Identifying and Controlling Pulmonary

Toxicants

June 1992

OTA-BP-BA-91

NTIS order #PB92-193457
For sale by the U.S. Government Printing Office

Superintendent of Document\, Mail Stop: SSOP, Washington, DC 20402-9328”

ISBN 0-16 -037923-7
Foreword

History reveals an enduring respect for lung function. In the biblical account of creation, man

becomes a living soul when he receives the breath of life. Edward I of England banned the use of coal

in 1273 because he found inhaling its smoke detrimental to human health. When asked how to ensure

a long life, Sophie Tucker replied, “Keep breathing.”

This Background Paper examines whether the agencies responsible for administering Federal

environmental and health and safety laws have taken this concern for respiratory health to heart.

Prepared at the request of the Senate Committee on Environment and Public Works and its Subcommittee on Toxic Substances, Environmental Oversight, Research and Development, the study describes

technologies available to identify substances toxic to the lung and Federal efforts to control human

exposure to such substances through regulatory and research programs. The analysis shows that new

technologies hold great promise for revealing the potential adverse effects on the lung of new and

existing substances, but that much remains to be learned. This Background Paper provides a partial

response to the committees’ request for an assessment of noncancer health risks in the environment and

follows OTA’s previous work on carcinogenic, neurotoxic, and immunotoxic substances.

OTA acknowledges the generous help of the workshop participants, reviewers, and contributors who

gave their time to ensure the accuracy and completeness of this study. OTA, however, remains solely

responsible for the contents of this Background Paper.

~f~

@’&# ‘ >

John H. Gibbons

Director

. . . 111
Workshop on Identifying and Controlling Pulmonary Toxicants, September 1991

Dr. Robert M. Friedman, Workshop Chair

Senior Associate

Oceans and Environment Program

Office of Technology Assessment

Dr. Margaret Becklake

Director, Respiratory Epidemiology Unit

McGill University

Dr. Arnold Brody

Head, Pulmonary Pathology

National Institute of Environmental

Health Sciences

Dr. Daniel L. Costa

Chief, Pulmonary Toxicology Branch

Inhalation Toxicology Division

Health Effects Research Laboratory

U.S. Environmental Protection Agency

Dr. Robert R. Mercer

Assistant Medical Research Professor

Department of Medicine

Duke University

Dr. Richard B. Schlesinger

Professor, Department of

Environmental Medicine

New York University School of Medicine

Dr. Mark J. Utell

Director, Pulmonary and Critical

Care Unit

University of Rochester Medical Center

Dr. Joe L. Mauderly Dr. Gregory Wagner

Director Director, Division of Respiratory

Inhalation Toxicology Research Institute Disease Studies

Lovelace Biomedical and Environmental National Institute for Occupational

Research Institute, Inc. Safety and Health

Dr. Roger O. McClellan Dr. Ronald K. Wolff

President Research Scientist

Chemical Industry Institute of Toxicology Lilly Research Laboratories

Note: OTA appreciates the valuable assistance and thoughtful critiques provided by the workshop participants.

The participants do not, however, necessarily approve, disapprove, or endorse this background paper. OTA

assumes full responsibility for the background paper and the accuracy of its contents.

iv
Reviewers and Contributors

In addition to the workshop participants, OTA acknowledges the following individuals who reviewed drafts or

otherwise contributed to this study.

Lois Adams

Office of Technology Assessment Liaison

Office of Legislative Affairs

U.S. Food and Drug Administration

Heinz W. Ahlers, J.D.

Division of Standards Development

and Technology Transfer

National Institute for Occupational Safety

and Health

John R. Balmes, M.D.

Assistant Professor of Medicine

Center for Occupational and Environmental Health

University of California, San Francisco

Rebecca Bascom, M.D.

Director, Environmental Research Facility

School of Medicine

University of Maryland

Robert P. Baughman, M.D.

Associate Professor of Medicine

Pulmonary/Critical Care Division

University of Cincinnati

Paul D. Blanc, M.D., M. S.P.H.

Assistant Professor of Medicine

Division of Occupational and

Environmental Medicine

University of California-San Francisco

James C. Bonner, Ph.D.

Staff Fellow

Laboratory of Pulmonary Pathobiology

National Institute of Environmental Health Sciences

Carroll E. Cross, M.D.

Division of Pulmonary-Critical Care Medicine

Department of Internal Medicine

University of California-Davis Medical Center

Roger Detels, M. D., M.S.

Professor of Epidemiology

School of Public Health

University of California-Los Angeles

Fran Du Melle

Deputy Managing Director

American Lung Association

June Friedlander

Staff Specialist

National Institute for Occupational Safety

and Health

Suzie Hazen

Director, 33/50 Program

Office of Air and Radiation

U.S. Environmental Protection Agency

Hillel S. Koren, Ph.D.

Acting Director

Human Studies Division

Health Effects Research Laboratory

U.S. Environmental Protection Agency

Martin Landry

Budget Analyst

Financial Management Office

National Institute for Occupational Safety

and Health

John L. Mason, Ph.D.

Vice President

Engineering and Technology

Allied Signal Aerospace Co. (Ret.)

Barbara Packard, M. D., Ph.D.

Associate Director for Scientific

Program Operations

National Heart, Lung, and Blood Institute

Jerry Phelps

Program Analyst

Office of Program Planning and Evaluation

Office of Director

National Institute of Environmental Health Sciences

William A. Pryor, Ph.D.

Director

Biodynamics Institute

Louisiana State University
Victor L. Roggli, M.D.

Associate Professor of Pathology

Department of Pathology

Duke University Medical Center

Robert Roth, Ph.D.

Professor

Department of Pharmacology and Toxicology

Michigan State University

Jonathan M. Samet, M.D.

Professor of Medicine

Medical Center

University of New Mexico

Anne P. Sassaman, Ph.D.

Director

Division of Extramural Research and Training

National Institute of Environmental Health Sciences

David A. Schwartz, M. D., M.P.H.

Director, Occupational Medicine

Pulmonary Disease Division

Department of Internal Medicine

University of Iowa

Joel Schwartz, Ph.D.

U.S. Environmental Protection Agency

Andrew Sivak, Ph.D.

President

Health Effects Institute

Frank E. Speizer, M.D.

Professor of Medicine and Environmental Science

School of Public Health

Harvard University

Jaro J. Vestal, M. D., Ph.D.

Environmental Activities Staff

General Motors Corp.

David B. Warheit, Ph.D.

Haskell Laboratory for Toxicology

and Industrial Medicine

I.E. Du Pont De Nemours and Co.

Jane Warren, Ph.D.

Research Committee Director

Health Effects Institute

vi
OTA Project Staff-Identifying and Controlling Pulmonary Toxicants

Roger C. Herdman, Assistant Director, OTA

Health and Life Sciences Division

Michael Gough, Biological Applications Program Manager

Holly L. Gwin, Project Director

Margaret McLaughlin, Analyst

Ellen Goode, Research Assistant

Katherine Kelly, Contractor

Desktop Publishing Specialists

Jene Lewis

Linda Rayford-Journiette

Carolyn Swarm

support staff

Cecile Parker, Office Administrator

vii
Contents

Chapter l: Introduction and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Chapter 2: The Respiratory System and Its Response to Harmful Substances . . . . . . . . . . . . . . . . . 15

Chapter 3: Pulmonary Toxicology and Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Chapter 4: Federal Attention to Pulmonary Toxicants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Boxes

Boxes

3-A—General Principles of Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

3-B—The UCLA Population Studies of Chronic Obstructive Respiratory Disease . . . . . . . . . . . . . . 42

Figures

Figures

l-l—The Human Respiratory Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2-l—The Human Respiratory Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

2-2—Branching of the Tracheobronchial Region (Human Lung Cast) . . . . . . . . . . . . . . . . . . . . . 16

2-3—Alveoli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2-4—Gas Exchange in the Pulmonary Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

2-5—Ciliated Cells and Alveolar Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

2-6—Effects of Emphysema on Alveolar Walls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

3-l—Framework for Exposure Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

3-2—Integrated Approach to Identifying Pulmonary Toxicants . . . . . . . . . . . . . . . . . . . . . . . . . . 35

3-3--Spectrum of Biological Response to Pollutant Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Tables

Tables

l-l—The Seventeen Chemicals of the 33/50 Program, 1989 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

2-l—Respiratory Tract Clearance Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

2-2—Causes of Occupational Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

2-3—Industrial Toxicants Producing Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

3-l—Defining Gases and Aerosols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

3-2-Summary of Characteristics of Physiologic Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

4-l—National Primary Ambient Air Quality Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

4-2—Hazardous Air Pollutants Regulated Under the CAA Due to NonCancer Health Effects

on the Pulmonary System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

4-3—Pulmonary Toxicants Controlled Under EPA’s Early Reduction and 33/50 Programs . . . . . . . . . 54

4-4—Regulated Levels of Pulmonary Toxicants Under RCRA . . . . . . . . . . . . . . . . . . . . . . . . . . 55

4-5—Pulmonary Toxicants Regulated Under FIFRA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

4-6—Air Contaminants Regulated by OSHA Because of Pulmonary Effects . . . . . . . . . . . . . . . . . . 56

. . . Vlll
Chapter 1

Introduction and Summary
Chapter 1

Introduction and Summary

INTRODUCTION

Breathing sustains life. Each day an individual inhales between 10,000 and 20,000 liters of air. In the

lungs, air releases oxygen to the bloodstream and picks

up carbon dioxide and other waste products, which are

then exhaled. Inhaled air contains many substances—

naturally occurring and anthropogenic--other than

oxygen. Some of these substances can injure the lungs

and impede their function.

The potential for chemicals and materials used in

industry, transportation, and households to be simultaneously beneficial and toxic to human life creates a

legislative and regulatory dilemma. The challenge of

balancing a strong economy, one that delivers products

people need and desire, with the health and safety of

the populace sometimes seems to be a tremendous

burden.

Technological advances add to the weight of that

burden. Thousands of new, potentially toxic substances

enter the market annually. Advanced instruments help

scientists measure the presence of new and existing

substances in minute quantities. Substances formerly

unknown or undetected suddenly become worrisome

as technology provides the means to predict human

risks from these substances.

Governmental concern that a substance might create an adverse health effect historically focused on

carcinogenicity. Most Federal legislative and regulatory efforts to prevent or minimize human exposure to

toxic substances have focused on identifying and controlling carcinogens. Physicians and researchers now

recognize the noncancer, toxic effects of many substances. Some of these effects, for instance teratogenicity, have become the subject of specific legislative

concern. Federal regulatory attention to other types of

toxic injury (e.g., to the respiratory system, the immune

system, the nervous system) depends on the more general mandate to protect human health. Some observers

fear that historical emphasis on carcinogenicity, combined with limited agency resources, has led to neglect

of noncancer health risks-risks that may be as widespread and severe as carcinogenicity.

The Senate Committee on Environment and Public

Works, and its Subcommittee on Toxic Substances,

Environmental Oversight, Research and Development, asked for assistance from the Office of Technology Assessment (OTA) in evaluating technologies to

identify and control noncancer health risks in the environment. The committee’s interests include advances

in toxicology, research and testing programs in Federal

agencies, and the consequences of exposure to toxic

substances. OTA has published studies on neurotoxicity and immunotoxicity (18,19).

In further response to the committee’s request, this

background paper describes the state-of-the-art of

identifying substances that can harm human lungs

when inhaled. Chapter 2 provides a primer on human

lung structure and function and describes lung diseases

that have been associated with inhalation of toxic substances. Chapter 3 examines the technologies and

methodologies used in laboratory, clinical, and epidemiologic studies to identify substances as toxic to the

lung. Chapter 4 summarizes Federal research efforts

and regulations designed to reduce human exposures

to these substances.

SCOPE

This study assesses whether regulators using available toxicologic and epidemiologic investigative methods can obtain health effects data sufficient to identify

airborne substances as pulmonary toxicants—substances toxic to the lung—when encountered at environmentally relevant exposure levels. Several terms

within this description of the scope of work require

definition to delineate the boundaries of OTA’s inquiry.

Regulators—Regulators are the agencies, and their

employees, with responsibility, under various environ-
4 . Identifying and Controlling Pulmonary Toxicants

mental statutes, for setting standards to control human

exposure to toxic substances. This study examines only

Federal regulatory programs, but many States have

environmental legislation and regulatory agendas that

require the types of technologies and data discussed in

this background paper.

Available toxicologic and epidemiologic investigative methods-This background paper reports on the

technologies and methodologies applied in laboratory

studies, human clinical studies, and field studies of

human exposure (epidemiology) to determine whether

substances exert toxic effects. As used in this study, the

term laboratory studies comprises in vitro tests on cells,

tissues, and fluids removed from animals and humans

and in vivo tests on whole animals. The term human

clinical studies refers to studies of the effects on humans of carefully controlled but purposeful exposures

to potentially toxic substances; exposure to the suspected toxicant occurs in a clinical setting, hence the

term. Epidemiologic studies are those in which investigators examine the effects on humans of exposures to

suspected toxicants that occur without the intervention

of the investigator and in a nonclinical setting, e.g., at

home, in the workplace, at school, in the outdoors.

Airborne substances—Combustion, industrial

processes, and other human activities can create inhalable gases and particles that may be toxic to the lungs.

Technologies that enable assessment of the health effects of inhaled substances are the focus of this background paper. Substances taken orally (e.g., certain

drugs) or absorbed through the skin (e.g., the pesticide

paraquat) can be toxic to the human lung; some of the

technologies discussed in this background paper could

be used to identify their effects. However, this study

limits itself to an examination of the technologies specifically applicable to investigation of the effects of

airborne substances on the lung and the regulatory

programs designed to control human exposure to such

substances. The background paper discusses some biologic substances, e.g., organic dusts, but excludes consideration of infectious agents.

Environmentally relevant exposure levels—OTA

defines “environmentally relevant exposure levels” as

those that can reasonably be anticipated (under noncatastrophic circumstances) to occur in outdoor, residential, educational, commercial, and occupational

environments in various regions of the United States.

This background paper describes a wide range of

technologies that measure the biological effects of exposure to toxic substances-from technologies that

identify minute changes in the cellular structure of the

lung to technologies useful in the diagnosis of disease.

Regulators use these technologies, singly or in combination, to determine not only whether a given dose of

a suspected toxicant creates a measurable, biological

effect but whether the measurable effect is itself adverse to respiratory health or correlates with development of an adverse condition. A definition for adverse

remains a topic of considerable debate.

For example, scientists have developed several tests

to detect decreases in lung function that result from

exposure to toxic substances. While they agree on the

technical capabilities of the tests, they disagree on the

level of decreased function that should be deemed

adverse for regulatory purposes. Using other tests, scientists are able to detect changes in the number of

certain types of cells found in the lung following relatively low-level exposures to toxic substances. Given

enough time and resources, scientists will be able to

determine whether such changes reverse themselves,

stabilize, or grow harmful under various types of exposure conditions. They will also learn whether those

cellular changes actually impair lung function. Until

those data are collected, however, regulators have insufficient evidence to deem the measurable effect adverse.

In this background paper, OTA describes the current technologies that measure the biological effects in

the lung of toxic substances. The study also reports on

Federal efforts to improve the technologies and regulate human exposures to substances deemed adverse.

OTA makes no independent judgment concerning an

appropriate definition of adverse effects or on the

adequacy of current regulatory standards.

SUMMARY

This background paper distills some of the information available about the basic and applied sciences that

enable the identification and control of pulmonary

toxicants. More detailed reviews of lung structure and

function, lung diseases, pulmonary toxicology, and epidemiology can be found in numerous sources

(1,2,5,10,11,12). The following sections summarize

much of the text that appears in subsequent chapters.
Chapter 1—Introduction and Summary 5

Lung Structure and Function

The lung comprises two of the three distinct regions

of the human respiratory tract (figure l-l). Air enters

the body through the nose and mouth and passes

through the nasopharyngeal region, where it is warmed

and humidified. Air moves next through the tracheobronchial region (where the lung begins), which acts

basically as a conducting passage. Finally air reaches

the pulmonary, or gas exchange, region of the lung,

where oxygen in the air is supplied to the blood, which

delivers it to cells throughout the body. In turn, the

blood releases a major waste product, carbon dioxide

(CO2

), and other gaseous components and metabolites

to air remaining in the lung, which is exhaled. The

pulmonary region has a tremendous surface area—in

adults about the size of a single’s tennis court-which

permits efficient gas exchange (oxygen for CO2).

The respiratory system is equipped with defense

mechanisms. The nasopharyngeal region can filter

large particles and absorb gases with high water solubility before they reach the lung. Cells that line the

tracheobronchial region secrete mucus that traps inhaled particles and reactive gases, and other cells sweep

the mucus up and out of the respiratory system to the

digestive system. Certain cells that reside in the pulmonary region can ingest and destroy particles that peneFigure l-l—The Human Respiratory Tract

Larynx, vocal co

‘rachea?’

9

Pulmonary

arteries $M

7

A

Pulmonary

veins

Ld

4

/

/

Alveoli A

SOURCE: Office of Technology Asessment, 1992.

trate to that region. Some toxic substances can bypass

or overwhelm these defense mechanisms, resulting in

lung injury or disease.

Lung Injury and Disease

Lung function suffers when resistance to airflow in

the conducting airways (tracheobronchial region) increases or when a loss of healthy surface area in the

pulmonary region prevents transfer of sufficient

amounts of oxygen to the blood. Many agents—manmade and natural, physical and biological-can cause

these basic problems, which are characteristic of several forms of disabling lung diseases (e.g., asthma, fibrosis, emphysema). Because of the limited types of

pulmonary responses and the large number of agents

to which individuals are exposed, the association of

individual agents with specific responses has been difficult. Careful observation and experimentation over

the years, however, has led to conclusions about the

potential of certain toxicants to cause or exacerbate

lung diseases.

Several outdoor air pollutants, e.g., sulfur dioxide,

increase the breathing difficulties of high-risk groups

(e.g., asthmatics). Tobacco smoke causes cancer (beyond the scope of this report), chronic bronchitis, and

emphysema, and contributes to an increased incidence

of respiratory disease in children of smoking parents,

which may lead to chronic lung problems as they age.

Occupational exposure to inhaled chemicals and fibers

has yielded some of the strongest evidence linking toxic

substances to lung disease.

Many tools for studying the toxicity of airborne

substances have been developed in recent years, but the

number of toxicants to be assessed and the amount of

data required to substantiate their toxicity present a

challenging task to toxicologists, epidemiologists, and

regulators. Studies are under way to determine

whether persistent human lung problems are correlated with exposures to many of the gases and particles

encountered in everyday life.

Pulmonary Toxicology and Epidemiology

Investigators use three, complementary lines of research to assess the effects on the lung of inhaled

pollutants: laboratory studies, including in vitro tests

and tests in whole animals, human clinical studies, and

epidemiology. Each type of study has strengths and

weaknesses. In in vitro tests, scientists examine the
6 = Identifying and Controlling Pulmonary Toxicants

structure or functional capability of tissues and cells to

determine the effects of toxic exposures. These studies

are informative but may not give a complete picture of

a toxicant’s effects. In in vivo studies, scientists use

animals whose respiratory systems resemble the human system and attempt to mimic expected human

exposure conditions as closely as possible. Such studies

are useful but are limited by the difficulty in extrapolating results from animals to humans. Clinical studies

allow careful control of exposure conditions and provide human data. However, they are restricted to relatively brief exposures that will create no lasting injury

and, like most animal studies, are limited to exposures

to one or two substances at a time rather than the

complex mixtures actually encountered in the environment. Epidemiologic studies analyze the effects created by toxicants under actual exposure conditions but

are limited by imprecise measurements of exposure to

the toxicant under study and by confounding factors

such as smoking, preexisting disease, and unknown

effects of other exposures.

Whether involving animals or humans, studies employ functional, structural, or biochemical methods of

investigation. Functional assays measure the mechanics of breathing, decreases or increases in gas-exchange

capacity, and the ability of the lungs to rid themselves

of foreign particles, among other things. Structural

studies employ the traditional techniques of pathology

to gather substantial information about pulmonary

toxicity. Prepared slices of excised lungs can be examined with microscopes for evidence of alterations in

structure. Various regions of the excised lung can be

examined for the presence of particles. Cells can be

examined for injury. Advances in cellular biology in

recent years contributed to some of the most important

new methods of pulmonary toxicology. Toxicologists

using biochemical methods can now study the cellular

interactions and biochemical mechanisms of the lung

using fluids recovered from lungs. In addition to biological tests on an exposed population, epidemiologists

can use various databases, including mortality and

morbidity statistics, hospital admissions records, and

diaries of respiratory symptoms, to correlate exposure

to toxicants with lung injury and disease.

In the laboratory and clinic, investigators can control the amount of the substance under study delivered

to the test subject and can exclude all other exposures.

The technologies used produce precise measurements

of exposure but cannot reproduce the actual exposure

conditions people encounter in their daily lives. Epidemiologists cannot control the dose of a toxicant received by their study subjects, but advances in stationary and personal exposure monitoring technologies

have improved the accuracy of exposure measurements

in epidemiologic studies. All scientists studying the

effects of pulmonary toxicants must consider the fact

that exposure—the amount of a toxicant found in the

inhalable air—frequently differs from biologically effective dose—the amount of toxicant actually retained in

the lung for sufficient time to cause problems. Differences in human and animal lungs have a major impact

on biologically effective dose and create many of the

difficulties in extrapolating test results from animals to

humans.

Integrated use of laboratory, clinical, and epidemiologic techniques often produces the best results. For

instance, increased respiratory symptoms in a working

population exposed to chemical fumes might suggest

the need for laboratory studies of the chemical’s health

effects. Following the laboratory experiments, clinical

studies might be performed to obtain more accurate

data about harmful and harmless levels of short-term

exposure in humans. Once a permissible exposure level

is established for the workplace, workers could be

monitored, in an epidemiologic study, to determine

whether long-term exposures created effects that did

not show up in the short-term studies. Pulmonary toxicologists, clinicians, and epidemiologists share the objective of identifying the health effects of airborne

substances to which humans are or will likely be exposed.

AIR QUALITY

Air comprises those gases that form the atmosphere of the earth. At altitudes below 80 kilometers

molecular nitrogen and oxygen dominate the mix.

When water vapor is removed from the air, nitrogen

and oxygen constitute 78 and 21 percent (by volume)

of the air, respectively. The remaining 1 percent of this

dry air consists principally of argon, but CO2 and small

quantities of neon, helium, krypton, xenon, hydrogen,

methane and nitrous oxide are also found as constant

components of air.

Human activities (agriculture, industry, transportation) contribute additional, variable components—

pollutants—to the mix of gases called air. Level of

industrialization creates most of the global variability

in air pollution. For instance, wood (and other

biomass) smoke may be the most common pollutant in

nonindustrialized countries, while fossil fuel combustion byproducts (e.g., sulfur oxides, nitrogen oxides,
Chapter 1—Introduction and Summary ● 7

particulate matter) constitute the major air pollutants

in heavily industrialized countries. Regional differences in pollutants depend on population, activity mix,

geography, and climatic conditions. Within a community, air quality may differ significantly upwind and

downwind of, for instance, a power plant. Family members may experience quite different pollutant exposure

conditions depending on how much time they spend at

work, school, or home.

In the United States, fossil fuel combustion contributes to both major types of outdoor air pollution—

chemically reducing pollution and chemically

oxidizing, or photochemical, pollution. Reducing type

pollution is characterized by sulfur dioxide and fossil

fuel smoke and by conditions of fog and cool temperatures. This type of pollution occurs mainly in the eastern part of the country, primarily in the Mid-Atlantic

and Northeastern States. Oxidizing type pollution is

characterized by hydrocarbons, oxides of nitrogen, and

photochemical oxidants and results from the action of

sunlight on polluted air masses. This pollution problem, infamous in several western U.S. cities (e.g., Los

Angeles), now strikes the northeast and southeast in

the summer months as well. Other types of pollutants

pose seasonal problems, for instance woodsmoke in

certain cities during the winter months. Toxic pollutants emitted from industrial sites or from hazardous

waste sites can present highly localized air quality problems (see table l-l). Outdoor air pollution is regulated

under the Clean Air Act and other environmental

statutes.

Some occupations involve significant potential for

exposure to airborne toxicants. These types of exposures generally are regulated under the Occupational

Safety and Health Act and the Federal Mine Safety and

Health Act. Health and safety regulations have reduced many of the acute exposure problems experienced by workers; experts are uncertain whether

Table l-l—The Seventeen Chemicals of the 33/50 Program, 1989

Total releases Total air releases

and transfers and transfers

Chemicals (pounds) (pounds) Industry

Cadmium and compounds*

Chromium and compounds*

Lead and compounds

Mercury and compounds*

Nickel and compounds*

Benzene*

Methyl ethyl ketone*

Methyl isobutyl ketone

Toluene

Xylenes (mixed isomers)*

Carbon tetrachloride

Chloroform (Trichloromethane)

Methylchloride (Dichloromethane)*

Tetrachloroethylene (Perchloroethylene)*

1, 1, l-Trichloroethane (Methyl chloroform)*

Trichloroethylene*

Cyanides

1,147,783

64,284,382

54,371,117

216,433

22,342,311

28,591,407

156,992,642

38,849,703

322,521,176

185,442,035

4,607,809

27,325,508

130,355,581

30,058,581

185,026,191

48,976,806

11,976,370

119,841

2,238,473

2,449,799

29,239

1,128,788

24,683,026

127,631,835

30,682,832

255,437,878

147,486,804

3,367,248

24,268,093

109,272,003

25,504,477

168,617,910

44,325,687

a

Primary metals

Chemicals

Primary metals

Chemicals

Primary metals

Primary metals

Plastics

Chemicals

Chemicals

Transport

Chemicals

Paper

Chemicals

Transport

Transport

Fabricated metals

Chemicals

*EPA notes a respiratory effect.

a Cyanide emissions to the air have been estimated to be in excess of 44 million pounds per year. The largest single source of air emissions is vehicle exhaust, which accounts for over 90 percent of this total. This type of emission is not reported under the EPA’s

Toxic Release Inventory National Report.

