Draft
Do Not Quote or Cite
External Review Draft No. 2
February 1981
Air Quality
for Particulate Matter
and Sulfur
Volume V
NOTICE
This document is a preliminary draft. It has not been formally released by EPA and should not at this stage be
construed to represent Agency policy. It is being circulated for comment on its technical accuracy and
policy implications.
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, N.C. 27711
-------
NOTE TO READER
The Environmental Protection Agency is revising the existing criteria
documents for participate matter and sulfur oxides (PM/SOx) under Sections 108
and 109 of the Clean Air Act, 42 U.S.C. §§ 7408, 7409. The first external
review draft of a revised combined PM/SO criteria document was made available
for public comment in April 1980.
The Environmental Criteria and Assessment Office (ECAO) filled more than
4,000 public requests for copies of the first external review draft. Because
all those who received copies of the first draft from ECAO will be sent copies
of the second external review draft, there is no need to resubmit a request.
To facilitate public review, the second external review draft will be
released in five volumes on a staggered schedule as the volumes are completed.
Volume I (containing Chapter 1), Volume II (containing Chapters 2, 3, 4, and 5),
Volume III (containing Chapters 6, 7, and 8), Volume IV (containing Chapters 9
and 10), and Volume V (containing Chapters 11, 12, 13, and 14) will be released
during January-February, 1981. As noted earlier, they will be released as
volumes are completed, not in numerical order by volume.
The first external review draft was announced in the Federal Register of
April 11, 1980 (45 FR 24913). ECAO received and reviewed 89 comments from the
public, many of which were quite extensive. The Clean Air Scientific Advisory
Committee (CASAC) of the Science Advisory Board also provided advice and
comments on the first external review draft at a public meeting of August 20-22,
1980 (45 FR 51644, August 4, 1980).
As with the first external review draft, the second external review draft
will be submitted to CASAC for its advice and comments. ECAO is also soliciting
written comments from the public on the second external review draft and
requests that an original and three copies of all comments be submitted to:
Project Officer for PM/SO , Environmental Criteria and Assessment Office, MD-52,
f\
U.S. Environmental Protection Agency, Research Triangle Park, N. C. 27711. To
facilitate ECAO's consideration of comments on this lengthy and complex docu-
ment, commentators with extensive comments should index the major points which
they intend ECAO to address, by providing a list of the major points and a
cross-reference to the pages in the document. Comments should be submitted
during the forthcoming comment period, which will be announced in the Federal
Register once all volumes of the second external review draft are available.
XD13A/E 2-15-81
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Draft
Do Not Quote or Cite
External Review Draft No. 2
February 1981
Air Quality Criteria
for Participate Matter
and Sulfur Oxides
Volume V
NOTICE
This document is a preliminary draft. It has not been formally released by EPA and should not at this stage be
construed to represent Agency policy. It is being circulated for comment on its technical accuracy and
policy implications.
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, N.C. 27711
-------
PREFACE
This document is a revision of External Review Draft No. 1, Air
Quality Criteria for Particulate Matter and Sulfur Oxides, released in
April 1980. Comments received during a public comment period from April
15, 1980 through July 31, 1980, and recommendations made by the Clean Air
Scientific Advisory Committee in August have been addressed here.
Volume V contains Chapters 11, 12, 13, and 14 which cover the respiratory
physiological, toxicological, clinical, and epidemiological aspects of exposure
to sulfur oxides and particulate matter.
n
XD13A/E 2-15-81
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CONTENTS
VOLUMES I, II, III, IV, AND V
Page
Volume I.
Chapter 1. Executive Summary 1-1
Volume II.
Chapter 2. Physical and Chemical Properties of Sulfur
Oxides and Particulate Hatter 2-1
Chapter 3. Techniques for the Collection and Analysis of
Sulfur Oxides, Particulate Matter, and Acidic
Precipitation 3-1
Chapter 4. Sources and Emissions 4-1
Chapter 5. Environmental Concentrations and Exposure 5-1
Volume III.
Chapter 6. Atmospheric Transport, Transformation and
Deposition 6-1
Chapter 7. Acidic Deposition 7-1
Chapter 8. Effects on Vegetation 8-1
Volume IV.
Chapter 9. Effects on Visibility and Climate 9-1
Chapter 10. Effects on Materials 10-1
Volume V.
Chapter 11. Respiratory Deposition and Biological Fate
of Inhaled Aerosols and S0? 11-1
Chapter 12. Toxicological Studies 12-1
Chapter 13. Controlled Human Studies 13-1
Chapter 14. Epidemiological Studies on the Effects of
Sulfur Oxides and Particulate Matter on
Human Health 14-1
XD13A/E
2-15-81
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CONTENTS
11. RESPIRATORY TRACT DEPOSITION AND FATE OF INHALED AEROSOLS AND SO,.. 11-1
11.1 INTRODUCTION 11-1
11.1.1 General Considerations 11-1
11.1.2 Aerosol and S0? Characteristics 11-2
11.1. 3 The Respi ratory Tract 11-4
11.1.4 Respiration 11-7
11.1.5 Mechanisms of Particle Deposition 11-11
11. 2 DEPOSITION IN MAN AND EXPERIMENTAL ANIMALS 11-16
11.2.1 Insoluble and Hydrophobic Solid Particles 11-16
11.2.1.1 Total Deposition 11-16
11.2.1.2 Deposition 11-20
11.2.1.3 Tracheobronchial Deposition 11-20
11.2.1.4 Pulmonary Deposition 11-25
11.2.1.5 Deposition in Experimental Animals 11-28
11.2.2 Soluble, Deliquescent, and Hygroscopic Particles.... 11-30
11.2.3 Surface Coated Particles 11-32
11.2.4 Gas Deposition 11-33
11.2.5 Aerosol-Gas Mixtures 11-37
11.3 TRANSFORMATIONS AND CLEARANCE FROM THE RESPIRATORY TRACT.... 11-38
11.3.1 Deposited Particulate Material 11-38
11.3.2 Absorbed S0? 11-48
11.3.3 Particles and S09 Mixtures 11-51
11.4 AIR SAMPLING FOR HEALTH ASSESSMENT 11-51
11.5 SUMMARY 11-55
11.6 REFERENCES 11-60
12. TOXICOLOGICAL STUDIES 12-1
12.1 INTRODUCTION 12-1
12.2 EFFECTS OF SULFUR DIOXIDE 12-2
12.2.1 Biochemistry of Sulfur Dioxide 12-2
12.2.1.1 Chemical Reactions of Bisulfite with
Biological Molecules 12-3
12.2.1.2 Metabolism of Sulfur Dioxide 12-5
12.2.1.2.1 Integrated metabolism 12-5
12.2.1.2.2 Sulfite oxidase 12-6
12.2.1.3 Activation and Inhibition of Enzymes by
Bisulfite 12-7
12.2.2 Mortal ity 12-8
12.2.3 Morphological Alterations 12-8
12.2A Alterations in Pulmonary Function 12-14
12.2. 5 Effects on Host Defenses 12-21
12. 3 EFFECTS OF PARTICULATE MATTER 12-22
12.3.1 Mortal ity 12-24
12.3.2 Morphological Alterations 12-25
12.3.3 Alterations in Pulmonary Function 12-28
12.3.3.1 Acute Exposure Effects 12-28
12.3.3.2 Chronic Exposure Effects 12-39
iv
XD13A/E 2-15-81
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12.3.4 Alteration in Host Defense 12-41
12.3.4.1 Mucociliary Clearance 12-41
12.3.4.2 Alveolar Macrophages 12-44
12.3.4.3 Interaction with Infectious Agents 12-50
12.3.4.4 Immune Suppression 12-51
12.4 INTERACTION OF SULFUR DIOXIDE AND OTHER POLLUTANTS 12-53
12.4.1 Sulfur Dioxide and Particulate Matter 12-53
12.4.1.1 Acute Exposure Effects 12-54
12.4.1.2 Chronic Exposure Effects 12-55
12.4.2 Interaction with Ozone 12-62
12.5 CARCINOGENESIS AND MUTAGENESIS OF SULFUR COMPOUNDS AND
ATMOSPHERIC PARTICLES 12-65
12.5.1 Airborne Particulate Matter 12-67
12.5.1.1 lf\ vitro Mutagenesis Assays of Particulate
Matter 12-67
12.5.1.2 Tumorigenesis of Particulate Extracts 12-69
12.5.2 Potential Mutagenic Effects of Sulfite and SOp 12-71
12.5.3 Tumori genes is in Animals Exposed to SO,, or S02 and
Benzo(a)pyrene 12-72
12.5.4 Effects of Trace Metals Found in Atmospheric
Particles 12-74
12.6 CONCLUSIONS 12-79
12.6.1 Sulfur Dioxide 12-79
12.6.2 Particulate Matter 12-82
12.6.3 Combinations of Gases and Particles 12-85
12.7 REFERENCES 12-87
13. CONTROLLED HUMAN STUDIES 13-1
13.1 INTRODUCTION 13-1
13.2 SULFUR DIOXIDE 13-2
13.2.1 Subjective reports 13-2
13.2.2 Sensory Effects 13-3
13.2.2.1 Odor Perception Threshold 13-3
13.2.2.2 Sensitivity of the Dark-Adapted Eye 13-5
13.2.2.3 Interruption of Alpha Rhythm 13-5
13.2.3 Respiratory and Related Effects 13-6
13.2.3.1 Respiratory Function 13-6
13.2.3.2 Water Solubility 13-12
13.2.3.3 Nasal Versus Oral Exposure 13-12
13.2.3.4 Subject Activity Level 13-13
13.2.3.5 Temporal Parameters 13-15
13.2.3.6 Mucociliary Transport 13-16
13.2.3.7 Health Status 13-18
13.3 PARTICULATE MATTER 13-18
13.4 SULFUR DIOXIDE AND OZONE 13-22
13. 5 SULFURIC ACID AND SULFATES 13-26
13.5.1 Sensory Effects 13-26
13.5.2 Respiratory and Related Effects 13-28
13.6 SUMMARY 13-33
13.7 REFERENCES 13-37
14. EPIDEMIOLOGICAL STUDIES ON THE EFFECTS OF SULFUR OXIDES AND
PARTICULATE MATTER ON HUMAN HEALTH 14-1
14.1 INTRODUCTION 14-1
14.1.1 Methodological Considerations 14-2
14.1.2 Guidelines for Assessment of Epidemiological
Studies 14-5
-------
14.2 AIR QUALITY MEASUREMENTS 14-7
14.2.1 Sulfur Oxides Measurements 14-7
14.2.2 Particulate Matter Measurements 14-8
14.3 ACUTE SO /PM EXPOSURE EFFECTS 14-11
14.3.1 Mortal i ty 14-11
14.3.1.1 Acute Episode Studies 14-11
14.3.1.2 Mortality Associated with Non-Episodic
Variations in Pollution 14-15
14.3.1.3 Morbidity 14-17
14. 3.2 Chronic SO?/PM Exposure Effects 14-23
14.3.2.1 Mortality 14-23
14.3.2.2 Morbidity 14-23
14.3.2.2.1 Respiratory effects in
adults 14-23
14.3.2.3 Respiratory Effects in Children 14-25
14.5 CHAPTER SUMMARY AND CONCLUSIONS 14-31
14.5.1 Health Effects Associated with Acute Exposures
to Sulfur Oxides and Particulate Matter 14-32
14. 6 REFERENCES 14-37
APPENDIX A A-l
APPENDIX B B-l
APPENDIX C C-l
VI
XD13A/E 2-15-81
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LIST OF FIGURES
FIGURE
11-1 Features of the respiratory tract of man used in the description
of the deposition of inhaled particles and gases with insert
showing parts of a silicon rubber cast of a human lung showing some
separated bronchioles to 3 mm diameter, some bronchioles from 3 mm
diameter to terminal bronchioles, and some separated respiratory
acinus bundles 11-5
11-2 Representation of five major mechanisms of deposition of inhaled
airborne particles in the respiratory tract 11-13
11-3 Deposition of monodisperse aerosols in the total respiratory tract
for nasal breathing as a function of aerodynamic diameter except
below 0.5 pm, where deposition is plotted vs. physical diameter... 11-17
11-4 Deposition of monodisperse aerosols in the total respiratory tract
for mouth breathing as a function of aerodynamic diameter except
below 0.5 urn, where deposition is plotted vs. physical diameter... 11-18
11-5 Deposition of monodisperse aerosols in extrathoracic region for
nasal breathing as a function of of D2Q, where Q is the average
inspiratory flow-rate in liters/min 11-21
11-6 Deposition of monodisperse aerosols in extrathoracic region for
mouth breathing as a function of D2Q, where Q is the average
inspiratory flow-rate in liters/min 11-22
11-7 Deposition of monodisperse aerosols in the tracheobronchial
region for mouth breathing in percent of the aerosols entering
the trachea as a function of aerodynamic diameter except below
0.5 urn where deposition is plotted vs. physical diameter as cited
by different investigators 11-24
11-8 Total and regional depositions of monodisperse aerosols as a
function of the aerodynamic diameter for three individual subjects
as cited by Stahlhofen et al 11-26
11-9 Deposition of monodisperse aerosols in the pulmonary region for
mouth breathing as a function of aerodynamic diameter, except
below 0.5 urn where deposition is plotted vs. physical diameter.... 11-27
11-10 Deposition of inhaled polydisperse aerosols of lanthanum oxide
(radio-labeled with 140La) in beagle dogs exposed in a nose-only
exposure apparatus showing the deposition fraction (A) total dog,
(B) tracheobronchial region, (C) pulmonary aveolar region, and
(D) extrathoracic region 11-29
11-11 Deposition of inhaled monodisperse aerosols of fused
aluminosilicate spheres in small rodents showing the deposition
in the extrathoracic region, the tracheobronchial region, the
pulmonary region, and in the total respiratory tract 11-31
11-12 Single exponential model, fit by weighted least-squares of the
buildup and retention of zinc in rat lungs 11-44
11-13 Example of the sum of exponential models for describing lung
uptake during inhalation exposure and retention after exposure
ends for three lung compartments with half-lives 50d, 350d,
500d, and 20-day exposure rates of 1.4 mg/day, 1.7 mg/day,
and 2.1 mg/day respectively 11-45
XD13A/E vli 2-15-81
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11-14 Example of the use of the power function model for describing
lung uptake during inhalation exposure and retention after
exposure ends for a 20-day exposure at 8.5 mg/d 11-47
11-15 Multicomponent model of the deposition, clearance, retention,
translocation and excretion of an example sparingly soluble
metallic compound inhaled by man or experimental animals 11-49
11-16 Example of the organ retention of an inhaled, sparingly soluble
metallic compound assuming a single acute exposure demonstrating
the translocation from lung and build-up and clearance from
other organs 11-50
11-17 Comparison of sampler acceptance curves of BMRC and ACGIH
conventions with the band for the experimental pulmonary
deposition data of Figure 11-9 11-54
11-18 Division of the thoracic fraction into the pulmonary and
tracheobronchial fractions for two sampling conventions (ACGIH
and BMRC) as a function of aerodynamic diameter except below
0.5 pm where deposition is plotted vs. physical diameter, from
International Standard Organization ad hoc group to TC-146,
1980 11-56
14-1 Graph showing effect on 29 bronchitic patients (St. Bartholomew's
Hospital) of high pollution without fog 14-19
VI 1 1
XD13A/E 2-15-81
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LIST OF TABLES
Table Page
12-1 Lethal Effects of SCL 12-9
12-2 Effects of sulfur dioxide on lung morphology 12-10
12-3 Effects of sulfur dioxide on pulmonary function 12-20
12-4 Effects of sulfur dioxide on host defenses 12-23
12-5 Effects of particulate matter on lung morphology 12-27
12-6 Respiratory response of guinea pigs exposed for 1 hour to
particles in the Amdur et al. studies 12-29
12-7 Effects of acute exposure to particulate matter on pulmonary
function 12-40
12-8 Effects of chronic exposure to particulate matter on pulmonary
function 12-42
12-9 Effects of sulfuric acid on mucociliary clearance 12-45
12-10 Effects of metals and other particles on host defense mechanisms. 12-46
12-11 Effects of acute exposure to sulfur dioxide in combination with
particulate matter 12-56
12-12 Pollutant concentrations for chronic exposure of dogs 12-59
12-13 Effects of chronic exposure to sulfur oxides and particulate
matter 12-63
12-14 Effects of interaction of sulfur oxides and ozone 12-66
12-15 Potential Mutagenic Effects of S02/Bisulfite 12-73
12-16 Tumorigenesis in animals exposed to S0? or S0? and
benzo(a)pyrene 12-75
13-1 Sensory effects of S02 13-4
13-2 Pulmonary effects of SOp 13-7
13-3 Pulmonary effects of aerosols 13-19
13-4 Pulmonary effects of S0? and other air pollutants 13-25
13-5 Sensory effects of sulfuric acid and sulfates 13-27
13-6 Pulmonary effects of sulfuric acid 13-32
14-1 Excess deaths and pollutant concentrations during severe air
pollution episodes in London (1948-75) 14-12
14-2 Acute air pollution episodes in New York City 14-14
14-3 Average deviation of respiratory and cardiac morbidity from
15-day moving average, by S0? level (London, 1958-1960) 14-21
14-4 Average deviation of respiratory and cardiac morbidity from
15-day moving average, by smoke level (BS) (London, 1958-1960)... 14-21
14-5 Symptom-prevalence ratios (persistent cough and phlegm)
standardised for age and smoking by air-pollution indices 14-24
14-6 Frequency of lower respiratory tract infections of children
in Britain by pollution levels, % 14-26
14-7 Summary of quantitative conclusions from epidemiological studies
relating health effects of acute exposure to SOp and particu-
late matter to ambient air levels 14-33
14-8 Summary of quantitative conclusions from epidemiological studies
relating health effects of chronic exposure to SO,, and
particulate matter to ambient air levels 14-35
IX
XD13A/E 2-15-81
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11. RESPIRATORY TRACT DEPOSITION AND FATE
OF INHALED AEROSOLS AND S02
11.1 INTRODUCTION
11-1.1 General Considerations
The respiratory system is the major route for exposure of people to airborne suspensions
of particles (aerosols) and SO- gas. During inhalation (and exhalation) a portion of the
inhaled aerosol and gas may be deposited by contact with airway surfaces or be transferred to
unexhaled air. The remainder is exhaled. The portion transferred to unexhaled air may be
either deposited by contact with airway surfaces or later exhaled. These phenomena are compli-
cated by interactions that may occur between the particles, the SO- gas, other gases such as
endogenous ammonia, and the water vapor present in the airways.
In inhalation toxicology, specific terminology is applied to these processes. The term
deposition refers specifically to the removal of inhaled particles or gases by the respiratory
tract and to the initial regional pattern of these deposited materials. The term clearance
refers to the subsequent translocation (movement of material within the lung or to other
organs), transformation, and removal of deposited substances from the respiratory tract or from
the body. It can also refer to the removal of reaction products formed from SOp or particles.
The temporal pattern of uncleared deposited particulate materials or gases and reaction
products is called retention. At the end of a brief aerosol or gas exposure, these three
concepts may be described by the relationship:
RETENTION (t) = DEPOSITION (t) - CLEARANCE (t) (1) .
where (t) refers to a function of time after deposition occurs.
The mechanisms involved in the deposition of inhaled aerosols and gases are affected by
physical and chemical properties, including aerosol particle size distribution, density, shape,
surface area, electrostatic charge, hygroscopicity or deliquescence, chemical composition, gas
diffusivity and solubility, and related reactions. The geometry of the respiratory airways
from nose and mouth to the lung parenchyma also influences aerosol deposition; the important
morphological parameters include the diameters, lengths, inclinations to vertical, and branch-
ing angles of airway segments. Physiological factors that affect deposition include breathing
patterns, air flow dynamics in the respiratory tract, and variations of relative humidity and
temperature within the airways. Clearance from the respiratory tract depends on many factors,
including site of deposition, chemical composition and properties of the deposited particles,
reaction products, mucociliary transport in the tracheobronchial tree, macrophage phagocytosis
in the deep lung, and pulmonary lymph and blood flow. Paramount to the interpretation of the
results of health effects studies described in Chapters. 12-14 is an understanding of the
regional deposition and clearance of particles and SO™.
Translocation of sulfur compounds or other materials from the lung to other organs is
also important, since the lung can be the portal of entry for toxic agents that have effects
SOX11A/A 11-1 2-9-81
-------
on other organs of the body. Hence, muHi compartment models of clearance from the respiratory
tract to other organs can provide predictive information about the potential for injury of
those other organs. Mathematical representations of lung retention and translocation require
data on the various factors that affect deposition and clearance.
Since many conclusions concerning the deposition, clearance, and health impact of inhaled
aerosols and S02 are based upon data obtained from animal experiments, care must be taken to
identify differences in physiological and anatomical factors between human beings and animals
that may influence these phenomena. Emphasis in the following discussion will be on the
regional deposition and clearance that occur in the human airways, but selected comparisons
are made with other mammalian species to clarify differences that may affect health impact
analyses of experimental data.
11.1.2 Aerosol and SO,, Characteristics
An aerosol may be defined as a relatively stable suspension of liquid or solid particles
in a gaseous medium. Airborne particulate materials in the environment are aerosols with a
variety of physical and chemical properties. In particular, a given aerosol may include
particles with a wide spectrum of physical sizes, even if all the particles have similar
chemical composition. Also, the concentration of toxic components in particles may be
different for different sized particles (Natusch et al., 1974) or morphologically identical
particles may have totally different chemical compositions (Pawley and Fisher, 1977). Common
assumptions that particles in a given aerosol have a relatively homogeneous chemical compo-
sition, toxic potential, and physical density may be seriously misleading, especially when
particles are found in combination with S0? gas.
It is essential for evaluation of the possible health effects associated with their inha-
lation that the relevant physical and chemical properties of aerosols and gases be appro-
priately characterized. These properties then can provide predictive information concerning
regional respiratory tract deposition and other important dosimetric factors that need to be
considered if biological responses described in Chapters 12-14 are to be adequately understood.
If particles in an aerosol are smooth and spherical or nearly spherical, their physical
sizes can be conveniently described in terms of their respective geometric diameters. However,
unagglomerated aerosols of solids rarely contain smooth, spherical particles. Various
conventions for describing physical diameters have been based upon available methods of
observing and measuring particle size. For example, the size of a particle may be described
in terms of its projected area diameter (D ), defined as the diameter of a circle with an area
equal to the apparent cross-sectional area of the particle when lying on a collection surface
and viewed with an optical or electron microscope. Other conventions for describing physical
size are based on measurements of scattered light, surface area, electrical mobility,
diffusional mobility, or other physical or chemical phenomena (see Mercer, 1973; Stockham and
Fochtman, 1979).
SOX11A/A H-2 2-9-81
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*
Aerodynamic properties of aerosol particles depend upon a variety of physical properties,
including the size and shape of the particles and their physical densities. Two important
aerodynamic properties of aerosol particles are the inertial properties, which are most
important for particles larger than 0.5 urn in diameter and are related to the settling speed
in air under the influence of the earth's gravity, and the diffusional properties, which are
most important for particles smaller than 0.5 urn in diameter and are related to the diffusion
coefficient (Fuchs, 1964) (see Section 11.2.1). When particles are inhaled, their aerodynamic
properties, combined with various anatomical and breathing characteristics, determine their
fractional deposition in various regions in the respiratory tract.
To avoid the complications associated with the effects of particle shape, size, and
physical density upon the inertial properties of inhaled airborne particles, "aerodynamic
diameters" have been defined and used to describe particles with common inertial properties
with the same "aerodynamic diameter." The aerodynamic diameter most generally used is the
aerodynamic equivalent diameter (D ), defined by Hatch and Gross (1964) as "the diameter of a
96
unit density sphere having the same settling speed (under gravity) as the particle in question
of whatever shape and density." Raabe (1976) has recommended the use of an aerodynamic
resistance diameter (D ), defined more directly with terms used in physics to describe the
ar
inertial properties of a particle. The difference between these two diameters is only 0.08 urn
or less over all sizes under normal conditions at sea level. Hence, the term aerodynamic
diameter can be used to refer to either or both of these two definitions.
Since not all particles in an aerosol are of the same physical or aerodynamic size, the
distribution of sizes must be described. If either the physical diameter (D) or the aero-
dynamic diameter is used to characterize particles, the distribution of particle sizes in a
mixed aerosol is most conveniently described as a probability density function. One such
generally useful function, the lognormal function, involves two parameters, the geometric mean
size (or median) and the geometric standard deviation (o ). Environmental aerosols have size
distributions that are more complicated, reflecting the production of particles in atmospheric
processes, emission sources or other anthropogenic activities, and the particle dynamics. They
may have several modes (Whitby, 1978). Photochemical reactions and certain combustion
processes create small particles that are generally smaller than 0.1 urn (the nuclei mode)
while other combustion, condensation, and mechanical particle generation processes yield
larger particles. Another mode, between 0.1 urn and 2 urn, is known as the accummulation mode
and includes primary emissions plus aggregates and droplets formed by coagulation of the
primary nuclei mode particles and the materials which condense on them from the vapor phase.
The particle size distribution within each of the three modes (nuclei, accumulation, and
coarse) is generally lognormal.
Since aerosols even from a single source, or in an atmospheric size mode, do not consist
of particles of a single size, they must be described in terms of parameters of size distri-
bution functions. It has become customary in the absence of detailed data and for the sake of
SOX11A/A 11-3 2-9-81
-------
generalization to describe aerosols in terms of their geometric mean or median diameter and
the geometric standard deviation (o ) of the size distribution. Hence, if the particle number
is being considered, the particle size may be reported as the count median (physical) diameter
(CMD) and o or the count median aerodynamic diameter (CMAD) and o if aerodynamic sizes have
been measured. Numerically, half the particles in an aerosol have physical sizes less than
the CMD and half have larger. Likewise, half the particles have aerodynamic diameters smaller
than the CMAD and half have larger aerodynamic diameters. Since the mass of a material is
usually more relevant to its potential toxicity, the mass median (geometrical) diameter (HMD)
or mass median aerodynamic diameter (MMAD) and a is usually preferred in describing aerosols
in inhalation toxicology research. Half the mass of particles in an aerosol is associated
with particles smaller than the MMD and half with larger particles. Likewise, half the mass
of particles is associated with particles whose aerodynamic diameters are smaller than the
MMAD and half with particles having larger aerodynamic diameters. If an aerosol is radioactive
or radiolabeled, mass measurements may be replaced by activity measurements. Interrelation-
ships among these various ways to express the diameter of the aerosol have been examined for
the lognormal distribution by Raabe (1971).
In addition to particle characteristics, conditions of the gas medium influence the
properties of aerosol dispersions. Such environmental conditions as relative humidity,
temperature, barometric pressure, and fluid flow conditions (e.g., wind velocity or state of
turbulence) affect the aerodynamics of aerosol particles.
The concentration of environmental aerosols or gases generally does not affect inhalation
3 3
deposition and particle dynamics. The mass concentration (mg/m or ug/m ) or concentration of
a specific potentially toxic species (mg of constituent/m ) provides information needed to
calculate inhalation exposure levels. For S09, the concentration may be expressed in parts
3
per million (ppm) by volume or in mass concentrations (mg/m ); each 1 ppm of SOp equals 2.62
mg/m3 (2620 ug/m3) at an air temperature of 25°C.
Sulfur dioxide gas is a rapidly diffusing reactive gas that is readily soluble in water
and body fluids (Aharonson, 1976). These properties are responsible for the large removal of
S09 in the extrathoracic region and in the upper generations of the tracheobronchial tree.
Extraction of S0? during nose breathing is significantly greater than during mouth breathing,
and over a four to six hour exposure to high levels of SOy, no saturation effect for absorption
can be seen (see Section 11.2.4). Through normal and catalyst mediated oxidation processes in
air, SOp gas is slowly oxidized to SO, which rapidly hydrolyzes to form H^SO., leading to
sulfate salts. Since NHL is formed in natural biological processes including endogenously in
the airways, (NH.)2S04 and NH4HS04 are important products of H2$04 neutralization.
11.1.3 The Respiratory Tract
The respiratory tract (Figure 11-1) includes the passages of the nose, mouth, nasal
pharynx, oral pharynx, epiglottis, larynx, trachea, bronchi, bronchioles, and small ducts and
alveoli of the pulmonary acini. With respect to respiratory tract deposition and clearance of
SOX11A/A 11-4 2-9-81
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LEFT WALL OF NASAL CAVITY
AND TURBINATES
ORAL CAVITY
RIGHT MAIN BRONCHUS
UPPER LOBE BRONCHUS
MEDIAL LOBE.
BRONCHUS
1
LOWER LOBE
BRONCHUS
LUNG PARENCHYMA
AND ALVEOLI
UPPER LOBE BRONCHUS
LOWER LOBE BRONCHUS
Figure 11-1. Features of the respiratory tract of man used in the description of the deposition of
inhaled particles and gases with insert showing parts of a silicon rubber cast of a human lung show-
ing some separated bronchioles to 3 mm diameter, some bronchioles from 3 mm diameter to term-
inal bronchioles, and some separated respiratory acinus bundles.
Source: Adapted from Hatch and Gross (1964) and Raabe (1979).
11-5
-------
*
inhaled aerosols, three regions can be considered: (1) extrathoracic (ET), the airways
extending from the nares down to the epiglottis and larynx at the entrance to the trachea (the
mouth is included in this region during mouth breathing); (2) tracheobronchial region (TB),
the primary conducting airways of the lung from the trachea to the terminal bronchioles (i.e.,
that portion of the lung respiratory tract having a ciliated epithelium); and (3) pulmonary
region (P), the parenchyma! airspaces of the lung, including the respiratory bronchioles,
alveolar ducts, alveolar sacs, atria, and alveoli (i.e., the gas-exchange region). The extra-
thoracic region, as defined above, corresponds exactly to the ICRP (Morrow et al., 1966)
definition of the nasopharynx.
The nose is a complex structure of cartilage and muscle supported by bone and lined with
mucosa (Holmes et al., 1950). The vestibule of the nares is unciliated but contains a
low-resistance filter consisting of small hairs. The nasal volume is separated into two
cavities by a 2- to 7-mm thick septum. The inner nasal fossae and turbinates are ciliated,
with mucus flow in thf> direction of the pharynx. The turbinates are shelf-like projections of
bone covered by ciliated mucous membranes with a high surface-to-volume ratio that facilitate
humidification of the incoming air. The larynx consists of two pairs of mucosal folds that
narrow the airway.
The trachea, an elastic tube supported by 16 to 20 cartilagenous rings that circle about
3/4 of its circumference, is the first and largest of a series of branching airway ducts
(Tenney and Bartlett, 1967). The left and right lungs are entered by the two major bronchi of
the trachea (Figure 11-1). The left lung consists of two clearly separated lobes, the upper
and lower lobes; and the right lung consists of three lobes, the upper, middle, and lower
lobes. The conductive airways in each lobe of the lung consist of up to 18 to 20 dichotomous
branches from the bronchi to the terminal bronchiole (Pump, 1964; Raabe et al., 1976).
The pulmonary, gas-exchange region of the lung begins with the partially alveolated
respiratory bronchioles. Pulmonary branching proceeds through a few levels of respiratory
bronchioles to completely alveolated ducts (Smith and Boyden, 1949; Whimster, 1970; Krahl,
1963) and alveolar sacs (Tenney and Remmers, 1963; Pattle, 1961b; Machlin, 1950; Fraser and
Pare, 1971). Alveoli are thin-walled polyhedron air pouches which cluster about the acinus
through connections with respiratory bronchioles, alveolar ducts, or alveolar sacs.
The airway spaces in the pulmonary region are coated with a complex aqueous liquid
containing several biochemically specialized substances (Green, 1974; Blank etal., 1969;
Balis et al., 1971; Pattle, 1961b; Kott et al., 1974; Henderson et al., 1975; Kanapilly, 1977).
An understanding of the chemical composition and dynamic nature of the acellular layer at the
air-alveolar surface is needed to understand the general behavior of material deposited in the
pulmonary region. This acellular layer consists of a surfactant film of < 0.01 urn thick and
a hypophase of about 0.1 - 0.2 urn thick (Clements and Tierney, 1965). A mixture of phospho-
lipids and neutral lipids are contained in the surfactant film (Scarpelli, 1968; Pfleger and
Thomas, 1971; Pruitt et al., 1971; Reifenath, 1973). The major phospholipid is dipaltnitoyl
SOX11A/A U'6 2-9-81
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lecithin, and cholesterol and its esters are the major neutral lipids. Protein content in
lung surfactant is less than 20 percent by weight (Pruitt et al., 1971; Klass, 1973). The
composition of the hypophase is not well understood, with lung surfactant materials, mucopoly-
saccharides, lipoproteins, and possibly serum proteins such as albumin likely being present
(Scarpelli, 1968; Reifenath, 1973; Tuttle and Westerberg, 1974). The pH of alveolar fluid may
be similar to that of blood fluid. Various factors favoring and opposing transudation of
fluid across the air-blood barrier result in the cyclic movement of fluid in and out of
alveoli, thereby helping to maintain the very thin layer of alveolar fluid (Kanapilly, 1977).
The concentrations of chelating and precipitating agents in the alveolar fluid influence the
retention and transport of particles deposited in the alveolar region. However, the concen-
trations of chelating agents are not sufficiently high to prevent the transformation of
polyvalent cations into an insoluble form (Kanapilly, 1977).
The deep lung parenchyma includes several types of tissue, circulating blood, lymphatic
drainage pathways, and lymph nodes. In man, the weight of the lung, including circulating
blood, is about 1.4 percent of the total body weight. Lung blood is equal to about 0.7 percent
of total body weight (10 percent of total blood volume) (Snyder, 1975). Because a portion of
lung is occupied by air, the average physical density of the parenchyma is about 0.26 g/cm
(Fowler and Young, 1959).
Models of the airways, which simplify the complex array of branching and dimensions into
workable mathematical functions, are useful in comparing theoretical predictions of deposition
with experimentally obtained deposition data, thereby leading to more refined models and
increasing our understanding of the processes which affect respiratory tract deposition. An
early idealized model of the airways of the human lung was developed by Findeisen (1935) for
estimating the deposition of inhaled particles. Findeisen's model assumed branching symmetry
within the lung, with each generation consisting of airways of identical size. Other models
based on a symmetry assumption have been proposed by Landahl (1950), Davies (1961), Weibel
(1963), and Horsfield and Gumming (1968). Asymmetric models which more closely approximate
the human lung have been developed by Weibel (1963), Horsfield et al. (1971), and Horsefield
and Cummings (1968). Yeh and Schum (1980) have proposed a typical pathway lung model and have
made particle deposition calculations for each lobe of the lungs. Although currently available
particle deposition models ignore the dynamic nature of the airways, future models should
consider this aspect.
11.1.4 Respiration and Other Factors
Both the humidity and temperature of inhaled aerosols and gases, as well as the subsequent
changes that occur as the aerosol-gas mixture passes through various parts of the airways,
have important influences on the inhalation deposition of airborne particles. Deposition of
hygroscopic aerosols will depend in part on the relative humidity in the airways, since the
growth of such particles will directly affect both the site and extent of inhalation deposition.
SOX11A/A 11-7 2-9-81
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*
The complex anatomical structure of the nose is well suited for humidification, regulation
of temperature, and removal of many particles and gases. The relative humidity of inhaled air
probably reaches near saturation in the nose (Verzar et al., 1953). Since the human nose is a
short passageway, tranquil diffusion alone cannot account for rapid humidification. Rather,
convective mixing must play a role, suggesting a mechanism for enhancing SO- collection in the
nose. The temperature of the inhaled air may not reach body temperature until relatively deep
in the lung. Deal et al. (1979a, b, c) measured retrocardiac and retrotracheal temperatures
under different ambient temperatures and found airway cooling associated with breathing cool
air. Raabe et al. (1976) found that the temperature of the air at major bronchi in a
nose-breathing dog averaged 35°C, 4°C less than the body temperature.
The air deflecting channels of the anterior nares cause impaction of large airborne
particles and create turbulent air flow conditions. As the cross-sectional area expands
beyond the entrance, flow separation occurs resulting in turbulence and eddies which continue
as the air traverses the passages around the turbinates. Proctor and Swift (1971) studied the
flow of water through a clear plastic model of the walls of the nasal passages and constructed
charts of the direction and linear velocity of airflow in the model. With a steady inspiratory
flow of 0.4 I/sec, they found that the linear inspiratory velocity at the nasal entrance
reached at least 4.5-5 m/sec and at most 10 - 12 m/sec, values which are significantly
greater than the 2 m/sec peak linear velocity in the tracheobronchial tree during quiet
breathing.
The caliber of the trachea and major bronchi and their cross-sectional geometry is about
15 percent larger during inspiration than during expiration (Marshall and Holden, 1963; Fraser
and Pare, 1971; Raabe et al., 1976). Bronchial caliber correlates with body size (Thurlbeck
and Haines, 1975). The caliber of the smaller conductive bronchioles may be up to 40 percent
greater during inspiration than during expiration (Marshall and Holden, 1963; Hughes et al.,
1972).
Schroter and Sudlow (1969) studied a wide variety of flow patterns and rates in large
scale symmetrical models of typical tracheobronchial tree junctions. For both inspiration and
expiration and irrespective of entry profile form, they observed secondary flows at all flow
rates in their single bifurcation model. When a second bifurcation was added a short distance
downstream of the first, the entering flow profile was found to influence the resulting flow
patterns. Also, different results were obtained depending upon the plane in which the second
bifurcation was located relative to the first bifurcation.
