Indoor Air Quality; Proposed Rule DEPARTMENT OF LABOR

SUMMARY: By this notice, the Occupational Safety and Health

Administration (OSHA) proposes to adopt standards addressing indoor air

quality in indoor work environments. The basis for this proposed action

is a preliminary determination that employees working in indoor work

environments face a significant risk of material impairment to their

health due to poor indoor air quality, and that compliance with the

provisions proposed in this notice will substantially reduce that risk.

The provisions of the standard are proposed to apply to all indoor

``nonindustrial work environments.'' In addition, all worksites, both

industrial and nonindustrial within OSHA's jurisdiction are covered

with respect to the proposed provisions addressing control of

environmental tobacco smoke. The proposal would require affected

employers to develop a written indoor air quality compliance plan and

implement that plan through actions such as inspection and maintenance

of building systems which influence indoor air quality.

Provisions under the standard also propose to require employers to

implement controls for specific contaminants and their sources such as

outdoor air contaminants, microbial contamination, maintenance and

cleaning chemicals, pesticides, and other hazardous chemicals within

indoor work environments. Designated smoking areas which are to be

separate, enclosed rooms exhausted directly to the outside are proposed

to be required in buildings where the smoking of tobacco products is

not prohibited. Specific provisions are also proposed to limit the

degradation of indoor air quality during the performance of renovation,

remodeling and similar activities. Provisions for information and

training of building system maintenance and operation workers and other

employees within the facility are also included in this notice.

Finally, proposed provisions in this notice address the

establishment, retention, availability, and transfer of records such as

inspection and maintenance records, records of written compliance

programs, and employee complaints of building-related illness.

The Agency invites the submission of written data, views and

comments on all regulatory provisions proposed in this notice, and on

all relevant issues pertinent to those provisions. OSHA is also

scheduling an informal public hearing where persons may orally submit

their views. It is noted here that subsequent Federal Register notices

may be published subsequent to this notice, if the public presents

views leading to a substantial change in focus or it is otherwise

determined to be appropriate.

DATES: Comments on the proposed standard must be postmarked by June 29,

1994. Notices of intention to appear must be postmarked by June 20,

1994. Testimony and evidence to be submitted at the hearing must be

postmarked by July 5, 1994. The hearing will commence at 9:30 a.m. on

July 12, 1994.

ADDRESSES: Comments are to be submitted in quadruplicate or 1 original

(hardcopy) and 1 disk (5\1/4\ or 3\1/2\) in WP 5.0, 5.1, 6.0 or Ascii

to: The Docket Office, Docket No. H-122, Room N-2625, U.S. Department

of Labor, 200 Constitution Avenue, NW., Washington, DC 20210, Telephone

No. (202) 219-7894. (Any information not contained on disk, e.g.,

studies, articles, etc., must be submitted in quadruplicate.)

Notices of intention to appear and testimony and evidence are to be

submitted in quadruplicate to: Mr. Tom Hall, Division of Consumer

Affairs, Occupational Safety and Health Administration, 200

Constitution Avenue, NW., room N3649, Washington, DC 20210; (202) 219-

8615.

The hearing will be held in the auditorium of the U.S. Department

of Labor, 200 Constitution Avenue, NW., Washington, DC.

FOR FURTHER INFORMATION CONTACT: Proposal: Mr. James F. Foster,

Director of Information and Consumer Affairs, Occupational Safety and

Health Administration, 200 Constitution Avenue, NW., room N3641,

Washington, DC 20210; (202) 219-8151.

Informal Hearing Information: Mr. Tom Hall, Division of Consumer

Affairs, Occupational Safety and Health Administration, 200

Constitution Avenue, NW., room N3649, Washington, DC 20210; (202) 219-

8615.

Table of Contents

I. Supplementary Information

A. Events Leading to This Action

II. Health Effects

A. Sick Building Syndrome

B. Building-Related Illness

1. Indoor Air Contaminants

2. Microbial Contaminants

C. Environmental Tobacco Smoke

1. Pharmacokinetics

(a) Absorption and Distribution

(b) Metabolism

2. Irritation

3. Pulmonary Effects

4. Cardiovascular Effects

(a) Thrombus Formation

(b) Vascular Wall Injury

(c) Possible Mechanisms of Effect

(d) Acute Heart Effects

(e) Chronic Heart Effects

5. Reproductive Effects

6. Cancer

(a) Evidence of Association

(b) Epidemiological and Experimental Studies

7. Genotoxicity

8. Conclusions

D. Case Reports

1. Sick Building Syndrome and Building-Related Illness

2. Environmental Tobacco Smoke

III. Exposure

A. Sources of Indoor Air Contaminants

B. Microbial Contamination

C. Exposure Studies

1. Low-level Contaminants

2. Bioaerosols

3. Environmental Tobacco Smoke

(a) Chemistry

(b) Human Activity Pattern Studies Used to Assess Workplace

Exposure

(c) Indoor Levels of Environmental Tobacco Smoke Constituents

(d) Levels of Respirable Suspended Particulates and Nicotine

Found in Field Studies

(e) Biomarkers of Environmental Tobacco Smoke Exposure

(f) Inadequacy of General Dilution Ventilation to Address

Environmental Tobacco Smoke Exposure Control

IV. Preliminary Quantitative Risk Assessment

A. Introduction

B. Review of Epidemiologic Studies and Published Risk Estimates

C. Data Sources

D. OSHA's Estimates of Risk-Environmental Tobacco Smoke Exposure

E. OSHA's Risk Estimates--Indoor Air Quality

F. Pharmacokinetic Modeling of Environmental Tobacco Smoke

Exposure

1. Considerations for Selection of a Biomarker for Environmental

Tobacco Smoke

2. Cardiovascular Effects

3. Carcinogenicity

4. Evaluation of Cotinine as a Biomarker for Environmental

Tobacco Smoke

5. Description of Pharmacokinetic Models for Nicotine and

Cotinine

6. Application of Pharmacokinetic Modeling for Environmental

Tobacco Smoke Exposure Estimation

7. Analysis of Uncertainty

(a) Physiological Parameters

(b) Distribution Parameters

(c) Kinetic Parameters

V. Significance of Risk

A. Environmental Tobacco Smoke

B. Indoor Air Quality

VI. Preliminary Regulatory Impact Analysis

A. Introduction

B. Industry Profile

1. Affected Industries

2. Indoor Contaminants-Sources

3. Controlling Indoor Air

4. Building Characteristics

5. Profile of Affected Buildings

6. Buildings with Indoor Air Problems

7. Number of Employees Affected

8. Environmental Tobacco Smoke

(a) Smoking Ordinances and Policies

(b) Number of Nonsmokers Working Indoors

C. Nonregulatory Alternatives

1. Introduction

2. Market Imperfections

3. Alternative Nonregulatory Options

(a) Tort Liability

(b) Workers' Compensation

4. Conclusion

D. Benefits

1. Indoor Air Quality

2. Environmental Tobacco Smoke

3. Cost Savings

(a) Worker Productivity

(b) Property Damage, Maintenance and Cleaning Costs

E. Technological Feasibility and Compliance Costs

1. Technological Feasibility

2. Compliance Costs

(a) Developing Indoor Air Quality Compliance Programs

(b) Indoor Air Quality Operation and Maintenance Program

(c) Training for HVAC Maintenance Workers and Informing

Employees About the Indoor Air Quality Standard

(d) Compliance with Related Standards

(e) Air Contaminant-Tobacco Smoke

(f) Air Quality During Renovation and Remodeling

F. Economic Impact and Regulatory Flexibility Analysis

1. Economic Feasibility

2. Regulatory Flexibility Analysis

3. Environmental Impact

VII. Summary and Explanation

A. Scope and Application: Paragraph (a)

B. Definitions: Paragraph (b)

C. Indoor Air Quality Compliance Program: Paragraph (c)

D. Compliance Program Implementation: Paragraph (d)

E. Controls for Specific Contaminant Sources: Paragraph (e)

F. Air Quality During Renovation and Remodeling: Paragraph (f)

G. Employee Information and Training: Paragraph (g)

H. Recordkeeping: Paragraph (h)

I. Dates: Paragraph (i)

J. Appendices: Paragraph (j)

K. Specific Issues

VIII. State-Plan Standards

IX. Federalism

X. Information Collection Requirements

XI. Public Participation

XII. List of Subjects in 29 CFR Parts 1910, 1915, 1926, and 1928

XIII. Authority and Signature

XIV. Part 1910, 1915, 1926, 1928--Proposed Occupational Safety and

Health Standards

Supplementary Information

A. Events Leading to This Action

Concern about the health hazards posed by occupational exposure to

environmental tobacco smoke (ETS) prompted three public interest groups

to petition the Agency in May 1987 for an Emergency Temporary Standard

under section 6(c) of the Occupational Safety and Health (OSH) Act, 29

U.S.C. 655(c). The American Public Health Association and Public

Citizen submitted a joint petition; Action on Smoking and Health (ASH)

also submitted a petition. The petitions requested the prohibition of

smoking in most indoor workplaces.

OSHA determined, that available data with respect to exposures were

insufficient to demonstrate the existence of a ``grave danger,'' within

the meaning of section 6(c) of the OSH Act, from workplace exposure to

ETS. OSHA denied the petitions in September 1989 but continued to

investigate regulatory options.

In October 1989 ASH filed suit in the U.S. Court of Appeals for the

District of Columbia Circuit for review of OSHA's denial of its

petition for an Emergency Temporary Standard. The court denied ASH's

petition for review in May 1991, finding that OSHA has reasonably

determined that it could not sufficiently quantify the workplace risk

associated with tobacco smoke to justify an Emergency Temporary

Standard.

OSHA issued on September 20, 1991, a Request for Information (RFI)

(56 FR 47892) on indoor air quality problems, in order to obtain

information necessary to determine whether it would be appropriate and

feasible to pursue regulatory action concerning Indoor Air Quality

(IAQ). Issues on which comments were requested in the RFI included

health effects attributable to poor IAQ, ventilation systems

performance, exposure assessment, and abatement methods. Information

concerning specific contaminants such as ETS and bioaerosols was also

requested.

In March 1992, the AFL-CIO petitioned OSHA to promulgate an overall

IAQ standard. OSHA responded in May 1992 that such a standard was under

consideration.

In response to the RFI, over 1,200 comments were submitted by

interested persons, groups, unions, and industries. Issues of

particular concern identified in the comments, in addition to health

effects considerations, include the lack of ventilation performance

standards; the lack of worker training on the operation and maintenance

of Heating Ventilation and Air Conditioning (HVAC) systems; the lack of

pollutant source control; and the lack of available technical guidance

on IAQ issues and control techniques.

Of the comments that specifically addressed the question of whether

OSHA should regulate IAQ, a majority (75%) indicate support for

regulation. Of those that commented on the need for regulation,

approximately 21% were explicitly in favor of a regulation on ETS, more

than 41% were in favor of an overall IAQ regulation, and approximately

13% were in favor of a combined IAQ regulation.

Numerous comments focused on the adverse health effects of tobacco

smoke and of general indoor air pollution. The health effects of

concern relevant to both tobacco smoke and indoor air pollutants ranged

from the acute irritant effects to cancer.

Comments submitted in response to the RFI indicated wide support

for a regulatory approach that would focus on the design, operation and

maintenance of building ventilation systems, source reduction

methodology, and worker information and training programs. Commenters

also recommended that provisions should require that employers receive

training about the regulation and the need for compliance, and that

their training regarding building HVAC maintenance and operation be

tailored to the level of complexity of the HVAC system and their

personal degree of involvement.

Many commenters particularly felt that regulation of IAQ was

necessary to eliminate exposures to ETS in the workplace. Commenters

urged the Agency to either ban smoking completely from the workplace or

allow smoking only in separately ventilated, designated smoking areas

that were separate from work areas.

OSHA believes that data submitted to the record, and other

evidence, support the conclusion that air contaminants and other air

quality factors can act to present a significant risk of material

impairment to employees working in indoor environments. Adverse health

effects associated with poor IAQ may include sensory irritation,

respiratory allergies, asthma, nosocomial infections, humidifier fever,

hypersensitivity pneumonitis, Legionnaires' disease, and the signs and

symptoms characteristic of exposure to chemical or biologic substances

such as carbon monoxide, formaldehyde, pesticides, endotoxins, or

mycotoxins.

The Agency believes that available data support proposing

regulation of IAQ, including exposure to ETS. Further stimulus for this

determination was provided by conclusions reached in a report published

in December, 1992 by the Environmental Protection Agency, addressing

hazards associated with exposure to ETS. In that study, Respiratory

Health Effects of Passive Smoking: Lung Cancer and Other Disorders [Ex.

4-311], EPA concluded that exposure to ETS presents an excess risk of

induction of cancer in humans. OSHA has submitted this proposed

standard to the U.S. Environmental Protection Agency which is reviewing

it in detail for purposes of submitting detailed comments to the

docket.

For the reasons noted above, and discussed in the following

sections, OSHA is proposing to address indoor air quality problems,

including exposure to ETS, as set forth in this notice.

II. Health Effects

Indoor air quality problems can occur in all types and ages of

buildings; in newly constructed buildings, in renovated or remodeled

buildings, and in old buildings. Problems in new, clean buildings are

rarely, if ever, related to microbial growth, since the physical

structures are new [Ex. 3-61]. Older buildings that have not been

adequately maintained and operated may have problems with bioaerosols

if parts of the building have been allowed to become reservoirs for

microbial growth. Also, if inadequate outside air is provided,

regardless of the age of the building, chemical and biological

contaminants will build up to levels that can cause health effects in

some workers. In addition, other physical factors such as lack of

windows, noise, and inadequate lighting, and ergonomic factors

involving uncomfortable furniture and intensive use of video display

units, etc., will cause discomfort in occupants that may be

inaccurately attributed to air quality.

Some information contained in the docket indicates that these

chronic health complaints are psychological, however, OSHA believes

that chronic health complaints related to poor indoor air quality are

unlikely to be due to mass psychogenic illness, even though a

psychological overlay is common. It is true that poor management,

boring work, poor lighting conditions, temperature variations, poor

ergonomic design, and noise may all lower the threshold for complaint.

Nevertheless, air quality complaints usually have some basis, although

they are often difficult to assess with specificity [Exs. 3-61C, 4-

144].

Indoor air quality problems are generally classified as Sick

Building Syndrome (SBS) or Building-related Illness (BRI). However, a

very important constituent of poor indoor air quality is ETS because of

the serious health effects that result from exposure. The following

discussion will first identify the health effects associated with SBS

and BRI. A discussion of the health effects associated with exposure to

ETS will follow.

It is important to note that OSHA considers these health effects to

be material impairments of health when the worker is clinically

diagnosed with a condition that is either caused or aggravated by poor

indoor air quality in the workplace. For example, in the formaldehyde

standard (29 CFR 1910.1048) [Ex. 4-107] OSHA determined that a

physician's diagnosis of irritation met the requirement of material

impairment of health. In addition, OSHA considers all the other health

effects discussed, which are more clinically severe than irritation, to

be material impairments of health as well.

A. Sick Building Syndrome

Typically, health effects caused by poor indoor air quality have

been categorized as SBS or BRI. In 1983, the World Health Organization

published a list of eight non-inclusive symptoms that characterize Sick

Building Syndrome [Ex. 4-325]. These include irritation of the eyes,

nose and throat; dry mucous membranes and skin; erythema; mental

fatigue and headache; respiratory infections and cough; hoarseness of

voice and wheezing; hypersensitivity reactions; and nausea and

dizziness. Generally, these conditions are not easily traced to a

specific substance, but are perceived as resulting from some

unidentified contaminant or combination of contaminants. Symptoms are

relieved when the employee leaves the building and may be reduced or

eliminated by modifying the ventilation system. Comments to the docket

indicate that such symptoms have been observed in and reported by

workers [Exs. 3-446, 4-87].

In some instances, outbreaks of SBS are identified with specific

pollutant exposures, but in general only general etiologic factors

related to building design, operation and maintenance can be identified

[Ex. 4-274]. In 1987, Woods et al. [Ex. 3-745] conducted a stratified

random telephone survey of 600 U.S. office workers across the national.

Twenty four percent reported that they were dissatisfied with the air

quality at the office; while 20% perceived their performance to be

hampered by poor indoor air quality. Women were nearly twice as likely

to report a productivity effect of poor indoor air quality than men

(28% versus 15%). Based on this, Woods et al. [Ex. 3-745] hypothesized

that 20% of U.S. office workers are exposed to indoor conditions which

manifest as SBS. In fact, complaints about SBS have become so numerous

that 37 out of 53 states and territories have designated a building

complaints investigation contact person [Ex. 4-310].

