identifying and controlling pulmonary toxicants

Identifying and Controlling PulmonaryToxicants

June 1992

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Foreword

History reveals an enduring respect for lung function. In the biblical account of creation, manbecomes a living soul when he receives the breath of life. Edward I of England banned the use of coalin 1273 because he found inhaling its smoke detrimental to human health. When asked how to ensurea long life, Sophie Tucker replied, “Keep breathing.”

This Background Paper examines whether the agencies responsible for administering Federalenvironmental 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 Subcom-mittee on Toxic Substances, Environmental Oversight, Research and Development, the study describestechnologies available to identify substances toxic to the lung and Federal efforts to control humanexposure to such substances through regulatory and research programs. The analysis shows that newtechnologies hold great promise for revealing the potential adverse effects on the lung of new andexisting substances, but that much remains to be learned. This Background Paper provides a partialresponse to the committees’ request for an assessment of noncancer health risks in the environment andfollows OTA’s previous work on carcinogenic, neurotoxic, and immunotoxic substances.

OTA acknowledges the generous help of the workshop participants, reviewers, and contributors whogave their time to ensure the accuracy and completeness of this study. OTA, however, remains solelyresponsible for the contents of this Background Paper.

~f~

@’&# ‘ >John H. GibbonsDirector

. . .111

Workshop on Identifying and Controlling Pulmonary Toxicants, September 1991

Dr. Robert M. Friedman, Workshop ChairSenior Associate

Oceans and Environment ProgramOffice of Technology Assessment

Dr. Margaret BecklakeDirector, Respiratory Epidemiology UnitMcGill University

Dr. Arnold BrodyHead, Pulmonary PathologyNational Institute of Environmental

Health Sciences

Dr. Daniel L. CostaChief, Pulmonary Toxicology BranchInhalation Toxicology DivisionHealth Effects Research LaboratoryU.S. Environmental Protection Agency

Dr. Robert R. MercerAssistant Medical Research ProfessorDepartment of MedicineDuke University

Dr. Richard B. SchlesingerProfessor, Department of

Environmental MedicineNew York University School of Medicine

Dr. Mark J. UtellDirector, Pulmonary and Critical

Care UnitUniversity of Rochester Medical Center

Dr. Joe L. Mauderly Dr. Gregory WagnerDirector Director, Division of RespiratoryInhalation Toxicology Research Institute Disease StudiesLovelace Biomedical and Environmental National Institute for Occupational

Research Institute, Inc. Safety and Health

Dr. Roger O. McClellan Dr. Ronald K. WolffPresident Research ScientistChemical 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. OTAassumes 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 orotherwise contributed to this study.

Lois AdamsOffice of Technology Assessment LiaisonOffice of Legislative AffairsU.S. Food and Drug Administration

Heinz W. Ahlers, J.D.Division of Standards Development

and Technology TransferNational Institute for Occupational Safety

and Health

John R. Balmes, M.D.Assistant Professor of MedicineCenter for Occupational and Environmental HealthUniversity of California, San Francisco

Rebecca Bascom, M.D.Director, Environmental Research FacilitySchool of MedicineUniversity of Maryland

Robert P. Baughman, M.D.Associate Professor of MedicinePulmonary/Critical Care DivisionUniversity of Cincinnati

Paul D. Blanc, M.D., M. S.P.H.Assistant Professor of MedicineDivision of Occupational and

Environmental MedicineUniversity of California-San Francisco

James C. Bonner, Ph.D.Staff FellowLaboratory of Pulmonary PathobiologyNational Institute of Environmental Health Sciences

Carroll E. Cross, M.D.Division of Pulmonary-Critical Care MedicineDepartment of Internal MedicineUniversity of California-Davis Medical Center

Roger Detels, M. D., M.S.Professor of EpidemiologySchool of Public HealthUniversity of California-Los Angeles

Fran Du MelleDeputy Managing DirectorAmerican Lung Association

June FriedlanderStaff SpecialistNational Institute for Occupational Safety

and Health

Suzie HazenDirector, 33/50 ProgramOffice of Air and RadiationU.S. Environmental Protection Agency

Hillel S. Koren, Ph.D.Acting DirectorHuman Studies DivisionHealth Effects Research LaboratoryU.S. Environmental Protection Agency

Martin LandryBudget AnalystFinancial Management OfficeNational Institute for Occupational Safety

and Health

John L. Mason, Ph.D.Vice PresidentEngineering and TechnologyAllied Signal Aerospace Co. (Ret.)

Barbara Packard, M. D., Ph.D.Associate Director for Scientific

Program OperationsNational Heart, Lung, and Blood Institute

Jerry PhelpsProgram AnalystOffice of Program Planning and EvaluationOffice of DirectorNational Institute of Environmental Health Sciences

William A. Pryor, Ph.D.DirectorBiodynamics InstituteLouisiana State University

Victor L. Roggli, M.D.Associate Professor of PathologyDepartment of PathologyDuke University Medical Center

Robert Roth, Ph.D.ProfessorDepartment of Pharmacology and ToxicologyMichigan State University

Jonathan M. Samet, M.D.Professor of MedicineMedical CenterUniversity of New Mexico

Anne P. Sassaman, Ph.D.DirectorDivision of Extramural Research and TrainingNational Institute of Environmental Health Sciences

David A. Schwartz, M. D., M.P.H.Director, Occupational MedicinePulmonary Disease DivisionDepartment of Internal MedicineUniversity of Iowa

Joel Schwartz, Ph.D.U.S. Environmental Protection Agency

Andrew Sivak, Ph.D.PresidentHealth Effects Institute

Frank E. Speizer, M.D.Professor of Medicine and Environmental ScienceSchool of Public HealthHarvard University

Jaro J. Vestal, M. D., Ph.D.Environmental Activities StaffGeneral Motors Corp.

David B. Warheit, Ph.D.Haskell Laboratory for Toxicology

and Industrial MedicineI.E. Du Pont De Nemours and Co.

Jane Warren, Ph.D.Research Committee DirectorHealth Effects Institute

vi

OTA Project Staff-Identifying and Controlling Pulmonary Toxicants

Roger C. Herdman, Assistant Director, OTAHealth 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 staffCecile Parker, Office Administrator

vii

Contents

Chapter l: Introduction and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Chapter 2: The Respiratory System and Its Response to Harmful Substances . . . . . . . . . . . . . . . . . 15Chapter 3: Pulmonary Toxicology and Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Chapter 4: Federal Attention to Pulmonary Toxicants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

BoxesBoxes3-A—General Principles of Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303-B—The UCLA Population Studies of Chronic Obstructive Respiratory Disease . . . . . . . . . . . . . . 42

FiguresFiguresl-l—The Human Respiratory Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52-l—The Human Respiratory Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152-2—Branching of the Tracheobronchial Region (Human Lung Cast) . . . . . . . . . . . . . . . . . . . . . 162-3—Alveoli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162-4—Gas Exchange in the Pulmonary Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172-5—Ciliated Cells and Alveolar Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182-6—Effects of Emphysema on Alveolar Walls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203-l—Framework for Exposure Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323-2—Integrated Approach to Identifying Pulmonary Toxicants . . . . . . . . . . . . . . . . . . . . . . . . . . 353-3--Spectrum of Biological Response to Pollutant Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . 36

TablesTablesl-l—The Seventeen Chemicals of the 33/50 Program, 1989 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72-l—Respiratory Tract Clearance Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192-2—Causes of Occupational Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212-3—Industrial Toxicants Producing Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233-l—Defining Gases and Aerosols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333-2-Summary of Characteristics of Physiologic Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404-l—National Primary Ambient Air Quality Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504-2—Hazardous Air Pollutants Regulated Under the CAA Due to NonCancer Health Effects

on the Pulmonary System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524-3—Pulmonary Toxicants Controlled Under EPA’s Early Reduction and 33/50 Programs . . . . . . . . . 544-4—Regulated Levels of Pulmonary Toxicants Under RCRA . . . . . . . . . . . . . . . . . . . . . . . . . . 554-5—Pulmonary Toxicants Regulated Under FIFRA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 554-6—Air Contaminants Regulated by OSHA Because of Pulmonary Effects . . . . . . . . . . . . . . . . . . 56

. . .Vlll

Chapter 1

Introduction and Summary

Chapter 1

Introduction and SummaryINTRODUCTION

Breathing sustains life. Each day an individual in-hales between 10,000 and 20,000 liters of air. In thelungs, air releases oxygen to the bloodstream and picksup carbon dioxide and other waste products, which arethen exhaled. Inhaled air contains many substances—naturally occurring and anthropogenic--other thanoxygen. Some of these substances can injure the lungsand impede their function.

The potential for chemicals and materials used inindustry, transportation, and households to be simul-taneously beneficial and toxic to human life creates alegislative and regulatory dilemma. The challenge ofbalancing a strong economy, one that delivers productspeople need and desire, with the health and safety ofthe populace sometimes seems to be a tremendousburden.

Technological advances add to the weight of thatburden. Thousands of new, potentially toxic substancesenter the market annually. Advanced instruments helpscientists measure the presence of new and existingsubstances in minute quantities. Substances formerlyunknown or undetected suddenly become worrisomeas technology provides the means to predict humanrisks from these substances.

Governmental concern that a substance might cre-ate an adverse health effect historically focused oncarcinogenicity. Most Federal legislative and regula-tory efforts to prevent or minimize human exposure totoxic substances have focused on identifying and con-trolling carcinogens. Physicians and researchers nowrecognize the noncancer, toxic effects of many sub-stances. Some of these effects, for instance teratogenic-ity, have become the subject of specific legislativeconcern. Federal regulatory attention to other types oftoxic injury (e.g., to the respiratory system, the immunesystem, the nervous system) depends on the more gen-eral mandate to protect human health. Some observersfear that historical emphasis on carcinogenicity, com-

bined with limited agency resources, has led to neglectof noncancer health risks-risks that may be as wide-spread and severe as carcinogenicity.

The Senate Committee on Environment and PublicWorks, and its Subcommittee on Toxic Substances,Environmental Oversight, Research and Develop-ment, asked for assistance from the Office of Technol-ogy Assessment (OTA) in evaluating technologies toidentify and control noncancer health risks in the en-vironment. The committee’s interests include advancesin toxicology, research and testing programs in Federalagencies, and the consequences of exposure to toxicsubstances. OTA has published studies on neurotoxic-ity and immunotoxicity (18,19).

In further response to the committee’s request, thisbackground paper describes the state-of-the-art ofidentifying substances that can harm human lungswhen inhaled. Chapter 2 provides a primer on humanlung structure and function and describes lung diseasesthat have been associated with inhalation of toxic sub-stances. Chapter 3 examines the technologies andmethodologies used in laboratory, clinical, and epide-miologic studies to identify substances as toxic to thelung. Chapter 4 summarizes Federal research effortsand regulations designed to reduce human exposuresto these substances.

SCOPE

This study assesses whether regulators using avail-able toxicologic and epidemiologic investigative meth-ods can obtain health effects data sufficient to identifyairborne substances as pulmonary toxicants—sub-stances toxic to the lung—when encountered at envi-ronmentally relevant exposure levels. Several termswithin this description of the scope of work requiredefinition to delineate the boundaries of OTA’s in-quiry.

Regulators—Regulators are the agencies, and theiremployees, with responsibility, under various environ-

4 . Identifying and Controlling Pulmonary Toxicants

mental statutes, for setting standards to control humanexposure to toxic substances. This study examines onlyFederal regulatory programs, but many States haveenvironmental legislation and regulatory agendas thatrequire the types of technologies and data discussed inthis background paper.

Available toxicologic and epidemiologic investiga-tive methods-This background paper reports on thetechnologies and methodologies applied in laboratorystudies, human clinical studies, and field studies ofhuman exposure (epidemiology) to determine whethersubstances exert toxic effects. As used in this study, theterm laboratory studies comprises in vitro tests on cells,tissues, and fluids removed from animals and humansand in vivo tests on whole animals. The term humanclinical studies refers to studies of the effects on hu-mans of carefully controlled but purposeful exposuresto potentially toxic substances; exposure to the sus-pected toxicant occurs in a clinical setting, hence theterm. Epidemiologic studies are those in which inves-tigators examine the effects on humans of exposures tosuspected toxicants that occur without the interventionof the investigator and in a nonclinical setting, e.g., athome, in the workplace, at school, in the outdoors.

Airborne substances—Combustion, industrialprocesses, and other human activities can create inhal-able gases and particles that may be toxic to the lungs.Technologies that enable assessment of the health ef-fects of inhaled substances are the focus of this back-ground paper. Substances taken orally (e.g., certaindrugs) or absorbed through the skin (e.g., the pesticideparaquat) can be toxic to the human lung; some of thetechnologies discussed in this background paper couldbe used to identify their effects. However, this studylimits itself to an examination of the technologies spe-cifically applicable to investigation of the effects ofairborne substances on the lung and the regulatoryprograms designed to control human exposure to suchsubstances. The background paper discusses some bio-logic substances, e.g., organic dusts, but excludes con-sideration of infectious agents.

Environmentally relevant exposure levels—OTAdefines “environmentally relevant exposure levels” asthose that can reasonably be anticipated (under non-catastrophic circumstances) to occur in outdoor, resi-dential, educational, commercial, and occupationalenvironments in various regions of the United States.

This background paper describes a wide range oftechnologies that measure the biological effects of ex-posure to toxic substances-from technologies thatidentify minute changes in the cellular structure of thelung to technologies useful in the diagnosis of disease.Regulators use these technologies, singly or in combi-nation, to determine not only whether a given dose ofa suspected toxicant creates a measurable, biologicaleffect but whether the measurable effect is itself ad-verse to respiratory health or correlates with develop-ment of an adverse condition. A definition for adverseremains a topic of considerable debate.

For example, scientists have developed several teststo detect decreases in lung function that result fromexposure to toxic substances. While they agree on thetechnical capabilities of the tests, they disagree on thelevel of decreased function that should be deemedadverse for regulatory purposes. Using other tests, sci-entists are able to detect changes in the number ofcertain types of cells found in the lung following rela-tively low-level exposures to toxic substances. Givenenough time and resources, scientists will be able todetermine whether such changes reverse themselves,stabilize, or grow harmful under various types of expo-sure conditions. They will also learn whether thosecellular changes actually impair lung function. Untilthose data are collected, however, regulators have in-sufficient evidence to deem the measurable effect ad-verse.

In this background paper, OTA describes the cur-rent technologies that measure the biological effects inthe lung of toxic substances. The study also reports onFederal efforts to improve the technologies and regu-late human exposures to substances deemed adverse.OTA makes no independent judgment concerning anappropriate definition of adverse effects or on theadequacy of current regulatory standards.

SUMMARY

This background paper distills some of the informa-tion available about the basic and applied sciences thatenable the identification and control of pulmonarytoxicants. More detailed reviews of lung structure andfunction, lung diseases, pulmonary toxicology, and epi-demiology can be found in numerous sources(1,2,5,10,11,12). The following sections summarizemuch 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 regionsof the human respiratory tract (figure l-l). Air entersthe body through the nose and mouth and passesthrough the nasopharyngeal region, where it is warmedand humidified. Air moves next through the tracheo-bronchial region (where the lung begins), which actsbasically as a conducting passage. Finally air reachesthe pulmonary, or gas exchange, region of the lung,where oxygen in the air is supplied to the blood, whichdelivers it to cells throughout the body. In turn, theblood releases a major waste product, carbon dioxide(CO2), and other gaseous components and metabolitesto air remaining in the lung, which is exhaled. Thepulmonary region has a tremendous surface area—inadults about the size of a single’s tennis court-whichpermits efficient gas exchange (oxygen for CO2).

The respiratory system is equipped with defensemechanisms. The nasopharyngeal region can filterlarge particles and absorb gases with high water solu-bility before they reach the lung. Cells that line thetracheobronchial region secrete mucus that traps in-haled particles and reactive gases, and other cells sweepthe mucus up and out of the respiratory system to thedigestive system. Certain cells that reside in the pulmo-nary region can ingest and destroy particles that pene-

Figure l-l—The Human Respiratory Tract

Larynx, vocal co

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Pulmonaryarteries

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SOURCE: Office of Technology Asessment, 1992.

trate to that region. Some toxic substances can bypassor overwhelm these defense mechanisms, resulting inlung injury or disease.

Lung Injury and Disease

Lung function suffers when resistance to airflow inthe conducting airways (tracheobronchial region) in-creases or when a loss of healthy surface area in thepulmonary region prevents transfer of sufficientamounts of oxygen to the blood. Many agents—man-made and natural, physical and biological-can causethese basic problems, which are characteristic of sev-eral forms of disabling lung diseases (e.g., asthma, fi-brosis, emphysema). Because of the limited types ofpulmonary responses and the large number of agentsto which individuals are exposed, the association ofindividual agents with specific responses has been dif-ficult. Careful observation and experimentation overthe years, however, has led to conclusions about thepotential of certain toxicants to cause or exacerbatelung diseases.

Several outdoor air pollutants, e.g., sulfur dioxide,increase the breathing difficulties of high-risk groups(e.g., asthmatics). Tobacco smoke causes cancer (be-yond the scope of this report), chronic bronchitis, andemphysema, and contributes to an increased incidenceof respiratory disease in children of smoking parents,which may lead to chronic lung problems as they age.Occupational exposure to inhaled chemicals and fibershas yielded some of the strongest evidence linking toxicsubstances to lung disease.

Many tools for studying the toxicity of airbornesubstances have been developed in recent years, but thenumber of toxicants to be assessed and the amount ofdata required to substantiate their toxicity present achallenging task to toxicologists, epidemiologists, andregulators. Studies are under way to determinewhether persistent human lung problems are corre-lated with exposures to many of the gases and particlesencountered in everyday life.

Pulmonary Toxicology and Epidemiology

Investigators use three, complementary lines of re-search to assess the effects on the lung of inhaledpollutants: laboratory studies, including in vitro testsand tests in whole animals, human clinical studies, andepidemiology. Each type of study has strengths andweaknesses. In in vitro tests, scientists examine the

6 = Identifying and Controlling Pulmonary Toxicants

structure or functional capability of tissues and cells todetermine the effects of toxic exposures. These studiesare informative but may not give a complete picture ofa toxicant’s effects. In in vivo studies, scientists useanimals whose respiratory systems resemble the hu-man system and attempt to mimic expected humanexposure conditions as closely as possible. Such studiesare useful but are limited by the difficulty in extrapo-lating results from animals to humans. Clinical studiesallow careful control of exposure conditions and pro-vide human data. However, they are restricted to rela-tively brief exposures that will create no lasting injuryand, like most animal studies, are limited to exposuresto one or two substances at a time rather than thecomplex mixtures actually encountered in the environ-ment. Epidemiologic studies analyze the effects cre-ated by toxicants under actual exposure conditions butare limited by imprecise measurements of exposure tothe toxicant under study and by confounding factorssuch as smoking, preexisting disease, and unknowneffects of other exposures.

Whether involving animals or humans, studies em-ploy functional, structural, or biochemical methods ofinvestigation. Functional assays measure the mechan-ics of breathing, decreases or increases in gas-exchangecapacity, and the ability of the lungs to rid themselvesof foreign particles, among other things. Structuralstudies employ the traditional techniques of pathologyto gather substantial information about pulmonarytoxicity. Prepared slices of excised lungs can be exam-ined with microscopes for evidence of alterations instructure. Various regions of the excised lung can beexamined for the presence of particles. Cells can beexamined for injury. Advances in cellular biology inrecent years contributed to some of the most importantnew methods of pulmonary toxicology. Toxicologistsusing biochemical methods can now study the cellularinteractions and biochemical mechanisms of the lungusing fluids recovered from lungs. In addition to bio-logical tests on an exposed population, epidemiologistscan use various databases, including mortality andmorbidity statistics, hospital admissions records, anddiaries of respiratory symptoms, to correlate exposureto toxicants with lung injury and disease.

In the laboratory and clinic, investigators can con-trol the amount of the substance under study deliveredto the test subject and can exclude all other exposures.The technologies used produce precise measurementsof exposure but cannot reproduce the actual exposureconditions people encounter in their daily lives. Epide-miologists cannot control the dose of a toxicant re-

ceived by their study subjects, but advances in station-ary and personal exposure monitoring technologieshave improved the accuracy of exposure measurementsin epidemiologic studies. All scientists studying theeffects of pulmonary toxicants must consider the factthat exposure— the amount of a toxicant found in theinhalable air—frequently differs from biologically effec-tive dose—the amount of toxicant actually retained inthe lung for sufficient time to cause problems. Differ-ences in human and animal lungs have a major impacton biologically effective dose and create many of thedifficulties in extrapolating test results from animals tohumans.

Integrated use of laboratory, clinical, and epidemi-ologic techniques often produces the best results. Forinstance, increased respiratory symptoms in a workingpopulation exposed to chemical fumes might suggestthe need for laboratory studies of the chemical’s healtheffects. Following the laboratory experiments, clinicalstudies might be performed to obtain more accuratedata about harmful and harmless levels of short-termexposure in humans. Once a permissible exposure levelis established for the workplace, workers could bemonitored, in an epidemiologic study, to determinewhether long-term exposures created effects that didnot show up in the short-term studies. Pulmonary toxi-cologists, clinicians, and epidemiologists share the ob-jective of identifying the health effects of airbornesubstances to which humans are or will likely be ex-posed.