Olson et al. (1973) studied convective airflow patterns in cast replicas of the human
respiratory tract during steady inspiration. They showed that the effect of the larynx is
such that flow patterns typical of smooth bifurcating tubes do not occur until the lobar
bronchi are reached. Small eddies were observed as far down as the sublobar bronchi with 200
ml/s flows in the trachea. In man the glottis of the larynx acts as a variable orifice since
the position of the vocal cords changes. During inspiration a jet of turbulent air enters the
SOX11A/A H-8 2-9-81
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trachea and is directed against its ventral wall imparting additional turbulence over that
associated with the corrugated walls and length of the trachea.
In the tracheobronchial tree with its many branches, changes in caliber and irregular wall
surfaces, it is difficult to establish exactly where flow is laminar, turbulent, or transi-
tional. Viscous forces predominate in laminar flow and streamlines persist for great
distances, while with turbulent flow there is rapid and random mixing downstream. As the flow
rate increases, unsteadiness develops and separation of the streamlines from the wall can occur
leading to the formation of local eddies. This type of flow is termed transitional. The
Reynolds number, the ratio of inertial to viscous forces, is useful in describing whether flow
is laminar or turbulent. In smooth walled tubes values between approximately 2000 and 4000
are ascribed to transitional flow with smaller Reynolds numbers reflecting laminar flow and
larger ones turbulent flow. Fully developed laminar flow probably only occurs in the very
small airways; flow is transitional in most of the tracheobronchial tree, while true turbu-
lence may occur in the trachea, especially during exercise when flow velocities are high
(West, 1977).
Turbulence will gradually decay in any branch in which the Reynolds number is less than
3000 (Owen, 1969). Decays of 15 percent, 16 percent, and 10 percent are predicted to occur in
the first three generations of bifurcation, respectively, using the theory of Batchelor (1953)
for the change in turbulent energy at regions of rapid flow contraction. While these decay
calculations neglect the possible effects of the strong secondary flows generated at the bifur-
cation, their validity is supported by the data of Pedley et al.(1971) which shows that the
boundary layer remains laminar in the daughter-tube for Reynolds numbers in the parent-tube up
to at least 10,000. Hence, the turbulent eddies are localized in the center.
Flow oscillations in the segmental bronchi attributed to beating of the heart are only
detectable during breathholding or during pauses between inspiration and expiration (West,
1961). A peak oscillatory flow rate of 0.5 1/min was measured, which is about 20 percent of
the peak flow rate in the segmental bronchi during quiet breathing. Gas mixing is improved by
these oscillations.
Gas flow dynamics within the upper airways may be expected to be turbulent in humans and
dogs but laminar everywhere in the airways of small rodents (Dekker, 1961; Fry, 1968; Schroter
and Sudlow, 1969; Olson et al., 1973; Martin and Jacobi, 1972; West, 1961). The larynx intro-
duces an important air flow disturbance that can influence tracheal deposition (Bartlett et
al., 1973; Schlesinger and Lippmann, 1976). In the smaller human bronchi and bronchioles,
where fluid flow is relatively tranquil, laminar flow prevails, but branching patterns,
filling patterns (Grant et al., 1974), flow reversals with varying velocity profiles, and
swirling complicate a description of flow in the small airways (Silverman and Billings, 1961;
Cinkotai, 1974). Because actual flow in the respiratory airways is difficult to describe,
simplifying assumptions, such as parabolic laminar or uniform velocity profiles, are usually
incorporated into analytic descriptions.
SOX11A/A H-9 2-9-81
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*
Inspiratory flow rate and depth of inhalation influence the deposition of inhaled
particles. The air inspired in one breath is the tidal volume (TV). The average inspiratory
flow rate, (Q), and tidal volume (Bake et al., 1974; Clement et al., 1973) affect both inertial
and diffusional deposition processes (Altshuler et al., 1967). The total air remaining in the
lungs at the end of normal expiration affects the relative mixing of inhaled particles and,
when compared with total lung capacity, is indicative of the extent of aerosol penetration
into the lung (West, 1974; Luft, 1958). Guyton (1947a, b) and Stahl (1967) have developed
interspecies relationships describing respiratory volumes and patterns.
The inspiratory capacity, the maximum volume of air that can be inhaled after a given
normal expiration, is contrasted to the vital capacity, which is the maximum volume of air
that can be expelled from the lungs with effort after maximum forced inspiration. Air that
remains in the conductive airways (from nose or mouth to terminal bronchioles) at end expi-
ration is considered to occupy the anatomical dead space, since the conductive airways are not
involved in gas exchange.
Representative values for normal human respiratory parameters, which can be used for
deposition and dosimetric predictions, are available from various sources (Zenz, 1975; Higgs
et al., 1967; American Heart Association, 1973; Jones et al., 1975; Intermountain Thoracic
Society, 1975; Snyder, 1975). It should be noted that considerable variability in respiratory
parameters may occur among individuals in the population, particularly when healthy adults are
contrasted with children, aged, and ill individuals. Average tidal volume has a reasonably
fixed relationship with body weight of 7-10 ml/kg from birth to adulthood (Doershuk et al.,
1970, 1975). Gas-exchange area increases proportionally with age, and more or less with
2
height, but not with body surface area. Average values for gas-exchange area are 6.5 m , 32
2 2
m , and 75 m at 3 months, 8 years, and adulthood, respectively (Dunnill, 1962). Respiratory
frequency decreases from about 35 breaths/min at birth to 12-16 breaths/min with normal respi-
ration in adulthood (Polgar and Weng, 1979).
In some instances, the total and regional deposition data presented in Section 11.2
exhibit considerable scatter. Some of this variability might be expected given the range of
breathing frequencies, tidal volumes, and average inspiratory flow rates used in the various
deposition experiments. Previously, an interlaboratory comparison study of lung deposition
data (Heyder et al., 1978), besides identifying possible sources of errors connected with the
experimental technique, identified different deposition data among the subjects. Yu and
coworkers (1979) used Monte Carlo techniques to determine the total and regional deposition of
inhaled particles in a population of human lungs by taking into account variability in airway
dimensions. Their results for particle sizes ranging from 0.1 urn to 8 pm D=Q suggest that
36
observed subject deposition variability is caused primarily by differences in airway dimensions.
When studying total respiratory tract deposition of particles between 0.3 pm and 1.5 urn D ,
36
expressing the data as a function of the relative expiratory reserve volume to the normal
expiratory reserve volume of a subject greatly reduces the intersubject variability (Tarroni
et al., 1980).
SOX11A/A H-10 2-9-81
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X
The vast majority of studies on the deposition of particles in man have been conducted
using young healthy adults. Consequently, there is a paucity of data on deposition in other
subpopulations, such as children, asthmatics, chronic bronchitics, etc. Significant pathologic
changes in airways and parenchyma can markedly alter the deposition of particles. For example,
Lippmann et al. (1971) found substantially increased bronchial deposition in chronic bronchitic
and asthmatic subjects. These increases may vary with different phases of the disease
(Goldberg and Lourenco, 1973). Tracheobronchial deposition appears to be enhanced at the
expense of pulmonary deposition in most abnormal states. For example, the deposition of 2 urn
particles in patients with bronchiostasis is frequently more central than that in normal
subjects (Lourenco et al., 1972). Partial or complete airway obstruction in bronchitis, lung
cancer, emphysema, fibrosis, and atelectasis may decrease or eliminate deposition of particles
in some regions of the lungs (Taplin et al., 1970). The numerous and complex mechanisms
responsible for alterations in the pattern of deposition in various disease states need to be
studied.
Currently available human deposition data have been collected from volunteers inhaling
aerosols through either mouthpieces or nose masks. Differences in mass burden of particles
between these controlled inhalations and normal, spontaneous mouth breathing or nose breathing
are possible. Studies in which the nose of the subject is completely occluded with a clip do
not simulate oronasal breathing since no air passes through the nose and the oral airway is
wider than usual. With partial nasal obstruction or in exercise, human beings resort to
oronasal breathing. However, a significant number of healthy persons breathe through the
mouth and nose even when at rest (Niinimaa, 1979). Also, with any of the common obstructive
forms of nasal pathology such as allergic, viral, or vasomotor rhinitis or septa! deviation,
the proportion of ventilation passing through the mouth is higher at rest and at any level of
exercise. Healthy young adults without nasal pathology, who breathe predominantly through the
nose at rest, shift to breathing through the nose and mouth when minute ventilation is approxi-
mately 35 liters/min (Niinimaa, 1979; Saibene et al., 1978). Niinimaa (1979) found that during
exercise requiring a rate of ventilation of 30-40 liters/min, 56 percent of the air passed
nasally. Thus, studies on subjects breathing through a mouthpiece at rest (minute ventilation
of 6-8 liters/min) provide conservative estimates of the mass burden of particles, since the
total quantity of ventilation passing through the mouth is significantly less than that which
would pass through the mouth in the same subjects breathing freely through the nose and mouth
while performing enough exercise to require a minute ventilation of 35 liters/min. A minute
ventilation of 35 liters/min corresponds anywhere from light to moderate exercise according to
various sources (Zenz, 1975; Higgs et al., 1967; American Heart Association, 1973; Jones et
al., 1975; Intermountain Thoracic Society, 1975; Snyder, 1975).
11.1.5 Mechanisms of Particle Deposition
The behavior of inhaled airborne particles in the respiratory airways and their alter-
native fate of either deposition or exhalation depend upon aerosol mechanics under the given
SOX11A/A 11-11 2-9-81
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physiological and anatomical .condition (Yeh et al., 1976; DuBois and Rogers, 1968). It is
usually described in terms of nonreactive stable spherical particles whose physical properties
do not vary during the breathing cycle. Behavior of hygroscopic and deliquescent particles is
more complex.
Figure 11-2 illustrates the five primary physical processes that lead to aerosol particle
contact with the wall of the airways. Contact of particles with moist airway walls results in
attachment and irreversible removal of the particle from the airstream. The contact process
can occur during inspiration or expiration of a single breath or subsequently if a particle
has been transferred to unexhaled lung air (Engel et al., 1973; Davies, 1972; Altshuler, 1961).
Electrostatic attraction of particles to the walls of the respiratory airways is probably
a minor mechanism of deposition in most circumstances. Pavlik (1967) predicted that light air
ions (which would include some atmospheric aerosol nuclei) would be deposited by electrostatic
attraction in the mouth and throat and suggested that the tonsils were naturally charged for
this purpose. Fraser (1966) found that an average of 1000 electronic units of charge per
aerosol particle, a very large charge not normally occurring, doubled the inhalation
deposition in experimental animals. Melandri et al. (1977) reported enhanced deposition of
inhaled monodisperse aerosols by people when the particles were charged. Longley (1960) and
Longley and Berry (1961) found the charge of the subject to have an influence on deposition.
Similar observations have been made in ijn vitro studies (Chan et al., 1978). The airways are
covered by a relatively conductive electrolytic liquid that probably precludes the buildup of
forceful electric fields. Charged particles are therefore collected primarily by image
charging as they near the wall of an airway or by mutual repulsion from a unipolarly charged
cloud with a high concentration of particles (Yu, 1977). The role of this mechanism depends
on particle source, concentration, age, and special electrical phenomena in the environment,
as well as the residence time of the aerosol in the airways. It is reasonable to expect this
mechanism to have a small role, if any, in the deposition of atmospheric environmental
aerosols.
Interception consists of noninertial incidental meeting of a particle and the lining of
the airway and thus depends on the physical size of the particle. It is important primarily
for particles with large aspect ratios, such as long fibrous particles of asbestos (Harris and
Fraser, 1976). Interception may be expected to play a minor role in the inhalation deposition
of most environmental aerosols.
Impaction dominates deposition of particles larger than 3 urn D in the nasopharyngeal
and tracheobronchial regions (Rattle, 1961a; Bohning et al., 1975). In this process, changes
in airstream direction or magnitude of air velocity streamlines or eddy components are not
followed by airborne particles because of their inertia. For example, if air is directed
toward an airway surface (such as a branch carina) but the forward velocity is suddenly reduced
because of change in flow direction, inertial momentum may carry larger particles across the
air streamlines and onto the surface of the airway. Impaction at an airway branch has been
SOX11A/A H-12 2-9-81
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INTERCEPTION
ELECTROSTATIC
ATTRACTION
IMP ACTION
BROWNIAN DIFFUSION
GRAVITATIONAL SETTLING
Figure 11-2. Representation of five major mechanisms of deposition of inhaled airborne particles
in the respiratory tract.
Source: Raabe (1979).
11-13
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*
likened to impaction at the bend of a tube, providing theoretical estimates of the impaction
probability (Johnston and Muir, 1973; Yeh, 1974; Cheng and Wang, 1975) and has been studied in
a bifurcating tube model by Johnstone and Schroter (1979). Aerodynamic separation of this
type is satisfactorily characterized in terms of the particle aerodynamic diameter. The
airflow in the trachea and major bronchi in man is turbulent and disturbed by the larynx so
that turbulent impaction plays a role in deposition in these larger airways (Schlesinger and
Lippmann, 1976). Breathing patterns involving higher volumetric flow rates would tend to
impact smaller particles. In contrast, the passages of the nose contain smaller airways, and
the convective mixing spaces of the nasal turbinates would be expected to collect some
particles as small as 1 or 2 urn D by impaction. Hence, impaction is an important process
ae
affecting the inhalation deposition in the human airways of environmental aerosol particles
greater than 1 urn in aerodynamic diameter.
Gravitational settling occurs because of the influence of the earth's gravity on airborne
particles. Deposition of particles by this mechanism can occur in all airways except those
very few that are vertical. The probability of gravitational deposition is usually estimated
with equations describing gravitational settling of particles in an inclined cylindrical tube
under laminar flow conditions (Wang, 1975; Heyder and Gebhart, 1977). This deposition depends
on the residence time and particle concentration distribution in the airway segments, the
incline angle with respect to gravity, and the aerodynamic diameter of the particle.
Deposition by gravitational settling is therefore characterized in terms of the particle aero-
dynamic diameter. This mechanism has an important influence on the deposition of particles
larger than 0.5 urn D . Settling has an important role in the deposition of environmental
36
aerosols in the distal region of the bronchial airways and in the alveolar region.
Deposition by diffusion results from the random (Brownian) motion of very small particles
caused by bombardment of the gas molecules in air. The magnitude of this motion can be
described by the diffusion coefficient for a given physical particle diameter. Since
particles larger than 0.5 (jm have relatively small diffusional mobility compared with sedimen-
tation or inertia, diffusion primarily affects deposition of particles with physical diameters
smaller than 0.5 urn. For particles of 0.5 urn with a physical density of about 1 g/cm , the
influences of inertial properties and diffusional properties on lung deposition are about
equal. Accurate calculation of the diffusional deposition of aerosols in the airways requires
information concerning the three-dimensional velocity profile of air flow in each airway
segment. If the flow of a given segment is laminar and approximately Poisueille, the proba-
bility of deposition by diffusion might be approximated using the Gormley-Kennedy (1949)
equation for a cylindrical pipe. However, this assumes the aerosol is mixed at the entrance
of the cylinder and that the flow is constant. It therefore overestimates deposition in lung
segments where there is minimal mixing between tidal and residual air and reversible laminar
flow between segments.
SOX11A/A 11-14 2-9-81
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*
It is important to note that the diffusivity and interception potential of a particle
depend on its physical size, while the inertial properties of settling and impaction depend on
its aerodynamic diameter. These two measures of size may be quite different, depending on
particle shape and physical density. Because the main mechanism of deposition is diffusion
for particles whose physical (geometric) size is less than 0.5 urn D and impaction and settling
above 0.5 urn Dae, it is convenient to use 0.5 urn as the boundary. Although this convention
may lead to confusion in the case of very dense particles, most environmental aerosols have
densities below 3 g/cm , and the deposition probability tends to have a minimum plateau
between 0.2 urn and 1 pm D .
3G
It is possible to use information concerning breathing patterns and respiratory physiology,
the anatomical and geometrical characteristics of the airways, and the physical behavior of
insoluble spherical particles to develop theoretical models of regional deposition (Findeisen,
1935; Landahl et al., 1951; Landahl, 1963; Beeckmans, 1965). In these models, deposition of
inhaled aerosols in a given region of the respiratory tract or in the entire tract is
expressed as a fraction of inhaled particles. Deposition fraction is the ratio of the number
or mass of particles deposited in the respiratory tract to the number or mass of particles
inhaled. The undeposited fraction represents those particles that are exhaled after inhala-
tion. For example, pulmonary (alveolar) deposition is the ratio of the number or mass of
particles deposited in the unciliated small airways and gas exchange spaces of the parenchyma
of the lung to the number or mass of particles entering the nose or mouth. The fraction not
deposited in the pulmonary region is either deposited in some other region or exhaled.
Similarly, deposition fractions can be defined for the other regions of the respiratory tract.
Most model calculations treat the various mechanisms of deposition as independently
occurring phenomena. However, such processes as Brownian diffusion and gravitational settling
will interfere with each other when their effects are of comparable magnitude, and that inter-
ference can reduce the combined deposition to less than the sum of the separate depositions
(Goldberg et al., 1978). Taulbee and Yu (1975) have developed a theoretical deposition model
which allows for the combined effects of the primary deposition mechanisms and features an
imaginary expanding tube model of the airway system (Weibel, 1963) based on cross-sectional
areas and airway lengths.
Historically, the most widely used models of regional deposition versus particle size
were developed by the International Commission on Radiological Protection Task Group on Lung
Dynamics under the chairmanship of P. E. Morrow (Morrow et al., 1966). These models were
developed to determine radiation exposure from inhaled radioactive aerosols. Although the ICRP
aerosol deposition and clearance models were not intended for broad application to environ-
mental aerosols, they have been so applied by some scientists. The ICRP Task Group used the
anatomical model and impaction and sedimentation equations of Findeisen (1935) and the general
methods of Landahl (1950, 1963) for calculating deposition in the tracheobronchial and
pulmonary regions. The Gormley-Kennedy (1949) equation for cylindrical tubes was used for
SOX11A/A 11-15 2-9-81
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*
calculating diffusional deposition. For head deposition, inhalation through the nose with a
deposition efficiency given by the empirical equation of Rattle (1961a) was used. Particles
were assumed to be insoluble, stable, and spherical with physical densities of 1 g/cm , and
the aerosols were assumed to be log normally distributed with a o as high as 4.5. When the
results were expressed in terms of the mass median diameter (HMD) for these various sized
distributions of unit density aerosols (equivalent to the MMAD), the range of the expected
regional deposition values was relatively narrow.
At the time the ICRP Task Group models were developed, the available human data were
primarily total deposition values for polydisperse and sometimes unstable aerosols (Landahl
and Herrmann, 1948; Davies, 1964b; Van Wijk and Patterson, 1940; Brown et al., 1950;
Dautrebande and Walkenhurst, 1966; Morrow et al., 1958; Landahl and Black, 1947). Since then,
the deposition in humans of monodisperse insoluble, stable aerosols of different sizes has
been measured under different breathing conditions. Extensive studies have been conducted by
Lippmann (1977), Heyder et al. (1975, 1980), Stahlhofen et al. (1980), Chan and Lippmann (1980),
and Giacomelli-Maltoni et al. (1972). Additional useful data are reported by Palmes and Wang
(1971), Shanty (1974), George and Breslin (1967), Altshuler et al. (1967), Hounam et al.
(1971a,b), Foord et al. (1976), Pavia et al. (1977), among others (Muir and Davies, 1967;
Taulbee et al., 1978; Hounam, 1971; Heyder, 1971; Heyder and Davies, 1971; Fry and Black,
1973).
11.2 DEPOSITION IN MAN AND EXPERIMENTAL ANIMALS
11.2.1 Insoluble and Hydrophobic Solid Particles
11.2.1.1 Total Deposition—With the background information in Section 11.1, it is evident
that understanding and interpreting the health effects associated with exposure to particles
and S0? is critically influenced by knowing where particles of different sizes deposit in the
respiratory tract and the extent of their deposition. As was seen, the respiratory tract can
be divided into regions on the basis of structure, size, and function. Insoluble particles
depositing in the various regions contact or affect different cell populations and have large
differences in retention times and clearance pathways (see Section 11.3).
If the quantity of aerosol exhaled is compared with that inhaled, the data can be
expressed as total deposition, but regional involvement cannot be distinguished. By tagging
the test aerosols with radio labels, investigators have been able to separate deposition by
region, beginning with either nasal and nasopharyngeal deposition for nose breathing or oral
and pharyngeal deposition for mouth breathing. The measurement of clearance of the radio-
labeled aerosol from the thorax can be used to separate early clearance, indicative of tracheo-
bronchial (TB) deposition, from more slowly cleared pulmonary (P) deposition.
Total respiratory tract deposition with nose breathing is given in Figure 11-3, and total
deposition with mouth breathing is depicted in Figure 11-4. Analyses based on the difference
between concentrations of inhaled and exhaled particles, as well as those based on external in
vivo measurements of radiolabeled particles, are represented in the studies comprising these
SOX11A/A H-16 2-9-81
-------
I
t—»
•-J
1.0
0.9
OS
0.7
0.6
g OA
ui
O
0.3
0.2
0.1
I I I I
SOURCE TIDAL VOL, ml
O GIACOMELU-MALTONI •! il. (1972) 1500
O HEYOER Mil. (19751 1000
" A SHANTY 11974) 1150
O GEORGE AND BRESLIN (19671 550-760
-—HEYDER, (til. (1980) 1000
— — HEYOER. «t •!. (1980) 1000
I I I I I I
0.1 0.2 0.4 0.5 0.6
PHYSICAL DIAMETER, ^m
0.8 1.0
2.0 4.0
AERODYNAMIC DIAMETER, ion
6.0 8.0 10.0
Figure 11-3. Deposition of monodisperse aerosols in the total respiratory tract for nasal breathing as a function of aerodynamic
diameter except below 0.5 (urn where deposition is plotted vs. physical diameter. The data are individual observations, averages.
and ranges as cited by the various investigations.
-------
I
I—•
CO
SOURCE TIDAL VOL, ml RES. RATE, breattw/min SOURCE TIDAL VOL, ml RES. HATE, br««
O LANDAHL tt al. (19511 500 15
DLANDAHL.ttl. (19521 1500 15
A ALTSHULER Mil. (1957) 500 15
V GEORGE AND BRESLIN (1967) 760 11
OGIACOMELLI-MALTONI«II. (1972) 1000 12
• CHAN & LIPPMANN (1980)* 1000 14
• FOORDm •1.11976) 1000 16
A MARTENS ft JACOB! (1973) 1000 14
1.0
0.9
0.8
0.7
0.6
ZO .5
v«v
O
1-
i o*
a.
^j
Q
03
0.2
0.1
0
•USED MMD FOR D < 0.5 Jim
I I I I I I I I I I
__
- *
^
~~ * * T T
— * ~ * o L •
T ^rn T
^ I I I
— ^** "? ^*" £
12 .
..til
i i i i i i i i i 1 1
T LEVER (1974) 600 16
4 MUIR & DAVIES (19671 500 16
O DAVIEStt 11.11972) 600 16
B HEYDER (1975) 1000 15
A SHANTY (19741 1140 18
T STAHLHOFEN at al. (1980) 1500 16
<> STAHLHOFEN it •!. (1980) 1000 7.6
^ SWIFT « •!. (1977) 500 IS
$$£ HEYDER 11973) 500 16
1 I 1 1 1 1 1 1 1 1 1 lo| 1 I
tl^ J* s~
•mjr\ «P * *
*T* Tf * **• ~~
if..* -
I *.'
V
a
j '
! * T t B
" T -fc. •** *
A F* °
A 1 A -L
4a » —
1 1 1 1 1 1 i II 1 1 1 1
0.01
0.02 0.04 0.06 0.080.10
PHYSICAL DIAMETER,/im
0.20
0.4 0.5 0.6 0.8 1.0 2.0 4.0 6.0 8.0 10.0
4> AERODYNAMIC DIAMETER, ion »
Figure 11-4. Deposition of monodisperse aerosols in the total respiratory tract for mouth breathing as a function of aerodynamic
diameter except below 0.5 pm, where deposition is plotted vs. physical diameter. The data are individual observations, averages,
and ranges as cited by the various investigators.
-------
figures. With nose breathing, complete deposition can be expected for particles larger than
about 4 um Dae- Mouth breathing bypasses much of the filtration capabilities of the naso-
pharyngeal region, and there is a shift upward to around 10 um 0 before there is complete
deposition of the inhaled particles.
The various studies all appear to show the same trend. The particle size for minimum
deposition is less clear for nasal breathing as compared to mouth breathing, for which minimum
deposition is at about 0.5 um diameter. Heyder and coworkers (1973a, 1973b, 1975) carefully
matched breathing patterns among subjects in studying the deposition of 0.5 um D particles
ac
upon which there were no electrical charges; their data are the deposition minima in Figure
11-4. Thus far, deposition of particles less than 0.1 um diameter has only been studied in
human subjects by Swift et al. (1977).
Comparison of the effects of respiratory parameters on aerosol deposition have been
conducted by Heyder and co-workers (1975, 1980) in systematic experiments comparing deposition
of different sized monodisperse aerosols in human volunteers at different tidal volumes, flow
rates, and breathing frequencies. For particles between 0.1 um and 4.0 um in diameter, Heyder
et al. (1975) measured total respiratory deposition during either nose or mouth breathing
while sequentially maintaining a given tidal volume, breathing rate, or inspiratory flow rate
and then varying the other two parameters. They demonstrated several important features of
aerosol deposition in the human respiratory airways. Heyder and co-workers (1980) extended
these studies to particles as large as 9 um D ; in the mouth-breathing experiments they also
ae
determined alveolar deposition.
With volumetric flow rate held at 15 liter/minute while breathing through the mouth, the
particle size yielding the lowest deposition changed from 0.66 um at TV 250 ml to 0.46 um at
TV 2000 ml. Breathing at TV 1000 ml changed this minimum deposition size from 0.58 um at 30
BPM to 0.46 um at 3.75 BPM. Hence, the particle size of minimum deposition was reduced with
increased residence time of particles in the lung and the net deposition for all particles was
increased. In fact, as the breathing rate went from 3.75 BPM to 30 BPM, the deposition at 1
um D went from 0.08 to 0.4, an increase of a factor of 5. In contrast to mouth breathing,
36
however, the particle size of minimum deposition with nose breathing was independent of the
residence time of particles in the respiratory tract when 1000 ml of aerosol at different flow
rates were inhaled.
When Heyder et al. (1975) kept the breathing frequency constant while changing the flow
rate and having the subjects breathe through the mouth, the deposition for particles smaller
than 1 um remained essentially unchanged, indicating that inertial impaction was of little
importance in the deposition of submicrometer aerosols. On the other hand, the deposition of
particles larger than 1 um D was enhanced at high flow rates, indicating the influence of
inertial impaction on the deposition of larger particles.
Sedimentation and impaction are competing deposition mechanisms, being governed by mean
residence time and flow rate, respectively. Hence, impaction will be the dominant mechanism
SOX11A/A H-19 2-9-81
-------
at high flowrates and short residence times, while most particles will be deposited by sedi-
mentation at low flow rates and long residence times. Heyder et al. (1980) showed that for 1
Mm Dae Partic1es, total deposition for mouth breathing at 1000 ml TV increased with increasing
mean residence time, indicating these particles were mainly deposited by sedimentation. For 8
Mm Dae, increasing flow rate increased deposition so that these particles were mainly deposited
by impaction. A transition region was observed for particles about 4 urn D . while Heyder and
aC
co-workers (1980) noted the transition region was shifted towards smaller particles for nose
breathing.
11.2.1.2 Deposition—The fraction of inhaled aerosol depositing in the extrathoracic region
can be quite variable, depending upon particle size, flow rate, breathing frequency, and whe-
ther breathing is through the nose or through the mouth. During exertion, the flow resistance
of the nasal passages cause a shift to mouth breathing in almost all individuals, thereby by-
passing much of the filtration capabilities of the head and leading to increased tracheobron-
chial deposition. Nasopharyngeal deposition is shown for nose breathing in Figure 11-5 and
for mouth breathing in Figure 11-6. Deposition in this region is usually plotted as a func-
2
tion of DO since this is a convenient parameter for normalizing impaction dominated deposi-
d6
tion data when the actual flowrates are not identical (Rattle, 1961a; Stahlnofen et al., 1980;
National Academy of Sciences, 1980; Hounam et al., 1969, 1971a). For reference, a scale show-
ing aerodynamic diameter when Q = 30 liters/min is also shown since this flow rate approximates
the average flow rate for the studies comprising these figures.
Particles entering the nose larger than about 10 urn D are effectively deposited in the
36
extrathoracic region (Figure 11-5). Also, deposition is slight (10 percent) for particles less
than 1 urn D . Similarly, for 10 urn and 1 urn D, particles under conditions of mouth breathing
36 36
(Figure 11-6), extrathoracic deposition is about 65 percent and 2 percent, respectively. The
regression curve shown in Figure 11-6 is from Chan and Lippmann (1980) who used their own data,
as well as the data of Lippmann (1977) and Stahlhofen et al. (1980) for Q = 45 liters/min in
their analysis. As indicated by Chan and Lippmann (1980), some of the lower values of extra-
thoracic deposition may be due to partial clearance to the stomach before the measurement of
head deposition was obtained. Particles can be swallowed even when the subject consciously
tries to avoid swallowing (Lippmann, 1977; Stahlhofen et al., 1980).
11.2.1.3 Tracheobronchial Deposition—As was seen earlier, when aerosols are inhaled through
the nose, relatively efficient extrathoracic filtration eliminates the passage of most parti-
cles larger than about 10 urn D,. to the tracheobronchial region. Mouth breathing markedly
dc
alters the deposition of inhaled particles in humans in that larger particles can enter both
the tracheobronchial and pulmonary regions (Morrow et al., 1966; Lippmann, 1977; Heyder et al.,
1980; Stahlhofen et al., 1980). For mouth-breathing tracheobronchial deposition expressed
as a fraction of the particles entering the trachea is shown in Figure 11-7 plotted against
particle size. Approximately 80-90 percent of 8-10 urn D particles entering the trachea are
deposited in the tracheobronchial region, as compared to less than 10 percent for particles
SOX11A/A 11-20 2-9-81
-------
1.0
0.9
OS
0.7
0.6
0.5
0.4
0.3
02
0.1
AERODYNAMIC DIAMETER (at 30 liters/min), pm
2 3 4 5
8 9 10
SOURCE
D HOUNAM.t .1.11969)
O LIPPMANN (1970)
O MARTENS & JACOB! (1973)
A GIACOMELLI-MALTONI « al. (1972)
O RUDOLF & HEYDER (1974)
TIDAL VOL, ml
I I
RESP. RATE, brmths/min
1000
1000
1000
I
I I I
10
20
40
60 80 100
200
400 600 800 1000
2000
4000 6000 10,000
D2Q
Figure 11-5. Deposition of monodisperse aerosols in extrathoracic region for nasal breathing as a function of D Q, where Q is the
average inspiratory flow rate in liters/min. The solid line is ICRP deposition model based on the data of Pattle (1961a), Other data
show the median and range of the observations as cited by the various investigators.
-------
AERODYNAMIC DIAMETER (at 30 liters/minium
2 345
8 9 10
14
0.9
0.8
0.7
0.6
Z0.5
80.4
CL.
0.3
0.2
0.1
O
D
V
O
SOURCE
LIPPMANN ( 1977)
STAHLHOFEN, «t al. (1980)
CHAN & LIPPMANN (1980)
STAHLHOFEN,« al. (1980a)
CHAN & LIPPMAN (1980)
TIDAL VOL, ml RESP. RATE, breattu/min
1000 14
1000 7.5
1000 14
1500 IS
REG. LINE OF ALL DATA
I I I I I II
10
20
40
60 80 100
200
400
D2Q_
600 800H 000
2000
4000 6000 8000 10,000
Figure 11-6. Deposition of monodisperse aerosols in extrathoracic region for mouth breathing as a function of D^Q, where Q is
the average inspiratory flow rate in liters/min. The data are the individual observations as cited by the various investigators. The
solid line is the overall regression derived by Chan and Lippmann (1980).
-------
*
less than 1 pm Dag. The increased penetration of large particles deeper into the respiratory
tract when a person breathes through the mouth can be seen from the 20-30 percent experimental
tracheobronchial deposition data for particles 8-10 urn D (Stahlhofen et al., 1980). The
36
solid curve in Figure 11-7 is from Chan and Lippmann (1980) depicting the experimental tracheo-
bronchial deposition data from their investigations using the average value of a new anatomic
parameter, the bronchial deposition size, for the average Q value measured in their study (Q =
39 liters/min). This parameter enables the classification of various individuals and popula-
tions according to their tracheobronchial deposition efficiencies.
Deposition in the tracheobronchial region is influenced by both impaction and sedimenta-
tion, with the relative contribution of these two mechanisms changing with particle size and
air flow rate. Impaction predominates for deposition of particles larger than about 3 pm D
ae
and flow rates greater than about 20 liters/min, while sedimentation deposition becomes a
larger fraction of a diminishing tracheobronchial component for smaller particles and lower
flows (Lippmann, 1977). Importance of impaction for tracheobronchial deposition is reflected
2
by deposition often being plotted against the inertial parameter, D Q (Stahlhofen et al.,
1980 and Lippmann, 1977).
For a given particle size, tracheobronchial deposition varies greatly from subject to
subject among nonsmokers, cigarette smokers, and patients with lung disease (Lippmann et al.,
1971). On the average, tracheobronchial deposition is slightly elevated in smokers and
greatly elevated in patients with lung-disease (Lippmann et al., 1977; Cohen, 1977). However,
each subject exhibits a characteristic and reproducible relationship between particle size and
deposition as indicated by the data of Stahlhofen et al. (1980), depicted in Figure 11-8. For
the two breathing patterns shown, the steep increase of the nasopharyngeal deposition values
with increasing particle size is accompanied by a corresponding decrease in tracheobronchial
deposition, so that tracheobronchial deposition, as a function of particle aerodynamic dia-
meter, may be described by a bell-shaped curve with a maximum (Stahlhofen et al., 1980).
Although these investigators did not experimentally study particles larger than 9 (jm D ,
CtC
extension of their bell-shaped curves would support the conclusion of Miller et al. (1979)
that about 10 percent of particles as large as 15 |jm D can enter the tracheo bronchial
ae
region during mouth breathing. Miller et al. (1979) had used the tracheobronchial deposition
data of Lippmann (1977) and aerodynamic diameters computed at a mean flow rate of 30 liters/
min. This flow rate is bracketed by the mean flow rates of 15 and 45 liters/min used by
Stahlhofen et al. (1980).
The data of Stahlhofen et al. (1980) in Figure 11-7 on three subjects show lower values
and less scatter than the other data contained in the figure. Chan and Lippmann (1980) cite
two possible explanations for the differences. Stahlhofen and coworkers (1980) used constant
respiratory flowrates in comparison to the variable flowrates used by Chan and Lippmann (1980).
Also, the two laboratories used different bases to separate the initial thoracic burden into
tracheobronchial and pulmonary components. Stahlhofen et al. (1980) extrapolated the thoracic
SOX11A/A 11-23 2-9-81
-------
1.0
0.9
0.8
0.7
0.6
O 05
K
V)
g 04
UJ
O
02
02
0.1
I
I
I
SOURCE
O LIPPMANN & ALBERT (1969)
O LIPPMANN (1977)
A STAHLHOFEN, et «l. (1980)
O CHAN AND LIPPMANN (1980)'
^—CHAN AND LIPPMANN (1980)
— ICRP MODEL FOR 1450 ml TV
•USEDMMD FOR O
-------
retention values measured during the week after the end of bronchial clearance back to the time
of inhalation; they considered pulmonary deposition to be the intercept at that time, with the
remainder of the thoracic burden considered as tracheobronchial deposition. This approach
yields results similar to, but not identical with those obtained by treating tracheobronchial
deposition as equivalent to the particles cleared within the first day.
Deposition calculations usually group lung regions without regard to nonuniformity of the
pattern of deposited particles within the regions. Schlesinger and Lippmann (1978) found that
nonuniform deposition in the trachea could be caused by the air flow disturbance of the larynx.
Bell and Friedlander (1973) and Bell (1978) observed and quantified particle deposition as it
occurs at a single airway bifurcation and found it to be highly nonuniform and heaviest around
the carinal arch. Raabe et al. (1977) observed that the relative lobar pulmonary deposition
of monodisperse aerosols was up to 60 percent higher in the right apical lobes of small
rodents (corresponding to the human right upper lobe) and that the difference was greater for
3.05 urn and 2.19 urn D particles than for smaller particles. In addition, Raabe et al.
d6
(1977) showed that these differences in relative lobar deposition were related to the geome-
tric mean number of airway bifurcations between trachea and terminal bronchioles in each lobe
for rats and hamsters. Since similar morphologic differences occur in human lungs, nonuniform
lobar deposition should also occur. Schlesinger and Lippman (1978) found nonuniform deposi-
tion in the lobar branches of a hollow model of the tracheobronchial airways with enhanced
carinal deposition and were able to demonstrate a correlation of higher lobar deposition and
the reported incidence of bronchogenic carcinoma in the different human lobar bronchi. Occu-
pational lung diseases, such as silicosis and asbestosis, also show distinctive distributional
features (Morgan and Seaton, 1975).
11.2.1.4 Pulmonary Deposition—Pulmonary deposition as a function of particle size is shown
in Figure 11-9. All of the experimental points plotted were obtained in mouth-breathing
studies on nonsmoking normal subjects who inhaled monodisperse aerosols.