Breysse [Ex. 4-32] reported on symptoms associated with new

carpeting in a state office building, in order of prevalence: headache,

eye and throat irritation, nausea, dizziness, eye tearing, chest

tightness, diarrhea, cough, muscle aches, burning nose, fatigue, dark

urine, and rashes. Twenty out of 35 persons were affected. Air sampling

was conducted before and after carpet removal; a similar range of

aliphatic hydrocarbons was found after removal, but in much lower

concentrations. Many individuals who believe the building they work in

is implicated in SBS, have described similar effects. Symptoms usually

include one or more of the following: mucous membrane (eye, nose, or

throat) irritation, dry skin, headache, nausea, fatigue, and lethargy

[Ex. 4-293]. These symptoms are generally believed to result from

indoor air pollution. There is no secondary spread of symptoms to

others outside the building who are exposed to the occupants (unlike

the situation faced by many chemical and asbestos workers). Anderson

[Ex. 4-10] suggested the possible causes for SBS as related to

psychosocial, chemical, physical, or biological factors.

Anderson [Ex. 4-10] distinguished SBS symptoms as different from

mass psychogenic illness; although in general the causes of SBS are

unknown, he suggested that most SBS symptoms could be explained by

stimulation of sensory nerve fibers in the upper airways and the face

(referred to as common chemical sense). Because these fibers can

respond in only one way, SBS cases largely have the same symptoms

irrespective of the cause [Ex. 4-10].

It is now known that there is a variety of important health effects

from indoor air pollution. In addition to the indoor environmental

disease caused by infectious agents, carcinogens or toxins; the indoor

environment may create conditions that can produce skin and mucosal

allergy and hyperactivity reactions, sensory effects (odors and

irritations), airways effects (from both acute and chronic exposures),

neuropsychological effects, and psychosocial effects, especially due to

the lack of social support [Ex. 4-200].

Indoor air pollution may be caused by physical, chemical, or

microbiological agents, and is aggravated by poor ventilation. The

causation of SBS by indoor air pollution was first objectively

demonstrated in 1984 in a study of 62 Danish subjects suffering from

``indoor climate symptoms'' [Ex. 4-20]. These subjects reported

primarily eye and upper respiratory irritation, but were otherwise

healthy individuals, and did not suffer from asthma, allergy, or

bronchitis. The subjects were exposed to a mixture of 22 volatile

organic chemicals commonly found in the indoor environment at

concentrations of 0, 5, and 25 mg/m3. These concentrations

corresponded respectively to ``clean'' air, average polluted air in

Danish houses, and maximum polluted air in Danish houses. After

exposure, the Digit Span test was administered. The Digit Span test

consists of the subject being allowed to view a series of random digits

for a short period of time; the numbers are then covered up and the

subject asked to repeat the sequence backwards. This test is reported

to be sensitive to situational anxiety and alertness, and therefore a

measure of stress and ability to concentrate. Bach et al. found

significant declines in performance on the digit span test following

exposure to these low levels of volatile organic chemicals,

demonstrating objectively the existence of SBS [Ex. 4-20].

Molhave et al. [Ex. 4-228], in reporting on the same 62 subjects,

found that subjects exposed for 2\3/4\ hrs did not adapt, and that the

subjects reacted to irritation of the mucous membranes and not to odor

intensity. The exposure was doubled-blind, and neither the subjects nor

the testers knew the exposure.

Although these problems have been demonstrated to be real, they may

affect only a small percentage of building occupants. Also, there are

various degrees of problems which may occur. Some individuals who

experience relatively mild and treatable symptoms such as headache, may

be able to cope with the sick building environment for extended

periods, although suffering from increased stress. Other individuals,

more seriously affected, may find symptoms so severe that they may be

unable to be in the building for extended periods, or at all. Still

others may become temporarily or permanently disabled.

It has been suggested that SBS may not be one syndrome but a number

of sub-syndromes [Ex. 4-170]. This hypothesis suggests that the

symptoms particularly associated with chemical exposure include

fatigue; headache; dry and irritated eyes, nose, and throat; and

sometimes include nausea and dizziness. Those symptoms most related to

microbial exposures would result in itchy, congested, or runny nose;

itchy watery eyes; and sometimes include wheezing, tight chest, or flu-

like symptoms. The overlapping symptoms in each case are eye, nose, and

throat irritation, perhaps making the two sub-syndromes, chemical and

microbial, difficult to distinguish. Jones concludes that there is a

need for a treatment protocol as well as a diagnostic protocol, which,

in addition to describing corrective actions available in response to

different diagnostic findings, would also provide guidelines for the

design and implementation of follow-up studies of buildings and

individuals in order to assess treatment effectiveness [Ex. 3-170].

Randolph and Moss [Ex. 4-258] have written about a number of

problems ascribed to indoor air pollution in the chemically sensitive

patient. These problems include irritability from natural gas fumes,

allergy to dust from forced air ventilation systems, intoxication and

even hallucination from paint fumes. Randolph describes chemical

sensitivity to dry cleaning chemicals, and rug shampoo, and implicates

moldy carpets in producing allergenic substances. He also describes

joint pain, malaise, and fatigue due to pesticide exposure; and skin

rashes from exposure to plasticizers. Randolph further describes

intolerance to highly scented products such as deodorant soaps, toilet

deodorants, and disinfectants, especially pine-scented ones. Other

patients have reported reacting to strong perfumes and other cosmetics.

So-called air fresheners often prove to be particularly troublesome. He

also describes that some patients are sensitive to the odors from hot

plastic-coated wires in electronic equipment.

There is little data on the perceptions of victims of SBS. Shapiro

[Ex. 4-282] has complied a summary of 16 case-histories of SBS in the

victims' own words. It is useful to review these for insight into the

problems from the victims' point of view.

One episode that Shapiro [Ex. 4-282] reported on was in a building

occupied by a government agency. As a result of problems related to

carpeting and other suspected causes, five workers were reported to

have left the agency, 11 were relocated to alternative workspace or

worked at home, and 100 reported to the agency's medical officer that

they had SBS related problems. The range of self-reported symptoms

included a variety of moderate and acute respiratory problems;

headache; sore throat; burning of the eyes, lungs, and skin; rashes;

fatigue; laryngitis; clumsiness; disorientation; loss of balance;

nausea; numbness in extremities and face; and difficulty with mental

tasks.

The patient's reported that the diagnoses of the occupational

health physicians they visited included upper and lower respiratory

irritation, intoxication-type syndrome, occupational asthma, and

chronic hypersensitivity pneumonitis.

The central nervous system effects reported by many do not lend

themselves to ready diagnosis [Ex. 4-282]. Some of the lesser affected

individuals either saw no physician at all or saw a family doctor or

allergist who was not familiar with occupational or environmental

health [Ex. 4-282].

The Air Force Procedural Guide [Ex. 4-199] on dealing with SBS

takes a practical view: ``* * * in most cases the sick building

syndrome does not have a clearly understood etiology and many of the

SBS studies and investigations were inconclusive. The significance of

exposure that [what chemical or physical agent concentrations cause

symptoms] can be pathogenic remains unanswered, but the realities of

worker complaints and discomfort are valid reasons to seriously address

this problem.''

In summary, SBS is not a well-defined disease with well-defined

causes. It appears to be a reaction, at least in part due to

stimulation of the common chemical sense, to a variety of chemical,

physical or biological stimuli. Its victims display all or some of a

pattern of irritation of the mucous membranes, and the worst affected

individuals have neurological symptoms as well.

B. Building-Related Illness

Building-related illness (BRI) describes specific medical

conditions of known etiology which can often be documented by physical

signs and laboratory findings. Such illnesses include sensory

irritation when caused by known agents, respiratory allergies,

nosocomial infections, humidifier fever, hypersensitivity pneumonitis,

Legionnaires' disease, and the symptoms and signs characteristic of

exposure to chemical or biologic substances such as carbon monoxide,

formaldehyde, pesticides, endotoxins, or mycotoxins [Exs. 3-61, 4-144].

Some of these conditions are caused by exposure to bioaerosols

containing whole or parts of viruses, fungi, bacteria, or protozoans.

These illnesses are often potentially severe and, in contrast to SBS

complaints, are often traceable to a specific contaminant source, such

as mold infestation and/or microbial growth in cooling towers, air

handling systems, and water-damaged furnishings. Symptoms may or may

not disappear when the employee leaves the building. Susceptibility is

influenced by host factors, such as age and immune system status.

Mitigation of building-related illnesses requires identification and

removal of the source, especially in cases involving hypersensitivity

responses.

1. Indoor Air Contaminants

Comments submitted to the docket in response to the RFI and

contained in the literature indicate that specific substances or

classes of substances have been implicated as contributing to poor

indoor air quality problems. These substances, either alone or in

synergy, have produced health effects that OSHA believes can be

considered material impairment [Ex. 4-124]. In most cases, people

likely to be at risk have specific susceptibility.

But such susceptibility is common and adverse effects can arise

suddenly following exposure. The relevant effects can be categorized

into six categories: irritation, pulmonary, cardiovascular, nervous

system, reproductive, and cancer.

Common chemical sense or irritation perception is mediated through

receptors found not only throughout the nasal, pharyngeal, and

laryngeal areas of the respiratory system but also on the surface of

the eyes, specifically the conjunctiva and cornea [Ex. 4-239]. It is

partially through the stimulation of these receptors that exposed

persons perceive irritation. Many comments to the docket, from

citizens, researchers, and indoor air consultants, raised the issue

about the irritating effects related to known indoor air contaminants.

The air contaminants of concern include formaldehyde [Exs. 3-14, 3-32,

3-38, 3-188, 3-440a, 3-446, 3-575, 4-125, 4-144, 4-214], volatile

organic compounds (VOCs) [Exs. 3-32, 3-446, 3-500, 4-145, 4-243, 4-

320], ozone [Exs. 3-14, 4-42, 4-134, 4-236, 4-237], carpet-associated

chemicals [Exs. 3-25, 3-444D, 3-576, 4-144, 4-214], vehicle exhausts

[Exs. 3-6, 3-63, 3-206, 3-238, 3-360, 3-437, 3-444D, 3-631, 3-659],

combustion gases [Ex. 3-32], particulates [Exs. 3-32, 3-446, 3-500],

man-made mineral fibers (fiberglass, glasswool and rockwool) [Ex. 4-

33], and pesticides [Ex. 3-446]. The irritation effects present as

sensory irritation of the skin and upper airways, irritation of eye,

nose and throat, dry mucous membranes, erythema, headache, and abnormal

taste [Ex. 3-14, 4-33]. The pulmonary effects include upper and lower

respiratory tract effects such as rapid breathing, fatigue, increased

infection rate, broncho-constriction, pulmonary edema, asthma,

allergies and flu-like symptoms. Acute exposure to low level of air

contaminants results in primarily reversible effects, while chronic

exposure may result in pulmonary fibrosis that can result in

irreversible damage [Exs. 3-14, 4-33].

These health effects were associated, as reported in many comments

to the docket, with specific contaminants, including asbestos [Exs. 3-

38, 3-440A, 3-500], combustion gases [Exs. 3-14, 3-34, 3-440A, 3-446,

3-500], formaldehyde [Exs. 3-32, 3-38, 3-188, 3-440A, 4-124], ozone

[Exs. 4-42, 4-237], VOCs [Ex. 3-32], vehicular exhaust [Ex. 3-63], and

particulates [Exs. 3-32, 3-38, 3-440A, 3-500].

Individuals with underlying pulmonary disease, such as asthma, are

more susceptible than others to acute exposure to these indoor air

contaminants and experience coughing and wheezing at low levels of

exposure. Synergism may occur between chemical contaminants, such as

ozone and VOCs, in aggravating asthma [Ex. 4-33]. These affected

individuals may also be at increased risk of pulmonary infections due

to the synergistic effect between chemical and microbial contaminants

[Ex. 4-33].

Cardiovascular effects have also been associated with poor indoor

air quality. These effects are presented as headache, fatigue,

dizziness, aggravation of existing cardiovascular disease, and damage

to the heart. These effects are associated with exposure to combustion

gases such as carbon monoxide [Exs. 3-38, 3-440A], VOCs [Ex. 3-500],

and particulates [Ex. 3-500].

Nervous system effects have also been produced due to exposure to

poor indoor air quality. These effects include headache, blurred

vision, fatigue, malaise with nausea, ringing in the ears, impaired

judgement, and polyneuritis. These effects are associated with exposure

to carbon dioxide [Ex. 3-14], carbon monoxide [Exs. 3-32, 3-38, 3-446,

3-500], formaldehyde [Exs. 3-32, 3-38, 3-446, 3-500], and VOCs [Exs. 3-

32, 3-446, 3-500].

Relevant reproductive effects include menstrual irregularities and

birth defects and are associated with exposure to formaldehyde [Exs. 3-

446, 3-500] and VOCs [Exs. 3-446, 3-500].

The occurrence of cancer has also been attributed to exposures

associated with poor indoor air quality. In particular, cancer of the

lung, including mesothelioma, esophagus, stomach, and colon have been

associated with exposure to asbestos [Exs. 3-6, 3-14, 3-38, 3-188, 3-

440A, 3-500], radon [Exs. 3-35, 3-38, 3-188, 3-440A, 3-500], vehicular

exhausts [Exs. 3-84, 3-206, 3-360H], combustion gases [Ex. 3-500], VOCs

[Exs. 3-446, 3-500, 4-294], and particulates [Ex. 3-500].

2. Microbial Contamination

Building-related illnesses can result in serious illness and death.

Indoor transmission of disease caused by obligate pathogens (microbes

that require a living host) is common in indoor environments,

especially those that are overcrowded and inadequately ventilated [Ex.

4-33]. Diseases in this category include influenza, rhinovirus or

colds, and measles. Indoor transmission of disease caused by

opportunistic microorganisms usually affects compromised individuals,

those with existing conditions that make them more susceptible to

infection, such as pulmonary disease or immunodeficiency. Legionnaires'

disease, pulmonary tract infections, and humidifier fever are diseases

that fall into this category. Diseases that affect the immune system

include allergic reactions, as seen in antibody-mediated responses

(asthma and rhinitis) and interstitial lung disease, as seen in cell-

mediated reactions (hypersensitivity pneumonitis) [Ex. 4-33]. All of

these diseases produce substantial amounts of illness each year [Exs.

4-33, 4-41, 4-214].

In the U.S., Legionnaires' disease is considered to be a fairly

common, serious form of pneumonia. The Legionella bacterium is one of

the top three bacterial agents in the U.S. which causes sporadic

community-acquired pneumonia. Because of the difficulty in clinically

distinguishing this disease from other forms of pneumonia, many cases

go unreported. Although approximately 1,000 cases are reported to the

Centers for Disease Control and Prevention annually, it has been

estimated that over 25,000 cases of the illness actually occur. This

disease burden is estimated to result in over 5,000 to 7,000 deaths per

year [Ex. 4-41]. Brooks et al. [Ex. 4-33] reported that as many as

116,000 cases occur each year. Of these cases, it is estimated that

between 35,000 and 40,000 die. The attack rate for L. pneumophila

ranges from 0.1 to 5%. The case fatality rate ranges from 15 to 20%

[Ex. 4-214].

Two serious allergic or hypersensitivity diseases are asthma and

hypersensitivity pneumonitis (extrinsic allergic alveolitis). An

estimated 3% of the U.S. population suffers from asthma (approximately

9,000,000 people) [Ex. 4-41]. These individuals may be more susceptible

to bioaerosol contamination or chemical contamination of the indoor

environment.

Hypersensitivity pneumonitis is triggered by recurrent exposure to

microbials, fumes, vapors, and dusts [Ex. 4-33]. The lung interstitium,

terminal bronchioles, and alveoli react in an inflammatory process that

can organize into granulomas and progress to fibrosis. The symptoms of

acute episodes of this disease are malaise, fever, chills, cough and

dyspnea. The symptoms of chronic episodes are serious respiratory

symptoms such as progressive dyspnea. Chronic disease can lead to

irreversible pulmonary structural and functional changes [Ex. 4-33].

Approximately 15% (20,250) of 135,000 hospital admissions per year

that last an average of more than eight days are due to allergic

disease [Ex. 4-41]. Burge and Hodgson estimate that these

hospitalizations cost five million work days per year. The prevalence

of symptoms consistent with hypersensitivity pneumonitis, an

interstitial lung disease caused by organic dusts or by aerosols has

been examined in subpopulations at well-defined, increased risk, such

as farmers (0.1-32%) or pigeon breeders (0.1-21%) [Exs. 4-41, 4-214].