AIR QUALITY

Air comprises those gases that form the atmos-phere of the earth. At altitudes below 80 kilometersmolecular nitrogen and oxygen dominate the mix.When water vapor is removed from the air, nitrogenand oxygen constitute 78 and 21 percent (by volume)of the air, respectively. The remaining 1 percent of thisdry air consists principally of argon, but CO2 and smallquantities of neon, helium, krypton, xenon, hydrogen,methane and nitrous oxide are also found as constantcomponents of air.

Human activities (agriculture, industry, transporta-tion) contribute additional, variable components—pollutants—to the mix of gases called air. Level ofindustrialization creates most of the global variabilityin air pollution. For instance, wood (and otherbiomass) smoke may be the most common pollutant innonindustrialized countries, while fossil fuel combus-tion byproducts (e.g., sulfur oxides, nitrogen oxides,

Chapter 1—Introduction and Summary ● 7

particulate matter) constitute the major air pollutantsin heavily industrialized countries. Regional differ-ences in pollutants depend on population, activity mix,geography, and climatic conditions. Within a commu-nity, air quality may differ significantly upwind anddownwind of, for instance, a power plant. Family mem-bers may experience quite different pollutant exposureconditions depending on how much time they spend atwork, school, or home.

In the United States, fossil fuel combustion contrib-utes to both major types of outdoor air pollution—chemically reducing pollution and chemicallyoxidizing, or photochemical, pollution. Reducing typepollution is characterized by sulfur dioxide and fossilfuel smoke and by conditions of fog and cool tempera-tures. This type of pollution occurs mainly in the east-ern part of the country, primarily in the Mid-Atlanticand Northeastern States. Oxidizing type pollution ischaracterized by hydrocarbons, oxides of nitrogen, and

photochemical oxidants and results from the action ofsunlight on polluted air masses. This pollution prob-lem, infamous in several western U.S. cities (e.g., LosAngeles), now strikes the northeast and southeast inthe summer months as well. Other types of pollutantspose seasonal problems, for instance woodsmoke incertain cities during the winter months. Toxic pollut-ants emitted from industrial sites or from hazardouswaste sites can present highly localized air quality prob-lems (see table l-l). Outdoor air pollution is regulatedunder the Clean Air Act and other environmentalstatutes.

Some occupations involve significant potential forexposure to airborne toxicants. These types of expo-sures generally are regulated under the OccupationalSafety and Health Act and the Federal Mine Safety andHealth Act. Health and safety regulations have re-duced many of the acute exposure problems experi-enced 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 compoundsMercury and compounds*Nickel and compounds*Benzene*Methyl ethyl ketone*Methyl isobutyl ketoneTolueneXylenes (mixed isomers)*Carbon tetrachlorideChloroform (Trichloromethane)Methylchloride (Dichloromethane)*Tetrachloroethylene (Perchloroethylene)*1, 1, l-Trichloroethane (Methyl chloroform)*Trichloroethylene*Cyanides

1,147,78364,284,38254,371,117

216,43322,342,31128,591,407

156,992,64238,849,703

322,521,176185,442,035

4,607,80927,325,508

130,355,58130,058,581

185,026,19148,976,80611,976,370

119,8412,238,4732,449,799

29,2391,128,788

24,683,026127,631,83530,682,832

255,437,878147,486,804

3,367,24824,268,093

109,272,00325,504,477

168,617,91044,325,687

a

Primary metalsChemicalsPrimary metalsChemicalsPrimary metalsPrimary metalsPlasticsChemicalsChemicalsTransportChemicalsPaperChemicalsTransportTransportFabricated metalsChemicals

*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 emis-

sions is vehicle exhaust, which accounts for over 90 percent of this total. This type of emission is not reported under the EPA’sToxic Release Inventory National Report.

SOURCE: U.S. Environmental Protection Agency, Office of Toxic Substances, Economics and Twhnology Division, Toxics in theCommunity: 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 persistentproblems that might be associated with long-term, low-level exposures.

Most people spend most of their time indoors-athome, at school, or in the office. The primary indoorair pollutants are tobacco smoke, nitrogen dioxide,carbon monoxide, woodsmoke, biological agents (e.g.,molds, animal dander), formaldehyde, various volatileorganic compounds, and radon. Indoor pollutants maybe generated by personal activities, such as cigarettesmoking, or by things outside an individual’s control,such as the geological formation on which a housesits,the source of radon. Indoor, airborne toxicants areimportant sources of individual exposure to toxicantsthat may appear in the outdoor air as well (e.g., nitro-gen dioxide) and should be considered in health effectsassessments. Outside of certain occupational settings,exposures to indoor, airborne toxicants remain largelyunregulated.

Airborne gases and particles emanate from multi-ple indoor and outdoor sources, and individuals expe-

rience multiple exposures to airborne toxicants as theygo about their lives. The mix of substances individualsinhale and the variety of circumstances under whichthey do it makes it very hard for scientists and policy-makers to sort out the effects of specific substances.Some individuals are more susceptible than others tothe effects of airborne toxicants, which makes it diffi-cult for regulators to determine acceptable levels ofexposure once the effects of specific substances havebeen determined. The technologies of air quality meas-urement, exposure assessment, and toxicological test-ing contribute to better risk assessment and betterpolicymaking, but currently leave many uncertaintiesin their wake.

CONCLUSIONS

Scientists and regulators have a high degree of con-fidence in existing laboratory, clinical, and epidemi-ologic methods for studying the adverse effects of acute(short-term, high-level) exposures to existing chemi-cals 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.


animal studies using controlled exposure conditionsand then couple those test results with information(when available) about the real-life experience of ex-posed humans. This method enables relatively clearassociation between exposure to a specific substanceand specific health effects, though evidence can still beequivocal. Analysis of the effects of chronic exposureis under way for many substances and data can readilybe acquired from animal studies (given time and re-sources). However, credible human data on the effectsof chronic exposure are more difficult to obtain be-cause of extraneous factors that can affect study results(e.g., difficulties in determining the effects of previousexposures; opportunities for exposure to multiple sub-stances). Where substances are regulated because oftheir pulmonary toxicity, the regulations are primarilybased on health effects observed following acute expo-sures.

A synopsis of the attempt to set a standard forozone that prevents adverse health effects illuminatesthe power and limitations of current technologieswithin the current regulatory framework for protectionof public health. Ozone is produced when its precur-sors, volatile organic compounds (VOC’s) and nitro-gen oxides (NOx), combine in the presence of sunlight.Current EPA regulations require States to maintainozone concentrations in the air below 0.12 ppm. Areaswhere ozone in the ambient air exceeds a peak l-houraverage concentration of 0.12 ppm more than 1 day peryear (averaged over 3 years) are labeled nonattainmentareas and are subject to legal sanctions (17).

EPA adopted the current standard for ozone expo-sure on the basis of evidence of the health effects ofshort-term exposures slightly above that level. At thetime the standard was set, scientists agreed that short-term exposures to ozone caused reductions in lungfunction and increases in respiratory symptoms, airwayreactivity, permeability, and inflammation in the gen-eral population. Asthmatics were known to suffer ad-ditional effects, including increased rates ofmedication usage and restricted activities (9).

The database on ozone’s health effects has contin-ued to grow since EPA set the standard for exposure in1979. Data from human clinical studies now show thatlung function decreases during exposure to 0.12 ppm(the current regulatory standard) and continues to de-crease during constant exposures of 6 hours or more(4,6). Biochemical studies on lung fluids removed fromindividuals who were exercising during exposure to

ozone above, at, and below the current regulatorystandard showed lung inflammation (8,9).

The acute effects of exposure to ozone have alsobeen the subject of epidemiologic studies. Lung func-tion in children engaged in outdoor recreation activi-ties decreased during exposure to ozone, and outdoorexposure caused a greater decrease than clinical expo-sure at the same concentration of ozone, indicatingthat other substances in the outdoor air potentiated theresponse to ozone (15,16). School children showedsimilar responses in another study (7).

Researchers have begun to study the effects ofchronic exposure to ozone in various populations. Astudy of residents in the Los Angeles area showed thatchronic exposure to oxidant pollution affects baselinelung function (3). Another study from the Los Angelesarea, this time on the autopsied lungs of young accidentvictims, showed structural abnormalities in the lungsthat were not expected in individuals of that age range(13). An analysis of pulmonary function data collectedin a national survey showed a clear association betweenreduced lung function and annual average ozone con-centrations in excess of 0.04 ppm ( 14). Based on epide-miologic research findings, a growing number ofscientists believes that chronic exposure to ozone maycause premature aging of the lung, and they find sup-port for this opinion in recent studies on rats andmonkeys (9).

Scientists disagree on the health significance of thedecreased lung function measured in the human clini-cal studies (9). EPA’s Clean Air Science AdvisoryCommittee (CASAC) split when asked to reach clo-sure concerning a scientifically supportable upperbound for a l-hour ozone standard, with half the mem-bers accepting the current standard and half recom-mending a reduction in permissible exposure levels(20). CASAC noted that “resolution of the adversehealth effect issue represents a blending of scientificand policy judgments.” Little information on the hu-man health effects of chronic ozone exposures has beenavailable to regulators or their advisors, and scientistscontinue to urge that results from such studies beassessed cautiously. Despite strong evidence thatozone is harmful to human health at currently allow-able exposure concentrations (9,21), EPA has not pro-posed a revision of the ozone standard.

Regulators face greater difficulties when develop-ing supportable exposure standards for substances with

10 ● Identifying and Controlling Pulmonary Toxicants

smaller health effects databases or with databases lim-ited to results of laboratory studies (as with new sub-stances). The difficulties lie in the technologiesthemselves (e.g., remaining uncertainties regarding ex-trapolating results from animals to humans) and inbalancing competing interests (e.g., dependence onautomobiles versus air pollutants’ harmful effects).

None of the technologies currently in use or underdevelopment for assessing pulmonary toxicity prom-ises to be a near term alternative to extensive (costly)studies involving animals and humans. Scientists study-ing the behavior of gases and particles in the lungs ofvarious animal species and humans hold out hope forcontinued improvements in techniques for extrapola-tion from animal studies to humans. Researchers in-vestigating the mechanisms of disease believe whatthey discover may enable extrapolation from study re-sults on existing chemicals to the likely effects of newsubstances with similar physical properties. At present,however, there is no scientific agreement that the ef-fects measured by new toxicologic methods are ad-verse-distinctly and permanently harmful—insteadof changes that may evince the recuperative propertiesof the lung. Therefore regulators can only continue tobalance the costs and benefits of different regulatorylevels rather than choose a regulatory level for pulmo-nary toxicants that will clearly avoid adverse humanhealth effects.

1.

2.

3.

4.

CHAPTER 1 REFERENCES

Amdur, M. O., Doull, J., and Klaassen, C.D.(eds.), Casarett and Doull’s Toxicology: The BasicScience ofPoisons, 4th ed. (Elms ford, NY: Perga-mon Press, 1991).Crystal, R. G., and West, J.B. (eds.), The Lung:Scientific Foundations (New York, NY: RavenPress, 1991).Detels, R., Tashkin, D. P., Sayre, J. W., et al., “TheUCLA Population Studies of Chronic Obstruc-tive Respiratory Disease. 9. Lung FunctionChanges Associated With Chronic Exposure toPhotochemical Oxidants: A Cohort StudyAmong Never-Smokers,” Chest 92(4):594-603,October 1987.Folinsbee, L.J., McDonnell, W. F., and Horst-man, D. H., “Pulmonary Function and SymptomResponses After 6.6 Hour Exposure to 0.12 ppmOzone With Moderate Exercise,” Journal of theAir Pollution Control Association 38:28-35, Janu-ary 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 ResponseRelationships for 6.6-Hour Exposures With FiveHours of Moderate Exercise to 0.08, 0.10, and0.12 ppm,” Am&an l?evkw of Rap&ztoy Dkease142(5):1158-1163, November 1990.Kinney, P.L., Ware, J. H., and Spengler, J. D., “ACritical Evaluation of Acute Ozone Epidemiol-ogy Results; Archives of Environmental Health43(2):168-73, March/April 1988.Koren, H. S., Devlin, R. B., Graham, D. E., et al.,“Ozone-Induced Inflammation in the Lower Air-ways of Human Subjects,” American Review ofRespiratory Disease 139:407-415, 1989.Lippmann, M., “Health Effects of TroposphericOzone,” Environmental Science and Technology25(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 theEpidemiology of Air Pollutants, Epiiiemiologyand Air Pollution (Washington, DC: NationalAcademy Press, 1985).National Research Council, Subcommittee onPulmonary Toxicology, Biologic Markers in Pu/-monary Toxicology (Washington, DC: NationalAcademy Press, 1989).Sherwin, R. P., and Richters, V., “CentriacinarRegion (CAR) Disease in the Lungs of YoungAdults: A Preliminary Report,” in TroposphericOzone and the Environment (Pittsburgh, PA: Airand Waste Management Association, 1991.)Schwartz, J., ‘Lung Function and Chronic Expo-sure to Air Pollution: A Cross-Sectional Analysisof NHANES II, ” Environment! Research50(2):309-321, December 1989.Spektor, D.M., Lippmann, M., Lioy, P.J., et al.,“Effects of Ambient Ozone on Respiratory Func-tion in Active, Normal Children” American Re-view of Respiratory Disease 137:313-320, 1988.Spektor, D. M., Thurston, G. D., Mao, J., et al.,“Effects of Single-and Multiday Ozone Exposureon Respiratory Function in Active Normal Chil-dren,” Environmental Research 55(2):107-122,August 1991.U.S. Congress, Office of Technology Assessment,Catching Our Breath: Next Steps for Reducing Ur-ban Ozone, OTA-O-412 (Washington, DC: U.S.Government Printing Office, July 1989).


18. U.S. Congress, Office of Technolo~Assessment,Neurotoxicity: Identifying and Controlling Poisonsof the Nervous System, OTA-BA-436 (Washing-ton, DC: U.S. Government Printing Office, April1990).

19. U.S. Congress, Office of Technolog Assessment,Identifying and Controlling Immunotoxic Sub-stances—Background Paper, OTA- BP- BA-75(Washington, DC: U.S. Government Printing Of-fice, April 1991).

20. U.S. Environmental Protection Agency, CleanAir Scientific Advisory Committee, Review of the,NMQS for Ozone, EPA-SAB-CASAC-89-1092(Washington, DC: U.S. Environmental Protec-tion Agenq, 1989).

21. Van Bree, L., Lioy, P.J., Rombout, P.J., et al., “AMore Stringent and Longer-Term Standard forTropospheric Ozone: Emerging New Data onHealth Effects and Potential Exposure,” Toxicol-ogy and Applied Pharmacology 103(3):377-382,May 1990.

Chapter 2

The Respiratory System and Its Response toHarmful Substances

Chapter 2

The Respiratory System and Its Response ToHarmful Substances

INTRODUCTION

People can live for days without food or water, butif they stop breathing, they die within minutes. Theapparatus of breathing—the respiratory system—sup-plies a critical component of life, oxygen, and disposesof a major waste product, carbon dioxide. To supplythe amount of oxygen required for survival, the respi-ratory system must be capable of handling between10,000 and 20,000 liters of air per day.

The air that enters the respiratory system containsmany substances other than oxygen, including naturalconstituents (e.g., nitrogen) and human contributions(e.g., fossil fuel combustion byproducts). Various de-fense mechanisms of the respiratory system eliminatethe unnatural components of air from the body andrepair any damage they do. But exposure to largeamounts of toxic substances or chronic exposure tolower levels can overwhelm the ability of the respira-tory system to protect and repair itself, sometimesresulting in impaired lung function.

This chapter describes the structure and function ofthe respiratory system and some of the ways the respi-ratory system protects itself against harmful sub-stances. It then briefly describes major diseasesassociated with exposure to toxic substances. Thischapter does not cover the effects of exposure to radia-tion or infectious agents, nor does it describe lungcancer. More detailed descriptions of the respiratorysystem and respiratory diseases are presented else-where (7,13,26,28,29).

STRUCTURE AND FUNCTION OF THERESPIRATORY SYSTEM

Air enters the body through the nose and mouthand moves through the major airways to deeper por-tions of the lungs (figure 2-l). There oxygen can passacross thin membranes to the bloodstream. Each re-gion of the respiratory system is made of specializedcells that work together to transport air, keep the lungclean, 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

Pulmonaryveins {t

Alveoli $?J

Lung ISOURCE: Office of Technology Assessment, 1992.

and provide a thin, large surface for the exchange ofoxygen and carbon dioxide.

Upper Respiratory Tract

The upper airways begin at the nose and mouth andextend through the pharynx to the larynx. Thisnasophoryngeal region is lined with ciliated cells andmucous membranes that warm and humidify the airand remove some particles. Gases that are very watersoluble are also absorbed readily by the mucus in thispart of the respiratory tract, protecting the more deli-cate tissues deeper in the respiratory tract from theeffects of exposure to such gases.

The Tracheobronchial Tree

After passing through the larynx, air flows throughthe trachea, or windpipe. The trachea divides into two

15

1 6 Identifying and Controlling Pulmonary Toxicants

bronchi which carry air into the two lungs. The bronchisubdivide repeatedly into smaller and smaller bronchiand then into bronchioles, which also successively di-vide and narrow (figure 2-2). The smallest bronchioles,found at the end of the tracheobronchial region, areless than a millimeter in diameter.

The Pulmonary Region

In the pulmonary region, the bronchioles divideinto alveolar ducts and alveolar sacs. Budding from thewalls of these last portions of the airways are tiny,cup-like chambers called alveoli (figure 2-3). The alve-oli 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 adense network of fine blood vessels, or capillaries. Gasexchange occurs when oxygen diffuses from the spaceinside an alveolus through its lining fluid, past thealveolar membrane and its supporting membrane,

Figure 2-2—Branching of the TracheobronchialRegion (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 capil-lary (“the interstitial space”), and finally across themembranes of the capillary. Carbon dioxide diffuses inthe opposite direction, from the red blood cells in thecapillaries to the space inside the alveolus (figure 2-4).

The adult human lung contains approximately 300million alveoli. Taken together, the alveoli give thehuman lung a huge internal surface, about 70 squaremeters. This large area allows for enough oxygen todiffuse into the blood to supply the body’s needs, but italso exposes a very large, thin-walled area, about thesize of a single tennis court, to toxic substances inhaledin the air.

The Pulmonary Circulation

Oxygen diffuses from the alveoli into the blood inthe capillaries. Red blood cells contain a specializedprotein, hemoglobin, which can reversibly bind mole-cules of oxygen. The heart pumps the blood to the restof the body. Deep within the tissues, the oxygen isreleased to be used by cells in generating energy. As thebody’s cells use oxygen, they produce carbon dioxide.Veins carry blood from body tissues back to the rightside of the heart, which pumps blood to the pulmonarycapillaries to be oxygenated again. Carbon dioxide dif-fuses from the capillaries into the alveoli and is ex-haled.

Chapter 2—The Respirator System and Its Response to Harm/id Substances 17

Figure 2-4--Gas Exchange in the Pulmonary RegionInterstitial space

Epithelialbasementmembrane

Alveolar Iepitheliums ~

\

“’”q

Fluid ands u r f a c t a n t —layer ‘!

AIY

Diffusion A..w..q.qr

Capillary basementmembrane

I ~ Capillary endothelium

L

/JE#w

. .Dif f usiomn:?

‘if” \~“ C a r b o n d~oxide;.

,.

SOURCE: Office of Technology Assessment, 1992.

The Pleural Cavity

The lungs are contained within the chest cavity, butare not attached to the wall of the chest. The pleuralspace that separates the lungs from the chest wallcontains a small amount of fluid and is bounded bymembranes called the pleura. This arrangement allowsthe lungs to move freely in the chest, permitting fullexpansion.

During inhalation, the muscles in the rib cage andthe diaphragm, a dome-shaped muscle beneath thelungs, contract. As the diaphragm contracts, it flattens,increasing the space in the chest. The ribs lift, furtherincreasing the space for the lungs to expand. As thechest expands, the pressure within the lungs falls belowatmospheric pressure, and air is drawn into the lungs,inflating them. As the muscles relax, air is exhaled, andthe lungs deflate. The rate of respiration changes in

response to physical and mental conditions, such assleep, exercise, or changes in altitude.

Cells of the Respiratory System

The respiratory system contains over 40 differenttypes of cells. Each cell type performs function impor-tant for efficient gas exchange.

A continuous sheet of cells forms a membrane,called the epitheliums, lining the airways. Healthy epi-thelium contains few or no gaps, so water, ions, or othersubstances that cross the epitheliums must pass throughcells. The specific permeability properties of the cellscontrol the rate at which substances, such as inhaledpollutants, cross the epitheliums.