The eye-fit band approximately encompasses the range of deposition values obtained in the
studies cited; a variety of tidal volumes and breathing frequencies were used. Also shown in
Figure 11-9 are the deposition curve from the predictive model of Yu (1978) and an estimate of
the alveolar deposition that could be expected for nose breathing (Lippmann, 1977). Lippmann
(1977) derived the estimate by analysis of the difference in head retention during nose breath-
ing and mouth breathing.
The pulmonary deposition curve peaks at about 3.5 urn D with the middle of the eye-fit
band in Figure 11-9 being located at about 50 percent deposition. However, the data of
Stahlhofen et al. (1980) for a tidal volume of 1000 ml and 7.5 breaths per minute (reflective
of breathing very slowly and deeply) show that pulmonary deposition of 3.5 pm D particles
can be as high as 70 percent.
For nose breathing, the size associated with maximum deposition shifts downward to about
2.5 pm D . Also, the deposition peak is much less pronounced (about 25 percent) with a nearly
ae
constant pulmonary deposition of about 20 percent for all sizes between 0.1 urn and 4 urn Dae-
SOX11A/A 11-25 2-9-81
-------
TV - 1000 ml. BPM - 7.5/min
i
ro
ui
Q
1.0
TV - 1500 ml, BPM - 15/min
0.8
0.4
0.2 -;
I SUBJ. 1
• SUBJ. 3
89 2 4 6891
AERODYNAMIC PARTICLE DIAMETER, urn
8 9
Figure 11-8. Total and regional depositions of monodisperse aerosols as a function of the aerodynamic diameter for three individual
subjects as cited by Stahlhofen et al. (1980). (T = Total, TB = Tracheobronchial, P = Pulmonary, ET = Extrathoracic, TV = Tidal
Volume. BPM = Breaths Per Minute)
-------
1.0
0.9
0.8
0.7
Z 0.6
O
I-
35 0.5
2
HI
0 0.4
0.3
0.2
0.1
O
&
O
O
I I I I I I I II I
SOURCE TIDAL VOL. ml
STAHLHOFEN at al. (19801
STAHLHOFEN at al. (198Ob)
STAHLHOFEN at al. (1980)
ALTSHULER at al. (1967)
GEORGE & BRESLIN (19671
SHANTYI1974)
LIPPMANN ft ALBERT (1969)
CHAN & LIPPMANN (19801*
•YU (19781
LIPPMANN (1977)
•USED MMD FOR D < 0.5 Jim
I I I I I II I
RES. RATE (BPM)
I I I I I I I II •*•
.01
.02 .04 .06 .08 .1
PHYSICAL DIAMETER,>
.2 .4 .5 .6 .8 1.0 2.0 4.0 6.0 8.0 10.0
AERODYNAMIC DIAMETER, fim
Figure 11-9. Deposition of monodisperse aerosols in the pulmonary region for mouth breathing as a function of aerodynamic dia-
meter, except below 0.5 pm where deposition is plotted vs. physical diameter. The eye-fit band envelops deposition data cited by the
different investigators. The dashed line is the theoretical deposition model of Yu (1978) and the broken line is an estimate of pul-
monary deposition for nose breathing derived by Lippmann (1977).
-------
Pulmonary and total deposition of Fe203 (density 3.2 g/cm3) particles and di-2-ethylhexyl
sebacate droplets for mouth breathing was evaluated by Heyder et al. (1980) as a function of
aerodynamic diameter for two breathing patterns. Some results with di-2-ethylhexyl sebacate
particles were reported by Heyder et al. (1980) in terms of particle diameter. They are
presented here for uniformity in terms of aerodynamic diameter since these particles were
close to unit density. Keeping the mean volumetric flow rate constant at 250 ml/sec and
allowing the mean residence time to vary between 2 and 8 sec, they observed that as the mean
residence time increased, there was a decrease for the particle size having the greatest pro-
bability of deposition. With this mean flow rate, particles smaller than about 2.4 urn Dge
were exclusively deposited in the alveolar region, indicating their inertia was not suffi-
ciently high for impaction loses. When the mean flow rate was increased to 750 ml/sec and the
mean residence time was 2 sec, particles with an aerodynamic diameter smaller than about 1.5
urn were exclusively deposited in the alveolar region of the respiratory tract. From the data
of Heyder et al. (1980) it can also be seen that the particle size associated with the peak of
the deposition curve and the magnitude of the peak decrease as the mean flow rate increases.
In the above studies, maximum pulmonary deposition was at 3.5 urn and 3 urn D when Q was
uC
15 liters/min and 45 liters/min, respectively.
11.2.1.5 Deposition in Experimental Animals—Since much information concerning inhalation
toxicology is collected with beagles or rodents, it is important to consider the comparative
regional deposition in these experimental animals to help interpret, from a dosimetric view-
point, the possible implications for man of animal toxicological results.
The study by Holma (1967) on rabbits examined mucociliary clearance rates but Lippmann
(1977) derived tracheobronchial deposition information by further analyzing the data. Lung
retention curves indicated that the tracheobronchial deposition of 6 urn polystyrene spheres
varied from 40 to 93 percent of the total lung deposition, with a median of 60 percent. A
median of 29 percent was found for 3 urn particles. The above values are remarkably close to
the available data for man. Cuddihy et al. (1973) measured the regional deposition of poly-
disperse aerosols in beagles with TV about 170 ml at about 15 BPM and expressed the results as
mass deposition percentage versus mass median aerodynamic resistance diameter (MMAD ) that
3T*
ranged from 0.42 urn to 6.6 urn with geometric standard deviation a = 1.8. These results are
summarized in Figure 11-10 and compared with the Task Group Values for man with TV 1450 ml,
integrated to account for a a = 1.8. In comparison to the tracheobronchial deposition of
large particles in rabbits exposed to monodisperse aerosols for one test at 6.6 pm D , the
3f*
tracheobronchial deposition was about 44 percent of the total lung deposition. With sizes
between 2.5 and 3 urn D . the tracheobronchial deposition ranged from 5 to 39 percent, with a
ar
median deposition of 9 percent. The particle size for minimum pulmonary deposition was
approximately 0.6 urn D , with pulmonary deposition at this size ranging from about 12-35
percent and total deposition from about 18-55 percent.
SOX11A/A H-28 2-9-81
-------
1.0
0.5
0.2
O 0.1
I"
oc
u.
O
§ 1-0
a.
8
050
0.20
0.10
0.05
V269A
O284A
I i i i i mi
0.5
1.0
I I I III
0.10
0.05
1 I I 1 | | IJ6T
B. TRACKED-
. BRONCHIAL
5.0 10
: 111 I
_C. PULMONARY
i tfl
^
0.03»—
0.1
= I I I I Mill I/TJ,
—1D. EXTRATHORACIC x
C>
0.1
0.05
0.02
1.0 2.0 5.0 10 0.1 0.2 0.5 1.0 2.0
ACTIVITY MEAN AERODYNAMIC DIAMETER, pm
5.0
10
Figure 11-10. Deposition of inhaled polydisperse aerosols of lanthanum oxide (radio-labeled with 140La)
in beagle dogs exposed in a nose-only exposure apparatus showing the deposition fraction (A) total dog,
(B) tracheobronchial region, (C) pulmonary aveolar region, and (D) extrathoracic region (adapted from
Cuddihy et al. 1973). Dashed lines represent range of observed values.
11-29
-------
Somewhat different results were obtained by Phalen and Morrow (1973) in dogs exposed to a
silver metal aerosol of 0.5 urn D with a a of 1.5 |jm. Total deposition averaged 17 percent,
oC y
with a range of 15-19 percent. In the Phalen and Morrow (1973) study, the dogs inhaled
through a tracheal tube so that there was no head deposition, while head deposition varied
from negligible to 5 percent for 0.5 urn particles in the study of Cuddihy et al. (1973). In
experiments using donkeys (Albert el al., 1968, 1969; Spiegelman et al., 1968), eight animals
were tested periodically with monodisperse 3-3.5 urn D Fe90, aerosol. Tracheobronchial depo-
36 c, -j
sition averaged 50-70 percent of the total lung deposition, with a median of 54 percent.
Raabe et al. (1977) have measured the regional deposition of 0.1 urn to 3.15 urn Dae mono-
disperse aerosols in rats (TV about 2 ml, 70 BPM) and Syrian hamsters (TV about 0.8 ml at
about 40 BPM). Their results are summarized in Figure 11-11. The pulmonary deposition of 1-3
urn Dae particles is about 6-9 percent in rats and hamsters, while in man deposition of these
same size particles varies from 21-24 percent for nose breathing and from 20-50 percent for
mouth breathing. For particles smaller than 1 urn D , differences in pulmonary deposition
36
between man and these species decrease. Tracheobronchial deposition of particles 5 urn D is
ac
slight (-v 5 percent) in rodents due to very efficient removal of these particles in the head.
In contrast, 50 percent of 5 urn D particles inhaled via the mouth deposit in the tracheo-
ae
bronchial region of man (Figure 11-7), so that large differences can exist between man and
rodents in the tracheobronchial deposition of large particles. In rodents, the relative
distribution among the respiratory regions of particles less than 3 urn D during nose breath-
ae
ing follows a pattern that is similar to human regional deposition during nose breathing.
Thus, in this instance, the use of rodents or dogs in inhalation toxicology research for extra-
polation to humans entails differences in regional deposition of insoluble particles less than
3 urn D „ that can be reconciled from available data.
ae
11.2.2 Soluble, Deliquescent, and Hygroscopic Particles
Most deposition studies and models tend to focus on insoluble and stable test aerosols
whose properties do not change during the course of inhalation and deposition. However,
environmental aerosols usually contain deliquescent or hygroscopic particles that may grow in
the humid respiratory airways. That growth will affect deposition (Scherer et al., 1979).
Although the ICRP Task Group on Lung Dynamics (Morrow et al., 1966) addressed this problem by
considering the equilibrium diameter for deliquescent materials at relative humidities near,
but less than, 100 percent, the residence times in the respiratory tract may be too short for
large particles to reach their equilibrium size (Nair and Vohra, 1975; Charlson et al., 1978).
Also, environmental aerosols may consist of a combination of components, including complex
mixtures, that may not behave like pure substances. Since the temperature of the inspired
aerosol will usually be less than that of the respiratory tract environment, supersaturation
of water vapor, with respect to the aerosol particles, may exist.
Ferron (1977) has described the factors affecting soluble particle growth in the airways
during breathing. His results suggest that particles 1 urn Dge will increase by a factor of
SOX11A/A H-30 2-9-81
-------
0.6
0.5
0.4
c
u.
Z 03
O
0.2
0.1
RAT
A
D
O
I I I I I I I
HAMSTER
A EXTRATHORACIC
• TRACHEOBRONCHIAL
• PULMONARY
Sr
^,.
&
"I
^
I "
--^-g.zi.rn
0.2 03 0.4
PHYSICAL DIAMETER, nm
0.5 0.6 0.7 1.0 2.0 3.0 4.0 5.0
AERODYNAMIC DIAMETER (Dar),Aim
Figure 11-11. Deposition of inhaled monodisperse aerosols of fused aluminosilicate spheres in small
rodents showing the deposition in the extrathoracic (ET) region, the tracheobronchial (TB) region, the
pulmonary (P) region, and in the total respiratory tract based upon Raabe et al. (1977).
11-31
-------
three to four in aerodynamic diameter during passage through the airways. Extrathoracic,
tracheobronchial, and pulmonary deposition of the enlarged particles would be greater than the
deposition expected for the original particle size. Submicrometer particles, including those
as small as 0.05 urn, will grow by a factor of two in physical diameter, with relatively little
effect on deposition. However, the hygroscopic growth of particles in the diffusion size
range (< 0.5 urn physical diameter) may alter their deposition pattern substantially as the
diffusional displacement is related to the actual size and not the aerodynamic diameter. Pul-
monary deposition of particles smaller than 0.3 urn may be reduced with growth because of
reduced diffusivity.
Atmospheric sulfate aerosols can be described as sulfuric acid partially or completely
neutralized by NH,. Growth of these particles will occur in the respiratory airways during
respiration. This growth involves chemical dilution of the electrolyte or acid with absorbed
water. A particle growing a factor of three in physical diameter must absorb a volume of
water equal to 26 times its original particle volume. Also, the increased size will enhance
losses by inertial mechanisms, including impaction in the upper airways. A 1 urn D particle
ac
of H2$04 or (NH4)2$04 may grow to nearly 3 urn D in the nasal region, increasing both nasal
deposition and tracheobronchial deposition by a factor of 2 or more over the deposition
expected for a 1 pm D particle, with the net result that pulmonary deposition is reduced.
ae
Particle growth in the airways may in some cases be protective since the reduced electrolyte
or acid concentration will probably reduce the level of local toxicity.
11.2.3 Surface Coated Particles
Some environmental particles may consist of a relatively insoluble core coated with
various chemical species including metallic salts, (NH.^SO., (NH.)HS04, H^SO,, organic com-
pounds including polynuclear aromatic hydrocarbons, and small particles of other sparingly
soluble materials. Although some surface growth due to water adsorption may occur in the air-
ways, growth will be limited by the availability of deliquescent or hygroscopic components on
the particle surface. In general, the increase in aerodynamic diameter that may occur would
be much less for coated particles than for more pure forms of insoluble materials.
Important examples of coated particles are the fly ash, soot, or other residual solid
particulate aerosols released into the environment by combustion of fossil fuels. The exact
chemical form of the relatively inert core of these particles will vary from nearly pure fused
aluminosilicate particles produced during the combustion of coal to carbonaceous or metal
oxide particles produced by internal combustion engines. Volatile trace metal compounds and
organic compounds condense on these particles during the cooling of the effluent stream in the
power plant smoke stack or engine exhaust line and during release to the atmosphere. In
addition, gases such as SO^ can adsorb to the particle surfaces or finer aerosols can aggre-
gate onto the particle surfaces. If these processes are diffusion limited, the condensation
and coagulation will be quantitatively proportional to particle diameter for particles larger
than 0.5 urn D and to particle surface for smaller particles. In either case the fractional
SOX11A/A 11'32 2-9-81
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mass of the surface coating material will be greater on smaller particles than on larger ones.
In other words, the condensed material coats the particles with a relative mass concentration
that increases with decreasing particle size. Important elements such as Se, Cd, As, V, Zn,
Sb, and Be have been found to exhibit this size dependence in coal fly ash aerosols (Davison
et al., 1974; Natusch et al., 1974; Gladney et al., 1976). Therefore, the growth of such
surface-coated particles in the airways should be expected to be much less than for pure deli-
quescent particles. Such growth should be only a minor influence on the deposition of large
particles. On the other hand, small submicrometer coated particles may be principally com-
posed of a deliquescent surface coating and subject to more extensive relative growth. (See
also Chapters 3, 5, and 6.)
11.2.4 Gas Deposition
The major factors affecting the uptake of gases in the respiratory tract are the mor-
phology of the respiratory tract, the physicochemical properties of the mucous and surfactant
layers, the route of breathing and the depth and rate of airflow, physicochemical properties
of the gas, and the physical processes which govern gas transport. A brief discussion of
these factors serves to illustrate their general role in the deposition of gases and convey
some aspects specific to the uptake of S02-
The complex morphological structure of the human respiratory tract has been discussed in
section 11.1.3. The nature and structure of the respiratory tract in man and animals criti-
cally influences the deposition of gases since the relative contribution of gas transport
processes varies as a result of this morphology. The human tracheobronchial tree is more
symmetric, with respect to diameter ratios and branching angles, than that of dogs, rats, or
hamsters, but is closest to that of the dog (Phalen et al., 1978). The structure of the
tracheobronchial tree is variable from species to species, from lobe to lobe within a given
lung, and from one depth to another in the lung.
Physicochemical properties of a gas relevant to respiratory tract deposition are its
solubility and diffusivity in mucus, surfactant, and water and its reaction-rate constants in
mucus, surfactant, water, and tissue. Henry's law relates the gas-phase and liquid-phase
interfacial concentrations and is a function of temperature and pressure. In general, the
more soluble a gas is in biological fluids the higher it is removed in the respiratory tract.
The solubility of most gases in mucus and surfactant is not known. However, Henry's law
constant for many gases in water is known, the value for SOp being 59.7 mole fraction in air
per mole fraction in water at 37°C and one atmosphere of pressure (Washburn, 1928). The
diffusivities of most gases in mucus, surfactant, tissue, and water are also unknown, thereby
complicating efforts to model gas uptake in the respiratory tract. Diffusivity may be much
smaller in a viscous mucous fluid than in water, but ciliary activity induces turbulence which
effectively increases mass transfer. In the general case, transport rates of the gas across
the mucus-tissue interface, tissue layer, and the tissue-blood interface are needed to fully
understand the absorption and desorption of gases in the respiratory tract. However,
SOX11A/A 11-33 2-9-81
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information on biochemical reactions may enable one or more of these compartments to be
ignored for a given gas.
The major processes affecting gas transport involve convection, diffusion, and chemical
reactions. The bulk movement of inspired gas in the respiratory tract is induced by a pres-
sure gradient and is termed convection. Molecular diffusion due to local concentration gra-
dients is superimposed on this bulk flow at all times, with the transport of the gas being
accomplished by the coupling of these two mechanisms. Convection can be decomposed into the
processes of advection and eddy dispersion. Advection is the horizontal movement of a mass of
air that causes changes in temperature or in other physical properties, while eddy dispersion
occurs when air is mixed by turbulence so that individual fluid elements transport the gas and
generate the flux. Due to the morphology of the respiratory tract and respiratory airflow
patterns, the relative contribution of the various processes to transport and deposition is a
function of location and point in the breathing cycle.
During the respiratory cycle, the volumetric flow rate of air varies from zero up to a
maximum (dependent upon tidal volume, breathing frequency, and breathing pattern) and then
back to zero. Usually expiration is longer than inspiration, and intervening pauses may occur.
The net result of these variables is to impart complicated flow patterns and turbulence in some
portions of the respiratory tract (see Section 11.1.4).
In studying the nature of gas mixing in the tracheobronchial tree and its effects on gas
transport there have been numerous modeling efforts utilizing an approach in which all pathways
from the mouth or trachea to the alveoli are combined into one effective pathway whose cross-
sectional area is equal to the summed cross-sectional area of all bronchial tubes at a given
distance from the mouth or trachea (Davidson and Fitz-Gerald, 1974; Paiva, 1973; Pedley, 1970;
Yu, 1975; Scherer et al., 1972). In this formulation, the mechanical mixing imparted by tube
bifurcations, turbulence, and secondary flows and the mixing due to molecular diffusion are
represented by the functional form of the effective axial diffusion coefficient (Scherer
et al., 1975). Thus, this coefficient of diffusion incorporates the effect of axial convection.
The effective axial diffusion coefficient is a constant equal to the molecular diffusivity only
in the alveolar region where gas velocity is very small. However, in other regions of the
tracheobronchial tree, the local average gas velocity and the tube geometry will jointly deter-
mine the value. Various functional forms have been proposed in the studies cited above for an
appropriate expression for the effective axial diffusion coefficient.
By constructing individual streamline pathways from the trachea to the alveoli, Yu (1975)
derived an expression for the effective axial diffusion coefficient which equalled the alge-
braic sum of the molecular diffusion coefficient and an apparent diffusion coefficient. The
apparent diffusion coefficient arises from two independent mechanisms: 1) the nonhomogeneous
ventilation distribution in the lung, and 2) the interaction of nonuniform velocity and con-
centration profiles due to Taylor's mechanism in individual airways. Using an average stand-
ard deviation of airway lengths based upon the data of Weibel (1963) and various flow theory
SOX11A/A 11-34 2-9-81
-------
limiting values, Yu (1975) demonstrated that Taylor diffusion is everywhere in the tracheo-
bronchial tree dominated by the apparent diffusion due to nonhomogeneous distribution of
ventilation, rather than being a major mechanism for gas transport in some airways as claimed
by Wilson and Lin (1970).
In all of the previously described studies the diffusivity expressions used assume fully
developed flow in straight pipes to describe gas mixing, a condition not truly applicable over
most of the tracheobronchial tree. Since flow patterns at tube bifurcations are different for
inspiration and expiration (Schroter and Sudlow, 1969), the mixing process and hence the
effective diffusivities are different. To obtain diffusivities applicable to the tracheo-
bronchial tree, Scherer et al. (1975) used airway lengths and diameters from Weibel (1963) and
branching angles from Horsfield and Cumming (1967) to construct a five-generation symmetrical
branched tube model and to experimentally determine effective axial diffusivity for laminar
flow of a gas as a function of mean axial velocities up to 100 cm/s in the zeroth generation
tube. The relationship was approximately linear and diffusivities for expiration were about
one-third those for inspiration. The values obtained by Scherer et al. (1975) for steady flow
can be applied to oscillating flow in the tracheobronchial tree provided the oscillating flow
can be considered quasi-steady, i.e., steady at any instant of time. This condition should
hold in the first ten generations whenever flow rates are approximately greater than 0.1 1/s
(Jaffrin and Kesic, 1974).
Additional experimental uptake data are needed to obtain a better understanding of the
effects of various factors affecting the transport and removal in the lung of gases, such as
SOp. Also needed along with these experimental data are refined theoretical approaches, as
well as more flexible computational models, such as that of Pack et al. (1977). The amount of
S0? removed depends upon solubility, the velocity and turbulence of the air, the diffusing
capacity across the air-tissue interface and through the tissue, the volume of tissue avail-
able for gas storage, and the rate of fluid exchange between these tissues and the storage
reservoirs in the body for S0? (Aharonson, 1976). The rate controlling factor in the deposi-
tion of SO, is probably the vapor pressure of dissolved S09 in buffered body fluids.
2
The diffusion coefficient of S0« in air at body temperature is 0.144 cm /sec at sea level
(Fish and Durham, 1971; Sherwood et al., 1975). The complicated flow patterns and turbulence
in the upper respiratory tract and upper generations of the tracheobronchial tree in combina-
tion with high solubility in body fluids are responsible for the large removal of S0« in these
regions. Frank et al. (1969) surgically isolated the upper respiratory tract of anesthetized
dogs with separate connections for the nose and mouth. Sulfur dioxide labeled with 35S was
passed through this isolated nasopharyngeal region for 5 min, and nearly complete removal was
33
observed for concentrations of 2.62 mg/m to 131 mg/m (1 to 50 ppm) at a flow rate through
the nose of 3.5 liters/min. Uptake of the mouth averaged more than 95 percent at 3.5 liters/min
3 3
with S0? levels of 2.62 mg/m and 26.2 mg/m (1 and 10 ppm). However, when flow was increased
tenfold to 35 liters/min, uptake by the mouth fell to under 50 percent. Strandberg (1964) used
SOX11A/A H-35 2-9-81
-------
a trachea! cannula with two outlets that allowed sampling of inspired and expired air to study
the uptake of S0? in the respiratory tract of rabbits. He observed 95 percent absorption in
the respiratory tract at 524 mg S02/m3 (200 ppm) but at 0.13 mg S02/m3 (0.05 ppm) absorption
was lowered to about 40 percent during inspiration, demonstrating an apparent concentration
effect. Absorption of SO, at expiration was 98% in the 524 mg/m (200 ppm) studies compared
o
to 80% for experiments using 0.13 mg/m (0.05 ppm). Dalhamn and Strandberg (1961) found that
rabbits exposed to 262-786 mg S02/m3 (100 - 300 ppm) absorbed 90% - 95% of the S02> They
noted that absorption was to some extent dependent upon the technique whereby tracheal air
samples were obtained.
Corn et al. (1976) studied the upper respiratory tract deposition of S02 in cats and
computed mass transfer coefficients which can be used with surface area data to calculate the
amount of SO- removed in various parts of the respiratory tract. Utilizing a theoretical
approach, their own empirical data, and information available from the literature, Aharonson
et al. (1974) examined the effect of respiratory airflow rate on nasal removal of soluble
vapors. The only assumption made regarding factors affecting local uptake was that there was
no back pressure in the blood. Hence, whether the rate of uptake is limited by diffusion
through the gas phase, diffusion through the tissue, chemical reactions in the tissue, or
local blood flow in the tissues, the analytical approach is valid, as long as the rate of
uptake is proportional to the gas phase pressure of the vapor. Their analysis for acetone,
ether, ozone, and sulfur dioxide showed that the uptake coefficient, which defines the average
flux of soluble vapors into the nasal mucosa per gas-phase unit partial pressure, increases
with increasing airflow rate.
In experiments described by Brain (1970b) there was a 32-fold increase in the amount of
S02 present in the trachea of dogs when the air flow-rate was increased 10-fold. However, had
the uptake coefficient not changed with the flow rate, Aharonson et al. (1974) pointed out
that penetration would have increased 500-fold. If the uptake coefficient for SO- is concen-
tration dependent, as the data of Strandberg (1964) suggest, increasing airflow rate may
increase uptake due to higher levels of S0? being present along the center of the airstream
for the same inspired concentration.
The deposition and clearance of sulfur dioxide also has been studied in j_n vitro model
systems. In a model of the tracheobronchial airways lined with a simulated airway fluid
(bovine serum albumin dissolved in saline), it was observed that S0? was primarily absorbed in
the upper third of the simulated airway with only a small fraction of the S0? reaching the
simulated alveolar or bronchiolar regions (Kawecki, 1978).
Uptake and release of S02 in the nose of human subjects breathing 42.2 mg/m (16.1 ppm)
through a mask during a 30 minute exposure period was studied by Speizer and Frank (1966).
During inspiration the concentration of S02 had dropped 14% at a distance 1-2 cm within the
nose and was too small to detect at the pharynx with the analytical method used. Expired gas
in the pharynx was also virtually free of S02, but in its transit through the nose the expired
SOX11A/A 11-36 2-9-81
-------
air acquired S02 from the nasal mucosa. The expired S02 concentration at the nose was 5.2
mg/m (2.0 ppm), or about 12% of the original mask concentration. In most subjects the nasal
mucosa continued to release small amounts of SCL during the first 15 minutes after cessation
of the S0? exposure (see Section 11.3.2).
o o
Melville (1970) exposed humans to S02 levels ranging from 4 mg/m to 9 mg/m (1.5 ppm to
3.4 ppm) for periods up to 10 min. Respiratory tract extraction of S0? during nose breathing
was significantly greater (p < 0.01) than during mouth breathing (85% versus 70%, respectively)
and was independent of the inspired concentration of S00. Andersen et al. (1974) found that
3
at least 99% of 65.5 mg S02/m (25.0 ppm) was absorbed in the nose of subjects during inspira-
tion. Values obtained after one to three hours of exposure were not different from those
obtained after four to six hours of exposure, thereby indicating there was no saturation
effect during this period of time.
11.2.5 Aerosol-Gas Mixtures
Gases readily diffuse to the surface of particles and can participate in a variety of
surface interactions. Surface adsorption related to temperature and gaseous vapor pressure
occurs if adsorption sites for the gas molecules are present on the particles. Such physical
adsorption can be described by the Langmuir isotherm or more complex isotherms (Gordieyeff,
1956). In addition chemical adsorption can occur involving chemical transformations and bonds
that enhance transfer of gaseous materials to the particulate phase. Such transformations can
include both inorganic and organic vapors. In addition, aerosols of liquid droplets can col-
lect and carry volatile species that are dissolved in the droplets. In these cases, aerosols
can serve as vectors carrying molecules of various substances deeper into the airways than
would occur if the substances were in their gaseous forms.
Sulfuric acid in the environment may be reduced in acidity by naturally occurring ammonia
(NH,) to form ammonium sulfate (NH.KSO. and ammonium bisulfate (NH.HSO.). Larson et al.
(1977) made short-term measurements which suggest that endogenously generated ammonia (NH^)
gas in the human airways may rapidly and completely neutralize sulfuric acid aerosols in the
concentrations that are normally encountered in the ambient environment. Also, ammonia is
generated from food and excreta in inhalation chambers used to expose experimental animals to
sulfuric acid (H?SO.) so that some neutralization of sulfuric acid in these test atmospheres
probably occurs.
Since S0? is found in the gas phase in various environmental aerosols, the reactions that
occur between S0? and aerosols, and the gas-to-particle conversions that may occur, can greatly
influence the regional deposition of biologically active chemical species. Since S02 is highly
soluble in water, droplet aerosols, including those formed by deliquescent particles, will
collect dissolved S0? and can carry some of the resulting sulfurous acid not neutralized by
NH., deep into the lung. The presence of certain sulfite species formed by such reactions in
*5
environmental aerosols has been suggested (Eatough et al. , 1978). S02 is also known to be
converted to sulfate by reactions catalyzed by some aerosols, including those containing iron
SOX11A/A 11-37 2-9-81
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*
or manganese. The simple adsorption of S0~ to aerosol surfaces by chemical reaction may lead
to the aerosol's acting as a vector for transporting SCL to the deep lung.
The deposition of the aerosol and gaseous fractions of the sulfur species can be pre-
dicted from the properties of these fractions. Hence, the problem of estimating deposition
(and subsequent biological effects) requires an understanding of the proportion of sulfur
species associated with the aerosol fraction and their chemical properties. Since these reac-
tions are dynamic processes, the rate and mechanics of the gas-particle chemical reactions,
especially as they may occur in the airways, must be understood, such as the potentiation of
increased airway resistance in guinea pigs with SCL by some particles (Amdur and Underhill,
1968).
11.3 TRANSFORMATIONS AND CLEARANCE FROM THE RESPIRATORY TRACT
Particulate material deposited in the respiratory tract may eventually be cleared by the
tracheobronchial mucociliary conveyor or nasal mucous flow to the throat and is either expec-
torated or swallowed. Other deposited material may be cleared by either the lymphatic system
or transfer to the blood. S02 reacts rapidly with biological constituents to produce
S-sulfonate (Gunnison and Denton, 1971). The role of clearance as a protective mechanism for
the respiratory tract depends on the physicochemical characteristics of the particles (or
gaseous species), the site of deposition, and respiratory physiology. If the particles dis-
solve rapidly in body fluids, their deposition in the nasal turbinates with subsequent absorp-
tion into the blood is important, and total deposition of soluble particles may be more criti-
cal than regional deposition. For relatively inert and insoluble particles, deposition in the
pulmonary region, where they may be tenaciously retained, may be more hazardous, unless their
action is mediated through nasal deposition. The deposition by dissolution of S0? in the
extrathoracic region may be protective, since it may involve less serious biological effects
than deposition in the bronchial or pulmonary airways. Mouth breathing would lessen the nasal
absorption and increase the S02 levels entering the lung. If the particles or S02 chemically
react with body fluids, transformations of the material can affect clearance. In all respi-
ratory regions, the dissolution of particles competes with other clearance processes.
Since respiratory tract clearance may begin immediately after the initial deposition, the
dynamics of retention can become quite complicated when additional deposition is superimposed
on clearance phenomena, especially if the deposited material affected clearance mechanisms.
Extended or chronic exposures are the general rule for environmental aerosols, and particulate
material may accumulate in some portions of the lung (Davies, 1963, 1964a; Walkenhorst, 1967;
Einbrodt, 1967).
11.3.1 Deposited Particulate Material
An understanding of regional deposition is requisite to an evaluation of respiratory
clearance and a description of the retention of deposited particulate materials. In addition,
there may be significant differences between the mechanisms of clearance in different mammalian
SOX11A/A 11-38 2-9-81
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species. Particle deposition, in the extrathoracic region is limited primarily to larger
particles deposited by inertial impaction. Deposition of various aerosol particles may lead
to specific biological effects associated with this region. For particles that do not quickly
dissolve or do not react with body fluids, clearance from this region is mechanical. The
anterior third of the human nose (where most particles >5 urn may deposit) does not clear
except by blowing, wiping, sneezing, or other extrinsic means, and particles may not be
removed until 1 or more days after deposition (Proctor and Swift, 1971; Proctor et al., 1969,
1973; Proctor and Wagner, 1965, 1967).
The posterior portions of the human nose, including the nasal turbinates, have muco-
ciliary clearance averaging 4 to 6 mm/min with considerable variation among individuals
(Proctor and Wagner, 1965 and 1967; Ewert, 1965; van Ree and van Dishoeck, 1962). Particles
are moved with this mucus to the throat and are swallowed or expectorated. Various reactions
can occur in the gastrointestinal tract, and some assimilation into the blood is possible even
for particles that were relatively insoluble in the nose. The ICRP Task Group (Morrow et al.,
1966) adopted a 4-minute half-time for physical clearance from the human extrathoracic (naso-
pharyngeal) region by mucociliary transport to the throat and subsequent swallowing.
Soluble particles or droplets are readily assimilated by the mucous membranes of the nose
directly into the blood. Solubility is graded from extremely insoluble to instantly soluble,
and the dissolution rate constant for the particles must be considered for each aerosol.
Since the tracheobronchial region includes both very large and very small airways, parti-
cles of various sizes can be deposited. The retention of deposited materials in this region
can differ markedly among individuals and can be affected by such factors as cigarette
smoking, pathological abnormalities, or responses to inhaled air pollutants. Clearly, the
more rapid the clearance, the less time available for untoward responses or latent injury at
the site of original deposition. In mouth breathing of aerosols, such as during smoking or
under physical exertion, the beneficial filtering of large particles in the nasal airways is
lost, and a greater fraction of these large particles can be deposited in the TB region.
An important characteristic of the TB region is that it is both ciliated and equipped with
mucus-secreting cells. Mucociliary clearance mechanisms have been reviewed by Schlesinger
(1973). For relatively insoluble and inert particles, the primary clearance mechanism for the
TB region is mucociliary transport to the glottis, with subsequent swallowing and passage into
the gastrointestinal tract. Mucous flow influences the ciliary mucous conveyor (Van As and
Webster, 1972; Besarab and Litt, 1970; Dadaian et al., 1971).
Th^e rate of mucous movement is slowest in the finer, more distal airways and greatest in
the major bronchi and trachea. In addition, coughing can accelerate tracheobronchial clear-
ance by the mucociliary conveyor. The size distribution of particles affects their distribu-
tion in the tracheobronchial tree. The average clearance time for small particles that
preferentially deposit deep in the lung is longer than for larger particles, which tend to
deposit in the larger airways (Albert et al., 1967, 1973; Camner et al., 1971; Luchsinger
et al., 1968).
SOX11A/A 11-39 2-9-81
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The clearance of material in the TB compartment cannot be described by a single rate.
Data from experimental studies imply that the larger airways clear with a half-time of about
0.5 hours, intermediate airways with a half-time of 2.5 hours, and finer airways with a half-
time of 5 hours (Morrow et al., 1967a; Morrow, 1973). There is also considerable variability
among individuals (Camner et al., 1972, 1973a,b; Camner and Philipson, 1972; Albert et al.,
1967). Material with slow dissolution rates in the TB compartment will usually not per-
sist longer than about 24 hours in healthy humans. Cigarette smoking has been reported under
various conditions to either increase, decrease, or have little effect on the efficiency and
speed of TB clearance (Camner and Philipson, 1972; LaBelle et al., 1966; Bohning et al., 1975;
Albert et al., 1974; Thomson and Pavia, 1973).
Particles smaller than about 10 (jm D are deposited to some extent in the pulmonary
36
region of the lung upon inhalation, although the deposition of particles smaller than 0.01 urn
may be quite limited because of the competing diffusional deposition in the NP and TB regions.
Particles that deposit in the pulmonary region land on surfaces kept moist by a complex liquid
containing pulmonary surfactants. Slowly dissolving materials that deposit in the human pul-
monary region are usually retained for years. For example, McEuen and Abraham (1978) reported
that birefringent particle counts were significantly higher in 37 cases of pulmonary alveolar
proteinosis both in regions of alveolar proteinosis and perivascular and peribronchiolar
regions (dust retention areas) than in 13 control subjects. Out of 8619 particles, 4817 were
< 1 urn in physical diameter, 3771 were 1-10 urn in physical diameter, and 31 were > 10 urn in
physical diameter, with 59 percent being round, 19 percent fibrous, and 22 percent irregular
in shape.
Usually, relatively insoluble particles are rapidly phagocytized by pulmonary macrophages
(LaBelle and Brieger, 1961; Sanders and Adee, 1968; Green, 1971, 1974; Ferin, 1967, 1976,
1977; Camner et al., 1973a,b, 1974; Chapman and Hibbs, 1977; Ferin et al., 1965; Brain and
Corkery, 1977; Brain et al., 1977; Brain, 1970a). Some particles may enter the alveolar inter-
stitium by pinocytosis (Strecker, 1967). Some particles may be cytotoxic to alveolar macro-
phages and thus influence this clearance mechanism (see Section 12.3.4.2). Migration and
grouping of macrophages laden with particles can lead to redistribution of evenly dispersed
particles into clumps and focal aggregations of particles in the deep lung. Such events have
been described in the sequence of pathological changes observed in experimentally-induced sili-
cosis (Heppleston, 1969). Silica particles ranging in size from less than 1 to 3 |jm in physi-
cal diameter have been found post mortem in fibrotic lesions associated with deposits of
crystalline silica (Craighead and Vallyatin, 1980). Sherwin and coworkers (1979) found an
abnormal number of birefringent particles in the lungs of seven patients in association with
early to late interstitial inflamation and fibrosis. Also, using scanning electron microscopy
and energy dispersive X-ray analysis of particles < 5 urn in physical diameter, they found
mostly silicates (especially aluminum, sodium, and potassium), with 5 to 10 percent silicon
dioxide.