The only unbiased source of complaint rates in unselected office

workers are control buildings used in the study of hypersensitivity

pneumonitis in the U.S. Arnow et al. [Ex. 4-15] reported complaints

consistent with hypersensitivity pneumonitis in 1.2 percent and Gamble

et al. [Ex. 4-116] in 4 percent of these populations. Since no clinical

data are available, it is not known how these complaints are related to

actual disease, and it is unknown whether these complaints are

associated with lost work time, doctor visits or hospital admissions

[Ex. 4-41].

Humidifier fever, a less serious variant of hypersensitivity

pneumonitis, also is caused by exposure to microorganisms contained in

an aerosol. Attack rates in building epidemics have been as high as

75%, whereas complaint rates are usually 2-3% in nonepidemic situations

[Ex. 4-41]. Because of the similarity of the individual symptoms to

other diseases (fever, headache, polyuria, weight loss and joint pain),

it is often difficult to separate actual disease from complaints

related to the common cold in nonepidemic situations [Exs. 4-33, 4-41].

While rare, a workplace epidemic of humidifier fever can virtually shut

down an entire building, and only removal of the contamination will end

the epidemic [Exs. 4-41, 4-144, 4-214].

Microbial contamination of building structures, furnishings, and

HVAC system components contribute to poor indoor air quality problems,

especially those related to building-related illnesses. OSHA believes

that consequent health effects constitute material impairment of health

[Exs. 3-61, 4-41]. These can be categorized as irritation, pulmonary,

cardiovascular, nervous system, reproductive, and cancer effects.

Irritation effects, either from the physical presence of

bioaerosols or from exposure to VOCs released by biologicals, have been

demonstrated in susceptible workers [Ex. 3-32]. In addition, water

leakage on furnishings or within building components can result in the

proliferation of microorganisms that can release acutely irritating

substances into the air. Typically, where microorganisms are allowed to

grow, a moldy smell develops. This moldy smell is often associated with

microbial contamination and is a result of VOCs released during

microbial growth on environmental substrates [Ex. 4-41].

Pulmonary effects which have been associated with exposure to

bioaerosols include rhinitis, asthma, allergies, hypersensitivity

diseases, humidifier fever, spread of infections including colds,

viruses, and tuberculosis, and the occurrence of Legionnaire's disease

[Exs. 3-17, 3-32, 3-38, 3-61B, 3-188, 3-440A, 3-446, 3-500, 4-41, 4-

144, 4-214].

Building-related asthma has also recently been documented in office

workers [Exs. 3-61, 4-43] and some case reports show it to be

associated specifically with humidifier use. Biocides used in

humidification systems are suspected causes of office-associated asthma

[Ex. 4-103].

Cardiovascular effects manifested as chest pain, and nervous system

effects manifested as headache, blurred vision, and impaired judgment,

have occurred in susceptible people following exposure to bioaerosols

[Exs. 3-32, 3-446]. It has been suggested that these effects may be

caused by VOCs released by the microbiologicals, or they may be a

complication of related pulmonary effects.

The development of cancer in susceptible people is possible

following exposure to certain types of toxigenic fungi and mycotoxins.

However, the probability of such exposures occurring in workplaces

covered by this standard is probably limited. Mycotoxins (toxins

produced as secondary metabolites by many fungi) are among the most

carcinogenic of known substances, and are also acutely toxic. The

American Conference of Governmental and Industrial Hygienists wrote

``[t]he toxigenic fungi are common contaminants of stored grain and

other food products and have caused well-described outbreaks of acute

systemic toxicosis as well as specific organ carcinogenesis when such

food is consumed * * * It appears clear that massive contamination with

a highly toxigenic fungus strain of a site in which aerial dispersion

of metabolic products occurred would be necessary to induce acute

symptoms. However, considering the carcinogenicity of many fungal

toxins, an examination of the risks of chronic inhalation exposure

appears justified'' [Ex. 3-61].

In summary, most of the health effects associated with SBS and BRI

occur in indoor environments were concentrations of pollutants are much

less than the OSHA Permissible Exposure Levels (PELs) (29 CFR

1910.1000) [Ex. 4-3]. It is important to point out that the PELs are

chemical-specific standards that are not only based on health effects

but also on technological feasibility, cost restraints and a

``healthy'' worker exposed for a 40-hour work week. In the industrial

workplace, hazards are minimized by the use of administrative and

engineering controls and the use of personal protective equipment. The

nonindustrial environment, however, does not have these controls.

Ventilation systems are designed only to remove occupant-generated

contaminants, such as carbon dioxide and odors. These types of systems

were not designed to dilute multiple point sources of contaminants that

are typically found in nonindustrial workplaces (see section III).

Unless adequate ventilation and source controls are utilized and

adequately maintained, many of the chemical contaminants can

concentrate to levels that induce symptoms. The possibility exists that

synergistic effects occur. These effects occur not only between

substances to enhance their toxicity but also by lowering the

resistance to lung infection in susceptible persons.

C. Environmental Tobacco Smoke

ETS is composed of exhaled mainstream and sidestream smoke. The

chemical composition and exposure sources of ETS are described in the

Exposure section of this preamble (see Section III). The

pharmacokinetics of ETS have been widely studied and are described in

the following section.

A wide spectrum of health effects have been associated with

exposure to ETS. These effects include mucous membrane irritation,

decrease in respiratory system performance, adverse effects on the

cardiovascular system, reproductive effects, and cancer. The following

section also presents more detailed information on these health

effects.

1. Pharmacokinetics

Whether a chemical elicits toxicity or not depends not only on its

inherent potency and site specificity but also on how the human system

can metabolize and excrete that particular chemical. To produce health

effects, the constituents of ETS must be absorbed and must be present

in appropriate concentration at the sites of action. After absorption,

some of these contaminants are metabolized to less toxic metabolites

while some carcinogens are activated by metabolism in the body.

Available biomarkers of ETS, such as nicotine, clearly show that

nonsmoker exposure is of sufficient magnitude to be absorbed and to

result in measurable levels of these biomarkers. There is sufficient

evidence in the literature to indicate that several components of

sidestream smoke are rapidly absorbed and widely distributed within the

body. However, the extent of absorption, distribution, retention and

metabolism of these contaminants in the body depends upon various

physiological and pharmacokinetic parameters that are influenced by

gender, race, age and smoking habits of the exposed individuals. These

parameters and others may result in differences in susceptibility among

exposed subpopulations. Nicotine is one of the most widely studied

constituents of tobacco smoke. There have been numerous studies on the

pharmacokinetics of nicotine in both animals and man.

(a) Absorption and distribution. Absorption and distribution of

tobacco smoke constituents are usually measured by using surrogate

markers. A correlation between nicotine absorption and exposure to

tobacco smoke has between demonstrated, thus making nicotine an

appropriate marker for tobacco smoke in pharmacokinetic studies. The

steady state volume of distribution for nicotine is large indicating

that it is widely distributed within the body [Ex. 4-185]. Nicotine has

been shown to bind with plasma proteins which may interfere with

elimination and thereby prolong retention in the body. The studies in

the docket clearly indicate that nicotine and other constituents of

tobacco smoke are readily absorbed and distributed throughout the body

thereby increasing the potential of producing adverse effects at more

then one target site.

(b) Metabolism. Nicotine is rapidly eliminated, primarily via

metabolism and urinary excretion. The investigation of metabolism in

vivo and in vitro, has resulted in the identification of more than 20

metabolic products in the plasma and urine of humans and animals. The

principle metabolic pathways of nicotine appear to involve oxidation of

the pyrrolidine ring to yield nicotine-1'-N-oxide and cotinine, the

latter being the major metabolite and the precursor of many of the

metabolic products of nicotine. Some of the metabolites detected in the

urine of rats after intravenous administration in a study by Kyerematen

et al. [Ex. 4-185] are listed in Table II-1. In humans, cotinine is the

major degradation product of nicotine metabolism and has a serum half-

life of about 17 hours compared to two hours for the parent compound,

nicotine [Exs. 4-27, 4-253]. Trans-3'-hydroxycotinine in the free form

constitutes the largest single metabolite in smokers' urine accounting

for 35-40% of the urinary nicotine metabolite [Exs. 4-48, 4-241].

Smokers and nonsmokers differ in their metabolism of nicotine and

cotinine [Exs. 4-133, 4-184, 4-279]. The half-life values for urinary

elimination of nicotine and cotinine were found to be significantly

shorter in smokers than nonsmokers [Ex. 4-186]. Plasma nicotine

clearance was faster in smokers than in nonsmokers in this study. More

rapid elimination of nicotine and cotinine has been attributed to the

inductive effects of chronic cigarette smoking on the hepatic

metabolism of many xenobiotic agents. However, Benowitz et al. [Ex. 4-

29] were unable to confirm published research suggesting that smokers

metabolize nicotine and cotinine more rapidly than nonsmokers.

Variations in nicotine metabolism occur among individuals.

Variations also occur due to differences in gender and race [Exs. 4-26,

4-186, 4-314]. It has also been suggested that the metabolism of

nicotine between smokers and nonsmokers may differ. Male smokers have

been shown to metabolize nicotine faster than do female smokers after

intravenous infusion of nicotine and active smoking. However, this

difference was not observed by Benowitz and Jacob [Ex. 4-23] during a

study of daily intake of nicotine in smokers versus nonsmokers. The

metabolism of nicotine has also been studied in animals. Male rats (4

strains) were shown to metabolize nicotine faster than did females [Ex.

4-185].

In summary, the potential effect of nicotine, and other ETS

constituents in the body, is governed by interactions between several

physiological and pharmacokinetics parameters. These interactions may

lead to longer retention of toxic constituents, thus prolonging the

effects on the target organs resulting in tissue injury.

2. Irritation

Exposure to ETS is capable of inducing eye and upper respiratory

tract irritation. Common chemical sense or irritation perception is

mediated through receptors in the fifth, ninth, and tenth cranial

nerves. These receptors are found throughout the nasal, pharyngeal, and

laryngeal areas of the respiratory system and also on the surface of

the eyes [Ex. 4-239]. It is partially through the stimulation of these

receptors that exposed persons perceive irritation.

Table II-1.--Urinary Excretion of Nicotine and Metabolites in Male and Female Rats After Intravenous

Administration of [\14\C]Nicotine (0.5 mg/kg)

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

Male Female

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

Recovery of Recovery of

Metabolite administered t1/2 administered t1/2

radioactivity (Hr) radioactivity (Hr)

(percentage) (percentage)

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

Nicotine........................................ 10.8 plus-

minuse> 1.5 2.5 plus-

minuse> 0.4 \1\24.0 plus-

minuse> 4.6 \2\5.6 plus-

minuse> 0.5

Cotinine........................................ 9.3 plus-

minuse> 0.8 6.0 plus-

minuse> 0.6 \1\5.7 plus-

minuse> 0.7 \2\6.8 plus-

minuse> 0.8

Nicotine-N-oxide................................ 10.8 plus-

minuse> 0.9 1.6 plus-

minuse> 1.4 7.8 plus-

minuse> 1.4 2.6 plus-

minuse> 0.3

Cotinine-N-oxide................................ 8.5 plus-

minuse> 1.6 7.5 plus-

minuse> 0.8 \1\3.7 plus-

minuse> 1.0 6.8 plus-

minuse> 0.6

3-Pyridylacetic acid............................ 1.8 plus-

minuse> 0.3 5.8 plus-

minuse> 0.3 1.2 plus-

minuse> 0.2 \3\ND

3-(3-Pyridyl)--oxobutyric acid 2.7 plus-

minuse> 0.6 5.3 plus-

minuse> 0.9 2.4 plus-

minuse> 0.7 6.0 plus-

minuse> 0.6

3-Hydroxycotinine............................... 5.7 plus-

minuse> 0.5 6.7 plus-

minuse> 0.8 5.6 plus-

minuse> 1.5 9.9 plus-

minuse>1.5

-(3-Pyridyl)--

methylaminobutyric acid........................ 4.2 plus-

minuse> 0.6 5.9 plus-

minuse> 0.8 \1\1.4 plus-

minuse> 0.4 ND

Nornicotine..................................... 8.1 plus-

minuse> 0.9 4.1 plus-

minuse> 0.6 8.1 plus-

minuse> 1.8 \1\8.3 plus-

minuse>1.3

Demethylcotinine................................ 0.8 plus-

minuse> 0.1 ND -(3-Pyridyl)--oxo-N-

Methylbutramide................................ 1.8 plus-

minuse> 0.3 3.5 plus-

minuse> 0.6 \1\0.6 plus-

minuse> 0.3 ND

Isomethylnicotinium ion......................... 2.1 plus-

minuse> 4.5 plus-

minuse> 0.7 plus-

minuse> 0.4 9.8 plus-

minuse> 1.4 1.9 plus-

minuse> 0.6 10.0 plus-

minuse>1.6

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

Total....................................... 69.4 plus-

minuse> 3.0 .............. 65.0 plus-

minuse> 3.6 ..............

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

\1\0.01 0.05.

\2\p 0.01.

\3\ND, not determined; concentration too low to estimate t1/2 accurately.

The ability of tobacco smoke to elicit irritation may be enhanced

by low relative humidity and varies according to concentration [Ex. 4-

239]. Irritating components of ETS are contained in both the vapor

phase and the particulate phase (see Tables III-6 and III-7). These

effects have been studied in both experimental (e.g., animals studies;

clinical and chamber studies on humans) and field (e.g., surveys and

epidemiological studies) studies. The NRC report [Ex. 4-239] summarized

these studies and concluded that even though the specific components of

ETS that cause irritation were not identified, the overall effects were

eye and throat irritation and immunological responses. Weber [Ex. 4-

317] reported the results of a field study that included 44 workrooms

where smoking was taking place. Eye irritation was reported by 52 out

of 167 workers. Nonsmokers reacted more than smokers to the ETS; 36 of

the 52 workers who reported eye irritation at work were nonsmokers [Ex.

4-317]. Asano et al. [Ex. 4-18] reported significant eye irritation, as

measured by blinking rates, in both healthy smoking and nonsmoking

adults following exposure to ETS. Nonsmokers reported more eye

irritation than smokers did. Effects such as eye irritation and nasal

stuffiness were reported to OSHA in comments to the docket [Exs. 3-38,

3-58, 3-59, 3-188, 3-438D, 3-440A].

3. Pulmonary Effects

Much of the literature relevant to the association between non-

cancerous health effects and ETS has focused on children. Because

children are undergoing development and maturation, they are not

physiologically equivalent to adults exposed to the same conditions.

Therefore, findings in studies conducted with respect to ETS and

children may not be directly applicable to adults. However, a number of

studies have investigated the relationship between ETS and pulmonary

health effects in adults.

Studies which are restricted to adults vary by numerous factors,

such as the population studied, the measures used to estimate exposure

to ETS, and the physiologic and health outcomes examined. The studies

also varied in the consideration of potential confounders. A number of

studies have found relationships between ETS exposure and pulmonary

health effects. These studies have: (1) used pulmonary function tests,

which may be more sensitive than methods used in other studies, to

detect physiological changes occurring in the small airways of the

lungs (e.g., forced mid-expiratory flow rate (FEF25-75), and

forced end-expiratory flow rate (FEF75-85)); (2) studied older

populations with a longer history of exposure to ETS; (3) stratified

the level of ETS exposure with significant findings more likely to

occur in persons with higher exposures; and (4) more frequently found

significant changes in lung function in men, although adverse pulmonary

effects to ETS have also been shown in women. The following discussion

summarizes the results of these studies [Exs. 4-18, 4-37, 4-62, 4-148,

4-173, 4-176, 4-178, 4-180, 4-209, 4-210, 4-278, 4-295, 4-321].

Asano et al. [Ex. 4-18] demonstrated the acute physiologic changes

which occur as a result of exposure to ETS. Nonsmokers had more

pronounced changes in eye blinking rates (a measure of eye irritation),

expired carbon monoxide, increased heart rate and systolic blood

pressure.

Studies of ETS and chronic health effects in adults differ by how

they define ``never smokers'', ``exsmokers'', and how other various

levels of ETS exposure are defined, either in nominal, ordinal or

interval scales; and whether or not they take into account exposure

both in the workplace and at home. The potential for misclassification

bias occurs when ``nonsmokers'' are loosely defined and used as the

comparative group to passive smokers. Several studies considered the

confounding impact of environmental air pollution [Ex. 4-278], indoor

cooking fuels [Exs. 4-37, 4-62] or occupational exposures to dusts and

fumes [Exs. 4-176, 4-178, 4-209, 4-210, 4-321].

