

this section.

(iii) All other requirements of this

section shall be complied with

according to the following schedule:

(A) For employers with fewer than 20

employees, within one (1) year after the

effective date of this section.

(B) For polyurethane foam

manufacturers with 20 to 99 employees,

within 270 days after the effective date

of this section.

(C) For all other employers, within

180 days after the effective date of this

section.

(3) Transitional dates. The exposure

limits for MC specified in 29 CFR

1910.1000 (1996), Table Z-2, shall

remain in effect until the start-up dates

for the exposure limits specified in

paragraph (n) of this section, or if the

exposure limits in this section are

stayed or vacated.

(o) Appendices. The information

contained in the appendices does not,

by itself, create any additional

obligations not otherwise imposed or

detract from any existing obligation.

Appendix A to Section 1910.1052:

Substance Safety Data Sheet and

Technical Guidelines for Methylene

Chloride

I. Substance Identification

A. Substance: Methylene chloride (CH2Cl2).

B. Synonyms: MC, Dichloromethane

(DCM); Methylene dichloride; Methylene

bichloride; Methane dichloride; CAS: 75–09–

2; NCI–C50102.

C. Physical data:

1. Molecular weight: 84.9.

2. Boiling point (760 mm Hg): 39.8°C

(104°F).

3. Specific gravity (water=1): 1.3.

4. Vapor density (air=1 at boiling point):

2.9.

5. Vapor pressure at 20° C (68° F): 350 mm

Hg.

6. Solubility in water, g/100 g water at 20°

C (68° F)=1.32.

7. Appearance and odor: colorless liquid

with a chloroform-like odor.

D. Uses:

MC is used as a solvent, especially where

high volatility is required. It is a good solvent

for oils, fats, waxes, resins, bitumen, rubber

and cellulose acetate and is a useful paint

stripper and degreaser. It is used in paint

removers, in propellant mixtures for aerosol

containers, as a solvent for plastics, as a

degreasing agent, as an extracting agent in the

pharmaceutical industry and as a blowing

agent in polyurethane foams. Its solvent

property is sometimes increased by mixing

with methanol, petroleum naphtha or

tetrachloroethylene.

E. Appearance and odor:

MC is a clear colorless liquid with a

chloroform-like odor. It is slightly soluble in

water and completely miscible with most

organic solvents.

F. Permissible exposure:

Exposure may not exceed 25 parts MC per

million parts of air (25 ppm) as an eight-hour

time-weighted average (8-hour TWA PEL) or

125 parts of MC per million parts of air (125

ppm) averaged over a 15-minute period

(STEL).

II. Health Hazard Data

A. MC can affect the body if it is inhaled

or if the liquid comes in contact with the

eyes or skin. It can also affect the body if it

is swallowed.

B. Effects of overexposure:

1. Short-term Exposure:

MC is an anesthetic. Inhaling the vapor

may cause mental confusion, lightheadedness, nausea, vomiting, and headache.

Continued exposure may cause increased

light-headedness, staggering,

unconsciousness, and even death. High vapor

concentrations may also cause irritation of

the eyes and respiratory tract. Exposure to

MC may make the symptoms of angina (chest

pains) worse. Skin exposure to liquid MC

may cause irritation. If liquid MC remains on

the skin, it may cause skin burns. Splashes

of the liquid into the eyes may cause

irritation.

2. Long-term (chronic) exposure:

The best evidence that MC causes cancer

is from laboratory studies in which rats, mice

and hamsters inhaled MC 6 hours per day,
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1607

5 days per week for 2 years. MC exposure

produced lung and liver tumors in mice and

mammary tumors in rats. No carcinogenic

effects of MC were found in hamsters.

There are also some human

epidemiological studies which show an

association between occupational exposure

to MC and increases in biliary (bile duct)

cancer and a type of brain cancer. Other

epidemiological studies have not observed a

relationship between MC exposure and

cancer. OSHA interprets these results to

mean that there is suggestive (but not

absolute) evidence that MC is a human

carcinogen.

C. Reporting signs and symptoms:

You should inform your employer if you

develop any signs or symptoms and suspect

that they are caused by exposure to MC.

D. Warning Properties:

1. Odor Threshold:

Different authors have reported varying

odor thresholds for MC. Kirk-Othmer and Sax

both reported 25 to 50 ppm; Summer and

May both reported 150 ppm; Spector reports

320 ppm. Patty, however, states that since

one can become adapted to the odor, MC

should not be considered to have adequate

warning properties.

2. Eye Irritation Level:

Kirk-Othmer reports that ‘‘MC vapor is

seriously damaging to the eyes.’’ Sax agrees

with Kirk-Othmer’s statement. The ACGIH

Documentation of TLVs states that irritation

of the eyes has been observed in workers

exposed to concentrations up to 5000 ppm.