SOX11A/A 11-40 2-9-81
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*
Macrophages containing particles may enter the boundary region between the ciliated
bronchioles and the respiratory ducts and then can be carried with the mucociliary flow of the
TB region. Some insoluble particles deposited in the lung are eventually trapped in the pul-
monary interstitium (Strecker, 1967), impeding mechanical redistribution or removal (Felicetti
et al., 1975). Although protein molecules may pass across the airblood barrier intact with a
clearance halftime of hours by pinocytotic vesicular transport (Bensch et al., 1967), there is
conflicting evidence at best on the passage of very small particles (< 10 nm in physical dia-
meter) across the airblood barrier. For example, the data of Kanapilly and Diel (1980) on the
239
dissolution of ultrafine Pu02 are in disagreement with the data and interpretations of
Raabe et al. (1978).
Another possible clearance route for migrating particles and particle-laden macrophages
is the pulmonary lymph drainage system with trans location first to the tracheobronchial lymph
nodes (Thomas, 1968; Lauweryns and Baert, 1977; Leeds et al., 1971). Little information is
available about the clearance rates for transfer from lung to lymph nodes in man, but half-
times of 1 to 2 years have been estimated from data on dogs and monkeys (Leach et al., 1970).
Like transfer to the TB region with clearance by the mucociliary escalator, transfer to lymph
nodes may affect only a portion of the material deposited in the lung.
Waligora (1971) reported the pulmonary clearance of extremely insoluble and inert parti-
95
cles of zirconium oxide radiolabeled with Nb. Although his results were not precise, the
biological clearance half-life in man was about 1 year, a value about the same as for beagles.
By contrast, murine species have a more rapid pulmonary clearance (Morgan et al., 1977).
Leach et al. (1970, 1973) exposed experimental animals to insoluble U02 (MMAD of about 3.5 urn)
and observed lung retention half-times of 19.9 months for dogs and 15.5 months for monkeys.
Ramsden et al. (1970) measured the retention of accidentally inhaled, relatively insoluble
239pug (piutonium dioxide) in a man's lungs and found the clearance half-time to be about 240
to 290 days; some of that material was dissolved into blood and excreted in the urine. Pul-
monary clearance half-times as long as 1000 days have been reported for extremely insoluble
particles of piutonium dioxide in dogs (Raabe and Goldman, 1979). Cohen et al. (1979)
reported an apparent half-time of about 100 days for nonsmokers and about 1 year for smokers
for pulmonary clearance of magnetite particles.
Because of the slow clearance by the various mechanical pathways, dissolution and asso-
ciated physical and biochemical transformations are often the dominant mechanisms of clearance
from the pulmonary region (Morrow, 1973). The term "dissolution" is taken in its broadest
context to include whatever processes cause material in a discrete particle to be dispersed
into the lung fluids and the blood (Green, 1975). Many chemical compounds deposited in the
lung in particulate form are mobilized faster than can be explained by known chemical proper-
ties at the normal lung fluid pH of about 7.4 (Kanapilly, 1977). Raabe et al. (1978)
suggested that the apparent dissolution of highly insoluble PuO,, actually may be due to frag-
mentation into particles small enough to move readily into the blood, rather than to true
dissolution.
SOX11A/A 11-41 2-9-81
-------
Mercer (1967) developed an analysis of pulmonary clearance based on particle dissolution
under nonequilibrium conditions. If the dissolution rate constant (k) is known for a mate-
rial, the time required to dissolve half the mass of (monodisperse) particles of initial physi-
cal diameter (D ) is given by:
= 0.618 a pD /a k (2)
with p the physical density of the particles and ay and a^ the volume and surface shape fac-
tors, respectively (for spherical particles a /a = 6).
The particles would be expected to be completely dissolved at a time, t^, given by:
tf = 3av p DQ/ask (3)
Mercer (1967) also calculated the expected dissolution half-time for polydisperse particles
when their mass median (physical) diameter in the lung is known:
Tl/2 = °'6 % P(MMQ)/ask W
Further, he showed that the resulting apparent lung retention function R(t) could be described
as the sum of two exponentials of the form:
R(t) = fl6~XlP + f2<
where f, = (l-f?), p = a Kt/a p(MMD) and f,, f2, A,, and \2 are functions of the geometric
standard deviations as defined by Mercer (1967).
For dissolution-controlled pulmonary clearance, smaller particles will exhibit propor-
tionately shorter clearance half-times. When the dissolution half-times are much shorter than
the half-times associated with the translocations of particles to the TB region or to lymph
nodes (i.e., much less than 1 year), dissolution will dominate retention characteristics.
Materials usually thought to be relatively insoluble (such as glass) may have high dissolution
rate constants and short dissolution half-times for the small particles found in the lung; the
dissolution half-time for 1 urn D glass spheres is about 75 days (Raabe, 1979). Changes in
structure or chemical properties, such as by heat treatment of aerosols (Raabe, 1971), can
lead to important changes in dissolution rates and observed pulmonary retention.
Usually the retention time of material in the respiratory tract is measured (such as with
radiolabeled aerosols) rather than the clearance rates (Sanchis et al. , 1972; Camner et al.,
1971; Edmunds et al., 1970; Luchsinger et al., 1968; Aldas et al., 1971; Ferin, 1967; Barclay
et al., 1938; Morrow et al., 1967a,b; Friberg and Holma, 1961; Holma, 1967; Kaufman and
Gamsus, 1974). The lung burden or respiratory tract burden can be represented by an appro-
priate retention function with time as the independent variable (Morrow, ,1970a,b). For models
SOX11A/A 11-42 2-9-81
-------
*
based on simple first-order kinetics, the lung burden, y, at a given time during exposure is
controlled by the instantaneous equation:
Ht = E ' V <6)
where E is the instantaneous deposition rate of particulate material deposited in the lung per
unit time during an inhalation exposure and \, is the fraction of material in the lung cleared
from the lung per unit time (Raabe, 1967). For an exposure that lasts a time t , the lung
burden from the exposure is given by:
-\,t
ye = (E - Ee ^ e)/\1 (7)
where E is the average exposure rate. After the exposure ends, the clearance is governed by:
dy. _ . A,y (8)
dt ~ 1
and the lung burden is given by:
y = ye e (9)
where y is the lung burden at the end of the exposure period (t ). Hollinger et al. (1979)
used this simple model to describe the deposition and clearance of inhaled submicronic ZnO in
rats (Figure 11-12) where the concentration of zinc (as Zn) in the lungs (as described by
Equations 7 and 9) is superimposed on the natural background concentration of zinc in lung
tissue. The normally insoluble zinc has only a 4.8-hour dissolution half-time (A., = 0.21 h )
for this aerosol. Of course, environmental aerosol exposures are likely to continue so that a
steady state lung burden may be expressed by:
yss = EAi do
If several deposition and clearance regions, subregions, or special pools are involved, a
more complicated multicompartmental model may be required to describe lung or respiratory
tract buildup and retention of inhaled aerosols. If each compartment can be described by first
order kinetics, a general model can be specified by 1) subscripting E, \, and Y with the sub-
script i whenever they appear on the right-hand side of Equations 7, 9, 10, and 2) performing
a summation over i from one to the number of compartments. Each of the X. values translates
to a clearance rate for each of the compartments given by half-time T,/? = In 2/X. (for
example see Figure 11-13).
For chronic exposures where the several pools are in complex arrays of change, a simple
power function may serve as a satisfactory model of pulmonary retention (Downs et al., 1967).
SOX11A/A 11-43 2-9-81
-------
Ul
3
v>
CO
Z
O
UJ
>
cc
0
p
o
Z
N
U
50
-20 -15
0 5 10 15 20 25 30
POST EXPOSURE TIME.hr
Figure 11-12. Single exponential model, fit by weighted least-squares of the buildup (based on text
equation 7) and retention (based on text equation 9) of zinc in rat lungs.
Source: Hollinger et at. (1979).
11-44
-------
100
CLEARANCE PHASE
E3 - 2.1 ma/day, T - SOOd
200
400
600 800
TIME, days
1000
1200
1400
Figure 11-13. Example of the use of the sum of exponential models for describing lung uptake during
inhalation exposure and retention (clearance phase) after exposure ends for three lung compartments
with half-lives 50d, 350d, 500d, and 20-day exposure rates of 1.4 mg/day (E^, 1.7 mg/day (E2), and
2.1 mg/day (£3), respectively.
Source: Raabe(1974).
11-45
-------
In such a model, the pulmonary region is treated as one complex, we 11 -mixed pool into which
material is added and removed during exposure, as given by the instantaneous equation:
dt
= E - Apy/t [y = 0 at t = 0] (11)
where y is the total lung burden at a given time, t, E is the average deposition rate of
inhaled particulate material in the lung, and \ is the fraction of available lung burden
being cleared. Unlike the A. of the exponential retention models, A is dimensionless. The
time coordinate is not arbitrary; time is taken as zero only at the beginning of the inhala-
tion exposure, when the lung burden is nil. Thus, during an exposure lasting until time (te),
the pulmonary burden (y ) is given by (Raabe, 1967):
ye = Ete/(Ap + 1) (12)
On this basis, no steady-state concentration is reached even though clearance is progressing
and the lung concentration continues to increase during chronic exposures to environmental
aerosols. This model is therefore not applicable to relatively soluble species. The lung
burden, y, after the exposure has ended for a time, t , is given by (Raabe, 1967):
y = ye te p t P = At p [t = te + tp] (13)
This model is illustrated in Figure 11-14.
Deposited particulate material cleared from the lung is usually transformed chemically
and transferred to other tissues of the body. The injurious properties of a toxic material
translocated from the lung may therefore be expressed in other organs. Identification of the
potential hazards associated with inhalation exposures to toxicants is compounded when the
respiratory tract is not the only target for injury but still serves as the portal of entry
into the body. The metabolic behavior and excretion of inhaled toxicants after deposition in
the lung may define the probable target organs and indicate potential pathogenesis of result-
ing disease.
Multicompartmental models that describe biological behavior can become extremely complex.
Each toxicant or component of aerosol particles deposited in the respiratory tract may need to
be described by a separate rate constant and pool or compartment. A general model of the
metabolic behavior of inhaled particles developed by Cuddihy (1969) identified 39 different
places where rate constants may need to be determined. In this general model, the pulmonary
region of the lung is visualized as consisting of three independent clearance compartments,
and the particles are presumed to be converted from their original particulate state to some
other physicochemical form or transformed state prior to clearance from the respiratory tract.
Such a transformed state can be used to describe, for example, the behavior of hydrolytic
aerosols in the respiratory tract.
SOX11A/A 11-46 2-9-81
-------
n 10
CD Q
0.1
I I I I I I I I I
II III 111 I I I I
1 2 5 10
102 103
TIME, days
104 105
Figure 11-14. Example of the use of the power
function model for describing lung uptake dur-
ing inhalation exposure (text Equation 12) and
retention (clearance phase) after exposure ends
(text Equation 13) for a 20-day exposure at
8.5mg/d(E).
Source: Adapted from Raabe (1967).
11-47
-------
To illustrate the potential complexity of models, a systemic metabolism model is shown in
Figure 11-15 for cerium trichloride (144CeC13) contained in particles of cesium chloride
(CsCl) with a MMAD of about 2 urn (Boecker and Cuddihy, 1974). The resultant pattern of com-
a i
bined uptake and retention in various organs after inhalation exposure is illustrated in
Figure 11-16. In this case, the exposure is short-term; the fate of relatively insoluble
materials in chronically inhaled environmental aerosols may involve more complex relation-
ships.
11.3.2 Absorbed SO,,
S09 coming in contact with the fluids lining the airways (pH 7.4) should dissolve into
2-
the aqueous fluid and form some bisulfite (HSCL-) and considerable sulfite (SO^ ) anions.
Because of the chemical reactivity of these anions, various reactions are possible, leading to
the oxidation of sulfite to sulfate (see Section 12.2.1).
Clearance of sulfite from the respiratory tract may involve several intermediate chemical
reactions and transformations (see Section 12.2.1.2). Gunnison and Denton (1971) have identi-
fied S-sulfonate in blood as a reaction product of inhaled SCL. The reaction rate is rapid,
if not nearly instantaneous, so that there is no long-term clearance to characterize. However,
intermediate and potentially toxic products may be formed. These products may have residence
times that are long enough to demonstrate an elevation of the sulfur content of the lung.
Desorption from the upper respiratory tract may be expected whenever the partial pressure
of SCL on mucosal surfaces exceeds that of the air flowing by. Desorption of SCL from mucosal
surfaces was still evident after 30 minutes of flushing with ambient air the airways of dogs
which had breathed 2.62 mg/m (1.0 ppm) for 5 min. (Frank et al., 1969). Frank et al. (1967)
reported S09 in the lungs of dogs that apparently was carried by the blood after nasal deposi-
3
tion. In human subjects breathing 42.2 mg/m (16.1 ppm) through a mask for 30 minutes, 12% of
the S0? taken up by the tissues in inspiration reentered the air stream in expiration and
another 3% was desorbed during the first 15 minutes after the end of S0? exposure (Speizer and
Frank, 1966). Thus, during expiration, SO- was desorbed from the nasal mucosa in quantities
totaling approximately 15% of the original inspired concentration.
The effects of S02 on tracheobronchial clearance in 9 healthy, nonsmoking adults were
studied by Wolff et al. (1975) (see Section 13.2.3.5). Technetium Tc 99m albumin aerosol (3
|jm MMAD, o = 1.6) was inhaled as a bolus under controlled conditions. A three hour exposure
9 3
to 13.1 mg SOp/m (5.0 ppm) had no significant effect on mucociliary clearance in resting sub-
jects, except for a small transient increase (p < 0.05) after 1 hour. A significant decrease
in nasal mucus flow rates during a six hour exposure of 15 young men to 13.1 mg S00/m (5.0
3 3
ppm) and 65.5 mg S02/m (25.0 ppm), but not 2.62 mg SOVm (1.0 ppm), was observed by Andersen
et al. (1974). Decreases were greatest in the anterior nose and in subjects with initially
slow mucus flow rates. Newhouse et al. (1978) assessed the effect of oral exposure to S02 on
bronchial clearance of a radioactive aerosol (3 \im MMAD) in healthy nonsmoking males and
SOX11A/A 11-48 2-9-81
-------
RESPIRATORY ENVIRONMENT
EXTRATHORACIC (ET)
TRACHEOBRONCHIAL (TB)
INITIAL
DISTRIBUTION
PERCENTAGES
COM
PART-
MENT
ET
TB
P a
b
c
d
39
7.0
7J2
41
34
2A
STOMACH
15
-1—
0.0005 -
SMALL
INTESTINE
I
LARGE
INTESTINE
0.85
a
b
c
d
30
0.5
0.02
0.00122
TRACHEOBRONCHIAL
LYMPH NODES
LIVER
•0.0001*"
— 0.1
0.04 -
SOFT TISSUE
0.2 —
- 1.0 —
"* 0.0001
SKELETON
0.1 —
- 0.04 «-
""* 0.0001
TRANSFER RATE CONSTANTS
EXPRESSED AS FRACTION OF
COMPARTMENTAL CONTENT
PER DAY
Figure 11-15. Multicomponent model of the deposition, clearance, retention, translocation and
excretion of an example sparingly soluble metallic compound ("^CeCIs continued in CsCI
particles) inhaled by man or experimental ai.imals; the rate constants are based upon first order
kinetics as in text Equation 8.
Source: Adapted from Boecker and Cuddihy (1974).
11-49
-------
100
i
-------
females who exercised periodically during exposure at an exertion level sufficient to keep the
heart rate at 70% - 75% of the predicted maximum. After a 2 hour exposure to 13.1 mg SO^/m
(5.0 ppm), clearance was increased.
11.3.3 Particles and S02 Mixtures
The presence of adsorbed S0? or other sulfur compounds on aerosol surfaces may alter the
clearance processes of both. Chemical reactions involving sulfur compounds on particle
surfaces may enhance the apparent solubility of the aerosol particles. These aerosol parti-
cles may also undergo reaction with sulfite or other species upon contact with body fluids.
The formation of sulfate anions by oxidation of S0? to SO, may be catalyzed by manganese,
iron, or other aerosol components. The S03 reacts immediately with water to form sulfuric
acid that can react with other materials, such as metal oxides on fly ash aerosols, to produce
sulfate compounds. Since sulfate is a normal constituent of body fluids (Kanapilly, 1977),
the clearance of sulfate anions probably involves simple dissolution into body fluids.
11.4 AIR SAMPLING FOR HEALTH ASSESSMENT
The objective of air sampling in relation to health assessment is to obtain data on the
nature and extent of potential nealth hazards resulting from the inhalation of airborne parti-
cles. To be effective the techniques used in air samplers must be based on a recognition of
the size-selecting characteristics of the human respiratory tract (see Section 11.2). Of
course the usual variables affecting the selection of methods, such as the physical limita-
tions of the collection process and sensitivity and specificity properties of the analytical
procedures, must still be addressed.
An increasing recognition of the importance of the selective sampling of "respirable" dusts
has occurred in recent years. The commonly measured index of gross air concentration provides
a crude and sometimes misleading indication of health hazard. Since most aerosols are poly-
disperse, with a a >2, the mass median size approaches the diameter of the largest particles
in the sample, resulting in a relatively few large particles strongly influencing the value
reported for the mass concentration. The measured total mass concentration then will not
relate to the inhalation hazard if these particles are not inhaled. Also, the true total air-
borne mass concentration may be underestimated when the aerosol contains very large particles
since every sampler has its own characteristic upper size cut-off. This cut-off is dependent
on its entry shape, dimensions and flowrate.
The best dose estimates for a substance whose toxicity is proportional to absorbed mass
are obtained from information on the mass concentrations within various size ranges. Lippmann
(1978) cites several ways such data can be obtained: (1) during the process of collection
separate the aerosol into size fractions which correspond to anticipated regional deposition;
(2) analyze the size distribution of the airborne aerosol; and (3) analyze the size distribu-
tion of the collected sample. The most reliable and useful information is obtained using
methods of fractionation based upon aerodynamic diameters similar to the way fractionation
occurs within the respiratory tract, thereby automatically compensating for differences in
particle shape and density.
SOX11A/A 11-51 2-9-81
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There have been many recent advances in the technologies needed to develop samples that
will separate particles during the process of collection into "respirable" and "nonrespirable"
fractions. The absence of uniform criteria for "respirable" mass concentrations has been a
major factor limiting the application of selective sampling concepts in the United States.
Regulations established on the basis of only gross concentration limits do not promote field
measurements of "respirable" mass.
The recommendations by Miller et al. (1979) on size considerations for establishing a
standard for "inhalable" particles indicate a possible future departure from the current
approach to the setting of a particulate standard in the United States. Also, the recent
report on respirable dust by the International Standards Organization ad hoc Group to TC 146
(1980) contains recommendations for size definitions for particle sampling for the healthy
normal segment of the population and high risk subpopulations. A perspective on these recent
events can be obtained by examining the development of the field of respirable dust sampling.
In 1952, the British Medical Research Council (BMRC) adopted a definition of "respirable
dust" which essentially considered respirable dust to be that dust reaching the alveoli,
thereby making "respirable dusts" applicable to pneumoconiosis producing dusts. The hori-
zontal elutriator was chosen as a particle size selector and respirable dust was defined as
that dust passing an ideal horizontal elutriator. The elutriator cut-off was chosen to result
in the best agreement with experimental lung deposition data. The Johannesburgh International
Conference on Pneumoconiosis in 1959 adopted the same standard (Orenstein, 1960).
In January 1961 at a meeting in Los Alamos sponsored by the Atomic Energy Commistion
(AEC) Office of Health and Safety a second standard was established, which defined "Respirable
Dust" as that portion of the inhaled dust which penetrates to the non-ciliated portions of the
lung (Hatch and Gross, 1964). This definition was not intended to be applicable to dusts
which are readily soluble in body fluids or are primarily chemical intoxicants, but rather
only for "insoluble" particles which exhibit prolonged retention in the lung. Criterion for
respirability were such that all 2 urn D particles were considered respirable, while
36
particles 10 pm D were considered to be nonrespirable.
3c
Other groups, such as the American Conference of Governmental Industrial Hygienists
(ACGIH), have incorporated respirable dust sampling concepts in setting acceptable exposure
levels to other toxic dusts. Such applications are more complicated since animal and human
exposure data, rather than predictive calculations, form the data base for standards. The
size-selector characteristic specified in the ACGIH standard for respirable dust (Threshold
Limits Committee, 1968) is almost identical to that of the AEC, differing only at 2 urn D ,
36
where it allows for 90 percent passing the first stage collector instead of 100 percent. The
difference between them appears to be a recognition of the properties of real particle separa-
tors so that for practical purposes the two standards may be considered equivalent (Lippmann,
1978).
SOX11A/A 11-52 2-9-81
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*
The sampler acceptance criteria of the BMRC and of the ACGIH and the pulmonary deposition
curves from Figure 11-9 are shown in Figure 11-17. The cut-off characteristics of the pre-
collectors preceding respirable dust samplers are defined by these criteria. The two sampler
acceptance curves have similar, but not identical, characteristics, due mainly to the use of
different types of collectors. Recall that the BMRC curve was chosen to give the best fit
between the calculated characteristics of an ideal horizontal elutriator and available lung
deposition data. On the other hand, the AEC curve was designed mainly after the upper respi-
ratory tract deposition data of Brown et al. (1950). The separation characteristics of cyclone
type collectors simulate the AEC curve. Whenever the particle size distribution has a a >2
urn, samples collected with instruments meeting either criterion will be comparable (Lippmann,
1978). Various comparisons of samples collected on the basis of the two criteria are avail-
able (Knight and Lichti, 1970; Breuer, 1971; Maguire and Barker, 1969; Lynch, 1970; Coenen,
1971; Moss and Ettinger, 1970).
The various definitions of respirable dust are somewhat arbitrary, with the BMRC and AEC
definitions being based upon the "insoluble" particles which reach the pulmonary region. Since
part of the aerosol which penetrates to the alveoli remains suspended in the exhaled air,
respirable dust samples are not intended to be a measure of pulmonary deposition but only a
measure of aerosol concentration for particles that are the primary candidates for pulmonary
deposition. Given that the "respirable" dust standards were intended for "insoluble dusts,"
most of the samplers developed to satisfy their criteria have been relatively simple two-stage
instruments. In addition to an overall size-mass distribution curve, multi-stage aerosol
sampler data can provide estimates of the "respirable" fraction and deposition in other func-
tional regions. Field sampling application of these samplers has been limited due to the in-
creased number and cost of sample analyses and the lack of suitable instrumentation. Many of
the various samplers, along with their limitations and deficiencies, have been reviewed by
Lippmann (1978).
Size definitions for particle sampling which expand the area of concern beyond just
"insoluble" dust penetrating to the pulmonary region have recently been advanced (Miller et
al., 1979; International Standards Organization ad hoc Group to TC 146, 1980). As our knowl-
edge of the regional deposition of particles increases through experimental studies, such as
those discussed in Section 11.2, it is logical to envisage using samplers which broadly simu-
late the relative collection efficiencies of the major regions of the respiratory tract.
These devices would first select from the total airborne material the inspirable fraction, and
then sequentially divide this fraction into extrathoracic (nasopharyngeal), tracheobronchial,
and pulmonary fractions.
Such a scheme has been recommended by the International Standards Organization §d hoc
Group to TC 146 (1980) with various options depending upon the at risk population (healthy
adults, children, sick and infirm) and upon the use of 10 IJID D or 15 urn 0 as the 50 percent
ac 36
SOX11A/A 11-53 2-9-81
-------
1.0
0.9
0.8
0.7
Z 0.6
O
5 °5
Ul
Q
0.4
0.3
0.2
0.1
T TT T
SAMPLER ACCEPTANCE CRITERIA
— — — ACGIH
— — VIANOSE
— -^ BMRC
0.1 0.2 0.4 0.50.6 0.8 1.0
PHYSICAL DIAMETER,/urn
2.0 4.0 6.0 8.0)10.0
• AERODYNAMIC DIAMETER, urn
20.0
Figure 11-17. Comparison of sampler acceptance curves of BMRC and ACGIH conventions with the
band for the experimental pulmonary deposition data of Figure 11-9.
-------
cut-point for material penetrating to the tracheobronchial region. Their division of the
thoracic fraction into the pulmonary and tracheobronchial fractions, where the target popu-
lation is healthy adults, is shown in Figure 11-18 using 15 urn D as the 50 percent cut-
36
point for the total thoracic fraction. The 50 percent cut-point refers to the aerodynamic
diameter for which 50 percent of the particles that enter the mouth or nose are considered to
pass the larynx. Thus, the material not passing the larynx forms the extrathoracic fraction,
which includes the oral pharynx. Particles larger than 15 (jm D can enter and be deposited
36
in the extrathoracic region. If any of these larger particles are readily soluble, they will
be absorbed into the bloodstream just as quickly as smaller particles, with one 20 urn D
36
particle contributing as much to the systemic dose as a thousand 2 urn D particles.
36
Also shown in the figure are the experimentally based pulmonary deposition curves from
Figure 11-9 and the tracheobronchial deposition data from one of the subjects studied by
Stahlhofen and coworkers (1980). The ad hoc group basically followed the BMRC and ACGIH con-
ventions for pulmonary deposition in healthy adults, although their definition of the pul-
monary fraction differs slightly because it is defined as a fraction of the inspirable material
rather than the total aerosol. A "high-risk" selection curve for children or the sick
and infirm used a 50 percent cut-point at 2.5 urn D instead of 3.5 urn D in recognition of
36 36
the fact that a similar shift is seen in lung deposition in these groups (Lippmann, 1977);
this strategy is surprising since a conservative approach for protection of these subpopula-
tions would not lower the cut-point. Taken to its ultimate, by using size selective samplers
that separate inspirable material into extrathoracic or nasopharyngeal, tracheobronchial, and
pulmonary components, standards for airborne particles could specify which of these regional
fractions should be measured, taking into account the biological effects of the material, and
in the case of the tracheobronchial and pulmonary fractions, the population at risk.
11.5 SUMMARY
\
Besides being a target of inhaled particles and gases, the respiratory tract is also the
portal of entry by which other organs may be affected. An understanding of the mechanisms and
patterns of translocation to other organ systems is required for evaluation of the potential
for injury or response in those organs. When aerosols or S0? are inhaled by man or experi-
mental animals, different fractions of the inhaled materials deposit by a variety of mecha-
nisms in various locations in the respiratory tract. Particle size distribution, particle
chemical properties, physicochemical properties of S0?, respiratory tract anatomy, and airflow
patterns all influence the deposition. The three functional regions (extrathoracic or naso-
pharyngeal, tracheobronchial, and pulmonary) of the respiratory tract can each be character-
ized by major mechanisms of deposition and clearance.
Of the five mechanisms of deposition, impaction, gravitational settling, and diffusion
predominate for the deposition of most types of particles in the respiratory tract, with
electrostatic attraction and interception being of relatively minor importance. Diffusivity
and interception potential of a particle depend on its geometrical size, while the inertial
SOX11A/A 11-55 2-9-81
-------
01
i -r-44J I I I
I
— ACGIH CONV.
— BMRC CONV.
_ STAHLHOFEN »t ll
(1980)
PULMONARY VIA
MOUTH
— PULMONARY VIA
NOSE
PULMONARY FRACTION
TRACHEO-
BRONCHIAL
l\ FRACTION
\
0.5 0.7 1.0
AERODYNAMIC DIAMETER,
0.1 0.2 0.3
PHYSICAL DIAMETER,
Figure 11-18. Division of the thoracic fraction into the pulmonary and tracheobronchial fractions for
two sampling conventions (ACGIH and BMRC) as a function of aerodynamic diameter except below
0.5 nm where deposition is plotted vs. physical diameter, from International Standard Organization ad
hoc group to TC-146, 1980. Also shown are the band for experimental pulmonary deposition data of
Figure 11-9 and the tracheobronchial deposition data of one subject from Stahlhofen et al. (1980).
-------
properties of settling and impaction depend on its aerodynamic diameter. Gravitational set-
tling is important for the deposition of particles in the tracheobronchial and pulmonary
regions, while impaction contributes to deposition in the extrathoracic and tracheobronchial
regions. Diffusion primarily affects respiratory tract deposition of particles with physical
diameters smaller than 1 urn. The major processes affecting the transport of SO- in the
respiratory tract are convection, diffusion, and chemical reactions. The rapid diffusivity of
SCK in combination with its high solubility in body fluids is responsible for the large removal
of SO^ in the extrathoracic region and upper generations of the tracheobronchial tree.
After deposition, inhaled particles will be translocated by processes that depend on their
character and site of deposition. The anterior third of the human nose does not clear except
by blowing, wiping, sneezing, or other extrinsic means, and particles may not be removed until
one or more days after deposition. If the particles are quite soluble in body fluids, they
will readily enter the bloodstream. Relatively insoluble material that lands on ciliated epi-
thelium, either in the extrathoracic region or tracheobronchial airways, will be translocated
with mucus flow to the throat and will be swallowed or expectorated. Depending on particle
size, relatively insoluble material that deposits on nonciliated surfaces in the pulmonary
region may be phagocytized, may enter the interstitium and remain in the lung for an extended
period, or may be translocated by phagocytic cells, blood, or lymphatic drainage. Some
material from the pulmonary region may enter the tracheobronchial region and be cleared by the
mucociliary conveyor. Dissolution can contribute to the clearance of particles in all regions
of the respiratory tract.
Nose breathing and mouth breathing provide somewhat contrasting deposition patterns for
some respiratory tract regions. With nose breathing nearly complete respiratory tract deposi-
tion can be expected for particles larger than about 4 urn D . Since mouth breathing bypasses
36
much of the filtration capabilities of the extrathoracic region, there is a shift upward to
about 10 urn D before there is complete deposition of inhaled particles. However, given the
36
three general regions into which the respiratory tract can be divided on the basis of anatomi-
cal structure, function, particle retention times, and clearance pathways, regional deposition
data for particles of various aerodynamic diameters are more useful than total respiratory
tract deposition information.
Particles about 10 urn D or larger are deposited in the extrathoracic region during nose
36
breathing as compared to about 65 percent deposition of 10 urn D particles under conditions
36
of mouth breathing. On the other hand, for both routes of breathing, extrathoracic deposition
of particles smaller than about 1 urn D._ is slight. The increased penetration of larger
QC
particles deeper into the respiratory tract when a person breathes through the mouth is reflec-
ted by experimental deposition data showing that tracheobronchial deposition of 8-10 um D
36
particles is on the order of 20-30 percent. Also, about 10 percent of particles as large as
15 um D are predicted to enter the tracheobronchial region during mouth breathing.
36
SOX11A/A 11-57 2-9-81
-------
For nose breathing, as compared to mouth breathing, the peak of the pulmonary deposition
curve shifts downward from 3.5 urn D to about 2.5 urn D . Also, the peak is much less pro-
etc 36
nounced (about 25 percent compared to about 50 percent for mouth breathing) with a nearly con-
stant pulmonary deposition of about 20 percent for all sizes between 0.1 urn and 4 urn Dge.
It should be stressed that the deposition data cited above are based upon studies in which
usually young healthy adult subjects were used. Although children are usually considered to
be a subpopulation more susceptible to the effects of environmental pollutants, deposition data
for children are not currently available, nor likely to be soon obtained. What little data is
available on other subpopulations, such as asthmatics and chronic bronchitics, indicates that
tracheobronchial deposition appears to be enhanced at the expense of pulmonary deposition in
most abnormal states. Partial or complete airway obstruction in bronchitis, lung cancer,
emphysema, fibrosis, and atelectasis may decrease or eliminate the deposition of particles in
some regions of the lungs.
Regional deposition studies of particles less than 3 urn D have been conducted using dogs
Oc
and some rodents. In these species, the relative distribution among the respiratory regions
of particles less than Sum D during nose breathing follows a pattern that is similar to
ae
regional deposition in man during nose breathing. Thus, in this instance, the use of rodents
or dogs in toxicological research for extrapolation to humans entails differences in regional
deposition of insoluble particles less than 3um D that can be reconciled from available data.
ac
When breathing through the nose under resting conditions, S02 removal by nasal absorption
is nearly complete in both man and laboratory animals. Expired air acquires S0? from nasal
mucosa with small amounts of S02 continuing to be released after cessation of exposure.
Extraction of S0? by the total respiratory tract during mouth breathing is significantly lower
than during nose breathing, although regional uptake has not been studied in man during mouth
or oronasal breathing. However, studies in which SO- was passed through the surgically iso-
lated extrathoracic (nasopharyngeal) airways of dogs showed that S0? absorption in the extra-
thoracic region can be decreased to less than 50 percent by mouth breathing at elevated air-
flow rates. Sulfur dioxide may also enter into a variety of gas-to-particle conversions or
gas-particle chemical reactions. As a consequence of these reactions with particles, SO- can
be carried deeper into the respiratory tract, thereby increasing the potential for adverse
effects.
Both deposition and retention play roles in determining the effects of inhaled particu-
late toxicants and SO-. Everyone is environmentally exposed to a variety of dusts, fumes,
sprays, mists, smoke, photochemical particles, and combustion aerosols, as well as S02 and
other potentially toxic gases. The particle size distribution and chemical and physical com-
position of airborne particulate material require special attention in toxicological evalua-
tions since a wide variety of physicochemical properties may be encountered in both experi-
mental and ambient inhalation exposures. The need to characterize the aerosols to which indi-
viduals are exposed so that potential health hazards can be identified requires the development
SOX11A/A 11-58 2-9-81
-------
of appropriate air sampling techniques. For insoluble dusts whose site of action is the
pulmonary region, inhalation hazard evaluations based on "respirable" mass are clearly
superior to estimates based on gross air concentrations. Appropriate selective sampling pro-
cedures can and are being developed to provide more meaningful data on inhalation hazard
potential for particles as a function of their regional deposition in the respiratory tract.
Gross concentration sampling techniques are appropriate for highly soluble aerosols or where
the particle size distribution is relatively constant. They can also be used if the particle
size distribution is relatively constant and there is a known fixed ratio between the gross
concentration and the concentration in the size range of interest.
SOX11A/A H-59 2-9-81
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*
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Waligora, S. J. , Jr. Pulmonary retention of zirconium oxide ( Nb) in man and beagle dogs.
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Wang, C. S. Gravitational deposition from laminar flows in inclined channels. J. Aerosol Sci.
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Washburn, E. W., ed. National Research Council of the U.S.A. International Critical Tables of
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Weibel, E. R. Morphometry of the Human Lung. Academic Press, New York, 1963.
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SOX11A/C n-76 2_9_81
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12. TOXICOLOGICAL STUDIES
12.1 INTRODUCTION
This chapter describes the toxicity of sulfur oxides and particulate matter in animals.
The health effects of sulfur oxides and particles have also been reviewed recently by the
National Academy of Sciences (Committee on Sulfur Oxides, 1978; National Academy of Sciences,
Airborne Particles, 1979). The toxic effects of sulfur oxides and of atmospheric aerosols
overlap because major components of atmospheric aerosols are salts of sulfuric acid (ammonium
sulfate, sodium sulfate, and related compounds) (see Chapters 3 and 5). The toxicology of all
forms of sulfur oxides must be considered as a whole. For example, in the ambient air, sulfur
dioxide (S0£) may interact with aerosols, may be absorbed on particles, or may be dissolved in
liquid aerosols. To a lesser degree, similar interactions may occur in the air within the
respiratory tract. Sulfuric acid aerosols may react with ammonia forming ammonium sulfate
[(NH4)2S04J and ammonium bisulfate (NH4HS04) in the ambient air, in the animal exposure chamber
atmosphere before inhalation, or, to a lesser degree, in the respiratory tract simultaneously
upon inhalation (see Section 12.3). Biological interaction can also occur, resulting in a
situation where the effect of a mixture of pollutants has additive, synergistic, or antagonis-
tic health effects compared to the effects of the single pollutants.
At the present time, it is clear that the major toxic effects of sulfur oxides are on the
respiratory tract. Discussions of the deposition and clearance of sulfur oxides are limited
here; the reader, therefore, should be familiar with the content of Chapter 11 which covers
this subject in detail. The toxic effects of sulfur oxides, whether induced by SO™, H-SO.,
or sulfate salts, include immediate irritation of the respiratory tract. Most measurements of
this irritation have been through studies of the respiratory mechanics of the experimental
animal. Similar studies of respiratory mechanics have been undertaken with human subjects
experimentally or environmentally exposed. The general effects of SO- on the respiratory
mechanics of animals and man are the same. The animal studies reviewed here present some
details of the metabolism of S0? and bisulfite, the effects of S0? on the biochemistry,
physiology and morphology of the respiratory tract, and the potential effects on organs other
than the lung.
A major problem area is the diversity of particulate matter in the atmosphere. Any
organic compound whose local concentration exceeds its vapor pressure will condense and occur
in the particulate fraction when sampled. Some may be sorbed on the surfaces of inorganic
particles. Inorganic particles can be of a wide chemical variety. Unfortunately, our knowl-
edge of the exact chemical nature and health effects of these materials is incomplete. Pro-
gress is being made toward a better understanding of the toxicity of these materials associ-
ated with particles, but at present inadequate data are available. There is no theoretical or
practical reason why these data should not be attainable; rather, the present deficiency repre-
sents the sophistication of our knowledge. A more complete treatment of the health effects of
XRD12A/A 12-1 2-5-81
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polycyclic organic matter is found in a recent review (Environmental Criteria and Assessment
Office, 1978). Overviews are provided for some of the heavy metals present in polluted air.