There have been fewer longitudinal studies [Exs. 4-148, 4-278, 4-

295] as compared to the majority which have been cross-sectional

studies. The duration of exposure, which is critical to producing a

measurable health effect, was quantified by number of years directly in

several studies [Exs. 4-37, 4-148, 4-173, 4-295, 4-321], or indirectly

by the age of the population under study [Exs. 4-176, 4-209, 4-210]. In

those studies which had carefully assessed for level of exposure and

had specified a duration of at least 10 years, significant pulmonary

function decrements were noted in both men and women [Exs. 4-37, 4-148,

4 176, 4-321]. Overall, changes in pulmonary indices are more likely to

occur in men than in women, however, several studies have documented

statistically significant physiological changes in pulmonary function

occurring in women [Exs. 4-37, 4-176, 4-178, 4-321].

Understanding the significance of findings is complicated because

studies used a variety of measures from spirometry. Although most

studies evaluated FVC (forced vital capacity) and FEV1 (forced

expiratory volume in one second), fewer studies have measured

FEF25-75 or FEF75-85 [Exs. 4-176, 4-180, 4-209, 4-210, 4-

321]. These later measures have been suggested as being more sensitive

to detecting changes in the small airways where effects of ETS are most

likely to occur [Exs. 4-46, 4-216, 4-230, 4-231]. However, there is no

clear consensus in the medical literature as to the routine clinical

use of FEF25-75 or FEF75-85, or their diagnostic value in

independently detecting small airway disease [Ex. 4-8].

Estimates of the decrement in FEV1 due to ETS exposure in

passive smokers as compared to never smokers, ranges from 80

milliliters (ml) [Ex. 4-148] to 190 ml [Ex. 4-37]. When this decrement

is expressed as a percent of FEV1, it has been estimated to be

5.7% in males, or 7.3% when these same subjects were matched for age

[Ex. 4-210]. As a means of comparison, the average loss in lung volume

per year due to aging alone is estimated to be 25 to 30 ml [Ex. 4-329].

The American Thoracic Society [Ex. 4-8] specifies that spirometry

equipment have a level of accuracy within 50 ml. Since pulmonary

function maneuvers are very effort dependent, intra-individual

variation between the three best efforts should be within 5% to be

acceptable. The importance of these spirometry criteria is emphasized

by the fact that the FEV1 may result in being 100 to 200 ml lower

than when a maximal effort is given by the subject. Furthermore, a

decrease of 15% must be achieved before certain pulmonary indices are

considered outside of normal limits. Given this perspective, although

changes in pulmonary function tests may truly occur as a result of

exposure to ETS over a number of years, the actual clinical impact may

not be apparent in the healthy, young individual. Older individuals and

those with preexisting pulmonary disease are more susceptible to the

pulmonary effects of exposure to ETS.

Outside of respiratory changes being documented through pulmonary

function testing, other symptoms have been found to be significantly

associated with ETS exposure. Hole et al. [Ex. 4-148] found a

significant increase in the prevalence of infected sputum, persistent

sputum, dyspnea and hypersecretion in passive smokers as compared to

controls. Furthermore, rates increased as those exposed were stratified

by level of exposure to passive smoke from low to high. Kauffmann et

al. [Ex. 4-178] noted a significant increased risk for dyspnea in

American (Odds Ratio (OR)=1.42) and French women (OR=1.43), and an

increased risk for wheeze in American women (OR=1.36). Schwartz and

Zeger [Ex. 4-278] found an increased risk for phlegm or sputum in a 3-

year longitudinal study (OR=1.41). This risk was raised to 1.76 when

asthmatics, who may be medicated, were excluded from the analysis.

As small airway disease progresses to chronic obstructive pulmonary

disease (COPD) (also referred to as chronic obstructive lung disease

(COLD)), the impact of ETS becomes more detectable. Kalandidi et al.

[Ex. 4-173] reported an adjusted odds ratio of 2.5 (90% Confidence

Interval (CI), 1.3 to 5.0) for Greek women never smokers exposed to

their husbands' tobacco smoke.

While there is a clear trend, and in several studies a

statistically significant finding of a demonstrated decrease in

pulmonary function indices, or an increase in respiratory symptoms in

passive smokers, the impairment nonsmokers suffer by the exposure may

not be immediately obvious. It is important to note that these findings

have been demonstrated in otherwise healthy individuals. Based upon the

finding of White and Froeb [Ex. 4-321], Fielding and Phenow [Ex. 4-102]

have described such changes as being equivalent to those found in light

smokers, who smoke from 1 to 10 cigarettes per day. Where a decrease of

100 to 200 ml of FVC or FEV1 may be clinically insignificant in

healthy persons, such a change may be significant for workers with

already impaired pulmonary function [Exs. 3-438D, 3-440A, 4-76, 4-182].

These changes may be the pivotal point at which a worker becomes unable

to continue to work.

Cellular effects on the pulmonary tissue have also been observed in

animals exposed to ETS during experimental studies. Several studies

reviewed by OSHA have demonstrated that chronic cigarette smoke

exposure produces an accumulation of alveolar macrophages (AM) (the

presence of AM indicates a body's response to environmental insults),

within the respiratory bronchioles of many animals species. This effect

is similar to that seen in human smokers [Exs. 4-31, 4-58, 4-109, 4-

110, 4-140, 4-147, 4-150, 4-179, 4-212, 4-249]. Increased elastase

secretion by alveolar macrophages from mice chronically exposed to

cigarette smoke has also been observed [Ex. 4-322].

Accumulation of polymorphonuclear leucocytes (PMNs) is also an

indication of the body's response to environmental insults. PMNs were

found in the alveolar septum of cigarette smoke-exposed hamsters,

similar to the PMNs observed in the lungs of human smokers [Ex. 4-204].

In contrast to the focal nature of the alveolar macrophages

accumulation, the accumulation of PMN is diffuse. Studies of PMN

leukocyte function have not been systematically evaluated in smoke-

exposed animals.

Other studies also show effects of ETS exposure at the cellular

level. For example, young lambs exposed to ETS for one month did not

develop detectable pulmonary system effects or alteration in lung

mechanics or airway responsiveness. However, the lambs did develop

inflammation of pulmonary cells [Ex. 4-290]. A cytotoxic effect of

tobacco smoke was also demonstrated by decreased intracellular

adenosine triphosphate (ATP) content in guinea pig alveolar macrophages

and lowered cell bacteriocidal activity in a study by Firlik [Ex. 4-

104]).

Exposure to tobacco smoke has been shown to increase the

permeability of the respiratory epithelial membrane to macromolecules.

Burns et al. [Ex. 4-45] have shown that exposure of guinea pigs to

tobacco smoke followed by fluorescein isothiocyanate-dextran (FITC-D,

molecular weight 10,000) increased the amount of intact FITC-D that

crossed the respiratory epithelium into the vascular space.

Transmission electron-microscopic studies showed that the FITC-D

diffused across damaged type I pneumocyte membranes and cytoplasm to

reach the basal lamina and entered the alveolar capillaries through the

endothelial junction. Damage to alveolar epithelium was more frequent

for the smoke-exposed animals than the room air-exposed animals.

Aryl hydrocarbon hydroxylase (AHH) participates in the activation

of various carcinogens, such as benzo(a)pyrene. This is one of the many

carcinogens found in ETS. Both mainstream and sidestream smoke are

capable of inducing pulmonary AHH activity. Gairola [Ex. 114] has

demonstrated the induction of pulmonary AHH activity in Sprague-Dawley

rats and male C57BL mice after exposure to either mainstream or

sidestream smoke from University of Kentucky Reference cigarettes (2R1)

for seven days per week for 16 weeks. However, no such induction was

noted in Hartley guinea-pigs under similar conditions, indicating a

species difference. The mainstream and the sidestream smoke were

equally effective in inducing the AHH activity.

There is consistent evidence that decrements in pulmonary function

and increases in respiratory symptoms occur in current smokers and in

exsmokers. However, in passive smokers these health effects are not as

easily demonstrated. The Environmental Protection Agency's December

1992 report, Respiratory Health Effects of Passive Smoking: Lung Cancer

and Other Disorders [Ex. 4-311], reviewed an abundance of evidence

showing persistent physiologic changes in children's respiratory

function and related health effects as a result of exposure to ETS.

Studies evaluating these same effects are not as plentiful in adults.

However, the EPA concluded, ``recent evidence suggests that passive

smoking has subtle but statistically significant effects on the

respiratory health of adults'' [Ex. 4-311].

The weight of the evidence shows that exposure to ETS results in

decreases in pulmonary function indices and increases in respiratory

symptoms in otherwise healthy men and women who are exposed to ETS for

periods of 10 or more years. The risk of developing COPD appears to be

increased in passive smokers with lifelong exposures to ETS. Whether

these changes impact upon respiratory function to a degree that

impairment occurs may be dependent upon the individual's pulmonary

status and overall health condition.

4. Cardiovascular Effects

A developing body of research indicates that the cardiovascular

effects of ETS exposure on the health of nonsmokers include acute

effects, such as exacerbation of angina, as well as chronic effects,

such as atherosclerosis [Exs. 4-123, 4-291, 4-330].

Cardiovascular diseases [Exs. 4-91, 4-136] such as myocardial

infarction [Ex. 4-12], sudden death, and arterial thrombosis occur more

frequently in cigarette smokers as opposed to nonsmokers [Exs. 4-86, 4-

233]. The same chemicals which produce these effects in active smokers

are present in ETS. These include nicotine, carbon monoxide, polycyclic

aromatic hydrocarbons (PAHs) and tobacco glycoproteins.

The following discussion on cardiovascular effects covers thrombus

formation, vascular wall injury and the possible mechanisms of these

effects in nonsmokers. Discussion of the acute and chronic health

effects follows.

(a) Thrombus Formation. Blood clots in the coronary arteries are an

important component of an acute myocardial infarction (MI). An

additional component of the acute MI is the presence of atherosclerotic

plaques in the walls of the coronary arteries. Platelets are involved

in both the acute formation of blood clots and the chronic formation of

atherosclerotic plaques.

There is evidence that ETS exposure can cause platelets to become

more easily activated thus predisposing the platelets to become

involved in forming clots and atherosclerotic plaques. For example,

evidence exists that demonstrates that the platelets of nonsmokers

exposed to ETS are more easily activated [Exs. 4-40, 4-80]. The study

by Burghuber [Exs. 4-40] demonstrates that the platelet activating

capabilities of ETS are more prominent in nonsmokers than in smokers.

The results of this study suggest that nonsmokers are at a greater risk

of blood clot formation secondary to ETS exposure than smokers.

Acute ETS exposure also results in an increased platelet

aggregation, which is an initial stage of the development of coronary

thrombosis or vasoconstriction. This vasoconstriction can lead to the

development of coronary atherosclerosis after chronic exposure [Exs. 4-

111, 4-123, 4-272]. Environmental smoke exposure also can increase

platelet-activating factor (PAF), platelet factor 4, beta-

thromboglobulin, and fibrinogen concentration which provides a marker

of its effect on coronary heart disease [Exs. 4-85, 4-157, 4-224].

(b) Vascular Wall Injury. Atherosclerotic plaque formation is a

complicated chronic process that can lead to constriction of the lumen

of the blood vessels, resulting in reduced blood supply to the

myocardial tissues. It is thought that an essential step in plaque

formation is injury to the endothelial lining of the arterial wall. ETS

has been implicated in causing injury to the endothelial cells which

line the arterial walls. This was demonstrated in the study by Davis et

al. [Ex. 4-80] which identified an increase in the number of

endothelial cell carcasses in the circulation of healthy people after

being exposed to ETS.

ETS has also been implicated in stimulating smooth muscle cell

proliferation and in altering blood lipids. Each of these can

contribute to plaque formation which leads to an increased

susceptibility to heart attacks.

(c) Possible Mechanisms of Effect. At least three mechanisms are

described in the literature by which ETS may place stress on the heart

by increasing myocardial oxygen demand, decreasing myocardial oxygen

supply or interfering with the cell's ability to utilize oxygen for

energy production.

One mechanism by which ETS may reduce oxygen supply is through the

formation of carboxyhemoglobin. Carboxyhemoglobin is formed when a

person is exposed to carbon monoxide, a component of ETS. The carbon

monoxide effectively competes with oxygen for the heme group of the

hemoglobin molecule in the red blood cell (RBC). In fact, carbon

monoxide has a much greater affinity for hemoglobin than does oxygen

and binds very strongly with hemoglobin making it unavailable for the

transport of oxygen. The heart muscle (myocardium) can experience

injury at the cellular level when the oxygen demanded by the heart

muscle exceeds the oxygen supplied by the blood. Therefore, the

formation of carboxyhemoglobin can decrease the ability of the blood to

deliver oxygen to the myocardium and can cause injury to the heart if

myocardial oxygen demand exceeds supply.

A number of studies have suggested that ETS exposure adversely

affects the myocardial oxygen supply-demand relationship; this would

predispose the heart to develop ischemia or exacerbate preexisting

ischemia. Direct or indirect exposure to tobacco smoke has been shown

to increase the hemodynamic determinants of myocardial oxygen demand

[Exs. 4-13, 4-242] at the same time that it potentially reduces both

myocardial oxygen supply and delivery by enhancing the development of

coronary atherosclerosis [Exs. 4-242, 4-323], causing coronary

vasoconstriction [Exs. 4-323, 4-324] and reducing the oxygen carrying

capacity of blood through increased carboxyhemoglobin levels [Ex. 4-

13]. As a result, fewer red blood cells are available to transport

oxygen to the body, and to the heart muscle itself. To compensate for

this reduced oxygen carrying capacity of the blood, the heart must work

harder, for example, by increasing the heart rate. This is an example

of one mechanism by which ETS may place even further stress on the

heart by increasing myocardial oxygen demand, precisely at a time when

the oxygen delivery capabilities of the blood are reduced.

A second mechanism by which ETS may increase myocardial oxygen

demand is via the direct effect of nicotine. The nicotine in ETS may

cause an increased resting heart rate and blood pressure in exposed

individuals.

One study examined the effects of ETS on healthy individuals during

exercise, and found that healthy individuals experienced fatigue at

lower work levels when exercising in the presence of ETS [Ex. 4-123].

The authors concluded that ETS exposure interfered with the heart

muscle cells' ability to utilize oxygen for energy production.

Consequently, ETS exposure may have an adverse impact on myocardial

metabolism and expose the heart muscle to an increased susceptibility

to injury. These mechanisms of cardiac stress and potential injury to

the heart are in agreement with accepted theories of cardiac injury.

(d) Acute Heart Effects. An acute effect of exposure to ETS is the

aggravation of existing heart conditions, such as angina. The National

Research Council (1986) reported, based on the effects of studies by

Anderson et al. [Ex. 4-9] and Aronow et al. [Exs. 4-14, 4-16, 4-17],

that angina patients are especially sensitive at carboxyhemoglobin

levels between 2 and 4%. Guerin et al. [Ex. 4-129] report that

physiologically adverse effects occur in humans at 2.5%

carboxyhemoglobin blood content. Cumulative carbon monoxide levels, due

to ETS that result in such an effect are not uncommon in work

environments [Ex. 4-129]. Acute exposure to ETS has been reported to

increase heart rate, elevate blood pressure, and increase

carboxyhemoglobin levels in both angina patients [Exs. 3-38, 4-222] and

in healthy subjects [Exs. 4-18, 4-217]. Acute exposure has also been

associated with slight changes in blood components thought to be

involved in the pathogenesis of atherosclerosis, such as endothelial

cell count, platelet aggregate ratio, and platelet sensitivity to

prostacyclin [Exs. 4-40, 4-80]. Many effects of ETS exposure, such as

ischemia, may be additionally aggravated by simultaneous exposure to

other compounds, such as solvents [Exs. 3-446, 4-99].

(e) Chronic Heart Effects. The occurrence of coronary heart disease

in ETS-exposed nonsmokers has been studied by various epidemiological

researchers [Exs. 4-85, 4-120, 4-122, 4-138, 4-139, 4-142, 4-148, 4-

154, 4-191, 4-277, 4-295]. Small, but statistically significant (at p

0.05), increases in coronary heart disease mortality [Exs.

4-85, 4-138, 4-139, 4-142, 4-277] indicate a modest impact of long-term

ETS tobacco smoke exposure on the cardiovascular health of nonsmokers.

The relative risks calculated in these studies ranged from 1.3 to 2.7.

The ability of ETS exposure to induce coronary heart disease has

also been studied in animals. Zhu et al. [Ex. 4-330] exposed rats to

ETS and showed a dose-related increase in myocardial infarct size and a

decrease in bleeding time. But there were no significant differences in

serum triglycerides, high density lipoprotein and cholesterol. This

study showed that air nicotine, carbon monoxide, and total particulate

concentrations increased with ETS exposure, and this increased exposure

led to a continuous increase in plasma carboxyhemoglobin, nicotine, and

cotinine levels in ETS-exposed rats. There was a positive relationship

between the infarct size and air nicotine, carbon monoxide, total

particulate concentrations and plasma carboxyhemoglobin, nicotine, and

cotinine levels. The average concentrations of air nicotine, carbon

monoxide and particulates, according to the authors, were 30-fold, 3-

fold and 10- fold higher, respectively, than in a heavy smoking

environment. The duration of exposure, however, was short compared to

even a rat's lifetime. Infarct size nearly doubled following only 180

hours of ETS exposure distributed over a six week period.