3. Evaluation of Warning Properties:

Since a wide range of MC odor thresholds

are reported (25–320 ppm), and human

adaptation to the odor occurs, MC is

considered to be a material with poor

warning properties.

III. Emergency First Aid Procedures

In the event of emergency, institute first

aid procedures and send for first aid or

medical assistance.

A. Eye and Skin Exposures:

If there is a potential for liquid MC to come

in contact with eye or skin, face shields and

skin protective equipment must be provided

and used. If liquid MC comes in contact with

the eye, get medical attention. Contact lenses

should not be worn when working with this

chemical.

B. Breathing:

If a person breathes in large amounts of

MC, move the exposed person to fresh air at

once. If breathing has stopped, perform

cardiopulmorary resuscitation. Keep the

affected person warm and at rest. Get medical

attention as soon as possible.

C. Rescue:

Move the affected person from the

hazardous exposure immediately. If the

exposed person has been overcome, notify

someone else and put into effect the

established emergency rescue procedures.

Understand the facility’s emergency rescue

procedures and know the locations of rescue

equipment before the need arises. Do not

become a casualty yourself.

IV. Respirators, Protective Clothing, and Eye

Protection

A. Respirators:

Good industrial hygiene practices

recommend that engineering controls be used

to reduce environmental concentrations to

the permissible exposure level. However,

there are some exceptions where respirators

may be used to control exposure. Respirators

may be used when engineering and work

practice controls are not feasible, when such

controls are in the process of being installed,

or when these controls fail and need to be

supplemented. Respirators may also be used

for operations which require entry into tanks

or closed vessels, and in emergency

situations.

If the use of respirators is necessary, the

only respirators permitted are those that have

been approved by the Mine Safety and Health

Administration (MSHA) or the National

Institute for Occupational Safety and Health

(NIOSH). Supplied-air respirators are

required because air-purifying respirators do

not provide adequate respiratory protection

against MC.

In addition to respirator selection, a

complete written respiratory protection

program should be instituted which includes

regular training, maintenance, inspection,

cleaning, and evaluation. If you can smell

MC while wearing a respirator, proceed

immediately to fresh air. If you experience

difficulty in breathing while wearing a

respirator, tell your employer.

B. Protective Clothing:

Employees must be provided with and

required to use impervious clothing, gloves,

face shields (eight-inch minimum), and other

appropriate protective clothing necessary to

prevent repeated or prolonged skin contact

with liquid MC or contact with vessels

containing liquid MC. Any clothing which

becomes wet with liquid MC should be

removed immediately and not reworn until

the employer has ensured that the protective

clothing is fit for reuse. Contaminated

protective clothing should be placed in a

regulated area designated by the employer for

removal of MC before the clothing is

laundered or disposed of. Clothing and

equipment should remain in the regulated

area until all of the MC contamination has

evaporated; clothing and equipment should

then be laundered or disposed of as

appropriate.

C. Eye Protection:

Employees should be provided with and

required to use splash-proof safety goggles

where liquid MC may contact the eyes.

V. Housekeeping and Hygiene Facilities

For purposes of complying with 29 CFR

1910.141, the following items should be

emphasized:

A. The workplace should be kept clean,

orderly, and in a sanitary condition. The

employer should institute a leak and spill

detection program for operations involving

liquid MC in order to detect sources of

fugitive MC emissions.

B. Emergency drench showers and

eyewash facilities are recommended. These

should be maintained in a sanitary condition.

Suitable cleansing agents should also be

provided to assure the effective removal of

MC from the skin.

C. Because of the hazardous nature of MC,

contaminated protective clothing should be

placed in a regulated area designated by the

employer for removal of MC before the

clothing is laundered or disposed of.

VI. Precautions for Safe Use, Handling, and

Storage

A. Fire and Explosion Hazards:

MC has no flash point in a conventional

closed tester, but it forms flammable vaporair mixtures at approximately 100°C (212°F),

or higher. It has a lower explosion limit of

12%, and an upper explosion limit of 19%

in air. It has an autoignition temperature of

556.1°C (1033°F), and a boiling point of

39.8°C (104°F). It is heavier than water with

a specific gravity of 1.3. It is slightly soluble

in water.

B. Reactivity Hazards:

Conditions contributing to the instability of

MC are heat and moisture. Contact with

strong oxidizers, caustics, and chemically

active metals such as aluminum or

magnesium powder, sodium and potassium

may cause fires and explosions.

Special precautions: Liquid MC will attack

some forms of plastics, rubber, and coatings.