More detail is found in documents dealing specifically with each heavy metal (Environmental
Criteria and Assessment Office, 1979; Office of Research and Development, 1977; Committee on
Biologic Effects of Atmospheric Pollutants, Vanadium, 1974; Committee on Medical and Biologic
Effects of Environmental Pollutants, Nickel, 1975; Committee on Biologic Effects of Atmospheric
Pollutants, Lead, 1972; Committee on Biologic Effects of Atmospheric Pollutants, Chromium,
1974; Committee on Medical and Biologic Effects of Environmental Pollutants, Arsenic, 1977;
National Academy of Sciences, Iron, 1979; National Academy of Sciences, Zinc, 1979). This
chapter deals primarily with sulfur oxide-derived aerosols, sulfuric acid, sulfate salts, and
related compounds. It is not intended to represent all of the health effects associated with
the complex mixture of materials present in atmospheric aerosols. The reader should supplement
his knowledge through reference to the additional documents cited above.
Interactions between sulfur oxides and other pollutants are reviewed briefly because of
the sparsity of the data available. Some of these studies are controversial and have not been
duplicated. Especially controversial are those studies dealing with the potential mutagenic
effects of S02 and the interaction of S02 and HLSO. with known carcinogens.
Another difficulty with a current review of the toxicology of sulfur oxides is the spar-
sity of recent studies. A hiatus occurred approximately 10 years ago with few studies appear-
ing subsequently. Work in progress is not included. As a consequence a certain degree of
sophistication is lacking in some of the intrepretations, not through a lack of appreciation
of the problem, but simply because insufficient information is available.
12.2 EFFECTS OF SULFUR DIOXIDE
12.2.1 Biochemistry of Sulfur Dioxide
Much of the discussion under Section 12.2.1 relates to j_n vitro experiments. J_n vitro
studies are those in which the potential target (i.e., cells, enzymes, other molecules, etc.)
is exposed to the toxicant outside the body. In such a system, some homeostatic or repair
mechanisms are absent. In some cases, pollutants act by indirect mechanisms. For example,
the pollutant affects target A which in turn alters target B. Thus, if only target B were pre-
sent, the effect would not be observed. In addition, the dosimetric relationships of jjn vitro
studies to jm vivo studies are not defined. Therefore, effective concentrations cannot be
extrapolated directly from HI vitro to i_n vivo studies. For the above reasons, there is some
controversy as to whether observed i_n vitro reactions can be extrapolated to HI vivo mechanisms
of toxicity. Nonetheless, sound j_n vitro investigations can show whether a given pollutant
has the potential of affecting a given target. In vitro studies are best used to provide guid-
ance for HI vivo investigations or when J_n vivo results have been observed. In the latter
case, the relatively simplified jn vitro system can sometimes elucidate the potential
mechanisms of toxicity. To these ends, they can be useful.
XRD12A/A 12-2
2-5-81
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Knowledge of the chemistry of sulfurous acid and S02 is necessary to understand the
physiological and toxicological properties of SO-. Sulfur dioxide is the gaseous anhydride of
sulfurous acid. It dissolves readily in water; and at physiological pH near neutrality,
hydrated S02 readily dissociates to form bisulfite and sulfite ions as illustrated by
Equations 12-1 and 12-2. The rate of hydration of SO,, is very rapid; the rate constant of
6 -1 -1
hydration, k,, is 3.4 x 10 M sec , and the rate constant of the reverse reaction is 2 x
8 -1 "I
10 M sec at 20°C (Equation 12-1) (Tartar and Garetson, 1941). The dissociation constants
of sulfurous acid are 1.37 and 6.25 (in dilute salt solutions) (Tartar and Garetson, 1941), so
at pH 7.4 sulfite ions are present at about 14 times those of bisulfite, but in rapid equili-
brium. Hence, S0» can be treated as bisulfite/sulfite and conversely.
k-,
S0 + H0 « HS0 12-1
PKa = i-37 PKa= 6-
H2S03 " H + HS03 " H + S0~3 12~2
Sulfur dioxide reacts readily with all major classes of biomolecules. Reactions of S02
or bisulfite with nucleic acids, proteins, lipids, and other biological components have been
repeatedly demonstrated j_n vitro.
12.2.1.1 Chemical Reactions of Bisulfite with Biological Molecules—There are three important
reactions of bisulfite with biological molecules: sulfonation, autooxidation, and addition to
cytosine.
Sulfonation (Gilbert, 1965) results from the nucleophilic attack of bisulfite on disul-
fides:
RSSR1 + HS03 > RSS03 + R'SH 12-3
This reaction is also known as sulf itolysis. The products of the reaction are S-sulfonates
(RSSO-j ) and thiols (R'SH). Direct evidence for the formation of plasma S-sulfonates i_n vivo
has been found (Gunnison and Benton, 1971; Gunnison and Palmes, 1973). Any plasma protein
containing a disulfide group could react to form an S-sulfonate. Small molecular weight
disulfides, such as oxidized glutathione, can also be reactants. Generally, analyses of
plasma S-sulfonates have been restricted to diffusable (dialyzable or small molecular weight
compounds) and nondiffusable (nondialyzable or protein) S-sulfonates. The exact molecular
species has not been determined, and the results of such determinations represent pools of the
two groups of compounds. S-sulfonates can react with thiols, either reduced glutathione or
protein thiol groups, to form sulfite and disulfide. Since this reverse reaction is facile,
S-sulfonates are hypothesized as being transportable forms of bisulfite within the body.
Sulfitolysis represents a mechanism of toxicity, a means of detoxification and a means of
redistribution of a reactive molecule, bisulfite.
XRD12A/A 12-3 2-5-81
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Similar reversible nucleophilic addition of bisulfite to j variety of biologically
important molecules has been reported, but the toxicological importance of these chemical
species is uncertain. It is not likely, for example, that the reactions of bisulfite with
pyridine nucleotides (NAD or NADP), reducing sugars, or thiamine are important to the toxicity
of bisulfite or S0?.
Autooxidation of bisulfite occurs through a multistep chain reaction (Hayon et al., 1972;
Backstrom, 1927; Fridovich and Handler, 1958, 1960; Asada and Kiso, 1973; Peiser and Yang,
1977; Yip and Hadley, 1966; Rotilio et al., 1970; Nakamura, 1970; Klebanoff, 1961; Yang, 1967,
1970; McCord and Fridovich, 1969a,b). These reactions may be important because they produce
hydroxyl (-OH) and superoxide (-0 ~) free radicals as well as singlet oxygen (-02). These
chemical species of oxygen are highly reactive and are also produced by ionizing radiation.
Hydroxyl free radicals are theoretically responsible for the lethal effects of ionizing radia-
tion. Autooxidation of bisulfite could lead to increased concentrations of these reactive
chemical species within the cell and could hypothetically lead to similar adverse effects.
The reactive forms of oxygen can also initiate peroxidation of the lipid bilayer of cells.
Peroxidation of cellular lipids, especially plasma membrane lipids, is thought to be highly
deleterious (Kaplan et al., 1975). No direct evidence has been presented to support peroxida-
tion of cellular lipids as a mechanism of toxicity of S0?.
Bisulfite addition to cytosine results in the formation of uracil. The reaction of
bisulfite with nucleic acids is as follows (Shapiro and Weisgras, 1970; Shapiro et al.,
1970a,b; Hayatsu, 1976):
NH2
HS°3 N^N H2°
Alteration of cytosine in the genome has not been reported iji vivo.
Of these three reactions, sulfonation or sulfitolysis, is clearly the most important.
The respiratory effects of S02 may be due to this reaction. Because all thiols in the
respiratory tract will undergo sulfonation, no single protein or small molecular weight com-
pound can presently be identified as the target or receptor for SO- in the toxic lesion.
XRD12A/A 12-4 2-5-81
-------
*
12.2.1.2 Metabolism of Sulfur Dioxide
12.2.1.2.1 Integrated metabolism. There are several studies of the metabolism of exogenously
supplied S02, sulfite, or bisulfite. Quantitative differences exist between inhaled and
ingested S0? with regard to the rate of clearance of the key intermediary in sulfite metabo-
lism, plasma S-sulfonates (Gunnison and Palmes, 1973), but no qualitative differences exist in
the metabolism of inhaled SO,, and injected or ingested bisulfite or sulfite. The importance
of the appearance of plasma S-sulfonates lies in their potential ability to serve as a circu-
lating pool of sulfite molecules (Gunnison and Palmes, 1973) as evidenced by the presence of
•\r ot
S from SO, in non-pulmonary tissues such as ovaries, for example (Frank et al., 1967).
3
Continuous inhalation of 26.2 mg/m (10 ppm) SO- resulted in the attainment of 38 ± 15 nmole
of plasma S-sulfonates/ml in rabbits after about 4 days (Gunnison and Palmes, 1973). The
clearance of plasma S-sulfonates generated by either inhalation of SO,, or ingestion of sulfite
in the drinking water was exponential, exhibiting only a single compartment in most rabbits.
The half-life was 4.1 days for S-sulfonates generated by inhalation vs. 1.3 days for those
generated by ingestion (Gunnison and Palmes, 1973). The mechanism for this quantitative dif-
ference in clearance rates has not yet been found.
Inhaled S0? quickly penetrates the nasal mucosa and airways as shown by the rapid appear-
ance of 35S in the venous blood of dogs inhaling 35SO, (Yokoyama et al., 1971). A significant
O t —
fraction of the blood S was probably in the form of plasma S-sulfonates (RSS03). Most of
the inhaled S0? is presumed to be detoxified by the sulfite oxidase pathway in the liver, form-
ing sulfate which is excreted in the urine. The dominance of this reaction has been supported
by studies of sulfite oxidase inhibition (Cohen, et al. 1972) which are discussed below and
by the appearance of about 85 percent of the inhaled S02 as urinary sulfate in dogs (Yokoyama
et al., 1971). Once oxidized by sulfite oxidase, most of the inhaled S derived from S02
appears in the urine as 35S-sulfate (Yokoyama et al., 1971). A small fraction (10 to 15
percent) of the urinary 35S was in the form of sulfuric acid esters and ethers (Yokoyama,
et al., 1971). Sulfate arising from the oxidation of sulfite can enter the sulfate pool and
could be incorporated into sulfate macromolecules including glycosaminoglycans and glycopro-
teins. These macromolecules are actively synthesized by the respiratory mucosa and could
account for the presence of radiolabeled sulfur in the respiratory tract following inhalation
of 35SO? (Yokoyama et al., 1971). Most of the nondialyzable S detected by Yokoyama et al.
(1971) was bound to the orglobulin fraction of plasma. The chemical form of the S was not
determined. Yokoyama et al. (1971) speculated that the 35S present in the orglobulin fraction
was in the form of sulfonated carbohydrates. The problem is in need of further clarification.
According to Gunnison and Palmes (1973), plasma S-sulfonated proteins may also have contained
the 35S. They have suggested that the slow clearance of plasma S-sulfonates is an important
factor in determining toxicity. They have not reported, however, intracellular levels of
S-sulfonates or sulfite.
XRD12A/A 12-5 2-5-81
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12.2.1.2.2 Sulfite oxidase. The biochemistry of sulfite oxidase will be discussed because of
its importance as a mechanism of detoxification of sulfite. A very rare genetic deficiency of
sulfite oxidase occurs in humans (Mudd et al., 1967; Irreverre et al., 1967; Shin et al.,
1977). Dietary factors can, however, alter the enzymatic activity (Cohen et al., 1973). Sul-
fite oxidase (EC 1.8.3.1) is a metallo-hemo protein with molybdenum and protoheme as the
prosthetic groups (Cohen et al., 1972). It exists in animals (Cohen et al., 1972,1974; Howell
and Fridovich, 1968; Cohen and Fridovich, 1971a,b; Wattiaux-DeConinck and Wattiaux, 1974),
bacteria (Lyric and Suzuki, 1970), and plants (Tager and Rautanen, 1955; Arrigoni, 1959;
Fromageot et al., 1960). In both plants and animals, the enzyme is located in the mitochon-
dria. Purified sulfite oxidase can utilize either cytochrome c or oxygen as the electron
acceptor (Cohen and Fridovich, 1971a). When coupled with cytochrome c to the mitochondria!
respiratory chain, sulfite oxidase reduces molecular oxygen to water (Equation 12-4), whereas
during oxygen reduction, the product formed is hydrogen peroxide (Equation 12-5).
2 Cyt c (Fe3+)
Cyt c (Fe2+) 1/2 02
12-4
S0~2 + H20 + 02 -» S0~2+ H202 12-5
Direct reduction of molecular oxygen by sulfite oxidase is prevented in the presence of ferric
cytochrome c. In intact mitochondria, therefore, sulfite oxidation occurs through the inter-
action of sulfite oxidase with the respiratory chain of the mitochondria, producing 1 mole of
ATP/mole of sulfite oxidase.
Sulfite oxidase is presumed to be necessary for the detoxification of sulfite. In three
reported cases in humans, a genetic defect in this enzyme resulted in severe neurological pro-
blems (Mudd et al., 1967; Irreverre et al., 1967; Shih et al., 1977). Cohen et al. (1973)
suggested that sulfite oxidase is the principal mechanism for detoxifying bisulfite and SO-.
This is supported by a study which showed that dogs exposed to 35SO_ (Yokoyama et al. , 1971)
35
excreted 80 to 90 percent of the inhaled S as sulfate in the urine. Because sulfite oxidase
requires molybdenum, Cohen et al. (1973) were able to deplete rats of sulfite oxidase by feed-
ing them a low molybdenum diet and treating them with 100 ppm of sodium tungstate in drinking
water. Tungsten competes with molybdenum and essentially abolishes the activity of sulfite
oxidase and xanthine oxidase (EC 1.2.3.2), the two major molybdo-proteins of rat liver.
Similar decreases were observed in the lung and other organs. The LD50 for interperitoneally
injected bisulfite was found to be 181 mg NaHS03/kg in the sulfite oxidase deficient rats
compared to 473 mg/kg in the nondeficient animals.
XRD12A/A 12-6 2-5-81
-------
The effect of inhaled S02 on lethality was more complex (Cohen et al., 1973). High
levels were used in all cases and two effects of inhaled S0? were observed. At 1,546 or 2,424
mg/m (590 or 925 ppm) S02 or less, the principal effect in control rats was respiratory
insufficiency resulting in death by asphyxiation. At 6,157 mg/m3 (2,350 ppm) SOp or greater
(up to 1.3 x 10 mg/m , 1,310,000 ppm), the principal effect appeared to be mediated by the
central nervous system (CNS) resulting in seizures and prostration followed by death. A
direct effect of bisulfite on the CNS has been suggested (Cohen et al., 1973). Mortality was
observed in both the control and tungsten-treated animals exposed to greater than 1,554 mg/m3
(593 ppm) S02 for 4 hr. Cohen et al. (1973) suggest that the shorter survival times and
greater mortality of the tungsten-treated rats are due to an inability to detoxify inhaled S02
to sulfate.
Attempts to induce higher levels of sulfite oxidase through pretreatment of the rats
with S02/bisulfite or phenobarbital failed (Cohen et al., 1973). Since sulfite oxidase is a
mitochondrial enzyme with a long half-life, it is not likely that phenobarbital or chronic
exposure to S02 would result in adaptation through induction of higher levels of sulfite oxi-
dase.
12.2.1.3 Activation and Inhibition of Enzymes by Bisulfite—Both inhibition and activation of
specific enzymes have been reported. This may be due to formation of S-thiosulfates, since
disulfide bonds often stabilize the tertiary structure of proteins. Sulfite ions activated
several phosphatases including ATP-ase (Marunouchi and Mori, 1967) and 2,3-diphosphoglyceric
acid phosphatase (Harkness and Roth, 1969). The mechanism by which activation occurs is not
known. Inhibition of several enzymes has been reported; these include aryl sulfatase
(Harkness and Roth, 1969), choline sulfatase (Takebe, 1961), rhodanase (Lyric and Suzuki,
1970), and hydroxyl amine reductase (Zucker and Nason, 1955). Malic dehydrogenase was inhi-
bited by micromolar concentrations of bisulfite (Ki = 5 uM) (Wilson, 1968; Ziegler, 1974).
Other dehydrogenases (Oshino and Chance, 1975) and flavoprotein oxidases are inhibited by
bisulfite.
Bisulfite effectively inhibits a number of other enzymes including potato and rabbit
muscle phosphorylase (Kamogawa and Fukui, 1973). Bisulfite inhibition was competitive with
respect to glucose-1-phosphate and inorganic phosphate, suggesting that the bisulfite inhibi-
tion was caused by competition of bisulfite with the phosphate binding site of phosphorylase.
Several important coenzymes (such as pyrodoxylphosphate, NAD , NADP , FMN, FAD, and folic
acid) may react with sulfite to form addition products as discussed above. As a result, these
coenzymes could theoretically aid in inhibition of a wide variety of critical enzymic reac-
tions. Pyridine coenzyme-bisulfite adduct (Tuazon and Johnson, 1977) and flavoenzyme-
bisulfite adduct (Muller and Massey, 1969; Massey et al., 1969) have been studied in detail;
these adducts have been shown to be biologically inactive.
Despite all of the data obtained using i_n vitro systems on the inhibition of enzymes by
bisulfite/SO?, no inhibition or activation has been determined iji vivo with S02 exposure.
XRD12A/A 12-7 2-5-81
-------
Such inhibition may occur, but there has been no concerted effort to search for inhibition of
specific enzymes during SO- exposure.
12.2.2 Mortality
The acute lethal effects of S02 have been examined mostly in the older literature and
have been reviewed in the previous Air Quality Criteria Document for Sulfur Oxides (National
Air Pollution Control Administration, 1970). In early studies, a number of different animal
species was examined for susceptibility to SO-. These data show that mortality was not
o ^
observed at exposures of 65.5 mg/m (25 ppm) for up to 45 days in either rats or mice; this
conclusion has been confirmed by subsequent studies (Laskin et al., 1970). Mortality could be
associated with long-term exposure to S02 at 134 mg/m (51 ppm) or higher. The clinical signs
of SO- intoxication appear to vary with the dose rate (Cohen et al., 1973). At concentrations
below approximately 1,310 mg/m3 (500 ppm), mortality is associated with respiratory insuffi-
ciency; above this concentration, mortality is ascribed to central nervous disturbances pro-
ducing seizures and paralysis of the extremities. These clinical signs depend upon the pre-
sence and activity of sulfite oxidase as discussed in Section 12.2.1.2.2. Injections of his-
tamine or adrenalectomy can increase the lethality of SO- (Leong et al., 1961).
Matsumura (1970a,b) examined the effect of a 30-min exposure to several air pollut-
ants on mortality consequent to the anaphylactic response of guinea pigs to protein antigens.
Sensitization to the antigen administered by aerosol was augmented by pretreatment with 786
mg/m (300 ppm) SO-, but not with 472 mg/m (180 ppm).
On the basis of mortality due to acute exposure, SO,, is far less toxic than ozone and is
similar in toxicity to nitrogen dioxide. Concentrations required to produce mortality from
S02 are far in excess of those which occur in the atmosphere due to pollution (Table 12-1).
12.2.3 Morphological Alterations
Because of the high solubility of SO,, in water, morphological and physiological effects
occur mostly in the upper airways. However, changes have also been detected in the lower air-
ways (Table 12-2). At relatively high concentrations of >26.2 mg/m3 (10 ppm) (used in most
studies designed to detect morphological alterations), most of the inhaled SO- is removed by
the nasopharyngeal cavity. (See Chapter 11, Section 11.2.4 for an expanded discussion of S02
absorption.) In rabbits, the concentration of inspired SO- determines how much is removed in
the nasopharyngeal cavity as opposed to the bronchial and alveolar regions of the lung
(Strandberg, 1964). At high S02 concentrations, greater than 26.2 mg/m3 (10 ppm), 90 to 95
percent is removed in the nasopharyngeal cavity. A small part, 3 to 5 percent, is removed by
the bronchiolar-alveolar region. So in this concentration range, most of the dose is
delivered to the nasal turbinates with only a small percentage going to the lung parenchyma.
At lower concentrations of inspired S02, [such as 0.13 mg/m3 (0.05 ppm)] which are closer to
ambient levels, only 40 percent of the dose is delivered to the nasopharyngeal cavity upon
inspiration, while another 40 percent is removed by the respiratory tract upon expiration.
XRD12A/A 12-8 2-5-81
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TABLE 12-1. LETHAL EFFECTS OF SO,
SO, Concentration
3
mg/m ppm Duration
26.2
134
275
(See Text)
1,598
2,392
3,086 1,
5,175 1,
9,165 3,
13,236 5,
5,782 2,
6,571 2,
7,205 2,
786
10
51
105
610
913
178
975
498
052
207
508
750
300
6 hr/day x 5 day/wk
x 113 day
113 days
22 day
5 min/day x 5 day/wk
> x lifetime
LT5Q 285.6 min
74.5 min
38.7 min
LT5Q 197.6 min
71.7
41.0
LT5Q 68.2 min
28.7
35.5
30 min
Species Remarks
Rat No mortality in excess of control
No mortality in excess of control
64% mortality (treated-control)
Mice No increased mortality; tumor formation
found
Mice IP injection of 200 to 300 mg histamine/mouse
(Connaught Med. increased toxicity
Res. Lab. Strain)
Rat (Sprague- IP injection of 200 to 300 mg histamine/rat
Dawley) or adrenal ectomy increased toxicity
Guinea Pig
Guinea Pig Increased mortality
Reference
Las kin et al. ,
1970
Peacock and Spence,
1967
Leong et al.
1961
Leong et al.
1961
Leong et al.
1961
Matsumura, 1970a,b,
due to anaphylaxis
from antigen challenge
to sensitized animals
-------
SOX12C/A 1 2-5-81
TABLE 12-2. EFFECTS OF SULFUR DIOXIDE ON LUNG MORPHOLOGY
Concentration
Duration
Species
Results
Reference
0.34. 2.65, or 15.0 mg/m3
(0.13, 1.01. or 5.72 ppm)
S02
0.37, 1.7 or 3.35 mg/m3 (0.14.
0.64 or 1.28 ppm)
12.3 mg/m3 (4.69 ppm) then
between 524 and 2620 mg/m3
(200-1000 ppm) then 0 mg/m3
13.4 mg/m3 (5.12 ppm)
13.4 mg/m3 (5.1 ppm)
26.2 mg/m3 (10 ppm)
91.7 mg/m3 (35 ppm) [rose on
occasion to 262 mg/m3(100 ppm)]
1048 mg/m3 (400 ppm)
1048 mg/m3 (400 ppm) S02
1 yr, continuous
78 wk, continuous
30 wk then 1 hr then
48 wk
18 mo, continuous
21 hr/day, 620 days
72 hr, continuous
1 to 6 wk
3 hr/day, 5 day/wk,
6 wk
3 hr/day, 5 day/wk,
3 wk
Guinea pig
Cynomolgus
monkey
Cynomolgus
monkey
Cynomolgus
monkey
Dog
House
Pig
Rat
Rat
Lungs of 15.0 mg/m3 (5.72 ppm) group, killed after
13 or 52 wk of exposure, showed less spontaneous
pulmonary disease than controls. Controls and 0.34
and 2.64 mg/m3 (0.13 and 1.01 ppm) animals had
evidence of lung disease. Tracheitis present in
all but 15.0 mg/m3 (5.72 ppm) group. Survival
greater in the latter group
No remarkable morphologic alterations in the lung
Persistent changes in lung morphomology including:
alterations in the respiratory bronchioles,
alveolar ducts, and alveolar sacs; proteinaceous
material within the alveoli; thicker alveolar
walls infiltrated with histocytes and leucocytes;
moderate hyperplasia of the epithelium of the
respiratory bronchioles; bronchiectasis and
bronchiolectasis; vacuolation of hepatocytes
No alterations in lung morphology
No alterations in lung morphology
Pathological changes in the nasal mucosa appeared
after 24 hr of exposure and increased in severity
after 72 hr. Mice free of upper respiratory patho-
gens were significantly less affected than the con-
ventionally raised animals. Morphological altera-
tions were qualitatively identical in both groups.
Loss of cilia in nasal cavity, disappearance of
goblet cells, metaplasia of the epithelium
Tracheal goblet cells increased in number and size.
Incorporation of 3SSO. into mucus increased.
Sialidase resistant mucus secreting cells were
found much more distally. Chemical composition
of mucus altered
Alarie et al., 1970
Alarie et al., 1972, 1973c
Alarie et al., 1972. 1973c
Increased mitosis of goblet cells.
not lost by 5 wk post-exposure
Alteration
Alarie et al., 1975
Lewis et al., 1973
Giddens and Fairchild,
1972
Martin and Willoughby,
1971
Reid, 1970
Lamb and Reid, 1968
-------
Thus, at lower concentrations,, the actual percentage of S02 removed in specific regions of the
respiratory tract is not known precisely. In the dog, over 95 percent was removed by the
upper airways and nose at concentrations between 2.62 and 131 mg/m3 (1 and 50 ppm) S0? (Frank
et al., 1967, 1969). A more detailed consideration of S02 extraction by airways is given in
Section 12.2.4 below.
Giddens and Fairchild (1972) pointed out that these differences in removal of inspired
S02 could explain the apparent anomaly of little damage to the lower respiratory tract at high
S02 concentrations. They undertook a study of the effects of inhaled S02 on the nasal mucosa
of mice. Two groups of mice were used; one group that was free of specific upper respiratory
pathogens, and an ordinary laboratory group that was presumed to be infected or to have a
latent infection of upper respiratory pathogens. Mice were exposed continuously to 26.2 mg/m
(10 ppm) S02 for a maximum of 72 hr. Pathological changes in the nasal mucosa appeared after
24 hr of exposure and increased in severity after 72 hr of exposure. Mice free of upper
respiratory pathogens had fewer pathological findings than the conventionally raised animals.
Giddens and Fairchild (1972) concluded that resident or acquired pathogens exacerbated the
morphological changes they nad observed. Morphological alterations were, however, qualita-
tively identical in both groups of animals. Cilia were lost from the nasal mucosa; vacuoli-
zation appeared; the mucosa decreased to about one half the normal thickness, and a watery
fluid accumulated. Desquamation of the respiratory and the olfactory epithelia was evident.
Alveolar capillaries were slightly congested, but edema and inflammatory cells were absent.
Martin and Willoughby (1971) reported loss of cilia, disappearance of goblet cells, and meta-
plasia of the epithelium of the nasal cavity of pigs exposed to 91.7 mg/m (35 ppm) S02 for 1
to 6 wk. This study, however, was marred by difficulties with the control of the SCL, rising
3
on occasion to 262 mg/m (100 ppm), and with high relative humidity occurring during cleaning
of the pig pens.
Lamb and Reid (1968) and Reid (1970) attempted to use S02-exposed rats in a model of
human chronic bronchitis. They presented favorable arguments that S0?-induced bronchial
hyperplasia is analogous to human chronic bronchitis. Most of their studies have been carried
out at high concentrations of S02 (1,048 mg/m or 400 ppm S02 for 3 hr/day, 5 days/wk) for up
to 6 wk. Under these conditions, the tracheal glands clearly increased. The goblet cell
density also increased in the proximal airways, main bronchi, trachea, and distal airways,
with proximal airways and main bronchi showing the largest changes. The incorporation of
S-sulfate by goblet cells into mucus also increased with exposure, reaching a plateau at
approximately 3 wk. The effects of S02 were concentrated in the central airways, again sug-
gesting that the solubility of S0? in water limits its accessibility to the periphery. Mitosis
reached a maximum after 2 or 3 exposures and declined rapidly as injured cells were replaced.
On repeated exposure for periods up to 6 wk, mitosis remained elevated in the proximal airways
compared to the distal airway in which the mitotic index returned to the control level. The
magnitude was proportional to the S0? concentration up to 524 mg/m (200 ppm) S02> but was
XRD12A/A 12-11 2-5-81
-------
less at 786 mg/m3 (300 ppm). An elevation of the mitotic index occurred at S02 concentrations
as low as 131 mg/m3 (50 ppm) when given for 3 hr/day, 5 days/wk. Major changes in the goblet
cell type or substance produced by the goblet cells were also detected. Goblet cells which
produced mucus resistant to digestion by sialidase increased in numbers, and their distribu-
tion extended distally from the upper bronchioles towards the respiratory bronchioles. Since
each molecular type of mucin, sialidase resistant or susceptible, could be produced by one
type of goblet cell, or each goblet cell could produce a different mucin, these results can be
interpreted in two ways. The elaboration of a specific type of goblet cell could occur, or
more goblet cells could be produced but with a change in their biochemical function towards
sialidase resistant mucins. These studies present an interesting means of studying experi-
mental bronchitis, but do not provide evidence that ambient SO- levels cause similar changes.
Alarie et al. (1970) examined the tissues of guinea pigs exposed continuously to 0, 0.34,
2.65, or 15.0 mg/m3 (0, 0.13, 1.01, or 5.72 ppm) SO, for 1 yr. The lungs of the guinea pigs
3
exposed to 15.0 mg/m (5.72 ppm) and killed after 13 or 52 wk of exposure showed less sponta-
neous pulmonary disease than the control group. The prevalence of pulmonary disease in the
control groups which was not observed prior to exposure suggests that they acquired pulmonary
disease during the exposure period. These (Alarie et al., 1970) and other studies by Alarie
and co-workers (1972, 1973c, 1975), were limited to light microscopic observations of conven-
tional hematoxylin-eosin stained paraffin sections. The results are of limited value compared
to more recent approaches using scanning electron microscopy of surfaces and transmission
electron microscopy of organelles. The control group, as well as those exposed to 0.34 and
2.64 mg/m (0.13 and 1.01 ppm) S0?, had evidence of lung disease as shown by histocytic infiltra-
tion of the alveolar walls. Tracheitis was also present in the above three groups, but not in
the 15.0 mg/m (5.72 ppm) group. Hepatocyte vacuolation was observed in the latter group, but
the pathological significance of this change needs further investigation. The survival was
greater (p <0.05) in the 15.0 mg/m (5.72 ppm) group than in the other groups including the
air-exposed control group. The authors do not address the significance of the hepatocyte
vacuolation. The possible effects of S02 in this study cannot be accurately determined
because of the disease in the control animals.
Subsequently these researchers (Alarie et al., 1972, 1973c) exposed cynomolgus monkeys
continuously to 0.37, 1.7 or 3.35 mg/m (0.14, 0.64 or 1.28 ppm) SO- for 78 wk but found no
remarkable morphological alterations. Another group exposed to 12.3 mg/m3 (4.69 ppm) S02 for
30 wk was accidentally exposed to concentrations of SO- not higher than 2,620 mg/m3 (1,000
3
2
ppm) or lower than 524 mg/m (200 ppm) for 1 hr, after which they were placed in a clean air
chamber and held for 48 more wk. Persistent changes were noted in this group. Alterations in
the respiratory bronchioles, alveolar ducts, and alveolar sacs were found. Proteinaceous
material was found within the alveoli. The distribution of such lesions was focal, but was
observed within all lobes of the lung. Alveoli containing proteinaceous material were
generally those which arose directly from respiratory bronchioles. Alveolar walls were
XRD12A/A 12-12 2-5-81
-------
thicker and were infiltrated with histocytes and leukocytes. Macrophages were present within
these foci. Moderate hyperplasia of the epithelia of the respiratory bronchioles was found,
and frequently the lumina of the respiratory bronchioles were plugged with proteinaceous
material, macrophages, and leukocytes. Bronchiectasis and bronchiolectasis were present in 8
of 9 monkeys. Vacuolation of hepatocytes was also observed, as with the guinea pig group
exposed to 15.0 mg/m (5.72 ppm) SCL in the prior study (Alarie et al., 1970).
3
In a replication of this study, cynomolgus monkeys were exposed to 13.4 mg/m (5.12 ppm)
S02 continuously for 18 mo. (Alarie et al., 1975). No alterations in lung morphology were
reported to be due to S02> The morphological alterations reported in the control group includ-
ed lung mite infections and associated "slight subacute bronchiolitis, alveolitis, and bronchi-
tis." Pulmonary function measurements were made in the above mentioned studies (Alarie et al.,
1970, 1972, 1973c, 1975) and are described in Section 12.2.4.
The absence of S02-induced morphological alterations as reported by Alarie et al. (1970,
1972, 1973c, 1975) and Lewis et al. (1973) who exposed dogs for 620 days (21 hr/day) to 13.4
mg/m (5.1 ppm) S02 is not in conflict with the bronchoconstriction induced by acute S02 expo-
sure reported by Amdur and co-workers (1973) at lower concentrations (see Section 12.2.4).
Alarie et al. (1970) pointed out, "As recent literature attests, there is also an obvious lack
of knowledge about the correlation between subtle microscopic alterations in the lung and con-
comitant changes in this physiological parameter (lung function)." Further, the transient
nature of the pulmonary function effects observed during short-term exposures would be diffi-
cult to detect morphologically unless the lungs were fixed during the time of exposure. Even
then, if the cause of the increased pulmonary resistance were a subtle alteration of smooth
muscle tone as has been hypothesized, it might be morphologically undetectable.
Most of the studies in which the lungs of S0?-exposed animals have been examined center
around tracheitis, bronchitis, ulceration, and mucosal hyperplasia (Table 12-2). The lowest
concentrations of SO, at which these alterations have been reported have been in the rat at
"\ 3
131 to 134 mg/m (50 to 51 ppm) for 30 to 113 days. At higher concentrations (1,048 mg/m or
400 ppm S02 for 3 hr/day, 5 days/wk for 3 wk), recovery to normal morphology did not occur
after 5 wk post-exposure. The possibility of recovery from lower concentrations and shorter
durations of exposure is not known (Lamb and Reid, 1968; Reid, 1970). Discounting their first
study (Alarie, et al., 1970) where the control group of guinea pigs had a higher level of pul-
monary infection than the exposed groups, Alarie et al. (1973c) reported no effect from S02
exposure up to 5 ppm. These observations were, however, restricted to light microscopy and
did not include scanning or transmission electron microscopic observations. This group also
reported no observable effects at 0.37, 1.7 or 3.35 mg/m3 (0.14, 0.64, and 1.28 ppm) S0?
o '-
(Alarie et al., 1975). The group of monkeys exposed to 12.3 mg/m (4.69 ppm) must also be
disregarded due to the accidental exposure to high levels of SO.- (Alarie et al., 1975). No
effects were reported for monkeys exposed to 13.5 or 13.7 mg/m (5.15 or 5.23 ppm) S0? and
33
sulfuric acid aerosols at 0.10 mg/m or fly ash at 0.44 mg/m (Alarie et al., 1975).
XRD12A/A 12-13 2-5-81
-------
12.2.4 Alterations in Pulmonary Function
Changes in breathing mechanics have been among the most sensitive parameters of S02 toxi-
city. They have likewise been useful in studying the effects of aerosols alone or in combina-
tion with S02 (Sections 12.3.3.1 and 12.4.1.1). A variety of methods have been used, some of
which have been applied to human exposures. A method for measuring increases in flow resist-
ance due to bronchoconstriction in guinea pigs has been developed by Amdur (Amdur and Mead,
1955, 1958). Animals are not anesthetized and breathe spontaneously, allowing sensitive
measurements of pulmonary function. Another method by Alarie and co-workers (1973d) measures
changes in respiratory rate. S0? also initiates bronchoconstriction in man, and is also more
closely related to human health effects.
Several investigators (Nadel et al. 1965a; Corn et al., 1972; Frank and Speizer, 1965;
Balchum et al., 1960; Nadel et al., 1965b) found that bronchoconstriction resulted from both
head-only and lung-only exposures in cats and dogs. When corrected for the amount of SCL
hypothesized to reach the lung, Amdur's study (1966) with guinea pigs has shown that S02 is
highly effective in producing bronchoconstriction through direct exposure of the lung. Two
sets of receptors are involved in the response of animals to SCL. At high concentrations of
S0? or following long durations of exposure, the nasopharyngeal receptors fatigue or become
unresponsive, whereas the bronchial receptors do not. Widdicombe (1954a) originally described
the receptors responsible for the S02-initiated bronchoconstriction. The bronchoconstriction
is initiated through the activation of a bronchial epithelial chemoreceptor whose efferent and
afferent pathways are through the vagus nerves (Nadel et al., 1965a,b; Grunstein et al., 1977;
Tomori and Widdicombe, 1969). Chilling the vagus prevents conduction of nervous impulses pro-
duced on inhalation of SO,,. Other receptors located in the same regions of the lung respond
to mechanical stimulation and particles such as talc (Widdicombe, 1954b; Widdicombe et al.,
1962). Intravenous injection of atropine blocks the efferent impulses, presumably at the
cholinergic preganglionic synapse (Grunstein et al., 1977). Sulfur dioxide-initiated broncho-
constriction involves smooth muscle contraction since p-adrenergic agonists, such as isopro-
terenol, reverse the SOp-bronchoconstriction (Nadel et al., 1965a,b). Histamine may be
involved in this response as implied by other studies of hyperreactive airways (Boushey, et al.
1980), but no definitive proof of histamine involvement is available. Release of acetylcholine
could also cause increased mucus secretion as noted during S0? exposure. Chronic exposure to
S02 could lead to mucus hypersecretion and altered airway caliber. Cholinomimetic drugs and
histamine applied as aerosols mimic the S02-initiated bronchoconstriction (Islam et al., 1972).
Cholinomimetic drugs act through either the same autonomic reflex arc or directly upon the
cholinergic receptors on smooth muscles and mucus secreting cells and glands. As discussed in
Chapter 13, S02 also produces bronchoconstriction in man through the same autonomic reflex arc.