SOURCE: U.S. Environmental Protection Agency, Office of Toxic Substances, Economics and Twhnology Division, Toxics in the

Community: National and Local Perspectives - The 1989 Toxics Release Inventory National Report, EPA-56014-91-014

(Washington, DC: September 1991).
8 Identifying and Controlling Pulmonary Toxicants

current exposure limits prevent the types of persistent

problems that might be associated with long-term, lowlevel exposures.

Most people spend most of their time indoors-at

home, at school, or in the office. The primary indoor

air pollutants are tobacco smoke, nitrogen dioxide,

carbon monoxide, woodsmoke, biological agents (e.g.,

molds, animal dander), formaldehyde, various volatile

organic compounds, and radon. Indoor pollutants may

be generated by personal activities, such as cigarette

smoking, or by things outside an individual’s control,

such as the geological formation on which a housesits,

the source of radon. Indoor, airborne toxicants are

important sources of individual exposure to toxicants

that may appear in the outdoor air as well (e.g., nitrogen dioxide) and should be considered in health effects

assessments. Outside of certain occupational settings,

exposures to indoor, airborne toxicants remain largely

unregulated.

Airborne gases and particles emanate from multiple indoor and outdoor sources, and individuals experience multiple exposures to airborne toxicants as they

go about their lives. The mix of substances individuals

inhale and the variety of circumstances under which

they do it makes it very hard for scientists and policymakers to sort out the effects of specific substances.

Some individuals are more susceptible than others to

the effects of airborne toxicants, which makes it difficult for regulators to determine acceptable levels of

exposure once the effects of specific substances have

been determined. The technologies of air quality measurement, exposure assessment, and toxicological testing contribute to better risk assessment and better

policymaking, but currently leave many uncertainties

in their wake.

CONCLUSIONS

Scientists and regulators have a high degree of confidence in existing laboratory, clinical, and epidemiologic methods for studying the adverse effects of acute

(short-term, high-level) exposures to existing chemicals and particles. When analyzing acute responses,

scientists isolate the effects of a specific substance in

Photo credit: South Coast Air Quality Management District, El Monte, CA.
Chapter 1—Introduction and Summary ● 9

animal studies using controlled exposure conditions

and then couple those test results with information

(when available) about the real-life experience of exposed humans. This method enables relatively clear

association between exposure to a specific substance

and specific health effects, though evidence can still be

equivocal. Analysis of the effects of chronic exposure

is under way for many substances and data can readily

be acquired from animal studies (given time and resources). However, credible human data on the effects

of chronic exposure are more difficult to obtain because of extraneous factors that can affect study results

(e.g., difficulties in determining the effects of previous

exposures; opportunities for exposure to multiple substances). Where substances are regulated because of

their pulmonary toxicity, the regulations are primarily

based on health effects observed following acute exposures.

A synopsis of the attempt to set a standard for

ozone that prevents adverse health effects illuminates

the power and limitations of current technologies

within the current regulatory framework for protection

of public health. Ozone is produced when its precursors, volatile organic compounds (VOC’s) and nitrogen oxides (NOx), combine in the presence of sunlight.

Current EPA regulations require States to maintain

ozone concentrations in the air below 0.12 ppm. Areas

where ozone in the ambient air exceeds a peak l-hour

average concentration of 0.12 ppm more than 1 day per

year (averaged over 3 years) are labeled nonattainment

areas and are subject to legal sanctions (17).

EPA adopted the current standard for ozone exposure on the basis of evidence of the health effects of

short-term exposures slightly above that level. At the

time the standard was set, scientists agreed that shortterm exposures to ozone caused reductions in lung

function and increases in respiratory symptoms, airway

reactivity, permeability, and inflammation in the general population. Asthmatics were known to suffer additional effects, including increased rates of

medication usage and restricted activities (9).

The database on ozone’s health effects has continued to grow since EPA set the standard for exposure in

1979. Data from human clinical studies now show that

lung function decreases during exposure to 0.12 ppm

(the current regulatory standard) and continues to decrease during constant exposures of 6 hours or more

(4,6). Biochemical studies on lung fluids removed from

individuals who were exercising during exposure to

ozone above, at, and below the current regulatory

standard showed lung inflammation (8,9).

The acute effects of exposure to ozone have also

been the subject of epidemiologic studies. Lung function in children engaged in outdoor recreation activities decreased during exposure to ozone, and outdoor

exposure caused a greater decrease than clinical exposure at the same concentration of ozone, indicating

that other substances in the outdoor air potentiated the

response to ozone (15,16). School children showed

similar responses in another study (7).

Researchers have begun to study the effects of

chronic exposure to ozone in various populations. A

study of residents in the Los Angeles area showed that

chronic exposure to oxidant pollution affects baseline

lung function (3). Another study from the Los Angeles

area, this time on the autopsied lungs of young accident

victims, showed structural abnormalities in the lungs

that were not expected in individuals of that age range

(13). An analysis of pulmonary function data collected

in a national survey showed a clear association between

reduced lung function and annual average ozone concentrations in excess of 0.04 ppm ( 14). Based on epidemiologic research findings, a growing number of

scientists believes that chronic exposure to ozone may

cause premature aging of the lung, and they find support for this opinion in recent studies on rats and

monkeys (9).

Scientists disagree on the health significance of the

decreased lung function measured in the human clinical studies (9). EPA’s Clean Air Science Advisory

Committee (CASAC) split when asked to reach closure concerning a scientifically supportable upper

bound for a l-hour ozone standard, with half the members accepting the current standard and half recommending a reduction in permissible exposure levels

(20). CASAC noted that “resolution of the adverse

health effect issue represents a blending of scientific

and policy judgments.” Little information on the human health effects of chronic ozone exposures has been

available to regulators or their advisors, and scientists

continue to urge that results from such studies be

assessed cautiously. Despite strong evidence that

ozone is harmful to human health at currently allowable exposure concentrations (9,21), EPA has not proposed a revision of the ozone standard.

Regulators face greater difficulties when developing supportable exposure standards for substances with
10 ● Identifying and Controlling Pulmonary Toxicants

smaller health effects databases or with databases limited to results of laboratory studies (as with new substances). The difficulties lie in the technologies

themselves (e.g., remaining uncertainties regarding extrapolating results from animals to humans) and in

balancing competing interests (e.g., dependence on

automobiles versus air pollutants’ harmful effects).

None of the technologies currently in use or under

development for assessing pulmonary toxicity promises to be a near term alternative to extensive (costly)

studies involving animals and humans. Scientists studying the behavior of gases and particles in the lungs of

various animal species and humans hold out hope for

continued improvements in techniques for extrapolation from animal studies to humans. Researchers investigating the mechanisms of disease believe what

they discover may enable extrapolation from study results on existing chemicals to the likely effects of new

substances with similar physical properties. At present,

however, there is no scientific agreement that the effects measured by new toxicologic methods are adverse-distinctly and permanently harmful—instead

of changes that may evince the recuperative properties

of the lung. Therefore regulators can only continue to

balance the costs and benefits of different regulatory

levels rather than choose a regulatory level for pulmonary toxicants that will clearly avoid adverse human

health effects.

1.

2.

3.

4.

CHAPTER 1 REFERENCES

Amdur, M. O., Doull, J., and Klaassen, C.D.

(eds.), Casarett and Doull’s Toxicology: The Basic

Science ofPoisons, 4th ed. (Elms ford, NY: Pergamon Press, 1991).

Crystal, R. G., and West, J.B. (eds.), The Lung:

Scientific Foundations (New York, NY: Raven

Press, 1991).

Detels, R., Tashkin, D. P., Sayre, J. W., et al., “The

UCLA Population Studies of Chronic Obstructive Respiratory Disease. 9. Lung Function

Changes Associated With Chronic Exposure to

Photochemical Oxidants: A Cohort Study

Among Never-Smokers,” Chest 92(4):594-603,

October 1987.

Folinsbee, L.J., McDonnell, W. F., and Horstman, D. H., “Pulmonary Function and Symptom

Responses After 6.6 Hour Exposure to 0.12 ppm

Ozone With Moderate Exercise,” Journal of the

Air Pollution Control Association 38:28-35, January 1988.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

Gardner, D.E., Crapo, J.D., and Massaro, E.J.

(eds.), Toxicology of the Lung (New York, NY:

Raven Press, 1988).

Horstman, D.H., Folinsbee, L.J., Ives, P.J., et al.,

“Ozone Concentration and Pulmonary Response

Relationships for 6.6-Hour Exposures With Five

Hours of Moderate Exercise to 0.08, 0.10, and

0.12 ppm,” Am&an l?evkw of Rap&ztoy Dkease

142(5):1158-1163, November 1990.

Kinney, P.L., Ware, J. H., and Spengler, J. D., “A

Critical Evaluation of Acute Ozone Epidemiology Results; Archives of Environmental Health

43(2):168-73, March/April 1988.

Koren, H. S., Devlin, R. B., Graham, D. E., et al.,

“Ozone-Induced Inflammation in the Lower Airways of Human Subjects,” American Review of

Respiratory Disease 139:407-415, 1989.

Lippmann, M., “Health Effects of Tropospheric

Ozone,” Environmental Science and Technology

25(12):1954-1%2, December 1991.

McClellan, R. O., and Henderson, R.F. (eds.),

Concepts in Inhalation Toxicology (New York,

NY: Hemisphere Publishing Corp., 1989).

National Research Council, Committee on the

Epidemiology of Air Pollutants, Epiiiemiology

and Air Pollution (Washington, DC: National

Academy Press, 1985).

National Research Council, Subcommittee on

Pulmonary Toxicology, Biologic Markers in Pu/-

monary Toxicology (Washington, DC: National

Academy Press, 1989).

Sherwin, R. P., and Richters, V., “Centriacinar

Region (CAR) Disease in the Lungs of Young

Adults: A Preliminary Report,” in Tropospheric

Ozone and the Environment (Pittsburgh, PA: Air

and Waste Management Association, 1991.)

Schwartz, J., ‘Lung Function and Chronic Exposure to Air Pollution: A Cross-Sectional Analysis

of NHANES II, ” Environment! Research

50(2):309-321, December 1989.

Spektor, D.M., Lippmann, M., Lioy, P.J., et al.,

“Effects of Ambient Ozone on Respiratory Function in Active, Normal Children” American Review of Respiratory Disease 137:313-320, 1988.

Spektor, D. M., Thurston, G. D., Mao, J., et al.,

“Effects of Single-and Multiday Ozone Exposure

on Respiratory Function in Active Normal Children,” Environmental Research 55(2):107-122,

August 1991.

U.S. Congress, Office of Technology Assessment,

Catching Our Breath: Next Steps for Reducing Urban Ozone, OTA-O-412 (Washington, DC: U.S.

Government Printing Office, July 1989).
Chapter 1—Introduction and Summary ● 11

18. U.S. Congress, Office of Technolo~Assessment,

Neurotoxicity: Identifying and Controlling Poisons

of the Nervous System, OTA-BA-436 (Washington, DC: U.S. Government Printing Office, April

1990).

19. U.S. Congress, Office of Technolog Assessment,

Identifying and Controlling Immunotoxic Substances—Background Paper, OTA- BP- BA-75

(Washington, DC: U.S. Government Printing Office, April 1991).

20. U.S. Environmental Protection Agency, Clean

Air Scientific Advisory Committee, Review of the,

NMQS for Ozone, EPA-SAB-CASAC-89-1092

(Washington, DC: U.S. Environmental Protection Agenq, 1989).

21. Van Bree, L., Lioy, P.J., Rombout, P.J., et al., “A

More Stringent and Longer-Term Standard for

Tropospheric Ozone: Emerging New Data on

Health Effects and Potential Exposure,” Toxicology and Applied Pharmacology 103(3):377-382,

May 1990.
Chapter 2

The Respiratory System and Its Response to

Harmful Substances
Chapter 2

The Respiratory System and Its Response To

Harmful Substances

INTRODUCTION

People can live for days without food or water, but

if they stop breathing, they die within minutes. The

apparatus of breathing—the respiratory system—supplies a critical component of life, oxygen, and disposes

of a major waste product, carbon dioxide. To supply

the amount of oxygen required for survival, the respiratory system must be capable of handling between

10,000 and 20,000 liters of air per day.

The air that enters the respiratory system contains

many substances other than oxygen, including natural

constituents (e.g., nitrogen) and human contributions

(e.g., fossil fuel combustion byproducts). Various defense mechanisms of the respiratory system eliminate

the unnatural components of air from the body and

repair any damage they do. But exposure to large

amounts of toxic substances or chronic exposure to

lower levels can overwhelm the ability of the respiratory system to protect and repair itself, sometimes

resulting in impaired lung function.

This chapter describes the structure and function of

the respiratory system and some of the ways the respiratory system protects itself against harmful substances. It then briefly describes major diseases

associated with exposure to toxic substances. This

chapter does not cover the effects of exposure to radiation or infectious agents, nor does it describe lung

cancer. More detailed descriptions of the respiratory

system and respiratory diseases are presented elsewhere (7,13,26,28,29).

STRUCTURE AND FUNCTION OF THE

RESPIRATORY SYSTEM

Air enters the body through the nose and mouth

and moves through the major airways to deeper portions of the lungs (figure 2-l). There oxygen can pass

across thin membranes to the bloodstream. Each region of the respiratory system is made of specialized

cells that work together to transport air, keep the lung

clean, defend it against harmful or infectious agents,

Figure 2-l—The Human Respiratory Tract

/

Pharynx

Larynx, vocal cords

\

Trachea /

F! \ Esophagus

3

 PuImona-ry

.

arteries %.L

7%

A

Pulmonary

veins {

t

Alveoli $?J

Lung I

SOURCE: Office of Technology Assessment, 1992.

and provide a thin, large surface for the exchange of

oxygen and carbon dioxide.

Upper Respiratory Tract

The upper airways begin at the nose and mouth and

extend through the pharynx to the larynx. This

nasophoryngeal region is lined with ciliated cells and

mucous membranes that warm and humidify the air

and remove some particles. Gases that are very water

soluble are also absorbed readily by the mucus in this

part of the respiratory tract, protecting the more delicate tissues deeper in the respiratory tract from the

effects of exposure to such gases.

The Tracheobronchial Tree

After passing through the larynx, air flows through

the trachea, or windpipe. The trachea divides into two

15
16 Identifying and Controlling Pulmonary Toxicants

bronchi which carry air into the two lungs. The bronchi

subdivide repeatedly into smaller and smaller bronchi

and then into bronchioles, which also successively divide and narrow (figure 2-2). The smallest bronchioles,

found at the end of the tracheobronchial region, are

less than a millimeter in diameter.

The Pulmonary Region

In the pulmonary region, the bronchioles divide

into alveolar ducts and alveolar sacs. Budding from the

walls of these last portions of the airways are tiny,

cup-like chambers called alveoli (figure 2-3). The alveoli are only one-quarter of a millimeter in diameter

(just barely visible to the unaided eye) and have ex-

tremely thin walls. Their outer surface is covered by a

dense network of fine blood vessels, or capillaries. Gas

exchange occurs when oxygen diffuses from the space

inside an alveolus through its lining fluid, past the

alveolar membrane and its supporting membrane,

Figure 2-2—Branching of the Tracheobronchial

Region (Human Lung Cast)

Photo credit: D. Costa, Environmental Protection Agency

Figure 2-3—Alveoli

Respirat

SOURCE: Office of Technology Assessment, 1992.

through the space between the alveolus and the capillary (“the interstitial space”), and finally across the

membranes of the capillary. Carbon dioxide diffuses in

the opposite direction, from the red blood cells in the

capillaries to the space inside the alveolus (figure 2-4).

The adult human lung contains approximately 300

million alveoli. Taken together, the alveoli give the

human lung a huge internal surface, about 70 square

meters. This large area allows for enough oxygen to

diffuse into the blood to supply the body’s needs, but it

also exposes a very large, thin-walled area, about the

size of a single tennis court, to toxic substances inhaled

in the air.

The Pulmonary Circulation

Oxygen diffuses from the alveoli into the blood in

the capillaries. Red blood cells contain a specialized

protein, hemoglobin, which can reversibly bind molecules of oxygen. The heart pumps the blood to the rest

of the body. Deep within the tissues, the oxygen is

released to be used by cells in generating energy. As the

body’s cells use oxygen, they produce carbon dioxide.

Veins carry blood from body tissues back to the right

side of the heart, which pumps blood to the pulmonary

capillaries to be oxygenated again. Carbon dioxide diffuses from the capillaries into the alveoli and is exhaled.
Chapter 2—The Respirator System and Its Response to Harm/id Substances 17

Figure 2-4--Gas Exchange in the Pulmonary Region

Interstitial space

Epithelial

basement

membrane

Alveolar I

epitheliums ~

\

“’”q

Fluid and

surfactant —

layer ‘!

AIY

Diffusion A..w..q.q

r

Capillary basement

membrane

I ~ Capillary endothelium

L

/

JE#w . . Dif f usiomn:?

‘if” \

~“ Carbon d~oxide;.

,.

SOURCE: Office of Technology Assessment, 1992.

The Pleural Cavity

The lungs are contained within the chest cavity, but

are not attached to the wall of the chest. The pleural

space that separates the lungs from the chest wall

contains a small amount of fluid and is bounded by

membranes called the pleura. This arrangement allows

the lungs to move freely in the chest, permitting full

expansion.

During inhalation, the muscles in the rib cage and

the diaphragm, a dome-shaped muscle beneath the

lungs, contract. As the diaphragm contracts, it flattens,

increasing the space in the chest. The ribs lift, further

increasing the space for the lungs to expand. As the

chest expands, the pressure within the lungs falls below

atmospheric pressure, and air is drawn into the lungs,

inflating them. As the muscles relax, air is exhaled, and

the lungs deflate. The rate of respiration changes in

response to physical and mental conditions, such as

sleep, exercise, or changes in altitude.

Cells of the Respiratory System

The respiratory system contains over 40 different

types of cells. Each cell type performs function important for efficient gas exchange.

A continuous sheet of cells forms a membrane,

called the epitheliums, lining the airways. Healthy epithelium contains few or no gaps, so water, ions, or other

substances that cross the epitheliums must pass through

cells. The specific permeability properties of the cells

control the rate at which substances, such as inhaled

pollutants, cross the epitheliums.

Interspersed among the cells that make up the surface of the lining of the airways area variety of secretory

cells. These secrete mucus which traps dust and other

particles. Most of the cells of the epitheliums have

microscopic hair-like structures on their surface called

cilia (figure 2-5). The cilia beat rhythmically, brushing

the mucus and particles trapped in it up to the pharynx

where they are usually swallowed unnoticed and pass

out of the body through the digestive system.

Different types of cells make up the lining of the

alveoli. The area of the lining consists primarily of Type

I cells, which are very thin and spread over a relatively

large area. The lining also includes the Type II cells.

Type II cells are more numerous, but because of their

more rounded shape, they make up only about 7 percent of the area of the lining of the aveoli. The Type II

cells release proteins and lipids that provide a thin,

fluid lining for the inside of the alveoli. The fluid

protects the delicate Type I cells and reduces the surface tension in the alveoli, preventing collapse of the

alveoli under pressure.

The alveoli also contain macrophages, specialized

defense cells that move freely over the surface of an

alveolus (figure 2-5). Macrophages ingest foreign particles by a process called phagocytosis. During phagocytosis, a microphage extends flaps to form a

membrane-bound pocket around a foreign body. The

microphage releases enzymes into the pocket that can

break down many foreign particles, especially organic

materials. The breakdown products may be released or

absorbed by the cell. Foreign matter that is not organic

often cannot be broken down and may remain stored
18 ● Identifying and Controlling Pulmonary Toxicants

in intracellular compartments. In addition to phagocytosis of foreign substances, macrophages also play important roles in immune responses in the lung.

The capillaries that surround the alveoli are also

lined by a continuous sheet of cells, the endothelium.

Unlike the lining of the airways, the endothelial lining

of the capillaries is slightly leaky, allowing some exchange of water and solutes between the blood and the

interstitial fluid.

The interstitial space, the small area separating

alveoli from surrounding capillaries, contains cells of

the immune system. It also contains fibroblasts, cells

that produce fibers of collagen and elastin that form an

elaborate network to provide a mechanical support

system for the lung. Collagen fibers are very strong but

cannot stretch much; elastin fibers are not as strong but

can be stretched considerably before breaking. These

collagen and elastin fibers are slowly but continually

broken down and renewed.
Chapter 2—The Respiratory System and Its Response to Harmful Substances ● 19

Smooth muscle cells occur as circular sleeves surrounding the bronchi and bronchioles. They dilate

when the body needs large volumes of air, for example,

during exercise. When these muscles contract, as on

exposure to irritant gases, they make the conducting

airways narrower, increasing resistance to air flow.

Smooth muscle cells also surround blood vessels that

enter the lung. They control the distribution of blood

flow to specific alveoli and determine how hard the

right side of the heart must work to pump blood

through the pulmonary blood vessels.

Defense Mechanisms

The respiratory system has elaborate defense

mechanisms against damage from exposure to potentially hazardous particles and gases (table 2-l). Particles of 1-2 micrometers are the optimal size for reaching

the alveoli. Relatively large particles get trapped in

nasal hairs and never enter the lower respiratory tract,

or they are removed by coughing or sneezing. Somewhat smaller particles (down to about 2 micrometers)

enter the trachea but land on the airway surfaces and

stick to the surface mucus. The finest particles settle

less efficiently and are usually exhaled (19).

In the alveoli, some material may dissolve and be

absorbed into the bloodstream or interstitial fluid. Particles that do not dissolve may be phagocytized by

macrophages and the phagocytic cells are either swept

up the tracheobronchial tree on the mucous blanket or

they migrate to the interstitial fluid. Some insoluble

particles may remain sequestered in the lung.

The immune system also plays an important role in

protecting the lungs. A detailed description is beyond

the scope of this background paper, but OTA has

previously addressed immune system responses to

toxic substances (23). Briefly, exposure to many substances, particularly those containing protein of animal

or vegetable origin, sensitizes cells of the immune system. The cells respond with a complex variety of reactions to destroy or immobilize the inhaled substance.

These processes, however, are often accompanied by

inflammation of the surrounding tissues, which is part

of the repair process necessary to restore normal function. Repeated exposure and inflammation is thought

to result in serious and permanent tissue damage.

RESPIRATORY RESPONSE TO

HARMFUL SUBSTANCES

When defenses are overcome or an agent is particularly toxic, the respiratory system can be injured. Damage occurs when defense and repair mechanisms

cannot keep pace with damage wrought by acute exposures to relatively large amounts of harmful substances

or by chronic exposures to small amounts of harmful

substances. Some damage may result from the repair

process itself. Some of the most common and best

understood conditions are described here, excluding

cancer, which is not being considered in this background paper.

Chronic Bronchitis

People with chronic bronchitis have increased

numbers of secretory cells in the bronchial tree. They

produce an excess of mucus and have a recurrent or

chronic cough, familiar to many as “smoker’s cough.”

This excess secretion of mucus may lead to impairment

of normal clearance mechanisms. The normal ciliary

movement cannot cope with this large volume of mucus, and consequently, it takes longer for particles to

Table 2-l—Respiratory Tract Clearance Mechanisms

Upper respiratory tract Tracheobronchial tree Pulmonary region

Mucociliary transport Mucociliary transport Microphage transport

Sneezing Coughing Interstitial pathways

Nose wiping and blowing Dissolution (for soluble Dissolution (for soluble

particles) and “insoluble” particles)

Dissolution (for soluble particles)

SOURCE: R.B. Schlesinger, “Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions, ” Air Pollution, the Automobile, and Public Health, A.Y. Watson (cd. ) (Washington, DC: National Academy Press,

1988).
20 “ Identifying and Controlling Pulmonary Toxicants

be removed from the lungs of patients with chronic eas, periods of heavy pollution with sulfur dioxide and

bronchitis than it does in healthy people. This reduced particulate have shown a correlation with increased

clearance makes people with chronic bronchitis more symptoms of chronic bronchitis or mortality due to

susceptible to respirator infections because bacteria chronic bronchitis (13,21,22,27).

entering the respiratory tract are not removed efficiently. Emphysema

Almost 12 million people in the United States suf- The lung is supported by a network of protein fibers

fer from chronic bronchitis (l). The epidemiologic made of collagen and elastin. In people with emphyevidence linking smoking and chronic bronchitis is sema, some of these fibers are lost and the structural

overwhelming (10,24). Epidemiologic studies have network is disrupted. The fiber network in the damaged

also shown a correlation between chronic bronchitis area becomes rearranged, resulting in destruction of

and exposure to industrial dust (5,15). In addition, the walls of the alveoli. The air spaces become enrecurrent infections may play a role in the development larged, and part of the surface area available for gas

of chronic bronchitis (4,6). In industrialized urban ar- exchange is lost (figure 2-6). Less force is needed to

Figure 2-6—Effects of Emphysema on Alveolar Walls

h “ “ *% *

. +< . w il. % s ‘~ “e # +$

The top photo in each column shows normal lung tissue while the bottom photos show destruction

Photo credit: D. Costa, Environmental Protection Agency

of the walls of the alveoli due to emphysema.
Chapter 2—The Respiratory System and Its Response to Harmful Substances ● 21

expand the lung, but air may remain trapped in the lung

during exhalation because its ability to recoil is impaired.