In the same study, the effect of ETS exposure on platelet function

and aortic and pulmonary artery atherosclerosis in New Zealand male

rabbits was demonstrated. The increase of atherosclerosis after

exposure to ETS was shown to be independent of changes in serum lipids

and exhibited a dose-response relationship in this study. Average air

nicotine, carbon monoxide and total particulate concentrations were

1,040 g/m\3\, 60.2 ppm and 32.8 mg/m\3\ for high dose group

and 30 g/m\3\, 18.8 ppm and 4.0 mg/m\3\ for low dose group and

g/m\3\, 3.1 ppm and 0.13 mg/m\3\ for the control group.

Atherosclerosis in this study was significantly increased in the high

dose group.

Olsen [Ex. 245] exposed rats daily to smoke from University of

Kentucky 2R1 Reference cigarettes for 10 minutes, 7 times a week for 4,

8 or 20 weeks. Sidestream (SS) smoke was collected by a moving column

of air spiked every minute with a puff of fresh mainstream (MS) smoke.

Rats were exposed to this SS smoke collected in a 2 L/min air flow

using a glass container placed over a burning cigarette. A fraction of

this air flow containing SS smoke was diluted with fresh room air and

continuously diverted to the rats as follows: 50%, 25% and 10% SS

smoke. Carboxyhemoglobin content for each treatment group was

determined immediately after the last smoke exposure and percent

carboxyhemoglobin for each group was found to be: 4 week exposure-

mainstream=7.2plus-minuss>1.2 and 25%

sidestream=11.8plus-minuss>0.7; 8 week exposure

mainstream=6.1plus-minuss>1.2 and 25%

sidestream=11.9plus-minuss>0.9; 20 week exposure

mainstream=8.3plus-minuss>0.9, 10%

sidestream=6.30plus-minuss>0.5, 25%

sidestream=10.8plus-minuss>0.8 and 50%

sidestream=18.3plus-minuss>1.2. This indicates a tobacco smoke-

related detrimental effect on blood components, thus increasing the

probability that coronary disease would develop over a longer exposure

period.

Research has shown that passive exposure to tobacco smoke damages

endothelial cells and increases the number of circulating anuclear

carcasses of endothelial cells [Ex. 4-80]. ETS appears to alter cardiac

cellular metabolism in such a way that renders the myocyte less capable

of producing adenosine triphosphate (ATP). Reduced oxidative

phosphorylation in cardiac mitochondrial fractions taken from rabbits

exposed to ETS has been demonstrated [Ex. 4-130]. Studies have

indicated that the reduction in mitochondrial respiration secondary to

ETS exposure is likely due to decreased cytochrome oxidase activity

[Exs. 4-130, 4-131].

Nicotine, a component of tobacco smoke, has been shown in in vitro

studies, to inhibit the release of prostacyclin, through inhibition of

cyclooxygenase, from the rings of rabbit or rat aorta. Nicotine could

also affect platelets by releasing catecholamines which lead to

increased thromboxane A2 [Ex. 4-25]. Passive smoke also increases blood

viscosity and hematocrit due to relative hypoxia induced by chronic

carbon monoxide exposure [Ex. 4-25]. Nicotine, contained in cigarette

smoke can lead to catecholamine release, which enhances platelet

adhesiveness and decreases the ventricular fibrillation threshold. This

threshold is also affected by carbon monoxide levels [Exs. 4-25, 4-

196]. Cigarette smoke also increases the lipolysis that increases

levels of plasma free fatty acids, which result in enhanced synthesis

of LDL [Ex. 4-234].

In conclusion, there are multiple pathways by which ETS may damage

the heart. ETS exposure has been demonstrated to both increase

myocardial oxygen demand and decrease myocardial oxygen supply. If

oxygen demand exceeds supply for a long enough period of time, then

myocardial cell injury or even cell death can occur. In addition, ETS

exposure may cause platelets to become less sensitive to the anti-

clotting regulatory substances in the blood and therefore increase the

tendency of the blood to clot. An increased tendency for the blood to

clot may lead to an increased susceptibility to heart attacks.

ETS exposure may also contribute to the chronic formation of

arterial wall plaques which are implicated in the event of an acute

myocardial infarction. The two mechanisms described by which ETS

exposure may stimulate plaque formation are endothelial cell injury and

increased platelet activation.

Different people will have different abilities to deal with the

increased stress on the heart and the increased tendency of the blood

to clot as a result of ETS exposure. For example, a young, otherwise

healthy individual may be able to tolerate short-term ETS exposure

without apparent difficulty, although asymptomatic arterial wall injury

may occur which can contribute to cardiac injury in the future.

However, an older person with pre-existing coronary artery disease and

therefore minimum cardiac reserve may not be able to tolerate short-

term ETS exposure, due to the increased stress on the heart.

5. Reproductive Effects

Data on the reproductive effects due to the exposure of nonsmoking

pregnant women to ETS has been presented in many studies [Exs. 3-438,

4-92, 4-132, 4-174, 4-208, 4-273, 4-285, 4-287, 4-299]. This is

important since many nonsmoking women continue to work throughout their

pregnancies. Pregnant women working in indoor environments without

tobacco smoking restrictions, as in restaurants, comprise one of the

most heavily ETS-exposed groups [Exs. 4-151, 4-287].

Low birthweight has also been shown to be associated with paternal

smoking, implying passive exposure to tobacco smoke by the nonsmoking

mother [Exs. 4-92, 4-273]. Passive exposure to tobacco smoke is

estimated to double the risk of low birthweight in a full-term baby

[Ex. 4-208]. Nonsmoking pregnant women who are exposed to ETS have been

reported to deliver neonates that range 24 to 120 grams lighter in

weight than those babies delivered by nonexposed pregnant women [Exs.

4-132, 4-174, 4-208, 4-273]. This relationship between passive smoking

and low birthweight remains statistically significant even after

accounting for mother's age, parity, social class, sex of baby, and

alcohol consumption. This effect is more apparent in neonates born to

actively smoking women who deliver babies that weigh, on average, 200

grams less than those of nonsmoking women [Ex. 4-101]. The reduction in

birthweight is clinically significant at the low end of the birthweight

distribution. These infants have higher perinatal mortality [Ex. 4-

239].

Other reproductive effects that have been ascribed to maternal ETS

exposure include miscarriage, an increase in congenital abnormalities

[Exs. 4-239, 4-299], and numerous other physiological effects [Ex. 4-

297]. It was reported that these effects may be part of a general

immunosuppressive condition associated with the occurrence of low

birthweight [Ex. 4-299]. This effect may predispose the baby to

respiratory tract infections.

The effects of environmental smoke exposure on the fetus may have

long-term sequelae into childhood and adulthood [Exs. 4-53, 4-181, 4-

213, 4-225, 4-239, 4-51, 4-297]. There is limited evidence which

suggests that growth retardation observed in the fetus is reflected in

the growing child as reductions in lung development [3-438]. This is

especially relevant if that child continues to be exposed to ETS

throughout childhood and into adulthood [Exs. 4-177, 4-297]. Prenatal

exposure to ETS and exposure to ETS as a child may also increase an

individual's cancer risk, perhaps by a factor of two (2) [Exs. 4-65, 4-

164, 4-252].

Experimental research on the adverse reproductive effects

associated with ETS exposure in animals is limited. However, one study

[Ex. 4-6] demonstrated such effects. Sciatic nerve tissue taken from

the offspring of ETS-exposed female mice revealed definite toxic

effects on the neonatal tissue [Ex. 4-6]. Pregnant female mice (C57BL/

KsJ) were exposed to low-tar cigarette smoke in a special smoking

chamber. Cigarette smoke was blown into the chamber for 4 minutes, 5

times daily, except on weekends when this was done 3 times daily. At 18

days of gestation, blood samples were taken and carbon monoxide levels

were measured. Ultrastructural abnormalities of fetal tissue revealed

swollen mitochondria with distorted cristae, some indication of

deformed mitochondria, darkened nuclei with condensations of nuclear

material, lamellar bodies, granules and myelin bodies similar to those

found in human toxicity studies. The blood samples from pregnant mice

revealed a mean carbon monoxide saturation in the hemoglobin of 9%

which is equivalent to that found in humans who actively smoke 10-20

cigarettes per day.

6. Cancer

Concern over the carcinogenic effects of ETS was expressed in many

comments submitted to the docket, such as Exs. 3-32, 3-35, 3-38, 3-207,

3-438, 3-440A, and 3-449. The results of epidemiological and

experimental studies indicate that exposure to ETS is causally

associated with cancer of the lung in chronically-exposed nonsmokers. A

discussion of this evidence follows.

(a) Evidence of Association.--The results of epidemiological

studies taken in the aggregate suggest that nonsmoker exposure to ETS

is causally-related to the development of lung cancer.

Evidence of specificity of effect is provided by active smoking

studies that report a causal association with lung cancer [Ex. 4-311].

It was therefore logical to examine nonsmokers with passive exposure to

tobacco smoke, since the chemicals found in passive smoke are

qualitatively similar to those in mainstream smoke. Active smoking

induces all four major histological types of human lung cancer--

squamous-cell carcinomas, small-cell carcinomas, large-cell carcinomas,

and adenocarcinomas [Ex. 4-311]. The results of lung cancer studies

that examined the variation in tumor cell type induced by ETS exposure

indicate that mostly adenocarcinomas and squamous cell carcinomas are

produced by ETS exposure. Some studies have reported an excess of

adenocarcinomas, while others have reported excesses in squamous cell

and small-cell carcinomas. From this information, it is apparent that

similar tumor cell types are induced by ETS exposure as are induced by

active smoking.

The unequivocal causal association between active tobacco smoking

and lung cancer in humans, as well as the corroborative evidence of the

carcinogenicity of tobacco smoke provided by animal bioassays and in

vitro studies and the chemical similarity between mainstream smoke and

ETS, clearly establish the plausibility that ETS is also a human lung

carcinogen (Table II-2). In addition, biomarker studies verify that ETS

exposure results in detectable uptake of tobacco constituents by

nonsmokers [Exs. 4-50, 4-311].

Table II-2.--43 Chemical Compounds Identified in Tobacco Smoke for

Which There is ``Sufficient Evidence'' of Carcinogenicity in Humans or

Animals [Ex. 4-160]

Acetaldehyde

Acylonitrile

Arsenic

Benz (a)anthracene

Benzene

Benzo (a)pyrene

Benzo(b)fluoranthene

Benzo (k)fluoranthene

Cadmium

Chromium VI

DDT

Dibenz(a,h)acridine

Dibenz(a,j)acridine

Dibenz(a,h)anthracene

Dibenzo (a,i)pyrene

Dibenzo (a,e)pyrene

Dibenzo (a,l)pyrene

Dibenzo (a,h)pyrene

Formaldehyde

Hydrazine

Lead

Nickel

N-nitrosodiethanolamine

N-nitrosodiethylamine

N'-nitrosodimethylamine

N'-nitrosonornicotine

N-nitrosopiperidine

N-nitrosodi-n-propylamine

N-nitrosopyrrolidine

N-nitrosodi-n-butylamine

ortho-toluidine

Styrene

Urethane

Vinyl chloride

1,1-dimethylhydrazine

2-nitropropane

2-napthylamine

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

4-aminobiphenyl

5-methylchrysene

7H-dibenzo(c,g)carbazole

Indeno (1,2,3,-cd)pryene

(b) Epidemiological and Experimental Studies. There are at least 32

epidemiological studies that have attempted to evaluate the

carcinogenic potential of ETS. OSHA analyzed these studies and

determined that 14 were positive for an association [Exs. 4-36, 4-65,

4-106, 4-119, 4-121, 4-142, 4-143, 4-153, 4-158, 4-187, 4-252, 4-275,

4-276, 4-292, 4-300], 5 were equivocal with a positive trend [Exs. 4-4,

4-47, 4-117, 4-122, 4-171], and 13 were equivocal [Exs. 4-35, 4-38, 4-

52, 4-118, 4-148, 4-164, 4-175, 4-183, 4-192, 4-283, 4-286, 4-296, 4-

326]. [See the Risk Assessment section for further discussion.]

OSHA considered the consistency of the association to determine if

the finding of the same exposure effect occurred in different

populations and different types of studies. The great number of

epidemiological studies available on ETS were conducted by different

researchers, on different populations, in various countries with

diverse study designs. This extensive amount of data increases

confidence that the associations seen between ETS exposure and the

development of lung cancer is externally consistent and is not due to

artifacts or a product of some unidentified, indirect factors unlikely

to be common to all of the studies. The fact that exposure to ETS is

common dilutes the risk estimates derived from these studies because

the comparison group has some exposure to ETS. A recent Centers for

Disease Control and Prevention (CDC) report [Ex. 4-50] found that 100%

of a subset of the National Health and Nutrition Evaluation Survey

(NHANES) III conducted by the National Center for Health Statistics had

detectable levels of cotinine in their bodies indicating that everyone

in the sample had detectable exposure to tobacco smoke [Ex. 4-50].

Cotinine is a metabolite of nicotine and is used as a surrogate of

exposure to tobacco smoke. This indicates that the cancer risk may

indeed be greater since the relationship in these studies has been more

exposed versus less exposed instead of exposed versus nonexposed.

Many potential sources of bias, such as publication bias (the

tendency of scientific journals to publish studies with positive

results), misclassification bias (smokers or former smokers claiming to

be nonsmokers), and recall bias (the reliance on self-reporting of both

personal smoking habits and exposure to others' tobacco smoke) can not

account for the elevation in risks seen in these various studies. Also,

the relative risks that were estimated from prospective study data are

similar to those estimated from case/control study data. Biases that

may be problematic to case-control studies are not a problem in

prospective studies. Since the results from both types of studies are

similar it is apparent that these biases are not important in the case-

control studies (e.g., misclassification bias and recall bias). This

information strengthens the confidence of a causal connection.

Animal studies have shown the carcinogenicity of cigarette smoke.

Limited existing data suggest that sidestream smoke may contain more

carcinogenic activity per milligram of cigarette smoke concentrate than

does mainstream smoke [Ex. 3-689D]. Currently, OSHA is aware of only a

few experimental inhalation studies with sidestream smoke or ETS

reported in the literature. A discussion of these studies follows.

Otto and Elmenhorst [Ex. 4-247] have shown that there are

carcinogenic constituents in the vapor phase of tobacco smoke. They

exposed C57B1 and BLH mice to the gas phase of cigarette mainstream

smoke of 12 cigarettes for 90 minutes daily over 27 months. The

particulate matter was removed by passing the smoke through a Cambridge

filter. The percentages of mice with lung adenomas were 5.5% and 32% in

the smoke-exposed C57B1 and BLH mice, as compared to 3.4% and 22% for

their respective controls. Leuchtenberger and Leuchtenberger [Ex. 4-

197] have also shown that the rate of tumors among mice exposed to the

gas phase was greater than animals exposed to the whole smoke.

Pulmonary adenomas and adenocarcinomas were induced in Snell's mice by

the gas phase but not by the whole smoke in this study. These studies

demonstrate that the carcinogenicity of tobacco smoke is not limited to

the particulate phase.

Studies have also reported hyperplasia and metaplasia in the

trachea and bronchi of mice exposed to cigarette smoke by the

inhalation route [Exs. 4-226, 4-327]. Four lung tumors and emphysema

were detected in 100 male and female C57B1 mice exposed, nose only, to

fresh mainstream smoke [Ex. 4-135].

Pulmonary squamous neoplasms were detected in female Wistar rats

exposed to a 1:5 smoke-to-air mixture for 15 seconds of every minute

during an 11 minute exposure twice a day, 5 days per week, for the

lifespan of the animals [Ex. 4-79]. Respiratory tumors were also

observed in Fischer-344 rats exposed, nose only, to a 1:10 smoke to air

mixture for approximately 30 seconds every minute, 7 hours per day, 5

days per week for 128 weeks [Ex. 4-77]. The incidence of laryngeal

leukoplakias in Syrian golden hamsters ranged from 11.3% for the

animals that received the low dose to 30.6% of those animals that

received the highest dose. These animals were exposed to a 1:7 smoke-

to-air mixture for 10 to 30 minutes, 5 days a week, nose only, for a

period of up to 52 weeks [Ex. 4-88]. Exposing hamsters twice a day, 5

days a week for up to 100 weeks resulted in almost 90% of the exposed

hamsters having hyperplastic or neoplastic changes in the larynx in a

study by Bernfeld et al. [Ex. 4-30]. Lung tumors have been reported in

beagle dogs exposed to the smoke from nonfilter cigarettes [Ex. 4-19].