XRD12A/A 12-14 2-5-81
-------
*
Exposure to S02 evokes an increased resistance to air flow in guinea pigs which can be
repeated by several exposures over a period of hours and exhibits none of the tachyphylaxis
found with other species (Corn et al., 1972; Frank and Speizer, 1965). However, different
techniques were used for these different species. Amdur (1973), in a review of her data,
reported that for a 1-hr exposure, a mean of 0.68 mg/m or 0.26 ppm (range of 0.08 to 1.57
mg/m or 0.03 to 0.6 ppm) was the lowest concentration of SOp that increased flow resistance
in guinea pigs. The response, a 12.8 percent increase (p < .001) at these (Amdur, 1973) low
levels of S02, was the average of 71 guinea pigs; the individual data points were reported in
other publications (Amdur and Underhill, 1968, 1970; Amdur, 1974). For a 1 hr exposure, the
lowest concentration these researchers tested which caused an increase (p <0.01) in resistance
was 0.42 mg/m (0.16 ppm) SO, (Amdur and Underhill, 1970). In a more recent study, Amdur et
' o
al. (1978) showed that a 1 hr exposure of guinea pigs to 0.84 mg/m (0.32 ppm) S0? caused a 12
percent increase in resistance (p <0.02) and a non-statistically significant decrease in com-
pliance. Investigations of the interaction of oil mists and SOp showed that 2.62 mg/m (1 ppm)
S09, the lowest concentration used, significantly increased resistance (Costa and Amdur,
3
1979a,b). At concentrations of SOp below 2.62 mg/m (1 ppm), the response of individual
animals varied considerably (Amdur, 1964, 1973, 1974). Of 1,028 guinea pigs, 135 were "suscep-
tible", responding to low concentrations of S02 with greater changes in resistance than the
predicted mean. Amdur cites comparative data for other species, including man, to suggest that
a certain fraction of all subjects may exhibit this phenomenon (Amdur, 1973, 1974; Horvath and
Folinsbee, 1977). On the other hand, Amdur et al. (1978) also point out that some groups of
animals may by chance not have a "susceptible" individual. In this study, 3 groups of 10
o
animals each or a total of 30 guinea pigs exposed to 0.52, 1.05, or 2.1 mg/m (0.2, 0.4, or
0.8 ppm) S02 had no significant increase in airway resistance above the control values. Based
on data from earlier work (Amdur and Underhill, 1968), Amdur concluded that 10 to 13 percent
of the guinea pig population is more responsive than the average (Amdur, 1974). In cats
(Corn et al., 1972) and dogs (Frank and Speizer, 1965), on the other hand, few were found to
3 3
be sensitive to short-term (< 1 hr) exposure to 52.4 mg/m (20 ppm) S02 (cats) or 18.3 mg/m
(7 ppm) SOp (dogs). Even with the relatively small sample sizes used, some cats and dogs
responded and others did not.
Some M the problem of "susceptible" vs. "non-susceptible" members of the experimental
population can be understood by considering a simple hypothesis. If one assumes that the
response to a given toxicant, such as SOp, is the result of a number of different genes within
the population and not just a single gene, then a single individual could have a number of
recessive or dominant genes which could contribute to either the "susceptibility" or "non-
susceptibility" of that individual. Since experimental animals and human subjects are drawn
on as random a basis as is possible (in most experimental designs), there will be a maximum
chance of getting some "susceptible" responders in each experiment. The total number of
"susceptible" responders will be small and variable because of the low incidence of
"susceptible" responders in the general animal population. A small, but variable, number of
XRD12A/A 12-15 2-5-81
-------
"susceptible" responders will tend to shift the dose- or concentration-response curve toward
lower concentrations and to decrease the slope of the curve (e.g., when the data are expressed
as the log-probit transformation). Such phenomena have been studied in detail for "resistant"
insects which have different genomes responsible for increased detoxification mechanisms. In
the case of SO-, the matter is further complicated by comparisons between groups of animals
and between different strains or species. Even with guinea pigs, the total number of animals
examined to date (about 1,000 to 2,000) is too small to give more than a crude estimate of
those animals having a "sensitive" genome. The incidence of "susceptibility" in the guinea
pigs (about 13 percent) is too low to have been detected clearly in the 100 or so cats and dogs
used in S0? experiments. Here only 1 or 2 "susceptible" animals would have been encountered
in each experiment. Further, the small number of animals has been studied in different labora-
tories and at different times, and the animals have come from different genetic stocks. It is
fortuitous that Amdur's laboratory has persisted in these studies with the same animal, the
guinea pig, using the same general methodology so this low incidence of "susceptibility" could
be detected. While the mechanism(s) responsible for "susceptibility" is not known, the ques-
tion of "susceptibility" is an important aspect deserving further study. A similar incidence
of some 10 percent "susceptible" individuals in man would present a major health problem.
3
Adverse reactions might occur among "susceptible" individuals at exposures less than 2.62 mg/m
(1 ppm) (Amdur, 1964, 1973, 1974). These concentrations of less than 2.62 mg/m (1 ppm) are
encountered in ambient air. Neither the frequency of susceptibility to S0? in man, nor the
physiological or biochemical basis, is known.
A broad dose-response curve has been noted also for histamine initiated bronchoconstric-
tion in man (Habib et al., 1979), guinea pigs (Douglas et al., 1973, 1977; Brink et al., 1980),
dogs (Loring et al., 1978; Snapper et al., 1978), and monkeys (Michoud, 1978). Among 12 normal
human subjects a 38-fold range of inhaled histamine in both the threshold and median doses
causing bronchoconstriction was observed (Habib et al., 1979). The dose required to produce a
50 percent change in dynamic lung compliance in 131 female guinea pigs varied over a 100-fold
range of concentrations (Douglas et al., 1973). While the interindividual dose varied consid-
erably, the values were log normally distributed indicating a single population (Douglas et
al., 1973, 1977). Dogs showed a 40-fold variation in the histamine dose needed to initiate
changes in airway diameter (Snapper et al., 1978). These values were also log normally dis-
tributed indicating a single population amongst the 102 mongrel dogs examined. A wide inter-
individual variation for histamine and methacholine initiated bronchoconstriction was found
amongst 8 rhesus monkeys, some of which were sensitive to Ascaris suum allergen (Michoud,
1978). No differences in sensitivity to histamine or methacholine could be found with Ascaris
sensitivity, however. While genetic differences in histamine sensitivity have been found in
quinea pigs, naturally occurring or acquired allergic reactions are, thus, not likely to cause
the large interindividual differences in sensitivity in either guinea pigs (Takino et al.,
1971) or monkeys (Michoud et al., 1978). A further complicating factor is the age-dependence
XRD12A/A 12-16 2-5-81
-------
of histamine and other drug initiated bronchoconstriction (Brink et al., 1980). Younger guinea
pigs were more sensitive to histamine than were older animals, for example. The decreasing
bronchial reactivity to histamine with age in the guinea pig has been suggested as a model of
human juvenile asthma. However, human bronchial hyperreactivity does not seem to decrease with
age in the same manner (Boushey et al., 1980). While large interindividual differences appar-
ently occur with a wide variety of chemical agents causing bronchial reactivity in both man
and animals, the response of the same individual is quite reproducible regardless of species.
The variability in the threshold dose of SO^ needed to evoke a given bronchoconstriction
(measured for example as an increased resistance to flow by the studies of Amdur) is apparently
an inherent part of the bronchial response to a broad range of chemicals and is not an artifact
of the method. Similar variations in threshold doses for S0? are likely to occur in man, judg-
ing from the variability to inhaled histamine. The general observation that asthmatic patients
are hypersensitive to a broad range of chemical and physical agents initiating bronchoconstric-
tion (Boushey et al., 1980) supports the contention that the most susceptible animal species
should be used as a surrogate for man. A major difference in pharmacology may exist between
the guinea pig and man. Autonomic mediators interact with histamine in bronchial reactivity
in guinea pigs but not in man. Beta adrenergic blockade by propranolol causes no difference
in bronchial reactivity in man (Habib et al., 1979) but potentiates histamine reactivity in
the guinea pig (Douglas et al., 1973). Insufficient numbers of animals and subjects have been
examined to predict the general shape of the dose-response curve for the human population, even
excluding the hypersensitive asthmatic population. These variations in interindividual dose
needed to evoke a specific amount of increased resistance to flow in guinea pigs by SO- like-
wise apply to the measurement of increased resistance to flow evoked by aerosols as discussed
below in Section 12.3.3.
Using Strandberg's (1964) data from the rabbit to correct for the concentration of SO™
hypothesized to reach the lung, Amdur (1966) was able to normalize the concentration-response
curve for S09-induced bronchoconstriction in the guinea pig resulting from nose-only exposures.
3
A break occurs in the concentration-response curve at about 52.4 mg/m (20 ppm) S0?, perhaps
due to the poorer extraction of gaseous S0? by the upper airways at low concentrations. How-
ever, it should be recognized that S0? extraction data for rabbits (Strandberg, 1964) and dogs
(Frank et al., 1967; Balchum et al., 1960; Frank et al., 1969) are in some conflict and that
the data for rabbits are not clear with respect to the site of S02 removal. Thus, use of the
rabbit data for guinea pig studies can be done only hypothetically. Sulfur dioxide introduced
directly into the lung by a tracheal cannula was much more effective in producing bronchial
constriction. Amdur (1966) suggests that at concentrations of 1.05 to 1.31 mg/m (0.4 to 0.5
ppm) very little removal of S0? occurs in the upper airways. These data contrast with the
radiotracer studies in dogs (Frank et al., 1967, 1969; Balchum et al., 1960). Others have
required concentrations greater than 18.3 mg/m (7 ppm) to evoke increases in flow resistance
in anesthetized cats (Corn et al., 1972) and dogs (Frank and Speizer, 1965). Differences in
XRD12A/A 12-17 2-5-81
-------
the sensitivity of the two models may lie in the use of anesthesia, in the use of different
species, or in a different incidence of "susceptible" individuals.
Using anesthetized, intubated, spontaneously breathing dogs exposed to 2.62, 5.24, 13.1,
or 26.2 mg/m3 (1, 2, 5, or 10 ppm) S02 for 1 hr, Islam et al. (1972) found an increased
bronchial reactivity to aerosols of acetylcholine, a potent bronchoconstrictive agent.
Acetylcholine is also the endogenous neuromuscular transmitter which causes bronchoconstric-
tion. Greatest response occurred at 5.24 mg/m (2 ppm), although 2.62 mg/m (1 ppm) also
caused an effect. The effect at 26.2 mg/m (10 ppm) was less than that at 2.62, 5.24, and 13.1
mg/m3 (1, 2, and 5 ppm). These results suggest that S02 may modify bronchial reactivity.
Animals chronically exposed to SO,, have also been examined for alterations in pulmonary
function. Guinea pigs exposed continuously to 0.34, 2.64, or 15 mg/m (0.13, 1.01, or 5.72
ppm) S02 for up to 1 yr showed no changes in pulmonary function; however, spontaneous pulmonary
disease was present in all animals (including controls) except those exposed to the highest
concentration (Alarie et al., 1970). Dogs exposed for 21 hr/day to 13.4 mg/m (5.1 ppm) S02
for up to 225 days demonstrated increased pulmonary flow resistance and decreased lung compli-
ance (Lewis et al., 1969). After 620 days' exposure, the mean nitrogen washouts of dogs were
increased (Lewis et al., 1969). Alarie and co-workers (Alarie et al., 1972, 1973c, 1975)
exposed cynomologus monkeys continuously to 0.37, 1.7, 3.4, or 13.4 mg/m (0.14, 0.64, 1.28,
or 5.12 ppm) S02. The latter concentration was used in an 18-mo study, whereas the others were
used for 78 wk exposures. Pulmonary function was unchanged in all of these groups. After 30
wk of exposure to 12.3 mg/m (4.69 ppm) SO,, monkeys were inadvertently exposed to concentra-
3
tions between 524 and 2,620 mg/m (200 and 1000 ppm) for 1 hr. This treatment resulted in
pulmonary function alterations which persisted for the remaining 48 wk of the study during
which the animals were exposed to clean air. Morphological alterations were also seen in this
group (see Section 12.2.3).
In summary, there are at least two sets of receptors responsible for changes in respira-
tory function in animals acutely exposed to SO,,. Decreases in respiratory rate or increased
resistance to flow are reproducible end points. Increased resistance to flow results from SO,
3
concentrations as low as 0.42 mg/m (0.16 ppm) using guinea pigs. Of the animals so far
examined, guinea pigs are the most sensitive to S0«. The reason for this is not known; poten-
tial factors include species, strains, and experimental technique used. Large interindividual
differences in dose-response curves for changes in pulmonary resistance to air flow exist in
all species. A single population of animals for this trait appears likely for guinea pigs,
dogs, and cats. The exact number of animals responding to a given dose will depend upon the
shape of the dose-response curve. The nature of the dose-response curve at low levels is
poorly understood and has not been investigated directly. While pulmonary function measure-
ments in guinea pigs appear to be highly sensitive to acute S0? exposures, chronic S02 exposure
has not been proven to have a similar effect. Chronic studies with guinea pigs are unclear,
however, because of disease in the control group. In other chronic studies, pulmonary
XRD12A/A 12-18 2-5-81
-------
*
function of monkeys was unchanged at S02 concentrations up to 13.4 mg/m3 (5.12 ppm); dogs
were affected by 225, but not 620, days of exposure to 13.4 mg/m3 (5.1 ppm). High levels of
S02 likely to initiate airway narrowing and hypersecretion of mucus do alter several parameters
of pulmonary function. These results are not contradictory in view of the physiology of S0»-
initiated bronchoconstriction. Sulfur dioxide appears to cause bronchoconstriction through
action on the smooth muscles surrounding the airways. Since smooth muscles fatigue or become
adjusted to altered tone over time, chronic exposure to SO. is not likely to cause a permanent
alteration in bronchial tone. Unfortunately, investigations of the reactivity of the airways
after chronic exposure to S02 have not appeared. We do not know if chronic exposure to SCL
causes an alteration in response to SO- itself, since only direct measurements of pulmonary
function were made on the animals after chronic exposure. It would be very informative to
learn if chronically exposed monkeys, for example, were more or less sensitive to S02 (Table
12-3).
The respiratory rate of mice has been used as an indication of sensory irritation by
Alarie et al. (1973d). Mice were exposed for 10 min to 0, 44.5, 83.8, 162, 233, 322, 519, or
781 mg/m (0, 17, 32, 62, 89, 123, 198, or 298 ppm) SO,. About a 12 percent decrease in res-
3
piratory rate was observed at 44.5 mg/m (17 ppm). The respiratory rate decreased inversely
to the logarithm of the concentration of inspired S0?. The decrease in respiratory rate, how-
ever, was transient, returning to nearly control levels within 10 min at all S02 concentrations.
Complete recovery to control values occurred within 30 min following all exposures to S02-
The time for maximum response was inversely related to the logarithm of the concentration of
S0?, being shortest at highest concentrations. Mice exposed to 262 mg/m (100 ppm) S0? for 10
min were allowed to recover in clean air prior to a subsequent 10 min exposure to the same con-
centration. As the length of the recovery period was decreased (from 12 min to 3 min), the
effect of the subsequent SO- exposure on respiratory rate was lessened. "Desensitization,"
thus, appeared to occur during the course of exposures. When another irritant, aerosols of
chlorobenzilidene malononitrile (CBM), was used during the refractory period following SO-
exposure, the respiratory rate decreased at a rate comparable to that following exposure to
CBM alone. Thus, the refractory period associated with S0» exposures appeared specific to S0?
7
and not to CBM. When 262 to 328 mg/m (100 to 125 ppm) S02 was provided repeatedly for dura-
tions of 90 sec, with each exposure separated by a 60-sec recovery period, the refractory
period was cumulative. Ten such exposures eventually abolished all respiratory rate responses
to S02. Breathing clean air for 60 min resulted in a return of the response to initial levels.
When mice were exposed to SO- by means of a tracheal cannula, no changes in the respiratory
rate were observed, indicating that the decrease in respiratory rate was mediated by a reflex
arc. This hypothesis has been developed in considerable detail in an extensive review by
Alarie (1973) who suggests that stimulation and desensitization occur via cholinergic nerve
endings of the afferent trigeminal nerve. Alarie et al. (1973d) also suggest that S02 is
XRD12A/A 12-19 2-5-81
-------
SOX12C/A 2 2-5-81
TABLE 12-3. EFFECTS OF SULFUR DIOXIDE ON PULMONARY FUNCTION
Concentration
Duration
Species
Results
Reference
0.37, 1.7, 3.4, or 13.4 mg/m3 72-78 wk, continuous
(0.14. 0.64. 1.28. or 5.12 ppm)
S02
0.42 or 0.84 mg/m3 (0.16 or 1 hr
0.32 ppm) S02
0.52. 1.04. or 2.1 mg/m3 (0.2. 1 hr
0.4, or 0.8 ppm) S02
2.62. 5.24, 13.1. or 26.2 mg/m3 1 hr
(1, 2, 5, or 10 ppm) S02
13.4 mg/m3 (5.1 ppm) S02
18 to 45 mg/m3 (7 to 17 ppm)
S02
0, 44.5, 83.8, 162. 233, 322, 10 min
519, or 781 mg/m3 (0, 17, 32,
62. 89, 123, 198, or 298 ppm)
S02
21 hr/day. 225 and
620 days
1 hr
>50 mg/m3 (>19 ppm) S02
1 hr
Cynomologus No change
monkey
Guinea pig Increase in resistance
Guinea pig No significant increase in airway resistance.
Dog
Dog
Guinea pig
Mouse
Guinea pig
Increased bronchial reactivity to aerosols of
acetylcholine, a potent bronchoconstrictive agent
Increased pulmonary flow resistance and decreased
lung compliance at 225 days; increased nitrogen
washout at 620 days
General decrease in tidal volume and an increase in
respiratory rate
Alarie et al., 1972,
1973c, 1975
Amdur et al., 1970, 1978a
Amdur et al., 1978c
Islam et al., 1972
Lewis et al., 1969
Lee and Danner, 1966
Respiratory rate decreased proportionally to the log Alarie et al., 1973d
of the concentration; complete recovery within 30
min following all exposures. The time for maximum
response was inversely related to the log of the con-
centration, being shortest at highest concentrations
Increase in tidal volume and a decrease In respiratory Lee and Danner, 1966
rate
-------
*
hydrated to bisulfite and sulfite which react with a receptor protein to form an S-thiosulfate
and a thiol, cleaving an existing disulfide bond. The receptor protein slowly regenerates to
its original disulfide configuration by the oxidation of S-thiosulfide and free thiol moieties
of the receptor protein to disulfide. No direct evidence for this hypothesis has been
presented.
12.2.5 Effects on Host Defenses
Because alterations in the ability to remove particles from the lung could lead to
increased susceptibility to airborne microorganisms or increased residence times of other non-
viable particles, the effects of S02 on particle removal and engulfment, as well as on
integrated defenses against respiratory infection, have been studied. Cilia function does not
appear to be affected by exposure. No changes were observed in the cilia beat frequency or
the relative number of alveolar macrophages laden with particles in rats exposed to 2.62 or
7.86 mg/m (1 or 3 ppm) S02 and graphite dust (mean diameter 1.5 urn, 1 mg/m ) for up to 119
consecutive days (Fraser et al., 1968). Donkeys (Spiegelman et al., 1968) were exposed by
3 3
nasal catheters to 68.1 to 1,868 mg/m (26 to 713 ppm) SO, for 30 min. Below 786 mg/m (300
3
ppm) clearance was not affected, but at high concentrations (786 to 1,868 mg/m or 376 to 713
ppm) clearance was depressed. Increased mucus flow and nasal irritation have been observed
with as little as 26.2 mg/m (10 ppm) SO, for 24 hr.
o
Ferin and Leach (1973) exposed rats to 0.26, 2.62, and 52.4 mg/m (0.1, 1, or 20 ppm) S02
for 7 hr/day, 5 days/wk, for a total of 10 to 15 days and then measured the clearance of an
aerosol of titanium oxide (TiO?). The aerosol was generated at about 15 mg/m (1.5 pm MMAD,
a 3.3). These investigators took the amount of TiO, retained at 10 to 25 days as a measure
" 3
of the "integrated alveolar clearance". Low concentrations of SO, (0.26 mg/m or 0.1 ppm)
3
accelerated clearance after 10 and 23 days, as did 2.62 mg/m (1 ppm) at 10 days but not after-
wards until 25 days when clearance was decreased. Hirsch et al. (1975) found that the trachea!
mucus flow was reduced in beagles exposed for 1 yr to 2.62 mg/m (1 ppm) S02 for 1.5 hr/day, 5
days/wk. No differences in pulmonary function were reported. Confirmation of this study and
determination of the persistence of the decreased mucus flow at this low level of S02 would be
important to confirm in light of other data available.
S02 may have more of an effect on anti-viral than on anti-bacterial defense mechanisms.
Bacterial clearance was not depressed or altered in guinea pigs exposed to 13.1 or 26.2 mg/m
(5 or 10 ppm) S02 for 6 hr/day for 20 days (Rylander, 1969; Rylander et al., 1970). Using the
infectivity model (see Section 12.3.4.3), Ehrlich (1978) found that short (3 hr/day for 1 to
15 days) or long (24 hr/day for 1 to 3 mo) exposures to 13.1 mg/m (5 ppm) S02 did not increase
mortality subsequent to a pulmonary streptococcal infection. Virus infections, however, are
augmented by simultaneous or subsequent SO, exposure. Mice were exposed to concentrations
o ^
varying from 0 to 52.4 mg/m (0 to 20 ppm) S02 continuously for 7 days (Fairchild et al.,
1972). Mice breathing 18.3 to 26.2 mg/m3 (7 to 10 ppm) S02 began to experience an increase in
XRD12A/A 12-21 2-5-81
-------
* 3
pneumonia. Lung consolidation. was significant at 65.5 mg/m (25 ppm). but not at 26.2 or 39.3
mg/m3 (10 or 15 ppm). The rate of growth of the virus within the lung was unaffected by S02
exposure. Further analysis of the data (Lebowitz and Fairchild, 1973) indicated that S02 and
virus exposure produced weight loss at concentrations as low as 9.43 mg/m (3.6 ppm). Exposure
to S02, whether alone or in combination with a viral agent, had more of an effect on weight
reduction than on pneumonia. Since Giddens and Fairchild (1972) showed that mice with apparent
respiratory infection were more susceptible to S02 (Section 12.2.3), a rebound effect may be
possible in which S02 and microbial agents each potentiate the effect of the other.
Several studies of the effects of S02 on alveolar macrophages have been conducted, since
these cells participate in clearance of viable and non-viable particles in the gaseous exchange
regions of the lung. Alveolar macrophages from rats exposed for 24 hr to 2.62, 13.1, 26.2,
and 52.4 mg/m3 (1, 5, 10, and 20 ppm) S02 were investigated by Katz and Laskin (1976). Expo-
sure to the 2 highest concentrations increased rn vitro phagocytosis of latex spheres for up
to 4 days in culture. At 13.1 mg/m (5 ppm) S02, phagocytosis was increased after 3 or 4 days
in culture, but not after 1 or 2 days. Histochemical studies of pulmonary macrophages from
rats exposed to 786 mg/m (300 ppm) S02 for 6 hr/day on 10 consecutive days showed no changes
in the lysosomal enzymes, p-glucuronidase, p-galactosidase, and N-acetyl-p-glucosaminidase
(Barry and Mawdesley-Thomas, 1970). Acid phosphatase activity was markedly increased. This
is in agreement with Rylander's observation (Rylander, 1969) which suggests that S0? exposure
3 '
(26.2 mg/m , 10 ppm, for 6 hr/day, 5 days/wk for 4 wk) does not affect the bactericidal
activity of the lung. (Table 12-4)
12.3 EFFECTS OF PARTICULATE MATTER
Sulfur dioxide is oxidized to sulfuric acid in the atmosphere. Sulfuric acid can react
with atmospheric ammonia to produce ammonium sulfate and bisulfate. Similar reactions can also
occur in the animal exposure chamber and confound the experiment. Ambient particulate matter
may be composed of sulfur compounds and definition of the effects of ambient aerosols indepen-
dent of sulfur compounds may be impossible. Sulfur dioxide is often present in polluted atmo-
spheres with complex mixtures of other compounds including heavy metals, which may be present
as oxides or as sulfate or nitrate salts. In addition, organic compounds present in the atmo-
sphere in the gaseous phase can be associated with the particulate fraction or become adsorbed
on particles either i_n situ or during collection. The diversity of these organic compounds
simply precludes any rational discussion of their toxicity at this time, since little or no
inhalation data is available. The details of the composition of atmospheric aerosols are dealt
with elsewhere (Chapter 5). The deposition and transport of particles are also discussed else-
where (Chapter 11).
Since very few studies have appeared on the toxicity of complex atmospheric particles
themselves, this section will deal primarily with the toxicity of the components of these
particles and the toxicology of those compounds which have been identified as constituents of
atmospheric particles. Therefore, these discussions, no matter how sophisticated for a single
component, are inherently simplistic. For aerosols other than H2SO., (NH ) SO., and NH.HSO,,
XRD12A/A 12-22 2-5-81
-------
SOX12C/A 4 1-30-81
TABLE 12-4. EFFECTS OF SULFUR DIOXIDE ON HOST DEFENSES
Concentration S02
Duration
Species
Results
Reference
0.26, 2.62, or 52.4 mg/m3
(0.1, 1, or 20 ppm)
2.62. 13.1, 26.2, and 52.4 mg/m3
(1, 5, 10, and 20 ppm)
2.62 mg/m3 (1 ppm)
£ 2.62 or 7.86 mg/m3 (1 or 3 ppm)
^ S02 + graphite dust (mean
«"• diameter 1.5 urn, 1 mg/m3)
9.43 to 52.4 mg/m3 (3.6 to 20
ppm)
13.1 or 26.2 mg/m3 (5 or 10 ppm)
13.1 mg/m3 (5 ppm)
Varying from 0 to 52.4 mg/m3
(0 to 20 ppm)
26.2 mg/m3 (10 ppm)
65.5 to 1868 mg/m3 (25 to 713
ppm)
786 mg/m3 (300 ppm)
7 hr/day, 5 day wk Rat
24 hr
7 days continuous
6 hr/day, 20 day
Rat
1.5 hr/day, 5 day/wk Dog
Up to 119 days Rat
Mouse
Low concentrations (0.26 mg/m3 or 0.1 ppm)
accelerated clearance of Ti02 aerosol after 10
and 23 days, as did 2.62 mg/m3 (1 ppm) at 10
days but not afterwards until 25 days when
clearance was decreased.
Exposure to the 2 higher concentrations increased
HI vitro phagocytosis of latex spheres for up to
4 days in culture. At 13.1 mg/m3 (5 ppm) phago-
cytosis was increased after 3 or 4 days in culture,
but not 1 or 2 days.
Trachea! mucous flow was reduced.
No changes in the cilia beat frequency or the
relative number of alveolar macrophages laden
with particles.
Exposure to S02 and a virus produced weight loss.
Guinea pig Bacterial clearance was not altered.
3 hr/day, 1-15 days Mouse
and 24 hr/day, 1-3 mo
7 days, continuous Mouse
6 hr/day for 20 days Rat
30 min Donkey
6 hr/day, 10 days Rat
continuous
Did not increase mortality subsequent to a pulmonary
streptococcal infection.
Increase in viral pneumonia at 18.3 to 26.2 mg/m3
(7 to 10 ppm). Rate of growth of virus unaffected.
Did not affect the bactericidal activity of the lung.
Below 786 mg/m3 (300 ppm) clearance was not affected,
but at high concentrations (786 to 1868 mg/m3 or 376
to 713 ppm) clearance was depressed.
No changes in selected lysosomal enzymes.
Ferin and Leach, 1973
Katz and Laskin, 1976
Hirsch et al., 1975
Fraser et al., 1968
Lebowitz and
Fair-child, 1973
Rylander, 1969, 1970
Ehrlich, 1979
Fairchild et al., 1972
Rylander, 1969
Spiegelman et al., 1968
Barry et al., 1970
-------
*
no attempt will be made to be as inclusive as separate documents would be for some of the
individual components. Rather, an attempt will be made to integrate this information in the
perspective of the potential biological effects of atmospheric particles.
As will be apparent from the discussion of the toxicity of sulfate aerosols in this sec-
tion, the chemical composition of the atmospheric particulates will determine the toxicity of
the aerosol. Atmospheric particles are likely to have direct toxic effects in themselves,
indirect toxic effects through interactions with other pollutants, and chronic effects through
cell transformation or chronic alteration in cell function. Direct toxic effects are best
substantiated by studies of cytotoxicity. Those reviewed here are for some specific compounds
which are known to occur in the particulate fraction. The studies cited are by no means com-
plete and could be expanded by including a number of other investigations carried out i_n vitro
or by exposures other than inhalation. The review was purposefully restricted to those most
applicable to the inhalation route of exposure. Major exceptions to this policy have been made
for silica and the limited data on compounds in the so-called "coarse-mode" particles fraction.
Most of the effects through interaction with other pollutants have previously been discussed
for S0?. Some additional data implicating interactions between SO- and particulate material,
between S0? and ozone, and between H?SO. and ozone are included here. One should recall that
a large fraction of the mass of atmospheric particles is composed of sulfate and nitrate com-
pounds.
Almost all of the studies (and all of the inhalation studies) discussed in this section
involve the health effects of particles in the "fine mode" size range and composition. Within
the category of fine mode particles, several investigators examined the influence of particle
size for a given chemical. For coarse mode particles, only a few i_n vitro and intratracheal
instillation studies could be found. This work is discussed separately-
12.3.1 Mortality
The susceptibility of laboratory animals to sulfuric acid aerosols varies considerably.
Amdur (1971) has reviewed the toxicity of sulfuric acid aerosols and pointed out that, of the
commonly used experimental animals, guinea pigs are the most sensitive and most similar to man
in their bronchoconstrictive response to sulfuric acid. The lethal concentration (LC) of
3 3
sulfuric acid depends upon the age of the animal (18 mg/m for 1 to 2 mo-old versus 50 mg/m
for 18 mo-old animals), the particle size (those near 2 urn being more toxic), and the tempera-
ture (extreme cold increasing toxicity). In a recent study (Wolff et al., 1979b), the LC50
(the concentration at which 50 percent of the animals die) in guinea pigs for an 0.8 pm (MMAD)
3 3
aerosol was 30 mg/m , whereas for a 0.4 pm (MMAD) aerosol, the LC50 was above 109 mg/m . In
determining acute toxicity, the concentration of the aerosol appears to be more important than
the length of exposure (Amdur et al., 1952). The animals that died did so within 4 hr.
Chronic studies have only recently been undertaken, and they support this conclusion that
mortality rarely occurs at moderate concentrations of sulfuric acid.
XRD12A/A 12-24 2-5-81
-------
*
Sulfun'c acid aerosol appears to have two actions. Laryngeal and/or bronchial spasm are
the predominant causes of death at high concentrations. When lower concentrations are used,
bronchostenosis and laryngeal spasm can still occur. Pathological lesions in the latter case
include capillary engorgement and hemorrhage. Such findings are in accord with anoxia as the
prime cause of death.
12.3.2 Morphological Alterations
Alarie et al. (1973a) investigated the effects of chronic H2SO. exposure. Guinea pigs
were exposed continuously for 52 wk to 0.1 mg/m3 H^SO. (2.78 urn, HMD) or to 0.08 mg/m3 H2$04
(0.84 urn, HMD). Monkeys were exposed continuously for 78 wk to 4.79 mg/m3 (0.73 urn, MMD),
2.43 mg/m3 (3.6 |jm, MMD), 0.48 mg/m3 (0.54 urn, MMD), or 0.38 mg/m3 H2$04, (1.15 urn, MMD).
Sulfuric acid had no significant hematological effects in either species. No light micro-
scopic lung alterations resulting from KLSO. exposure were observed in guinea pigs after 12 or
52 wk of exposure in this study (Alarie et al., 1973a) or in a later study (Alarie et al.,
1975). Morphological changes were evident in the lungs of monkeys. At the two highest con-
centrations, there were changes (more prevalent in the 4.79 mg/m H?SO, group) regardless of
the particle size. Major findings included bronchiolar epithelial hyperplasia and thickening
of the walls of the respiratory bronchioles. Alveolar walls were thickened in monkeys exposed
3 3
to 2.43 mg/m , but not to 4.79 mg/m , H9SO... However, particle size had an impact at lower
3
HpSO. concentrations. No significant alterations were seen after exposure to 0.48 mg/m of
the smaller particle size (0.54 urn). However, bronchiolar epithelial hyperplasia and thicken-
ing of the walls of the respiratory bronchioles were seen after exposure to the larger size
(1.15 urn) and lower concentration (0.38 mg/m ). These results are not those predicted from
strict considerations of particle deposition within the lung. The larger particles should
have been deposited mostly in the upper airways, with less deposition in the lower airways
(See Chapter 11). Pulmonary function changes followed a slightly different pattern (See
Section 12.3.4.2). In these studies, the cynomolgus monkey was much more sensitive than the
guinea pig. Dogs also appear to be relatively insensitive to H~SO. alone as judged by morpho-
logical changes. Lewis et al. (1973) found no morphological changes after the dogs had been
exposed for 21 hr/day for 620 days to 0.89 mg/m H-SO. aerosol (90 percent of the particles
were <0.5 urn in di"meter)
Recently, Co<: rell and Busey (1978) and Ketels et al. (1977) studied the morphological
changes resulting from sulfuric acid aerosols. Cockrell and Busey (1978) examined the effects
of 25 mg/m H?SO. (1 urn, MMD, o 1.6) for 6 hr/day for 2 days in guinea pigs. Segmented
alveolar hemorrhage, type 1 pneumocyte hyperplasia, and proliferation of pulmonary macrophages
were reported. Ketels et al. (1977) examined the response of mice to 100 mg/m sulfuric acid;
these exposures produced injury to the top and middle of the trachea, but none to the lower
trachea and distal airways. In an attempt to investigate the dose-response relationship for
sulfuric acid, mice received either 5 daily 3 hr exposures to 200 mg/m , 10 daily exposures to
100 mg/m , 20 daily exposures to 50 mg/m , or any one of these doses combined with 5 mg/m
carbon particles. The damage was judged to be proportional to the concentration (C) of H-SO^,
XRD12A/A 12-25 2-5-81
-------
*
but not to the integrated dosp (C x T) or to the time of exposure (T). (All of the exposures
had the same C x T and therefore their equivalence might have been hypothesized.)
A number of other studies of the morphological effects of H2$04 when combined with other
pollutants have been conducted. (See Section 12.4.1.2. and Table 12-5)
Inhalation of Si results in silicosis which is characterized by morphological changes of
the lungs. Because the extensive information on the health effects of Si has been reviewed
elsewhere (Ziskind et al., 1976; NIOSH, 1974; Reiser and Last, 1979; Singh, 1978), it will not
be discussed in detail in this document. Due to the toxicity of Si a Threshold Limit Value
(American Conference of Governmental Hygenists, 1979) has been set. Because of the involvement
of alveolar macrophages in its toxicity and its presence in ambient particles, however, some
of the effects of Si will be summarized briefly here. All the information given below for
silicon is derived from reviews by Ziskind et al. (1976) and NIOSH (1974).
Silicon is ubiquitous in the earth's crust. Silicon dioxide (Si02), which is responsible
for the disease silicosis, is found in 3 crystalline forms (quartz, cristobalite, and tridymite)
As a generalization, the ranking of toxicity is tridymite >cristobalite > quartz. These uncom-
bined forms of SiO,, are generally called "free silica." SiCL is also found combined with
cations, in which case the term silicates is applied. Very few animal toxicological studies
of silicates exist. Several hypotheses of the etiology of silicosis have been developed, but
no single one has been proven definitively. One widely accepted hypothesis was developed from
both animal and human studies. According to this theory, alveolar macrophages ingest the par-
ticles, die, and release their intracellular contents, including lysosomal enzymes and SiO?.
This is followed by a recycling of particle ingestion by macrophages and their death, slow
accumulation of other macrophage cells, increased collagen synthesis in response to macrophage
lysosomal enzymes, hyalinization, and perhaps complicating factors. Since the alveolar macro-
phage hypothesis does not explain completely the etiology and pathogenesis of the disease, it
is likely that additional factors contribute to the disease. These might include auto immunity,
co-existing tuberculosis or other infections, and/or alterations of lung lipid content and
metabolism.
Many animal toxicological studies of Si02 exist. Unfortunately, comparisons are diffi-
cult because of the species and strain of animal used, accidental infections, the size of SiCL
particle used, and the crystalline form of SiO? used.
Silicosis, similar to that observed in man, has been produced in animals exposed to high
concentrations of quartz and other Si02 dusts via intratracheal instillation (30-50 mg) or
chronic inhalation. Chronic exposures (2.5 yr) of dogs to earth containing 61 percent
cristobalite produced fibrotic nodules in hilar lymph nodes, but not the lungs.
Several studies of the hemolysis of red blood cell by particles have been reported. This
model may correlate with the ability of mineral dusts to cause lung fibrosis ui vivo and thus
is used for screening. Ottery and Gormley (1978) studied the influence of particle size of
quartz (Min-u-sil) and other materials on red cell hemolysis. The particle size of the quartz
XRD12A/A 12-26 2-5-81
-------
SOX12C/A 5 2-5-81
TABLE 12-5. EFFECTS OF PARTICIPATE MATTER ON LUNG MORPHOLOGY
Concentration
Duration
Species
Results
Reference
0.08 mg/m3 H,S04 (0.84 MID, MHO),
or 0.1 mg/m5 H2S04 (2.78 M".