Nearly 2 million Americans, mostly adults overage

45, have emphysema (l). Emphysema usually develops

gradually. Impairment progresses steadily and includes

labored breathing and wheezing. It frequently occurs

along with chronic bronchitis.

There is a strong correlation between emphysema

and heavy cigarette smoking (2). Industrial exposure to

cadmium is also associated with emphysema (8). Some

people have a genetic predisposition to the development of emphysema. In particular, people who have an

inherited deficiency in the amount of a serum protein

called alphal-antitrypsin are more likely to develop

emphysema (14,31), especially if they smoke.

Byssinosis

Textile workers exposed to cotton, hemp, flax, and

sisal dusts for several years may develop acute symptoms, such as chest tightness, wheezing, and cough.

After long-term exposure, they may develop chronic

symptoms of respiratory disease indistinguishable

from chronic bronchitis but called byssinosis. Bronchoconstriction in this disease is not the result of an

allergic response. It is apparently caused by a substance

(“a histamine releasing agent”) found, for example, in

cotton seeds that are present as contaminants in raw

cotton fiber.

Asthma

Asthma is a chronic disease of the airways in which

symptoms appear intermittently. In healthy people, the

smooth muscle surrounding the airways responds to

strong environmental stimuli by contracting, increasing the resistance to airflow. Patients with asthma develop more intense constriction of the smooth muscle

in response to milder stimuli than do healthy people.

The reasons for this response are unclear. Inflammation is usually present, and is thought to play a key role

in the disease. In addition to bronchial hyper-responsiveness, people with asthma have intermittent symptoms of wheezing, chest tightening, or cough.

The disease varies from individual to individual not

only in its severity, but in the types of agents that

provoke an attack. Some people develop symptoms

Table 2-2-Causes of Occupational Asthma

Complex salts of platinum

Ammonium hexachloroplatinate

Isocyanates

Toluene di-isocyanate; hexamethylene di-isocyanate;

naphthalene di-isocyanate

Epoxy resin curing agents

Phthalic acid anhydride; trimellitic acid anyhydride;

triethylene tetramine

Colophony fumes

Proteolytic enzymes

Bacillus subtilis (alkalase)

Laboratory animal urine

Rats, mice, guinea pigs, rabbits, locusts

Flour and grain dusts

Barley, oats, rye, wheat

Formaldehyde

Antibiotics

Penicillin

Wood dusts

South African boxwood (Gonioma kamassi):

Canadian red cedar

(Thuja plicata); Mansonia (Sterculiacea altissima)

Natural gums

Gum acacia, gum arabic, tragacanth

SOURCE: D.J. Weatherall, J.G.G. Ledingham, and D.A.

Warren (eds.), Oxford Textbook of Medicine (New

York, NY: Oxford University Press, 1987).

1 Emphysema and chronic bronchitis are two distinct processes.Emphysema, however, can only be diagnosed definitively after death, by

direct examination of lung tissue. Incidence data are derived from postmortem surveys. These surveys show that almost all adult lungs have

some signs of emphysema, although only a minority of adults have symptoms or disability. Clinicians and epidemiologists dealing with the

living use the synonymous terms chronic obstructive pulmonary disease (COPD), chronic obstructive airway disease (COAD), and chronic

obstructive lung disease (COLD) to describe patients whose airflow is limited as a result of bronchitis, emphysema, or a combination of the

two.
2 2 ” Identifying and Controlling Pulmonary Toxicants

only in response to one stimulus. In the United States,

for example, many people with asthma develop symptoms only during the ragweed pollen season in late

summer. Others have clear responses to particular occupational agents (table 2-2). But other patients respond to many substances. Even the mechanisms of

the disease vary among individuals. In some people

with asthma, the response seems to occur through an

immunologic reaction, but in other people, the immune system does not seem to be involved in the

response. Other mechanisms are the subject of active

research. It may be that asthma is a family of diseases

with similar symptoms but different underlying causes

and mechanisms.

In the United States, about 11.5 million people

have asthma (l). Children, African-Americans, and

inner city residents are affected disproportionately

(11). Both the prevalence and the severity of asthma in

the United States have been increasing in recent years

(12,30).

Although its causes are not precisely known, over

200 substances have been identified that can induce

symptoms (16). In addition, attacks can be provoked by

exercise, cold air, airway drying, infections, and emotional upsets. Sulfur dioxide, a component of air pollution, causes severe narrowing of asthmatic airways at

concentrations as low as 0.5 parts per million (3,20).

Exposure to respirable particles has been associated

with reduced lung function and increased symptoms in

asthmatic children (18), increased hospital visits (17)

and increased rates of acute bronchitis, particularly in

asthmatic children (9).

Pulmonary Fibrosis

Pulmonary fibrosis is a family of related disorders

characterized by scar tissue in the lungs. Chronic injury

and inflammation can result in the formation of scar

tissue in the lung, similar to the process of normal

wound-healing. In pulmonary fibrosis, however, the

wounding and formation of scar tissue is not a specific

event in a specific location. Rather it can be a chronic,

continuing process that involves the entire lung or

there may be scattered, nonuniform scarring. People

with pulmonary fibrosis must work harder to breathe,

have poor gas exchange, and often have a dry cough.

The inflammatory response of the lung varies depending on the substance causing the injury. In many

cases, causative agents are clearly established. Pulmonary fibrosis is known to be caused by exposure to high

concentrations of silica, asbestos, and other dusts (table 2-3).

Extrinsic Allergic Alveolitis

Workers sometimes develop severe immune responses to substances in the workplace, particularly to

inhaled plant and animal dusts. The disease is easy to

recognize in its acute form because workers themselves

quickly learn to associate the flu-like symptoms with

dust exposure. The chronic form, which seems to occur

in response to low-level chronic exposures to dusts

rather than high-level exposures, is more insidious.

The chronic form of the disease usually progresses very

slowly, but can result in pulmonary fibrosis.

Many causative agents have been identified. Most

are molds or fungi contaminating organic material, or

they are proteins found in animal or bird droppings.

The best known form is probably farmers’ lung, which

is caused by allergies to Micropolyspora faeni, found in

moldy hay, straw, and grain. There are many other

examples, however, including bird fanciers’ lung, associated with proteins found in parakeet and pigeon

droppings; dog house disease, associated with a mold

found in straw dog bedding; paprika splitters’ lung,

associated with a mold found in paprika; and maple

bark strippers’ lung, also associated with a mold.

LUNG DISEASE AND EXPOSURE TO

TOXIC SUBSTANCES

The Federal Government, as described further in

chapter 4, funds research in pulmonary diseases. Some

research is aimed at understanding the mechanisms by

which a particular substance damages the respiratory

system. Often, this knowledge can provide insight into

the mechanisms by which other toxic substances cause

damage. Many toxic substances cause similar reactions

in the respiratory system simply because the respiratory system has a limited range of responses to insults.

Asthmatic attacks, for example, are induced by a wide

variety of substances, and, similarly, many substances

cause pulmonary fibrosis. Careful study of the effect of
Chapter 2—The Respiratory System and Its Response to Harmful Substances 23

Table 2-3—Industrial Toxicants Producing Lung Disease

Toxicant Common name Occupational source Chronic effect Acute effect

of disease

Ammonia

Arsenic

Beryllium

Aluminosis

Asbestos Asbestosis Mining, construction,

shipbuilding, manufacture of asbestos-containing material

Aluminum dust Manufacture of aluminum products, fireworks,

ceramics, paints, electrical goods, abrasives

Aluminum abrasives Shaver’s disease, corun- Manufacture of abradum smelter’s lung, sives, smelting

bauxite lung

Ammonia production,

manufacture of fertilizers, chemical production,

explosives

Manufacture of pesticides, pigments, glass

alloys

Ore extraction, manufacture of alloys, ceramicsBerylliosis

Cadmium oxide Welding, manufacture of

electrical equipment, alloys, pigments, smelting

Carbides of tungsten, Hard metal disease Manufacture of cutting

titanium, tantalum edges on tools

Chromium (VI)

Coal dust

Cotton dust

Pneumoconiosis

Byssinosis

Chlorine Manufacture of pulp and

paper, plastics, chlorinated chemicals

Production of Cr compounds, paint pigments,

reduction of chromite ore

Coal mining

Manufacture of textiles

Hydrogen fluoride Manufacture of chemicals, photographic film,

solvents, plastics

Fibrosis, pleural calcification, lung cancer,

pleural mesothelioma

Cough, shortness of Interstitial fibrosis

breath

Alveolar edema Interstitial fibrosis,

emphysema

Upper and lower Chronic bronchitis

respiratory tract irritation,

edema

Bronchitis Lung cancer, bronchitis, laryngitis

Severe pulmonary edema, Fibrosis, progressive

pneumonia dyspnea, interstitial

granulomatosis, cor

pulmonale

Cough, pneumonia Emphysema, cor pulmonale

Hyperplasia and Peribronchical and

metaplasia of bronchial perivascular fibrosis

epitheliums

Cough, hemoptysis,

dyspnea,

tracheobronchitis,

bronchopneumonia

Nasal irritation, bronchitis Lung cancer fibrosis

Fibrosis

Chest tightness, Reduced pulmonary

wheezing, dyspnea function, chronic bronchitis

Respiratory irritation,

hemorrhagic pulmonary

edema
24 ● Identifying and Controlling Pulmonary Toxicants

Table 2-3—Industrial Toxicants Producing Lung Disease (Cent’d)

Toxicant Common name Occupational source Chronic effect Acute effect

of disease

Iron oxides Siderotic lung disease;

silver finisher’s lung,

hematite miner’s lung,

arc welder’s lung

Isocyanates

Kaolin

Manganese

Nickel

Oxides of nitrogen

Ozone

Phosgene

Perchloroethylene

Silica

Sulfur dioxide

Talc

Tin

Kaolinosis

Manganese pneumonia

Welding, foundry work,

steel manufacture, hematite mining, jewelry making

Manufacture of plastics,

chemical industry

Pottery making

Chemical and metal

Talcosis

Stanosis

industries

Nickel ore extraction,

smelting, electronic electroplating, fossil fuels,

Welding, silo filling,

explosive manufacture

Welding, bleaching flour,

deodorizing

Production of plastics,

pesticides, chemicals

Dry cleaning, metal

decreasing, grain fumigating

Silicosis, pneumoconioi- Mining, stone cutting,

sis construction, farming,

quarrying

Manufacture of chemicals, refrigerant ion,

bleaching, fumigation

Rubber industry, cosmetics

Mining, processing of tin

Cough

Airway irritation, cough,

dyspnea

Acute pneumonia, often

fatal

Pulmonary edema,

delayed by 2 days

(NiCO)

Pulmonary congestion

and edema

Pulmonary edema

Edema

Silver finisher’s: subpleural and perivascular aggregations of

macrophages; hematite miner’s: diffuse

fibrosis-like pneumonconiosis; arc welder’s; bronchitis

Asthma, reduced pulmonary function

Fibrosis

Recurrent pneumonia

Squamous cell carcinoma of nasal cavity

and lung

Emphysema

Bronchitis

Edema

Fibrosis

Bronchoconstriction,

cough, chest tightness

Fibrosis

Widespread mottling

of x-ray without clinical signs

Vanadium Steel manufacture Airway irritation and Chronic bronchitis

mucus production

SOURCE: T. Gordon, and M.O. Amdur ” Responses of the Respiratory System to Toxic Agents, “ Casarett and Doull’s Toxicology.” The Basic Science

of Poisons, M.O. Amdur, I. Doull and C.D. K]a.ssen, (cd.) (New York, NY: Pergamon Press, 1991).
Chapter 2—The Respiratory System and Its Response to Harmful Substances 25

one substance helps researchers to understand the effects of other substances.

Other research is aimed at identifying which substances cause the development of disease, what levels

of exposure are harmful, and why responses to toxicants differ among subgroups of the population (25).

Identifying specific causes of respiratory diseases is no

simple matter because different substances can cause

similar kinds of damage, and, conversely, one substance

can cause several kinds of damage. It is easier to establish causal relationships when a defined population

exposed to high levels of a particular substance exhibits

characteristic symptoms or changes in respiratory

function. Dozens of examples among occupational

groups illustrate how high-level exposures have allowed identification of many causes of occupational

asthma, pulmonary fibrosis, and extrinsic allergic alveolitis (table 2-3).

It is more difficult to determine the effects of substances to which many people are exposed at much

lower levels than the heavy occupational exposures.

Five major components of air pollution, carbon monoxide, sulfur oxides, hydrocarbons, particulate, and

oxidants, are widely distributed in varying concentrations throughout the United States. No single, well-defined group is exposed to any one of these at

exceptionally high levels; instead virtually everyone is

exposed at some level. Large proportions of the population are also exposed to varying concentrations of

common indoor air pollutants such as environmental

tobacco smoke; nitrogen oxides (from gas stoves);

woodsmoke; allergens of the house dust mite, cats,

rodents, and cockroaches; and formaldehyde and other

volatile organic compounds. Sorting out particular effects of each of these substances is quite different from

identifying the cause of bird fanciers’ lung or maple

bark strippers’ lung. The high background level of

respiratory disease in the population at large also

makes pinpointing particular causal agents more difficult. The kinds of tests and studies aimed at elucidating

the relationships between respiratory diseases and exposure to indoor and outdoor air pollutants are explored in the next chapter.

CHAPTER 2 REFERENCES

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Barker, D.J.P., and Osmond, C., “Childhood Respiratory Infection and Adult Chronic Bronchitis

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Crystal, R. G., West, J. B., Barnes, P.J., et al.,

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J., et al., “Cadmium Fume Inhalation and Emphysema,” The Lancet Mar. 26, 1988, pp. 663-667.

Dockery, D. W., Speizer, F. E., Strain, D. O., et al.,

“Effects of Inhalable Particles on Respiratory

Health of Children, ’’American Review of Respirato~ Disease 139(3):587-594, March 1989.

Doll, R., and Pete, R., “Mortality in Relation to

Smoking: 20 Years’ Observations on Male British

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Gordon, T., and Amdur, M.O. “Responses of the

Respiratory System to Toxic Agents,” Casarett

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Pergamon Press, 1991).

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Morgan, W.KC., ‘Industrial Bronchitis,” British

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Newman Taylor, A.J., ‘Occupational Asthma,”

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26 ● Identifying and Controlling Pulmonary Toxicants

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American Review of Respiratory Disease 123Y186-

491, 1981.

Sherrill, D. L., Lebowitz, and Burrows, B., “Epidemiology of Chronic Obstructive Pulmonary Disease,” Clinics in Chest Medicine 11:375-387, 1990.

Speizer, F., ‘Studies of Acid Aerosols in Six Cities

and in a New Multi-city Investigation: Design

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Identifying and Controlling Immunotoxic Substances-Background Paper, OTA- BP- BA-75

(Washington, DC: U.S. Government Printing Office, April 1991).

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The Health Consequences of Smokz”ng. Chronic

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Human Services, Public Health Service, Office on

Smoking and Health, 1984.

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Inhaled Pollutants, ASTM STP 1024, (Philadelphia, PA: American Society for Testing and Materials, 1989).

Utell, M.J., and Samet, J. M., “Environmentally

Mediated Disorders of the Respiratory Tract,”

Medical Clinics of North America 74(2):291-306,

1990.

Wailer, R. E., “Atmospheric Pollution,” Chest

%(3):363S-368S, 1989.

Weatherall, D.J., Ledingham, J. G. G., and Warren, D.A. (eds.), Oxford Textbook of Medicine

(New York, NY: Oxford University Press, 1987).

Weibel, E. R., The Pathway for Orygen: Structure

and Function in the Mammalian Respiratory System (Cambridge, MA: Harvard University Press,

1984).

Weiss, KB., and Wagener, D.K, “Changing Patterns of Asthma Mortality,” Journal of the American Medical Association 264:1683-1687, 1990.

Welch, M. H., Guenter, C.A., Hammerstein, J.F.,

“Precocious Emphysema and alphal-Antitrypsin Deficiency,” Advances in Internal Medicine 17:379-

92, 1971.
Chapter 3

Pulmonary Toxicology and Epidemiology
Chapter 3

Pulmonary Toxicology and Epidemiology

INTRODUCTION

As individuals move from home to work to various

outdoor environments, they breathe air of divergent

composition and quality. In addition to the oxygen

needed for survival, people inhale a “soup” of gases and

particles. The ingredients of that soup range from benign to lethal in their potential and actual effects on

the human lung.

Obvious health concerns in the outdoor air include

particulate matter, sulfur oxides, nitrogen oxides,

ozone, and carbon monoxide—those pollutants associated with a heavily industrialized, fossil-fuel based

economy. Workplace concerns differ greatly among

occupations, but typically include organic and inorganic dusts and the vapors from various chemicals.

Concerns also focus on “indoor” (e.g., home, school,

office) air, where substances as ubiquitous as formaldehyde, tobacco smoke, asbestos, woodsmoke, and

molds stand accused as potential contributors to respiratory disease.

Exposure to airborne toxicants varies considerably

among individuals and among populations. A taxi

driver who cooks over a gas stove receives a regulated

(vehicle emissions) and unregulated (stove emissions)

dose of nitrogen dioxide, while a homemaker in an

all-electric home may receive a wholly unregulated

dose of formaldehyde (offgassing from furnishings or

insulation). A school-age child of smoking parents may

be exposed to air pollutants subject to legislative controls (e.g., asbestos in schools) and uncontrolled pollutants (e.g., tobacco smoke in the home) with known

synergistic effects. Residents downwind of a coal-burning power plant may worry about sulfur dioxide and

particulate matter, while the miners who supply the

fuel may worry more about coal dust. Policymakers and

regulators must determine how best to protect human

health from the potential ill effects of these multiple

exposures to toxicants. They wrestle with technical

questions (e.g., is there solid evidence that Substance

X causes human health problems? If so, at what concentrations?) and socio-economic questions (e.g., does

the benefit of avoiding a particular health problem

outweigh the cost of reducing the toxic exposure that

causes it?).

This chapter examines how toxicology and epidemiology contribute to decisions on whether or how to

regulate substances because of pulmonary toxicity (box

3-A). The chapter first describes the framework for

most regulatory decision making—risk assessment—

and then describes the types of technologies available

to complete each step of that process with regard to

inhaled pulmonary toxicants. The technologies covered include those that enable assessment of exposure

and dose and assessment of health effects. Finally, this

chapter examines whether remaining questions about

the noncancer health risks of pulmonary toxicants

merely await application of existing technologies or

whether answers will require development of new

tools.

FRAMEWORK FOR STUDYING

TOXICANTS

Early efforts to identify and control pulmonary

toxicants in the United States were directed at substances that induced obvious disease in highly exposed

individuals. In recent years efforts have focused more

on attempts to protect the general population from the

more nebulous “unacceptable risk of disease” at much

lower exposure levels (34). But the objective of reducing mortality and morbidity remains. The statutes that

authorize control of pollutants to protect human

health explicitly or implicitly require a substantial

amount of proof that a substance causes disease or

injury before the substance can be subjected to regulatory controls. The framework in which such proof is

sought is generally referred to as risk assessment.

Risk assessment is the process of characterizing

and quantifying potential adverse health effects that

29
30 ● Identifying and Controlling Pulmonary Toxicants

Box 3-A-General Principles of Toxicology

To evaluate the toxic nature of a substance, including its pulmonary toxicity, scientists have developed

several general criteria for consideration, including:

Nature of the Toxic Substance. Toxicologists try to determine the characteristics that render a chemical

toxic. Individual molecules may not be toxic in their native states but become toxic after being metabolized.

The size and shape of particles may affect their toxicity.

Dose and Length of Exposure. These parameters, together with rates of metabolism and excretion,

determine what quantity of a substance is actually affecting the body. A given substance maybe toxic in

high doses but nontoxic under conditions of chronic low-dose exposure.

Route of Exposure. The pathway by which a toxicant enters the body (e.g., skin, eye, lungs, or

gastrointestinal tract) affects its toxicity. The amount of absorption, ability of the toxicant to combine with

native molecules at the entry point (e.g., heavy metals with skin collagen), vulnerability of sensitive areas

(e.g., lining of the lung), and condition of the organ at time of contact (e.g., pH a nd content of the stomach)

all play a role in subsequent toxicity. This study examines inhalation exposures.

Species Affected. Toxicants exhibit different levels and effects of toxicity depending on the species on

which it is tested.

Age. Susceptibility to a toxicant varies with age—the young and the old generally being the most

susceptible.

State of Health. The health status of an individual, including the presence of disease, can greatly affect

toxicity response. For example, people with asthma may suffer adverse effects from substances that do no

harm to most individuals.

Individual Susceptibility. Host factors such as genetic predisposition affect the response of an individual

to a toxicant.

Presence of Other Agents. Toxicology often involves evaluating one substance in isolation, yet the body

is seldom exposed to agents in this manner. Knowledge about toxic effects of multiple substances is not

well-developed because of the practical limitations of testing the infinite number of combinations.

Adaptation/Tolerance. Biological adaptation to a toxicant often occurs when chronically low doses are

presented. Adaptation/tolerance must be factored into evaluating the range of individual responsiveness

to a toxicant.

SOURCE: Office of Technology Assessment, 1992, based on M.A. Ottoboni, l%eDoseh4akes the Pofion (Berkeley, C& Vineente

Books, 19$4).

may result from exposures to harmful physical or assessment applies measurement and extrapolation

chemical agents in the environment. As practiced in technologies to determine what level of human expoU.S. Federal agencies, it generally involves four essen- sure can be anticipated. Risk characterization integrates

tial elements: the results of the first three steps to estimate the inci-

.

.

.

.

dence of a health effect for a given population under

hazard identification; various conditions of human exposure (24,27).

dose-response assessment;

exposure assessment; and Bringing a risk assessment of a suspected pulmorisk characterization (9,27). nary toxicant to a satisfactory conclusion poses tricky

problems for an investigator. Hazard identification

The process of hazard identification attempts to may involve laboratory and field studies. In vitro tests

determine whether a particular substance or mixture of at the cellular level may indicate that a substance

substances can create a measurable health effect. Dose- causes a biological response but fail to address whether

response assessment identifies the health effects caused the effect would be adverse in the whole animal, where

by a given dose of the substance understudy. Exposure defense mechanisms may prevent the toxicant from
Chapter 3—Pulmonary Toxicology and Epidemiology 31

reaching the cells being tested. Dose-response assessments often are performed on animals rather than

humans (particularly when new substances are being

studied), which requires knowledge of whether animals

and humans would respond similarly to the substance

under study. Animal tests of acute exposures can be

conducted with relative ease, but tests of low-level,

chronic exposures are time-consuming and costly. Lack

of emissions data, lack of knowledge about how substances are transported in the air, and lack of adequate

monitoring devices typically complicate the exposure

assessment. The following sections on Exposure Assessment and Dosimetry and on Health Effects Assessment describe technologies available for risk

assessment of pulmonary toxicants and limits of those

technologies.

EXPOSURE ASSESSMENT AND

DOSIMETRY

Exposure to a contaminant has been defined as

contact between a person and a physical or chemical

agent. Exposure differs from biologically effective dose,

which is the amount of a contaminant that interacts

with cells and results in altered physiologic function.

Regulators direct their efforts toward controlling exposures to populations that can reasonably be expected

to result in harmful, biologically effective doses to

individuals within those populations. The technologies

of exposure assessment and dosimetry contribute to

these efforts.

Exposure assessment is the estimation of the magnitude, frequency, duration, and route of exposure to a

substance with the potential to cause adverse health

effects. Dosimetry is the estimation of the amount of a

toxicant that reaches the target site, in this case the

lung, following exposure (30). The following subsections first describe devices that can be used to estimate

exposure and determine the amount of a toxicant actually retained by the lung, and then describe technologies available to help scientists predict the biologically

effective dose that will be produced by a given human

exposure (figure 3-l).

Estimating Exposure and Biologically

Effective Dose

A series or combination of physical and biological

events may affect whether a toxicant that becomes

airborne will create a health effect. Toxicants may be

transported and transformed in the environment before human contact. Defense mechanisms in the respiratory system may remove or transform a toxicant before it causes damage. This section describes technologies to measure actual and potential exposures to

toxicants and technologies to measure retention by the

lung.

Exposure

Exposure to airborne toxic substances traditionally has been estimated by sampling community and

workplace air. Continuous samplers, used to measure

gases, and integrating samplers, used to measure particles, are placed atone or more fixed sites in urban and

nonurban areas (22). Contaminant concentrations derived from such measurements of the outdoor air have

often been used to estimate an individual’s average

acute or lifetime exposure. Such estimates assume that

all contact with pollutants occurs in the outdoors and

that the breathing zone concentration is identical to

that at fixed-site monitors.