Interspersed among the cells that make up the sur-face of the lining of the airways area variety of secretorycells. These secrete mucus which traps dust and otherparticles. Most of the cells of the epitheliums havemicroscopic hair-like structures on their surface calledcilia (figure 2-5). The cilia beat rhythmically, brushingthe mucus and particles trapped in it up to the pharynxwhere they are usually swallowed unnoticed and passout of the body through the digestive system.

Different types of cells make up the lining of thealveoli. The area of the lining consists primarily of TypeI cells, which are very thin and spread over a relativelylarge area. The lining also includes the Type II cells.Type II cells are more numerous, but because of theirmore rounded shape, they make up only about 7 per-cent of the area of the lining of the aveoli. The Type IIcells release proteins and lipids that provide a thin,fluid lining for the inside of the alveoli. The fluidprotects the delicate Type I cells and reduces the sur-face tension in the alveoli, preventing collapse of thealveoli under pressure.

The alveoli also contain macrophages, specializeddefense cells that move freely over the surface of analveolus (figure 2-5). Macrophages ingest foreign par-ticles by a process called phagocytosis. During phago-cytosis, a microphage extends flaps to form amembrane-bound pocket around a foreign body. Themicrophage releases enzymes into the pocket that canbreak down many foreign particles, especially organicmaterials. The breakdown products may be released orabsorbed by the cell. Foreign matter that is not organicoften cannot be broken down and may remain stored


in intracellular compartments. In addition to phagocy-tosis of foreign substances, macrophages also play im-portant roles in immune responses in the lung.

The capillaries that surround the alveoli are alsolined by a continuous sheet of cells, the endothelium.Unlike the lining of the airways, the endothelial liningof the capillaries is slightly leaky, allowing some ex-change of water and solutes between the blood and theinterstitial fluid.

The interstitial space, the small area separatingalveoli from surrounding capillaries, contains cells ofthe immune system. It also contains fibroblasts, cellsthat produce fibers of collagen and elastin that form anelaborate network to provide a mechanical supportsystem for the lung. Collagen fibers are very strong butcannot stretch much; elastin fibers are not as strong butcan be stretched considerably before breaking. Thesecollagen and elastin fibers are slowly but continuallybroken down and renewed.

Chapter 2—The Respiratory System and Its Response to Harmful Substances ● 19

Smooth muscle cells occur as circular sleeves sur-rounding the bronchi and bronchioles. They dilatewhen the body needs large volumes of air, for example,during exercise. When these muscles contract, as onexposure to irritant gases, they make the conductingairways narrower, increasing resistance to air flow.Smooth muscle cells also surround blood vessels thatenter the lung. They control the distribution of bloodflow to specific alveoli and determine how hard theright side of the heart must work to pump bloodthrough the pulmonary blood vessels.

Defense Mechanisms

The respiratory system has elaborate defensemechanisms against damage from exposure to poten-tially hazardous particles and gases (table 2-l). Parti-cles of 1-2 micrometers are the optimal size for reachingthe alveoli. Relatively large particles get trapped innasal hairs and never enter the lower respiratory tract,or they are removed by coughing or sneezing. Some-what smaller particles (down to about 2 micrometers)enter the trachea but land on the airway surfaces andstick to the surface mucus. The finest particles settleless efficiently and are usually exhaled (19).

In the alveoli, some material may dissolve and beabsorbed into the bloodstream or interstitial fluid. Par-ticles that do not dissolve may be phagocytized bymacrophages and the phagocytic cells are either sweptup the tracheobronchial tree on the mucous blanket orthey migrate to the interstitial fluid. Some insolubleparticles may remain sequestered in the lung.

The immune system also plays an important role inprotecting the lungs. A detailed description is beyondthe scope of this background paper, but OTA has

previously addressed immune system responses totoxic substances (23). Briefly, exposure to many sub-stances, particularly those containing protein of animalor vegetable origin, sensitizes cells of the immune sys-tem. The cells respond with a complex variety of reac-tions to destroy or immobilize the inhaled substance.These processes, however, are often accompanied byinflammation of the surrounding tissues, which is partof the repair process necessary to restore normal func-tion. Repeated exposure and inflammation is thoughtto result in serious and permanent tissue damage.

RESPIRATORY RESPONSE TOHARMFUL SUBSTANCES

When defenses are overcome or an agent is particu-larly toxic, the respiratory system can be injured. Dam-age occurs when defense and repair mechanismscannot keep pace with damage wrought by acute expo-sures to relatively large amounts of harmful substancesor by chronic exposures to small amounts of harmfulsubstances. Some damage may result from the repairprocess itself. Some of the most common and bestunderstood conditions are described here, excludingcancer, which is not being considered in this back-ground paper.

Chronic Bronchitis

People with chronic bronchitis have increasednumbers of secretory cells in the bronchial tree. Theyproduce an excess of mucus and have a recurrent orchronic cough, familiar to many as “smoker’s cough.”This excess secretion of mucus may lead to impairmentof normal clearance mechanisms. The normal ciliarymovement cannot cope with this large volume of mu-cus, 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 transportSneezing Coughing Interstitial pathwaysNose 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 Emis-sions, ” 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 andbronchitis than it does in healthy people. This reduced particulate have shown a correlation with increasedclearance makes people with chronic bronchitis more symptoms of chronic bronchitis or mortality due tosusceptible to respirator infections because bacteria chronic bronchitis (13,21,22,27).entering the respiratory tract are not removed effi-ciently. Emphysema

Almost 12 million people in the United States suf- The lung is supported by a network of protein fibersfer from chronic bronchitis (l). The epidemiologic made of collagen and elastin. In people with emphy-evidence linking smoking and chronic bronchitis is sema, some of these fibers are lost and the structuraloverwhelming (10,24). Epidemiologic studies have network is disrupted. The fiber network in the damagedalso shown a correlation between chronic bronchitis area becomes rearranged, resulting in destruction ofand exposure to industrial dust (5,15). In addition, the walls of the alveoli. The air spaces become en-recurrent infections may play a role in the development larged, and part of the surface area available for gasof 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 destructionPhoto 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 lungduring exhalation because its ability to recoil is im-paired.

Nearly 2 million Americans, mostly adults overage45, have emphysema (l). Emphysema usually developsgradually. Impairment progresses steadily and includeslabored breathing and wheezing. It frequently occursalong with chronic bronchitis.

There is a strong correlation between emphysemaand heavy cigarette smoking (2). Industrial exposure tocadmium is also associated with emphysema (8). Somepeople have a genetic predisposition to the develop-ment of emphysema. In particular, people who have aninherited deficiency in the amount of a serum proteincalled alphal-antitrypsin are more likely to developemphysema (14,31), especially if they smoke.

Byssinosis

Textile workers exposed to cotton, hemp, flax, andsisal dusts for several years may develop acute symp-toms, such as chest tightness, wheezing, and cough.After long-term exposure, they may develop chronicsymptoms of respiratory disease indistinguishablefrom chronic bronchitis but called byssinosis. Bron-choconstriction in this disease is not the result of anallergic response. It is apparently caused by a substance(“a histamine releasing agent”) found, for example, incotton seeds that are present as contaminants in rawcotton fiber.

Asthma

Asthma is a chronic disease of the airways in whichsymptoms appear intermittently. In healthy people, thesmooth muscle surrounding the airways responds tostrong environmental stimuli by contracting, increas-

ing the resistance to airflow. Patients with asthma de-velop more intense constriction of the smooth musclein response to milder stimuli than do healthy people.The reasons for this response are unclear. Inflamma-tion is usually present, and is thought to play a key rolein the disease. In addition to bronchial hyper-respon-siveness, people with asthma have intermittent symp-toms of wheezing, chest tightening, or cough.

The disease varies from individual to individual notonly in its severity, but in the types of agents thatprovoke an attack. Some people develop symptoms

Table 2-2-Causes of Occupational Asthma

Complex salts of platinumAmmonium hexachloroplatinate

IsocyanatesToluene di-isocyanate; hexamethylene di-isocyanate;

naphthalene di-isocyanateEpoxy resin curing agents

Phthalic acid anhydride; trimellitic acid anyhydride;triethylene tetramine

Colophony fumesProteolytic enzymes

Bacillus subtilis (alkalase)Laboratory animal urine

Rats, mice, guinea pigs, rabbits, locustsFlour and grain dusts

Barley, oats, rye, wheatFormaldehydeAntibiotics

PenicillinWood 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 (NewYork, NY: Oxford University Press, 1987).

1 Emphysema and chronic bronchitis are two distinct processes. Emphysema, however, can only be diagnosed definitively after death, bydirect examination of lung tissue. Incidence data are derived from postmortem surveys. These surveys show that almost all adult lungs havesome signs of emphysema, although only a minority of adults have symptoms or disability. Clinicians and epidemiologists dealing with theliving use the synonymous terms chronic obstructive pulmonary disease (COPD), chronic obstructive airway disease (COAD), and chronicobstructive lung disease (COLD) to describe patients whose airflow is limited as a result of bronchitis, emphysema, or a combination of thetwo.

2 2 ” Identifying and Controlling Pulmonary Toxicants

only in response to one stimulus. In the United States,for example, many people with asthma develop symp-toms only during the ragweed pollen season in latesummer. Others have clear responses to particular oc-cupational agents (table 2-2). But other patients re-spond to many substances. Even the mechanisms ofthe disease vary among individuals. In some peoplewith asthma, the response seems to occur through animmunologic reaction, but in other people, the im-mune system does not seem to be involved in theresponse. Other mechanisms are the subject of activeresearch. It may be that asthma is a family of diseaseswith similar symptoms but different underlying causesand mechanisms.

In the United States, about 11.5 million peoplehave asthma (l). Children, African-Americans, andinner city residents are affected disproportionately(11). Both the prevalence and the severity of asthma inthe United States have been increasing in recent years(12,30).

Although its causes are not precisely known, over200 substances have been identified that can inducesymptoms (16). In addition, attacks can be provoked byexercise, cold air, airway drying, infections, and emo-tional upsets. Sulfur dioxide, a component of air pollu-tion, causes severe narrowing of asthmatic airways atconcentrations as low as 0.5 parts per million (3,20).Exposure to respirable particles has been associatedwith reduced lung function and increased symptoms inasthmatic children (18), increased hospital visits (17)and increased rates of acute bronchitis, particularly inasthmatic children (9).

Pulmonary Fibrosis

Pulmonary fibrosis is a family of related disorderscharacterized by scar tissue in the lungs. Chronic injuryand inflammation can result in the formation of scartissue in the lung, similar to the process of normalwound-healing. In pulmonary fibrosis, however, thewounding and formation of scar tissue is not a specificevent in a specific location. Rather it can be a chronic,continuing process that involves the entire lung orthere may be scattered, nonuniform scarring. Peoplewith pulmonary fibrosis must work harder to breathe,have poor gas exchange, and often have a dry cough.

The inflammatory response of the lung varies de-pending on the substance causing the injury. In manycases, causative agents are clearly established. Pulmo-nary fibrosis is known to be caused by exposure to highconcentrations of silica, asbestos, and other dusts (ta-ble 2-3).

Extrinsic Allergic Alveolitis

Workers sometimes develop severe immune re-sponses to substances in the workplace, particularly toinhaled plant and animal dusts. The disease is easy torecognize in its acute form because workers themselvesquickly learn to associate the flu-like symptoms withdust exposure. The chronic form, which seems to occurin response to low-level chronic exposures to dustsrather than high-level exposures, is more insidious.The chronic form of the disease usually progresses veryslowly, but can result in pulmonary fibrosis.

Many causative agents have been identified. Mostare molds or fungi contaminating organic material, orthey are proteins found in animal or bird droppings.The best known form is probably farmers’ lung, whichis caused by allergies to Micropolyspora faeni, found inmoldy hay, straw, and grain. There are many otherexamples, however, including bird fanciers’ lung, asso-ciated with proteins found in parakeet and pigeondroppings; dog house disease, associated with a moldfound in straw dog bedding; paprika splitters’ lung,associated with a mold found in paprika; and maplebark strippers’ lung, also associated with a mold.

LUNG DISEASE AND EXPOSURE TOTOXIC SUBSTANCES

The Federal Government, as described further inchapter 4, funds research in pulmonary diseases. Someresearch is aimed at understanding the mechanisms bywhich a particular substance damages the respiratorysystem. Often, this knowledge can provide insight intothe mechanisms by which other toxic substances causedamage. Many toxic substances cause similar reactionsin the respiratory system simply because the respira-tory system has a limited range of responses to insults.Asthmatic attacks, for example, are induced by a widevariety of substances, and, similarly, many substancescause 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, manufac-ture of asbestos-contain-ing material

Aluminum dust Manufacture of alumi-num products, fireworks,ceramics, paints, electri-cal goods, abrasives

Aluminum abrasives Shaver’s disease, corun- Manufacture of abra-dum smelter’s lung, sives, smeltingbauxite lung

Ammonia production,manufacture of fertiliz-ers, chemical production,explosives

Manufacture of pesti-cides, pigments, glassalloys

Ore extraction, manufac-ture of alloys, ceramics

Berylliosis

Cadmium oxide Welding, manufacture ofelectrical equipment, al-loys, pigments, smelting

Carbides of tungsten, Hard metal disease Manufacture of cuttingtitanium, tantalum edges on tools

Chromium (VI)

Coal dust

Cotton dust

Pneumoconiosis

Byssinosis

Chlorine Manufacture of pulp andpaper, plastics, chlori-nated chemicals

Production of Cr com-pounds, paint pigments,reduction of chromite ore

Coal mining

Manufacture of textiles

Hydrogen fluoride Manufacture of chemi-cals, photographic film,solvents, plastics

Fibrosis, pleural calci-fication, lung cancer,pleural mesothelioma

Cough, shortness of Interstitial fibrosisbreath

Alveolar edema Interstitial fibrosis,emphysema

Upper and lower Chronic bronchitisrespiratory tract irritation,edema

Bronchitis Lung cancer, bronchi-tis, laryngitis

Severe pulmonary edema, Fibrosis, progressivepneumonia dyspnea, interstitial

granulomatosis, corpulmonale

Cough, pneumonia Emphysema, cor pul-monale

Hyperplasia and Peribronchical andmetaplasia of bronchial perivascular fibrosisepitheliums

Cough, hemoptysis,dyspnea,tracheobronchitis,bronchopneumoniaNasal irritation, bronchitis Lung cancer fibrosis

Fibrosis

Chest tightness, Reduced pulmonarywheezing, dyspnea function, chronic bron-

chitisRespiratory irritation,hemorrhagic pulmonaryedema


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

Toxicant Common name Occupational source Chronic effect Acute effectof 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, hema-tite mining, jewelry mak-ing

Manufacture of plastics,chemical industry

Pottery making

Chemical and metal

Talcosis

Stanosis

industries

Nickel ore extraction,smelting, electronic elec-troplating, fossil fuels,

Welding, silo filling,explosive manufacture

Welding, bleaching flour,deodorizing

Production of plastics,pesticides, chemicals

Dry cleaning, metaldecreasing, grain fumi-gating

Silicosis, pneumoconioi- Mining, stone cutting,sis construction, farming,

quarrying

Manufacture of chemi-cals, refrigerant ion,bleaching, fumigation

Rubber industry, cosmet-ics

Mining, processing of tin

Cough

Airway irritation, cough,dyspnea

Acute pneumonia, oftenfatal

Pulmonary edema,delayed by 2 days(NiCO)

Pulmonary congestionand edema

Pulmonary edema

Edema

Silver finisher’s: sub-pleural and perivascu-lar aggregations ofmacrophages; hema-tite miner’s: diffusefibrosis-like pneu-monconiosis; arc weld-er’s; bronchitisAsthma, reduced pul-monary function

Fibrosis

Recurrent pneumonia

Squamous cell carci-noma of nasal cavityand lung

Emphysema

Bronchitis

Edema

Fibrosis

Bronchoconstriction,cough, chest tightness

Fibrosis

Widespread mottlingof x-ray without clini-cal signs

Vanadium Steel manufacture Airway irritation and Chronic bronchitismucus production

SOURCE: T. Gordon, and M.O. Amdur ” Responses of the Respiratory System to Toxic Agents, “ Casarett and Doull’s Toxicology.” The Basic Scienceof 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 ef-fects of other substances.

Other research is aimed at identifying which sub-stances cause the development of disease, what levelsof exposure are harmful, and why responses to toxi-cants differ among subgroups of the population (25).Identifying specific causes of respiratory diseases is nosimple matter because different substances can causesimilar kinds of damage, and, conversely, one substancecan cause several kinds of damage. It is easier to estab-lish causal relationships when a defined populationexposed to high levels of a particular substance exhibitscharacteristic symptoms or changes in respiratoryfunction. Dozens of examples among occupationalgroups illustrate how high-level exposures have al-lowed identification of many causes of occupationalasthma, pulmonary fibrosis, and extrinsic allergic alve-olitis (table 2-3).

It is more difficult to determine the effects of sub-stances to which many people are exposed at muchlower levels than the heavy occupational exposures.Five major components of air pollution, carbon mon-oxide, sulfur oxides, hydrocarbons, particulate, andoxidants, are widely distributed in varying concentra-tions throughout the United States. No single, well-de-fined group is exposed to any one of these atexceptionally high levels; instead virtually everyone isexposed at some level. Large proportions of the popu-lation are also exposed to varying concentrations ofcommon indoor air pollutants such as environmentaltobacco smoke; nitrogen oxides (from gas stoves);woodsmoke; allergens of the house dust mite, cats,rodents, and cockroaches; and formaldehyde and othervolatile organic compounds. Sorting out particular ef-fects of each of these substances is quite different fromidentifying the cause of bird fanciers’ lung or maplebark strippers’ lung. The high background level ofrespiratory disease in the population at large alsomakes pinpointing particular causal agents more diffi-cult. The kinds of tests and studies aimed at elucidatingthe relationships between respiratory diseases and ex-posure to indoor and outdoor air pollutants are ex-plored in the next chapter.


1. Adams, P. F., and Benson, V., Current EstimatesFrom the National Health Interview Survey, 1989,National Center for Health Statistics, VitalHealth Stat. 10(176), 1990.

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Auerbach, O., Hammond, E. C., Garfinkel, L., etal., “Relation of Smoking and Age to Emphy-sema: Whole-Lung Section Study,” New EnglandJournal of Medicine 286:853-857, 1972.Balmes, J. R., Fine, J. M., and Sheppard, D.,“Symptomatic Bronchoconstriction After Short-term Inhalation of Sulfur Dioxide, ”American Re-view of Respirato~ Disease 136:1117-1121, 1987.Barker, D.J.P., and Osmond, C., “Childhood Res-piratory Infection and Adult Chronic Bronchitisin England and Wales,” British Medical Journal293:1271-1275, 1986.Becklake, M. R., “Chronic Airflow Limitation: ItsRelationship to Work in Dusty Occupations,”Chest 88:608-17, 1985.Coney, J.R.T., Douglas, J. W. B., and Reid, D.D.,“Respiratory Disease in Young Adults: Influenceof Early Childhood Respiratory Tract Illness, So-cial Class, Air Pollution and Smoking,” BritishMedical Journal 3:195-198, 1973.Crystal, R. G., West, J. B., Barnes, P.J., et al.,(eds.), The Lung: Scientific Foundations (NewYork NY: Raven Press, 1991).Davison, A. G., Newman Taylor, A.J., Derbyshire,J., et al., “Cadmium Fume Inhalation and Emphy-sema,” The Lancet Mar. 26, 1988, pp. 663-667.Dockery, D. W., Speizer, F. E., Strain, D. O., et al.,“Effects of Inhalable Particles on RespiratoryHealth of Children, ’’American Review of Respira-to~ Disease 139(3):587-594, March 1989.Doll, R., and Pete, R., “Mortality in Relation toSmoking: 20 Years’ Observations on Male BritishDoctors,” British Medical Journal 2:1525-1536,1976.Evans, R., Mullally, D. I., Wilson, R. W., et al.,‘National Trends in the Morbidity and Mortalityof Asthma in the U.S.,” Chest 91(suppl. 6):65S-74S, 1987.Gergen, P. J., and Weiss, KB., “Changing Patternsof Asthma Hospitalization Among Children:1979- 1987,” Journal of the American Medical As-sociation 264:1688-1692, 1990.Gordon, T., and Amdur, M.O. “Responses of theRespiratory System to Toxic Agents,” Casarettand Doullk Toxicology: The Basic Science of Poi-sons M.O. Amdur et al. (eds.) (New York, NY:Pergamon Press, 1991).Mittman, C., “Summary of Symposium of Pulmo-nary Emphysema and Proteolysis,” American Re-view of Respiratory Disease 105:430-448, 1972.Morgan, W.KC., ‘Industrial Bronchitis,” BritishJournal of Industrial Medicine 35:285-91, 1978.Newman Taylor, A.J., ‘Occupational Asthma,”Thorax 35:241-245, 1980.