C. Toxicity:

Liquid MC is painful and irritating if

splashed in the eyes or if confined on the

skin by gloves, clothing, or shoes. Vapors in

high concentrations may cause narcosis and

death. Prolonged exposure to vapors may

cause cancer or exacerbate cardiac disease.

D. Storage:

Protect against physical damage. Because

of its corrosive properties, and its high vapor

pressure, MC should be stored in plain,

galvanized or lead lined, mild steel

containers in a cool, dry, well ventilated area

away from direct sunlight, heat source and

acute fire hazards.

E. Piping Material:

All piping and valves at the loading or

unloading station should be of material that

is resistant to MC and should be carefully

inspected prior to connection to the transport

vehicle and periodically during the

operation.

F. Usual Shipping Containers:

Glass bottles, 5- and 55-gallon steel drums,

tank cars, and tank trucks.

Note: This section addresses MC exposure

in marine terminal and longshore

employment only where leaking or broken

packages allow MC exposure that is not

addressed through compliance with 29 CFR

parts 1917 and 1918, respectively.

G. Electrical Equipment:

Electrical installations in Class I hazardous

locations as defined in Article 500 of the

National Electrical Code, should be installed

according to Article 501 of the code; and

electrical equipment should be suitable for

use in atmospheres containing MC vapors.

See Flammable and Combustible Liquids

Code (NFPA No. 325M), Chemical Safety

Data Sheet SD–86 (Manufacturing Chemists’

Association, Inc.).

H. Fire Fighting:

When involved in fire, MC emits highly

toxic and irritating fumes such as phosgene,

hydrogen chloride and carbon monoxide.

Wear breathing apparatus and use water

spray to keep fire-exposed containers cool.

Water spray may be used to flush spills away

from exposures. Extinguishing media are dry
1608 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

chemical, carbon dioxide, foam. For purposes

of compliance with 29 CFR 1910.307,

locations classified as hazardous due to the

presence of MC shall be Class I.

I. Spills and Leaks:

Persons not wearing protective equipment

and clothing should be restricted from areas

of spills or leaks until cleanup has been

completed. If MC has spilled or leaked, the

following steps should be taken:

1. Remove all ignition sources.

2. Ventilate area of spill or leak.

3. Collect for reclamation or absorb in

vermiculite, dry sand, earth, or a similar

material.

J. Methods of Waste Disposal:

Small spills should be absorbed onto sand

and taken to a safe area for atmospheric

evaporation. Incineration is the preferred

method for disposal of large quantities by

mixing with a combustible solvent and

spraying into an incinerator equipped with

acid scrubbers to remove hydrogen chloride

gases formed. Complete combustion will

convert carbon monoxide to carbon dioxide.

Care should be taken for the presence of

phosgene.

K. You should not keep food, beverage, or

smoking materials, or eat or smoke in

regulated areas where MC concentrations are

above the permissible exposure limits.

L. Portable heating units should not be

used in confined areas where MC is used.

M. Ask your supervisor where MC is used

in your work area and for any additional

plant safety and health rules.

VII. Medical Requirements

Your employer is required to offer you the

opportunity to participate in a medical

surveillance program if you are exposed to

MC at concentrations at or above the action

level (12.5 ppm 8-hour TWA) for more than

30 days a year or at concentrations exceeding

the PELs (25 ppm 8-hour TWA or 125 ppm

15-minute STEL) for more than 10 days a

year. If you are exposed to MC at

concentrations over either of the PELs, your

employer will also be required to have a

physician or other licensed health care

professional ensure that you are able to wear

the respirator that you are assigned. Your

employer must provide all medical

examinations relating to your MC exposure at

a reasonable time and place and at no cost

to you.

VIII. Monitoring and Measurement

Procedures

A. Exposure above the Permissible

Exposure Limit:

1. Eight-hour exposure evaluation:

Measurements taken for the purpose of

determining employee exposure under this

section are best taken with consecutive

samples covering the full shift. Air samples

must be taken in the employee’s breathing

zone.

2. Monitoring techniques: The sampling

and analysis under this section may be

performed by collection of the MC vapor on

two charcoal adsorption tubes in series or

other composition adsorption tubes, with

subsequent chemical analysis. Sampling and

analysis may also be performed by

instruments such as real-time continuous

monitoring systems, portable direct reading

instruments, or passive dosimeters as long as

measurements taken using these methods

accurately evaluate the concentration of MC

in employees’’ breathing zones.

OSHA method 80 is an example of a

validated method of sampling and analysis of

MC. Copies of this method are available from

OSHA or can be downloaded from the

Internet at http://www.osha.gov. The

employer has the obligation of selecting a

monitoring method which meets the

accuracy and precision requirements of the

standard under his or her unique field

conditions. The standard requires that the

method of monitoring must be accurate, to a

95 percent confidence level, to plus or minus

25 percent for concentrations of MC at or

above 25 ppm, and to plus or minus 35

percent for concentrations at or below 25

ppm. In addition to OSHA method 80, there

are numerous other methods available for

monitoring for MC in the workplace.