In reality, people come into contact with polluted

air in many different environments. Sophisticated

monitoring devices now permit consideration of the

multiple opportunities for people to come into contact

with polluted air. Indirect (microenvironmental) and

direct (personal) monitoring, combined with outdoor

measurements, help scientists arrive at more accurate

estimates of individuals’ total exposure to airborne

pollutants. Indirect monitoring uses traditional air

sampling techniques but applies them to microenvironments—various indoor (e.g., homes, commercial

buildings, worksites, vehicles) and outdoor (e.g., highways, industrial sites, backyards) sites. Personal monitoring requires individuals to wear or carry a sampling

device throughout the study period and, generally, to

log their daily activities to help associate measured

exposures with their sources. Studies have demonstrated the effectiveness of personal monitoring devices (45), but scientists generally agree that detection

limits and reliability need improvement. Techniques to

enhance or supplement personal activity logs, such as

personal location monitors, would also increase the

precision achievable with personal monitoring

devices (22).

Biologically Effective Dose

Several factors influence the amount of an inhaled

contaminant that actually reaches lung tissues and cells

following exposure. An individual at rest inhales less

air than an exercising individual because exercise increases the ventilation rate. The ambient exposure can
32 ● Identifyingand Controlling Pulmonary Toxicants

Figure 3-l—Framework for Exposure Assessment

o

Outdoor

o

Indoor

emission emission

sources sources

Dispersion, conversion, Dispersion, conversion,

and removal factors and removal factors

(including weather) (including ventilation)

Outdoor

Building penetration,

>

Indoor

concentration <

air exchange, conversion,

concentration

\/

and removal factors

Time-activity Tree-activity

patterns patterns

w

Host factors

J

I

Internal dose I

1 I

I

l-lost factors

L-J Biologically

effective dose

(to critical target

tissue)

Host factors

Health effect

1 1

SOURCE: National Research Council, Committee on Epidemiology of Air Pollutants, EpidernioZo~ andAirPoZZution (Washington, DC:

National Academy Press, 1985).

be the same for each, but exercise increases the biologically effective dose. Inhaled toxicants maybe removed

from the inspired air before they reach the tracheobronchial and pulmonary regions (the predominant

sites of injury that may lead to changes in pulmonary

performance; see ch. 2). But individuals who breathe

through their mouths rather than noses (e.g., asthmatics) may lose the benefit of that respiratory defense

mechanism. Techniques ranging from measurements

of exhaled air to examination of excised lung samples

can be used to estimate how much of a substance

reaches and is retained by various regions of the lung.

Analysis of exhaled air—Gas chromatography/mass spectroscopy can be used to measure exhaled

air for contaminants that were absorbed by the lung.

Breath measurements have been shown to correlate

with preceding exposures for selected volatile organic

compounds (45).

Analysis of body fluids-Sputum and fluid obtained by nasal lavage can be analyzed for the presence

of toxic substances. Blood and urine can be analyzed

for the presence of toxicants, but current measurements of these fluids generally yield very little or no
Chapter 3—Pulmonary Toxicology and Epidemiology 33

information about the delivered dose of a toxicant to

the lung.

Analysis of the whole lung—Invasive and relatively noninvasive techniques can be used to determine

the quantity of particles in the lungs of living subjects.

Whole-lung scanning for particles labeled with radioactive tags (performed on an experimental basis) permits determination of the total concentration in the

lung of certain types of inhaled particles and the size of

the particles. Open-lung biopsy (an invasive technique

requiring strong justification in humans) permits direct counting of particles or determination of fiber

burden per gram of lung tissue (29). A noninvasive

technique, magnetopneumography (MPG), provides a

means of actively monitoring the dust retained in the

lungs of people exposed to magnetic or magnetizable

dusts. MPG can be used intermittently, for test purposes only, or to monitor individuals (particularly

workers) for unacceptable rates of dust accumulation.

Only magnetic or magnetizable dusts (e.g., asbestos,

coal) can be monitored with MPG.

Analysis of samples of lung tissue-Scanning electron microscopy has been used to determine the deposition site, in rat, mouse, and hamster lungs, of particles

small enough to reach the conducting airways. It also

has permitted quantification of the particles present at

selected deposition sites. Transmission electron microscopy has been used to locate inorganic particles in

lung tissue, which can then be analyzed to identify the

particle type. The techniques allow determination of

the chemical composition and structure of a wide

range of particles of varying sizes and elemental composition (31).

Determining Physical Properties of a

Toxicant

Determination of the physical properties of a toxicant may allow an investigator to predict how a gas or

particle will behave in the environment (how it will be

dispersed following emission) and in the lung (how it

will be deposited and cleared from the respiratory system). This background paper does not address methods for determining atmospheric dispersion but is

concerned with methods for determining regional

deposition within the lung.

Toxicants are inhaled as gases, vapors, or aerosols

(table 3-l). Many factors influence deposition of gases

and aerosols in the lung. For instance, exercise-induced

oral (as opposed to nasal) breathing increases the

amount of gas or particles that bypasses the nasopharyngeal region and reaches the deep airways. Doses of

toxicants that overwhelm normal lung defenses (see ch.

2) can also affect the deposition of gases and particles.

The most influential factors in deposition are the

physical properties of the substances understudy (and

the species in which they are tested.

As a general rule, water soluble gases inhaled

through the nose will be partially extracted in the upper

airways. Less soluble gases will reach the small airways

and alveoli. Particle size generally determines the region of the lung affected by particles. Particles with an

Table 3-l—Defining Gases and Aerosols

Gases

Vapors

Aerosols

Dusts

Fumes

Smoke

Mist

Fog

Smog

Substances that are in the gaseous state at room temperature and pressure.

The gaseous phase of a material that is ordinarily a solid or liquid at room temperature and pressure.

Relatively stable suspensions of solid particles or liquid droplets in air.

Solid particles formed by grinding, milling, or blasting.

Vaporized material formed by combustion, sublimation, or condensation.

Aerosol produced by combustion of organic material.

Aerosols of liquid droplets formed by condensation of liquid on particulate nuclei in the air or by the uptake

of liquid by hydroscopic particles.

See mist.

Complex mixture of particles and gases formed in the atmosphere by sunlight’s effects on nitrogen oxides and

volatile organic compounds.

SOURCE: T. Gordon and M. Amdur, “Responses of the Respiratory System to Toxic Agents, “ in Cassarett and Doulls Toxicology:

The Basic Science of Poisons, 4th edition (Elmsford, NY: Pergamon Press, 1991), pp. 383-406.
34 ● Identifyingand Controlling Pulmonary Toxicants

aerodynamic size greater than 10 micrometers are

mostly removed in the upper airways, while smaller

particles penetrate deeper. Extremely small or extremely thin particles can cross the alveolar epithelial

barrier and cause interstitial lung injury (see ch. 2).

Knowledge of the physical properties of a toxicant,

coupled with the resultant knowledge of the probable

site of deposition, points an investigator to the likely

site and type of toxic injury. Actual behavior often

differs from predicted behavior, but differences are

generally revealed during the investigation.

Determining Species Differences

Toxicologists often try to predict the human health

effects of toxicants by first studying them in animals.

Animals provide useful models for studying toxicant

exposure, but differences in anatomy, biochemistry,

physiology, cell biology, and pathology affect the way

species respond to airborne toxicants (8,46). Risk assessments of toxic substances generally depend on experimental data obtained from a variety of species, and

it is essential to consider and study species differences

before selecting the appropriate animal for study and

making judgments about whether an exposure/dose

administered to an animal has relevance for human

health (23).

Respiratory tract anatomy differs significantly among species. Although most mammals have

similar respiratory tract components, the structure of

those components—which affects how substances behave in the lung—varies (e.g., humans differ from most

other animals in the size and shape of the nasal airways,

in the pattern of tracheobronchial tree branching, and

in alveolar size). In addition to direct study of differences, computer modeling techniques now permit

three-dimensional reconstructions of the lung, based

on tissue samples, that improve the ability to extrapolate from test results in animals to likely health effects

in humans (25).

Breathing patterns and lung defense mechanisms

also affect the fate of toxicants in the lung. For instance,

humans often breathe through their noses and their

mouths, while some other animals (notably the rodents

used in toxicology) can only breathe through their

noses. These differences have a major impact on deposition of particles. Also, scientists now know that alveolar clearance mechanisms, which are designed to clean

out the lung and prevent the type of damage that

derives from prolonged exposure, are much faster in

some species than in others.

Relative distribution of lung cell types differs

among species, which affects the type of damage toxicants can inflict. Similarly, the mechanism of injury

may differ among species and by exposure type (e.g.,

chronic exposure to beryllium causes an immune reaction in human lungs, but beryllium acts through direct

cytotoxicity in rat and human lungs at acute exposure

levels (19)). Only certain species can be used to test

disease states of interest to scientists. For example, rats

are generally the species of choice for pulmonary toxicologists, but toxicologists often use guinea pigs when

asthmatic responses are in question because guinea

pigs have airways more sensitive to bronchoconstriction than most species, and hence share a similarity

with human asthmatics.

No single species makes a perfect physical surrogate for humans in studying the health effects of airborne toxicants. In addition to scientific issues,

toxicologists must also consider the availability and

expense of different species, especially when the effects

of chronic, rather than acute, exposure are being studied. Much has been learned about species differences,

and scientists are beginning to account for those differences when extrapolating from effects in animals to

humans. Most experts agree, however, that increased

interspecies comparisons and studies of the mechanisms of injury would increase the utility of animal tests

in the risk assessment process.

Summary of Exposure Assessment and

Dosimetry Technologies

Technologies that measure the presence of gases

and aerosols in the ambient air and at target sites within

the body play an essential role in risk assessment of

airborne toxicants. These technologies have evolved

rapidly and continue to improve estimates of human

exposure to toxic substances. Scientists point to important gaps in the “exposure assessment knowledge base,”

however (29,35). These include, generally:

. Lack of knowledge about the disposition of inhaled gases, vapors, and extremely small particles

within the respiratory tract;
Chapter 3—Pulmonary Toxicology and Epidemiology ● 35

.—

● Lack of knowledge about the disposition of gases

and aerosols within the respiratory tracts of sensitive individuals and groups within the population;

● Inadequate knowledge of the species differences

that may affect interpretation of test results; and

● Lack of a sound basis for extrapolating the effects

of exposure from high to low concentrations.

The gaps present no insurmountable barriers to

effective risk assessment but will require time and resources to fill.

HEALTH EFFECTS ASSESSMENT

A health effects assessment completes two steps of

the risk assessment process: hazard identification, by

determining whether a substance causes damage, and

dose-response assessment, by determining the damage

caused by a specific dose. Health effects assessments

utilize controlled exposure conditions, as with laboratory and clinical studies, or uncontrolled exposure conditions, as with epidemiologic studies. Each type of

study has advantages and disadvantages. To compensate, scientists try to integrate the results of multiple

studies in their conclusions (figure 3-2). For instance,

laboratory, clinical, and epidemiologic studies have

contributed to the decision-making process on permissible ozone exposure levels. The following subsections

describe the types of tests that can help investigators

reach conclusions about the pulmonary effects of airborne toxicants.

Figure 3-2—Integrated Approach to Identifying

Pulmonary Toxicants

Responses to

acute exposures

in animals G=====O ;:55?:;’0s

o

u) c II

.o=

I’J

2

g @

;

I g“ \

p

.- I“l a K-’

Diseases in ————— Diseases in

animals with Projections ‘) humans with

chronic exposure — — — — —/ chronic exposure

SOURCE: Office of Technology Assessment, 1992, based on M.

McClellan, R. O., “Reflections on the Symposium:

Susceptibility to Inhaled Pollutants,” American Society

for Testing and Materials Special Technical Publication

1024,1989.

Laboratory and Clinical Studies

Laboratory studies and human clinical studies control exposure conditions as closely as possible to limit

the influence of extraneous factors on the study. This

means, in part, investigators must understand “host

factors”—the physical conditions, activity level, and

personal habits of the test subject-and other factors,

such as time of day or season of the year, that may affect

the outcome of a study. It also means investigators

choose not only the health effect to study but the

amount of toxicant to which tissues and cells, animals,

or human volunteers are exposed.

There are drawbacks to studies involving controlled exposure conditions. The fundamental limitation of experiments involving whole animals lies in

extrapolating results to humans. As discussed above,

techniques are progressing, but scientists are not yet

satisfied with their ability to account for the differences

in human and animal lungs when predicting the effects

of a toxicant. In addition, studies using whole animals

involve considerable expense and, in some instances,

problems with the public’s views on animal experimentation. Ethical restraints on human clinical studies—

investigators may not inflict harm—place inherent

limitations on their use for predicting a toxicant’s likelihood of causing a deadly or disabling condition. The

intentional simplicity of experiments involving controlled exposures also limits their value for revealing

the effects of exposure under “real world” conditions.

To isolate the effects of one substance, investigators

eliminate other potential toxicants from the air, which

may alter the effect the test substance has on the lung.

Technologies to Measure Exposure

Toxicologists performing animal experiments

must have the capability to generate the types of chemicals and particles they want to test and the capability to

expose the animals to fixed amounts of the test substance(s). Technologies to generate gases and aerosols

are well developed (2,26). However, the aerosols generated tend to be far more homogeneous than those

encountered in typical urban environments. Exposure

occurs in whole-body chambers and in apparatuses

permitting head-only and nose-only exposures. Existing systems provide for adequate exposure control and

measurement and do not constrain evaluation of test

results when system limitations are properly accounted

for in the analysis (6). However, continued research is

important to understand the implications of the differ-
36 Identifying and Controlling Pulmonary Toxicants

ences in complex, naturally occurring aerosols and

those generated for experimental purposes.

Participants in human clinical studies can be exposed to the test substance in exposure chambers

(whole-body systems) or through systems using either

a facemask, hood, or mouthpiece. Each system has

advantages (e.g., exposure chambers permit unencumbered breathing and most accurately simulate normal

conditions; mouthpieces are very simple) and disadvantages (e.g., facemasks are difficult to seal; exposure

chambers can be expensive to construct and maintain,

part of the reason why only four chambers in the

United States are effectively operating (37)). It is possible to calibrate the limitations of each system sufficiently to permit adequate evaluation of test results

(17). Development of portable exposure chambers

could enhance use of that exposure system (37).

Measurements of Effects

Toxicologists can identify pulmonary toxicants

through physiologic assays of living subjects, structural

analysis of tissues and cells removed from animals or

humans, and tests of biochemical responses in removed

fluids and cells. The following subsections describe

various testing measures.

Physiologic tests—Assays of physiologic function

fall into four major categories: measures of ventilatory

or gas-exchange functions; measures of increased airway reactivity; measures of particle clearance from the

Photo credit: South Coast Air Quality Management District, El Monte, CA

A volunteer undergoes lung function tests while exercising.
Chapter 3—Pulmonary Toxicology and Epidemiology 37

lung; and measures of increased permeability of the

air-blood barrier. These assays can be used to demonstrate transient and lasting changes in lung function.

Functional assays are applied to animals and humans,

though specific tests performed vary by species.

Spirometry, which includes various measures of

how much and how quickly air can be expelled following a deep breath, constitutes the most common group

of respiratory function tests performed in humans. A

very frequently used spirometric test measures the

amount of air that can be forcibly expelled in 1 second

and is referred to as FEV1 (forced expiratory volume

in 1 second). Physicians agree that an FEV1 below 80

percent of the predicted value (which varies with age,

height, and sex) indicates an adverse health effect. EPA

has used evidence of decrements in FEV1 greater than

or equal to 10 percent as the basis for regulations. Some

studies show that a decrease in FEV1 following shortterm exposure correlates with development of obstructive disease following chronic exposure, but much

research remains to be done.

The total amount of air that can be expelled following a deep breath is referred to as forced vital

capacity (FVC), and this measure is also a commonly

used test. Practitioners of spirometry can chart the air

flow rate after 50 percent or 75 percent of the volume

has been forcibly expelled (forced expiatory flow of 50

or 75 percent, or FEF50 or FEF75). Alternatively, the

flow rate between 25 percent and 75 percent of the

FVC (maximal midexpiratory flow, or MMEF) can be

measured. Some researchers believe that FEF50,

FEF75, and MMEF may identify early and subtle damage to airways, which maybe the first stage of the type

of severe or irreversible damage reflected in the more

common measures of FEV1 or FVC.

Ventilator function tests that do not require voluntary exhalation maneuvers can be performed in experimental animals. Such tests include measures of the

mechanical properties of the lung, i.e., the amount of

work required to stretch the lung (inhale) and the work

required to push air out of the lung (exhale). Traditional measures of lung mechanics have been used

widely in animal studies of toxicants that are pulmonary irritants (7).

The distribution of gases and particles within the

lung can also be measured with ventilator function

tests. Single- and multi-breath nitrogen washout tests

determine the point in exhalation when the airways

begin to close (as evinced by an increase in the nitrogen

content of exhaled air). A transient increase in the

amount of air left in the lung when the limits of forced

exhalation are reached appears to correlate with exposure to pulmonary toxicants. Particle distribution can

be examined by measuring the number of particles,

administered as an aerosol, in exhaled air and with

radioimaging techniques. Efforts are underway to validate such tests, which are not yet in widespread use.

Tests of how well gas diffuses from the lung into

the blood system—the diffusing capacity of the lung for

carbon monoxide (DLcO)-are sometimes included

among ventilator function tests. The tests use carbon

monoxide (at harmless dose levels) because it is readily

absorbed by the hemoglobin in the blood. The most

common DLCO test requires the subject to inhale a

mixture of inert gas and carbon monoxide. Changes in

the ratio of inert gas to carbon monoxide, as measured

in air captured at the end of exhalation, can indicate

changes in the lung’s diffusing capacity (e.g., if unusually high levels of carbon monoxide remain in the

exhaled air, it indicates alterations in the transfer of CO

from the lung to the bloodstream).

Measures of airway hyper-reactivity are another

type of physiologic test of pulmonary toxicity. These

tests assess whether the bronchoconstrictor response

to stimuli increases (i.e., whether the airways become

hyper-reactive and resist air flow) during or following

exposure to inhaled toxicants. In nonspecific airway

hyper-reactivity tests, the stimulus for the bronchoconstrictor response may be cold air, exercise, or various

pharmacologic agents. This type of testing has proved

useful for measuring airway responses to low concentrations of environmental pollutants. In specific airway

hyper-reactivity testing, the stimulus is often a common antigen. In nonspecific and specific tests of airway

hyper-reactivity, the tests applied following stimulation of the airways involve an airway resistance measurement and a pulmonary function test, usually FEV1

.

Airway hyper-reactivity is characteristic of asthma, although it can occur in nonasthmatics. Some researchers suggest airway hyper-reactivity may play an

important role in the development of chronic lung

diseases.

Particle clearance assessments also provide physiologic evidence of pulmonary toxicity. These assays

determine how exposure to toxicants alters the lung’s

ability to clean itself out. Though several tests are

under development, their utility is hindered by the fact
38 ● Identifying and Controlling Pulmonary Toxicants

that as yet there is no generally accepted range of

normal clearance performance. Most tests trace the

transport and removal of radiolabeled particles following exposure to a toxicant.

The final, major type of physiologic assay of pulmonary toxicity attempts to measure injury to the airblood barrier, usually equating injury with increased

permeability. Permeability Can be determined by measuring ion transport through airway epithelial cells or

by measuring the transepithelial transport of molecules into the blood. These tests currently have many

drawbacks, and though research appears to be worthwhile, much remains to be done. Permeability of the

endothelial cells that line the blood vessels can also be

measured, but nondestructive techniques require further validation before they can come into common use.

In 1989, the National Academy of Sciences (NAS)

summarized the utility of physiologic assays in identifying pulmonary toxicants (29). A portion of that analysis is reproduced here as table 3-2. The preceding

section provides only a cursory overview of the basic

types of physiologic tests of pulmonary toxicity, and the

reader is referred to the NAS report for detailed descriptions of these and additional tests.

In summary, physiologic function tests provide

reasonable measures of response to toxicants but are

not particularly specific or sensitive. Changes in function are not unique to individual toxicants (i.e., lung

responses to insult are limited). Current tests have

limited value in identifying the effects of chronic exposure (which tend to occur insidiously) (44). But when

used in tandem with knowledge of exposure, these tests

can help identify toxicants.

Structure tests—Injury to lung tissues and cells

can, in some instances, be assessed with the naked eye.

For instance, in advanced asbestosis the damage asbestos causes to the pleura can be seen unaided in an open

chest cavity, and a microscope can provide even greater

detail of the damage. Whole lungs or tissues and cells

taken from autopsied humans or animals can be directly examined for evidence of toxic effects. X-ray

technologies are also useful in structural studies.

Scientists also know that cells of the pulmonary

system normally appear in relatively constant numbers

and sites within the lung. Examination of tissue from

specific regions of the lung can indicate changes in cell

populations that are evidence of toxic effects. Morphometry, a technique that employs microscopy to

quantify cell populations and structure size using fixed

tissue samples, has been widely used to study toxic

substances suspected of causing a specific type of injury

throughout the lung. Morphometry is more difficult to

use to measure toxic effects on small or scattered regions of the lung because tissue samples reflective of

the region can be hard to obtain, but improved techniques are under development to assess the gas exchange region of the lung (18). Morphometry can also

be used to examine changes in the structure of the

pulmonary vasculature. Structural tests may show abnormalities long before changes are detectable by pulmonary function testing. A substantial amount

remains to be learned about whether such changes will

result in harm, however.

Tests of biochemical and molecular response—

Phagocytic pulmonary cells, physiologic mediators,

metabolizes, enzymes, and other biochemical substances that can be associated with toxic response can

be removed from the system by lavage (washing) and

the lavage fluid can be analyzed for cellular and biochemical content (20,21). Pulmonary inflammatory responses and immune responses can be measured by

examining bronchoalveolar lavage fluid (BALF).

An inflammatory response to a toxic exposure produces enzymes and cells not normally present in BALF.

BALF analysis can reveal the degree of inflammation

and corresponding stage of any disease process. Aspects of an immune response, such as increased numbers of lymphocytes, can also be measured in BALF.

Importantly, immune system cells recovered from

BALF can be tested in vitro to determine whether they

respond properly to antigen challenge or if they respond to a particular antigen of interest. The functional characteristics of other cell lines obtained from

BALF can also be assessed.

Development of safe lavage techniques has contributed immensely to the prospects for pulmonary

toxicology. The ability to measure the presence of biochemical substances in BALF has grown faster than

knowledge of how those substances correlate to toxicity, but current research is quite promising.

Summary of Technologies Applicable to Laboratory

and Clinical Studies

Effective laboratory and clinical studies require

technologies to control the dose of a toxicant adminis-
Chapter 3—Pulmonary Toxicology and Epidemiology 39

tered to a test subject and to limit and account for

confounding factors. Scientists have developed several

exposure technologies and have characterized their

potential and drawbacks.

Many established and recently developed technologies exist to measure changes in lung structure and

function following exposure to toxic substances. A substantial database exists on the physiological effects of

toxicants on animals. Spirometry--as a stand alone

measure of ventilator function and as a component of

airway reactivity testing—is the most frequently and

easily used technique in human health effects assessments of pulmonary toxicity; additional physiologic

measures are under development and may eventually

improve the predictive powers of clinical studies of

pulmonary toxicity. Microscopy continues to play an

important role in laboratory studies, particularly as

enhanced by morphometric techniques. The importance of biochemical and molecular measurements, as

performed on lavage fluids, is increasing (20,47). Each

of these technologies performs well as a diagnostic tool

when changes in the lung are gross, but many also

measure milder changes that may only represent physiologic variability and, as yet, are not well correlated

with changes in pulmonary performance.

Health effects assessments can be performed under acute or chronic exposure conditions. The database

on acute exposures is much larger than that on chronic

exposures. While this background paper focuses on

technologies that identify whether a substance causes a

toxic effect, it is important to acknowledge that data

regarding how that effect results in harm should also

improve policymakers’ ability to deal appropriately

with toxic substances.

Epidemiologic Studies

Epidemiology-the study of the distribution and

determinants of disease in populations—provides information about the impacts of air pollutants on human populations. It can be used to associate pollutants

with disease even before precise mechanisms of cause

and effect are understood, although observed associations are often attenuated by serious confounding factors.

Epidemiologic investigations of airborne toxicants

share the difficulties inherent in any observational,

rather than experimental, studies. For instance, exposure may be hard to assess. Some observers note that

knowledge of exposure need not be precise to be meaningful (4), e.g., self-reported exposures to fumes or

smoke have correlated well to later measurements, but

results based on precise exposure measurements lend

themselves more readily to important regulatory decisions. Another problem with epidemiologic studies is

that most lung diseases can have more than one cause,

and it is difficult to isolate the effects of one airborne

substance from another. Finally, it may take studies of

quite large populations to reveal small but important

effects of airborne toxicants, and such studies can be

difficult and costly to undertake. Though hard (sometimes impossible) to conduct, these types of studies can

provide evidence of association between exposure and

disease that lay and technical people alike find more

credible than evidence from laboratory or clinical studies (28).

Epidemiologic studies take many forms. It is possible to study living or deceased populations; diseased

populations can be studied for evidence of exposure;

healthy populations can be studied for changes in

health status following exposure. In all cases, however,

some knowledge of exposure and evidence of a defined

health effect must be available for results to be meaningful. The following subsections describe the tools

available to measure exposure and health effects in

epidemiologic studies. Epidemiology uses some of the

same technologies as employed in laboratory or clinical

studies; some techniques are unique to epidemiology.