HMD)
0.38 mg/m3 (1.15 urn, MMO).
0.48 mg/m3 (0.54 um, MMO),
2.43 mg/m3 (3.6 um, MMO), or
4.79 mg/m3 (0.73 um. MMO)
0.89 mg/m3 (90X <0.5 MID in
diameter) H2S04 aerosol
25 mg/m3 (1 um. MMD, o 1.6)
H2S04 aerosol 9
50 mg/m3 H2S04, or
100 mg/m3 H2S04, or
200 mg/m3 H2S04, or any of
of these doses combined with
5 mg/m3 carbon particles
(at all three duration schedules)
52 wk, continuous
78 wk, continuous
Guinea pig
Monkey
21 hr/day, 620 days Dog
6 hr/day, 2 days Guinea pig
3 hr/day, 20 days; or Mouse
3 hr/day, 10 days; or
3 hr/day, 5 days
No significant hematological effect. No microscopic
lung alterations after 12 or 52 weeks exposure.
No significant hematological effect. Morphological
changes in the lungs. At the two highest concentra-
tions there were changes, regardless of the particle
size. Major findings included bronchiolar epithelia
hyperplasia and thickening of the respiratory bron-
chioles. Alveolar walls were thickened with 2.43
mg/m3, but not 4.79 mg/m3. No alterations with
0.48 mg/m3 (0.54 urn), but with larger size (1.15 um,
0.38 mg/m3) hyperplasia and bronchiole thickening.
No morphological changes.
Segmented alveolar hemorrhage, type 1 pneumocyte
hyperplasia, and proliferation of pulmonary
macrophages.
Damage was proportional to the concentration.
Alarie et al.,
1973a, 1975
Alarie et al., 1973a
Lewis et al., 1973
Cockrell et al.,
1978
Ketels et al., 1977
-------
was from 2.7 to 6.8 urn (mean volume diameter, MVD). At lower concentrations (0.025 to about
0.15 mg/ml), there was a linear dose-response increase in hemolysis for quartz (1.35 and 3.55
urn, MVD), kaolin (4.7 urn, MVD), cristobalite (3.05 urn, MVD), and bentonite (5 urn MVD). In this
experiment, the effectiveness for increasing hemolysis was ranked as bentonite >kaolin > quartz
> cristobalite. Even though this test is typically used to predict fibrotic potential, it
should be noted that usually cristobalite is more fibrogenic than quartz. In another experi-
ment, kaolin and quartz were additive when mixed. Linear increases in hemolysis were also
observed with increasing numbers of particles. When the various sizes of Min-u-sil were
directly compared, as particle size decreased from 6.8 urn to 2.7 urn, a smaller concentration
was required to produce 5% hemolysis. For example, at the largest size tested, 2.7 mg/ml was
required, whereas at the smallest size tested, 0.21 mg/ml was needed.
12.3.3 Alterations in Pulmonary Function
12.3.3.1 Acute Exposure Effects—On short-term exposure, respiratory mechanics are very sensitiv
to inhaled H?SO. and some other compounds. Amdur (1971) has cautioned that her method for mea-
suring airway resistance (Amdur and Mead, 1955, 1958) should not be used as an indication of
chronic toxicity and should be considered only for very short-term toxicity. As pointed out
above, the Mead-Amdur method uses unanesthetized guinea pigs in which a transpleural catheter
has been implanted. Amdur suggests (1971) that, if anything, this procedure increases rather
than decreases the sensitivity of the guinea pigs to inhaled irritants.
Using this method, Amdur and co-workers (Amdur and Underhill, 1968, 1970; Amdur, 1954;
1958, 1959, 1961; Amdur and Corn, 1963; Amdur et al., 1978a,b,c,) have studied the effects of
aerosols alone (see Table 12-6) or in combination with S0?. The combination studies are
described in Section 12.4.1.1. In all of their studies, exposures were for 1 hr. The method
records resistance to air flow in and out of the lungs and airways, compliance (a measure of
lung distensibility), tidal volume (the volume of air moved during normal breathing), respira-
tory frequency, and minute volume. While increased flow resistance is often the most striking
feature of the response to aerosols, calculations of the elastic, resistive, and total work of
breathing can also be made. The method is, therefore, nearly as elaborate and inclusive an
evaluation of pulmonary mechanics as could be made in small laboratory animals until very
recently (Drazen, 1976).
The importance of particle size on the site of pulmonary deposition is described in
Chapter 11. The impact of these factors on the effects on human health is clear from an early
study (Amdur, 1958). Sulfuric acid aerosols of concentrations ranging from 1.9 to 43.6 mg/m
were generated in three particle sizes: 0.8 urn (a , 1.32 urn), 2.5 urn (a , 1.38 urn), or 7 urn
(a , 2.03 urn) MMD. Particles of the largest size (7 urn, at 30 mg/m ) produced a significant
increase in flow resistance but no other detectable changes in respiration. At the lowest
concentration tested, 1.9 mg/m , the 0.8 urn particles produced an increase in resistance to
flow and in elastic, resistive, and total work of breathing; but they produced a decrease in
compliance. The 2.5 urn particles also increased the resistance to flow at concentrations
from 2.3 to 43.6 mg/m . The relative efficacy of the 0.8 and 2.5 urn particles differed. At
XRD12A/A 12-28 2-5-81
-------
SOX12C/A 15 2-5-81
ro
vo
TABLE 12-6. RESPIRATORY RESPONSE OF GUINEA PIGS EXPOSED FOR 1 HR TO PARTICLES
IN THE AMDUR et al. STUDIES
Concentration
Compound mg/m3
H2S04 0.10
0.51
1.00
1.90
5.30
15.40
26.1
42.00
0.11
0.40
0.69
0.85
2.30
8.90
15.40
43.60
30.50
(NH4)9S04 0.50
* 2.14
1.02
9.54
NH4HS04 0.93
2.60
10.98
Particle
size, urn, HMD
0.3
0.3
0.3
0.8
0.8
0.8
0.8
0.8
1.0
1.0
1.0
1.0
2.5
2.5
2.5
2.5
7.0
0.13
0.20
0.30
0.81
0.13
0.52
0.77
Resistance
cm H20/ml/sec
% difference
from control
+41*
+60*
+78*
+51*
+54*
+69*
+89*
+120*
+14*
+30*
+47*
+60*
+39*
+61*
+96*
+317*
+42*
+23*
-4
+29*
0
+15*
+28*
+23*
Compliance
ml/cm H20
% difference
from control
-27*
-33*
-40*
-35*
-40*
-24*
-38*
-26*
-13
-8
-25*
-28*
-16
-26*
-43*
-76*
-17
-27*
-13*
-23*
-12*
-15*
-30*
-19*
Reference
Amdur et al . ,
Amdur, 1975
Amdur et al . ,
Amdur et al . ,
1978b;
1978b
1978b
Amdur, 1969; Amdur,
1958
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur et al . ,
Amdur et al . ,
Amdur et al . ,
Amdur et al . ,
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur, 1958
Amdur et al . ,
Amdur et al . ,
Amdur and Corn
Amdur et al . ,
Amdur, 1974
Amdur et al . ,
Amdur et al . ,
Amdur et al . ,
Amdur et al . ,
1978b
1978b
1978b
1978b
1978a
1978a
, 1963;
1978a;
1978a
1978a
1978a
1978a
-------
SOX12C/A 16 2-5-81
CO
O
NaV04
FeS04
TABLE 12-6. (continued).
Compound
Na2S04
ZnS04
ZnS04-
(NH4)2S04
CuS04
Concentration
mg/m3
0.90
0.91
0.25
0.50
1.10
1.80
1.50
2.48
1.40
1.10
3.60
0.43
2.05
2.41
Particle
size, M"I» MMD**
0.11
1.4
0.29
0.29
0.29
0.29
0.51
0.51
0.74
1.4
1.4
0.11
0.13
0.33
Resistance
cm H20/ml/sec
% difference
from control
+2
+41*
+22*
+40*
+81*
+129*
+43*
+68*
+29*
+6
+32*
+9
+25*
+14*
Compliance
ml/cm H20
% difference
from control Reference
-7 Amdur et al. , 1978a
Amdur and Corn, 1963;
Amdur, 1974
Amdur and Corn, 1963;
Amdur, 1975
Amdur and Corn, 1963
Amdur and Corn, 1963;
Amdur, 1974
Amdur, 1969; Amdur and
Corn, 1963
Amdur and Corn, 1963;
Amdur, 1975
Amdur and Corn, 1963
Amdur, 1969; Amdur and
Corn, 1963; Amdur,
1975
Amdur and Corn, 1963;
Amdur, 1975
Amdur and Corn, 1963
-11* Amdur et al. , 1978a
-15* Amdur et al. , 1978a
-11* Amdur et al. , 1978a
0.70
1.00
+2
Amdur and Underbill,
1968
Amdur and Underbill,
1968
-------
SOX12C/A 17 1-30-81
TABLE 12-6. (continued)
Compound
Fe203 (2hr)
(Fumes)
MnCl2
Mn02
HnS04
Open hearth
dust
Activated
carbon
Spectographic
carbon
Concentration
mg/m3
11.70
21.00
1.00
9.70
4.00
0.16
7.00
8.70
2.00
8.00
Resistance
cm H20/ml/sec
Particle % difference
size, urn, MHO from control
0.076 (GMD) -9
0.076 (GMD) 0
+4
-6
-1
0.037 (GMO) +9
0.037 (GMO) +6
-3
+7
+17
Compliance
ml /cm H20
% difference
from control Reference
5 Amdur and Underbill,
1968; 1970
0 Amdur and Underbill,
1968; 1970
Amdur and Underhill,
1968
Amdur and Underhill,
1968
Amdur, 1974
0 Amdur and Underhill,
1968; 1970
-16 Amdur and Underhill,
1968; 1970
Amdur and Underhi 1 1 ,
1968
Amdur and Underhi 1 1 ,
1968
Amdur and Underhi 1 1 ,
1968
*p < 0.05
**Diameters are provided as mass median diameter (MMO) unless specified as geometric median
diameter by count (GMD).
-------
concentrations of 2 mg/m3, the. 0.8 |jm particles were more effective than the 2.5 |jm particles.
The time course of the response also varied with the particle size, since the 2.5 urn particles
did not evoke their major effects until the last 15 to 20 min of the 1 hr exposure. These dif-
ferences in response were probably associated with the degree and site of obstruction within the
bronchi. The 2.5 urn particles affected the larger bronchi producing obstruction, whereas the
0.8 urn particles caused narrowing of the smaller bronchi. While the results of the experiments
are reported in a straightforward concentration-response curve, the physiological mechanisms
producing the measurable effects are obviously highly complex. Detailed understanding is lack-
ing.
In a more recent investigation, Amdur et al. (1978b) exposed guinea pigs for 1 hr to
3
either 0.3 or 1 urn (MMD) H?SO. in concentrations ranging from 0.1 to 1 mg/m . The concentra-
tion-response for percent change in resistance was linear for both particle sizes. However,
the smaller particle caused a greater response, particularly at 0.1 mg/m where a 26 percent
increase in airway resistance was observed. Except for exposure to 0.11 mg/m HpSO^ (1 urn),
all increases in resistance were statistically significant. The smaller particle size also
decreased compliance at all concentrations tested. However, for the 1 urn particle the lowest
effective concentration tested was 0.69 mg/m . For equivalent concentrations, the 0.3 urn par-
ticle decreased compliance more than the 1 urn particle. Animals were also examined 30 min
after exposure ceased. At this time, after exposure to 0.1 mg/m H-SO. (0.3 urn) resistance
was still elevated above control in guinea pigs; but for the 1 urn particle, recovery had
occurred. These exposures caused no alterations of tidal volume, respiratory frequency, or
minute volume. In comparing these results to earlier work with S0? (Amdur, 1966), Amdur et al.
(1978b) describe how the same amount of sulfur when given as H?SO. produces 6 to 8 times the
response observed than when given as S0?.
Silbaugh et al. (1980) exposed Hartley guinea pigs for 1 hr to 1 urn (MMAD) sulfuric acid
aerosols at concentrations and relative humidities of 0 mg/m (control group) (40 or 80 percent
RH), 1.2 mg/m3 (40 percent RH), 1.3 mg/m3 (80 percent RH), 14.6 mg/m3 (80 percent RH), 24.3
mg/m (80 percent RH), or 48.3 mg/m (80 percent RH). Ten animals were exposed at each concen-
tration except for the 24.3 and 48.3 mg/m groups, which consisted of 9 and 8 animals, respec-
tively. Measurements of tidal volume, breathing frequency, minute volume, peak inspiratory
and expiratory flow, tidal transpulmonary pressure excursions, total pulmonary resistance and
dynamic lung compliance were obtained every 15 min during (1) a 30 min baseline period, (2)
the 60 min exposure period, and (3) a 30 min recovery period. Pulmonary function changes in
sulfuric acid-exposed guinea pigs did not differ from controls, except for 1 animal exposed to
3 3 ^
14.6 mg/m , 3 animals exposed to 24.3 mg/m , and 4 animals exposed to 48.3 mg/m . Pulmonary
function changes in these 8 responsive animals included marked increases in total pulmonary
resistance and marked decreases in dynamic compliance. Four of these 8 guinea*pigs died during
exposure. The proportion of responsive to non-responsive animals increased with exposure
concentration, but the magnitude of pulmonary function change was similar for all responsive
animals. Compared to non-responders, responsive animals tended to have higher pre-exposure
XRD12A/A 12-32 2-5-81
-------
values of total pulmonary resistance and lower pre-exposure values of dynamic compliance.
Authors suggested that guinea pigs react to acute sulfuric acid exposure with an essentially
all-or-none airway constrictive response. The finding that resistance and compliance changes
are important components of the guinea pig's airway response to sulfuric acid aerosols is con-
sistent with results published by Amdur et al. (1978b). The presence of high pre-exposure
pulmonary resistance values in responsive animals is similar to the finding by Amdur (1964)
that guinea pigs with high pre-exposure resistance values were those most severely affected
during irritant aerosol exposure. However, the lack of effects at lower concentrations and
the essentially all-or-none airway constrictive response observed in these studies differs
markedly from the graded response observed by Amdur et al. (1958, 1978b) during similar
exposures. The bifurcating and declining airway diameter of the lung make all-or-none
responses as measured by changes in airflow unlikely. The graded response observed by Amdur
et al. (1958, 1978b) seems more reasonable. The reasons for the differences in experimental
results are unclear, but may be at least partially related to differences in animal strains
and techniques. These results indicate that changes in respiratory function do not occur at
environmental concentrations of sulfuric acid in most animals, but suggest that susceptible
subpopulations might exist. (See discussion above about susceptible individuals.)
Sackner et al. (1978) evaluated pulmonary function in anesthetized dogs immediately after
3 3
or 2 hr after exposure to approximately 18 mg/m H?SO. for 7.5 min or to 4 mg/m H,,S04 for 4
hr. The MMAD was < 0.2 urn. There were no significant changes in respiratory resistance,
specific respiratory conductance, specific lung compliance, or functional residual capacity.
At the higher concentration, cardiovascular parameters (e.g., blood pressure, cardiac output,
heart rate, and stroke volume) and arterial blood gas tensions were also studied, but no sig-
nificant changes were observed. The pulmonary function (pulmonary resistance and dynamic com-
pliance) of donkeys was not affected by HUSO, exposure (1.51 mg/m , 0.3 to 0.6 MMAD, 1 hr)
(Schlesinger et al., 1979).
Studies of the irritant potential of sulfate salts have shown that these aerosols are not
innocuous but evoke increased flow resistance similar to sulfuric acid aerosols. The influ-
ence of particle size on the effects of zinc ammonium sulfate has also been investigated by
Amdur and Corn (1963). They showed, in guinea pigs exposed for 1 hr, that zinc sulfate had
about half the potency of zinc ammonium sulfate, with ammonium sulfate being one-third to one-
fourth as potent as zinc ammonium sulfate. Zinc ammonium sulfate was chosen for study because
it had been reported as a major component of the aerosol from the Donora, PA episode of 1948
(Hemeon, 1955). Zinc ammonium sulfate is not a common species found in urban air. Four sizes
of aerosols were administered: 0.29, 0.51, 0.74, and 1.4 |jm (particle mean size by weight).
When the aerosol concentration was held constant at 1 mg/m , the smaller particles produced
greater increased resistance to flow. This response was thought to be the result of the
number of particles rather than of differential sites of deposition. The dose-response curve
also became steeper with decreasing particle size. These data should be carefully compared
with those from similar human exposures (Chapter 13, pp. 26-29) where no response occurred.
XRD12A/A 12-33 2-5-81
-------
Amdur et al. (1978a) recently compared the effects of (NH4)2S04, NH4HS04> CuS04, and
Na2S04. Although particle sizes and concentrations were not precisely matched throughout the
study, statistical analyses for ranking were not applied, and the degree of response increased
with decreased size (size range, 0.1 to 0.8 urn, MMD), the authors suggest that the order of
irritant potency was (NH4)2$04 > NH4HS04 > CuS04- Sodium sulfate (0.11 mg/m , 0.11 MMD)
caused no significant effects on either resistance or compliance. At the lowest concentrations
used, (NH4)2S04 (0.5 mg/m3, 0.13 urn MMD), NH4HS04 (9.93 mg/m3, 0.13 urn MMD), and CuS04 (0.43
mg/m3, 0.11 |jm MMD) decreased compliance. These concentrations of (NH4)2$04 and NH4HS04 also
increased resistance. For CuSOA, the lowest concentration tested which caused an increase in
o ^
resistance was 2.05 mg/m (0.13 urn MMD). All of these compounds are less potent than H2$04 in
the Amdur studies.
Comparisons between sulfuric acid and sulfate salt aerosols are difficult to make because
of the marked dependence of the efficacy on the aerosol size. If the particles are of
identical size, sulfuric acid is more efficacious than zinc ammonium sulfate; but if the zinc
ammonium sulfate were present as a submicron aerosol and the sulfuric acid as a large aerosol,
then zinc ammonium sulfate would be more efficacious at the same concentration (Amdur, 1971).
Regardless of the particle size, the equivalent amount of sulfur present as S02 is much less
efficacious than if it were present as a sulfate salt or sulfuric acid. When present as S02,
•3 O
2.62 mg/m (1 ppm) S02 is equivalent to 1.3 mg/m S and produces a 15 percent increase in flow
resistance. If this amount of sulfur were present as a 0.7 urn aerosol of sulfuric acid, it
would evoke a 60 percent increase in flow resistance or be about 4 times more efficacious. If
the sulfur were present as zinc ammonium sulfate as a 0.3 urn aerosol, the increase in flow
resistance would be about 300 percent or a 20-fold increase in efficacy. Some sulfate salt
aerosols are not irritating. For example, though ferrous sulfate and manganous sulfate do not
cause an increase in flow resistance, ferric sulfate does cause this response. A summary of
irritant potency is presented below.
Relative Irritant Potency of Sulfates In Guinea Pigs
Exposed for One Hour3 (Amdur et al., 1978a)
Sulfuric acid 100
Zinc ammonium sulfate 33
Ferric sulfate 26
Zinc sulfate 19
Ammonium sulfate 10
Ammonium bisulfate 3
Cupric sulfate 2
Ferrous sulfate 0.7
Sodium sulfate (at 0.1 urn) 0.7
Manganous sulfate -0.9
aData are for 0.3 pm (MMD) particles. Increases in airway resistance were
related to sulfuric acid (0.41% increase in resistance per ug of sulfate
as sulfuric acid) which was assigned a value of 100.
XRD12A/A 12-34 2-5-81
-------
*
Nadel et al. (1967) faund that zinc ammonium sulfate (no concentration given) and
histamine aerosols produced similar increases in resistance to flow and decreases in pulmonary
compliance in the cat. Histamine was more potent than zinc ammonium sulfate. The increase in
flow resistance could not be blocked by intravenous administration of atropine sulfate, but
was blocked by either intravenous or inhaled isoproterenol. The increased flow resistance was
suggested to be due to an increase in bronchial smooth muscle tone. Histamine appears to be a
likely mediator of the bronchoconstriction following inhalation of sulfate salt aerosols.
Charles and Menzel (1975a) investigated the release of histamine from guinea pig lung fragments
incubated with varying concentrations of sulfate salts. Almost complete release of tissue
histamine occurred with 100 mM ammonium sulfate. Intratracheal injection of ammonium sulfate
also released all of the histamine from perfused and ventilated rat lungs (Charles et al.,
1977a). The potency ranking of different sulfate salts in the release of histamine from lung
fragments (Charles and Menzel, 1975a; Charles et al., 1977a) was equivalent to that causing
increased resistance to flow (Amdur et al., 1978a). Bronchoconstriction of the perfused lung
occurred on intratracheal injection of sulfate salts or histamine (Charles et al., 1977a).
About 80 percent of the constriction could be blocked by prior treatment of the isolated lungs
with an H-l antihistamine. These experiments, as well as the original observations of Nadel et
al. (1967) and Amdur et al. (1978a), support the concept that an intermediary release of hista-
mine or some other vasoactive hormone is involved in the irritant response of sulfate aerosols.
An ammonium sulfate particle is calculated to reach a concentration of about 275 mM at equilib-
ration with the 99.5 percent relative humidity of the respiratory tract (Committee on Sulfur
Oxides, MAS, 1978). Thus, the concentration of the hydrated particle on striking the mucosa
would be within the range found to cause release of histamine in guinea pig and rat lung frag-
ments (Charles and Menzel, 1975a; Charles et al., 1977a). A recently published estimate of the
dose of inhaled ammonium sulfate needed to release histamine in the lung is in error
(Committee on Sulfur Oxides, MAS, 1978). Complete release of histamine (100 percent) occurred
with 1 umole of ammonium sulfate/lung and not 1 uM solution for the entire lung (Charles et
al., 1977a). Further, total release of all histamine stores of a tissue rarely, if ever,
occurs under physiological conditions. Only about 10 percent of the total histamine is
released during degranulation reactions i_n vivo, producing anaphylactic shock and death.
Therefore, even if the calculations were correct, only a small fraction of the ammonium
sulfate dose would be required to produce the far less violent increases in flow resistance
reported by Amdur et al. (1978a) for ammonium bisulfate and ammonium sulfate. Assuming the
calculation of ammonium sulfate to be correct, a 4 hr, not a 2 day, inhalation would produce a
marked increase in resistance to flow. Additionally, Charles et al. (1977b) found the rate of
35 -2
removal of SO. from the rat lung both in vivo and in vitro to be a function of the cation
4
associated with the salt and to follow the same order of potency as reported by Amdur and
co-workers (1978a) in the guinea pig irritancy test. Especially noteworthy is the fact that
manganous sulfate was removed at essentially the same rate as sodium sulfate, both of which
did not produce increased resistance to flow in the guinea pig.
XRD12A/A 12-35 2-5-81
-------
Hackney (1978) has presented a preliminary summary of the effects of aerosols of H2$04
and nitrate and sulfate salts on squirrel monkeys (Saimiri sciurens). Monkeys were exposed
(head-only) to aerosols at 2.5 mg/m3 of the respective salts or sulfuric acid, 40 or 85 per-
cent RH at 25°C. The exposure system was designed to reduce stress on the unanesthetized
monkey. A non-invasive method of pulmonary function measurement was used in which total res-
piratory resistance was measured by the forced pressure oscillation technique at sine wave
frequencies of either 10 or 20 Hz. The measurement of pulmonary resistance included the
resistance of the chest wall which was assumed to be irrelevant to pollutant response and to
be constant throughout the experiments. To correct for stress, control values were taken as
those for a given monkey exposed on the previous day to an aerosol of distilled water (for
aerosol experiments).
Hackney (1978) reports that the measurement of respiratory resistance was frequency-
dependent, with changes in resistance appearing greater in the 10 Hz than the 20 Hz measurement
frequency. (The measurement frequency is net to be confused with the breathing frequency.)
The exposure period in the experiments was either 1 or 2 hr. Some aerosols were studied at
only 40 percent RH. No attempt was made at a dose-response curve for aerosols and all expo-
o
sures were at or near 2.5 mg/m . At low relative humidity (40 percent RH; MMAD 0.3 urn, °a 2.0),
there were no differences between (NH.^SO.-exposed and control values, while at high relative
humidity (85 percent RH, MMAD 0.6 urn, o 2.3), 3 of 5 monkeys had increased airway resistance
by 1 hr. Zinc ammonium sulfate aerosols produced increased resistance at low humidity (40 per-
cent RH; MMAD 0.3 urn, o 2.5) but no consistent increases over control values at high humidity
(85 percent RH; MMAD 0.6 urn, a 1.6). Ammonium bisulfate (40 percent RH; MMAD 0.4 urn, o 1.8)
9 o 9
also produced increased resistance at 2.7 mg/m .
Data (Hackney, 1978) from exposures to sulfuric acid and NH.NO., aerosols were analyzed by
computer and differed quantitatively from the data reported above for those exposures which
were reduced by hand. Differences were probably due to a systematic error in the hand reduced
data which required a judgement in selection of raw data points. The biological interpreta-
tion does not appear to be altered by these two approaches, but it does point out the experi-
mental difficulties in interpretation of pulmonary function data from experimental animals.
While H2S04 aerosols (40 percent RH; MMAD 0.4 urn, o 2.0) caused no statistically significant
increases, there was a trend toward increased resistance after 60 min which then tended to
decline. Ammonium nitrate exposures produced no changes.
Multiple contrast analysis of the above data (Hackney, 1978) showed that no significant
differences between baseline or control values could be found for any exposure using data
collected at the 20 Hz measurement frequency. At the 10 Hz measurement frequency, the data
were more variable, but significant differences indicative of increased airway resistance could
be found for animals exposed to 2nS04, (NH4)2$04 and H2$04 at 40 percent relative humidity.
Several procedural aspects should be recognized. First, data were analyzed on a group mean
basis, even though large differences between individual monkeys existed in both variability
XRD12A/A 12-36
2-5-81
-------
*
and absolute magnitude. Second, the time course of exposure to the aerosols illustrated a
trend indicative of a transient response on the part of monkeys to sulfate, nitrate, or
sulfuric acid aerosols. The use of group means tended to reduce the magnitude of the response
and flatten the response-time curve. This is certainly true for the S02 exposures. Third,
there were major differences in the response measured at either 10 or 20 Hz. Fourth, the
response estimated by both manual and computer reduction differed by as much as 40 percent.
However, compared to the data reported for guinea pigs, these experiments support the general
trends originally proposed from the guinea pig data.
Sackner and co-workers (1976, 1977a,b,c, 1978b) have noted that neither ammonium
sulfate or sulfuric acid aerosols alters cardiovascular and pulmonary function in dogs or
tracheal mucus velocity in sheep. Some of these reports are at variance with the previously
cited published experiments. No significant alterations in pulmonary resistance and dynamic
compliance were observed in donkeys exposed to 0.4 to 2.1 mg/m (NH.)2S04 (0.3 to 0.6 urn MMAD)
for 1 hr (Schlesinger et al., 1978). The small size of the particles may be responsible for
the lack of an effect. Larger particles in other studies may be more potent.
Larson and co-workers (1977) have proposed that breath ammonia is important in neutrali-
zing inhaled sulfuric acid. Ammonia is released in the breath from blood ammonia and
bacterial decay products in the buccal cavity. Ammonia in the breath could react with
sulfuric acid to produce ammonium bisulfate or ammonium sulfate, depending upon the amount of
ammonia and sulfuric acid present in the aerosol droplet. Complete neutralization of sulfuric
acid would produce ammonium sulfate. This theory has been discussed at some length (Committee
on Sulfur Oxides, NAS, 1978). Much of the data has not yet been published, so a critical
review of the model given for the neutralization of sulfuric acid aerosol droplets by gaseous
ammonia is not available. Calculation of the relationship between inhaled sulfuric acid aerosol
and neutralization by breath ammonia is not simple, and the model needs to be validated.
The biological effects of sulfuric acid aerosols could be due to a combination of several
factors. First, the pH of the particle could be very important. Larson et al. (1977) have
calculated the neutralization capacity of the breath ammonia. Once the neutralization capa-
city of the ammonia present in the breath is exceeded, the pH of the aerosol reaching the lung
may fall rapidly. Under low pH, the physical properties of the mucous layer lining the upper
airways may be altered (Holma et al., 1977) or the permeability of the lung may be increased
(Charles, 1976). Second, the chemical composition of the sulfate aerosol, if other than
sulfuric acid, may also alter the permeability of the lung to sulfate (Charles et al., 1977b;
Charles, 1976; Charles and Menzel, 1975b). Third, the cation associated with the sulfate
compound may have pharmacological properties in itself. The permeability of the lung to
sulfate ion presented as various sulfate salts (Charles et al., 1977b) is in the same relative
order as the irritant potential found for aerosols of the same sulfate salts (Amdur et al.,
1978a).
XRD12A/A 12-37 2-5-81
-------
It is likely that ammonia functions within pulmonary tissue as a source of protons to
increase the flux of sulfate to the site of action. Ammonia can diffuse readily across cell
membranes as unionized ammonia to react with protons forming ammonium ion. Intracellular
transport of negatively charged sulfate would result in the concomitant accumulation of
positively charged protons to preserve electrochemical neutrality. At physiological pH
values, a significant fraction of ammonium salts is present as ammonia. Ammonium salts could
augment the local ammonia concentration and thus increase the uptake of sulfate ions and result
in release of histamine. Ammonia increased the uptake of sulfate by the lung (Charles et al.,
1977a; Charles, 1976), possibly by this mechanism.
In relation to sulfuric acid, ammonium sulfate and bisulfate are less irritating to the
lung because of their higher pH values once dissolved in the milieu of the lung. Thus,
neutralization of sulfuric acid aerosols by breath ammonia could be an important detoxifica-
tion step. The concept of breath ammonia does not negate the histamine release hypothesis
since ammonium sulfate is active in the release of histamine in guinea pig lung fragments
(Charles, 1976) and in rat lungs (Charles and Menzel, 1975b).
An important problem is the relation of these observations to human effects. Unfortunate-
ly, histamine release by non-immune mediate reactions, such as the apparent ion exchange
process due to sulfate interaction with mast cell granules (Charles, 1976), is poorly under-
stood. Metabolism of histamine by man and rodents could have important differences. Also,
not all of the pharmacological action of ammonium sulfate instilled intratracheally in the
perfused rat lung could be blocked by an H-l antihistamine (Charles et al., 1977a). A number
of other inflammatory hormones, aside from histamine, mediate bronchial tone in man. Slow
reacting substance of anaphylaxis (SRS-A or leukotrienes), prostaglandins, and kinins would
not be blocked by an H-l antihistamine. Thus, species differences are not unanticipated, but
should be clarified so the potential applicability of these data to man is understood.
The biological effect of sulfate compounds is highly dependent upon the chemical composi-
tion of the compound. For example, for pulmonary function sulfuric acid is much more potent
than any sulfate salt, but the sulfate salts also are of differing potency. The cations
associated with the sulfate ion may promote the transport of the sulfate ion and, thereby,
increase the biological response. The cation has biological effects by itself as discussed
here. It is not possible, then, to predict the potential toxicity of a sulfate aerosol based
solely on the sulfate content. Clearly, the acidity of the aerosol plays an important role in
the toxicity as do particle size and other physical properties.
An important experimental problem is raised by the ammonia neutralization of sulfuric
acid. Ammonia is produced in all animal experimental exposure systems through the accumulation
of urine and feces. This is particularly so in whole-body chronic exposures. Few exposure
systems provide a rapid turnover of the chamber air, e.g., 1 chamber volume/min, and given the
technological problems in monitoring NH3, even this rate of air flow may be insufficient. The
XRD12A/A 12-38 2-5-81
-------
usual turnover rate is 10 to 15 chamber volumes of air/hr or less. Under these conditions,
animals exposed to sulfuric acid aerosols may, in fact, be inhaling ammonium sulfate and
ammonium bisulfate aerosols as well. The high concentrations of sulfuric acid aerosols needed
to produce significant pathological effects on chronic exposure may be due to these chemical
conversions. Since human exposure chambers would not be expected to have comparably high
levels of ammonia, there could be difficulty in comparing results of human and animal studies
of H2$04- The level of ammonia in the breath of animals is also unknown and is sure to vary
with the diet of the animals. Some commercial animal diets are low in protein, while others
are high. The blood ammonia will depend, in part, on the total amount of protein and quality
of the protein as well as on the kidney function of the animal. What effects, if any, the
buccal flora have on the exhalation of ammonia in animals is totally unknown. Certainly, the
propensity of S02~ and sulfuric acid-exposed animals to develop nasal infections raises
disturbing questions. The buccal flora of animals may be very different from that of man in
its ability to produce ammonia. This technical problem of ammonia in the exposure atmosphere
should be addressed and solved before further reliance can be placed on these data for
sulfuric acid (Table 12-7).
12.3.3.2 Chronic Exposure Effects—The influence of chronic exposure to HpSO. on pulmonary
function was investigated by Alarie et al. (1973a, 1975). Guinea pigs exposed continuously to
either 0.9 mg/m3 (0.49 urn, MMD) (Alarie et al., 1975), 0.1 mg/m3 (2.78 urn, MMD) (Alarie et al.,
1973a), or 0.08 mg/m3 (0.84 urn, MMD) (Alarie et al., 1973a) for 52 wk had no significant
changes of pulmonary mechanics (including measurements of flow resistance, respiratory
rate, lung volumes, and work of breathing) that could be attributed to H-SO.. However,
cynomolgus monkeys exposed continuously and tested periodically during 78 wk were affected by
some treatment regimens (Alarie et al., 1973a). Monkeys exposed to 0.48 mg/m (0.54 urn, MMD)
experienced an altered distribution of ventilation (increased N? washout) early in the
exposure period, but recovery occurred during exposure. Animals exposed to a similar con-
centration (0.38 mg/m ) but a larger particle size (2.15 urn, MMD) had no change in this
parameter. Higher concentrations altered distribution of ventilation, with the lesser
concentration (2.43 mg/m ) and larger particle size (3.6 urn, MMD) causing an onset sooner (at
17 wk compared to 49 wk) in monkeys exposed to 4.79 mg/m H9SO. (0.73 urn, MMD). Beginning at
3 3
approximatey 8 to 12 wk of exposure, 0.38 mg/m (2.15 urn, MMD), 2.43 mg/m (3.6 urn, MMD) and
4.79 mg/m3 (0.73 pm, MMD) H2S04 increased respiratory rate. The only alteration in arterial
partial pressure of 0? was a decrease observed in monkeys exposed to 2.43 mg/m . Except for
respiratory rate as described above, mechanical properties (including resistance, compliance,
tidal volume, minute volume, and work of breathing) were not significantly altered by the
chronic H?S04 exposures. Morphological studies of these animals are described in Section
12.3.2.
Chronic studies of dogs were performed by Lewis et al. (1969, 1973). The animals were
exposed for 21 hr/day for 225 or 620 days to 0.89 mg/m H2S04 (90 percent < 0.5 um in
XRD12A/A 12-39 2-5-81
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SOX12C/A 6 1-30-81
TABLE 12-7. EFFECTS OF ACUTE EXPOSURE TO PARTICULATE MATTER ON PULMONARY FUNCTION*
Concentration
Duration
Species
Results
Reference
0 mg/ro3 (40 or 80% RH) 1.2 mg/ms 1 hr
(40% RH), 1.3 mg/ma (80% RH),
14.6 mg/m3 (80% RH). 24.3 mg/ms
(80% RH), and 48.3 mg/m3 (80% RH)
1 pm (MMAO) H2S04 aerosol
0.8 - 1.51 mg/m3 H2S04 1 hr
(0.3 - 0.6 M">, MMAD) or
0.4 - 2.1 mg/m3 (NH4)2S04
(0.3 - 0.6 M">, MMAO)
2.5 mg/m3 (NH4)2S04. 1 hr
ZnS04,(NH4)2S04, H2S04,
and NH4N03; 2.7 mg/m3
NH4HS04
Guinea pig Pulmonary function changes observed in one animal
(out of 10) exposed to 14.6 mg/m3, three animals
(out of 9) exposed to 24.3 mg/m3, and four animals
(out of 8) exposed to 48.3 mg/m3
Donkey No significant alterations in pulmonary resistance
and dynamic compliance
Monkey Increased airway resistance at high relative humidity
for (NH4)2S04, and low relative humidity for
ZnS04 (NH4)2S04. NH4HS04 also increased resistance.
No significant effects with H2S04 or NH4N03
Silbaugh et al., 1980
Schlesinger et al.,
1978
Hackney, 1978
K3
O
•See Table 12-6 for the Amdur et al. studies on pulmonary function effects in guinea pigs.
-------
*
diameter) alone and in combination with S02 (see Section 12.4.1.2 for expanded discussion).
After 225 days (Lewis et al., 1969), dogs receiving H2$04 had a significantly lower diffusing
capacity for CO than animals that did not receive H2$04. After 620 days of exposure, CO dif-
fusing capacity was still decreased (p < 0.05) (Lewis et al., 1973). In addition, residual
volume and net lung volume (inflated) were decreased (p < 0.05), and total expiratory re-
sistance was increased (p < 0.05). Total lung capacity, inspiratory capacity, and functional
residual capacity were also decreased (p = 0.1). Other pulmonary function measurements were
not significantly affected (see Table 12-8).