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Pope, C.& III, “Respiratory Hospital Admis-sions Associated With PM1o Pollution in Utah,Salt Lake, and Cache Valleys,” Archives of Envi-ronmentalHealth 46(2):90-97, March/April 1991.Pope, C.A. HI, Dockery, D.W., Spengler, J.D., etal., “Respiratory Health and PM1o Pollution: ADaily Time Series Analysis,” American Review ofRespirato~ Disease 144(3 Pt. 1)668-674, 199LSchlesinger, R.B., “Biological Disposition of Air-borne Particles: Basic Principles and Applicationto Vehicular Emissions,” Air PolZution, the Auto-mobile, and Public Health, A.Y. Watson, et al.(eds.) (Washington, DC: National AcademyPress, 1988).Sheppard, D., Saisho, A., Nadel, J.A., et al., “Ex-ercise Increases Sulfur Dioxide-Induced Bron-choconstriction in Asthmatic Subjects,”American Review of Respiratory Disease 123Y186-491, 1981.Sherrill, D. L., Lebowitz, and Burrows, B., “Epide-miology of Chronic Obstructive Pulmonary Dis-ease,” Clinics in Chest Medicine 11:375-387, 1990.Speizer, F., ‘Studies of Acid Aerosols in Six Citiesand in a New Multi-city Investigation: DesignIssues,” Environmental Health Perspectives 79:61-68, 1989.U.S. Congress, Office of Technology Assessment,Identifying and Controlling Immunotoxic Sub-stances-Background Paper, OTA- BP- BA-75(Washington, DC: U.S. Government Printing Of-fice, April 1991).

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U.S. Department of Health and Human Services,The Health Consequences of Smokz”ng. ChronicObstructive Airways Disease: A Repoti of the Sur-geon General, U.S. Department of Health andHuman Services, Public Health Service, Office onSmoking and Health, 1984.Utell, M.J., and Frank, R. (eds.), Susceptibility toInhaled Pollutants, ASTM STP 1024, (Philadel-phia, PA: American Society for Testing and Ma-terials, 1989).Utell, M.J., and Samet, J. M., “EnvironmentallyMediated 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 War-ren, D.A. (eds.), Oxford Textbook of Medicine(New York, NY: Oxford University Press, 1987).Weibel, E. R., The Pathway for Orygen: Structureand Function in the Mammalian Respiratory Sys-tem (Cambridge, MA: Harvard University Press,1984).Weiss, KB., and Wagener, D.K, “Changing Pat-terns of Asthma Mortality,” Journal of the Ameri-can Medical Association 264:1683-1687, 1990.Welch, M. H., Guenter, C.A., Hammerstein, J.F.,“Precocious Emphysema and alphal-Antitrypsin De-ficiency,” Advances in Internal Medicine 17:379-92, 1971.

Chapter 3

Pulmonary Toxicology and Epidemiology

Chapter 3

Pulmonary Toxicology and EpidemiologyINTRODUCTION

As individuals move from home to work to variousoutdoor environments, they breathe air of divergentcomposition and quality. In addition to the oxygenneeded for survival, people inhale a “soup” of gases andparticles. The ingredients of that soup range from be-nign to lethal in their potential and actual effects onthe human lung.

Obvious health concerns in the outdoor air includeparticulate matter, sulfur oxides, nitrogen oxides,ozone, and carbon monoxide—those pollutants asso-ciated with a heavily industrialized, fossil-fuel basedeconomy. Workplace concerns differ greatly amongoccupations, but typically include organic and inor-ganic dusts and the vapors from various chemicals.Concerns also focus on “indoor” (e.g., home, school,office) air, where substances as ubiquitous as formal-dehyde, tobacco smoke, asbestos, woodsmoke, andmolds stand accused as potential contributors to respi-ratory disease.

Exposure to airborne toxicants varies considerablyamong individuals and among populations. A taxidriver who cooks over a gas stove receives a regulated(vehicle emissions) and unregulated (stove emissions)dose of nitrogen dioxide, while a homemaker in anall-electric home may receive a wholly unregulateddose of formaldehyde (offgassing from furnishings orinsulation). A school-age child of smoking parents maybe exposed to air pollutants subject to legislative con-trols (e.g., asbestos in schools) and uncontrolled pol-lutants (e.g., tobacco smoke in the home) with knownsynergistic effects. Residents downwind of a coal-burn-ing power plant may worry about sulfur dioxide andparticulate matter, while the miners who supply thefuel may worry more about coal dust. Policymakers andregulators must determine how best to protect humanhealth from the potential ill effects of these multipleexposures to toxicants. They wrestle with technicalquestions (e.g., is there solid evidence that Substance

X causes human health problems? If so, at what con-centrations?) and socio-economic questions (e.g., doesthe benefit of avoiding a particular health problemoutweigh the cost of reducing the toxic exposure thatcauses it?).

This chapter examines how toxicology and epide-miology contribute to decisions on whether or how toregulate substances because of pulmonary toxicity (box3-A). The chapter first describes the framework formost regulatory decision making—risk assessment—and then describes the types of technologies availableto complete each step of that process with regard toinhaled pulmonary toxicants. The technologies cov-ered include those that enable assessment of exposureand dose and assessment of health effects. Finally, thischapter examines whether remaining questions aboutthe noncancer health risks of pulmonary toxicantsmerely await application of existing technologies orwhether answers will require development of newtools.

FRAMEWORK FOR STUDYINGTOXICANTS

Early efforts to identify and control pulmonarytoxicants in the United States were directed at sub-stances that induced obvious disease in highly exposedindividuals. In recent years efforts have focused moreon attempts to protect the general population from themore nebulous “unacceptable risk of disease” at muchlower exposure levels (34). But the objective of reduc-ing mortality and morbidity remains. The statutes thatauthorize control of pollutants to protect humanhealth explicitly or implicitly require a substantialamount of proof that a substance causes disease orinjury before the substance can be subjected to regula-tory controls. The framework in which such proof issought is generally referred to as risk assessment.

Risk assessment is the process of characterizingand quantifying potential adverse health effects that

29


Box 3-A-General Principles of Toxicology

To evaluate the toxic nature of a substance, including its pulmonary toxicity, scientists have developedseveral general criteria for consideration, including:

Nature of the Toxic Substance. Toxicologists try to determine the characteristics that render a chemicaltoxic. 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 inhigh 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, orgastrointestinal tract) affects its toxicity. The amount of absorption, ability of the toxicant to combine withnative 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 onwhich it is tested.

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

State of Health. The health status of an individual, including the presence of disease, can greatly affecttoxicity response. For example, people with asthma may suffer adverse effects from substances that do noharm to most individuals.

Individual Susceptibility. Host factors such as genetic predisposition affect the response of an individualto a toxicant.

Presence of Other Agents. Toxicology often involves evaluating one substance in isolation, yet the bodyis seldom exposed to agents in this manner. Knowledge about toxic effects of multiple substances is notwell-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 arepresented. Adaptation/tolerance must be factored into evaluating the range of individual responsivenessto a toxicant.

SOURCE: Office of Technology Assessment, 1992, based on M.A. Ottoboni, l%eDoseh4akes the Pofion (Berkeley, C& VineenteBooks, 19$4).

may result from exposures to harmful physical or assessment applies measurement and extrapolationchemical agents in the environment. As practiced in technologies to determine what level of human expo-U.S. Federal agencies, it generally involves four essen- sure can be anticipated. Risk characterization integratestial elements: the results of the first three steps to estimate the inci-

.

.

.

.

dence of a health effect for a given population underhazard identification; various conditions of human exposure (24,27).dose-response assessment;exposure assessment; and Bringing a risk assessment of a suspected pulmo-risk characterization (9,27). nary toxicant to a satisfactory conclusion poses tricky

problems for an investigator. Hazard identificationThe 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 substancesubstances can create a measurable health effect. Dose- causes a biological response but fail to address whetherresponse assessment identifies the health effects caused the effect would be adverse in the whole animal, whereby 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 assess-ments often are performed on animals rather thanhumans (particularly when new substances are beingstudied), which requires knowledge of whether animalsand humans would respond similarly to the substanceunder study. Animal tests of acute exposures can beconducted with relative ease, but tests of low-level,chronic exposures are time-consuming and costly. Lackof emissions data, lack of knowledge about how sub-stances are transported in the air, and lack of adequatemonitoring devices typically complicate the exposureassessment. The following sections on Exposure As-sessment and Dosimetry and on Health Effects Assess-ment describe technologies available for riskassessment of pulmonary toxicants and limits of thosetechnologies.

EXPOSURE ASSESSMENT ANDDOSIMETRY

Exposure to a contaminant has been defined ascontact between a person and a physical or chemicalagent. Exposure differs from biologically effective dose,which is the amount of a contaminant that interactswith cells and results in altered physiologic function.Regulators direct their efforts toward controlling ex-posures to populations that can reasonably be expectedto result in harmful, biologically effective doses toindividuals within those populations. The technologiesof exposure assessment and dosimetry contribute tothese efforts.

Exposure assessment is the estimation of the mag-nitude, frequency, duration, and route of exposure to asubstance with the potential to cause adverse healtheffects. Dosimetry is the estimation of the amount of atoxicant that reaches the target site, in this case thelung, following exposure (30). The following subsec-tions first describe devices that can be used to estimateexposure and determine the amount of a toxicant actu-ally retained by the lung, and then describe technolo-gies available to help scientists predict the biologicallyeffective dose that will be produced by a given humanexposure (figure 3-l).

Estimating Exposure and BiologicallyEffective Dose

A series or combination of physical and biologicalevents may affect whether a toxicant that becomesairborne will create a health effect. Toxicants may betransported and transformed in the environment be-fore human contact. Defense mechanisms in the respi-

ratory system may remove or transform a toxicant be-fore it causes damage. This section describes technolo-gies to measure actual and potential exposures totoxicants and technologies to measure retention by thelung.

Exposure

Exposure to airborne toxic substances tradition-ally has been estimated by sampling community andworkplace air. Continuous samplers, used to measuregases, and integrating samplers, used to measure par-ticles, are placed atone or more fixed sites in urban andnonurban areas (22). Contaminant concentrations de-rived from such measurements of the outdoor air haveoften been used to estimate an individual’s averageacute or lifetime exposure. Such estimates assume thatall contact with pollutants occurs in the outdoors andthat the breathing zone concentration is identical tothat at fixed-site monitors.

In reality, people come into contact with pollutedair in many different environments. Sophisticatedmonitoring devices now permit consideration of themultiple opportunities for people to come into contactwith polluted air. Indirect (microenvironmental) anddirect (personal) monitoring, combined with outdoormeasurements, help scientists arrive at more accurateestimates of individuals’ total exposure to airbornepollutants. Indirect monitoring uses traditional airsampling techniques but applies them to microenvi-ronments—various indoor (e.g., homes, commercialbuildings, worksites, vehicles) and outdoor (e.g., high-ways, industrial sites, backyards) sites. Personal moni-toring requires individuals to wear or carry a samplingdevice throughout the study period and, generally, tolog their daily activities to help associate measuredexposures with their sources. Studies have demon-strated the effectiveness of personal monitoring de-vices (45), but scientists generally agree that detectionlimits and reliability need improvement. Techniques toenhance or supplement personal activity logs, such aspersonal location monitors, would also increase theprecision achievable with personal monitoringdevices (22).

Biologically Effective Dose

Several factors influence the amount of an inhaledcontaminant that actually reaches lung tissues and cellsfollowing exposure. An individual at rest inhales lessair than an exercising individual because exercise in-creases the ventilation rate. The ambient exposure can

32 ● Identifyingand Controlling Pulmonary Toxicants

Figure 3-l—Framework for Exposure Assessment

o

Outdoor

o

Indoor

emission emissionsources sources

Dispersion, conversion, Dispersion, conversion,

and removal factors and removal factors(including weather) (including ventilation)

OutdoorBuilding penetration,

>Indoor

concentration <air exchange, conversion,

concentration

\/

and removal factors

Time-activity Tree-activitypatterns patterns

wHost factors

J

I Internal dose I1 I

Il-lost factors

L-JBiologically

effective dose(to critical target

tissue)

Host factors

Health effect1 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 biologi-cally effective dose. Inhaled toxicants maybe removedfrom the inspired air before they reach the tracheo-bronchial and pulmonary regions (the predominantsites of injury that may lead to changes in pulmonaryperformance; see ch. 2). But individuals who breathethrough their mouths rather than noses (e.g., asthmat-ics) may lose the benefit of that respiratory defensemechanism. Techniques ranging from measurementsof exhaled air to examination of excised lung samplescan be used to estimate how much of a substancereaches and is retained by various regions of the lung.

Analysis of exhaled air—Gas chromatogra-phy/mass spectroscopy can be used to measure exhaledair for contaminants that were absorbed by the lung.Breath measurements have been shown to correlatewith preceding exposures for selected volatile organiccompounds (45).

Analysis of body fluids-Sputum and fluid ob-tained by nasal lavage can be analyzed for the presenceof toxic substances. Blood and urine can be analyzedfor the presence of toxicants, but current measure-ments of these fluids generally yield very little or no


information about the delivered dose of a toxicant tothe lung.

Analysis of the whole lung—Invasive and rela-tively noninvasive techniques can be used to determinethe quantity of particles in the lungs of living subjects.Whole-lung scanning for particles labeled with radio-active tags (performed on an experimental basis) per-mits determination of the total concentration in thelung of certain types of inhaled particles and the size ofthe particles. Open-lung biopsy (an invasive techniquerequiring strong justification in humans) permits di-rect counting of particles or determination of fiberburden per gram of lung tissue (29). A noninvasivetechnique, magnetopneumography (MPG), provides ameans of actively monitoring the dust retained in thelungs of people exposed to magnetic or magnetizabledusts. MPG can be used intermittently, for test pur-poses only, or to monitor individuals (particularlyworkers) 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 elec-tron microscopy has been used to determine the depo-sition site, in rat, mouse, and hamster lungs, of particlessmall enough to reach the conducting airways. It alsohas permitted quantification of the particles present atselected deposition sites. Transmission electron mi-croscopy has been used to locate inorganic particles inlung tissue, which can then be analyzed to identify theparticle type. The techniques allow determination ofthe chemical composition and structure of a wide

range of particles of varying sizes and elemental com-position (31).

Determining Physical Properties of aToxicant

Determination of the physical properties of a toxi-cant may allow an investigator to predict how a gas orparticle will behave in the environment (how it will bedispersed following emission) and in the lung (how itwill be deposited and cleared from the respiratory sys-tem). This background paper does not address meth-ods for determining atmospheric dispersion but isconcerned with methods for determining regionaldeposition within the lung.

Toxicants are inhaled as gases, vapors, or aerosols(table 3-l). Many factors influence deposition of gasesand aerosols in the lung. For instance, exercise-inducedoral (as opposed to nasal) breathing increases theamount of gas or particles that bypasses the nasopha-ryngeal region and reaches the deep airways. Doses oftoxicants that overwhelm normal lung defenses (see ch.2) can also affect the deposition of gases and particles.The most influential factors in deposition are thephysical properties of the substances understudy (andthe species in which they are tested.

As a general rule, water soluble gases inhaledthrough the nose will be partially extracted in the upperairways. Less soluble gases will reach the small airwaysand alveoli. Particle size generally determines the re-gion 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 uptakeof liquid by hydroscopic particles.See mist.

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


aerodynamic size greater than 10 micrometers aremostly removed in the upper airways, while smallerparticles penetrate deeper. Extremely small or ex-tremely thin particles can cross the alveolar epithelialbarrier and cause interstitial lung injury (see ch. 2).

Knowledge of the physical properties of a toxicant,coupled with the resultant knowledge of the probablesite of deposition, points an investigator to the likelysite and type of toxic injury. Actual behavior oftendiffers from predicted behavior, but differences aregenerally revealed during the investigation.

Determining Species Differences

Toxicologists often try to predict the human healtheffects of toxicants by first studying them in animals.Animals provide useful models for studying toxicantexposure, but differences in anatomy, biochemistry,physiology, cell biology, and pathology affect the wayspecies respond to airborne toxicants (8,46). Risk as-sessments of toxic substances generally depend on ex-perimental data obtained from a variety of species, andit is essential to consider and study species differencesbefore selecting the appropriate animal for study andmaking judgments about whether an exposure/doseadministered to an animal has relevance for humanhealth (23).

Respiratory tract anatomy differs signifi-cantly among species. Although most mammals havesimilar respiratory tract components, the structure ofthose components—which affects how substances be-have in the lung—varies (e.g., humans differ from mostother animals in the size and shape of the nasal airways,in the pattern of tracheobronchial tree branching, andin alveolar size). In addition to direct study of differ-ences, computer modeling techniques now permitthree-dimensional reconstructions of the lung, basedon tissue samples, that improve the ability to extrapo-late from test results in animals to likely health effectsin humans (25).

Breathing patterns and lung defense mechanismsalso affect the fate of toxicants in the lung. For instance,humans often breathe through their noses and theirmouths, while some other animals (notably the rodentsused in toxicology) can only breathe through theirnoses. These differences have a major impact on depo-sition of particles. Also, scientists now know that alveo-

lar clearance mechanisms, which are designed to cleanout the lung and prevent the type of damage thatderives from prolonged exposure, are much faster insome species than in others.

Relative distribution of lung cell types differsamong species, which affects the type of damage toxi-cants can inflict. Similarly, the mechanism of injurymay differ among species and by exposure type (e.g.,chronic exposure to beryllium causes an immune reac-tion in human lungs, but beryllium acts through directcytotoxicity in rat and human lungs at acute exposurelevels (19)). Only certain species can be used to testdisease states of interest to scientists. For example, ratsare generally the species of choice for pulmonary toxi-cologists, but toxicologists often use guinea pigs whenasthmatic responses are in question because guineapigs have airways more sensitive to bronchoconstric-tion than most species, and hence share a similaritywith human asthmatics.

No single species makes a perfect physical surro-gate for humans in studying the health effects of air-borne toxicants. In addition to scientific issues,toxicologists must also consider the availability andexpense of different species, especially when the effectsof chronic, rather than acute, exposure are being stud-ied. Much has been learned about species differences,and scientists are beginning to account for those differ-ences when extrapolating from effects in animals tohumans. Most experts agree, however, that increasedinterspecies comparisons and studies of the mecha-nisms of injury would increase the utility of animal testsin the risk assessment process.

Summary of Exposure Assessment andDosimetry Technologies

Technologies that measure the presence of gasesand aerosols in the ambient air and at target sites withinthe body play an essential role in risk assessment ofairborne toxicants. These technologies have evolvedrapidly and continue to improve estimates of humanexposure to toxic substances. Scientists point to impor-tant gaps in the “exposure assessment knowledge base,”however (29,35). These include, generally:

. Lack of knowledge about the disposition of in-haled gases, vapors, and extremely small particleswithin the respiratory tract;

Chapter 3—Pulmonary Toxicology and Epidemiology ● 35.—

● Lack of knowledge about the disposition of gasesand aerosols within the respiratory tracts of sensi-tive individuals and groups within the population;

● Inadequate knowledge of the species differencesthat may affect interpretation of test results; and

● Lack of a sound basis for extrapolating the effectsof exposure from high to low concentrations.

The gaps present no insurmountable barriers toeffective risk assessment but will require time and re-sources to fill.

HEALTH EFFECTS ASSESSMENT

A health effects assessment completes two steps ofthe risk assessment process: hazard identification, bydetermining whether a substance causes damage, anddose-response assessment, by determining the damagecaused by a specific dose. Health effects assessmentsutilize controlled exposure conditions, as with labora-tory and clinical studies, or uncontrolled exposure con-ditions, as with epidemiologic studies. Each type ofstudy has advantages and disadvantages. To compen-sate, scientists try to integrate the results of multiplestudies in their conclusions (figure 3-2). For instance,laboratory, clinical, and epidemiologic studies havecontributed to the decision-making process on permis-sible ozone exposure levels. The following subsectionsdescribe the types of tests that can help investigatorsreach conclusions about the pulmonary effects of air-borne toxicants.

Figure 3-2—Integrated Approach to IdentifyingPulmonary Toxicants

Responses toacute exposuresin animals G=====O ;:55?:;’0s

o

u)c IIo.= I’Jg

@2;

I g“ \p.- I“la K-’

Diseases in—————

Diseases inanimals with Projections ‘) humans withchronic exposure — — — — —/ chronic exposure

SOURCE: Office of Technology Assessment, 1992, based on M.McClellan, R. O., “Reflections on the Symposium:Susceptibility to Inhaled Pollutants,” American Societyfor Testing and Materials Special Technical Publication1024,1989.

Laboratory and Clinical Studies

Laboratory studies and human clinical studies con-trol exposure conditions as closely as possible to limitthe influence of extraneous factors on the study. Thismeans, in part, investigators must understand “hostfactors”—the physical conditions, activity level, andpersonal habits of the test subject-and other factors,such as time of day or season of the year, that may affectthe outcome of a study. It also means investigatorschoose not only the health effect to study but theamount of toxicant to which tissues and cells, animals,or human volunteers are exposed.