Measurements of Exposure

Many of the exposure assessment technologies described previously are applicable to epidemiologic

studies. Outdoor, indoor, and personal monitoring devices can be used to provide current exposure information. Records of outdoor measurements collected by

public agencies provide historical data of exposure.

Population groups can be examined for biological evidence of exposure (e.g., toxic substances found in exhaled air or in autopsied lungs). These measurements

typically lack the precision—with regard to exposure

to the toxicant under study and to exposure to substances that may alter (confound) the results--obtainable in laboratory and clinical studies, but are used by

the scientific community. Moreover, some epidemiologic studies proceed on the basis of self-reported,

rather than measured, exposure information.

Measurements of Health Effects

Epidemiologists use many kinds of data to determine health status. Epidemiologic measures include
40 ● Identifying and Controlling Pulmonary Toxicants

Table 3-2—Summary of Characteristics of Physiologic Assays

Characteristics a and Ratingsb

Measure A B c D E F

Respiratory function

Spirometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ++

Lung mechanics

Dynamic compliance, resistance, . . . . . . . . . . +

and conductance

Oscillation impedance . . . . . . . . . . . . . . . . . . . +-

Static pressure-volume . . . . . . . . . . . . . . . . . . +

Intrapulmonary distribution . . . . . . . . . . . . . . . . .

Single-breath gas washout . . . . . . . . . . . . . . . +

Particle distribution

Exhaled particles . . . . . . . . . . . . . . . . . . . +-

Particle deposition . . . . . . . . . . . . . . . . . . +-

Alveolar-capillary gas transfer . . . . . . . . . . . . . . .

CO diffusing capacity . . . . . . . . . . . . . . . . . . . ++

Exercise gas exchange . . . . . . . . . . . . . . . . . . ++

Airway reactivity

Nonspecific reactivity . . . . . . . . . . . . . . . . . . . . . ++

Specific reactivity . . . . . . . . . . . . . . . . . . . . . . . . +

Particle clearance

Radiolabeled aerosol . . . . . . . . . . . . . . . . . . . . . . +

Magnetopneumography . . . . . . . . . . . . . . . . . . . . -

Air-blood barrier function

Conducting-airway permeability

Clearance of inhaled DTPA . . . . . . . . . . . . . . +-

Transepithelial potential . . . . . . . . . . . . . . . . . . . . +-

Alveolar permeability by . . . . . . . . . . . . . . . . . . . +

radiolabeled aerosal

Vascular permeability

Radiolabeled protein leakage . . . . . . . . . . . . . +

Chest x-ray for edema . . . . . . . . . . . . . . . . . . . ++

Extravascular lung water by . . . . . . . . . . . . . . +

indicator dilution, PET, or NMR

Rebreathing soluble gases . . . . . . . . . . . . . . . . . . +

Endothelial metabolic function . . . . . . . . . . . . . . . . . +

+ ++ ++ ++ +

+

+-

++

+-

+-

+-

+

+

+

++

+-

+-

+-

+-

+-

+

+-

+-

+

+-

+ ++ + +

+

+-

++

+

++

+-

+-

+

++ + +

++

+

++

+

0

0

++

+-

+-

+

++

++

+-

+

+-

+

+-

+

++

+

++

+-

+

++

+ +- +-

+ 0

0

0

+-

+

+

+

+

+

+

+-

0

+-

+

+

++

++

+

+

+-

+ + +- ++

+ + +-

some of the same technologies applied in laboratory the effects of air pollution on the respiratory health of

and clinical studies (e.g., spirometry) and some unique residents of the Los Angeles area.

technologies (e.g., questionnaires, historical records).

Health effects assessment technologies useful in epide- Biological tests--Spirometry is often used in epimiologic studies are described briefly below. Box 3-B demiologic studies because it is noninvasive and relaprovides details of a long-term, epidemiologic study of tively simple to perform in the field; many
Chapter 3—Pulmonary Toxicology and Epidemiology . 41

a Characteristics:

A. Current State of Development. Considerations in this category included the number of groups using the technique, the availability of the required equipment, the magnitude of the present data base, and the degree of standardization of procedures.

B. Estimated Potential for Development. This category reflected the current estimate of the potential for substantial development of

the assay beyond its present state. Although it was recognized that advancements are possible for any assay, this category was

intended to reflect potential for substantial technical refinements, adaptation for use in large populations, or advancements in ability

to interpret results.

C. Current Applicability of Assay to Humans. Primary considerations were the invasiveness of the technique and the requirement for

radionuclides. All the assays can be applied to animals, but some are less suitable than others for evaluating humans.

D. Suitability for Measuring Large Numbers of Subjects. The focus of this category was the suitability of the assay for use in studies

of large populations of people, as might be required for evaluating effects of some environmental exposures. Considerations

included adaptability of equipment for mobile use, length and nature of subject interaction (i.e., degree of cooperation required),

resources required to analyze samples and data, and subject safety. For example, a low rating might suggest a low suitability for

field use in evaluating hundreds of subjects of various ages and both sexes, whereas the assay might be quite suitable for studies of

dozens of selected subjects brought to a stationary facility.

E. Reproducibility. This category focuses on the variability of results within and between subjects.

F. Interpretability. This category reflects the current understanding of (and degree of consensus as to) pathophysiologic correlates,

anatomic sites of effect, and causative agents. For many of the assays, there is little disagreement on the physiologic function

affected, but the specific mechanism or site of change is uncertain. For example, it is agreed that reduced carbon monoxide diffusing capacity reflects reduced efficiency of alveolar-capillary gas transfer, but the test does not distinguish among the effects of a

thickened membrane, reduced surface area, and reduced capillary blood volume.

bRatings:

O = Unknown, or information is insufficient.

- = Current information suggests inadequate development, little potential for development, little applicability to humans, poor suitability for large populations, poor reproducibility, or poor interpretability.

+- = Current information suggests some development, some potential for development, limited applicability to humans, limited suitability for large populations, questionable reproducibility, or questionable interpretability.

+ = Current information suggests adequate development, potential for further development applicable to humans, suitability for

large populations, reproducibility, and interpretability.

++ = Current information suggests high development or good potential for substantial development, great applicability to humans,

great suitability for large populations, reproducibility, or very good interpretability.

SOURCE: National Research Council, Subcommittee on Pulmonary Toxicology, Biologic Markers in Pulmonary Toxicology

(Washington, DC: National Academy Press, 1989).

epidemiologic studies use FEV1 as their measure of

toxic effect in the large airways. Nitrogen washout tests

have been used to measure small airways effects, but

the sensitivity and specificity of that test has been called

into question (29). Epidemiologists sometimes test for

airway reactivity (28).

Bronchoalveolar lavage (BAL) could be performed in epidemiologic studies, either on living subjects or on autopsied lungs. BAL is invasive, however,

and requires high-level skills to perform safely, adding

to its expense and detracting from its utility in largescale studies.

Assessments of data-Certain types of epidemiologic studies rely on routinely collected data rather

than biological tests performed in the community.

Death certificates provide mortality data that can be

coupled with historical exposure data to draw some

conclusions about the effects of inhaled pollutants on

a population. Morbidity data obtained from diverse

sources-hospital admissions and discharge records

(3,48), emergency room visits (33), hotline phone calls

and follow-up interviews (5), reports of days lost from

work or school—provide some indications about the

effects of airborne toxicants as well. These sources may

be affected by error. For instance, cause of death may

be listed inaccurately; social and economic factors influence decisions to seek health care or miss work.

Some epidemiologists believe that these errors tend to

reduce (rather than increase) the possibility of finding

a significant effect. Epidemiologists have relied on

these types of information in studies that are widely

accepted as indicative of a connection between exposure to inhaled substances and lung injury or disease.

Participants in epidemiologic studies of pulmonary toxicity often complete questionnaires to assess

respiratory health (16). Quality control measures for

standardized questionnaires have been assessed, and
42 ● Identifying and Controlling Pulmonary Toxicants

Box 3-B—The UCLA Population Studies of Chronic Obstructive Respiratory Disease

In the early 1970s, researched at the University of California at Los Angeles (UCLA) initiated a 10-part epidemiologic study of

the respiratory effects of air pollution. By comparing the respiratory health of several communities exposed to different concentrations

of common air pollutants, the researched hoped to elucidate the connections between inhaled toxicants and chronic obstructive

respiratory disease, The researchers chose Los Angeles as the study area because of the great variation in the types and concentrations

of pollutants within a relatively small but highly populated geographical region. The existence of a uniform network of air quality

monitoring stations throughout the area ensured the availability of exposure data, which also influenced the decision to perform the

studies in the Los Angeles area.

Four Los Angeles area communities with similar demographics-Lancaster, Burbank, Long Beach, and Glendora--were chosen

for study. Lancaster residents were exposed to relatively low levels of chemical air pollutants, while residents of Burbank, Long Beach,

and Glendora were variously exposed to higher levels of chemical air pollutants including photochemical oxidants, sulfur dioxide,

nitrogen dioxide, particulate, hydrocarbons, and sulfates.

For the initial part of the study, the investigators interviewed participants about respiratory symptoms, residence history,

environmental and occupational exposures, and smoking history. Participants also performed lung function tests. The interview% and

lung function tests were all performed at the same Mobile Lung Function Laboratory for which the reliability was determined and

sensitivity and specificity were estimated. Thoughresearchers noted that long-term studies were necessary, initiaI data led to the

following hypotheses:

1. Adverse effects of long-term exposure to high concentrations of photochemical/oxidant pollutants may occur primarily in larger

airways both among smokers and never smokers (comparisons of Lancaster and Burbank residents).

2. Long-term exposure to high concentrations of photochemical/oxidant pollutants and of sulfur dioxide, hydrocarbons, and

particulate pollutants is associated with respiratory impairment, manifested by dysfunction of the large airways (comparisons of

Lancaster, Burbank, and Long Beach residents).

3. Long-term exposure to high concentrations of photochemical oxidants, nitrogen dioxide, sulfates, and particulate pollutants may

result in measurable impairment in lung function in smokers and never smokers (comparisons of Lancaster and Glendora

residents).

Extensive follow-up enabled researched to observe the populations from Lancaster, Burbank, Long Beach, and Glendora in

long-term studies. Five years after the initial testing, participants still living in the study area (a substantial number) were reinterviewed

and retested at the Mobile Lung Function Laboratory. These reexamination lent support to the following hypotheses:

1. Chronic exposures to mixtures of photochemical oxidants, sulfates and particulate are associated with increased loss of lung

function, which is especially evident in the small airways (comparison of Lancaster and Glendora residents.)

2. Chronic exposure to mixtures of sulfur dioxide, sulfates, oxides of nitrogen and/or hydrocarbons ultimately adversely affects the

large airways as well as small airways (comparison of Lancaster and Long Beach residents).

3. Passive exposure teat least maternal smoking (but not to paternal smoking alone) affects the airways of younger boys (analysis

of all four communities).

4+ Smoking cessation leads to relatively early and sustained improvement in indexes of small airway function and other indices of

respiratory health (analysis of all four communities).

The UCLA population studies of chronic obstructive respiratory disease add support to certain hypotheses regarding lung function

and pollutant exposures. Nonetheless, the data reflect the types of problems that have characterized large epidemiologic studies.

Exposure data are crude; experts fault the researchers controls for the effects of migration and self-selection. EPA concluded that the

studies could not support standards setting for any of the pollutants involved. The studies do, however, point toward productive avenues

for laboratory and clinical research that could clarify the effects of the pollutants found in the Los Angeles area on lung function.

SOURCE: Office of Technology Assessment, 1992, based on chapter 3 references 10,11,12,13,14,15,32,38,39,40,41,42.

though recall bias (sick or highly exposed individuals diaries of short-term symptoms have become more

generally remember exposures or illnesses better than prominent in recent years. They avoid the recall bias

healthy or unexposed individuals) enters into play, found in annual questionnaires and appear to be more

questionnaires generally are considered useful. Daily sensitive (36).
Chapter 3—Pulmonary Toxicology and Epidemiology . 43

Summary of Technologies Applicable to

Epidemiologic Studies

In epidemiologic studies, exposure information is

supplied with exposure assessment technologies and

self-reported exposure data. Because “free-living” humans have knowing and unknowing encounters with

multiple possible toxicants, exposure data in epidemiologic studies are necessarily imprecise. Many investigators believe that when confounding factors are

properly accounted for, the ability to gather information on environmentally relevant exposures renders

epidemiologic studies worthwhile even given the problems of collecting exposure data.

Biological tests applied in epidemiologic studies

have the same advantages and disadvantages they present in laboratory and clinical studies, with the added

requirement that they be easy to use in the field or on

large populations. Reliance on public health records

and population survey is a feature common to all epidemiology, including investigations of respiratory disease.

Summary of Health Effects Assessment

Technologies

Each type of study (laboratory, clinical, or epidemiologic) has technological advantages and disadvantages, and individual studies within each type have

strengths and weaknesses. Clear evidence of change in

lung structure or function is unpersuasive if exposure

data are problematic; evidence of health effects in animals under tightly controlled exposure conditions may

be unpersuasive if no human data are available. Despite the availability of many testing technologies, certainty about the pulmonary toxicity of many

commercial substances has eluded investigators and

regulators because of the lack of a full array of information sources. The database on the acute effects of

short-term, high-dose exposures to toxicants is relatively large and growing, and forms the basis for existing regulations of pulmonary toxicants. Fewer data are

available on the effects of chronic, “environmentally

relevant” (i.e., low dose) exposures to suspected toxicants. On one hand, animal data on chronic exposures

can be obtained using current testing technologies, but

problems remain in extrapolating results from animals

to humans. On the other hand, human data may be

impractical or impossible to obtain given the ethical

constraints of clinical testing and the length of time and

large populations necessary to conduct meaningful

epidemiologic studies.

LIMITS OF TECHNOLOGY

The previous sections establish that current technology can measure the biological effects of toxic substances on the lung, but that conclusion begs an

important question: Are the measured effects adverse? Humans come equipped to survive in a hostile

environment; most organ systems—the lung included-are resilient and operate with a reserve capacity that accommodates some level of change or damage

(43). In the case of pulmonary toxicology, it appears

science has learned to measure biological effects more

quickly than it has learned to correlate those effects

with persistent changes in performance or with disease

processes. This disjuncture creates problems for regulators.

Most researchers recognize a hierarchy of biological effects of exposure to toxic substances, ranging from

mortality (inarguably adverse) to measurable traces of

toxicants in tissue (arguably adverse) (figure 3-3). Because some people or populations are more sensitive

to toxic effects than others, and because some people

or populations are more highly exposed to toxic substances than others, severe, unquestionably adverse

effects are likely to occur in a smaller segment of the

population than less severe, more questionably adverse

effects. Effects may be reversible or irreversible, with a

tendency among researchers to concern themselves

more with irreversible effects. Concern for reversible

effects increases, however, if chronic exposures prevent

reversal. Evidence to support a clear demarcation between adverse and nonadverse effects remains elusive.

If, as in the case of many suspected pulmonary toxicants, evidence does not exist to associate early changes

with later, more extensive or irreversible changes, effects that are measurable may still be adjudged nonadverse.

The American Thoracic Society (ATS) has defined

adverse respiratory health effects in humans as “medially significant physiologic or pathologic changes generally evidenced by one or more of the following:

(1) interference with the normal activity of the affected

person; (2) episodic respiratory illness; (3) incapacitating illness; (4) permanent respiratory injury; or (5)

progressive respiratory dysfunction” (l). Most often,

however, regulators must use a combination of limited
44 ● Identifyingand Controlling Pulmonary Toxicants

Figure 3-3—Spectrum of Biological Response to Pollutant Exposure

Adverse health

————

+__———— Proportion of population affected —>

SOURCE: Arneriean Thoricic Society, “Guidelines as to What Constitutes an Adverse Respiratory Health Effect, with Special Referenee to

Epidemiologic Studies of Air Pollution,’’Arn Rev. Respir. ilk. 131:666-668, 1985.

animal data and limited human data to reach conclusions about existing substances, and always must rely

on animal data or extrapolations based on knowledge

of chemical structures to predict the potential effects

of new substances. Decisions about regulations most

often are made in the absence of data that would enable

a determination of adversity as precise as that found in

the ATS definition.

Researchers and regulators agree that the integrated results of laboratory, clinical, and epidemiologic

studies of short-term exposures can yield conclusive

information about the acute effects of pulmonary toxicants. Current regulations generally are designed to

prevent acute effects. Researchers and regulators generally are not satisfied that current technologies or

current data provide them with a sufficient basis to

regulate exposure to airborne toxicants because of the

potential effects on the lung of chronic exposures.

Much research is directed at developing improved

methods for studying chronic exposures, but many

questions remain. Chapter 4 provides more detail on

regulations based on pulmonary toxicity and describes

current Federal efforts to improve the basis for decision making with regard to chronic, low-dose exposure

to inhaled toxics.

1.

2.

3.

4.

5.

6.

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Dahl, A.R., Schlesinger, R. B., Heck, H.D’A., et

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and Never Smokers,” Amen-can Review of Respirato~ Disease 124(6):673-680, December 1981.

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1982.

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Folinsbee, L.J., “Human Clinical Inhalation Exposures: Experimental Design, Methodology,

and Physiological Responses,” in Toxicology of the

Lung D.E. Gardner, et al. (eds.) (New York, NY:

Raven Press, 1988), pp. 175-199.

Gehr, P., and Crapo, J. D., ‘MorphometricAnalysis of the Gas Exchange Region of the Lung,” in

Toxicology of the Lung, D.E. Gardner, et al. (eds.)

(New York, NY: Raven Press, 1988), pp. 1-42.

Haley, P.J., ‘Finch, G.L., Hoover, M.D., et al.,

‘The Acute Toxicity of Inhaled Beryllium Metal

in Rats,” Fundamental and Applied Toxicology

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Henderson, R. F., ‘Use of Bronchoalveolar IAWage to Detect Lung Damage,n in ToxicoZo~ of the

Lung D.E. Gardner, et al. (eds.) (New York, NY:

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Henderson, R. F., Benson, J. M., Hahn, F. F., et al.,

‘New Approaches for the Evaluation of Pulmonary Toxicity: Bronchoalveolar Lavage Fluid

Analysis, n Fundamental and Applied Toxicology

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Lioy, P.J., ‘Assessing Total Human Exposure to

Contaminants, n Environmental Science and Technology 24(7):938-945, 1990.

Mauderly, J. L., “Comparisons of Respiratory

Function Responses of Laboratory Animals and

Humans,n in Inhalation Toxicology, Mohr (cd.)

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McClellan, R. O., “Health Effects of Diesel Exhaust: A Case Study in Risk Assessment, nAmerican Industrial Hyp”enists Association Journal

47(1):1-13, January 1986.

Mercer, R. R., and Crapo, J. D., ‘Structure of the

Gas Exchange Region of the Lungs Determined

by Three-Dimensional Reconstructions,n in Toxicology of the Lung, D.E. Gardner, et al. (eds.)

(New York, NY: Raven Press, 1988), pp. 117-146.

Moss, O. R., and Cheng, Y.-S., “Generation and

Characterization of Test Atmospheres: Particles,” in Concepts in Inhalation Toxicology, R.O.
46 ● Identifyingand Controlling Pulmonary Toxicants

27.

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McClellan and R.F. Henderson (eds.) (New

York, NY: Hemisphere Publishing Corp., 1989),

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the Federal Government: Mana@”ng the Process

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1983).

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Air Pollution (Washington, DC: National Academy Press, 1985).

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Pulmona~ Toxicology, Biologic Markz?rs in Pulmona~ Toxicolo~ (Washington, DC: National

Academy Press, 1989).

Overton, J. H., and Miller, F.J., “Absorption of

Inhaled Reactive Gases,” in Toxicology of ?he

Lung D.E. Gardner, et al. (eds.) (New York, NY:

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(New York, NY: Raven Press, 1988), pp. 117-146.

Rokaw, S. N., Detels, R., Coulson, A. H., et al.,

“The UCLA Population Studies of Chronic Obstructive Respiratory Disease. 3. Comparison of

Pulmonary Function in Three Communities Exposed to Photochemical Oxidants, Multiple Primary Pollutants, or Minimal Pollutants,” Chest

78(2):252-262, August 1980.

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Between Parental Smoking and Children’s Lung

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Chapter 4

Federal Attention to Pulmonary Toxicants
Chapter 4

Federal Attention to Pulmonary Toxicants

INTRODUCTION

Congress has enacted a diverse body of laws to help

control human exposure to toxicants. These laws require the Federal Government to regulate the public’s

exposure to toxic substances and to conduct and sponsor research that will improve identification and regulation of toxicants. This chapter describes regulatory

and research programs of the Federal Government

specifically related to the control and investigation of

airborne pulmonary toxicants. The chapter provides

examples of Federal activities but is not an exhaustive

listing.

FEDERAL REGULATORY ACTIVITIES

Several Federal laws authorize administrative

agencies to regulate substances to prevent adverse

health effects, including respiratory effects. This section focuses on the laws and regulations used to control

human exposures to pulmonary toxicants. The Environmental Protection Agency (EPA) and the Occupational Safety and Health Administration (OSHA), part

of the Department of Labor (DOL), implement most

of the statutes designed to limit human exposures to

environmental and occupational pollutants. The Mine

Safety and Health Administration (MSHA), also part

of DOL, regulates pollution in the mining industry.

The Consumer Product Safety Commission (CPSC)

and the Food and Drug Administration (FDA) also

have some authority over pulmonary toxicants.

Environmental Protection Agency

EPA administers a variety of laws that require protection of human health and the environment, including the Clean Air Act (CAA; 42 U.S.C. 7401 et seq.),

the Resource Conservation and Recovery Act (RCRA;

42 U.S.C. 6901 et seq.), the Toxic Substances Control

Act (TSCA; 15 U.S.C. 2601 et seq.), and the Federal

Insecticide, Fungicide, and Rodenticide Act (FIFRA;

7 U.S.C. 136 et seq.). These statutes authorize EPA to

control human exposure to substances that cause adverse human health effects, and the agency has, in fact,

regulated some substances on the basis of pulmonary

toxicity.

Clean Air Act

The CAA requires EPA to identify airborne substances that may “cause or contribute to air pollution

which may reasonably be anticipated to endanger public health or welfare” and to set national ambient air

quality standards (NAAQS) for those ‘criteria” pollutants. NAAQS, which apply only to outdoor concentrations of pollutants, have been set for sulfur oxides,

particulate matter, carbon monoxide, ozone, nitrogen

dioxide, and lead. EPA regulated sulfur oxides, particulate matter, ozone, and nitrogen dioxide because of

their adverse effects on the pulmonary system (22,23).

Table 4-1 presents the (health-based) primary ambient

air quality standard for each criteria pollutant and lists

adverse effects on the pulmonary system.

The CAA also requires EPA to control “hazardous

air pollutants,” defined by law as substances for which

no ambient air quality standard can be set and that ‘may

reasonably be anticipated to result in an increase in

mortality or an increase in serious irreversible, or incapacitating reversible, illness.” Between 1970 and 1984,

seven substances were placed on the hazardous air

pollutants list: asbestos, benzene, beryllium, inorganic

arsenic, mercury, radionuclides, and vinyl chloride

(3,23). Coke oven emissions were added to this list in

1984 (3). The 1990 amendments to the CAA substantially augmented the list of hazardous air pollutants—

bringing it to 189—and required EPA to regulate them

at the level possible under maximum achievable control technology (MACT) (23). Table 4-2 lists hazardous air pollutants known to be pulmonary toxicants.

Incentive Programs Under the CAA. Following

adoption of the 1990 amendments to the CAA, EPA

developed the Early Reduction Program (ERP), which

provides incentives for companies to make immediate,

major reductions (90 percent for gases and 95 percent

49
50 ● Identifying and Controlling Pulmonary Toxicants

Table 4-1—National Primary Ambient Air Quality Standards

Pollutant Primary standard Effects on the lung

Sulfur oxides 80 micrograms/m3

Can aggravate asthma, decrease lung func0.03 ppm annual arithmetic mean tion via inflammation; tendency develop allergies

0.14 ppm maximum 24-hour concentration not

to be exceeded more than once a year

Particulate matter

Carbon monoxide

Ozone

Nitrogen dioxide

150 micrograms/m3 24-hour average concentration

50 micrograms/m3 annual arithmetic mean

10 milligrams/m3

9 ppm for an 8-hour average concentration not

to exceed more than once a year

40 milligrams/m3

35 ppm for a l-hour average concentration not

to be exceeded more than once a year

235 micrograms/m3

0.12 ppm

Depending on specific particle, causes decreased lung function, bronchitis, and pneumonia; can aggravate asthma; some can

cause fibrosis; increase deaths

Can cause death or damage to lungcells by

passing into the bloodstream inhibiting the

ability of red blood cells to carry oxygen to

cells of the body

Can irritate and inflame the lungs, cause

shortness of breath, increased susceptibility

to respiratory infections, accelerated aging

of the lungs, and emphysema; fatal at high

concentrations (effects have been shown below the current standard

100 micrograms/m3 Can cause acute respiratory disease at high

0.053 ppm annual arithmetic mean concentra- concentrations, increased susceptibility to

tion viral infections; can aggravate asthma; can

cause inflammation

Lead 1.5 micrograms/m3 maximum arithmetic mean Lung acts as site of entry for lead which in

averaged over a calendar quarter turn can damage the nervous system, kidneys, and reproductive system

SOURCES: 40 CFR 50, July 1, 1991; U.S. Congress, United States Code Congressional and A&ninistrative News, 95th Congress,

1st Sess. 1977 (St. Paul, MN: West Publishing Co., 1977), pp. 1187-88; U.S. Congress, United States Code Congressiorzul

and Administrative News, IOlst Congress, 2d Sess., 1990 (St. Paul, MN: West Publishing Co., 1990), pp. 3392-94.

for particulate) in their emissions of hazardous air voluntary reductions will not receive the compliance

pollutants. Companies that participate in the ERP will extension (24).

be allowed a 6-year compliance extension after emissions standards (anticipated to require reductions in The ERP covers all 189 hazardous air pollutants

excess of 90 to 95 percent) are developed. EPA moni- listed in the CAA, but it identifies 35 substances

tors company compliance with the ERP and focuses on deemed ‘highly toxic pollutants” as its most important

specific sources, even sources within a plant’s bounda- targets. Each of these substances is weighted according

ries. Participating companies who fail to make the to its toxicity, and volume and total toxicity must both
Chapter 4—Federal Attention to Pulmonary Toxicants 51

be reduced in order to fulfill the requirements of the

ERP (24). Table 4-3 lists substances covered by the

ERP that are known to be pulmonary toxicants.