However, no tumors were seen in rabbits exposed to cigarette smoke for

up to 5\1/2\ years [Ex. 4-149].

Sidestream condensates have also been shown to cause

carcinogenicity when implanted into female Osborne-Mendel rat lungs

[Ex. 4-127]. Cigarette smoke condensate fraction from sidestream smoke

was implanted at a dose level of one cigarette per animal in this

study.

Coggins et al. [Ex. 4-59] reported epithelial hyperplasia in the

nasal cavity of high-dosed rats exposed to environmental tobacco smoke.

They exposed Sprague-Dawley rats of both sexes, nose only, to ``aged

and diluted sidestream smoke'' (ADSS) at 0.1, 1 or 10 mg of

particulates per meter for 14 days and found ``slight to mild''

epithelial hyperplasia and inflammation in the most rostral part of the

nasal cavity in the 10 mg group only. They also found that these

changes were reversible if the animals were kept without further

exposure for an additional 14 days. No effects in the lung were

reported. Similar results of mild hyperplasia were also obtained when

male rats were exposed to the same concentrations for up to 13 weeks

[Ex. 4-60]. In this study the authors reported hypercellularity and the

thickening of the respiratory epithelium of the dorsal nasal conchae

and adjacent wall of the middle meatus.

Rats are obligatory nose-breathers, and the anatomy and physiology

of the respiratory tract and the biochemistry of the lung differ

between rodents and humans. Because of these distinctions, laboratory

animals and humans are likely to have different deposition and exposure

patterns for the various cigarette smoke components in the respiratory

system. For example, rodents have extensive and complex nasal

turbinates where significant particle deposition could occur,

decreasing exposure to the lung. These anatomical and physiological

differences, aside from the subchronic exposure, may partially account

for absence of any lung tumors in the study by Coggins et al.

The application of cigarette smoke condensate (CSC) to mouse skin

is a widely employed assay for the evaluation of carcinogenic

potential. CSC assays may not, however, reveal all of the carcinogenic

activity of actual cigarette smoke, because these condensates lack most

of the volatile and semi-volatile components of whole smoke. Benign

skin tumors and carcinomas were seen in Swiss-ICR mice exposed to

cigarette tar from the sidestream smoke of nonfilter cigarettes

suspended in acetone and applied to skin for 15 months [Ex. 4-327]. In

lifetime rat studies, intrapulmonary implants of mainstream smoke

condensate in a lipid vehicle caused a dose-dependent increase in the

incidence of lung carcinomas [Exs. 4-75, 4-289].

The polyamines contained in tobacco smoke, spermidine, spermine,

and their diamine precursor, putrescine, are believed to have an

essential role in cellular proliferation and differentiation. Formation

of putrescine from ornithine is catalyzed by ornithine decarboxylase

(ODC), the rate-limiting enzyme in polyamine biosynthesis. A

significant increase in lung and trachea ornithine decarboxylase

activity was observed by Olsen [Ex. 4-245] after an eight week exposure

of male Sprague-Dawley rats to MS smoke. All dilutions of SS smoke

exposure caused significant increase in trachea ODC activity but did

not influence the lung ODC activity.

Environmental tobacco smoke induced carcinogenicity is also

supported by a case-control study of lung cancer in pet dogs [Ex. 4-

259]. The study compared the incidence of lung cancer in pet dogs

exposed to their owners' smoking versus dogs whose owners did not

smoke. Dogs have a very low natural incidence of lung cancer. There was

an elevated risk of lung cancer (Relative Risk = 1.6) observed in pets

with smoking owners. However, the analysis was statistically

insignificant, perhaps in part due to small sample size.

7. Genotoxicity

Short-term mutagenicity tests have gained widespread acceptance as

an initial step in the identification of potential carcinogens.

Extensive use of these tests has come about because they are easy to

perform and are inexpensive and also because of the reported high

positive correlations between short-term mutagenicity tests and

carcinogenicity. It has been reported that 90 percent of the

carcinogens tested are mutagens and 90 percent of the noncarcinogens

are nonmutagens.

Several short-term bioassays have been performed to evaluate the

genotoxicity of cigarette smoke. While most of them have evaluated the

effect of cigarette smoke condensate, some have attempted to evaluate

either the gas phase or the whole smoke.

The most commonly employed assay for mutagenic activity employs

various strains of Salmonella typhimurium. Whole smoke as well as

cigarette smoke condensate of tobacco have been shown to be mutagenic

in Salmonella typhimurium strain TA 1538 [Ex. 4-21]. Sidestream smoke

was also found to be mutagenic in a system where the smoke was tested

directly on the bacterial plates [Ex. 4-246]. Sidestream smoke and

extracts of ETS collected from indoor air [Exs. 4-202, 4-5, 4-198, 4-

201, 4-203] also exhibited mutagenic activity in this bacterial strain.

Claxton et al. [Ex. 4-55] found that sidestream smoke accounted for

approximately 60% of the total S. typhimurium mutagenicity per

cigarette, 40% from the sidestream smoke particulates and 20% from the

semi-volatiles. The highly volatile fraction, from either mainstream or

sidestream smoke was not mutagenic.

Condensates from both mainstream [Exs. 4-89, 4-193] and sidestream

smoke [Ex. 4-90] have also been reported to have mutagenic activity.

Doolittle et al. [Ex. 4-89] demonstrated the genotoxicity of the

sidestream smoke from the Kentucky Reference cigarette (1R4F) by

employing several different assays. In their study, sidestream smoke

produced positive results in Salmonella typhimurium strains TA98,

TA100, TA1537, and TA1538 in the presence of S9 mix from aroclor-

induced rat liver but produced negative results in strain TA1535. They

also showed that sidestream smoke produced positive results in the

Chinese hamster ovary cells chromosomal aberration assay and in the

Chinese hamster ovary cell sister-chromatid exchange assay both with

and without metabolic activation. They demonstrated that the sidestream

smoke was weakly positive in inducing DNA repair in cultured rat

hepatocytes. However, sidestream smoke was nonmutagenic in the Chinese

hamster ovary cell-HGPRT assay both with and without metabolic

activation but it was found to be cytotoxic in this system.

In their further studies, Doolittle et al. [Ex. 4-90] observed

similar responses when they measured the genotoxic activity of

mainstream cigarette smoke condensate (CSC) from Kentucky reference

research cigarette (1R4F). As seen with sidestream smoke, CSC in this

study was mutagenic in Salmonella typhimurium strain TA98, TA100,

TA1537, and TA1538 in the presence of S9 mix but was negative in strain

TA1535. CSC was also positive in the Chinese hamster ovary (CHO) cells-

chromosomal aberration assay and in the CHO-sister-chromatid exchange

assay both with and without metabolic activation. CSC was weakly

positive in inducing DNA repair in cultured rat hepatocytes. However,

again as seen with sidestream smoke, CSC was nonmutagenic in the CHO-

HGPRT assay, with or without metabolic activation but was found to be

cytotoxic in this system. The results from these two studies appear to

indicate that sidestream smoke behaves very much like mainstream smoke

in these assays.

Mohtashamipur et al. [Ex. 4-227] demonstrated significant mutagenic

activity in the urine of rats exposed to sidestream smoke. In this

study, cigarettes were machine smoked under standardized laboratory

conditions and the sidestream smoke of two cigarettes was directed

through metabolism cages containing rats. The urine of these rats was

collected 24 hours prior to the SS exposure and 24 hours after the

onset of the exposure. The individual urine samples of all (10) rats

after exposure showed significantly higher activity for direct-acting

mutagens (in strain TA1538) than the urine samples of the same rats

before the exposure.

The formation of DNA adducts is widely accepted as an initial step

in the carcinogenesis process. The measurement of DNA adducts by the

\32\P-postlabeling assay has been used as a way to assess DNA damage

following exposure to cigarette smoke. Lee et al. [Ex. 4-194] exposed

Sprague-Dawley rats to 0.1, 1.0 and 10 mg total particulate matter/m\3\

of aged and diluted sidestream smoke (ADSS) for 6 hours per day for 14

consecutive days. They examined the DNA from lung, heart, larynx and

liver after 7 and 14 days of exposure and after 14 days of recovery.

They also examined alveolar macrophages for chromosomal aberrations.

Exposure related DNA adducts were found in the highest dose test.

However, no elevation in chromosomal aberrations was observed in

alveolar macrophages in this study. Similar results were also obtained

when animals were exposed to the same three concentrations for up to 90

days. DNA adducts were seen in lung, heart and larynx DNA of the

animals exposed to the highest concentration of ADSS [Ex. 4-195]. The

adduct levels were highest after 90 days of exposure and were

significantly reduced in all target tissues 90 days after cessation of

exposure. Again, chromosomal aberrations in alveolar macrophages were

not elevated in any group after 90 days of exposure. The authors

concluded that the concentration of DNA adducts formed in the lung

tissue did not increase linearly as the ADSS concentration was

increased from 1 to 10 mg.

Several short-term tests have been performed in eukaryotic systems.

A solution of the gas phase of mainstream cigarette smoke has been

shown to induce reciprocal mitotic recombination in Saccharomyces

cerevisiae D3 and petite mutants in an isolate of strain D3 [Ex. 4-

163]. Whole mainstream cigarette smoke induced mitotic gene conversion,

reverse mutation, and reciprocal mitotic recombination in strain D7 of

Saccharomyces cerevisiae [Ex. 4-113]. Transformation of mammalian cells

was induced in several cell systems using the cigarette smoke

condensate from mainstream cigarette smoke [Exs. 4-22, 4-161, 4-188, 4-

267, 4-268, 4-298].

Another in vitro assay that measures the number of sister-chromatid

exchanges (SCEs) induced has been employed widely to determine the

mutagenic activity of cigarette smoke. Valadand-Berrieu and Izard [Ex.

4-313] used a solution of the gas phase from cigarette mainstream smoke

and showed that this solution induced a significant dose-related

increase in sister-chromatid exchanges. Putman et al. [Ex. 4-257] have

also demonstrated dose-dependent increases in sister chromatid exchange

frequencies in bone-marrow cells of mice exposed to cigarette smoke for

2 weeks.

Review of the literature clearly demonstrates that MS smoke and ETS

exposure causes cancer in humans. These results are supported not only

by animal studies but also by studies that show SS smoke to be both

genotoxic and clastogenic.

8. Conclusions

The epidemiological and clinical studies, taken in aggregate,

indicate that exposure to environmental tobacco smoke may produce

mucous membrane irritation, pulmonary, cardiovascular, reproductive,

and carcinogenic effects in nonsmokers. Exposure to ETS may aggravate

existing pulmonary or cardiovascular disease in nonsmokers. In

addition, animal studies show that both mainstream and sidestream

tobacco smoke produce similar adverse effects.

D. Case Reports

1. Sick Building Syndrome and Building-Related Illness

Many case reports of material impairment of health due to

occupational exposure to poor IAQ have been reported to OSHA through

submission to the indoor air quality docket [H-122]. These adverse

health effects range from irritation effects to more severe, life-

threatening building-related illnesses, such as Legionnaire's disease,

and cancer.

Ford Motor Company responded in docket comment 3-447, that

``[p]resently, at Ford, we investigate an average of two IAQ complaints

per month which are predominantly classified as Sick Building Syndrome.

We have seen Building-Related Illness, but these incidents have been

rare and associated with specific contaminant episodes. The IAQ

complaints we generally investigate are characterized by general

malaise, headache, and flu-like symptoms that are said to disappear

when the occupants leave the building * * * Of the IAQ problems

investigated, about 20 percent can be attributed to PTS [passive

tobacco smoke]/ETS. Upper respiratory irritation or eye irritation

typically are associated with these complaints.'' Similar types of

health effects were reported to the agency in docket comments 3-1, 3-

22, 3-58, 3-142C, 3-367, 3-413, 3-529, 3-632, 3-634, 3-642, 3-659, and

3-698.

One comment [Ex. 3-433 reported that ``based upon approximately 30

IAQ investigations in a member company over the past two and one-half

years, the following adverse health effects have been reported in

office environments: eye, nose, and throat irritations; headaches,

nausea, dizziness, fatigue; cough, shortness of breath, chest

tightness. These so-called ``sick building syndrome (SBS)'' symptoms

often disappear when the person leaves the building environment. These

symptoms are usually subjective and non-specific, lacking a physician's

diagnosis of a definite illness.'' Others have reported [Ex. 3-377]

that ``as air flow and ventilation are cut back, our workers are

becoming sick. Many are exposed to contaminants or other harmful

substances; and, without ventilation, these sources linger and cause

nausea, skin irritations and other unhealthy symptoms of illness. In

severe cases, these contaminants and bacteria have been known to

contribute to upper respiratory infections.'' Comment 3-570 reported

similar health effects due to poor indoor air quality.

More serious health conditions have been reported ranging from

severe asthma to central nervous systems disorders. For example,

Comment 3-158 responded that ``I have developed a serious asthma

condition due to indoor air quality problems. Besides, three of the

remaining five employees at the branch office have been diagnosed with

chronic fatigue syndrome. In conversations with various health care

professionals, I have come to the conclusion that the diagnoses of

chronic fatigue syndrome were actually sick building syndrome. Of the

six employees at the branch office, four of the six are moderate to

heavy smokers. This does not take into consideration the other factors

that could be causing poor indoor air quality problems in the office.''

Comment 3-631 was a collection of reports from the workers in one

building that illustrate the poor conditions of a building that can

lead to serious health effects in workers. Health problems experienced

by workers in this building included chronic sinus infections;

headaches; fatigue; eye, nose and throat irritations; difficulty

breathing and congestion; allergies; and asthma. These health problems

seem to clear up when the workers were out of the building over a

weekend or a vacation.

The physical condition of this building was obviously in disrepair

since the commenters reported pails of stagnant water, collected from

leaks in the roof, were left in hallways. Water in ``[t]hese pails

ha[d] overflowed and run down the stairs. What [wa]s left in the pails

evaporate[d] leaving a gross residue of who knows what.'' The water

leaks from the roof caused mold infestation and water damage. Water

logged insulation hung in the ceiling out in a hallway. There was an

obvious lack of routine, sufficient cleaning. Dust and particulate

matter were visible in the air. The bathrooms were dirty. Smells of

sewer gas, mold, and diesel and other vehicular fumes permeated the

office space. Ventilation problems were evident since paint or varnish

fumes lingered whenever part of the inside physical structure of the

building was painted. Tar fumes were evident from constant patching of

the leaky roof. Insect infestation of the building was evident.

Pesticide fumes lingered whenever the building was spray[ed] for

roaches and steam bugs. Workers sighted cockroaches, silverfish, and

steam bugs near the coffee shop and on back stairs. The comment

continued that ``a sink faucet in the lunch room has been leaking for

years and water runs on the counter under the toaster and microwave.

The water heater had leaked for about 2 months before it was fixed. At

that time the carpet was soaked and water was running under the wall

into a supervisor's office. There is a moldy odor from this carpet and

the floor below.''

Cancer has also been reported to be associated with poor indoor air

quality. A courthouse in San Diego, California [Ex. 3-55], ``is

notorious for poor air quality and employee respiratory illness and

cancer.'' It was reported to OSHA that many long-term employees have

cancer (stomach and lung cancer), terminal lung disease, chronic ear

and throat infections, and bronchial problems'' [Exs. 3-585, 3-635, 3-

637, 3-68].

Comment 3-630 from a union reported that ``[a]fter surveying

thousands of workers across the country, SEIU compiled actual survey

responses that list adverse health effects caused by indoor air

pollution. These include headaches, nose congestion or irritation,

throat irritation, dry cough, dry or itchy skin, dizziness, nausea,

lethargy or fatigue, colds, asthma/wheezing, chest tightness, runny

nose/post nasal drip, eye or contact lens irritation, respiratory

difficulties. In addition, EPA estimates that pollutants found in

indoor air are responsible for 2,500 to 6,500 cancer deaths each year''

[refer to Ex. 3-630L].

These concerns are not just relevant to office workers but also to

maintenance and other nonindustrial workers that work in indoor

environments. For example, comment 3-347 responded that ``[i]n our

closed, indoor work environments, air quality is a very real health and

safety concern to professional painters. I have seen firsthand

otherwise healthy men and women pass out or get violently ill as a

result of being exposed to indoor air contaminants.'' Comment 3-412

responded ``[o]ur locals have encountered air-pollution problems

ranging from ink mist and photocopier emissions to asbestos and

microbial disease. The level of toxic chemical contaminants is often

alarmingly high in our darkrooms, and carbon-monoxide emissions from

trucks at newspaper loading docks frequently penetrate the ventilation

system. In 1985 microbial contamination from a water tower infected six

New York Times employees with Legionnaires' Disease and 34 others with

less serious respiratory infections.''