There are drawbacks to studies involving con-trolled exposure conditions. The fundamental limita-tion of experiments involving whole animals lies inextrapolating results to humans. As discussed above,techniques are progressing, but scientists are not yetsatisfied with their ability to account for the differencesin human and animal lungs when predicting the effectsof a toxicant. In addition, studies using whole animalsinvolve considerable expense and, in some instances,problems with the public’s views on animal experimen-tation. Ethical restraints on human clinical studies—investigators may not inflict harm—place inherentlimitations on their use for predicting a toxicant’s like-lihood of causing a deadly or disabling condition. Theintentional simplicity of experiments involving con-trolled exposures also limits their value for revealingthe effects of exposure under “real world” conditions.To isolate the effects of one substance, investigatorseliminate other potential toxicants from the air, whichmay alter the effect the test substance has on the lung.

Technologies to Measure Exposure

Toxicologists performing animal experimentsmust have the capability to generate the types of chemi-cals and particles they want to test and the capability toexpose the animals to fixed amounts of the test sub-stance(s). Technologies to generate gases and aerosolsare well developed (2,26). However, the aerosols gen-erated tend to be far more homogeneous than thoseencountered in typical urban environments. Exposureoccurs in whole-body chambers and in apparatusespermitting head-only and nose-only exposures. Exist-ing systems provide for adequate exposure control andmeasurement and do not constrain evaluation of testresults when system limitations are properly accountedfor in the analysis (6). However, continued research isimportant to understand the implications of the differ-


ences in complex, naturally occurring aerosols andthose generated for experimental purposes.

Participants in human clinical studies can be ex-posed to the test substance in exposure chambers(whole-body systems) or through systems using eithera facemask, hood, or mouthpiece. Each system hasadvantages (e.g., exposure chambers permit unencum-bered breathing and most accurately simulate normalconditions; mouthpieces are very simple) and disad-vantages (e.g., facemasks are difficult to seal; exposurechambers can be expensive to construct and maintain,part of the reason why only four chambers in theUnited States are effectively operating (37)). It is pos-sible to calibrate the limitations of each system suffi-ciently to permit adequate evaluation of test results

(17). Development of portable exposure chamberscould enhance use of that exposure system (37).

Measurements of Effects

Toxicologists can identify pulmonary toxicantsthrough physiologic assays of living subjects, structuralanalysis of tissues and cells removed from animals orhumans, and tests of biochemical responses in removedfluids and cells. The following subsections describevarious testing measures.

Physiologic tests—Assays of physiologic functionfall into four major categories: measures of ventilatoryor gas-exchange functions; measures of increased air-way reactivity; measures of particle clearance from the

Photo credit: South Coast Air Quality Management District, El Monte, CAA volunteer undergoes lung function tests while exercising.


lung; and measures of increased permeability of theair-blood barrier. These assays can be used to demon-strate 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 ofhow much and how quickly air can be expelled follow-ing a deep breath, constitutes the most common groupof respiratory function tests performed in humans. Avery frequently used spirometric test measures theamount of air that can be forcibly expelled in 1 secondand is referred to as FEV1 (forced expiratory volumein 1 second). Physicians agree that an FEV1 below 80percent of the predicted value (which varies with age,height, and sex) indicates an adverse health effect. EPAhas used evidence of decrements in FEV1 greater thanor equal to 10 percent as the basis for regulations. Somestudies show that a decrease in FEV1 following short-term exposure correlates with development of obstruc-tive disease following chronic exposure, but muchresearch remains to be done.

The total amount of air that can be expelled fol-lowing a deep breath is referred to as forced vitalcapacity (FVC), and this measure is also a commonlyused test. Practitioners of spirometry can chart the airflow rate after 50 percent or 75 percent of the volumehas been forcibly expelled (forced expiatory flow of 50or 75 percent, or FEF50 or FEF75). Alternatively, theflow rate between 25 percent and 75 percent of theFVC (maximal midexpiratory flow, or MMEF) can bemeasured. Some researchers believe that FEF50,FEF75, and MMEF may identify early and subtle dam-age to airways, which maybe the first stage of the typeof severe or irreversible damage reflected in the morecommon measures of FEV1 or FVC.

Ventilator function tests that do not require vol-untary exhalation maneuvers can be performed in ex-perimental animals. Such tests include measures of themechanical properties of the lung, i.e., the amount ofwork required to stretch the lung (inhale) and the workrequired to push air out of the lung (exhale). Tradi-tional measures of lung mechanics have been usedwidely in animal studies of toxicants that are pulmo-nary irritants (7).

The distribution of gases and particles within thelung can also be measured with ventilator functiontests. Single- and multi-breath nitrogen washout testsdetermine the point in exhalation when the airways

begin to close (as evinced by an increase in the nitrogencontent of exhaled air). A transient increase in theamount of air left in the lung when the limits of forcedexhalation are reached appears to correlate with expo-sure to pulmonary toxicants. Particle distribution canbe examined by measuring the number of particles,administered as an aerosol, in exhaled air and withradioimaging techniques. Efforts are underway to vali-date such tests, which are not yet in widespread use.

Tests of how well gas diffuses from the lung intothe blood system—the diffusing capacity of the lung forcarbon monoxide (DLcO)-are sometimes includedamong ventilator function tests. The tests use carbonmonoxide (at harmless dose levels) because it is readilyabsorbed by the hemoglobin in the blood. The mostcommon DLCO test requires the subject to inhale amixture of inert gas and carbon monoxide. Changes inthe ratio of inert gas to carbon monoxide, as measuredin air captured at the end of exhalation, can indicatechanges in the lung’s diffusing capacity (e.g., if unusu-ally high levels of carbon monoxide remain in theexhaled air, it indicates alterations in the transfer of COfrom the lung to the bloodstream).

Measures of airway hyper-reactivity are anothertype of physiologic test of pulmonary toxicity. Thesetests assess whether the bronchoconstrictor responseto stimuli increases (i.e., whether the airways becomehyper-reactive and resist air flow) during or followingexposure to inhaled toxicants. In nonspecific airwayhyper-reactivity tests, the stimulus for the bronchocon-strictor response may be cold air, exercise, or variouspharmacologic agents. This type of testing has proveduseful for measuring airway responses to low concen-trations of environmental pollutants. In specific airwayhyper-reactivity testing, the stimulus is often a com-mon antigen. In nonspecific and specific tests of airwayhyper-reactivity, the tests applied following stimula-tion of the airways involve an airway resistance meas-urement and a pulmonary function test, usually FEV1.Airway hyper-reactivity is characteristic of asthma, al-though it can occur in nonasthmatics. Some re-searchers suggest airway hyper-reactivity may play animportant role in the development of chronic lungdiseases.

Particle clearance assessments also provide physi-ologic evidence of pulmonary toxicity. These assaysdetermine how exposure to toxicants alters the lung’sability to clean itself out. Though several tests areunder development, their utility is hindered by the fact


that as yet there is no generally accepted range ofnormal clearance performance. Most tests trace thetransport and removal of radiolabeled particles follow-ing exposure to a toxicant.

The final, major type of physiologic assay of pul-monary toxicity attempts to measure injury to the air-blood barrier, usually equating injury with increasedpermeability. Permeability Can be determined by meas-uring ion transport through airway epithelial cells orby measuring the transepithelial transport of mole-cules into the blood. These tests currently have manydrawbacks, and though research appears to be worth-while, much remains to be done. Permeability of theendothelial cells that line the blood vessels can also bemeasured, but nondestructive techniques require fur-ther validation before they can come into common use.

In 1989, the National Academy of Sciences (NAS)summarized the utility of physiologic assays in identi-fying pulmonary toxicants (29). A portion of that analy-sis is reproduced here as table 3-2. The precedingsection provides only a cursory overview of the basictypes of physiologic tests of pulmonary toxicity, and thereader is referred to the NAS report for detailed de-scriptions of these and additional tests.

In summary, physiologic function tests providereasonable measures of response to toxicants but arenot particularly specific or sensitive. Changes in func-tion are not unique to individual toxicants (i.e., lungresponses to insult are limited). Current tests havelimited value in identifying the effects of chronic expo-sure (which tend to occur insidiously) (44). But whenused in tandem with knowledge of exposure, these testscan help identify toxicants.

Structure tests—Injury to lung tissues and cellscan, in some instances, be assessed with the naked eye.For instance, in advanced asbestosis the damage asbes-tos causes to the pleura can be seen unaided in an openchest cavity, and a microscope can provide even greaterdetail of the damage. Whole lungs or tissues and cellstaken from autopsied humans or animals can be di-rectly examined for evidence of toxic effects. X-raytechnologies are also useful in structural studies.

Scientists also know that cells of the pulmonarysystem normally appear in relatively constant numbersand sites within the lung. Examination of tissue fromspecific regions of the lung can indicate changes in cellpopulations that are evidence of toxic effects. Mor-

phometry, a technique that employs microscopy toquantify cell populations and structure size using fixedtissue samples, has been widely used to study toxicsubstances suspected of causing a specific type of injurythroughout the lung. Morphometry is more difficult touse to measure toxic effects on small or scattered re-gions of the lung because tissue samples reflective ofthe region can be hard to obtain, but improved tech-niques are under development to assess the gas ex-change region of the lung (18). Morphometry can alsobe used to examine changes in the structure of thepulmonary vasculature. Structural tests may show ab-normalities long before changes are detectable by pul-monary function testing. A substantial amountremains to be learned about whether such changes willresult in harm, however.

Tests of biochemical and molecular response—Phagocytic pulmonary cells, physiologic mediators,metabolizes, enzymes, and other biochemical sub-stances that can be associated with toxic response canbe removed from the system by lavage (washing) andthe lavage fluid can be analyzed for cellular and bio-chemical content (20,21). Pulmonary inflammatory re-sponses and immune responses can be measured byexamining bronchoalveolar lavage fluid (BALF).

An inflammatory response to a toxic exposure pro-duces enzymes and cells not normally present in BALF.BALF analysis can reveal the degree of inflammationand corresponding stage of any disease process. As-pects of an immune response, such as increased num-bers of lymphocytes, can also be measured in BALF.Importantly, immune system cells recovered fromBALF can be tested in vitro to determine whether theyrespond properly to antigen challenge or if they re-spond to a particular antigen of interest. The func-tional characteristics of other cell lines obtained fromBALF can also be assessed.

Development of safe lavage techniques has con-tributed immensely to the prospects for pulmonarytoxicology. The ability to measure the presence of bio-chemical substances in BALF has grown faster thanknowledge of how those substances correlate to toxic-ity, but current research is quite promising.

Summary of Technologies Applicable to Laboratoryand Clinical Studies

Effective laboratory and clinical studies requiretechnologies to control the dose of a toxicant adminis-


tered to a test subject and to limit and account forconfounding factors. Scientists have developed severalexposure technologies and have characterized theirpotential and drawbacks.

Many established and recently developed tech-nologies exist to measure changes in lung structure andfunction following exposure to toxic substances. A sub-stantial database exists on the physiological effects oftoxicants on animals. Spirometry--as a stand alonemeasure of ventilator function and as a component ofairway reactivity testing—is the most frequently andeasily used technique in human health effects assess-ments of pulmonary toxicity; additional physiologicmeasures are under development and may eventuallyimprove the predictive powers of clinical studies ofpulmonary toxicity. Microscopy continues to play animportant role in laboratory studies, particularly asenhanced by morphometric techniques. The impor-tance of biochemical and molecular measurements, asperformed on lavage fluids, is increasing (20,47). Eachof these technologies performs well as a diagnostic toolwhen changes in the lung are gross, but many alsomeasure milder changes that may only represent physi-ologic variability and, as yet, are not well correlatedwith changes in pulmonary performance.

Health effects assessments can be performed un-der acute or chronic exposure conditions. The databaseon acute exposures is much larger than that on chronicexposures. While this background paper focuses ontechnologies that identify whether a substance causes atoxic effect, it is important to acknowledge that dataregarding how that effect results in harm should alsoimprove policymakers’ ability to deal appropriatelywith toxic substances.

Epidemiologic Studies

Epidemiology-the study of the distribution anddeterminants of disease in populations—provides in-formation about the impacts of air pollutants on hu-man populations. It can be used to associate pollutantswith disease even before precise mechanisms of causeand effect are understood, although observed associa-tions are often attenuated by serious confounding fac-tors.

Epidemiologic investigations of airborne toxicantsshare the difficulties inherent in any observational,rather than experimental, studies. For instance, expo-sure may be hard to assess. Some observers note thatknowledge of exposure need not be precise to be mean-

ingful (4), e.g., self-reported exposures to fumes orsmoke have correlated well to later measurements, butresults based on precise exposure measurements lendthemselves more readily to important regulatory deci-sions. Another problem with epidemiologic studies isthat most lung diseases can have more than one cause,and it is difficult to isolate the effects of one airbornesubstance from another. Finally, it may take studies ofquite large populations to reveal small but importanteffects of airborne toxicants, and such studies can bedifficult and costly to undertake. Though hard (some-times impossible) to conduct, these types of studies canprovide evidence of association between exposure anddisease that lay and technical people alike find morecredible than evidence from laboratory or clinical stud-ies (28).

Epidemiologic studies take many forms. It is pos-sible to study living or deceased populations; diseasedpopulations can be studied for evidence of exposure;healthy populations can be studied for changes inhealth status following exposure. In all cases, however,some knowledge of exposure and evidence of a definedhealth effect must be available for results to be mean-ingful. The following subsections describe the toolsavailable to measure exposure and health effects inepidemiologic studies. Epidemiology uses some of thesame technologies as employed in laboratory or clinicalstudies; some techniques are unique to epidemiology.

Measurements of Exposure

Many of the exposure assessment technologies de-scribed previously are applicable to epidemiologicstudies. Outdoor, indoor, and personal monitoring de-vices can be used to provide current exposure informa-tion. Records of outdoor measurements collected bypublic agencies provide historical data of exposure.Population groups can be examined for biological evi-dence of exposure (e.g., toxic substances found in ex-haled air or in autopsied lungs). These measurementstypically lack the precision—with regard to exposureto the toxicant under study and to exposure to sub-stances that may alter (confound) the results--obtain-able in laboratory and clinical studies, but are used bythe scientific community. Moreover, some epidemi-ologic studies proceed on the basis of self-reported,rather than measured, exposure information.

Measurements of Health Effects

Epidemiologists use many kinds of data to deter-mine health status. Epidemiologic measures include


Table 3-2—Summary of Characteristics of Physiologic Assays

Characteristics a and Ratingsb

Measure A B c D E F

Respiratory functionSpirometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ++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 reactivityNonspecific reactivity . . . . . . . . . . . . . . . . . . . . . ++Specific reactivity . . . . . . . . . . . . . . . . . . . . . . . . +

Particle clearanceRadiolabeled aerosol . . . . . . . . . . . . . . . . . . . . . . +Magnetopneumography . . . . . . . . . . . . . . . . . . . . -

Air-blood barrier functionConducting-airway permeability

Clearance of inhaled DTPA . . . . . . . . . . . . . . +-Transepithelial potential . . . . . . . . . . . . . . . . . . . . +-Alveolar permeability by . . . . . . . . . . . . . . . . . . . +

radiolabeled aerosalVascular permeability

Radiolabeled protein leakage . . . . . . . . . . . . . +Chest x-ray for edema . . . . . . . . . . . . . . . . . . . ++Extravascular lung water by . . . . . . . . . . . . . . +

indicator dilution, PET, or NMRRebreathing soluble gases . . . . . . . . . . . . . . . . . . +

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

+ ++ ++ ++ +

+

+-++

+-

+-+-

++

+++

+-+-

+-+-+-

++-+-

+

+-

+ ++ + +

++-

+++

+++-

+-+

++ + +

+++

+++

00

+++-

+-+

++++

+-+

+-+

+-+

+++

+++-

+++

+ +- +-0+

00+-

+++

+++

+-

0

+-

+

+

+++++

++-

+ + +- ++

+ + +-

some of the same technologies applied in laboratory the effects of air pollution on the respiratory health ofand 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 epi-miologic studies are described briefly below. Box 3-B demiologic studies because it is noninvasive and rela-provides 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 availabil-

ity 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 wasintended to reflect potential for substantial technical refinements, adaptation for use in large populations, or advancements in abilityto interpret results.

C. Current Applicability of Assay to Humans. Primary considerations were the invasiveness of the technique and the requirement forradionuclides. 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 studiesof large populations of people, as might be required for evaluating effects of some environmental exposures. Considerationsincluded 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 forfield use in evaluating hundreds of subjects of various ages and both sexes, whereas the assay might be quite suitable for studies ofdozens 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 functionaffected, but the specific mechanism or site of change is uncertain. For example, it is agreed that reduced carbon monoxide diffus-ing capacity reflects reduced efficiency of alveolar-capillary gas transfer, but the test does not distinguish among the effects of athickened 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 suit-

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

ability 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 oftoxic effect in the large airways. Nitrogen washout testshave been used to measure small airways effects, butthe sensitivity and specificity of that test has been calledinto question (29). Epidemiologists sometimes test forairway reactivity (28).

Bronchoalveolar lavage (BAL) could be per-formed in epidemiologic studies, either on living sub-jects or on autopsied lungs. BAL is invasive, however,and requires high-level skills to perform safely, addingto its expense and detracting from its utility in large-scale studies.

Assessments of data-Certain types of epidemi-ologic studies rely on routinely collected data ratherthan biological tests performed in the community.Death certificates provide mortality data that can becoupled with historical exposure data to draw someconclusions about the effects of inhaled pollutants on

a population. Morbidity data obtained from diversesources-hospital admissions and discharge records(3,48), emergency room visits (33), hotline phone callsand follow-up interviews (5), reports of days lost fromwork or school—provide some indications about theeffects of airborne toxicants as well. These sources maybe affected by error. For instance, cause of death maybe listed inaccurately; social and economic factors in-fluence decisions to seek health care or miss work.Some epidemiologists believe that these errors tend toreduce (rather than increase) the possibility of findinga significant effect. Epidemiologists have relied onthese types of information in studies that are widelyaccepted as indicative of a connection between expo-sure to inhaled substances and lung injury or disease.

Participants in epidemiologic studies of pulmo-nary toxicity often complete questionnaires to assessrespiratory health (16). Quality control measures forstandardized questionnaires have been assessed, and


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 ofthe respiratory effects of air pollution. By comparing the respiratory health of several communities exposed to different concentrationsof common air pollutants, the researched hoped to elucidate the connections between inhaled toxicants and chronic obstructiverespiratory disease, The researchers chose Los Angeles as the study area because of the great variation in the types and concentrationsof pollutants within a relatively small but highly populated geographical region. The existence of a uniform network of air qualitymonitoring stations throughout the area ensured the availability of exposure data, which also influenced the decision to perform thestudies in the Los Angeles area.

Four Los Angeles area communities with similar demographics-Lancaster, Burbank, Long Beach, and Glendora--were chosenfor 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% andlung function tests were all performed at the same Mobile Lung Function Laboratory for which the reliability was determined andsensitivity and specificity were estimated. Thoughresearchers noted that long-term studies were necessary, initiaI data led to thefollowing hypotheses:

1. Adverse effects of long-term exposure to high concentrations of photochemical/oxidant pollutants may occur primarily in largerairways 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, andparticulate pollutants is associated with respiratory impairment, manifested by dysfunction of the large airways (comparisons ofLancaster, Burbank, and Long Beach residents).

3. Long-term exposure to high concentrations of photochemical oxidants, nitrogen dioxide, sulfates, and particulate pollutants mayresult in measurable impairment in lung function in smokers and never smokers (comparisons of Lancaster and Glendoraresidents).

Extensive follow-up enabled researched to observe the populations from Lancaster, Burbank, Long Beach, and Glendora inlong-term studies. Five years after the initial testing, participants still living in the study area (a substantial number) were reinterviewedand 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 lungfunction, 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 thelarge 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 (analysisof all four communities).

4+ Smoking cessation leads to relatively early and sustained improvement in indexes of small airway function and other indices ofrespiratory health (analysis of all four communities).

The UCLA population studies of chronic obstructive respiratory disease add support to certain hypotheses regarding lung functionand 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 thestudies could not support standards setting for any of the pollutants involved. The studies do, however, point toward productive avenuesfor 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 moregenerally remember exposures or illnesses better than prominent in recent years. They avoid the recall biashealthy or unexposed individuals) enters into play, found in annual questionnaires and appear to be morequestionnaires generally are considered useful. Daily sensitive (36).

Chapter 3—Pulmonary Toxicology and Epidemiology . 43

Summary of Technologies Applicable toEpidemiologic Studies

In epidemiologic studies, exposure information issupplied with exposure assessment technologies andself-reported exposure data. Because “free-living” hu-mans have knowing and unknowing encounters withmultiple possible toxicants, exposure data in epidemi-ologic studies are necessarily imprecise. Many investi-gators believe that when confounding factors areproperly accounted for, the ability to gather informa-tion on environmentally relevant exposures rendersepidemiologic studies worthwhile even given the prob-lems of collecting exposure data.