EPA also designed the 33/50 Program to encourage

companies to make voluntary reductions in pollutant

emissions before MACT standards are in place. The

33/50 Program asks companies to voluntarily reduce

aggregate releases and off site transfers of 17 high

priority toxic substances by a total of 33 percent by 1992

and a total of 50 percent by 1995. This program does

not focus on reducing emissions at or within particular

plants but concentrates on national goals (25).

Each substance covered by the 33/50 Program:

.

.

.

.

.

●

appears on the CAA’s list of hazardous air pollutants;

is included in the Toxic Release Inventory (TRI);

is a multimedia pollutant on the agenda of every

department of EPA

is produced in large quantities and has a high

release to production ratio;

has been shown to be amenable to pollution control; and

is known to be toxic to both human health and the

environment (8).

Table 4-3 lists the chemicals targeted by the 33/50

Program that are known to be pulmonary toxicants.

Participants in the 33/50 Program set their own goals

for emissions reductions, and EPA has no enforcement mechanism. Compliance is measured through

TRI reporting and is not as closely monitored as in the

ERP (24).

Resource Conservation and Recovery Act

RCRA attempts to safeguard public health and the

environment by controlling waste disposal. It requires

EPA to identify and list hazardous wastes, defined as

solid wastes, which due to potency, volume, or physical,

chemical, or infectious qualities may:

. cause or considerably add to deaths or serious

irreversible or incapacitating reversible illness, or

. create significant present or potential dangers to

human and environmental health if improperly

handled.

Several chemicals regulated under RCRA have adverse effects on the pulmonary system; see table 4-4.

Toxic Substances Control Act

TSCA calls on EPA to regulate chemicals in premarketing and post-marketing phases to avoid unreasonable risk of injury to public health and the

environment. TSCA requires the manufacturer to provide EPA with a pre-manufacturing notice (PMN),

including test results on the chemical, at least 90 days

before manufacturing begins. If EPA does not request

further data within the 90-day period, the manufacturer is free to begin production (2). If EPA finds that

the chemical may pose an unreasonable risk to human

health or the environment, or that insufficient data

exist to make a determination about risk, or that the

chemical will be produced in substantial quantities,

EPA may require additional testing. This testing is

conducted by the chemical manufacturer or processor.

Many of the regulations issued under TSCA (40

CFR 790 et seq.) provide guidelines for testing chemicals. Guidelines exist for testing acute, sub-chronic,

and chronic inhalation toxicity. Acute inhalation toxicity testing provides information on health hazards

likely to result from short-term exposure to a substance. Acute inhalation tests involve a single, 4- to

24-hour exposure to a particular substance followed by

a 14-day observation period. The sub-chronic inhalation tests assess the effects of toxicants from repeated

daily exposures to a substance for approximately 10

percent of the animal’s lifespan. These tests involve

repeated daily exposures for at least 90 days. Chronic

toxicity inhalation testing is designed to determine the

health effects that are cumulative or have along latency

period. These tests involve repeated daily exposures to

a substance for at least 12 months.

If tests show that a chemical poses an unreasonable

risk to human health or the environment, EPA can

limit or prohibit its use, manufacture, and distribution.

EPA has taken action under TSCA due to the possibility that certain chemicals pose pulmonary health

threats. For example, EPA has required manufacturers

to report health and safety study data on 26 diisocyanates because of concern that acute and chronic exposures could cause respiratory tract effects and nose

irritation (5). EPA has also required significant new

use evaluations for substituted oxirane, substituted al-
5 2 . Identifying and Controlling Pulmonary Toxicants

Table 4-2-Hazardous Air Pollutants Regulated Under the CAA Due to Non-Cancer Health Effects on the

Pulmonary System

Chemical Pulmonary health effect

Acetaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acrolein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acrylic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Allyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzylchloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Beryllium compounds . . . . . . . . . . . . . . . . . . . . . . . .

Caprolactam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Catechol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chlorine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-Chloroacetophenone . . . . . . . . . . . . . . . . . . . . . . .

Chloroprene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cresol (o-, m-,& p-) . . . . . . . . . . . . . . . . . . . . . . . . .

Diazomethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dichloroethyl ether . . . . . . . . . . . . . . . . . . . . . . . . . .

1,3-Dichloropropene . . . . . . . . . . . . . . . . . . . . . . . . .

Dimethyl sulfate . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2,4-Dinitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . .

l,4-Dioxane (l,4-Diethleneoxide) . . . . . . . . . . . . . .

l,2-Epoxybutane . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Epichlorohydrin . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethyl acrylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethyl benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene glycol . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene imine(Aziridine) . . . . . . . . . . . . . . . . . . . .

Ethylene oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorobutadiene . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorocyclopentadiene . . . . . . . . . . . . . . . . . . .

Hexamethylene-1,6-diisocyanate . . . . . . . . . . . . . . .

Respiratory tract irritation

Respiratory tract irritation

Lung injury, and possibly death

Pulmonary irritation and histologic lesions of the lung

Asbestosis

Pulmonary edema and hemorrhage; tightness in chest, breathlessness; unconsciousness may occur and death may follow due to respiratory paralysis in cases

of extreme exposure

Lung damage and pulmonary edema

Non-malignant respiratory disease and berylliosis

Upper respiratory tract irritation and congestion

Acute respiratory toxicity and upper respiratory tract irritation

Necrosis of tracheal and bronchial epithelium, bronchitis, bronchopneumonia

and fatal pulmonary edema

Difficulty in breathing

Lung irritation

Pulmonary disease (unspecified)

Obliterative bronchiolitis, ademonatosis, and hypersentivity reactions, chronic

interstitial pneumonitis and occasional fatalities

Chest pain, respiratory irritation, damages to mucous membranes

Respiratory system irritation and pulmonary damage

Respiratory irritation

Lung edema

Respiratory collapse

Lung edema; can cause death

Lung irritation, edema, and pneumonitis

Lung edema, dyspnea, bronchitis, and throat irritation

Respiratory irritation, pneumonia and pulmonary edema

Lung congestion

Throat and respiratory irritation

Lung edema and secondary bronchial pneumonia

Respiratory irritation and lung injury (unspecified)

Difficulty breathing, severe respiratory tract injury leading to pulmonary edema,

pneumonitis, and bronchial irritation which may lead to death

Pulmonary irritation

Pulmonary irritation, bronchitis, and bronchiolitis

Pulmonary edema, chronic bronchitis, chronic asthma; pulmonary edema; may

be fatal
Chapter 4—Federal Attention to Pulmonary Toxicants 53

Table 4-Z-Hazardous Air Pollutants Regulated Under the CAA Due to Non-Cancer Health Effects on the

Pulmonary System (Cent’d)

Chemical Pulmonary health effect

Hydrochloric acid . . . . . . . . . . . . . . . . . . . . , . . . . . .

Hydrogen fluoride . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hydrogen sulfide . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Maleic anhydride . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl bromide. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl ethyl ketone . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl iodide (Iodomethane) . . . . . . . . . . . . . . . . . .

Methyl isocyanate . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl methacrylate . . . . . . . . . . . . . . . . . . . . . . . . .

Methylene diphenyl diisocyanate (MDI) . . . . . . . . .

Napthalene . . . . . . . . . . . . . . . . . . . . . .

2-Nitropropane . . . . . . . . . . . . . . . . . . .

p-Phenylenediamine . . . . . . . . . . . . . . .

Phosgene . . . . . . . . . . . . . . . . . . . . . . . .

Phosphine . . . . . . . . . . . . . . . . . . . . . . .

Phthalic anhydride . . . . . . . . . . . . . . . .

Propionaldehyde . . . . . . . . . . . . . . . . . .

Propoxur (Baygon) . . . . . . . . . . . . . . . .

Propylene oxide . . . . . . . . . . . . . . . . . .

l,2-Propylenimine (2-Methyl aziridine)

Styrene . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

Tetrachloroethylene (Perchloroethylene) . . . . . . . . .

2,4-Toluene diisocyanate . . . . . . . . . . . . . . . . . . . . .

Toxaphene (Chlorinated camphene) . . . . . . . . . . . . .

1,2,4-Trichlorobenzene . . . . . . . . . . . . . . . . . . . . . . .

Trichloroethylene . . . . . . . . . . . . . . . . . . . . . . . . . . .

Triethylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2,2,4-Trimethylpentane . . . . . . . . . . . . . . . . . . . . . . .

Vinyl acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Pulmonary edema

Respiratory tract irritation and lung damage

Pulmonary edema

Chronic bronchitis

Bronchopneumonia

Upper respiratory tract irritation

Lung irritation

Pulmonary edema and lung injury

Fatal pulmonary edema

Restricted pulmonary function

Lung damage

Pulmonary edema

Allergic asthma and inflammation of larynx and pharynx

Extreme lung damage;severe pulmonary edema after a latent period of exposure;

bleeding and painful breathing; death

Pulmonary edema and acute dyspnea

Respiratory irritation and pulmonary sensitization

Fatal pulmonary edema

Severe bronchoconstriction and paralysis of respiratory muscles

Pulmonary irritation

Diphtheria-like mutations of trachea and bronchi; bronchitis, lung edema, secondary bronchial pneumonia

Abnormal pulmonary function, upper respiratory tract irritation, wheezing, chest

tightness, and shortness of breath

Acute pulmonary edema

Pulmonary sensitization and long-term decline in lung function

Lung inflammation

Lung and upper respiratory tract irritation

Lung adenomas

Vapors cause severe coughing, difficulty breathing, and chest pain; pulmonary

edema

Pulmonary lesions

Upper respiratory tract imitation

SOURCES: 42 U.S.C. 7412; Tim Simpson, U.S. Environmental Protection Agency, Research Triangle Park, NC, personal communication, August 1991; 54 Federal Register 2329-2984 (Jan. 19, 1989).
54 ● Identifying and Controlling Pulmonary Toxicants

Table 4-3—Pulmonary Toxicants Controlled Under EPA’s Early Reduction and 33/50 Programs

Early Reduction Program Effect

Asbestos

Acrolein

Acrylic acid

Benzene

Beryllium compounds

Chloroprene

Chromium compounds

Dichloroethyl ether

Methyl isocyanate

Methylene diphenyl diisocyanate (MDI)

Phosgene

2,4 Toluene diisocyanate

Asbestosis

Respiratory irritation

Lung injury and possible death

Pulmonary edema and hemmorhage; tightness of chest, breathlessness; unconsciousness may occur and death may follow due to paralysis in cases of extreme

exposure

Non-malignant respiratory disease and berylliosis

Lung irritation

Pulmonary disease and other toxic effects

Respiratory system irritation and damage

Pulmonary edema

Restricted pulmonary function

Extreme lung damage; severe pulmonary edema after a latent period of exposure;

bleeding and painful breathing; death

Pulmonary sensitization and long-term decline in lung function

33/50 Program Effect

Benzene Pulmonary edema and hemmorhage; tightness of chest, breathlessness and unconsciousness may occur and death may follow due to respiratory paralysis in

cases of extreme exposure

Chromium & chromium compounds Pulmonary disease and other toxic effects

Methyl ethyl ketone Upper respiratory tract irritation

Nickel & nickel compounds Pulmonary irritation, pulmonary damage, hyperplasia, and interstitial fibrotic

lesions

Tetrachloroethylene Acute pulmonary edema

Trichloroethylene Lung adenomas

SOURCES: U.S. Environmental Protection Agency, Office of Air and Radiation, “Early Reduction Program,” unpublished memo,

Washington, DC, July 1991; U.S. Environmental Protection Agency, “EPA’s 33/50 Program: A Progress Report,”

unpublished memo, Washington, DC, July 1991; Tim Simpson, U.S. Environmental Protection Agency, Research Triangle

Park, NC, personal communication, August 1991; 54 FederaZRegister 2329-2984 (Jan. 19, 1989).

kyl halides, and perhalo alkoxy ether due to the threat

of pulmonary edema. EPA imposed the same requirement on silane because data showed that it causes

irreversible lung toxicity (6).

Federal Insecticide, Fungicide, and Rodenticide Act

FIFRA was enacted to help avoid unreasonable

adverse effects on the environment, including humans,

due to exposure to pesticides. It requires those who sell

or distribute pesticides to register the product with

EPA. A product maybe classified and registered for

general or restricted use, or both. If a pesticide is

classified for restricted use because it poses an inhalation toxicity hazard to the applicator or other persons,

then the product may only be applied by or used under

the direct supervision of a certified applicator. Substances that pose inhalation hazards are substances

that are dangerous to some organ and that enter the

body through the lung. Not all inhalable toxicants af-
Chapter 4—Federal Attention to Pulmonary Toxicants 55

Table 4-4-Regulated Levels of Pulmonary Toxicants Under RCRA

Contaminant Pulmonary effect Regulatory level (mg/L)

Arsenic Respiratory irritation and inflammation 5.0

Benzene Pulmonary edema and hemmorhage; tightness of chest, breath- 0.5

lessness and unconsciousness may occur and death may follow

due to respiratory paralysis in cases of extreme exposure

Chromium Pulmonary disease and other toxic effects 5.0

Cresol (o-, m- & p-) Obliterative broncholitis, adenomatosis, and hypersensitivity re- 200.0

actions; chronic interstitial pneumonitis and occasional fatalities

Methyl ethyl ketone Upper respiratory tract irritation 200.0

Tetrachloroethylene Acute pulmonary edema 0.7

Toxaphene Lung inflammation 0.5

SOURCES: 40 CFR261.24, July 1, 1991; Tim Simpson, U.S. Environmental Protection Agency, Research Triangle Park, NC, personal

communication, August 1991; 54 Federal Register 2329-2984 (Jan. 19, 1989).

Table 4-5—Pulmonary Toxicants Regulated Under FIFRA

Active ingredient Criteria influencing

in pesticide restriction

Acrolein Respiratory tract irritant

Allyl alcohol Upper respiratory tract irritant

Hydrocyanic acid Upper respiratory tract irritant

Methyl bromide Lung irritant; causes pulmonary

edema

Methyl parathion Excessive exposure may cause

bronchoconstriction

Paraquat (dichloride) and Pulmonary irritant; can cause pulparaquat bis(methyl sulfate) monary edema, intra-alveolar

hemmorhage, and death

SOURCES: 40 CFR 152.175, July 1, 1991; 54 Federal Register 2329-2984 (Jan. 19, 1989).

feet the lung; table 4-5 lists active pesticide ingredients

regulated under FIFRA that are pulmonary toxicants.

Department of Labor

Two entities within DOL regulate human exposure

to airborne toxicants. OSHA administers the Occupational Safety and Health Act (OSH Act; 29 U.S.C. 651

et seq.). MSHA administers the Federal Mine Safety

and Health Act (FMSHA; 30 U.S.C. 801), which operates similarly to the OSH Act but is restricted to the

mining industry.

Occupational Safety and Health Administration

OSHA’s task is to develop regulations for the use

of toxic substances in the workplace. OSHA can require specific handling procedures, training for workers, recordkeeping, and testing of hazardous materials.

It can also establish or modify permissible exposure

limits (PELs) for toxic substances. Many substances

are regulated by OSHA because of their detrimental

effects on the pulmonary system. Table 4-6 lists air

contaminants regulated by OSHA because of pulmonary toxicity.
56= Identifying and Controlling Pulmonary Toxicants

Table 4-6-Air Contaminants Regulated by OSHA Because of Pulmonary Effects

Substance Effects

Acetyladehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acetic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acetic anhydride . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acetone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acetylsalicyclic acid . . . . . . . . . . . . . . . . . . . . . . . . .

Acrolein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acrylic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Allyl alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Allyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Allyl glycidyl ether . . . . . . . . . . . . . . . . . . . . . . . . . .

Allyl propyl disulfide . . . . . . . . . . . . . . . . . . . . . . . .

Aluminum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ammonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ammonium chloride fume . . . . . . . . . . . . . . . . . . . .

Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Barium sulfate.. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Beryllium & beryllium compounds . . . . . . . . . . . . .

Bismuth telluride . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Berates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Boron oxide... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Boron tribromide . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Bromine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-Butoxyethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . .

n-Butyl acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

n-Butyl lactate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

o-sec-Butylphenol . . . . . . . . . . . . . . . . . . . . . . . . . . .

Calcium hydroxide . . . . . . . . . . . . . . . . . . . . . . . . . .

Calcium oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Camphor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Caprolactam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Captofol (Difolatan) . . . . . . . . . . . . . . . . . . . . . . . . .

Carbonyl fluoride . . . . . . . . . . . . . . . . . . . . . . . . . . .

Catechol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cesium hydroxide . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chlorine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chlorine dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . .

a-Chloroacetophenone . . . . . . . . . . . . . . . . . . . . . . .

Chloroacetyl chloride . . . . . . . . . . . . . . . . . . . . . . . .

Respiratory tract irritation

Bronchial constriction, respiratory tract irritation, bronchitis, and pharyngitis

Nose and throat irritation; bronchial and lung irritation

Pharyngial and lung irritation; inflammation of respiratory tract; irritation and

infections of respiratory tract

Respiratory tract irritation

Respiratory irritation

Lung injury and possible death

Upper respiratory tract irritation

Histologic lesions of the lung and pulmonary irritation

Respiratory irritation

Upper respiratory tract irritation

Pulmonary fibrosis and respiratory irritation

Upper respiratory tract irritation

Respiratory tract irritation

Respiratory irritation and inflammation

Causes asbestosis

Upper respiratory tract imitation and pneumoconiosis

Pulmonary edema and hemorrhage; tightness of chest, breathlessness; unconsciousness may occur and death may follow due to respiratory paralysis in cases

of extreme exposure

Shown to cause lung damage and pulmonary edema in animals

Non-malignant respiratory disease and berylliosis

Granulomatous lesions in lungs

Upper respiratory tract irritation

Upper respiratory tract imitation

Pneumonia and pneumonitis

Respiratory tract irritation and lung edema

Toxic lung changes

Respiratory imitation

Upper respiratory tract imitation

Respiratory tract irritation

Severe caustic irritation to upper respiratory tract

Inflammation of respiratory tract and pneumonia

Inflammation of upper respiratory tract;dyspnea

Congestion and irritation of upper respiratory tract

Respiratory sensitization

Respiratory tract irritation

Acute respiratory toxicity and upper respiratory tract irritation

Respiratory tract irritation

Necrosis of tracheal and bronchial epithelium, bronchitis, broncho pneumonia

and fatal pulmonary edema

Respiratory irritation and bronchitis

Difficulty in breathing

Respiratory irritation, cough, dyspnea, and pulmonary edema
Chapter 4—Federal Attention to Pulmonary Toxicants 57

Table 4-6-Air Contaminants Regulated by OSHA Because of Pulmonary Effects (Cent’d)

Substance Effects

o-Chlorobenzylidene malononitrile . . . . . . . . . . . . .

Chromium metal . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Coal dust (greater and less than 5 percent quartz)

Cobalt (metal, dust, and fume) . . . . . . . . . . . . . . . . .

Cobalt carbonyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cobalt hydrocarbonyl . . . . . . . . . . . . . . . . . . . . . . . .

Cotton dust . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cresol (all isomers) . . . . . . . . . . . . . . . . . . . . . . . . . .

Cyanogen chloride . . . . . . . . . . . . . . . . . . . . . . . . . .

Cyclohexanone . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cyhexatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1,2-dibromo-3-chloropropane . . . . . . . . . . . . . . . . . .

Dibutyl phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dichloroacetylene . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dicholorethyl ether . . . . . . . . . . . . . . . . . . . . . . . . . .

1,3-dichloropropene . . . . . . . . . . . . . . . . . . . . . . . . .

2,2-dichloropropionic acid . . . . . . . . . . . . . . . . . . . .

Dicyclopentadiene . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diethylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diethylene triamine . . . . . . . . . . . . . . . . . . . . . . . . . .

Diglycidyl ether . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diisobutyl ketone . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dimethyl sulfate . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dioxane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Divinyl benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Emery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Epichlorohydrin . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethanoamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethyl acrylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethyl benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethyl bromide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethyl silicate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene chlorohydrin . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene glycol . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene imine . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ferbam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ferrovanadium dust . . . . . . . . . . . . . . . . . . . . . . . . .

Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Upper respiratory tract incitation and dyspnea

Pulmonary disease (unspecified)

Pneumoconiosis and fibrosis after long-term exposure

Obliterative bronchiolitis adenomatosis, asthma, and chronic interstitial pneumonia

Coughing and dyspnea

Lung damage (unspecified)

Byssinosis

Obliterative bronchiolitis; adenomatosis; hypersensitivity reactions; chronic

interstitial pneumonitis and occasional fatalities

Pulmonary edema and upper respiratory tract irritation

Respiratory tract irritation

Respiratory irritation

Upper respiratory tract irritation

Respiratory tract irritation

Pulmonary edema

Lung injury (unspecified)

Respiratory irritation

Respiratory irritation

Respiratory irritation and lung hemorrhage

Tracheitis, bronchitis, pneumonitis, and pulmonary edema

Respiratory tract sensitization

Respiratory irritation

Upper respiratory tract irritation

Lung edema

Pulmonary edema; can cause death through repeated exposures at low concentrations

Respiratory irritation

Respiratory tract irritation and pneumonconisis

Lung edema, respiratory tract irritation, dyspnea, and bronchitis

Lung damage (unspecified)

Respiratory irritation, pneumonia and pulmonary edema

Lung congestion

Respiratory tract irritation; lung irritation and congestion

Lung damage (unspecified)

Respiratory tract and lung irritation

Respiratory tract irritation

Lung edema and secondary bronchial pneumonia

Respiratory irritation and lung injury (unspecified)

Upper respiratory tract irritation

Chronic bronchitis and chronic lung inflammation

Difficulty breathing, severe respiratory tract injury leading to pulmonary

edema, pneumonitis, and bronchial irritation which may lead to death depending on concentration of exposure; chronic exposure may lead to development

of bronchitis and asthma
5 8 Identifying and Controlling Pulmonary Toxicants

Table 4-6-Air Contaminants Regulated by OSHA Because of Pulmonary Effects (Cent’d)

Substance Effects

Furfural . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Furfuryl alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Gluteraldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Glycidol ...,...., . . . . . . . . . . . . . . . . . . . . . . . . . .

Grain dust (oat,wheat,barley) . . . . . . . . . . . . . . . . .

Graphite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorobutadiene . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorocyclopentadiene . . . . . . . . . . . . . . . . . . .

Hexalene glycol ”. . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hydrogen bromide . . . . . . . . . . . . . . . . . . . . . . . . . .

Hydrogen cyanide . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hydrogen fluoride . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hydrogen sulfide . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hydrogenated terphenyls . . . . . . . . . . . . . . . . . . . . .

Indene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Indium & Indium compounds . . . . . . . . . . . . . . . . . .

Iron oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Iron pentacarbonyl . . . . . . . . . . . . . . . . . . . . . . . . . .

Isoamyl alcohol.. . . . . . . . . . . . . . . . . . . . . . . . . . . .

Isophorone diisocyanate . . . . . . . . . . . . . . . . . . . . . .

n-Isopropylamine . . . . . . . . . . . . . . . . . . . . . . . . . . .

Isopropy glycidyl ether . . . . . . . . . . . . . . . . . . . . . . .

Kaolin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ketene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Limestone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Magnesium oxide fume . . . . . . . . . . . . . . . . . . . . . .

Maleic anhydride . . . . . . . . . . . . . . . . . . . . . . . . . . .

Manganese cyclopentadienyl tricarbonyl . . . . . . . . .

Manganese fume . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Manganese tetroxide . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl bromide. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl demeton . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl ethyl ketone . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl ethyl ketone peroxide . . . . . . . . . . . . . . . . . .

Methyl formate . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl iodide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl isocyanate . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl mercaptan . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl methacrylate . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl parathion . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl cyclohexanol . . . . . . . . . . . . . . . . . . . . . . . . .

Methylene bis(4-cyclohexylisocyanate) . . . . . . . . . .