B. Since many of the duties relating to

employee exposure are dependent on the

results of measurement procedures,

employers must assure that the evaluation of

employee exposure is performed by a

technically qualified person.

IX. Observation of Monitoring

Your employer is required to perform

measurements that are representative of your

exposure to MC and you or your designated

representative are entitled to observe the

monitoring procedure. You are entitled to

observe the steps taken in the measurement

procedure, and to record the results obtained.

When the monitoring procedure is taking

place in an area where respirators or personal

protective clothing and equipment are

required to be worn, you or your

representative must also be provided with,

and must wear, protective clothing and

equipment.

X. Access To Information

A. Your employer is required to inform you

of the information contained in this

Appendix. In addition, your employer must

instruct you in the proper work practices for

using MC, emergency procedures, and the

correct use of protective equipment.

B. Your employer is required to determine

whether you are being exposed to MC. You

or your representative has the right to

observe employee measurements and to

record the results obtained. Your employer is

required to inform you of your exposure. If

your employer determines that you are being

over exposed, he or she is required to inform

you of the actions which are being taken to

reduce your exposure to within permissible

exposure limits.

C. Your employer is required to keep

records of your exposures and medical

examinations. These records must be kept by

the employer for at least thirty (30) years.

D. Your employer is required to release

your exposure and medical records to you or

your representative upon your request.

E. Your employee is required to provide

labels and material safety data sheets (MSDS)

for all materials, mixtures or solutions

composed of greater than 0.1 percent MC. An

example of a label that would satisfy these

requirements would be:

Danger Contains Methylene Chloride

Potential Cancer Hazard

May worsen heart disease because

methylene chloride is converted to carbon

monoxide in the body.

May cause dizziness, headache, irritation

of the throat and lungs, loss of consciousness

and death at high concentrations (for

example, if used in a poorly ventilated room).

Avoid Skin Contact. Contact with liquid

causes skin and eye irritation.

XI. Common Operations and Controls

The following list includes some common

operations in which exposure to MC may

occur and control methods which may be

effective in each case:

Operations Controls

Use as solvent in

paint and varnish

removers; manufacture of aerosols;

cold cleaning and

ultrasonic cleaning;

and as a solvent in

furniture stripping.

General dilution ventilation; local exhaust ventilation;

personal protective

equipment; substitution.

Use as solvent in

vapor degreasing.

Process enclosure;

local exhaust ventilation; chilling

coils; substitution.

Use as a secondary

refrigerant in air

conditioning and

scientific testing.

General dilution ventilation; local exhaust ventilation;

personal protective

equipment.

Appendix B to Section 1910.1052:

Medical Surveillance for Methylene

Chloride

I. Primary Route of Entry

Inhalation.

II. Toxicology

Methylene Chloride (MC) is primarily an

inhalation hazard. The principal acute

hazardous effects are the depressant action

on the central nervous system, possible

cardiac toxicity and possible liver toxicity.

The range of CNS effects are from decreased

eye/hand coordination and decreased

performance in vigilance tasks to narcosis

and even death of individuals exposed at

very high doses. Cardiac toxicity is due to the

metabolism of MC to carbon monoxide, and

the effects of carbon monoxide on heart

tissue. Carbon monoxide displaces oxygen in

the blood, decreases the oxygen available to

heart tissue, increasing the risk of damage to

the heart, which may result in heart attacks

in susceptible individuals. Susceptible

individuals include persons with heart

disease and those with risk factors for heart

disease.

Elevated liver enzymes and irritation to the

respiratory passages and eyes have also been

reported for both humans and experimental

animals exposed to MC vapors.

MC is metabolized to carbon monoxide and

carbon dioxide via two separate pathways.

Through the first pathway, MC is

metabolized to carbon monoxide as an endproduct via the P–450 mixed function

oxidase pathway located in the microsomal
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1609

fraction of the cell. This biotransformation of

MC to carbon monoxide occurs through the

process of microsomal oxidative

dechlorination which takes place primarily

in the liver. The amount of conversion to

carbon monoxide is significant as measured

by the concentration of carboxyhemoglobin,

up to 12% measured in the blood following

occupational exposure of up to 610 ppm.

Through the second pathway, MC is

metabolized to carbon dioxide as an end

product (with formaldehyde and formic acid

as metabolic intermediates) via the

glutathione dependent enzyme found in the

cytosolic fraction of the liver cell.

Metabolites along this pathway are believed

to be associated with the carcinogenic

activity of MC.