Biological tests applied in epidemiologic studieshave the same advantages and disadvantages they pre-sent in laboratory and clinical studies, with the addedrequirement that they be easy to use in the field or onlarge populations. Reliance on public health recordsand population survey is a feature common to all epi-demiology, including investigations of respiratory dis-ease.

Summary of Health Effects AssessmentTechnologies

Each type of study (laboratory, clinical, or epide-miologic) has technological advantages and disadvan-tages, and individual studies within each type havestrengths and weaknesses. Clear evidence of change inlung structure or function is unpersuasive if exposuredata are problematic; evidence of health effects in ani-mals under tightly controlled exposure conditions maybe unpersuasive if no human data are available. De-spite the availability of many testing technologies, cer-tainty about the pulmonary toxicity of manycommercial substances has eluded investigators andregulators because of the lack of a full array of infor-mation sources. The database on the acute effects ofshort-term, high-dose exposures to toxicants is rela-tively large and growing, and forms the basis for exist-ing regulations of pulmonary toxicants. Fewer data areavailable on the effects of chronic, “environmentallyrelevant” (i.e., low dose) exposures to suspected toxi-cants. On one hand, animal data on chronic exposurescan be obtained using current testing technologies, butproblems remain in extrapolating results from animalsto humans. On the other hand, human data may beimpractical or impossible to obtain given the ethicalconstraints of clinical testing and the length of time and

large populations necessary to conduct meaningfulepidemiologic studies.

LIMITS OF TECHNOLOGY

The previous sections establish that current tech-nology can measure the biological effects of toxic sub-stances on the lung, but that conclusion begs animportant question: Are the measured effects ad-verse? Humans come equipped to survive in a hostileenvironment; most organ systems—the lung in-cluded-are resilient and operate with a reserve capac-ity that accommodates some level of change or damage(43). In the case of pulmonary toxicology, it appearsscience has learned to measure biological effects morequickly than it has learned to correlate those effectswith persistent changes in performance or with diseaseprocesses. This disjuncture creates problems for regu-lators.

Most researchers recognize a hierarchy of biologi-cal effects of exposure to toxic substances, ranging frommortality (inarguably adverse) to measurable traces oftoxicants in tissue (arguably adverse) (figure 3-3). Be-cause some people or populations are more sensitiveto toxic effects than others, and because some peopleor populations are more highly exposed to toxic sub-stances than others, severe, unquestionably adverseeffects are likely to occur in a smaller segment of thepopulation than less severe, more questionably adverseeffects. Effects may be reversible or irreversible, with atendency among researchers to concern themselvesmore with irreversible effects. Concern for reversibleeffects increases, however, if chronic exposures preventreversal. Evidence to support a clear demarcation be-tween adverse and nonadverse effects remains elusive.If, as in the case of many suspected pulmonary toxi-cants, evidence does not exist to associate early changeswith later, more extensive or irreversible changes, ef-fects that are measurable may still be adjudged nonad-verse.

The American Thoracic Society (ATS) has definedadverse respiratory health effects in humans as “medi-ally significant physiologic or pathologic changes gen-erally evidenced by one or more of the following:(1) interference with the normal activity of the affectedperson; (2) episodic respiratory illness; (3) incapacitat-ing illness; (4) permanent respiratory injury; or (5)progressive respiratory dysfunction” (l). Most often,however, regulators must use a combination of limited


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

Adverse health

————

+__———— Proport ion of populat ion af fected —>

SOURCE: Arneriean Thoricic Society, “Guidelines as to What Constitutes an Adverse Respiratory Health Effect, with Special Referenee toEpidemiologic Studies of Air Pollution,’’Arn Rev. Respir. ilk. 131:666-668, 1985.

animal data and limited human data to reach conclu-sions about existing substances, and always must relyon animal data or extrapolations based on knowledgeof chemical structures to predict the potential effectsof new substances. Decisions about regulations mostoften are made in the absence of data that would enablea determination of adversity as precise as that found inthe ATS definition.

Researchers and regulators agree that the inte-grated results of laboratory, clinical, and epidemiologicstudies of short-term exposures can yield conclusiveinformation about the acute effects of pulmonary toxi-cants. Current regulations generally are designed toprevent acute effects. Researchers and regulators gen-erally are not satisfied that current technologies orcurrent data provide them with a sufficient basis toregulate exposure to airborne toxicants because of thepotential effects on the lung of chronic exposures.Much research is directed at developing improvedmethods for studying chronic exposures, but manyquestions remain. Chapter 4 provides more detail onregulations based on pulmonary toxicity and describescurrent Federal efforts to improve the basis for deci-sion making with regard to chronic, low-dose exposureto inhaled toxics.

1.

2.

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al., “Comparative Dosimet~ of Inhaled Materi-als: Differences Among Animal Species and Ex-trapolation to Man: Symposium Overview,”Fundamental and Applied Toxicology 16:1-13,1991.Department of Health and Human Services, TaskForce on Health Risk Assessment, DeterminingRisks to Health: Federal Policy and Practice(Dover, MA: Auburn House Publishing Com-pany: MA 1986).Detels, R., Rokaw, S. N., Coulson, A. H., et al., “The UCLA Population Studies of Chronic Ob-structive Respiratory Disease. I. Methodologyand Comparison of Lung Function in Areas ofHigh and Low Pollution,” American Journal ofEpidemioloW 109(1):33-58, January 1979.Detels, R., Sayre, J. W., Coulson, A. H., et al., “TheUCLA Population Studies of Chronic Obstruc-tive Respiratory Disease. IV. Respiratory Effectof Long-Term Exposure to Photochemical Oxi-dants, Nitrogen Dioxide, and Sulfates on Currentand Never Smokers,” Amen-can Review of Respi-rato~ Disease 124(6):673-680, December 1981.Detels, R., Sayre, J. W., Tashkin, D. P., et al., “TheUCLA Population Studies of Chronic Obstruc-tive Respiratory Disease. VI. Relationship ofPhysiologic Factors to Rate of Change in ForcedExpiatory Volume in One Second and ForcedVital Capacity,n American Review of RespiratoryDtiease 129(4):533-537, April 1984.Detels, R., Tashkin, D. P., Sayre, J. W., et al., “TheUCLA Population Studies of Chronic Obstruc-tive Respiratory Disease. 9. Lung FunctionChanges Associated With Chronic Exposure toPhotochemical Oxidants; A Cohort StudyAmong Never-Smokers,” Chest 92(4):594-603,October 1987.Detels, R., Tashkin, D.P., Sayre, J. W., et al., “TheUCLA Population Studies of CORD: X. A Co-hort Study of Changes in Respiratory FunctionAssociated With Chronic Exposure to S@, NG,and Hydrocarbons,n American Journal of PublicHealth 81(3):350-359, March 1991.

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Critical Reviews in Toxicology 20(1):1-29, 1989.Warheit, D. B., Carakostas, M. C., Hartsky, M.&et al., “Development of a Short-Term InhalationBioassay to Assess Pulmonary Toxicity of InhaledParticles: Comparisons of Pulmonary Responsesto Carbonyl Iron and Silica,” Toxicology and Ap-p!ied Pharmacology 107:350-368, 1991.Windau, J., Rosenman, K, Anderson, H., et al.,“The Identification of Occupational Lung Dis-ease From Hospital Discharge Data,” Journal ofOccupational Medicine 33(10):1060-1066, Octo-ber 1991.

Chapter 4

Federal Attention to Pulmonary Toxicants

Chapter 4

Federal Attention to Pulmonary ToxicantsINTRODUCTION

Congress has enacted a diverse body of laws to helpcontrol human exposure to toxicants. These laws re-quire the Federal Government to regulate the public’sexposure to toxic substances and to conduct and spon-sor research that will improve identification and regu-lation of toxicants. This chapter describes regulatoryand research programs of the Federal Governmentspecifically related to the control and investigation ofairborne pulmonary toxicants. The chapter providesexamples of Federal activities but is not an exhaustivelisting.

FEDERAL REGULATORY ACTIVITIES

Several Federal laws authorize administrativeagencies to regulate substances to prevent adversehealth effects, including respiratory effects. This sec-tion focuses on the laws and regulations used to controlhuman exposures to pulmonary toxicants. The Envi-ronmental Protection Agency (EPA) and the Occupa-tional Safety and Health Administration (OSHA), partof the Department of Labor (DOL), implement mostof the statutes designed to limit human exposures toenvironmental and occupational pollutants. The MineSafety and Health Administration (MSHA), also partof DOL, regulates pollution in the mining industry.The Consumer Product Safety Commission (CPSC)and the Food and Drug Administration (FDA) alsohave some authority over pulmonary toxicants.

Environmental Protection Agency

EPA administers a variety of laws that require pro-tection of human health and the environment, includ-ing 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 ControlAct (TSCA; 15 U.S.C. 2601 et seq.), and the FederalInsecticide, Fungicide, and Rodenticide Act (FIFRA;7 U.S.C. 136 et seq.). These statutes authorize EPA tocontrol human exposure to substances that cause ad-

verse human health effects, and the agency has, in fact,regulated some substances on the basis of pulmonarytoxicity.

Clean Air Act

The CAA requires EPA to identify airborne sub-stances that may “cause or contribute to air pollutionwhich may reasonably be anticipated to endanger pub-lic health or welfare” and to set national ambient airquality standards (NAAQS) for those ‘criteria” pollut-ants. NAAQS, which apply only to outdoor concentra-tions of pollutants, have been set for sulfur oxides,particulate matter, carbon monoxide, ozone, nitrogendioxide, and lead. EPA regulated sulfur oxides, particu-late matter, ozone, and nitrogen dioxide because oftheir adverse effects on the pulmonary system (22,23).Table 4-1 presents the (health-based) primary ambientair quality standard for each criteria pollutant and listsadverse effects on the pulmonary system.

The CAA also requires EPA to control “hazardousair pollutants,” defined by law as substances for whichno ambient air quality standard can be set and that ‘mayreasonably be anticipated to result in an increase inmortality or an increase in serious irreversible, or inca-pacitating reversible, illness.” Between 1970 and 1984,seven substances were placed on the hazardous airpollutants list: asbestos, benzene, beryllium, inorganicarsenic, mercury, radionuclides, and vinyl chloride(3,23). Coke oven emissions were added to this list in1984 (3). The 1990 amendments to the CAA substan-tially augmented the list of hazardous air pollutants—bringing it to 189—and required EPA to regulate themat the level possible under maximum achievable con-trol technology (MACT) (23). Table 4-2 lists hazard-ous air pollutants known to be pulmonary toxicants.

Incentive Programs Under the CAA. Followingadoption of the 1990 amendments to the CAA, EPAdeveloped the Early Reduction Program (ERP), whichprovides incentives for companies to make immediate,major reductions (90 percent for gases and 95 percent

49


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 func-

0.03 ppm annual arithmetic mean tion via inflammation; tendency develop al-lergies

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 concentra-

tion

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 de-creased lung function, bronchitis, and pneu-monia; can aggravate asthma; some cancause fibrosis; increase deaths

Can cause death or damage to lungcells bypassing into the bloodstream inhibiting theability of red blood cells to carry oxygen tocells of the body

Can irritate and inflame the lungs, causeshortness of breath, increased susceptibilityto respiratory infections, accelerated agingof the lungs, and emphysema; fatal at highconcentrations (effects have been shown be-low 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; cancause 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, kid-neys, 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 Congressiorzuland 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 compliancepollutants. Companies that participate in the ERP will extension (24).be allowed a 6-year compliance extension after emis-sions standards (anticipated to require reductions in The ERP covers all 189 hazardous air pollutantsexcess of 90 to 95 percent) are developed. EPA moni- listed in the CAA, but it identifies 35 substancestors company compliance with the ERP and focuses on deemed ‘highly toxic pollutants” as its most importantspecific sources, even sources within a plant’s bounda- targets. Each of these substances is weighted accordingries. 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 theERP (24). Table 4-3 lists substances covered by theERP that are known to be pulmonary toxicants.

EPA also designed the 33/50 Program to encouragecompanies to make voluntary reductions in pollutantemissions before MACT standards are in place. The33/50 Program asks companies to voluntarily reduceaggregate releases and off site transfers of 17 highpriority toxic substances by a total of 33 percent by 1992and a total of 50 percent by 1995. This program doesnot focus on reducing emissions at or within particularplants but concentrates on national goals (25).

Each substance covered by the 33/50 Program:

.

.

.

.

.

●

appears on the CAA’s list of hazardous air pollut-ants;is included in the Toxic Release Inventory (TRI);is a multimedia pollutant on the agenda of everydepartment of EPAis produced in large quantities and has a highrelease to production ratio;has been shown to be amenable to pollution con-trol; andis known to be toxic to both human health and theenvironment (8).

Table 4-3 lists the chemicals targeted by the 33/50Program that are known to be pulmonary toxicants.Participants in the 33/50 Program set their own goalsfor emissions reductions, and EPA has no enforce-ment mechanism. Compliance is measured throughTRI reporting and is not as closely monitored as in theERP (24).

Resource Conservation and Recovery Act

RCRA attempts to safeguard public health and theenvironment by controlling waste disposal. It requiresEPA to identify and list hazardous wastes, defined assolid wastes, which due to potency, volume, or physical,chemical, or infectious qualities may:

. cause or considerably add to deaths or seriousirreversible or incapacitating reversible illness, or

. create significant present or potential dangers tohuman and environmental health if improperlyhandled.

Several chemicals regulated under RCRA have ad-verse effects on the pulmonary system; see table 4-4.

Toxic Substances Control Act

TSCA calls on EPA to regulate chemicals in pre-marketing and post-marketing phases to avoid unrea-sonable risk of injury to public health and theenvironment. TSCA requires the manufacturer to pro-vide EPA with a pre-manufacturing notice (PMN),including test results on the chemical, at least 90 daysbefore manufacturing begins. If EPA does not requestfurther data within the 90-day period, the manufac-turer is free to begin production (2). If EPA finds thatthe chemical may pose an unreasonable risk to humanhealth or the environment, or that insufficient dataexist to make a determination about risk, or that thechemical will be produced in substantial quantities,EPA may require additional testing. This testing isconducted by the chemical manufacturer or processor.

Many of the regulations issued under TSCA (40CFR 790 et seq.) provide guidelines for testing chemi-cals. Guidelines exist for testing acute, sub-chronic,and chronic inhalation toxicity. Acute inhalation tox-icity testing provides information on health hazardslikely to result from short-term exposure to a sub-stance. Acute inhalation tests involve a single, 4- to24-hour exposure to a particular substance followed bya 14-day observation period. The sub-chronic inhala-tion tests assess the effects of toxicants from repeateddaily exposures to a substance for approximately 10percent of the animal’s lifespan. These tests involverepeated daily exposures for at least 90 days. Chronictoxicity inhalation testing is designed to determine thehealth effects that are cumulative or have along latencyperiod. These tests involve repeated daily exposures toa substance for at least 12 months.

If tests show that a chemical poses an unreasonablerisk to human health or the environment, EPA canlimit or prohibit its use, manufacture, and distribution.EPA has taken action under TSCA due to the possibil-ity that certain chemicals pose pulmonary healththreats. For example, EPA has required manufacturersto report health and safety study data on 26 diisocy-anates because of concern that acute and chronic expo-sures could cause respiratory tract effects and noseirritation (5). EPA has also required significant newuse 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 thePulmonary 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


Lung injury, and possibly death

Pulmonary irritation and histologic lesions of the lung

Asbestosis

Pulmonary edema and hemorrhage; tightness in chest, breathlessness; uncon-sciousness may occur and death may follow due to respiratory paralysis in casesof 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, bronchopneumoniaand fatal pulmonary edema

Difficulty in breathing

Lung irritation

Pulmonary disease (unspecified)

Obliterative bronchiolitis, ademonatosis, and hypersentivity reactions, chronicinterstitial pneumonitis and occasional fatalities

Chest pain, respiratory irritation, damages to mucous membranes

Respiratory system irritation and pulmonary damage

Respiratory irritationLung 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; maybe fatal


Table 4-Z-Hazardous Air Pollutants Regulated Under the CAA Due to Non-Cancer Health Effects on thePulmonary 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 edemaAllergic 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


Severe bronchoconstriction and paralysis of respiratory muscles


Diphtheria-like mutations of trachea and bronchi; bronchitis, lung edema, sec-ondary bronchial pneumonia

Abnormal pulmonary function, upper respiratory tract irritation, wheezing, chesttightness, 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; pulmonaryedema

Pulmonary lesions

Upper respiratory tract imitation

SOURCES: 42 U.S.C. 7412; Tim Simpson, U.S. Environmental Protection Agency, Research Triangle Park, NC, personal communi-cation, August 1991; 54 Federal Register 2329-2984 (Jan. 19, 1989).


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; uncon-sciousness may occur and death may follow due to paralysis in cases of extremeexposure


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 un-consciousness may occur and death may follow due to respiratory paralysis incases 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 fibroticlesions

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 TrianglePark, NC, personal communication, August 1991; 54 FederaZRegister 2329-2984 (Jan. 19, 1989).

kyl halides, and perhalo alkoxy ether due to the threatof pulmonary edema. EPA imposed the same require-ment on silane because data showed that it causesirreversible lung toxicity (6).

Federal Insecticide, Fungicide, and Rodenticide Act

FIFRA was enacted to help avoid unreasonableadverse effects on the environment, including humans,due to exposure to pesticides. It requires those who sell

or distribute pesticides to register the product withEPA. A product maybe classified and registered forgeneral or restricted use, or both. If a pesticide isclassified for restricted use because it poses an inhala-tion toxicity hazard to the applicator or other persons,then the product may only be applied by or used underthe direct supervision of a certified applicator. Sub-stances that pose inhalation hazards are substancesthat are dangerous to some organ and that enter thebody through the lung. Not all inhalable toxicants af-


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- 0.5lessness and unconsciousness may occur and death may followdue 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- 200.0actions; 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, personalcommunication, August 1991; 54 Federal Register 2329-2984 (Jan. 19, 1989).

Table 4-5—Pulmonary Toxicants Regulated Under FIFRA

Active ingredient Criteria influencingin pesticide restriction

Acrolein Respiratory tract irritant

Allyl alcohol Upper respiratory tract irritant

Hydrocyanic acid Upper respiratory tract irritant

Methyl bromide Lung irritant; causes pulmonaryedema

Methyl parathion Excessive exposure may causebronchoconstriction

Paraquat (dichloride) and Pulmonary irritant; can cause pul-paraquat 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 ingredientsregulated under FIFRA that are pulmonary toxicants.

Department of Labor

Two entities within DOL regulate human exposureto airborne toxicants. OSHA administers the Occupa-tional Safety and Health Act (OSH Act; 29 U.S.C. 651et seq.). MSHA administers the Federal Mine Safetyand Health Act (FMSHA; 30 U.S.C. 801), which oper-ates similarly to the OSH Act but is restricted to themining industry.

Occupational Safety and Health Administration

OSHA’s task is to develop regulations for the useof toxic substances in the workplace. OSHA can re-quire specific handling procedures, training for work-ers, recordkeeping, and testing of hazardous materials.It can also establish or modify permissible exposurelimits (PELs) for toxic substances. Many substancesare regulated by OSHA because of their detrimentaleffects on the pulmonary system. Table 4-6 lists aircontaminants regulated by OSHA because of pulmo-nary 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 . . . . . . . . . . . . . . . . . . . . . . . .


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 andinfections of respiratory tract



Lung injury and possible death


Histologic lesions of the lung and pulmonary irritation



Pulmonary fibrosis and respiratory irritation



Respiratory irritation and inflammation

Causes asbestosis

Upper respiratory tract imitation and pneumoconiosis

Pulmonary edema and hemorrhage; tightness of chest, breathlessness; uncon-sciousness may occur and death may follow due to respiratory paralysis in casesof extreme exposure

Shown to cause lung damage and pulmonary edema in animals


Granulomatous lesions in lungs



Pneumonia and pneumonitis

Respiratory tract irritation and lung edema

Toxic lung changes

Respiratory imitation



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


Acute respiratory toxicity and upper respiratory tract irritation


Necrosis of tracheal and bronchial epithelium, bronchitis, broncho pneumoniaand fatal pulmonary edema

Respiratory irritation and bronchitis

Difficulty in breathing

Respiratory irritation, cough, dyspnea, and pulmonary edema


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 pneu-monia

Coughing and dyspnea

Lung damage (unspecified)

Byssinosis

Obliterative bronchiolitis; adenomatosis; hypersensitivity reactions; chronicinterstitial pneumonitis and occasional fatalities

Pulmonary edema and upper respiratory tract irritation





Pulmonary edema

Lung injury (unspecified)



Respiratory irritation and lung hemorrhage

Tracheitis, bronchitis, pneumonitis, and pulmonary edema

Respiratory tract sensitization



Lung edema

Pulmonary edema; can cause death through repeated exposures at low concen-trations


Respiratory tract irritation and pneumonconisis

Lung edema, respiratory tract irritation, dyspnea, and bronchitis


Respiratory irritation, pneumonia and pulmonary edema

Lung congestion

Respiratory tract irritation; lung irritation and congestion


Respiratory tract and lung irritation


Lung edema and secondary bronchial pneumonia

Respiratory irritation and lung injury (unspecified)


Chronic bronchitis and chronic lung inflammation

Difficulty breathing, severe respiratory tract injury leading to pulmonaryedema, pneumonitis, and bronchial irritation which may lead to death depend-ing on concentration of exposure; chronic exposure may lead to developmentof bronchitis and asthma



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) . . . . . . . . . .