Respiratory tract irritation

Asthma

Upper respiratory tract irritation

Respiratory tract and lung irritation, pneumonitis and emphysema

Chronic bronchitis, asthma, dyspnea, wheezing, and reduced pulmonary function

Pneumoconosis and anthracosilicosis

Pulmonary irritation

Pulmonary irritation, bronchitis, and bronchiolitis

Respiratory irritation

Upper respiratory tract irritation

Upper respiratory tract irritation and dyspnea

Respiratory tract irritation

Pulmonary edema; fatal at high concentrations

Lung damage (unspecified)

Chemical pneumonitis, pulmonary edema and lung hemorrhage

Widespread alveolar edema

Siderosis

Pulmonary injury and dyspnea

Upper respiratory tract irritation

Respiratory tract irritation, decreased pulmonary function, and sensitization

Respiratory tract irritation

Upper respiratory tract irritation

Respiratory effects (unspecified)

Respiratory tract irritation and pulmonary edema

Upper respiratory tract irritation

Chronic respiratory disease (unspecified)

Chronic bronchitis

Pulmonary edema

Pneumonia and lung damage (unspecified)

Pneumonitis and other respiratory effects

Pulmonary irritation

Bronchopneumonia, lung irritation, and pulmonary edema

Lung congestion

Upper respiratory tract irritation

Upper respiratory tract irritation and lung damage (unspecified)

Pulmonary edema, lung inflammation, and dyspnea

Lung irritation

Pulmonary edema and lung irritation

Pulmonary edema

Fatal pulmonary edema

Bronchioconstriction

Respiratory irritation

Pulmonary irritation
Chapter 4—Federal Attention to Pulmonary Toxicants ● 59

Table 4-6-Air Contaminants Regulated by OSHA Because of Pulmonary Effects (Cent’d)

Substance Effects

Mica. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Morpholine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Nickel (soluble compounds) . . . . . . . . . . . . . . . . . . .

Nitric acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Nitrogen dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-Nitropropane . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Oil mist(mineral) . . . . . . . . . . . . . . . . . . . . . . . . . . .

Osmium tetroxide . . . . . . . . . . . . . . . . . . . . . . . . . . .

Oxalic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Oxygen difluoride . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ozone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Paraquat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Particulates (not otherwise regulated) . . . . . . . . . . .

Perchloryl fluoride . . . . . . . . . . . . . . . . . . . . . . . . . .

Phenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phenyl glycidyl ether . . . . . . . . . . . . . . . . . . . . . . . .

p-Phenylenediamine . . . . . . . . . . . . . . . . . . . . . . . . .

Phenylhydrazine . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phenyl mercaptan . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phosgene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phosphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phosphoric acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phosphorous oxychloride . . . . . . . . . . . . . . . . . . . . .

Phosphorous pentasulfide . . . . . . . . . . . . . . . . . . . . .

Phosphorous trichloride . . . . . . . . . . . . . . . . . . . . . .

Phthalic anhydride . . . . . . . . . . . . . . . . . . . . . . . . . .

Picric acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Piperazine dihydrochloride . . . . . . . . . . . . . . . . . . . .

Portland cement . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Potassium hydroxide . . . . . . . . . . . . . . . . . . . . . . . . .

Propionic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

n-Propyl acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Propylene oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Rhodium compounds . . . . . . . . . . . . . . . . . . . . . . . .

Rosin core solder pyrolysis products . . . . . . . . . . . .

Rouge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Silica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Silicon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Silicon carbide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Silicon tetrahydride . . . . . . . . . . . . . . . . . . . . . . . . . .

Soapstone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Symptoms resembling those of silicosis and pneumoconiosis

Thickened alveoli, emphysema, and respiratory irritation

Pulmonary irritation, interstitial fibrotic lesions, hyperplasia

Chronic bronchitis and pneumonitis

Chronic bronchitis, emphysema, and decreased lung capacity

Pulmonary edema from severe exposure

Respiratory tract irritation

Respiratory irritation

Respiratory tract irritation

Pulmonary edema and hemorrhage

Significant reduction in pulmonary vital capacity and pulmonary congestion

Pulmonary irritation, pulmonary edema, and intra-alveolar hemorrhage

Upper respiratory tract irritation

Alveolar hemorrhage, emphysema, and alveolar edema

Guinea pigs died after inhalation exposure; no human inhalation data

Respiratory tract irritation

Allergic asthma and inflammation of the larynx and pharynx from industrial

exposure

Lung adenomas

Lung toxicity

Extreme lung damage; severe pulmonary edema after latent period of exposure;

bleeding and painful breathing; causes death

Pulmonary edema and acute dyspnea; at concentrations of 400 t0 600 pm death

may occur 30 minutes to 1 hour after exposure

Respiratory irritation

Respiratory tract irritation and pulmonary edema

Respiratory irritation

Bronchitis and pneumonia

Respiratory irritation and pulmonary sensitization

Edema, papules, vesicles, and desquamations of the nose

Pulmonary sensitization

Respiratory irritation

Respiratory irritation

Respiratory tract irritation

Respiratory irritation

Respiratory irritation

Respiratory sensitization

Upper respiratory tract irritation

Upper respiratory tract irritation

Silicosis

Pulmonary lesions

Aggravates pulmonary tuberculosis

Upper respiratory tract irritation

Pneumoconiosis
6 0 . Identifying and Controlling Pulmonary Toxicants

Table 4-6-Air Contaminants Regulated by OSHA Because of Pulmonary Effects (Cent’d)

Substance Effects

Sodium azide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sodium bisulfite . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sodium hydroxide . . . . . . . . . . . . . . . . . . . . . . . . . . .

Stoddard solvent . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Styrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Subtilisins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sulfur dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sulfur monochloride . . . . . . . . . . . . . . . . . . . . . . . . .

Sulfur pentafluoride . . . . . . . . . . . . . . . . . . . . . . . . .

Sulfur tetrafluoride . . . . . . . . . . . . . . . . . . . . . . . . . .

Sulfuryl fluoride . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Talc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Tantalum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Terphenyls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Tetrachloroethylene . . . . . . . . . . . . . . . . . . . . . . . . .

Tetrasodium pyrophosphate . . . . . . . . . . . . . . . . . . .

Tin oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Toluene-2,4-diisocyanate . . . . . . . . . . . . . . . . . . . . .

Toxaphene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Tributyl phosphate . . . . . . . . . . . . . . . . . . . . . . . . . .

1,2,4-Trichlorobenzene . . . . . . . . . . . . . . . . . . . . . . .

1,2,3-Trichloropropane . . . . . . . . . . . . . . . . . . . . . . .

Triethylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Trimellitic anhydride . . . . . . . . . . . . . . . . . . . . . . . .

Trimethyl phosphite . . . . . . . . . . . . . . . . . . . . . . . . .

Trimethylamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Trimethylbenzene . . . . . . . . . . . . . . . . . . . . . . . . . . .

Tungsten &tungsten compounds (insoluble) . . . . . .

Vanadium dust . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Vanadium fume . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Vinyl acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

VM&P Naphtha . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Welding fumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Wood dust . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Zinc chloride fume . . . . . . . . . . . . . . . . . . . . . . . . . .

Zinc oxide fume . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Zinc oxide dust . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Zinc stearate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Zirconium compounds . . . . . . . . . . . . . . . . . . . . . . .

Bronchitis

Respiratory irritation

Upper respiratory tract irritation and pneumonitis

Lung congestion and emphysema

Upper respiratory tract imitation and abnormal pulmonary function

Bronchoconstrictions and respiratory tract irritation

Accelerated loss of pulmonary function, bronchoconstriction, and dyspnea

Lung irritation

Lung congestion, lesions, and pulmonary edema

Emphysema, pulmonary edema, and difficulty breathing

Pulmonary edema

Pneumoconiosis, pleural thickening and calcification,reduced pulmonary function, and fibrotic changes in lung tissue

Lung lesions, bronchitis, hyperemia, and interstitial pneumonitis

Respiratory tract irritation

Long-term decline in lung function and pulmonary edema

Respiratory tract irritation

Stannosis and reduced pulmonary capacity

Pulmonary sensitization and long term decline in lung function

Lung inflammation

Lung toxicity

Upper respiratory tract irritation

Upper respiratory tract irritation

Pulmonary irritation

Intra-alveolar hemorrhage

Lung irritation

Upper respiratory tract irritation

Asthmatic bronchitis

Proliferation of intra-alveolar septa, pulmonary fibrosis, and dyspnea

Bronchial irritation and tracheobronchitis

Bronchitis, emphysema, tracheitis, pulmonary edema, and bronchial pneumonia

Upper respiratory tract irritation

Upper respiratory tract irritation

Damage to small airways causing interstial pneumonia; respiratory irritation

Allergic respiratory effects, decrease in pulmonary function

Damage to respiratory tract, severe pneumonitis, and advanced pulmonary

fibrosis

Shortness of breath and pneumonia

Respiratory effects (unspecified)

Pulmonary fibrosis

Granulomas in the lung

SOURCES: 29CFR 1910.1000, July l,1991;29CFR 1910.1001,July l,1991; 29 CFR1910.1018, July l, 1991; 29 CFR1910.1028,July 1,1991;29

CFR1910.1044,July l, 1991; 29 CFR1910.1043,July l, 1991; 29 CFR1910.1044,July l, 1991; 29 CFR1910.1047,July 1,1991;29CFR

1910.1048, July l,1991; 53 FederalRegister21062 (June7, 1988); 54 F’eu!enzZRegister2329-2984 (Jan. 19,1989).
Chapter 4—Federal Attention to Pulmonary Toxicants 61

Mine Safety and Health Administration

MSHA develops regulations to protect the health

and safety of miners. It administers FMSHA, which is

clearly concerned about pulmonary toxicants. FMSHA

uses the framework for health guidelines presented in

the Federal Coal Mine Health and Safety Act of 1%9,

which was primarily concerned with black lung disease,

a form of pneumoconiosis common to coal miners

(21,22). The statute and regulations require air sampling, medical examinations for miners, and dust control measures. A stated purpose of the health standards

was to ensure that mines are “sufficiently free of respirable dust concentrations . . . to permit each miner the

opportunity to work underground during the period of

his entire adult working life without incurring any

disability from pneumoconiosis or any other occupation-related disease during or at the end of such period.”

Other Federal Regulatory Activities

EPA and DOL exercise the main regulatory authority over airborne pulmonary toxicants. Other agencies

also administer laws that can be used to control these

substances, however. CPSC enforces the Consumer

Product Safety Act (CPSA; 15 U.S.C. 2051 et seq.) and

the Federal Hazardous Substances Act (FHSA; 15

U.S.C. 1261 et seq.). The FDA regulates chemicals

found in foods, drugs and cosmetics under the Federal

Food, Drug, and Cosmetic Act (FDCA; 21 U.S.C. 301

et seq.).

Consumer Product Safety Commission

The CPSC conducts research on injuries and diseases caused by consumer products and disperses information. The commission is also charged with the duty

of generating consumer product safety standards and

monitoring compliance.

Consumer Product Safety Act—CSPA is intended

to protect the American public from undue risk of

injury from consumer products and to help consumers

judge the comparative safety of articles available in the

marketplace. CPSA gives CPSC the authority to ban or

recall hazardous products. Few regulations issued under CPSA (16 CFR 1000 et seq.) deal specifically with

health hazards to the pulmonary system posed by unsafe consumer products. However, several products

containing asbestos are mentioned specifically as

banned materials. Consumer patching compounds

containing respirable free-form asbestos are prohibited on the American market. Also, artificial emberizing materials (e.g., artificial fireplace logs) containing

respirable free-form asbestos are forbidden. The regulations for these products specify the reason for the ban

as the unreasonable risk of lung cancer, noncancerous

lung diseases and injury due to inhaling asbestos fibers.

Federal Hazardous Substances Act. FHSA is intended to protect the public from health problems by

requiring that hazardous substances be labeled to warn

individuals of associated health risks. Regulations issued under FHSA control a number of pulmonary

toxicants, including formaldehyde, which is a strong

sensitizer (a substance that causes normal living tissue,

through an allergic or photodynamic process, to become severely hypersensitive on re-exposure to the

substance).

The regulations also control “hazardous substances,” which are defined as materials that have the

potential to cause substantial personal injury or substantial illness as a result of any customary or reasonably foreseeable use or handling. Benzene, products

containing 5 percent or more by weight of benzene, and

products containing 10 percent or more by weight of

toluene, xylene, turpentine, or petroleum distillates

(e.g., kerosene, naphtha, and gasoline) are listed as

hazardous substances. Such products must be clearly

labeled with several words and symbols including “danger” and “harmful or fatal if swallowed” since these

materials may be aspirated into the lungs causing

chemical pneumonitis, pneumonia, and pulmonary

edema.

Food and Drug Administration

FDA regulates chemicals found in foods, drugs, and

cosmetics, primarily through FDCA. Some of FDA’s

actions under this statute have been taken to protect

pulmonary health. For example, sulfites are subject to

a number of FDA regulatory requirements because

they have been found to cause severe, and potentially

lethal, asthma attacks in sensitive individuals. Sulfites

are no longer considered safe for use in meats, fruits

and vegetables to be served or sold raw or presented to

consumers as fresh (21 CFR 182). The presence of

sulfites in food must be declared when these chemicals
62 ● Identifying and Controlling Pulmonary Toxicants

are present at levels above 10 parts per million. However, FDA has not regulated airborne substances because of pulmonary toxicity.

FEDERAL RESEARCH ACTIVITIES

Knowledge of the pulmonary system and the

mechanisms and causes of pulmonary disease helps

Federal agencies create effective regulations. Federal

research in these areas is conducted mainly under the

direction of EPA the Department of Health and Human Services (DHHS), and the Department of Energy

(DOE). EPA’s Health Effects Research Laboratory

(HERL) conducts research in pulmonary toxicology

and epidemiology. DHHS conducts noncancer pulmonary research through several agencies, including the

National Institutes of Health (NIH), the Centers for

Disease Control (CDC), and the FDA. The Office of

Health and Environmental Research, part of the Office

of Energy Research, handles DOE’s research in pulmonary toxicology.

Environmental Protection Agency

Two divisions within HERL conduct research on

pulmonary toxicants. The Environmental Toxicology

Division, through its Pulmonary Toxicology Branch,

primarily tests the effects of air pollutants on animals

to develop a basis for regulations under the CAA. In

addition, it conducts pulmonary research with volatile

organic compounds, sulfuric acid, and nitric acid. The

Clinical Research Branch of the Human Studies Division conducts research on the effects on humans from

exposures to ozone and other criteria pollutants regulated under CAA. The Epidemiology Branch of the

Human Studies Division also carries out epidemiologic studies on the criteria pollutants.

HERL, located in Research Triangle Park, NC,

collaborates with the University of North Carolina

Center for Environmental Medicine and Lung Biology

(CEMLB), which provides important support for the

clinical and epidemiologic studies. HERL also works

with the Duke University Center for Extrapolation

Modeling, which works to confirm that animal models

used in the Toxicology Division accurately predict responses in humans, and develops generic models to be

used in risk assessment programs.

HERL’s work in pulmonary toxicology takes several forms. The laboratory studies extrapolation techniques-applying knowledge gained from animal test

results to human risk. HERL also performs acute exposure studies and attempts to apply those results to

chronic exposure scenarios. HERL is engaged in the

effort to define adversity of response, i.e., deciding at

what point a response, which may be a normal compensatory activity of the body, can be considered “adverse.” HERL also focuses on susceptible populations,

such as asthmatics, to determine why some persons

exhibit more detrimental effects from air pollution

than others.

Current funding for the Pulmonary Toxicology

Branch is approximately $2.6 million. The Clinical Research Branch is funded at a level of about $4.1 million,

and the Epidemiology Branch receives approximately

$2.4 million (4,15).

Department of Health and Human Services

The National Institute of Environmental Health

Sciences (NIEHS), part of the NIH, had a budget of

approximately $5,230,000 for intramural noncancer

pulmonary research in fiscal year 1991. NIEHS also

made over $15 million in extamural grants to various

universities and institutions in fiscal year 1991 for study

of pulmonary toxicants. An additional $3,190,000 was

spent on extramural contracts. The studies funded employ a wide range of techniques, including microbiology, whole animal studies, human clinical studies, and

epidemiology. Substances researched include those affecting small sub-groups of the population, as well as

those affecting the general population. The following

projects provide examples of the extramural research

funded by NIEHS.

.

.

Scientists at the University of Iowa Department of

Medicine received approximately $77,000 to study

the effects of silica on the epithelial cells of the

lungs in order to better understand how silicosis

can be prevented.

Researchers at the Medical College of Wisconsin

received over $77,000 to study growth factor secretion in dust-induced lung disease in rats. This study

was undertaken in order to clarify how alveolar
Chapter 4—Federal Attention to Pulmonary Toxicants 63

macrophages react to dust, eventually leading to

pneumonconiosis.

● The National Jewish Center for Immunology and

Respiratory Medicine received nearly $76,000 to

study the immunologic and toxic mechanisms of

beryllium disease in mice and humans in order to

better understand the pathology of chronic beryllium disease in humans.

● Scientists at the University of California at Davis

received $530,000 to study the effects of ozone on

the lungs of rats, mice, hamsters, and monkeys as

a basis to predict the effects of ozone in ambient

air on humans.

. Researchers at the University of Rochester School

of Medicine received $175,000 to conduct clinical

inhalation studies on healthy humans and those

with chronic pulmonary disease to investigate the

respiratory effects of particulate and oxidant air

pollutants (26).

● Scientists at the University of Iowa Pulmonary

Disease Division received close to $53,000 to conduct epidemiologic studies of vegetable dust-induced airway disease in humans. The purpose of

this study is to evaluate the feasibility of using the

current threshold safety limit in the handling of

cereal grain (oats, wheat, rye and barley) to protect

the health of noncereal grain and vegetable (corn

and soybean) handlers.

● Harvard University received $864,000 to conduct

an epidemiologic study of the effects of acid aerosols, ozone, and particulate matter on the respiratory health of children in 24 cities in North

America.

Using a model of asbestosis in laboratory animals,

NIEHS intramural scientists have found that as macrophages engulf asbestos particles, growth factors are

secreted that induce an increase in the number of

fibroblasts. The fibrotic condition that results disrupts

gas exchange. Current studies focus on stopping the

release of the growth factors or preventing their biological activity. In fiscal year 1991, this project received

funding of nearly $821,000 (19).

Other NIEHS intramural scientists are studying the

regulation of the pulmonary surfactant system and its

modification by toxic agents such as silica dusts. These

studies are focused on identifying cellular factors released by inflammatory cells in response to a toxic

agent that regulates surfactant production in alveolar

Type II cells. This project received almost $575,000 in

fiscal year 1991 (19).

NIEHS also contracts for a variety of inhalation

toxicology studies on drugs, naturally occurring agents,

and industrial compounds. For example, the IIT Research Institute in Chicago, IL, was awarded over

$495,000 to investigate the toxicity of isobutyl nitrite

(IBN). IBN is a component of some room deodorizers

and is sold illicitly in ampules known as “Poppers.” In

the prechronic study, the lungs, bone-marrow, spleen,

and nasal-cavity were identified as target organs for

toxicity (19).

The National Heart, Lung, and Blood Institute

(NHLBI), also part of NIH, conducts noncancer pulmonary research through its Division of Lung Diseases. This program includes studies on environmental

lung disease caused by air pollutants and occupational

lung disease. Approximately half of this research is

carried out on animals and the other half is done on

human subjects.

Extramural grants from NHLBI support research

on pulmonary toxicology at a number of universities.

Examples of environmental research include:

.

●

✎

✎

●

✎

Researchers at Louisiana State University are currently studying the effects of ozone, automobile

exhaust, and tobacco smoke on the lung. This project is funded at approximately $127,000 per year.

Scientists at the State University of New York at

Stony Brook are studying ozone and respiratory

mucus permeability, and receive about $79,000 for

this project.

Researchers at Pennsylvania State University are

conducting tests on oxidant stress in the respiratory system at a funding level of approximately

$185,000 per year.

Two groups of scientists at the University of California at Irvine are conducting human research on

inhaled particle deposition and animal research on

the effects of air pollution. They receive approximately $325,000 per year for these studies.

Researchers at the University of Maryland received approximately $100,000 to study the effect

of environmental tobacco smoke on human lungs.

Scientists at the University of California at Berkeley receive approximately $240,000 to conduct a

human study of the physical and chemical proper-
64 Identifying and Controlling Pulmonary Toxicants

ties of smoke and of the deposition of smoke particles in the lung.

● Researchers at Harvard University are conducting

human and animal studies of inhaled retention of

particulate matter, for which they receive approximately $134,000 per year.

. Scientists at the University of California at Santa

Barbara received funding of about $190,000 for a

study of the mechanisms of human response to

ozone.

A number of research projects supported by

NHLBI relate to occupational exposure to pulmonary

toxicants. For example:

● Specialized Centers of Research (SCOR) investigators at the University of Iowa are studying the

epidemiology and pulmonary responses to organic

dust exposures in farm workers, for which they

have received $127,000.

. The Iowa investigators and investigators at the

University of New Mexico, are studying mechanisms of hypersensitivity pneumonitis, also known

as farmer’s lung, for which they have received over

$135,000.

● A group of SCOR researchers at Tulane University received approximately $933,000 for a study of

the respiratory effects of exposure to irritant gases

and vapors in a population of 25,000 workers in the

chemical manufacturing industry.

● At the University of Vermont, SCOR scientists

received over $230,000 for an assessment of the

mechanisms involved in injury and inflammation

in occupationally related fibrotic lung disease associated with exposure to asbestos.

● Researchers at the State University of New York

at Buffalo received $354,054 for a study of the

pathogenesis of disease associated with exposures

in the textile industry.

For fiscal years 1992 and 1993, the Division of Lung

Diseases is developing two special initiatives. One is

related to the mechanisms of ozone-induced lung injury and a second is on basic mechanisms of asbestos

and nonasbestos fiber-related lung disease (13,14).

NHLBI conducts basic research not specifically linked

to any particular legislation or regulations. For fiscal

year 1991, the total budget for lung research was

$205,255,000; of that, $26,980,000 was dedicated to

research on asthma, and approximately $22,619,000

was used to study chronic bronchitis and emphysema (12).

The National Institute for Occupational Safety and

Health (NIOSH), part of the CDC, studies the pulmonary system through its Division of Respiratory Disease Studies (DRDS) at the Appalachian Laboratories

for Occupational Health and Safety at Morgantown,

WV. In addition, an extramural grant program is directed through NIOSH’s administrative offices in Atlanta, GA. The overall budget for NIOSH in fiscal year

1992 is $103,450,000 with $13,400,000 designated for

the study of occupational respiratory diseases. This is

an increase from the approximately $7,687,112 allocated to intramural research and $3,1%,218 spent on

extramural research in the area of occupational lung

disease in fiscal year 1991 (7,16).

NIOSH conducts research stimulated by the advice

of DOL and investigator initiated research. Additionally, the Mine Health Research Advisory Committee

suggests areas of study where gaps exist in the knowledge base. Other research suggestions come from

NIOSH’s Board of Scientific Counselors. NIOSH has

specific authority from the OSH Act and FMSHA to

conduct research and to make recommendations for

health and safety standard regulations (27).

DRDS conducts epidemiologic research on pulmonary diseases related to the mining, milling, agricultural, construction, and other industries. Among the

research programs in this area are a medical surveillance program for living coal miners (the National

Coal Worker’s X-ray Surveillance Program), and an

autopsy program (the National Coal Workers’

Autopsy Study) required by FMSHA. An ongoing surveillance program examines whether current coal mine

dust standards protect miners’ health. This study has

continued for more than 20 years and is conducted

through voluntary x-rays and an organized epidemiologic investigation. DRDS also conducts epidemiologic studies of occupational asthma and pulmonary

disease caused by exposure to cotton dust. The agency

monitors trends in the incidence of all occupational

lung diseases. Clinical studies are conducted to determine the effects of occupational exposure to specific

substances and to better understand human response

mechanisms (28).

DRDS also conducts research in such areas as

physiology, pathology, and microbiology to better understand the dangers of substances and the mechanisms of disease. Scientists choose animal models

suitable for the study of particular agents and develop

new laboratory techniques.
Chapter 4—Federal Attention to Pulmonary Toxicants . 65

Extramural research is conducted through such

programs as the NIOSH Centers for Agricultural Research, Education, and Disease and Injury Prevention

Program. This program funds centers at the University

of California at Davis, the University of Iowa at Iowa

City, the National Farm Medicine Center in Marshfield, WI, and the Colorado State University at Fort

Collins. Most of the program’s pulmonary studies are

conducted at the University of Iowa center, which conducts research in such areas as grain dust exposures and

respiratory diseases in dairy farmers (7).

Unlike other Federal research agencies, NIOSH

responds to requests from workers and their representatives to investigate the causes of accidents and

illnesses in the workplace. In fiscal year 1992, NIOSH

issued 40 final reports of respiratory disease health

hazard evaluations. Onsite evaluations of possible pulmonary health hazards are performed by DRDS.

DRDS medical personnel, industrial hygienists, and

epidemiologists analyze the workplace situation and

present suggestions for diminishing harmful

exposures (28).