MC has been tested for carcinogenicity in

several laboratory rodents. These rodent

studies indicate that there is clear evidence

that MC is carcinogenic to male and female

mice and female rats. Based on

epidemiologic studies, OSHA has concluded

that there is suggestive evidence of increased

cancer risk in MC-related worker

populations. The epidemiological evidence is

consistent with the finding of excess cancer

in the experimental animal studies. NIOSH

regards MC as a potential occupational

carcinogen and the International Agency for

Research Cancer (IARC) classifies MC as an

animal carcinogen. OSHA considers MC as a

suspected human carcinogen.

III. Medical Signs and Symptoms of Acute

Exposure

Skin exposure to liquid MC may cause

irritation or skin burns. Liquid MC can also

be irritating to the eyes. MC is also absorbed

through the skin and may contribute to the

MC exposure by inhalation.

At high concentrations in air, MC may

cause nausea, vomiting, light-headedness,

numbness of the extremities, changes in

blood enzyme levels, and breathing

problems, leading to bronchitis and

pulmonary edema, unconsciousness and

even death.

At lower concentrations in air, MC may

cause irritation to the skin, eye, and

respiratory tract and occasionally headache

and nausea. Perhaps the greatest problem

from exposure to low concentrations of MC

is the CNS effects on coordination and

alertness that may cause unsafe operations of

machinery and equipment, leading to selfinjury or accidents.

Low levels and short duration exposures

do not seem to produce permanent disability,

but chronic exposures to MC have been

demonstrated to produce liver toxicity in

animals, and therefore, the evidence is

suggestive for liver toxicity in humans after

chronic exposure.

Chronic exposure to MC may also cause

cancer.

IV. Surveillance and Preventive

Considerations

As discussed above, MC is classified as a

suspect or potential human carcinogen. It is

a central nervous system (CNS) depressant

and a skin, eye and respiratory tract irritant.

At extremely high concentrations, MC has

caused liver damage in animals.

MC principally affects the CNS, where it

acts as a narcotic. The observation of the

symptoms characteristic of CNS depression,

along with a physical examination, provides

the best detection of early neurological

disorders. Since exposure to MC also

increases the carboxyhemoglobin level in the

blood, ambient carbon monoxide levels

would have an additive effect on that

carboxyhemoglobin level. Based on such

information, a periodic post-shift

carboxyhemoglobin test as an index of the

presence of carbon monoxide in the blood is

recommended, but not required, for medical

surveillance.

Based on the animal evidence and three

epidemiologic studies previously mentioned,

OSHA concludes that MC is a suspect human

carcinogen. The medical surveillance

program is designed to observe exposed

workers on a regular basis. While the medical

surveillance program cannot detect MCinduced cancer at a preneoplastic stage,

OSHA anticipates that, as in the past, early

detection and treatments of cancers leading

to enhanced survival rates will continue to

evolve.

A. Medical and Occupational History:

The medical and occupational work

history plays an important role in the initial

evaluation of workers exposed to MC. It is

therefore extremely important for the

examining physician or other licensed health

care professional to evaluate the MC-exposed

worker carefully and completely and to focus

the examination on MC’s potentially

associated health hazards. The medical

evaluation must include an annual detailed

work and medical history with special

emphasis on cardiac history and neurological

symptoms.

An important goal of the medical history

is to elicit information from the worker

regarding potential signs or symptoms

associated with increased levels of

carboxyhemoglobin due to the presence of

carbon monoxide in the blood. Physicians or

other licensed health care professionals

should ensure that the smoking history of all

MC exposed employees is known. Exposure

to MC may cause a significant increase in

carboxyhemoglobin level in all exposed

persons. However, smokers as well as

workers with anemia or heart disease and

those concurrently exposed to carbon

monoxide are at especially high risk of toxic

effects because of an already reduced oxygen

carrying capacity of the blood.

A comprehensive or interim medical and

work history should also include occurrence

of headache, dizziness, fatigue, chest pain,

shortness of breath, pain in the limbs, and

irritation of the skin and eyes.

In addition, it is important for the

physician or other licensed health care

professional to become familiar with the

operating conditions in which exposure to

MC is likely to occur. The physician or other

licensed health care professional also must

become familiar with the signs and

symptoms that may indicate that a worker is

receiving otherwise unrecognized and

exceptionally high exposure levels of MC.

An example of a medical and work history

that would satisfy the requirement for a

comprehensive or interim work history is

represented by the following:

The following is a list of recommended

questions and issues for the self-administered

questionnaire for methylene chloride

exposure.

Questionnaire For Methylene Chloride

Exposure

I. Demographic Information

1. Name

2. Social Security Number

3. Date

4. Date of Birth

5. Age

6. Present occupation

7. Sex

8. Race

II. Occupational History

1. Have you ever worked with methylene

chloride, dichloromethane, methylene

dichloride, or CH2Cl2 (all are different names

for the same chemical)? Please list which on

the occupational history form if you have not

already.