Operation engineers are also affected by poor indoor air quality.

Comment 3-452 responded that ``[t]his is particularly important for the

operation engineers who appear healthy and then suffer from respiratory

problems, much like allergic reactions, after working in a building

with poor ventilation.''

2. Environmental Tobacco Smoke

Many case reports of severe material impairment of health due to

occupational exposure to ETS have been reported to OSHA through

submission to the indoor air quality docket [H-122]. Information

contained in these comments indicate that adverse health effects in

workers due to environmental tobacco smoke exposure while at work range

from mucous membrane irritation (eye, nose, and throat effects) to more

severe, life-threatening conditions, such as status asthma, other

chronic lung diseases and heart diseases. For example, comment 3-309

responded [Regarding ETS exposure in a cafeteria], ``By the time I have

finished lunch my eyes are tearing, my nose is plugged, and I have a

headache'' as well as comment 3-315, ``I had fewer headaches and fewer

respiratory ailments; my chronic sore throat disappeared [after a

company-wide no smoking policy was implemented]''. Comment 3-22

responded ``[m]y patients find it hard to obtain smoke free workplaces.

I have seen patients who have suffered status asthma from workplace

smoking, patients who have had to quit their jobs because of ETS in the

workplace. Recently, one of my never smoking patients sustained vocal

cord lesions seen almost entirely in smokers.'' Comment 3-104 continued

that ``[p]assive tobacco smoke (PTS) is the principal indoor air

contaminant in my office building in Rockefeller Center. While smoking

is limited to `private offices', the smoke flows freely from these

private offices throughout the entire general office areas since the

smokers will not keep their doors closed, and even when they do, they

have to come out sometime. And, as soon as the door is opened, the

dense smoke accumulation within the office is diffused to all adjacent

work areas. Because office buildings have closed ventilation systems,

only a `smoke free' office policy can be effective. Half measures only

cause further stress, frustration and irritation to both smokers and

nonsmokers.'' Comment 3-289 responded that ``I have been exposed to

asbestos culminating in my getting asbestosis (plural plaque) of the

lungs. The combination of asbestos exposure plus second-hand smoke from

my smoking co-workers has posed and is currently posing a health risk

to me.''

III. Exposure

Contaminants which contribute to poor indoor air quality can be

attributed to both outside air and inside air. Outside air contaminants

can be introduced into a building through the ventilation intakes,

doors, building envelope, and windows. Outside air contaminants include

vehicular exhausts, industrial emissions, microbiologicals, and pollen.

Inside air contaminants are emitted from building materials and

furnishings, appliances, office equipment and supplies, biological

organisms, and of course, pollutants introduced by the building

occupants themselves. Inside air contaminants include tobacco smoke,

volatile organic compounds, combustion gases such as carbon monoxide,

and occupant-generated bioeffluents. The concentration of these

contaminants in buildings can increase if ventilation systems are

inadequately designed, maintained and operated or if strong local

contaminant sources are not controlled.

A. Sources of Indoor Air Contaminants

A wide variety of substances are emitted by building construction

materials and interior furnishings, appliances, office equipment, and

supplies, human activities, and biological agents. For example,

formaldehyde is emitted from various wood products, including particle

board, plywood, pressed-wood, paneling, some carpeting and backing,

some furniture and dyed materials, urea-formaldehyde insulating foam,

some cleaners and deodorizers, and from press textiles. Volatile

organic compounds, including alkanes, aromatic hydrocarbons, esters,

alcohols, aldehydes, and ketones are emitted from solvents and cleaning

compounds, paints, glues, caulks, and resins, spray propellants, fabric

softeners and deodorizers, unvented combustion sources, dry-cleaning

fluids, arts and crafts, some fabrics and furnishings, stored gasoline,

cooking, building and roofing materials, waxes and polishing compounds,

pens and markers, binders and plasticizers. Pesticides also contain a

variety of toxic organic compounds.

Building materials are point sources of emissions that include a

variety of VOCs (Table III-1). Some of these materials have been linked

to indoor air quality problems. The probability of a source emitting

contaminants is related to the age of the material. The newer the

material, the higher the potential for emitting contaminants. These

materials include adhesives, carpeting, caulks, glazing compounds, and

paints [Ex. 4-33]. These materials, as well as furnishings can act as a

sponge or sink in which VOCs are absorbed and then re-emitted later.

Appliances, office equipment, and supplies can emit VOCs and also

particulates [Ex. 4-33]. Table III-2 lists the many contaminants that

can be emitted from these point sources. There is an indirect

relationship between the age of the point source and the potential rate

of contaminant emission [Ex. 4-33].

Table III-1.--Emissions From Building Materials or Interior Furnishings

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

Material Typical pollutants emitted

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

Adhesives.......................... Alcohols.

Amines.

Benzene.

Decane.

Dimethylbenzene.

Formaldehyde.

Terpenes.

Toluene.

Xylenes.

Caulking Compounds................. Alcohols.

Alkanes.

Amines.

Benzene.

Diethylbenzene.

Formaldehyde.

Methylethylketone.

Xylenes.

Carpeting.......................... Alcohols.

Formaldehyde.

4-Methylethyl- benzene.

4-Phenylcyclohexene.

Styrene.

Ceiling Tiles...................... Formaldehyde.

Clipboard/Particle Board........... Alcohols.

Alkanes.

Amines.

Benzene.

3-Carene.

Formaldehyde.

Terpenes.

Toluene.

Floor and Wall Coverings........... Acetates.

Alcohols.

Alkanes.

Amines.

Benzenes.

Formaldehyde.

Methyl styrene.

Xylenes.

Paints, Stains & Varnishes......... Acetates.

Acrylates.

Alcohols.

Alkanes.

Amines.

Benzenes.

Formaldehyde.

Limonene.

Polyurethane.

Toluene.

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

Table III-2.--Emissions From Appliances, Office Equipment and

Supplies\1\

Appliances......................... Carbon Monoxide.

Nitrogen Dioxide.

Sulfur Dioxide.

Polyaromatic hydrocarbons.

Carbonless Copy Paper.............. Chlorobiphenyl.

Cyclohexane.

Dibutylphthalate.

Formaldehyde.

Computers/Video Display Terminals.. n-Butanol.

2-Butanole.

2-Butoxyethanol.

Butyl-2-Methylpropyl phthalate.

Computer/Video Display Terminals... Caprolactam.

Cresol.

Diisooctyl phthalate.

Dodecamethyl cyclosiloxane.

2-Ethoxyethyl acetate.

Ethylbenzene.

Hexanedioic acid.

3-Methylene-2-pentanone.

Ozone.

Phenol.

Phosphoric Acid.

Toluene.

Xylene.

Duplicating Machines............... Ethanol.

Methanol.

1,1,1-Trichloroethane.

Trichloroethylene.

Electrophotographic Printers, Ammonia.

Photocopiers & Related Supplies. Benzaldehyde.

Benzene.

Butyl methacrylate.

Carbon black.

Cyclotrisiloxane.

Ethylbenzene.

Isopropanol.

Methylmethacrylate.

Nonanal.

Ozone.

Styrene.

Terpene.

Toluene.

1,1,1-Trichloroethane.

Trichloroethylene.

Xylenes.

Zinc stearate combustion Products.

Microfiche Developers/Blueprint Ammonia.

Machines.

Preprinted Paper Forms............. Acetaldehyde.

Acetic Acid.

Acetone.

Acrolein.

Benzaldehyde.

Butanal.

1,5-Dimethylcyclopentene.

2-Ethyl furan.

Heptane.

Hexamethyl cyclosiloxane.

Hexanal.

4-Hydroxy-4-methyl pentanone.

Isopropanol.

Paper dust.

Propionaldehyde.

1,1,1-Trichloroethane.

Typewriter Corrections Fluid....... Acetone.

1,1,1-Trichloroethane.

\1\Source: [Ex. 4-33]

Emissions from equipment, such as computers, will decrease over

time compared to emissions from equipment that continually use

chemicals. Emissions from such equipment (e.g., laser printers) that

use chemicals continually, will obtain a steady state concentration

dependent upon the chemicals used and frequency of equipment use.

B. Microbial Contamination

Three conditions must exist in buildings before microbial

contamination can occur: high humidity (over 60%), appropriate

temperatures (varies according to microbe), and appropriate growth

media [Exs. 3-61, 4-33]. These conditions are found in heating,

ventilating, and air conditioning (HVAC) systems. HVAC systems provide

multiple sites for microbes to grow (reservoir) and also the means to

disperse the microbes throughout the ventilated space. These reservoirs

of microbial growth, if allowed to proliferate unchecked, can lead to

indoor air quality problems once the microbes or microbe-related

products, such as endotoxins, are dispersed.

Building materials that have been soaked with water, such as

fiberglass insulation in air handlers, furnishings and fabrics, ceiling

tiles, and carpeting are excellent media for microbial growth.

Biological organisms, including fungal spores, bacteria, viruses,

pollens, and protozoa derived from mold growth have been identified in

humidifiers with stagnant water, water damaged surfaces and materials,

condensing coils and drip-pans in HVAC systems, drainage pans in

refrigerators, dirty heating coils, and are also associated with

mammals, arthopods and insects. Table III-3 gives examples of

biologicals found in indoor environments.

Various allergens have been associated with the development of

allergic rhinitis, asthma, or airway hyperresponsiveness (Table III-3)

[Ex. 4-33]. Many of these allergens are common to the nonindustrial

work environment. These include chemical volatiles and dusts,

arthropods, and dusts, particulates & fibers.

Table III-3.--Examples of Biologicals Found in Indoor Environments\1\

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

Class Agent or component Origin

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

Arthopods and Insects........................... Whole organism, body parts, feces................. Furnishings, building materials, food.

Microbes:

Algae....................................... Whole organism, cellular components............... Outdoor air, HVAC (rare).

Bacteria.................................... Whole organism, spores and cell walls, endotoxin.. Stagnant water, floods, cooling towers, industrial

processes.

Fungi....................................... Whole organism spores and hyphae toxins and Moist surfaces, HVAC system, bird droppings,

volatiles. outdoor air.

Protozoa.................................... Whole organism cellular components................ Water reservoirs, pets (rare).

Viruses..................................... Whole organism.................................... Humans and pets (rare).

Pets............................................ Skin, scales danders, urine, saliva, feces........ Pets, pet litter, pet cages, pet toys, pet

bedding.

Plants.......................................... Stems, leaves and pollens......................... Outdoor and indoor air.

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

\1\Adapted from Ex. 4-33.

Table III-4.--Indoor Air Allergens Associated With Asthma\1\

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

Class Typical examples

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

Animal:

Avian................ High and low molecular weight proteins from

feathers and droppings.

Canine and Feline.... High and low molecular weight proteins from

dander, saliva, and feces.

Arthropods:

Mites, Cockroaches, Structural proteins, carbohydrates and

Crickets and Moths. metabolites.

Dusts, Particulates and

Fibers:

Household............ Pollens, fungi, danders and mites.

Metal................ Chromium, cobalt, nickel, platinum, and

vanadium.

Plant................ Castor bean, coffee, cotton, flour, and

grain.

Wood................. Oak, mahogany, redwood, red cedar.

Chemical Volatiles and Acrylates, amines, anhydrides, colophony,

Dusts. enzymes, epoxy resins, freon, furfuryl

alcohol, resins, isocyanates, latex,

organophosphates, polyvinyl chloride,

vegetable gums.

Microbes and Microbial

Products:

Bacteria............. Bacillus spp.

Fungi................ Alternaria spp., Aspergillus spp., Botrytis

spp., Cladosporium spp., Penicillium spp.,

Pullularia spp.

Pollens.................. Agrostis spp., Alopecurus spp., Anthoxanthum

spp. Cynosurus spp., Dactylis spp., Holcus

spp., Lolium spp., Secale spp.

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

\1\Source: Ex. 4-33.

Exposures that cause hypersensitivity reactions include

microorganisms, fumes, vapors, and dusts (Table III-5). These exposures

are associated with the development of hypersensitivity pneumonitis or

a less serious variant, humidifier fever [Ex. 4-33]. Many of these

contaminants are found in the nonindustrial workplace. Birds and

rodents are common pests. Air intakes can be contaminated with bird

droppings and other avian-associated problems when used as nesting

sites. These problems can affect the quality of the air being brought

into the ventilation system through these air intakes. Rodent

infestations affect work areas directly. Many of the chemicals listed

in Table III-5 are commonly found in most workplaces.

In summary, exposure to contaminants in nonindustrial workplaces

will vary according to the characteristics of the building. These

include its age, types of materials used in construction and the type

of equipment and supplies that are used by building occupants. The

design, maintenance, and operation of the building's HVAC system as

well as the general housekeeping of the building, can greatly influence

the levels of contaminants that exist.

OSHA requests data on the levels of these contaminants in

nonindustrial workplaces.

Table III-5.--Indoor Air Contaminants Associated With Hypersensitivity

Pneumonitis\1\

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

Class Typical examples

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

Animals:

Avian................ High and low molecular weight proteins from

feathers and droppings.

Rodent............... Low molecular weight proteins from urine and

feces.

Arthropods:

Weevils.............. Sitophilus spp.

Mites................ Ascaris spp.

Altered Host Proteins or Amines, anhydrides, epoxy resins vegetable

Chemical Hapten-Carrier gums, and isocyanates.

Conjugates.

Microbes:

Bacteria............. Thermoactinomycetes spp., Bacillus spp.

Fungi................ Aspergillus spp., Auerobasillium spp.,

Cephalosporium spp., Penicillium spp.

Organic Dusts &

Particulates:

Wood................. Bark, Sawdust and Pollen.

Grain................ Arthropod- and microbially-contaminated

grains and flours.

Cleaning Products.... Dust residues from carpet cleaning agents.

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

\1\Source: Ex. 4-33.

C. Exposure Studies

1. Low-level Contaminants

Experimental studies have demonstrated that exposure of susceptible

people to low level mixtures of VOCs have induced mucous membrane

irritation and pulmonary effects. Some of these studies are discussed

below.

The potential of indoor air contamination to produce adverse

effects in humans was demonstrated by Molhave et al. in Denmark [Ex. 4-

20]. These researchers studied 62 subjects suffering from ``indoor

climate symptoms''. These subjects reported primarily eye and upper

respiratory tract irritation, but were otherwise healthy individuals

that did not suffer from asthma, allergy, or bronchitis. The subjects

were exposed to a mixture of VOCs in concentrations of 0, 5, or 25 mg/

m3. These concentrations respectively represented ``clean'' air,

average polluted air, and the maximum polluted air in Danish

households. After exposure, a Digit Span test was administered. The

study found significant declines in performance on this test;

demonstrating that low-level exposures to volatile organic compounds

had an adverse effect on the ability to concentrate [Ex. 4-20].

Otto et al. [Ex. 4-248], repeating the Molhave et al. (1984)

experiment, studied 66 healthy subjects with no history of eye and

upper respiratory tract irritation. These subjects were exposed at 0

and 25 mg/m3 VOC-contaminated air. Otto et al. reported that while

subjects found the odor of chemicals unpleasant, to degrade indoor air

quality, to increase headache, and produce general discomfort, VOC

exposure for 2.75 hours duration did not affect performance on any

behavioral tests. These results imply that persons who experience

symptoms of SBS may have a lower threshold for certain health effects

compared to nonreactive people. This suggests that those with

compromised immune response (e.g. allergy sufferers) may be at elevated

risk of SBS.

Ahlstrom, et al. [Ex. 4-2] found that synergistic effects may occur

when one strong indoor irritant interacts with other indoor

contaminants present at low-level concentrations. Ahlstrom et al. found

that there was almost a 4-fold increase in the perceived odor strength

of formaldehyde at low concentration (0.08 ppm) when mixed with 100%

indoor air from a building where SBS was reported, relative to 10%

indoor air from the same building.

The Report of the Canadian Interministerial Committee on Indoor Air

Quality [Ex. 4-264] adopts the World Health Organization's definition

of health: ``Health refers to a state of complete physical, mental, and

social well being, and not just the absence of disease or infirmity.''

This definition was adopted to allow the setting of indoor air quality

guidelines based on ``comfort'' as well as ``health''. The report

observes that the symptoms of SBS are sufficiently general or

subjective that they may be indicative of several other medical

conditions. Therefore, perhaps the best indicator that workplace

exposure may play a role in the symptoms reported by an individual is

the observation that symptoms worsen during the work day, and disappear

shortly after leaving work. They state that because there is a wide

variation in individual susceptibility, based on genetics, age,

medication, previous exposure to pollutants, gender, and state of

health, especially those with allergies, that certain individuals may

be more sensitive to SBS than others.