Asthma


Respiratory tract and lung irritation, pneumonitis and emphysema

Chronic bronchitis, asthma, dyspnea, wheezing, and reduced pulmonary func-tion

Pneumoconosis and anthracosilicosis


Pulmonary irritation, bronchitis, and bronchiolitis



Upper respiratory tract irritation and dyspnea


Pulmonary edema; fatal at high concentrations


Chemical pneumonitis, pulmonary edema and lung hemorrhage

Widespread alveolar edema

Siderosis

Pulmonary injury and dyspnea


Respiratory tract irritation, decreased pulmonary function, and sensitization



Respiratory effects (unspecified)

Respiratory tract irritation and pulmonary edema


Chronic respiratory disease (unspecified)

Chronic bronchitis

Pulmonary edema

Pneumonia and lung damage (unspecified)

Pneumonitis and other respiratory effects


Bronchopneumonia, lung irritation, and pulmonary edema

Lung congestion


Upper respiratory tract irritation and lung damage (unspecified)

Pulmonary edema, lung inflammation, and dyspnea

Lung irritation

Pulmonary edema and lung irritation

Pulmonary edema


Bronchioconstriction



Chapter 4—Federal Attention to Pulmonary Toxicants ● 59


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




Pulmonary edema and hemorrhage

Significant reduction in pulmonary vital capacity and pulmonary congestion

Pulmonary irritation, pulmonary edema, and intra-alveolar hemorrhage


Alveolar hemorrhage, emphysema, and alveolar edema

Guinea pigs died after inhalation exposure; no human inhalation data


Allergic asthma and inflammation of the larynx and pharynx from industrialexposure

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 deathmay occur 30 minutes to 1 hour after exposure


Respiratory tract irritation and pulmonary edema


Bronchitis and pneumonia

Respiratory irritation and pulmonary sensitization

Edema, papules, vesicles, and desquamations of the nose

Pulmonary sensitization






Respiratory sensitization



Silicosis

Pulmonary lesions

Aggravates pulmonary tuberculosis


Pneumoconiosis



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


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 func-tion, and fibrotic changes in lung tissue

Lung lesions, bronchitis, hyperemia, and interstitial pneumonitis


Long-term decline in lung function and pulmonary edema


Stannosis and reduced pulmonary capacity

Pulmonary sensitization and long term decline in lung function

Lung inflammation

Lung toxicity




Intra-alveolar hemorrhage

Lung irritation


Asthmatic bronchitis

Proliferation of intra-alveolar septa, pulmonary fibrosis, and dyspnea

Bronchial irritation and tracheobronchitis

Bronchitis, emphysema, tracheitis, pulmonary edema, and bronchial pneumo-nia



Damage to small airways causing interstial pneumonia; respiratory irritation

Allergic respiratory effects, decrease in pulmonary function

Damage to respiratory tract, severe pneumonitis, and advanced pulmonaryfibrosis

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;29CFR1910.1044,July l, 1991; 29 CFR1910.1043,July l, 1991; 29 CFR1910.1044,July l, 1991; 29 CFR1910.1047,July 1,1991;29CFR1910.1048, July l,1991; 53 FederalRegister21062 (June7, 1988); 54 F’eu!enzZRegister2329-2984 (Jan. 19,1989).


Mine Safety and Health Administration

MSHA develops regulations to protect the healthand safety of miners. It administers FMSHA, which isclearly concerned about pulmonary toxicants. FMSHAuses the framework for health guidelines presented inthe 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 sam-pling, medical examinations for miners, and dust con-trol measures. A stated purpose of the health standardswas to ensure that mines are “sufficiently free of respir-able dust concentrations . . . to permit each miner theopportunity to work underground during the period ofhis entire adult working life without incurring anydisability from pneumoconiosis or any other occupa-tion-related disease during or at the end of such pe-riod.”

Other Federal Regulatory Activities

EPA and DOL exercise the main regulatory author-ity over airborne pulmonary toxicants. Other agenciesalso administer laws that can be used to control thesesubstances, however. CPSC enforces the ConsumerProduct Safety Act (CPSA; 15 U.S.C. 2051 et seq.) andthe Federal Hazardous Substances Act (FHSA; 15U.S.C. 1261 et seq.). The FDA regulates chemicalsfound in foods, drugs and cosmetics under the FederalFood, Drug, and Cosmetic Act (FDCA; 21 U.S.C. 301et seq.).

Consumer Product Safety Commission

The CPSC conducts research on injuries and dis-eases caused by consumer products and disperses infor-mation. The commission is also charged with the dutyof generating consumer product safety standards andmonitoring compliance.

Consumer Product Safety Act—CSPA is intendedto protect the American public from undue risk ofinjury from consumer products and to help consumersjudge the comparative safety of articles available in themarketplace. CPSA gives CPSC the authority to ban orrecall hazardous products. Few regulations issued un-der CPSA (16 CFR 1000 et seq.) deal specifically withhealth hazards to the pulmonary system posed by un-safe consumer products. However, several products

containing asbestos are mentioned specifically asbanned materials. Consumer patching compoundscontaining respirable free-form asbestos are prohib-ited on the American market. Also, artificial emberiz-ing materials (e.g., artificial fireplace logs) containingrespirable free-form asbestos are forbidden. The regu-lations for these products specify the reason for the banas the unreasonable risk of lung cancer, noncancerouslung diseases and injury due to inhaling asbestos fibers.

Federal Hazardous Substances Act. FHSA is in-tended to protect the public from health problems byrequiring that hazardous substances be labeled to warnindividuals of associated health risks. Regulations is-sued under FHSA control a number of pulmonarytoxicants, including formaldehyde, which is a strongsensitizer (a substance that causes normal living tissue,through an allergic or photodynamic process, to be-come severely hypersensitive on re-exposure to thesubstance).

The regulations also control “hazardous sub-stances,” which are defined as materials that have thepotential to cause substantial personal injury or sub-stantial illness as a result of any customary or reason-ably foreseeable use or handling. Benzene, productscontaining 5 percent or more by weight of benzene, andproducts containing 10 percent or more by weight oftoluene, xylene, turpentine, or petroleum distillates(e.g., kerosene, naphtha, and gasoline) are listed ashazardous substances. Such products must be clearlylabeled with several words and symbols including “dan-ger” and “harmful or fatal if swallowed” since thesematerials may be aspirated into the lungs causingchemical pneumonitis, pneumonia, and pulmonaryedema.

Food and Drug Administration

FDA regulates chemicals found in foods, drugs, andcosmetics, primarily through FDCA. Some of FDA’sactions under this statute have been taken to protectpulmonary health. For example, sulfites are subject toa number of FDA regulatory requirements becausethey have been found to cause severe, and potentiallylethal, asthma attacks in sensitive individuals. Sulfitesare no longer considered safe for use in meats, fruitsand vegetables to be served or sold raw or presented toconsumers as fresh (21 CFR 182). The presence ofsulfites in food must be declared when these chemicals


are present at levels above 10 parts per million. How-ever, FDA has not regulated airborne substances be-cause of pulmonary toxicity.

FEDERAL RESEARCH ACTIVITIES

Knowledge of the pulmonary system and themechanisms and causes of pulmonary disease helpsFederal agencies create effective regulations. Federalresearch in these areas is conducted mainly under thedirection of EPA the Department of Health and Hu-man Services (DHHS), and the Department of Energy(DOE). EPA’s Health Effects Research Laboratory(HERL) conducts research in pulmonary toxicologyand epidemiology. DHHS conducts noncancer pulmo-nary research through several agencies, including theNational Institutes of Health (NIH), the Centers forDisease Control (CDC), and the FDA. The Office ofHealth and Environmental Research, part of the Officeof Energy Research, handles DOE’s research in pul-monary toxicology.

Environmental Protection Agency

Two divisions within HERL conduct research onpulmonary toxicants. The Environmental ToxicologyDivision, through its Pulmonary Toxicology Branch,primarily tests the effects of air pollutants on animalsto develop a basis for regulations under the CAA. Inaddition, it conducts pulmonary research with volatileorganic compounds, sulfuric acid, and nitric acid. TheClinical Research Branch of the Human Studies Divi-sion conducts research on the effects on humans fromexposures to ozone and other criteria pollutants regu-lated under CAA. The Epidemiology Branch of theHuman Studies Division also carries out epidemi-ologic studies on the criteria pollutants.

HERL, located in Research Triangle Park, NC,collaborates with the University of North CarolinaCenter for Environmental Medicine and Lung Biology(CEMLB), which provides important support for theclinical and epidemiologic studies. HERL also workswith the Duke University Center for ExtrapolationModeling, which works to confirm that animal modelsused in the Toxicology Division accurately predict re-sponses in humans, and develops generic models to beused in risk assessment programs.

HERL’s work in pulmonary toxicology takes sev-eral forms. The laboratory studies extrapolation tech-niques-applying knowledge gained from animal testresults to human risk. HERL also performs acute ex-posure studies and attempts to apply those results tochronic exposure scenarios. HERL is engaged in theeffort to define adversity of response, i.e., deciding atwhat point a response, which may be a normal com-pensatory activity of the body, can be considered “ad-verse.” HERL also focuses on susceptible populations,such as asthmatics, to determine why some personsexhibit more detrimental effects from air pollutionthan others.

Current funding for the Pulmonary ToxicologyBranch is approximately $2.6 million. The Clinical Re-search 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 HealthSciences (NIEHS), part of the NIH, had a budget ofapproximately $5,230,000 for intramural noncancerpulmonary research in fiscal year 1991. NIEHS alsomade over $15 million in extamural grants to variousuniversities and institutions in fiscal year 1991 for studyof pulmonary toxicants. An additional $3,190,000 wasspent on extramural contracts. The studies funded em-ploy a wide range of techniques, including microbiol-ogy, whole animal studies, human clinical studies, andepidemiology. Substances researched include those af-fecting small sub-groups of the population, as well asthose affecting the general population. The followingprojects provide examples of the extramural researchfunded by NIEHS.

.

.

Scientists at the University of Iowa Department ofMedicine received approximately $77,000 to studythe effects of silica on the epithelial cells of thelungs in order to better understand how silicosiscan be prevented.Researchers at the Medical College of Wisconsinreceived over $77,000 to study growth factor secre-tion in dust-induced lung disease in rats. This studywas undertaken in order to clarify how alveolar


macrophages react to dust, eventually leading topneumonconiosis.

● The National Jewish Center for Immunology andRespiratory Medicine received nearly $76,000 tostudy the immunologic and toxic mechanisms ofberyllium disease in mice and humans in order tobetter understand the pathology of chronic beryl-lium disease in humans.

● Scientists at the University of California at Davisreceived $530,000 to study the effects of ozone onthe lungs of rats, mice, hamsters, and monkeys asa basis to predict the effects of ozone in ambientair on humans.

. Researchers at the University of Rochester Schoolof Medicine received $175,000 to conduct clinicalinhalation studies on healthy humans and thosewith chronic pulmonary disease to investigate therespiratory effects of particulate and oxidant airpollutants (26).

● Scientists at the University of Iowa PulmonaryDisease Division received close to $53,000 to con-duct epidemiologic studies of vegetable dust-in-duced airway disease in humans. The purpose ofthis study is to evaluate the feasibility of using thecurrent threshold safety limit in the handling ofcereal grain (oats, wheat, rye and barley) to protectthe health of noncereal grain and vegetable (cornand soybean) handlers.

● Harvard University received $864,000 to conductan epidemiologic study of the effects of acid aero-sols, ozone, and particulate matter on the respira-tory health of children in 24 cities in NorthAmerica.

Using a model of asbestosis in laboratory animals,NIEHS intramural scientists have found that as macro-phages engulf asbestos particles, growth factors aresecreted that induce an increase in the number offibroblasts. The fibrotic condition that results disruptsgas exchange. Current studies focus on stopping therelease of the growth factors or preventing their bio-logical activity. In fiscal year 1991, this project receivedfunding of nearly $821,000 (19).

Other NIEHS intramural scientists are studying theregulation of the pulmonary surfactant system and itsmodification by toxic agents such as silica dusts. Thesestudies are focused on identifying cellular factors re-leased by inflammatory cells in response to a toxicagent that regulates surfactant production in alveolar

Type II cells. This project received almost $575,000 infiscal year 1991 (19).

NIEHS also contracts for a variety of inhalationtoxicology studies on drugs, naturally occurring agents,and industrial compounds. For example, the IIT Re-search Institute in Chicago, IL, was awarded over$495,000 to investigate the toxicity of isobutyl nitrite(IBN). IBN is a component of some room deodorizersand is sold illicitly in ampules known as “Poppers.” Inthe prechronic study, the lungs, bone-marrow, spleen,and nasal-cavity were identified as target organs fortoxicity (19).

The National Heart, Lung, and Blood Institute(NHLBI), also part of NIH, conducts noncancer pul-monary research through its Division of Lung Dis-eases. This program includes studies on environmentallung disease caused by air pollutants and occupationallung disease. Approximately half of this research iscarried out on animals and the other half is done onhuman subjects.

Extramural grants from NHLBI support researchon pulmonary toxicology at a number of universities.Examples of environmental research include:

.

●

✎

✎

●

✎

Researchers at Louisiana State University are cur-rently studying the effects of ozone, automobileexhaust, and tobacco smoke on the lung. This pro-ject is funded at approximately $127,000 per year.Scientists at the State University of New York atStony Brook are studying ozone and respiratorymucus permeability, and receive about $79,000 forthis project.Researchers at Pennsylvania State University areconducting tests on oxidant stress in the respira-tory system at a funding level of approximately$185,000 per year.Two groups of scientists at the University of Cali-fornia at Irvine are conducting human research oninhaled particle deposition and animal research onthe effects of air pollution. They receive approxi-mately $325,000 per year for these studies.Researchers at the University of Maryland re-ceived approximately $100,000 to study the effectof environmental tobacco smoke on human lungs.Scientists at the University of California at Berke-ley receive approximately $240,000 to conduct ahuman study of the physical and chemical proper-


ties of smoke and of the deposition of smoke par-ticles in the lung.

● Researchers at Harvard University are conductinghuman and animal studies of inhaled retention ofparticulate matter, for which they receive approxi-mately $134,000 per year.

. Scientists at the University of California at SantaBarbara received funding of about $190,000 for astudy of the mechanisms of human response toozone.

A number of research projects supported byNHLBI relate to occupational exposure to pulmonarytoxicants. For example:

● Specialized Centers of Research (SCOR) investi-gators at the University of Iowa are studying theepidemiology and pulmonary responses to organicdust exposures in farm workers, for which theyhave received $127,000.

. The Iowa investigators and investigators at theUniversity of New Mexico, are studying mecha-nisms of hypersensitivity pneumonitis, also knownas farmer’s lung, for which they have received over$135,000.

● A group of SCOR researchers at Tulane Univer-sity received approximately $933,000 for a study ofthe respiratory effects of exposure to irritant gasesand vapors in a population of 25,000 workers in thechemical manufacturing industry.

● At the University of Vermont, SCOR scientistsreceived over $230,000 for an assessment of themechanisms involved in injury and inflammationin occupationally related fibrotic lung disease as-sociated with exposure to asbestos.

● Researchers at the State University of New Yorkat Buffalo received $354,054 for a study of thepathogenesis of disease associated with exposuresin the textile industry.

For fiscal years 1992 and 1993, the Division of LungDiseases is developing two special initiatives. One isrelated to the mechanisms of ozone-induced lung in-jury and a second is on basic mechanisms of asbestosand nonasbestos fiber-related lung disease (13,14).NHLBI conducts basic research not specifically linkedto any particular legislation or regulations. For fiscalyear 1991, the total budget for lung research was$205,255,000; of that, $26,980,000 was dedicated toresearch on asthma, and approximately $22,619,000was used to study chronic bronchitis and emphy-sema (12).

The National Institute for Occupational Safety andHealth (NIOSH), part of the CDC, studies the pulmo-nary system through its Division of Respiratory Dis-ease Studies (DRDS) at the Appalachian Laboratoriesfor Occupational Health and Safety at Morgantown,WV. In addition, an extramural grant program is di-rected through NIOSH’s administrative offices in At-lanta, GA. The overall budget for NIOSH in fiscal year1992 is $103,450,000 with $13,400,000 designated forthe study of occupational respiratory diseases. This isan increase from the approximately $7,687,112 allo-cated to intramural research and $3,1%,218 spent onextramural research in the area of occupational lungdisease in fiscal year 1991 (7,16).

NIOSH conducts research stimulated by the adviceof DOL and investigator initiated research. Addition-ally, the Mine Health Research Advisory Committeesuggests areas of study where gaps exist in the know-ledge base. Other research suggestions come fromNIOSH’s Board of Scientific Counselors. NIOSH hasspecific authority from the OSH Act and FMSHA toconduct research and to make recommendations forhealth and safety standard regulations (27).

DRDS conducts epidemiologic research on pulmo-nary diseases related to the mining, milling, agricul-tural, construction, and other industries. Among theresearch programs in this area are a medical surveil-lance program for living coal miners (the NationalCoal Worker’s X-ray Surveillance Program), and anautopsy program (the National Coal Workers’Autopsy Study) required by FMSHA. An ongoing sur-veillance program examines whether current coal minedust standards protect miners’ health. This study hascontinued for more than 20 years and is conductedthrough voluntary x-rays and an organized epidemi-ologic investigation. DRDS also conducts epidemi-ologic studies of occupational asthma and pulmonarydisease caused by exposure to cotton dust. The agencymonitors trends in the incidence of all occupationallung diseases. Clinical studies are conducted to deter-mine the effects of occupational exposure to specificsubstances and to better understand human responsemechanisms (28).

DRDS also conducts research in such areas asphysiology, pathology, and microbiology to better un-derstand the dangers of substances and the mecha-nisms of disease. Scientists choose animal modelssuitable for the study of particular agents and developnew laboratory techniques.

Chapter 4—Federal Attention to Pulmonary Toxicants . 65

Extramural research is conducted through suchprograms as the NIOSH Centers for Agricultural Re-search, Education, and Disease and Injury PreventionProgram. This program funds centers at the Universityof California at Davis, the University of Iowa at IowaCity, the National Farm Medicine Center in Marsh-field, WI, and the Colorado State University at FortCollins. Most of the program’s pulmonary studies areconducted at the University of Iowa center, which con-ducts research in such areas as grain dust exposures andrespiratory diseases in dairy farmers (7).

Unlike other Federal research agencies, NIOSHresponds to requests from workers and their repre-sentatives to investigate the causes of accidents andillnesses in the workplace. In fiscal year 1992, NIOSHissued 40 final reports of respiratory disease healthhazard evaluations. Onsite evaluations of possible pul-monary health hazards are performed by DRDS.DRDS medical personnel, industrial hygienists, andepidemiologists analyze the workplace situation and

present suggestions for diminishing harmfulexposures (28).

The National Center for Toxicological Research(NCTR) in Jefferson, AR, conducts methods develop-ment and toxicological research for the FDA. Thepurposes of the Center are to increase knowledge ofhuman health risks associated with exposure to artifi-cial and natural substances and to elucidate the mecha-nisms and impact of these risks. Pulmonary toxicitystudies conducted at NCTR deal primarily with chroniclong-term exposure to carcinogenic or mutagenic com-pounds. Currently research is focused on compoundsof interest to FDA unrelated to pulmonary toxicity (l).

Department of Energy

DOE funds research on pulmonary toxicants con-ducted by the Inhalation Toxicology Research Institute(ITRI) in Albuquerque, NM. ITRI is owned by DOEand is operated under along-term contract by a private,

Photo Credit: G. Wagner, National Institute for Occupational Safety and Health


nonprofit corporate entity, the Lovelace Biomedicaland Environmental Research Institute. ITRI receivesapproximately 75 percent of its funding from DOE,with the other 25 percent coming from other govern-ment agencies, nongovernment associations, and indi-vidual companies. Funding by DOE remains constant,while other government agencies and private sourcesprovide funding for particular studies in areas of theirinterest.

All research at ITRI is lung related, and it rangesfrom molecular studies focusing on cellular changescaused by inhaled materials to clinical studies of humansubjects. Studies are related to two general areas: thosewhich examine the effects of specific substances on therespiratory system and those which explore the struc-ture and function of the respiratory tract and the gen-eral behavior of gases, vapors, and particles in therespiratory tract (17).