2. If you have worked in any of the

following industries and have not listed them

on the occupational history form, please do

so.

Furniture stripping

Polyurethane foam manufacturing

Chemical manufacturing or formulation

Pharmaceutical manufacturing

Any industry in which you used solvents to

clean and degrease equipment or parts

Construction, especially painting and

refinishing

Aerosol manufacturing

Any industry in which you used aerosol

adhesives

3. If you have not listed hobbies or

household projects on the occupational

history form, especially furniture refinishing,

spray painting, or paint stripping, please do

so.

III. Medical History

A. General

1. Do you consider yourself to be in good

health? If no, state reason(s).

2. Do you or have you ever had:

a. Persistent thirst

b. Frequent urination (three times or more

at night)

c. Dermatitis or irritated skin

d. Non-healing wounds

3. What prescription or non-prescription

medications do you take, and for what

reasons?

4. Are you allergic to any medications, and

what type of reaction do you have?

B. Respiratory

1. Do you have or have you ever had any

chest illnesses or diseases? Explain.

2. Do you have or have you ever had any

of the following:

a. Asthma

b. Wheezing

c. Shortness of breath

3. Have you ever had an abnormal chest Xray? If so, when, where, and what were the

findings?

4. Have you ever had difficulty using a

respirator or breathing apparatus? Explain.

5. Do any chest or lung diseases run in

your family? Explain.
1610 Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations

6. Have you ever smoked cigarettes, cigars,

or a pipe? Age started:

7. Do you now smoke?

8. If you have stopped smoking completely,

how old were you when you stopped?

9. On the average of the entire time you

smoked, how many packs of cigarettes,

cigars, or bowls of tobacco did you smoke per

day?

C. Cardiovascular

1. Have you ever been diagnosed with any

of the following: Which of the following

apply to you now or did apply to you at some

time in the past, even if the problem is

controlled by medication? Please explain any

yes answers (i.e., when problem was

diagnosed, length of time on medication).

a. High cholesterol or triglyceride level

b. Hypertension (high blood pressure)

c. Diabetes

d. Family history of heart attack, stroke, or

blocked arteries

2. Have you ever had chest pain? If so,

answer the next five questions.

a. What was the quality of the pain (i.e.,

crushing, stabbing, squeezing)?

b. Did the pain go anywhere (i.e., into jaw,

left arm)?

c. What brought the pain out?

d. How long did it last?

e. What made the pain go away?

3. Have you ever had heart disease, a heart

attack, stroke, aneurysm, or blocked arteries

anywhere in you body? Explain (when,

treatment).

4. Have you ever had bypass surgery for

blocked arteries in your heart or anywhere

else? Explain.

5. Have you ever had any other procedures

done to open up a blocked artery (balloon

angioplasty, carotid endarterectomy, clotdissolving drug)?

6. Do you have or have you ever had

(explain each):

a. Heart murmur

b. Irregular heartbeat

c. Shortness of breath while lying flat

d. Congestive heart failure

e. Ankle swelling

f. Recurrent pain anywhere below the waist

while walking

7. Have you ever had an electrocardiogram

(EKG)? When?

8. Have you ever had an abnormal EKG? If

so, when, where, and what were the

findings?

9. Do any heart diseases, high blood

pressure, diabetes, high cholesterol, or high

triglycerides run in your family? Explain.

D. Hepatobiliary and Pancreas

1. Do you now or have you ever drunk

alcoholic beverages? Age started: llll

Age stopped: llll.

2. Average numbers per week:

a. Beers: llll, ounces in usual container:

b. Glasses of wine: llll, ounces per

glass:

c. Drinks: llll, ounces in usual

container:

3. Do you have or have you ever had

(explain each):

a. Hepatitis (infectious, autoimmune, druginduced, or chemical)

b. Jaundice

c. Elevated liver enzymes or elevated

bilirubin

d. Liver disease or cancer

E. Central Nervous System

1. Do you or have you ever had (explain

each):

a. Headache

b. Dizziness

c. Fainting

d. Loss of consciousness

e. Garbled speech

f. Lack of balance

g. Mental/psychiatric illness

h. Forgetfulness

F. Hematologic

1. Do you have, or have you ever had

(explain each):

a. Anemia

b. Sickle cell disease or trait

c. Glucose-6-phosphate dehydrogenase

deficiency

d. Bleeding tendency disorder

2. If not already mentioned previously,

have you ever had a reaction to sulfa drugs

or to drugs used to prevent or treat malaria?

What was the drug? Describe the reaction.