2. Bioaerosols

The levels of bioaerosols in the indoor environment should reflect

those found in the outdoor environment. A rank order assessment,

comparing the abundance of microorganisms in the outdoor versus indoor

environment is one way of assessing this relationship [Exs. 3-61, 4-

229]. If indoor and outdoor sampling results are not comparable, then

it is possible that a reservoir of a particular microbe may be

amplifying in the indoor environment; especially if moisture and a

nutrient-rich substrate are available [Ex. 4-229]. An example of this

would be Legionella. Commonly found in the outdoor environment, the

bacteria are as expected, commonly found in untreated potable and

nonpotable water. Situations can occur that allow these reservoirs to

amplify not only in potable water and hot water service systems but

also water used in cooling towers and evaporative condensers [Ex. 4-

229]. Infection occurs if the bacteria are disseminated, either through

the HVAC system or potable water system (e.g., showers) to the

breathing zone of a susceptible person. A healthy individual may

develop the less severe Pontiac Fever. An individual that smokes or is

older may develop the more serious pneumonia [Exs. 4-33, 4-229].

3. Environmental Tobacco Smoke

The burning of tobacco in enclosed workplaces releases an aerosol

containing a large variety of solid, liquid, and gas phase chemical

compounds. Generation of tobacco smoke is governed by the source

emission characteristics of smokers and their tobacco products, whereas

removal is primarily determined by the rate of replacement of building

air by outside air, with re-emission of surface-sorbed compounds

playing a minor role. Natural and mechanical ventilation systems are

designed primarily to limit the accumulation of the products of human

respiratory metabolism, and secondarily to limit odor; not to control

the byproducts of biomass combustion. Thus, smoking indoors creates air

pollution which is not adequately abated by customary ventilation

systems.

Exposure to tobacco smoke primarily occurs through the inhalation

route. Such an exposure can be measured by the determination of the

absorption, distribution, metabolism and excretion of tobacco smoke

constituents and/or their metabolites. However, relatively few of these

individual constituents have been identified and characterized. Also,

measurement of all components in tobacco smoke is not feasible.

Therefore, it becomes necessary to identify a marker which, when

measured, will accurately represent the frequency, duration and

magnitude of the exposure to environmental tobacco smoke.

This discussion reviews available data for the purposes of

assessing exposure to ETS in the workplace. Nonsmokers are exposed to

mainstream smoke after it has been exhaled by smokers, and to diluted

sidestream smoke. Issues covered include activity patterns affecting

the duration of nonsmokers' exposures, the concentrations of ETS in

buildings, the comparison of ETS components in indoor workplaces,

levels of biomarkers in workers, and the inadequacy of general dilution

ventilation to address ETS exposure control. This discussion will

indicate not only that exposure occurs, but that nonsmokers absorb ETS

components.

(a) Chemistry. Pipe, cigar, and cigarette smoke all contribute to

environmental tobacco smoke (ETS) but cigarette smoke is of principal

interest because it is by far the most common. Tables III-6 and III-7

list some of the known constituents of tobacco smoke.

The combustion of tobacco leads to the formation of mainstream

smoke (MS) and sidestream smoke (SS). MS is generated during puff-

drawing in the burning cone and hot zones; it travels through the

tobacco column and is inhaled by the smoker. The smoke which is exhaled

by the smoker, while different from the inhaled smoke, is also

considered ``mainstream.'' SS is formed in between puff-drawing and is

emitted directly from the smoldering tobacco product into the ambient

air.

Table III-6.--Vapor Phase Constituents of Tobacco Smoke and Related Health Effects

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

Constituent Amount in MS Ratio in SS/MS Health effects

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

Carbon monoxide............................................ 10-23 mg............. 2.5-4.7 Nervous system, cardiovascular system.\1\

Carbon dioxide............................................. 20-40 mg............. 8-11 Nervous system, cardiovascular system.\1\

Carbonyl sulfide........................................... 12-42 g..... 0.03-0.13 Irritant, cardiovascular, and nervous systems.\1\

Benzene.................................................... 12-48 g..... 5-10 Known human\3\ carcinogen.

Toluene.................................................... 100-200 g... 5.6-8.3 Irritant, nervous system.\1\

Formaldehyde............................................... 70-100 g.... 0.1- Probable human carcinogen.\3\

50

Acrolein................................................... 60-100 g.... 8-15 Irritant, pulmonary.\1\

Acetone.................................................... 100-250 g... 2-5 Irritant.\1\

Pyridine................................................... 16-40 g..... 6.5-20 Irritant, nervous system, liver, kidney.\1\

3-methylpyridine........................................... 12-36 g..... 3-13 Irritant.\2\

3-vinylpyridine............................................ 11-30 g..... 20-40 Irritant.\2\

Hydrogen cyanide........................................... 400-500 g... 0.1-0.25 Irritant, nervous, cardiovascular and pulmonary

system.\1\

Hydrazine.................................................. 32 ng................ 3 Probable human carcinogen.\3\

Ammonia.................................................... 50-130 g.... 3.7-5.1 Irritant.\1\

Methylamine................................................ 11.5-28.7 g. 4.2-6.4 Irritant.\1\

Dimethylamine.............................................. 7.8-10 g.... 3.7-5.1 Irritant\1\.

Nitrogen oxides............................................ 100-600 g... 4-10 Pulmonary and cardiovascular system.\1\

N-nitrosodimenthylamine.................................... 10-40 ng............. 20-100 Probable human carcinogen.\3\

N-nitrodiethylamine........................................ ND-25 ng............. g... 1.4-1.6 Irritant, skin, kidney, liver\1\.

Acetic acid................................................ 330-810 g... 1.9-3.6 Irritant.\1\

Methyl chloride............................................ 150-600 g... 1.7-3.3 Nervous system.\1\

1,3-butadiene.............................................. 69.2 g...... 3-6 Probable human carcinogen.\3\

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

\1\NIOSH Pocket Guide to Chemical Hazards. U.S. Department of Health and Human Services. Public Health Services, 1990. Ex. 4-238.

\2\Hazards in the Chemical Laboratory. Ed: L. Bretherick, The Royal Society of Chemistry, 1986. [Ex. 4-137]

\3\EPA: Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders, 1992. [Ex. 4-311]

Table III-7.--Particulate Phase Constituents of Tobacco Smoke and Related Health Effects

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

Constituent Amount in MS Ratio in SS/MS Health effects

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

Particulate matter contains di- and polycyclic aromatic 15-40 mg............. 1.3-1.9 Animal carcinogen.\4\

hydrocarbon.

Nicotine................................................... 1-2.5 mg............. 2.6-3.3 Nervous and cardiovascular system.\1\

Anatabine.................................................. 2-20 g...... g.... 1.6-3.0 Irritant.\1\

Catechol................................................... 100-360 g... 0.6-0.9 Irritant.\3\

Hydroquinone............................................... 110-300 g... 0.7-0.9 N/A.\5\

Aniline.................................................... 360 ng............... 30 Probable human carcinogen.\4\

2-Toluidine................................................ 160 ng............... 19 Irritant, cardiovascular system.\1\

2-Naphthylamine............................................ 1.7 ng............... 30 Known human carcinogen.\4\

4-Aminobiphenyl............................................ 4.6.................. 31 Known human carcinogen.\4\

Benz[a]anthracene.......................................... 20-70 ng............. 2-4 Animal carcinogen.\4\

Benzo[a]pyrene............................................. 20-40 ng............. 2.5-3.5 Probable human carcinogen.\4\

Cholesterol................................................ 22 g........ 0.9 N/A.\5\

-butyrolactone.................................... 10-22 g..... 3.6-5.0 Animal carcinogen.\4\

Quinoline.................................................. 0.5-2 g..... 3-11 Irritant.\3\

Harman [1-methyl-9H-pyrido[3,4-b]-indole................... 1.7-3.1 g... 0.7-1.7 N/A.\5\

N-nitrosonornicotine....................................... 200-3000 ng.......... 0.5-3 Animal carcinogen.\4\

NNK [4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone].. 100-1000 ng.......... 1-4 N/A.\5\

N-nitrosodiethanolamine.................................... 20-70 ng............. 1.2 Probable human carcinogen.\4\

Cadmium.................................................... 110 ng............... 7.2 Probable human carcinogen.\4\

Nickel..................................................... 20-80 ng............. 13-30 Known human carcinogen.\4\

Zinc....................................................... 60 ng................ 6.7 Irritant, nausea, vomiting.\2\

Polonium-210............................................... 0.04-0.1 pCi......... 1.04.0 Known human carcinogen.\4\

Benzoic acid............................................... 14-28 g..... 0.67-0.95 Irritant.

Lactic acid................................................ 63-174 g.... 0.5-0.7 Irritant.\3\

Glycolic acid.............................................. 37-126 g.... 0.60.95 Irritant.\2\

Succinic acid.............................................. 110-140 g... 0.43-0.62 N/A.\5\

PCDD's and PCDF's\6\....................................... 1 pg................. 2 N/A.\5\

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

\1\NIOSH Pocket Guide to Chemical Hazards. U.S. Department of Health and Human Services. Public Health Services, 1990. Ex. 4-238.

\2\The Merck Index, 10th Edition, Merck & Co., Inc., 1983. Ex. 4-220.

\3\Hazards in the Chemical Laboratory. Ed: L. Bretherick, The Royal Society of Chemistry, 1986. [Ex. 4-137]

\4\EPA: Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders, 1992. [Ex. 4-311]

\5\N/A--Relevant information not available.

\6\PCDDs--Polychlorinated dibenzo-p-dioxins; PCDFs--Polychlorinated dibenzofurans.

MS and SS cigarette smoke are chemically and physically complex

mixtures consisting of electrically charged submicron liquid particles

at very high concentration consisting of permanent gases, reactive

gases, and a large variety of organic chemicals. The composition of the

smoke and especially the total quantities of individual constituents

delivered are dependent on the conditions of smoke generation [Ex. 4-

311].

Nicotine, while found in the particulate phase in MS, is found

predominantly in the gas phase in ETS [Ex. 4-100]. The differences in

size distribution for MS and SS particles, as well as the different

breathing patterns of smokers and nonsmokers, affect deposition of the

produced particle contaminants in various regions of the respiratory

tract.

There are substantial similarities and some differences between MS

and SS emissions from cigarettes [Exs. 3-689D, 4-129, 4-239].

Differences in MS and SS emissions are due to differences in the

temperature of the combustion of tobacco, pH, and degree of dilution

with the air, which is accompanied by a correspondingly rapid decrease

in temperature. SS is generated at a lower temperature (approximately

600 deg.C between puffs versus 800 to 900 deg.C for MS during puffs)

and at a higher pH (6.7-7.5 versus 6.0-6.7) than MS. Being slightly

more alkaline, SS contains more ammonia, is depleted of acids, contains

greater quantities of organic bases, and contains less hydrogen cyanide

than MS. Differences in MS and SS are also ascribable to differences in

the oxygen concentration (16% in MS versus 2% in SS). SS contaminants

are generated in a more reducing environment than those in MS, which

will affect the distribution of some compounds. Nitrosamines, for

example, are present in greater concentrations in SS than in MS.

Many of the compounds found in MS, which were identified as human

carcinogens, are also found in SS emissions [Exs. 3-689D, 4-93, 4-129,

4-239, 4-269] and at emission rates considerably higher than for MS. SS

contains ten times more polycyclic aromatic hydrocarbons, aza-arenes

and amines as compared with MS [Ex. 4-126]. All of the five known

carcinogens, nine probable human carcinogens, and three animal

carcinogens are emitted at higher levels in SS than in MS, several by

an order of magnitude or more. Several toxic compounds found in MS are

also found in SS (carbon monoxide, ammonia, nitrogen oxides, nicotine,

acrolein, acetone, etc.), in some cases by an order of magnitude or

higher (Tables III-6 and III-7).

SS emissions, quantitatively, show little variability as a function

of a number of variables (puff volume, filter versus nonfilter

cigarette, and filter ventilation [Exs. 4-1, 4-34, 4-54, 4-128, 4-129,

4-141]. The lack of substantial variability in SS emissions is related

to the fact that they are primarily related to the weight of tobacco

and paper consumed during the smoldering period, with little influence

exerted by cigarette design [Ex. 4-129].

(b) Human Activity Pattern Studies Used to Assess Workplace

Exposure. Human activity pattern studies utilize random samples of

human activity patterns using questionnaires and time-diary data to

provide detailed generalizable data about human behavior. Such studies

have been used to assess exposure to ETS. In 1987-1988, the California

Air Resources Board sponsored a probability-based cross-sectional

sample of 1,579 Californians aged 18 years and older, called the

California Activity Pattern Survey (CAPS) [Exs. 4-168, 4-271]. The

study was designed to provide information on time spent in various

locations, including indoors, outdoors, and in transit, as well as

specific microenvironments, such as living rooms, kitchens,

automobiles, or buses. The study focused on time spent in activities

such as cooking or playing sports, but more specifically targeted

activities and environments that had implications for air pollution

exposure, such as the presence of smokers, use of cooking equipment or

solvents.

In analyzing the data from CAPS, Jenkins et al. [Ex. 4-168] and

Robinson et al. [Ex. 4-271] found that time spent at work had a high

correlation with exposure to ETS. This association of ETS exposure with

work settings remained strong after controlling for the length of the

activity episode, and hence was not simply a function of longer time

intervals at work. Robinson et al. [Ex. 4-271] also found that men

reported higher levels of exposure than women, even after controlling

for age, employment status, shorter working hours, etc. This finding

suggests that the epidemiological studies of passive smoking and lung

cancer, which have focussed on women, may be underestimating the effect

of ETS on lung cancer.

Further analysis of the CAP study [Ex. 4-169] verifies the high

percentage of nonsmokers who are exposed to ETS while at work. This is

indicated when the data are analyzed by employed nonsmoker status. As

indicated in Table III-8, 51% of male and 38% of female nonsmokers

reported ETS exposure at work. The average duration of this exposure

was 313 minutes for males and 350 minutes for females. When the group

that reported exposure at the workplace is analyzed further it becomes

apparent that the overwhelming exposure location for these employed

nonsmokers is the workplace (Table III-9). As indicated in Table III-9,

77% of males and 85% of females were exposed an average of 313 minutes

and 350 minutes, respectively.

One other finding is that the more time spent at work, the higher

the likelihood of greater ETS exposure. For example, the average

duration of exposure to homemakers was approximately 2 hours a day, for

workers the average duration of exposure was approximately 3 hours a

day.

Table III-8.--Percentage of Employed Nonsmokers Exposed to ETS and

Average Minutes of Exposure (in Parentheses)\1\

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

Exposure location Males Females Total

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

Home............................. 9(134) 13(109) 11(123)

Work............................. 51(313) 38(350) 46(324)

Other indoor..................... 28(89) 35(77) 31(85)

Outdoor.......................... 12(118) 14(79) 13(104)

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

\1\Source: [Ex. 4-169].

Table III-9.--Percentage of Employed Nonsmokers Exposed to ETS and

Average Minutes of Exposure (in Parentheses) of Those Who Reported ETS

Exposure at Work\1\

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

Exposure location Males Females Total

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

Home............................. 1(147) 2(180) 2(158)

Work............................. 77(313) 85(350) 80(324)

Other indoor..................... 15(92) 9(102) 13(94)

Outdoor.......................... 6(176) 4(140) 5(166)

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

\1\Source: [Ex. 4-169].

Work breaks and meals at work were the work activities most closely

associated with ETS exposure, 51% and 35% respectively versus 27% for

work per se [Ex. 4-271]. In other words, nonsmokers experienced ETS

exposure in break areas more than in general work areas.

When white collar versus blue collar workplaces were compared, 37%

of factories/plants versus 22% of offices had episodes of ETS exposure,

suggesting that blue collar nonsmoking workers have a greater exposure

to ETS than white collar workers. For the CAP population, twice as many

workers were employed in offices as were in factories [Ex. 4-271]. The

most ETS exposed nonsmokers were those with 10 or more hours per day of

work (especially at plants/factories), more than 2 hours per day of

restaurant time, and more than 1 hour per day of bar or nightclub time.

Robinson et al. [Ex. 4-271] concluded that the probability of

passive smoking is highest for a combination of various social and work

activities, consistent with the notion that activities that involve

more people involve a greater chance of contact with people who smoke.

A limitation of the CAP survey is that the data do not provide

information on the intensity of exposure in the various

microenvironments [Ex. 4-271].

In summary, the CAP study showed that the most powerful predictor

of potential exposure to ETS was being employed. Respondents who spent

more than ten hours a day at the workplace were found to report more

ETS exposure tha

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