Research on noncancer pulmonary toxicity is cur-rently being conducted on ozone, nitrogen oxides, sul-fur oxides, and the components of engine exhaust.Some studies focus on occupational exposures to pul-monary toxicants, including benzene, butadiene,nickel, and beryllium. Other research examines theeffects of exposure to natural fibers, such as asbestos,and synthetic fibers, such as fiberglass. Studies on res-piratory system structure and function focus on theuptake, deposition, and excretion of toxicants, andnatural defenses of the respiratory system to inhaledmaterials (17).

ITRI proposes studies it decides need to be con-ducted, and DOE allocates funds according to its inter-ests and resources. The scientific research budget forITRI in fiscal year 1992 is approximately $13.5 million.In 1992 ITRI has allocated approximately 54 percentof its budget to cancer research. The other 46 percentis designated for noncancer research. Of the noncancerbudget, a little over half is spent on general toxicology,including the study of the mechanisms of diseases,mathematical models of effects, and studies of themetabolism of compounds. Approximately one quar-ter of the budget is allocated for the study of the natureof airborne materials (vapors, particulate matter andgases). The remaining quarter is designated for do-simetry studies (18).

Cooperative Federal and Private Research

The Health Effects Institute (HEI) supports andevaluates research on the health effects of motor vehi-

cle emissions. Its research program focuses on sub-stances regulated by the NAAQS in the CAA, as wellas other pollutants, such as diesel exhaust particles,methanol, and aldehydes (10). Because all researchtargets emissions, the majority of HEI’s research fo-cuses on the lung (20). All research at HEI is extramu-ral, with funding mainly going to universities, but alsoto research centers (e.g., ITRI and the Los AmigosResearch and Education Institute). Both cancer andnoncancer research is funded, but no clear breakdownis available because research is pollutant-focusedrather than effect-focused (29).

HEI receives one-half of its funding from EPA andthe other half from all companies who make or sellautomobiles, trucks, or engines in the United States.Currently, EPA and 28 private companies fund HEI.HEI bills the companies separately based proportion-ally on the number of vehicles or engines they sell thatyear in the United States. Contributing companies in-clude American, European, and Japanese corpora-tions. The total budget for HEI in fiscal year 1992 is $6million (9).

A separate nonprofit organization, the Health Ef-fects Research Institute—Asbestos Research (HEI-AR), was established in September 1989 to supportscientific studies to evaluate airborne levels of asbestosin buildings, to assess exposure, and to examine asbes-tos handling and control strategies. HEI-AR is mod-eled after HEI but is an independent entity.

Beginning in fiscal year 1990 HEI-AR was sched-uled to receive $2 million annually for 3 years fromEPA. It secures an additional $2 million per year fromcombined sources in the real estate, insurance, andasbestos manufacturing industries, as well as from pub-lic and private organizations interested in asbestos. In1991, HEI-AR published a report including literaturereview of current knowledge of asbestos in buildingsand identifying areas where more knowledge is needed.It has also begun a program of support and evaluationfor scientific asbestos studies (11).

SUMMARY

The Federal Government plays an active role in theprotection of pulmonary health through regulationsand research. Regulations promulgated under theCAA, RCRA, TSCA, FIFRA, CPSA, and FDCA aredesigned to protect pulmonary health in the generalpopulation. Regulations promulgated under the OSHAct and FMSHA are designed to safeguard workers

Chapter 4—Federal Attention to Pulmonary Toxicants ● 67

and miners respectively from exposure to pulmonarytoxicants within the scope of their employment. Fed-eral regulations call for a variety of measures to controlthe risk of exposure to pulmonary toxicants, includingsetting exposure levels, banning certain materialswhich pose an unmanageable risk of pulmonary injury,and requiring safety devices and education in the work-place.

Federal research on pulmonary toxicants is con-ducted primarily under the auspices of EPA, DHHS,and DOE. Research by these organizations is con-ducted on an intramural basis and on an extramuralbasis through grants to universities and other researchinstitutes. An effort has been made to combine publicand private funding of pulmonary toxicology researchin HEI. Federally funded research includes studiesinvolving human and animal subjects that employ re-search techniques ranging from cellular studies to epi-demiology. Applying the knowledge gained throughthese studies, Federal agencies have been able to de-sign regulations which should more effectively reducehealth risks to the pulmonary system.


1.

2.

3.

4.

5.6.7.

8.

9.

Adams, L., Office of Legislative Affairs, Food andDrug Administration, Washington, DC, personalcommunication, February 1992.Anderson, F., Environmental Protection: Law ad,Policy (Boston, MA: Little, Brown & Co., 1990).Blodgett, J. Hazardous Air Pollutants: RevtiingSection l120fthe CleanAirAct, Environment andNatural Resources Policy Division, Congres-sional Research Serviee, Library of Congress(Washington, DC: Library of Congress, February1991).Costa, D., Pulmonary Toxicology Branch, HealthEffects Research Laboratory, U.S. Environ-mental Protection Ageney, Research TrianglePark, NC, personal communication, September1991.52 Federal Register 16022 (May 1, 1987).52 Federal Register 46766 (Nov. 6, 1990).Friedlander, J., Centers for Disease Control, At-lanta, GA personal eommunieation, February1992.Hazen, S., 33/50 Program, Environmental Pro-tection Ageney, Washington, DC, personal com-munication, August 1991.Health Effeets Institute, “Annual Report: 1990-1991,” unpublished booklet, Cambridge, MA.

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Health Effeets Institute, “Requests for Applica-tions: 1991 Research Agenda,” unpublishedbooklet, Cambridge, ~ October 1991.Health Effects Institute—Asbestos Research,“Requests for Applications,” unpublished book-let, Cambridge, N@ October 1990.Hymiller, J., Budget Office, National Heart,Lung, and Blood Institute, National Institutes ofHealth, Washington, DC, personal communica-tion, Februag 1992.Kalica, A., Airways Division, National Heart,Lung, and Blood Institute, National Institutes ofHealth, Washington, DC, personal eommuniea-tion, February 1992.Kiley, J., Airways Division, National Heart, Lung,and Blood Institute, National Institutes ofHealth, Washington, DC, personal communica-tion, February 1992.Koren, H., Health Effects Research Laborato-ries, U.S. Environmental Protection Agency, Re-sea rch Tr iang le Park , NC, persona lcommunication, March 1992.Landry, M., Financial Management Office, tlm-ters for Disease Control, Atlanta, GA personalcommunication, November 1991.Mauderly, J., Inhalation Toxicology Research In-stitute, Albuquerque, NM, personal eommuniea-tion, September 1991.Mauderly, J., Inhalation Toxicology Research In-stitute, Albuquerque, NM, personal communica-tion, January 1992.Phelps, J., National Institute of EnvironmentalHealth 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 CongressionalandAdministrative 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 Congressionaland 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 ofAir and Radiation, “Early Reduction Program;unpublished memo, Washington, DC, May 1991.U.S. Environmental Protection Agency, “EPA’s33/50 Program: A Progress Report,” unpublishedmemo, Washington, DC, July 1991.


26. Utell, M., University of Rochester Medical Cen- 28. Wagner, G., Division of Respiratory Diseaseter, Rochester, NY, personal communication, Studies, National Institute for OccupationalDecember 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 ofthe bronchioles.

Antigen: A substance that brings about an immuneresponse when introduced into the body.

Asthma: A chronic respiratory disease accompanied bylabored breathing, chest constriction, and coughing.

Biologically effective dose: The amount of a contami-nant that interacts with cells and results in alteredphysiologic function.

Black lung disease: An occupational disease of coalworkers resulting from deposition of coal dust in thelungs.

Bronchoalveolar lavage fluid: Fluid obtained from thebronchoalveolar region of the lungs by lavage.

Bronchoconstriction: Narrowing of a bronchus causedby constriction of bronchial smooth muscle.

Bronchus: One of the large conducting air passages ofthe lungs commencing at the bifurcation of the tra-chea and terminating in the bronchioles.

Byssinosis: An occupational respiratory disease of cot-ton, flax, soft-hemp, and sisal workers characterizedby symptoms of chest tightness.

Chronic bronchitis: Chronic inflammation of bronchiresulting in cough, sputum production, and oftenprogressive breathlessness.

Cilia: Long slender microscopic structures extendingfrom 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 reason-ably be anticipated to endanger public health orwelfare.

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 toinfection.

Endothelium: The layer of cells lining the blood ves-sels.

Epidemiology: The scientific study of the distributionand occurrence of human diseases and health condi-tions and their determinants.

Epitheliums: The thin layer of cells lining the inside ofthe respiratory tract.

Extrinsic allergic alveolitis: Severe immune responsesto 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 carbondioxide and other gaseous components and metabo-lites in the blood stream to the exhalable air.

In vitro: Literally, in glass; pertaining to a biologicalprocess taking place in an artificial environment,usually a laboratory.

In vivo: Literally, in the living; pertaining to a biologi-cal process or reaction taking place in a living organ-ism.

Larynx: Part of the respiratory tract containing thevocal 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 tech-nique which provides a means of actively monitoringthe dust retained in the lungs of people exposed tomagnetic or magnetizable dusts.

Microscopy: The use of an instrument to obtain mag-nified images of small objects.

Morphometry: The measurement of the structure andforms of organisms, as opposed to the measurementof their functions.

Mucus: The viscous fluid secreted by the mucousglands.

Nasopharyngeal region: Region of the lung compris-ing the nasal cavity and pharynx.

Phagocytosis: Consumption of foreign particles bycells.

Pharynx: The portion of the alimentary canal whichintervenes between the mouth cavity and theesophagus and serves both for the passage of foodand the performance of respiratory functions.

Pleura: The serous membrane lining the pulmonarycavity.

Pleural cavity: The space that separates the lungs fromthe chest wall. It contains a small amount of fluid

71


and is bounded by membranes called the pleura.Pneumoconiosis: A condition characterized by the

deposition of mineral dust in the lungs as a result ofoccupational or environmental exposure.

Pulmonary edema: The accumulation of abnormallylarge amounts of watery fluid within the pulmonaryalveoli.

Pulmonary fibrosis: The accumulation of abnormalquantities of fibrous tissue in the lung.

Pulmonary region: The region of the lung where oxy-gen in the air is supplied to the blood and carbondioxide and other gaseous components and metabo-lites are released from the blood to the air remainingin the lungs.

Respiratory system: An interconnected series of airpassages, cavernous organs, and cells that permit theintroduction of oxygen, the-exchange of gases, andthe removal of carbon dioxide from the body as wellas the production of speech.

Risk assessment: The analytical process by which thenature and magnitude of risk are identified. Foursteps make up a complete risk assessment: hazardidentification, dose-response assessment, exposureassessment, 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 com-

prising 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 forthe inside of the alveoli.

AcronymsATS —American Thoracic SocietyBAL —Bronchoalveolar lavageBALF —Bronchoalveolar lavage fluidC M —Clean Air ActCASAC —Clean Air Science Advisory Committee

(EPA)CDC —Centers for Disease ControlCFR —Code of Federal Regulationsc o —Carbon monoxideC 02 -Carbon dioxide

COAD —Chronic obstructive airway diseaseCOLD —Chronic obstructive lung diseaseCOPD —Chronic obstructive pulmonary diseaseCPSA —Consumer Product Safety ActCPSC —Consumer Product Safety CommissionDHHS —Department of Health and Human ServicesDLco —Diffusing capacity of the lung for carbon

monoxideDOE —Department of EnergyDRDS —Division of Respiratory Disease Studies

(NIOSH)EPA —Environmental Protection AgencyERP —Early Reduction ProgramFDA —Food and Drug AdministrationFDCA —Food, Drug, and Cosmetic ActFEF5o —Forced expiratory flow of 50 percentFEF75 —Forced expiatory flow of 75 percentFEV1 —Forced expiratory volume in 1 secondFHSA —Federal Hazardous Substances ActFIFRA —Federal Insecticide, Fungicide, and

Rodenticide ActFMSHA —Federal Mine Safety and Health ActFVC —Forced vital capacityHEI —Health Effects InstituteHERL —Health Effects Research LaboratoryITRI —Inhalation Toxicology Research InstituteMACT —Maximum achievable control technologyMMEF —Maximal midexpiratory flowMPG —MagnetopneumographyMSHA —Mine Safety and Health AdministrationNAAQS —National Ambient Air Quality StandardsNAS —National Academy of SciencesNCTR —National Center for Toxicological

ResearchNHLBI —National Heart, Lung, and Blood InstituteNIEHS —National Institute of Environmental

Health SciencesNIH —National Institutes of HealthNIOSH —National Institute for Occupational Safety

and HealthNOX —Nitrogen oxidesNRC —National Research CouncilOSHA —Occupational Safety and Health

AdministrationOTA —Office of Technology AssessmentPEL —Permissible exposure limitRCRA —Resource Conservation and Recovery ActTRI —Toxics Release InventoryTSCA —Toxic Substances Control ActUCLA —University of California at Los AngelesVOC —Volatile organic compounds

Index

Adverse health effects, 4,9-10,43Air

amount inhaled, 3, 15composition of, 6, 15,29contaminants, 56hazardous pollutants of, 7,49,52pollutants, 6-8,25,31,62-65quality, 6-8

Airborne substances, 4,6,8Aldehydes, 66Alkyl halide, substituted, 51Alpha1 -antitrypsin, 21American Thoracic Society (ATS), 43Animal, selection of appropriate test, 6,34Arsenic, inorganic, 49Asbestos, 22,29,49,61,63-64,66Asthma, 5,21,22,64Benzene, 49,61,66Beryllium, 34,49,62,66Biological agents, 4,8Biologically effective dose, 6,31-33Black lung disease, 61Bronchitis, chronic, 19-20,21Bronchoalveolar lavage (BAL), 41Bronchoalveolar lavage fluid (BALF), 38Bronchoconstriction, 21,34Butadiene, 66Bysinossis, 21Cadmium, 21Carbon monoxide (CO), 8,25,29,49Centers for Disease Control (CDC), 64Chemical pneumonitis, 61Chronic bronchitis, 5,19,64Chronic obstructive airway disease (COAD), 21Chronic obstructive lung disease (COLD), 21Chronic obstructive pulmonary disease (COPD), 21Clean Air Act (CAA), 7,49-51Clean Air Science Advisory Committee (CASAC), 9Clinical studies, 35-40Coal, 61,64Coke oven emissions, 49Colorado State University, 65Consumer Product Safety Act (CPSA), 61

Department of Health and Human Services(DHHS), 62-65

Department of Labor (DOL), 49,55Diesel exhaust, 66Diisocyanates, 51Division of Respiratory Disease Studies (DRDS), 64Dose-response assessment, 30-31Dosimetry, 31,34-35,66Duke University, 62Dust, 4,21-22,29,62-65Early Reduction Program (ERP), 49-51,54Emphysema, 5,20-21,64Environmental Protection Agency (EPA),

regulation, 9,49-55research, 9,62,66-67

Epidemiologic studies, 40-43Epidemiology, defined, 4,6Exposure

acute, 7-9,31,43,51,62chronic, 9,31,43,51,62defined, 6,31environmentally relevant levels of, 4,43indoor, 8, 29occupational, 4,5,7,25,66outdoor, 4, 29technologies to measure, 35-36,41

Exposure assessment, 8,30-31,34-35Extrinsic allergic alveolitis, 22Farmers, 22,65Federal Hazardous Substances Act (FHSA), 61Federal Insecticide, Fungicide, and Rodenticide Act

(FIFRA), 49,54-55Federal Mine Safety and Health Act (FMSHA), 7,

55,64Fiberglass, 66Fibrosis, 5Food and Drug Administration (FDA), 49,61-62Food, Drug, and Cosmetics Act (FDCA), 61Formaldehyde, 8,25,29,61Gas exchange, 16,20,22,63Gasoline, 61Harvard University, 63,64Hazard identification, 30-31

Consumer Product Safety commission (CPSC), 49,61 Health effects assessment, 35-43Data, assessments of, 41 Health Effects Institute (HEI), 66Department of Energy (DOE), 65-66 Health Effects Institute—Asbestos Research

75


(HEIAR), 66Health Effects Research Laboratory (HERL), 62Hydrocarbons, 25Immune

responses, 19,22system, 19,38

Indoor air, 8,29Inhalation Toxicology Research Institute (ITRI),

65-66Isobutyl nitrite (IBN), 63Kerosene, 61Laboratories studies, 35-40Lead, 49Los Amigos Research and Education Institute, 66Los Angeles, CA 7,9,42Louisiana State University, 63Lung

injury and disease, 5, 19-22structure and function, 5, 15-19toxicology and epidemiology of, 5-6,29-33

Magnetopneumography, 33Maximum achievable control technology (MACT), 49Medical College of Wisconsin, 62Mercury, 49Methanol, 66Microscopy, 33,39Mine Safety and Health Administration (MSHA),

49,61Miners, 64Morgantown, WV, 64Morphometry, 38Naphtha, 61Nasopharyngeal region, 5,15National Academy of Sciences (NAS), 38National Ambient Air Quality Standards (NAAQS),

49,50National Center for Toxicological Research (NCTR), 65National Coal Workers’ Autopsy Study, 64National Farm Medicine Center, 65National Heart Lung and Blood Institute (NHLBI),

63-64National Institute for Occupational Safety andHealth (NIOSH), 64National Institutes of Health (NIH), 62National Institute of Environmental Health Sciences

(NIEHS), 62National Jewish Center for Immunology and Respira-

tory Medicine, 63Nickel, 66Nitric acid, 62Nitrogen dioxide, 8,29,49

Nitrogen oxides, 6,9,25,29,66Occupational Safety and Health Act (OSH Act), 7,55Occupational Safety and Health Administration

(OSHA),49, 55-60Office of Technology Assessment

scope of the report, 3-4studies on neurotoxicity and immunotoxicity, 6, 19terminology used by, 3-4

Oxidants, 25Oxirane, substituted, 51Ozone, 9,29,49,62-64,66Particulate, 6,20,25,29,49,63Pennsylvania State University, 63Perhalo alkoxy ether, 54Pesticides, 55Pleural cavity, 17Pneumoconiosis, 61,Pneumonia, 61Pulmonary circulation, 16Pulmonary edema, 54,61Pulmonary fibrosis, 22Pulmonary region, 5,16,32Pulmonary toxicants, 3,29,51,62,67Pulmonary toxicity, 9,37,43,66Radionuclides, 49Radon, 8Regulators, 3-4,8,10,29,44Regulatory activities, Federal

Consumer Product Safety Commission, 49,61Department of Labor, 49,55Environmental Protection Agency, 49-55Food and Drug Administration, 49,61Occupational Safety and Health Administra-

tion, 49,55Mine Safety and Health Administration, 49,61

Research, FederalCenters for Disease Control, 64Department of Energy, 65-66Department of Health and Human Services, 62-65Environmental Protection Agency, 9,62,66-67National Center for Toxicological Research, 65National Heart Lung and Blood Institute, 63-64National Institute for Occupational Safety and

Health, 64National Institute of Environmental Health Sci-

ences, 62-63National Institutes of Health, 62see also Studies.

Research Triangle Park, NC, 62Resource Conservation and Recovery Act (RCRA),

49,51,55

Index ● 7 7

Respirable particles, 22Respiratory system

cells of the, 17-19defense mechanisms, 5, 15,19,32responses to harmful substances, 5, 19-22species differences, 34structure and function, 5, 15-19

Risk assessment, 29-31Risk characterization, 30-31Senate, Committee on Environment and Public

Works, Subcommittee on Toxic Substances, Environ-mental Oversight, Research and Development, 3

Silane, 54Silicosis, 62Smoking, 5,20,21,29,40Spirometry, 37,39,41State University of New York at Buffalo, 64State University of New York at Stony Brook, 63Studies

clinical, 3,5-6,8-9,35-40,43,44, 62,64epidemiologic, 3,5-6,8-9,20,35,40-43, 62,64laboratory, 3,5-6,8,34-35,38,43-44limitations of, 43-44see also Research; Tests

Sulfur dioxide, 5,20,22,29Sulfur oxides, 6,25,29,49,66Sulfuric acid, 62Susceptible populations, 8,44,62Tests

biochemical, 6,9,38biological, 40-43molecular, 38

physiologic, 36-38structure, 38see also Studies

Textiles, 21,6433/50 Program, 51,54Tobacco smoke, 5,8,25,29,42,63Toluene, 61Toxic Release Inventory (TRI), 51Toxic Substances Control Act (TSCA), 49,51-54Toxicants

Federal regulation of, 49-62Federal research on, 62-66industrial, 23monitoring of, 31physical properties of, 33-34

Toxicology, 4,5-6,30Tracheobronchial region, 5, 15,32,62Turpentine, 61University of California at Berkeley, 63-64University of California at Davis, 63,65University of California at Irvine, 63University of California at Los Angeles (ULCA), 42University of California at Santa Barbara, 64University of Maryland, 63University of New Mexico, 64University of North Carolina, 62University of Rochester School of Medicine, 63University of Vermont, 64Vinyl chloride, 49Volatile organic compounds, 8-9,25,32,62Woodsmoke, 6,8,25Workers, 6,64,66Xylene, 61

U.S. GOVERNMENT PRINTING OFFICE : 1992 0 – 297-932 : QL 3

identifying and controlling pulmonary toxicants

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