B. Physical Examination

The complete physical examination, when

coupled with the medical and occupational

history, assists the physician or other

licensed health care professional in detecting

pre-existing conditions that might place the

employee at increased risk, and establishes a

baseline for future health monitoring. These

examinations should include:

1. Clinical impressions of the nervous

system, cardiovascular function and

pulmonary function, with additional tests

conducted where indicated or determined by

the examining physician or other licensed

health care professional to be necessary.

2. An evaluation of the advisability of the

worker using a respirator, because the use of

certain respirators places an additional

burden on the cardiopulmonary system. It is

necessary for the attending physician or other

licensed health care professional to evaluate

the cardiopulmonary function of these

workers, in order to inform the employer in

a written medical opinion of the worker’s

ability or fitness to work in an area requiring

the use of certain types of respiratory

protective equipment. The presence of facial

hair or scars that might interfere with the

worker’s ability to wear certain types of

respirators should also be noted during the

examination and in the written medical

opinion.

Because of the importance of lung function

to workers required to wear certain types of

respirators to protect themselves from MC

exposure, these workers must receive an

assessment of pulmonary function before

they begin to wear a negative pressure

respirator and at least annually thereafter.

The recommended pulmonary function tests

include measurement of the employee’s

forced vital capacity (FVC), forced expiratory

volume at one second (FEV1), as well as

calculation of the ratios of FEV1 to FVC, and

the ratios of measured FVC and measured

FEV1 to expected respective values corrected

for variation due to age, sex, race, and height.

Pulmonary function evaluation must be

conducted by a physician or other licensed

health care professional experienced in

pulmonary function tests.

The following is a summary of the

elements of a physical exam which would

fulfill the requirements under the MC

standard:

Physical Exam

I. Skin and appendages

1. Irritated or broken skin

2. Jaundice

3. Clubbing cyanosis, edema

4. Capillary refill time

5. Pallor

II. Head

1. Facial deformities

2. Scars

3. Hair growth

III. Eyes

1. Scleral icterus

2. Corneal arcus

3. Pupillary size and response

4. Fundoscopic exam

IV. Chest

1. Standard exam

V. Heart

1. Standard exam

2. Jugular vein distension

3. Peripheral pulses

VI. Abdomen

1. Liver span

VII. Nervous System

1. Complete standard neurologic exam

VIII. Laboratory

1. Hemoglobin and hematocrit

2. Alanine aminotransferase (ALT, SGPT)

3. Post-shift carboxyhemoglobin

IX. Studies

1. Pulmonary function testing

2. Electrocardiogram

An evaluation of the oxygen carrying

capacity of the blood of employees (for

example by measured red blood cell volume)

is considered useful, especially for workers

acutely exposed to MC.

It is also recommended, but not required,

that end of shift carboxyhemoglobin levels be

determined periodically, and any level above

3% for non-smokers and above 10% for

smokers should prompt an investigation of

the worker and his workplace. This test is

recommended because MC is metabolized to

CO, which combines strongly with

hemoglobin, resulting in a reduced capacity

of the blood to transport oxygen in the body.

This is of particular concern for cigarette

smokers because they already have a

diminished hemoglobin capacity due to the

presence of CO in cigarette smoke.

C. Additional Examinations and Referrals

1. Examination by a Specialist

When a worker examination reveals

unexplained symptoms or signs (i.e. in the

physical examination or in the laboratory

tests), follow-up medical examinations are

necessary to assure that MC exposure is not
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules and Regulations 1611

adversely affecting the worker’s health. When

the examining physician or other licensed

health care professional finds it necessary,

additional tests should be included to

determine the nature of the medical problem

and the underlying cause. Where relevant,

the worker should be sent to a specialist for

further testing and treatment as deemed

necessary.

The final rule requires additional

investigations to be covered and it also

permits physicians or other licensed health

care professionals to add appropriate or

necessary tests to improve the diagnosis of

disease should such tests become available in

the future.

2. Emergencies

The examination of workers exposed to MC

in an emergency should be directed at the

organ systems most likely to be affected. If

the worker has received a severe acute

exposure, hospitalization may be required to

assure proper medical intervention. It is not

possible to precisely define ‘‘severe,’’ but the

physician or other licensed health care

professional’s judgement should not merely

rest on hospitalization. If the worker has

suffered significant conjunctival, oral, or

nasal irritation, respiratory distress, or

discomfort, the physician or other licensed

health care professional should instigate

appropriate follow-up procedures. These

include attention to the eyes, lungs and the

neurological system. The frequency of

follow-up examinations should be

determined by the attending physician or

other licensed health care professional. This

testing permits the early identification

essential to proper medical management of

such workers.