The National Center for Toxicological Research

(NCTR) in Jefferson, AR, conducts methods development and toxicological research for the FDA. The

purposes of the Center are to increase knowledge of

human health risks associated with exposure to artificial and natural substances and to elucidate the mechanisms and impact of these risks. Pulmonary toxicity

studies conducted at NCTR deal primarily with chronic

long-term exposure to carcinogenic or mutagenic compounds. Currently research is focused on compounds

of interest to FDA unrelated to pulmonary toxicity (l).

Department of Energy

DOE funds research on pulmonary toxicants conducted by the Inhalation Toxicology Research Institute

(ITRI) in Albuquerque, NM. ITRI is owned by DOE

and is operated under along-term contract by a private,

Photo Credit: G. Wagner, National Institute for Occupational Safety and Health
6 6 . Identifying and Controlling Pulmonary Toxicants

nonprofit corporate entity, the Lovelace Biomedical

and Environmental Research Institute. ITRI receives

approximately 75 percent of its funding from DOE,

with the other 25 percent coming from other government agencies, nongovernment associations, and individual companies. Funding by DOE remains constant,

while other government agencies and private sources

provide funding for particular studies in areas of their

interest.

All research at ITRI is lung related, and it ranges

from molecular studies focusing on cellular changes

caused by inhaled materials to clinical studies of human

subjects. Studies are related to two general areas: those

which examine the effects of specific substances on the

respiratory system and those which explore the structure and function of the respiratory tract and the general behavior of gases, vapors, and particles in the

respiratory tract (17).

Research on noncancer pulmonary toxicity is currently being conducted on ozone, nitrogen oxides, sulfur oxides, and the components of engine exhaust.

Some studies focus on occupational exposures to pulmonary toxicants, including benzene, butadiene,

nickel, and beryllium. Other research examines the

effects of exposure to natural fibers, such as asbestos,

and synthetic fibers, such as fiberglass. Studies on respiratory system structure and function focus on the

uptake, deposition, and excretion of toxicants, and

natural defenses of the respiratory system to inhaled

materials (17).

ITRI proposes studies it decides need to be conducted, and DOE allocates funds according to its interests and resources. The scientific research budget for

ITRI in fiscal year 1992 is approximately $13.5 million.

In 1992 ITRI has allocated approximately 54 percent

of its budget to cancer research. The other 46 percent

is designated for noncancer research. Of the noncancer

budget, a little over half is spent on general toxicology,

including the study of the mechanisms of diseases,

mathematical models of effects, and studies of the

metabolism of compounds. Approximately one quarter of the budget is allocated for the study of the nature

of airborne materials (vapors, particulate matter and

gases). The remaining quarter is designated for dosimetry studies (18).

Cooperative Federal and Private Research

The Health Effects Institute (HEI) supports and

evaluates research on the health effects of motor vehicle emissions. Its research program focuses on substances regulated by the NAAQS in the CAA, as well

as other pollutants, such as diesel exhaust particles,

methanol, and aldehydes (10). Because all research

targets emissions, the majority of HEI’s research focuses on the lung (20). All research at HEI is extramural, with funding mainly going to universities, but also

to research centers (e.g., ITRI and the Los Amigos

Research and Education Institute). Both cancer and

noncancer research is funded, but no clear breakdown

is available because research is pollutant-focused

rather than effect-focused (29).

HEI receives one-half of its funding from EPA and

the other half from all companies who make or sell

automobiles, trucks, or engines in the United States.

Currently, EPA and 28 private companies fund HEI.

HEI bills the companies separately based proportionally on the number of vehicles or engines they sell that

year in the United States. Contributing companies include American, European, and Japanese corporations. The total budget for HEI in fiscal year 1992 is $6

million (9).

A separate nonprofit organization, the Health Effects Research Institute—Asbestos Research (HEIAR), was established in September 1989 to support

scientific studies to evaluate airborne levels of asbestos

in buildings, to assess exposure, and to examine asbestos handling and control strategies. HEI-AR is modeled after HEI but is an independent entity.

Beginning in fiscal year 1990 HEI-AR was scheduled to receive $2 million annually for 3 years from

EPA. It secures an additional $2 million per year from

combined sources in the real estate, insurance, and

asbestos manufacturing industries, as well as from public and private organizations interested in asbestos. In

1991, HEI-AR published a report including literature

review of current knowledge of asbestos in buildings

and identifying areas where more knowledge is needed.

It has also begun a program of support and evaluation

for scientific asbestos studies (11).

SUMMARY

The Federal Government plays an active role in the

protection of pulmonary health through regulations

and research. Regulations promulgated under the

CAA, RCRA, TSCA, FIFRA, CPSA, and FDCA are

designed to protect pulmonary health in the general

population. Regulations promulgated under the OSH

Act and FMSHA are designed to safeguard workers
Chapter 4—Federal Attention to Pulmonary Toxicants ● 67

and miners respectively from exposure to pulmonary

toxicants within the scope of their employment. Federal regulations call for a variety of measures to control

the risk of exposure to pulmonary toxicants, including

setting exposure levels, banning certain materials

which pose an unmanageable risk of pulmonary injury,

and requiring safety devices and education in the workplace.

Federal research on pulmonary toxicants is conducted primarily under the auspices of EPA, DHHS,

and DOE. Research by these organizations is conducted on an intramural basis and on an extramural

basis through grants to universities and other research

institutes. An effort has been made to combine public

and private funding of pulmonary toxicology research

in HEI. Federally funded research includes studies

involving human and animal subjects that employ research techniques ranging from cellular studies to epidemiology. Applying the knowledge gained through

these studies, Federal agencies have been able to design regulations which should more effectively reduce

health risks to the pulmonary system.

CHAPTER 4 REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

Adams, L., Office of Legislative Affairs, Food and

Drug Administration, Washington, DC, personal

communication, February 1992.

Anderson, F., Environmental Protection: Law ad,

Policy (Boston, MA: Little, Brown & Co., 1990).

Blodgett, J. Hazardous Air Pollutants: Revtiing

Section l120fthe CleanAirAct, Environment and

Natural Resources Policy Division, Congressional Research Serviee, Library of Congress

(Washington, DC: Library of Congress, February

1991).

Costa, D., Pulmonary Toxicology Branch, Health

Effects Research Laboratory, U.S. Environmental Protection Ageney, Research Triangle

Park, NC, personal communication, September

1991.

52 Federal Register 16022 (May 1, 1987).

52 Federal Register 46766 (Nov. 6, 1990).

Friedlander, J., Centers for Disease Control, Atlanta, GA personal eommunieation, February

1992.

Hazen, S., 33/50 Program, Environmental Protection Ageney, Washington, DC, personal communication, August 1991.

Health Effeets Institute, “Annual Report: 1990-

1991,” unpublished booklet, Cambridge, MA.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

Health Effeets Institute, “Requests for Applications: 1991 Research Agenda,” unpublished

booklet, Cambridge, ~ October 1991.

Health Effects Institute—Asbestos Research,

“Requests for Applications,” unpublished booklet, Cambridge, N@ October 1990.

Hymiller, J., Budget Office, National Heart,

Lung, and Blood Institute, National Institutes of

Health, Washington, DC, personal communication, Februag 1992.

Kalica, A., Airways Division, National Heart,

Lung, and Blood Institute, National Institutes of

Health, Washington, DC, personal eommunieation, February 1992.

Kiley, J., Airways Division, National Heart, Lung,

and Blood Institute, National Institutes of

Health, Washington, DC, personal communication, February 1992.

Koren, H., Health Effects Research Laboratories, U.S. Environmental Protection Agency, Research Triangle Park, NC, persona l

communication, March 1992.

Landry, M., Financial Management Office, tlmters for Disease Control, Atlanta, GA personal

communication, November 1991.

Mauderly, J., Inhalation Toxicology Research Institute, Albuquerque, NM, personal eommunieation, September 1991.

Mauderly, J., Inhalation Toxicology Research Institute, Albuquerque, NM, personal communication, January 1992.

Phelps, J., National Institute of Environmental

Health Scienees, Research Triangle Park, NC,

personal communication, February 1992.

Sivak, A., Health Effects Institute, Cambridge,

W personal communication, January 1992.

U.S. Congress, United States’ Code Congressional

andAdministrative News, 91st Cong., 1st Sess. (St.

Paul, MN: West Publishing Co., 1%9), p. 2506.

U.S. Congres$ United States ’Code Congressional.

and Administrative News, 95th Cong., 1st Sess.

(St. Paul, MN: West Publishing Co., 1977), pp.

1187-97,3405.

U.S. Congress, United States’ Code Congressional

and Administrative News, IOlst Cong., 2d Sm.

(St. Paul, MN: West Publishing Co., 1990), pp.

3392-94,3513,3518,3532-50.

U.S. Environmental Protection Ageney, Office of

Air and Radiation, “Early Reduction Program;

unpublished memo, Washington, DC, May 1991.

U.S. Environmental Protection Agency, “EPA’s

33/50 Program: A Progress Report,” unpublished

memo, Washington, DC, July 1991.
6 8 Identifying and Controlling Pulmonary Toxicants

26. Utell, M., University of Rochester Medical Cen- 28. Wagner, G., Division of Respiratory Disease

ter, Rochester, NY, personal communication, Studies, National Institute for Occupational

December 1991. Safety and Health, Morgantown, WV, personal

27. Wagner, G., Division of Respirator Disease communication, January 1992.

Studies, National Institute for Occupational 29. Warren, J., Health Effects Institute, Cambridge,

Safety and Health, Morgantown, WV, personal MA personal communication, February 1992.

communication, September 1991.
Appendix
Appendix

Glossary of Terms and Acronyms

Glossary

Alveolus/i: An air sac of the lungs at the termination of

the bronchioles.

Antigen: A substance that brings about an immune

response when introduced into the body.

Asthma: A chronic respiratory disease accompanied by

labored breathing, chest constriction, and coughing.

Biologically effective dose: The amount of a contaminant that interacts with cells and results in altered

physiologic function.

Black lung disease: An occupational disease of coal

workers resulting from deposition of coal dust in the

lungs.

Bronchoalveolar lavage fluid: Fluid obtained from the

bronchoalveolar region of the lungs by lavage.

Bronchoconstriction: Narrowing of a bronchus caused

by constriction of bronchial smooth muscle.

Bronchus: One of the large conducting air passages of

the lungs commencing at the bifurcation of the trachea and terminating in the bronchioles.

Byssinosis: An occupational respiratory disease of cotton, flax, soft-hemp, and sisal workers characterized

by symptoms of chest tightness.

Chronic bronchitis: Chronic inflammation of bronchi

resulting in cough, sputum production, and often

progressive breathlessness.

Cilia: Long slender microscopic structures extending

from a cell surface and capable of rhythmic motion.

Collagen: Family of fibrous proteins.

Criteria pollutants: Airborne substances that may

cause or contribute to air pollution and may reasonably be anticipated to endanger public health or

welfare.

Cytotoxicity: The quality of being deadly to cells.

Dosimetry: The estimation of the amount of a toxicant

that reaches the target site following exposure.

Elastin: The protein base of connective tissues.

Emphysema: A condition of the lungs characterized by

labored breathing and increased susceptibility to

infection.

Endothelium: The layer of cells lining the blood vessels.

Epidemiology: The scientific study of the distribution

and occurrence of human diseases and health conditions and their determinants.

Epitheliums: The thin layer of cells lining the inside of

the respiratory tract.

Extrinsic allergic alveolitis: Severe immune responses

to inhaled plant and animal dusts.

Fibroblast: The main cell of connective tissue.

Fibrosis: The formation of fibrous tissue as a result of

injury or inflammation.

Gas exchange: The process of delivering oxygen in

inhaled air to the bloodstream and delivering carbon

dioxide and other gaseous components and metabolites in the blood stream to the exhalable air.

In vitro: Literally, in glass; pertaining to a biological

process taking place in an artificial environment,

usually a laboratory.

In vivo: Literally, in the living; pertaining to a biological process or reaction taking place in a living organism.

Larynx: Part of the respiratory tract containing the

vocal cords.

Lavage: Irrigation or washing out of a cavity.

Microphage: A type of large, amoeba-like cell, found

in the blood and lymph, which ingests dead tissue,

tumor cells, and foreign particles.

Magnetopneumography (MPG): A non-invasive technique which provides a means of actively monitoring

the dust retained in the lungs of people exposed to

magnetic or magnetizable dusts.

Microscopy: The use of an instrument to obtain magnified images of small objects.

Morphometry: The measurement of the structure and

forms of organisms, as opposed to the measurement

of their functions.

Mucus: The viscous fluid secreted by the mucous

glands.

Nasopharyngeal region: Region of the lung comprising the nasal cavity and pharynx.

Phagocytosis: Consumption of foreign particles by

cells.

Pharynx: The portion of the alimentary canal which

intervenes between the mouth cavity and the

esophagus and serves both for the passage of food

and the performance of respiratory functions.

Pleura: The serous membrane lining the pulmonary

cavity.

Pleural cavity: The space that separates the lungs from

the chest wall. It contains a small amount of fluid

71
72 Identifying and Controlling Pulmonary Toxicants

and is bounded by membranes called the pleura.

Pneumoconiosis: A condition characterized by the

deposition of mineral dust in the lungs as a result of

occupational or environmental exposure.

Pulmonary edema: The accumulation of abnormally

large amounts of watery fluid within the pulmonary

alveoli.

Pulmonary fibrosis: The accumulation of abnormal

quantities of fibrous tissue in the lung.

Pulmonary region: The region of the lung where oxygen in the air is supplied to the blood and carbon

dioxide and other gaseous components and metabolites are released from the blood to the air remaining

in the lungs.

Respiratory system: An interconnected series of air

passages, cavernous organs, and cells that permit the

introduction of oxygen, the-exchange of gases, and

the removal of carbon dioxide from the body as well

as the production of speech.

Risk assessment: The analytical process by which the

nature and magnitude of risk are identified. Four

steps make up a complete risk assessment: hazard

identification, dose-response assessment, exposure

assessment, and risk characterization.

Secretory cells: Cells that secret mucus.

Spirometry: The measurement of the air inhaled and

exhaled during respiration.

Toxicology: The study of adverse effects of natural or

synthetic chemicals on living organisms.

Trachea: The windpipe.

Tracheobronchial region: The region of the lung comprising the trachea and bronchi.

Type I cells: Cells lining the alveoli which are very thin

and delicate and spread over a relatively large area.

Type II cells: Cells lining the alveoli which release

proteins and lipids providing a thin, fluid lining for

the inside of the alveoli.

Acronyms

ATS —American Thoracic Society

BAL —Bronchoalveolar lavage

BALF —Bronchoalveolar lavage fluid

C M —Clean Air Act

CASAC —Clean Air Science Advisory Committee

(EPA)

CDC —Centers for Disease Control

CFR —Code of Federal Regulations

c o —Carbon monoxide

C 02-Carbon dioxide

COAD —Chronic obstructive airway disease

COLD —Chronic obstructive lung disease

COPD —Chronic obstructive pulmonary disease

CPSA —Consumer Product Safety Act

CPSC —Consumer Product Safety Commission

DHHS —Department of Health and Human Services

DLco —Diffusing capacity of the lung for carbon

monoxide

DOE —Department of Energy

DRDS —Division of Respiratory Disease Studies

(NIOSH)

EPA —Environmental Protection Agency

ERP —Early Reduction Program

FDA —Food and Drug Administration

FDCA —Food, Drug, and Cosmetic Act

FEF5o —Forced expiratory flow of 50 percent

FEF75 —Forced expiatory flow of 75 percent

FEV1 —Forced expiratory volume in 1 second

FHSA —Federal Hazardous Substances Act

FIFRA —Federal Insecticide, Fungicide, and

Rodenticide Act

FMSHA —Federal Mine Safety and Health Act

FVC —Forced vital capacity

HEI —Health Effects Institute

HERL —Health Effects Research Laboratory

ITRI —Inhalation Toxicology Research Institute

MACT —Maximum achievable control technology

MMEF —Maximal midexpiratory flow

MPG —Magnetopneumography

MSHA —Mine Safety and Health Administration

NAAQS —National Ambient Air Quality Standards

NAS —National Academy of Sciences

NCTR —National Center for Toxicological

Research

NHLBI —National Heart, Lung, and Blood Institute

NIEHS —National Institute of Environmental

Health Sciences

NIH —National Institutes of Health

NIOSH —National Institute for Occupational Safety

and Health

NOX —Nitrogen oxides

NRC —National Research Council

OSHA —Occupational Safety and Health

Administration

OTA —Office of Technology Assessment

PEL —Permissible exposure limit

RCRA —Resource Conservation and Recovery Act

TRI —Toxics Release Inventory

TSCA —Toxic Substances Control Act

UCLA —University of California at Los Angeles

VOC —Volatile organic compounds
Index
Index

Adverse health effects, 4,9-10,43

Air

amount inhaled, 3, 15

composition of, 6, 15,29

contaminants, 56

hazardous pollutants of, 7,49,52

pollutants, 6-8,25,31,62-65

quality, 6-8

Airborne substances, 4,6,8

Aldehydes, 66

Alkyl halide, substituted, 51

Alpha1 -antitrypsin, 21

American Thoracic Society (ATS), 43

Animal, selection of appropriate test, 6,34

Arsenic, inorganic, 49

Asbestos, 22,29,49,61,63-64,66

Asthma, 5,21,22,64

Benzene, 49,61,66

Beryllium, 34,49,62,66

Biological agents, 4,8

Biologically effective dose, 6,31-33

Black lung disease, 61

Bronchitis, chronic, 19-20,21

Bronchoalveolar lavage (BAL), 41

Bronchoalveolar lavage fluid (BALF), 38

Bronchoconstriction, 21,34

Butadiene, 66

Bysinossis, 21

Cadmium, 21

Carbon monoxide (CO), 8,25,29,49

Centers for Disease Control (CDC), 64

Chemical pneumonitis, 61

Chronic bronchitis, 5,19,64

Chronic obstructive airway disease (COAD), 21

Chronic obstructive lung disease (COLD), 21

Chronic obstructive pulmonary disease (COPD), 21

Clean Air Act (CAA), 7,49-51

Clean Air Science Advisory Committee (CASAC), 9

Clinical studies, 35-40

Coal, 61,64

Coke oven emissions, 49

Colorado State University, 65

Consumer Product Safety Act (CPSA), 61

Department of Health and Human Services

(DHHS), 62-65

Department of Labor (DOL), 49,55

Diesel exhaust, 66

Diisocyanates, 51

Division of Respiratory Disease Studies (DRDS), 64

Dose-response assessment, 30-31

Dosimetry, 31,34-35,66

Duke University, 62

Dust, 4,21-22,29,62-65

Early Reduction Program (ERP), 49-51,54

Emphysema, 5,20-21,64

Environmental Protection Agency (EPA),

regulation, 9,49-55

research, 9,62,66-67

Epidemiologic studies, 40-43

Epidemiology, defined, 4,6

Exposure

acute, 7-9,31,43,51,62

chronic, 9,31,43,51,62

defined, 6,31

environmentally relevant levels of, 4,43

indoor, 8, 29

occupational, 4,5,7,25,66

outdoor, 4, 29

technologies to measure, 35-36,41

Exposure assessment, 8,30-31,34-35

Extrinsic allergic alveolitis, 22

Farmers, 22,65

Federal Hazardous Substances Act (FHSA), 61

Federal Insecticide, Fungicide, and Rodenticide Act

(FIFRA), 49,54-55

Federal Mine Safety and Health Act (FMSHA), 7,

55,64

Fiberglass, 66

Fibrosis, 5

Food and Drug Administration (FDA), 49,61-62

Food, Drug, and Cosmetics Act (FDCA), 61

Formaldehyde, 8,25,29,61

Gas exchange, 16,20,22,63

Gasoline, 61

Harvard University, 63,64

Hazard identification, 30-31

Consumer Product Safety commission (CPSC), 49,61 Health effects assessment, 35-43

Data, assessments of, 41 Health Effects Institute (HEI), 66

Department of Energy (DOE), 65-66 Health Effects Institute—Asbestos Research

75
76 ● Identifying and Controlling Pulmonary Toxicants

(HEIAR), 66

Health Effects Research Laboratory (HERL), 62

Hydrocarbons, 25

Immune

responses, 19,22

system, 19,38

Indoor air, 8,29

Inhalation Toxicology Research Institute (ITRI),

65-66

Isobutyl nitrite (IBN), 63

Kerosene, 61

Laboratories studies, 35-40

Lead, 49

Los Amigos Research and Education Institute, 66

Los Angeles, CA 7,9,42

Louisiana State University, 63

Lung

injury and disease, 5, 19-22

structure and function, 5, 15-19

toxicology and epidemiology of, 5-6,29-33

Magnetopneumography, 33

Maximum achievable control technology (MACT), 49

Medical College of Wisconsin, 62

Mercury, 49

Methanol, 66

Microscopy, 33,39

Mine Safety and Health Administration (MSHA),

49,61

Miners, 64

Morgantown, WV, 64

Morphometry, 38

Naphtha, 61

Nasopharyngeal region, 5,15

National Academy of Sciences (NAS), 38

National Ambient Air Quality Standards (NAAQS),

49,50

National Center for Toxicological Research (NCTR), 65

National Coal Workers’ Autopsy Study, 64

National Farm Medicine Center, 65

National Heart Lung and Blood Institute (NHLBI),

63-64

National Institute for Occupational Safety and

Health (NIOSH), 64

National Institutes of Health (NIH), 62

National Institute of Environmental Health Sciences

(NIEHS), 62

National Jewish Center for Immunology and Respiratory Medicine, 63

Nickel, 66

Nitric acid, 62

Nitrogen dioxide, 8,29,49

Nitrogen oxides, 6,9,25,29,66

Occupational Safety and Health Act (OSH Act), 7,55

Occupational Safety and Health Administration

(OSHA),49, 55-60

Office of Technology Assessment

scope of the report, 3-4

studies on neurotoxicity and immunotoxicity, 6, 19

terminology used by, 3-4

Oxidants, 25

Oxirane, substituted, 51

Ozone, 9,29,49,62-64,66

Particulate, 6,20,25,29,49,63

Pennsylvania State University, 63

Perhalo alkoxy ether, 54

Pesticides, 55

Pleural cavity, 17

Pneumoconiosis, 61,

Pneumonia, 61

Pulmonary circulation, 16

Pulmonary edema, 54,61

Pulmonary fibrosis, 22

Pulmonary region, 5,16,32

Pulmonary toxicants, 3,29,51,62,67

Pulmonary toxicity, 9,37,43,66

Radionuclides, 49

Radon, 8

Regulators, 3-4,8,10,29,44

Regulatory activities, Federal

Consumer Product Safety Commission, 49,61

Department of Labor, 49,55

Environmental Protection Agency, 49-55

Food and Drug Administration, 49,61

Occupational Safety and Health Administration, 49,55

Mine Safety and Health Administration, 49,61

Research, Federal

Centers for Disease Control, 64

Department of Energy, 65-66

Department of Health and Human Services, 62-65

Environmental Protection Agency, 9,62,66-67

National Center for Toxicological Research, 65

National Heart Lung and Blood Institute, 63-64

National Institute for Occupational Safety and

Health, 64

National Institute of Environmental Health Sciences, 62-63

National Institutes of Health, 62

see also Studies.

Research Triangle Park, NC, 62

Resource Conservation and Recovery Act (RCRA),

49,51,55
Index ● 7 7

Respirable particles, 22

Respiratory system

cells of the, 17-19

defense mechanisms, 5, 15,19,32

responses to harmful substances, 5, 19-22

species differences, 34

structure and function, 5, 15-19

Risk assessment, 29-31

Risk characterization, 30-31

Senate, Committee on Environment and Public

Works, Subcommittee on Toxic Substances, Environmental Oversight, Research and Development, 3

Silane, 54

Silicosis, 62

Smoking, 5,20,21,29,40

Spirometry, 37,39,41

State University of New York at Buffalo, 64

State University of New York at Stony Brook, 63

Studies

clinical, 3,5-6,8-9,35-40,43,44, 62,64

epidemiologic, 3,5-6,8-9,20,35,40-43, 62,64

laboratory, 3,5-6,8,34-35,38,43-44

limitations of, 43-44

see also Research; Tests

Sulfur dioxide, 5,20,22,29

Sulfur oxides, 6,25,29,49,66

Sulfuric acid, 62

Susceptible populations, 8,44,62

Tests

biochemical, 6,9,38

biological, 40-43

molecular, 38

physiologic, 36-38

structure, 38

see also Studies

Textiles, 21,64

33/50 Program, 51,54

Tobacco smoke, 5,8,25,29,42,63

Toluene, 61

Toxic Release Inventory (TRI), 51

Toxic Substances Control Act (TSCA), 49,51-54

Toxicants

Federal regulation of, 49-62

Federal research on, 62-66

industrial, 23

monitoring of, 31

physical properties of, 33-34

Toxicology, 4,5-6,30

Tracheobronchial region, 5, 15,32,62

Turpentine, 61

University of California at Berkeley, 63-64

University of California at Davis, 63,65

University of California at Irvine, 63

University of California at Los Angeles (ULCA), 42

University of California at Santa Barbara, 64

University of Maryland, 63

University of New Mexico, 64

University of North Carolina, 62

University of Rochester School of Medicine, 63

University of Vermont, 64

Vinyl chloride, 49

Volatile organic compounds, 8-9,25,32,62

Woodsmoke, 6,8,25

Workers, 6,64,66

Xylene, 61

U.S. GOVERNMENT PRINTING OFFICE : 1992 0 – 297-932 : QL 3