D. Employer Obligations

The employer is required to provide the

responsible physician or other licensed

health care professional and any specialists

involved in a diagnosis with the following

information: a copy of the MC standard

including relevant appendices, a description

of the affected employee’s duties as they

relate to his or her exposure to MC; an

estimate of the employee’s exposure

including duration (e.g., 15hr/wk, three 8-

hour shifts/wk, full time); a description of

any personal protective equipment used by

the employee, including respirators; and the

results of any previous medical

determinations for the affected employee

related to MC exposure to the extent that this

information is within the employer’s control.

E. Physicians’ or Other Licensed Health Care

Professionals’ Obligations

The standard requires the employer to

ensure that the physician or other licensed

health care professional provides a written

statement to the employee and the employer.

This statement should contain the

physician’s or licensed health care

professional’s opinion as to whether the

employee has any medical condition placing

him or her at increased risk of impaired

health from exposure to MC or use of

respirators, as appropriate. The physician or

other licensed health care professional

should also state his or her opinion regarding

any restrictions that should be placed on the

employee’s exposure to MC or upon the use

of protective clothing or equipment such as

respirators. If the employee wears a respirator

as a result of his or her exposure to MC, the

physician or other licensed health care

professional’s opinion should also contain a

statement regarding the suitability of the

employee to wear the type of respirator

assigned. Furthermore, the employee should

be informed by the physician or other

licensed health care professional about the

cancer risk of MC and about risk factors for

heart disease, and the potential for

exacerbation of underlying heart disease by

exposure to MC through its metabolism to

carbon monoxide. Finally, the physician or

other licensed health care professional

should inform the employer that the

employee has been told the results of the

medical examination and of any medical

conditions which require further explanation

or treatment. This written opinion must not

contain any information on specific findings

or diagnosis unrelated to employee’s

occupational exposures.

The purpose in requiring the examining

physician or other licensed health care

professional to supply the employer with a

written opinion is to provide the employer

with a medical basis to assist the employer

in placing employees initially, in assuring

that their health is not being impaired by

exposure to MC, and to assess the employee’s

ability to use any required protective

equipment.

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BILLING CODE 4510–26–C
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PART 1915—[AMENDED]

6. The authority citation for 29 CFR

part 1915 continues to read as follows:

Authority: Sec. 41, Longshore and Harbor

Workers Compensation Act (33 U.S.C. 941);

secs. 4, 6, 8, Occupational Safety and Health

Act of 1970 (29 U.S.C. 653, 655, 657);

Secretary of Labor’s Order No. 12–71 (36 FR

8754), 8–76 (41 FR 25059), 9–83 (48 FR

35736) or 1–90 (55 FR 9033), as applicable;

29 CFR part 1911.

7. In Table Z of section 1915.1000, Air

Contaminants, the entire entry for

methylene chloride is removed and

replaced with the following entry added

in the substance column: ‘‘Methylene

chloride: see § 1910.1052’’.

8. Subpart Z of part 1915 is amended

by adding § 1915.1052, as follows:

§ 1915.1052 Methylene chloride.

Note: The requirements applicable to

shipyard employment under this section are

identical to those set forth at 29 CFR

1910.1052.

PART 1926—[AMENDED]

Subpart D—[Amended]

9. The authority citation for subpart D

of part 1926 continues to read as

follows:

Authority: Sec. 107, Contract Work Hours

and Safety Standards Act (40 U.S.C. 333),

secs. 4, 6, and 8, Occupational Safety and

Health Act of 1970 (29 U.S.C. 653, 655, 657);

Secretary of Labor’s Orders No. 12–71 (36 FR

8754), 8–76 (41 FR 25059), 9–83 (48 FR

35736), or 1–90 (55 FR 9033), as applicable.

10. In Appendix A of section 1926.55,

Gases, vapors, fumes, dusts and mists,

the entire entry for methylene chloride

is removed and replaced by the

following entry added in the substance

column: ‘‘Methylene chloride: see

§ 1910.1052’’.

Subpart Z—[Amended]

11. The authority citation for subpart

Z of part 1926 continues to read as

follows:

Authority: Secs. 6 and 8, Occupational

Safety and Health Act (29 U.S.C. 655, 657);

section 41, Secretary of Labor’s Orders Nos.

12–71 (36 FR 8754), 8–76 (41 FR 25059), 9–

83 (48 FR 35736), or 1–90 (55 FR 9033), as

applicable; and 29 CFR part 1911.

12. Subpart Z of part 1926 is amended

by adding § 1926.1152, as follows:

§ 1926.1152 Methylene chloride.

Note: The requirements applicable to

construction employment under this section

are identical to those set forth at 29 CFR

1910.1052.

[FR Doc. 97–198 Filed 1–9–97; 8:45 am]

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