12.3.4 Alteration in Host Defenses
To protect itself against inhaled microorganisms and inanimate particles, the host has
several mechanisms of defense. Microbes reaching the gaseous exchange regions of the lung can
be phagocytized and killed by alveolar macrophages. Later these macrophages can move to the
ciliated airways where they are cleared from the lung, along with other particles that are
deposited on the airways, by the mucociliary escalator. Inanimate particles can also be en-
gulfed and removed from the lung by this means (See Chapter 11). Mucociliary clearance is an
important defense against both microorganisms and inanimate particles. It is likely then that
an impairment of mucociliary clearance might not be expressed as increased infections. These
and other means of defense against microbes are discussed here.
12.3.4.1 Mucociliary C1earance--Fairchi1d et al. (1975b) investigated the influence of a 1 hr
exposure to H^SO. on deposition of inhaled nonviable bacteria (Streptococcus pyogenes, 2.6 urn
MMAD) in guinea pigs. All exposure regimens used caused no significant alterations of breath-
ing frequency, tidal volume, or minute ventilation. After exposure to 3.02 mg/m (1.8 urn CMD),
a 60 percent increase (p < 0.01) in total pulmonary bacterial deposition and a proximal shift
in the deposition pattern to the nasopharynx were observed. No alteration in deposition was
observed in the trachea or lung. After exposure to 0.32 mg/m (0.6 urn CMD), no significant
effect on total or regional deposition was seen. However, at a lower concentration and parti-
cle size (0.03 mg/m3, 0.25 urn CMD), the deposition pattern did shift (p < .05) to the trachea
but without a significant change in total pulmonary deposition.
After studying effects of HpSO. on deposition of bacteria, these investigators (Fairchild
et al., 1975a) turned their attention to effects on clearance of bacteria. They showed that 4
hr exposures to 15 mg/m3 H2S04 (3.2 urn, CMD) after exposure to a nonviable radiolabeled strep-
tococcal aerosol reduced the rate of ciliary clearance of the bacteria from the lungs and
noses of mice. When mice received a 90 min exposure to 15 mg/m H2$04 (3.2 urn, CMD) 4 days
prior to the bacterial aerosol, clearance of nonviable bacteria was reduced in the nose but
not in the lungs. Neither regimen affected clearance of viable streptococci. No significant
O
effects were seen at concentrations of 1.5 mg/m H2$04 (0.6 urn, CMD).
Schlesinger et al. (1978) demonstrated that 1 hr exposures to 0.3 to 0.6 |jm H2S04 mist at
concentrations in the range of 0.19 to 1.36 mg/m produced transient slowing of bronchial
mucociliary particle clearance in 3 of 4 donkeys tested. In addition, 2 of the 4 donkeys
XRD12B/A 12-41 2-5-81
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SOX12C/A 7 1-30-81
ro
ro
TABLE 12-8. EFFECTS OF CHRONIC EXPOSURE TO PARTICULATE MATTER ON PULMONARY FUNCTION
Concentration
Duration Species Results Reference
0.08 mg/m3 HoS04 (0.84 pm, MMD) 52 wk, continuous Guinea pig No effects on pulmonary function. Alarie et al., 1975,
or 0.1 mg/ms H2S04 (2.78 u». MHO) 1973
0.38 mg/m3 (1.15 urn, MHO)
78 wk, continuous Monkey Exposure to 0.48 mg/m3 altered distribution of Alarie et al., 1973
.. .. mg/m3 (0.54 urn, HMO)
2.43 mg/m3 (3.6 pm. MMD)
4.79 mg/m3 (0.73 jim. MMD)
HaS04
0.89 mg/m3 HZS04 (90X
-------
developed persistently slowed, clearance after about 6 exposures. Similar exposures had no
effects on regional particle deposition or respiratory mechanics, and corresponding exposures
to (NH4)2S04 up to 2 mg/m had no measurable effects. In subsequent experiments (Schlesinger
et al., 1979), the 2 animals showing only transient responses and 2 previously unexposed
animals were given daily 1 hr exposures, 5 days/wk, to H2$04 at 0.1 mg/m3. Within the first
few wk of exposure, all 4 donkeys developed erratic clearance rates, i.e., rates which, on
specific test days, were either significantly slower than or significantly faster than those
in their pre-exposure period. However, the degree and the direction of change in rate
differed to some extent in the different animals. These changes may herald subsequent
alterations and, like many other toxicant effects, may represent important low level signals
at the detection limit of the method. The 2 previously unexposed animals developed
persistently slowed bronchial clearance during the second 3 mo of exposure and during 4 mo of
follow-up clearance measurements, while the 2 previously exposed animals adapted to the
exposures in the sense that their clearance times consistently fell within the normal range
after the first few wk of exposure. The sustained, progressive slowing of clearance observed
in 2 initially healthy and previously unexposed animals is a significant observation, since
any persistent alteration of normal mucociliary clearance can have important implications.
Lippmann et al. (1980) have conducted similar experiments in human subjects which are reviewed
in Chapter 13.
Tracheal mucociliary transport rates have been measured in several other animal studies.
Sackner et al. (1978a) failed to find significant changes in tracheal mucus velocity following
short-term exposures to 14 mg/m (0.12 urn) H-SO. in sheep. Similarly, Schlesinger et al.
(1978) saw no effect on tracheal transport in donkeys after 1-hr exposures to concentrations
up to 1.4 mg/m3 (0.3 to 0.6 ^m MMAD) H9SO.. On the other hand, Wolff et al. (1979a) reported
3
a depression in tracheal transport rate in anesthesized dogs exposed for 1 hr to 1.0 mg/m
(0.9 urn, MMAD, a 1.4) which persisted at 1 wk postexposure. Recovery had occurred when the
9 3
animals were examined again at 5 wk post exposure. Following a 1 hr exposure to 0.5 mg/m
H-SO., there were slight increases (p >0.05) in tracheal mucous velocities immediately and 1
day after exposure. However, 1 wk after exposure, clearance was significantly decreased. The
latter results are quite similar to those observed in the bronchi of individual humans in the
Lippmann et al. (1980) study (see Chapter 13), although they recorded no significant change in
the mean tracheal mucociliary transport rates.
Clearly, the results of the donkey studies support the human experiments (Chapter 13)
which indicate that H2S04 aerosol affects mucociliary clearance in the distal conductive
airways. Mucociliary clearance is dependent upon both the physicochemical properties of the
mucus and the coordinated beat of the underlying cilia. Mucus is excreted into the airway
lumen in an alkaline form which is then acidified by C02 (Holma et al., 1977). In vitro
studies have shown that mucus is a sol in high pH solutions, while at lower pH it becomes
viscous (Breuninger, 1964). The H+ supplied by the H2S04 may stiffen the mucus and increase
XRD12B/A 12-43 2-5-81
-------
the efficiency of removal. This is consistent with the increase in bronchial clearance rate
observed in humans following exposure to 0.1 mg/m3. Major changes in mucous viscosity could
also impair clearance by making the mucus so stiff that ciliary movement is not possible.
Other studies (Grose et al., 1980; Schiff et al., 1979) have shown that exposures to 0.9 to
1.1 mg/m3 H2$04 can cause a depression of tracheal ciliary beat frequency in hamsters which
may lead to a depression in overall bronchial clearance. See Sections 12.4.1.1 and 12.4.2 for
more details on these latter studies (Grose et al., 1980; Schiff et al., 1979) which were con-
ducted with pollutant mixtures.
Based on the results summarized above, it is possible that chronic H^SO^ exposures at
concentrations of about 0.1 mg/m could produce persistent changes in mucociliary clearance
and exacerbate preexisting respiratory disease (see Table 12-9).
Cadmium and nickel chlorides also disrupt the activity of the ciliated epithelium (Adalis
et al., 1977, 1978). Tracheal rings have been isolated from hamsters and the beat frequency
and morphology of the ciliated epithelium have been observed. Concentrations of CdCl« as low
as 6 uM i_n vitro resulted in decreased beat frequency and degradation of the ciliated
epithelium architecture (Adalis et al., 1977). A prior 2-hr exposure i_n vivo to 2 urn aerosols
of CdCl9 at 0.05 to 1.42 mg/m caused a significant decrease in cilia beat frequency
3
proportional to the aerosol concentration. When hamsters were exposed to 1.33 mg/m Cd for 2
hr/day for 2 days, the beat frequency did not return to control values until 6 wk after
exposure. Nickel chloride aerosols or solutions had similar, but less marked, effects (Adalis
et al., 1978). The beat frequency decreased by 60 beats/min on exposure to 0.1 mg/m Ni for 2
hr. The decrement in beat frequency was proportional to the concentration of Ni aerosol or
solution. A single 2 hr exposure to 0.1 mg/m Ni depressed cilia beat frequency 24 hr after
exposure, but the frequency returned to near normal values after 72 hr. After exposure to 0.1
ng/m , Cd was about 20 percent more effective than Ni in slowing cilia beat (Table 12-10).
12.3.4.2 Alveolar Macrophages—Cytotoxicity of components of atmospheric aerosols has been
studied with alveolar macrophages (AM). The physiological role of AM in the prevention of
infection and in the defense of the lung through removal of inhaled particles has been amply
demonstrated (Green, 1970).
The viability of guinea pig alveolar macrophages was decreased by Min-u-sil silica (6.8,
4.5, and 2.7 urn MVD), with the effect increasing as particle size decreased (Ottery and
Gormley, 1978).
Aranyi et al. (1979) reported cytotoxic effects to AM with fly ash particles coated with
PbO, NiO, or Mn02- The percentage of metal adsorbed on the fly ash was fairly similar across
particle size for a given metal. The fly ash particles were of three size ranges: <2, 2 to
5, or 5 to 8 urn in diameter. All of the particles, regardless of the coating or particle
size, decreased cell viability and were phagocytized by the AM. Within a given chemical
series of coated particles, the effects were both concentration and size related, with smaller
particles and greater concentrations producing greater effects. The greater surface area of
XRD12B/A 12-44 2-5-81
-------
SOX12C/A 8 2-5-81
TABLE 12-9. EFFECTS OF SULFURIC ACID ON MUCOCIL1ARY CLEARANCE
Concentration
Duration
Species
Results
Reference
0.1 mg/ra3 H2S04
0.19 to 1.4 mg/m3 H2S04 (0.3
to 0.6 MI". MMAD)
0.5 mg/m3 H2S04
1.0 mg/m3 H2S04 (0.9 urn, MMAD,
o 1.4)
9
1.4 mg/m3 H2S04 (0.3 to 0.6 urn.
MMAD)
1.5 mg/m3 H2S04 (0.6 urn, CMO)
14 mg/m3 H2S04 (0.12 UB HMAD)
15 mg/m3 H2SO« (3.2 urn, CHO) 4 hr
15 mg/m3 H2S04 (3.2 urn. CMD)
1 hr/day, 5 day wk,
several mo
1 hr
1 hr
1 hr
1 hr
90 min
Short-term
90 min
Donkey Within the first few wk, all 4 animals developed
erratic bronchial mucociliary clearance rates,
either slower than or faster than those before
exposure. Those animals never pre-exposed before
the 0.1 mg/m3 H2S04 had slowed clearance during
the second 3 mo of exposure.
Donkey Bronchial mucociliary clearance was slowed.
Dog Slight increases in tracheal mucociliary transport
velocities immediately and 1 day after exposure.
One wk later clearance was significantly decreased.
Dog Depression in tracheal mucociliary transport rate
persisted at 1 wk post-exposure.
Donkey No effect on tracheal transport..
House No significant effects.
Sheep No significant changes In tracheal mucociliary
transport rate.
House Exposure to H2S04 after exposure to a nonviable
streptococcal aerosol reduced the rate of ciliary
clearance of the bacteria from the lungs and nose.
House Exposure to H2S04 4 days prior to bacterial aerosol.
Clearance of nonviable bacteria reduced in nose,
but not lungs.
Schlesinger et al.,
1979
Schlesinger et al.,
1978
Wolff et al., 1979a
Wolff et al., 1979a
Schlesinger et al.,
1978
Fairchild et al., 1975a
Sackner et al., 1978a
Fairchild et al., 1975a
Fairchild et al., 1975a
-------
SOX12C/A 9 2-5-81
TABLE 12-10. EFFECTS OF METALS AND OTHER PARTICLES ON HOST DEFENSE MECHANISMS
Concentration
0.01 or 0.15 mg/m3 Pb20s
(0.18 um, MMAD)
Duration Species
3 mo Rat
Results
Decreased the number of alveolar macrophages/lung.
Reference
Bingham et al. ,
1968
0.01 mg/m3 (0.17 urn, MMAD) PbCl2
or 0.11 mg/m3 (0.32 urn, MMAD)
NiCl2 or 0.15 mg/m3 (0.15 urn.
MMAD) Pb203 or 0.12 mg/m3 (0.17
pm, MMAD) NiO
0.05 to 1.42 ng/m3 CdCl2
0.1 mg/3 NiCl2
Graded concentrations:
0.075 to 1.94 mg/m3 CdCl2
0.1 to 0.67 mg/m3 NiCl2, or
0.5 to 5 mg/m3 Mn304;
all aerosols (94-99%) <1.4 um
in diameter
109 mg/m3 Mn02 (0.70 um, mean
diameter)
0.2 mg/m3 CdS04, 0.6 mg/m3 CuS04.
1.5 mg/m3 2nS04, 2.2 mg/m3
A12(S04)3, or 3.6 mg/m5 MgS04
Ammonium sulfate at 5.3 mg/m3
S04. NH4HS04, at,6.7 mg/m S04,
N02S04 at 4 mg/mj S04, Fe2(S04)2
at 2.9 mg/in3 S04, or
Fe(NH4)2S04 at 2.5 mg/m3 S0«
12 hr/day, 6 day/wk,
2 mo with PbCl2,
NiCl2, or NiO; con-
tinuously for 2 mo
with Pb203
2 hr
2 hr
2 hr
Rat
Hamster
Hamster
Mouse
3 hr/day
Mouse
3 hr
3 hr
Mouse
Mouse
Exposure to Pb20,, but not PbCl2, resulted in a
depression of the number of alveolar macrophages
(AM) for up to 3 mo but returned to control levels
within 3 days after discontinuation. NiO produced
a marked AM elevation, while NiCl2 did not. NiCl2
resulted In marked increases in mucus secretion and
bronchial hyperplasia. No morphological alterations
with PbCl2 or Pb203.
Decreased ciliary beating frequency in trachea.
Decreased ciliary beating frequency in trachea.
The aerosols increased the mortality from the sub-
sequent standard airborne streptococcal infection:
CdCl2 affect the response at 0.1 mg/m3 Cd, NiCl2 at
0.5 mg/m3 Ni. and Mn304 at 1.55 mg/m3 Mn.
Increased mortality after 3 or 4 days exposure when
mice received bacterial aerosol immediately after
exposure. When the bacteria were administered 5 hr
post pollutant exposure, a single 3 hr exposure
increased mortality. In mice exposed to aerosols
of virus 1 or 2 days prior to Mn02, there were also
increased mortality and pulmonary viral lesions.
Estimated concentrations which caused a 20% enhance-
ment of bacterial-induced mortality over controls.
No significant alterations of host defense
mechanisms.
Bingham et al., 1972
Adalis et al., 1977
Adalis et al., 1978
Gardner et al., 1977b
Adkins et al., 1979,
1980C
Mai getter
et al., 1976
Ehrlich et al.
1978, 1979
Ehrlich et al.
1978, 1979
5.0 mg/m3 carbon black or 2.5 2 hr
mg/m5 iron oxide
0.19 mg/m3 CdCl2 2 hr
0.25 mg/m3 NiCl2
Mouse No significant increases in mortality resulted on Gardner, 1981
subsequent exposure to airborne infection.
Mouse Decreased number of antibody-producing spleen cells. Graham et al., 1978
-------
*
the smaller particles was suggested as being responsible for the greater toxicity of the small
particles. Total cellular protein and lactic acid dehydrogenase also decreased after treat-
ment, probably as a non-specific result of the death of the cultured AM. For each particle
size, Pb-coated particles were most toxic, NiO- and MnCycoated particles had intermediate
effects, and the untreated fly ash was least toxic. The toxicity did not appear related to
the solubility of the metal oxide coating, since no soluble metal could be found using the AM
themselves as a bioassay. The toxicity appeared to be associated with the uptake of the
intact particle. No changes were observed in the total lysosomal enzyme content, but the
latency or intactness of the lysosomal membrane was not examined. Toxicity could have
resulted from the disruption of the intracellular lysosomal membrane, which in turn could have
released intracellular lysosomal enzymes. Lysosomal enzyme release has been proposed as one
potential mechanism for the toxicity of asbestos and silica particles (Heppleston, 1962).
These results support the concept that the surface activity of particles determines the
toxicity of the particle (Allison and Morgan, 1979).
Camner et al. (1974) exposed rabbit alveolar macrophages HI vitro to 5 pm Teflon
particles coated with Al, Be, C, Pb, Mn, Ag, and U. All particles were phagocytized by the
cells, but only Be caused a decrease in viability.
Although White and Kohn (1980) did not consider particle size in their investigation,
they did conduct i_n vitro alveolar macrophage studies with iron carbonyl (0.5-5 |jm, diameter),
SiO? (size not given), crocidolite and crysotile asbestos (size not given), kaolinite (size
not given), and polystyrene latex beads (1.1 urn, diameter). Although particle to cell ratios
were roughly equivalent (10-15 particles/cell), the particle concentration differed markedly
for each chemical. Enzyme release was measured. Compared to a no particle control group,
iron carbonyl, SiO?, both forms of asbestos and latex beads, but not kaolinite, increased (p <
0.02) the percent of extracellular p-glucuronidase (a lysosomal enzyme). Similar results were
obtained for % extracellular LDH, except for this parameter, latex beads had no significant
effect. All particles, except crocidile asbestos and latex beads increased elastase
secretion.
Allison and Morgan (1979) have summarized the evidence that AM ingest both toxic and
non-toxic particles in the same manner. In the case of fibers, ingestion appears more
dependent upon the length of the fiber (Allison, 1973). Short fibers of >5 urn are almost
always ingested, while fibers >30 pm are seldom ingested completely and remain in contact with
the plasma as well as with the lysosomal surface. Intermediate sized particles (5 to 20 urn)
are sometimes completely ingested and sometimes not. Once ingested, particles have two
effects. An immediate cytotoxicity appears which is apparently due to the interaction of the
particle with the plasma membrane (Allison and Morgan, 1979). This interaction is similar to
the hemolytic effects described for silica particles. The second effect results in delayed
cytotoxicity and occurs after the particle has been ingested into a primary phagocytic vacuole
which then combines with a primary lysosome to yield a secondary lysosome containing the
XRD12B/A 12-47 2-5-81
-------
particle (Allison and Morgan, 1979). Here toxic particles exert an effect upon the
permeability of the lysosomal membrane, resulting in the release of lysosomal enzymes into the
cell and into the external medium. These proteolytic enzymes have the potential of causing
tissue damage.
Hatch et al. (1980) examined the influence of iji vitro exposure to a variety of particles
on AM oxidant production (0~ and H?0?) and found the response to be chemical specific. All
the particles studied stimulated the chemiluminescence, with amphibole asbestos being the most
active. Silica, chrysotile asbestos, and metal oxide (Pb, Ni, Mn)-coated fly ash had inter-
mediate activity. Fugitive dusts and fly ash had the lowest activity.
Waters et al. (1974) found that AM cultured with particulate forms of vanadium had
decreased cell viability, indicating a direct cytotoxicity. Alveolar macrophages were
cultured in medium containing vanadium pentoxide (VpOr), vanadium trixoide (V^,), or vanadium
dioxide (V0?). Cytotoxicity was directly proportional to the solubility of the vanadium
compound: V20& > V203 > V02- The concentration of V required to produce a 50 percent
decrease in viability after 20 hr of culture was found to be: 13 ug V/ml as VpOr, 21 ug V/ml
as V203% and 33 ug V/ml as V0?. When V?05 was dissolved in the medium prior to incubation
with the AM, only about 9 (jg V/ml were required to reduce viability by 50 percent, thus
indicating that the soluble V was responsible for toxicity. Phagocytosis, an essential
function for the defense of the lung, was decreased by 50 percent with 6 ug V/ml as dissolved
VpOr. Acid phosphatase, a lysosomal degradation enzyme necessary for digestion of phago-
cytized bacteria, was inhibited by 1 ug V/ml as VpOr, while the lysosomal enzymes, lysozyme
and p-glucuronidase, were not inhibited by concentrations as high as 50 ug V/ml.
The effects of Fe?0- on AM have also been investigated. Rabbits were exposed for 3 hr to
186-222 mg/m3 Fe203 (0.17-0.31 um, MMAD), and AM were removed 0, 12, 18, and 24 hr later
(Grant et al., 1979). When selected lysosomal enzyme activites were determined for the first
three post-exposure times, there were no significant differences from control. However,
since an increased (p < 0.02) number of cells were recovered 12, 18, and 24 hr post-exposure,
the total amount of some of the lysosomal enzymes in the lung was increased. It appears that
the increased number of cells was due to the influx of smaller cells into the lung.
Alveolar macrophages exposed J_n vitro for 20 hr to metallic salts were also studied by
Graham et al. (1975b) using a technique to determine phagocytosis of viable cells only. The
chlorides of Cd (2.2 x 10~5M), Cr (3.1 x 10~3M), Mn (1.8 x 10~3M), and Ni (5.1 x 10~4M)
significantly inhibited phagocytosis. Ammonium vanadate (6.9 x 10 M) had no effect on
phagocytosis, but did lyse and kill cells. Nickel, which caused the greatest reduction in
phagocytosis, had very little effect on viability or cell lysis. Antibody-mediated rosette
formation of AM was also inhibited iji vitro by low concentrations of CdClp (2.2 x 10~5M) or
NiCl2 (10 M) (Hadley et al., 1977). Inhibition was proportional to the Mi"*"*" or Cd++ con-
centration and reached its maximum within 20 min. These studies showed that the antibody
dependent recognition system of AM was inhibited by trace concentrations of NT"*"*" and Cd++
XRD12B/A 12-48 2-5-81
-------
almost immediately after contact with the metal. Such an effect implies that these metals may
affect receptors for phagocytosis of the opsonized bacteria. Depression of AM viability,
phagocytosis, and receptors for phagocytosis may be a mechanism by which these heavy metal
salts increase the susceptibility to airborne infections as discussed later (Section
12.3.4.3).
Bingham and co-workers (1968, 1972) have examined the effects of Pb and Ni inhalation on
the number and type of AM present in the lungs of rats. In a preliminary report, Bingham et
al. (1968) showed that a 3 mo exposure to 0.01 or 0.15 mg/m3 Pb,0, (0.18 |jm, MMAD) decreased
c. <3
the number of AM/lung. The specificity of this response was investigated in a subsequent
study (Bingham et al. 1972) using soluble PbCl2 (0.1 mg/m3, 0.17 urn MMD) and NiCl- (0.11
mg/m , 0.32 \m MMD) and insoluble Pb203 (0.15 mg/m3, 0.15 urn MMD) and NiO (0.12 mg/m3, 0.25 ^m
MMD) aerosols. Rats were exposed for 12 hr/day, 6 days/wk for 2 mo. The only exceptions were
those exposed to Pb203 continuously. Exposure to Pb203, but not PbCl2, aerosols resulted in a
depression of the number of AM which persisted throughout the experiment. The number of AM
was depressed on inhalation of 0.15 mg/m Pt>2°3 for UP to 3 mo> but returned to control levels
within 3 days after discontinuation of the exposure. The solubility of the Ni compound also
had marked effects on the biological response. Nickel oxide produced a marked elevation in
the number of AM/lung, while NiCl2 did not. The most significant effects in NiCl2-exposed
rats were marked increases in mucus secretion and bronchial hyperplasia. No morphological
alterations were observed in those rats exposed to PbCl,, or Pb?0^. Isolated AM also varied in
diameter with the exposure, but the biological significance of this size variation is not
known at present. Perhaps different cell populations were recruited into the lung with the
differing exposure conditions.
Cadmium chloride aerosols also altered the number and kind of cells recoverable by lavage
following exposure (Gardner, 1977b, 1981). The total number of AM isolated from exposed rats
decreased following exposure to 1.5 mg/m Cd (99 percent <3 urn in diameter) but returned to
normal values within 24 hr. The viability of the isolated cells decreased by 11.2 percent
immediately after exposure and was still depressed 24 hr later. There was an influx of
polymorphonuclear leukocytes, especially 24 hr post-exposure, but no increase in lymphocytes.
These effects were not observed at 0.5 mg/m Cd, indicating that the minimum effective dose
may lie somewhere between these two concentrations.
Nickel chloride aerosols (Adkins et al., 1979; Gardner 1981) produced neither an effect
on the number of AM isolated by lavage of rats the day following a 2 hr exposure to 0.65 mg/m
Ni nor an influx of polymorphonuclear leukocytes. The phagocytic capacity of the isolated AM
was, however, depressed. A 2-hr exposure of mice to 0.9 mg/m Mn304 reduced the number of AM
which could be recovered by lavage, but did not result in an influx of other cell types
(Adkins et al., 1980a). The AM had a reduced concentration of ATP and total protein and acid
phosphatase activity. Viability and phagocytic activity of AM were normal.
XRD12B/A 12-49 2-5-81
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The number, function and kind of cells isolated from the lung by lavage are influenced by
the prior exposure to heavy metal aerosols. Not all metals produced the same effect but Cd,
Ni, and Mn also enhanced the susceptibility of mice to subsequent airborne infections (Gardner,
1981). The observations of two independent laboratories (Bingham et al., 1968, 1972; Adkins
et al., 1979) on NiCl? aerosols are essentially in agreement (Table 12-10).
12.3.4.3 Interaction with Infectious Agents—Gardner (1981) and Ehrlich (1978) have reviewed
their groups' studies and presented new data on the effects of aerosols on host defense mecha-
nisms against infectious pulmonary disease in mice. In all of the Gardner studies, 94 to 99
percent of the aerosols was less than 1.4 urn in diameter (Gardner et al., 1977b; Gardner,
1981). Animals were placed in a head-only exposure system for 2 hr and were given graded con-
centrations ranging from 0.075 to 1.94 mg/m Cd (Gardner et al., 1977b), from 0.1 to 0.67
mg/m Ni (Adkins et al., 1979), or from 0.5 to 5 mg/m Mn (Adkins et al., 1980c). In mice,
these exposures to Cd and Ni chlorides and Mn,0. resulted in the deposition of 0.002 to 0.026
mg Cd (Gardner et al., 1977b), 0.001 to 0.012 mg Ni (Adkins et al., 1979), or 0.005 to 0.042
mg Mn (Adkins et al., 1980b) per g dry weight of lung respectively. Nickel clearance (Graham
et al., 1978) from the lungs of mice had a half-life of 3.4 days; while Mn (Adkins et al.,
1980b) clearance was rapid, with a half-life of only 4.6 hr. None of the exposures appeared
to be edematogenic as judged by the ratio of dry weight to wet weight of the lung. After
metal exposure, mice were challenged with an aerosol of Streptococcus pyogenes (S. pyogenes).
The aerosols of CdCl2 (Gardner et al., 1977b), NiCl2 (Adkins et al., 1979), or MnCl2 (Gardner,
1981) increased the mortality from the subsequent standard airborne infection. Cadmium was
more toxic than Ni, which was more toxic than Mn. Exposure to Cd and Mn resulted in a signi-
ficant linear concentration response. The lowest concentration tested at which a significant
increase in mortality was detected was 0.1 mg/m Cd or 0.5 mg/m Ni. Manganese, as Mn^O^
(Adkins et al., 1980c), was statistically estimated to produce a 10 percent increase in mor-
tality at 1.55 mg/m Mn, while MnCl_ (Gardner, 1981) required a higher concentration to pro-
duce a measurable increase in mortality. Using a different infectivity model (Maigetter et
al. , 1976), 3 or 4 days (3 hr/day) of exposure to 109 mg/m MnO? (0.70 urn, mean diameter) were
required to increase mortality consequent to Klebsiella pneumoniae infection when the mice
received the bacterial aerosol immediately after exposure.
The toxicity of NiCl2 was complex (Adkins et al., 1979). Nickel exposure had no effect
on the S. pyogenes infection if the bacteria was given immediately after Ni aerosol exposure.
When the bacterial exposure was delayed by 24 hr, Ni aerosols increased the mortality in a
concentration-related fashion. In contrast, effects of CdC1? (Gardner et al., 19J7b) and Mn
(Gardner, 1981) were observed when the bacterial challenge immediately followed exposure. The
concentration-response curve of Ni was very steep compared to those of Cd and Mn exposures
(Gardner, 1981). No explanation has been offered for the delay in effect of Ni. Perhaps the
delayed effects represent either redistribution of Ni to the site of action or some major
change in the lung such as death of a specific cell type. The delayed toxicity does raise the
possibility of carry-over of effects from a single exposure to a second.
XRD12B/A 12-50 2-5-81
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The influence of a variety of sulfate species on host defense mechanisms against
infectious respiratory disease has been investigated by Ehrlich (1979) and Ehrlich et al.
(1978) using the infectivity model with S. pyogenes. Mice were exposed for 3 hr. The
estimated concentrations of the compounds which caused a 20 percent enhancement of
bacterial-induced mortality over controls were 0.2 itig/m3 CdS04> 0.6 mg/m3 CuSO., 1.5 mg/m3
ZnS04, 2.2 mg/m A12(S04)3, 2.5 mg/m Zn(NH4)2(S04)2, and 3.6 mg/m3 MgS04- Ammonium sulfate
at 5.3 mg/m S04, NH4HS04 at 6.7 mg/m3 S04> Na2S04 at 4 mg/m3 S04, Fe2(S04)3 at 2.9 mg/m3 S04>
and Fe(NH4)2S04 at 2.5 mg/m S04 did not cause significant alterations. The nitrates of Pb,
Ca, Na, K, and NH4 did not cause an effect at concentrations of 2 mg/m3 or higher. However,
Zn(N03)2 caused effects similar to ZnS04- From this body of work, it appears that the NH4 ion
rendered the compound less toxic, and that the toxicity is primarily due to the cation. With
the infectivity model, ZnS04 and Zn(NH4)2(S04)2 ranked differently than with airway resistance
experiments (Amdur et al., 1978a). This is not unexpected as airway resistance primarily
detects alterations of the medium to large conducting airways, while the infectivity model
(Gardner and Graham, 1977) is hypothesized to reflect alveolar level changes.
When mice were exposed for 2 hr to 5.0 mg/m carbon black or 2.5 mg/m3 iron oxide, no
significant increases in mortality resulted on subsequent exposure to airborne infection
(Gardner, 1981).
Death from S. pyogenes exposure in this infectivity model is due to septicemia (Gardner
et al., 1977b). Septicemia occurs when the bacteria have grown to 10 organisms per lung.
Removal and killing of the inhaled organisms will reduce the growth of the bacteria within the
host and prevent the occurrence of septicemia. For these reasons, the infectivity model is an
integrative assessment of toxicity for host defense systems against infectious pulmonary
disease. As reported above, the number, kind, function and viability of the cells isolated by
lavage from the lungs of animals exposed to heavy metal aerosols are different from those of
control animals. Studies of trachea! rings isolated from aerosol-exposed hamsters also
indicate depression of mucociliary clearance. Both mucocilary and AM clearance of bacteria
are depressed by aerosols of these heavy metals (Gardner, 1981) (Table 12-10).
12.3.4.4 Immune Suppression--Antibodies play a significant role in the ability of macrophages
to recognize and engulf pathogenic bacteria. The functioning of the immune system interlocks
with the macrophage system in other ways also. In mice, intramuscular injections of NiCl2
depressed the number of antibody-producing cells in the spleen (Graham et al., 1975a). Using
the Jerne plaque assay, a negative linear dose-response curve was found with injections
ranging from 9.26 to 12.34 ug Ni/g body weight. No effect was observed with a dose of 3.09 ug
Ni/g body weight. The inhalation of NiCl2 aerosols (99 percent less than 3 urn in diameter)
was more effective in suppressing the primary immune response. Graham et al. (1978)
calculated that exposure to an aerosol of 0.25 mg/m3 Ni for 2 hr would result in a maximum
deposition of 0.98 ug Ni, assuming complete retention and a minute volume of 1.45 ml/g body
weight. This concentration was found to be the lowest tested which produced a significant
XRD12B/A 12-51 2-5-81
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*
depression in the immune response. The lowest dose found to produce a similar effect by
injection was 208 ug Mi/mouse (Graham et a!., 1975a). The inhalation dose was, therefore,
approximately 200 times more potent. Ni was found to follow first order removal kinetics from
the lung, but measurable elevations remained in the lung up to 4 days after exposure. Similar
kinetics of removal have been found using the isolated, ventilated, and perfused rat lung
(Williams et al., 1980) and human, rat, and cat type II pneumocytes in culture (Saito and
Menzel, 1978).
Inhaled Cd also depresses the number of antibody producing cells and is more potent than
intramuscularly injected Cd. The highest intramuscular dose of CdCK examined by Graham et
al. (1978) was 11.81 ug Cd/g body weight (about 266 ug Cd/mouse), and it produced no immuno-
suppression. When mice were exposed to 0.19 mg/m Cd for 2 hr, a significant suppression was
observed. In both cases the Cd was administered as CdClp, a highly soluble salt. The inhala-
tion dose can be calculated on the same basis as that given above for Ni to be at a maximum at
0.74 |jg Cd/mouse. The inhaled dose was, therefore, at least 350-fold more potent. Inhalation
also appeared to be more potent than ingestion or interperitoneal injection (Exon et al.,
1975; Keller et al., 1975). Koller et al. (1975) found that 150 ug Cd given orally was
required to produce immunosuppression.
For comparative purposes, the lowest inhalation exposure of CdCl9 found to be immuno-
00 ^
suppressive was 0.19 mg/m; 0.2 mg/m was the 1971 Threshold Limit Value (TLV). The current
TLV is 0.05 mg/m . The human intake from air has been estimated to be 7.4 |jg/day and from
water to be 160 ug/day (Schroeder, 1970). NiCl, was found to be immunosuppressive at an
3 3
inhalation exposure of 0.25 mg/m while its TLV is 1 mg/m . The human exposure is estimated
to be 2.36 (jg/day from inhalation and 600 ug/day from ingestion (Schroeder, 1970). Should the
effectiveness of inhaled aerosols be equivalent in mice and men, then the inhaled doses are
biologically almost equivalent to those ingested.
Inhaled Cd or Ni aerosols impair the bacterial defenses of the lung through direct cyto-
toxicity to AM, depression of antibody production, and inhibition of antibody dependent
aggregation reactions. All of these mechanisms can help to explain the increased suscepti-
bility of mice to airborne pathogens following inhalation of Ni or Cd aerosols. The rapidity
of clearance of Ni and Cd from the lung may allow rapid recovery (see Table 12-10).
Mouse splenic lymphocytes have also been exposed i_n vitro to 500 ug of various sizes of
silica (Wirth et al., 1980) and mitogen-induced transformation measured (a reflection of
immune function). Four silica samples were tested unfractionated, or size-fractionated into 2
categories (0.3 and 5.3 urn). All the unfractionated samples depressed the blastogenic
response to Conconavalin A (a measure of T cell function) and LPS (a measure of B cell
function). The T cell response was decreased by the 0.3 urn size fraction of all samples.
However, the 5.3 urn particles of 2 samples increased the response, while one sample caused no
change and another caused a small decrease. When B cell function was examined, it was more
depressed by the 0.3 urn silca than the 5.3 urn particles, although 3 of the 4 larger-sized
samples did cause a decrease.
XRD12B/A 12-52 2-5-81
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Kysela et al. (1973) administered high concentrations (50 mg) of 9 sizes of quartz dust
(0.7 to 35 Mm) to rats by intratracheal instillation. A variety of biochemical determinations
as well as a histological examination of the lungs were made 3 mo after dosing. As particle
size decreased, there was a trend towards increased wet weight of the lung, hydroxyproline con-
tent, total lipids, esterified fatty acids and phospholipids. Only cholesterol showed a
slight increase. For hydroxyproline in total lung, the increase was stepwise, with increments
occurring at about 0.9, 5, 7, and 10 urn. Between 0.7 and 14 urn, the increase was significant
(p < 0.05). Lipid changes, based on gram of tissue, exhibited a trend towards linearity with
particle size decrease. The larger particles (14-35 urn) caused a stationary granulamatous
response. With the intermediate particles (5-10 Mm), the lungs had cellular nodules with a
few collagenous fibers and an increased tissue cellularity and endoalveolar foam cells. With
the smaller particles, the nodules were more numerous and collagenous.
Goldstein and Webster (1966) also investigated the effects of size graded quartz parti-
cles in rats exposed by intratracheal instillation and examined 4 months later. The sizes and
concentrations used (< 1 M"), 13.99 mg; 1-3 MI", 46.1 mg; and 2-5 M"i, 92.7 M9) were such that
the rats were exposed to an equivalent surface area (600 sq. cm.) for each of the size ranges.
The < 1 Mm particles caused more numerous nodules. The two other size ranges produced an
equivalent number of lungs with nodules, but there were many more lungs with confluent
nodules, compared to the smallest size quartz. The degree of fibrosis was similar in the 1-3
Mm and 2-5 iim groups and was more severe than that observed in the < 1 \jirn group. The weight
of collagen in lungs increased as particle size increased. However, it should be recalled
that the concentration of particles was increased as particle size increased.
Particle size also has an influence on the immunological effects of silica (Wirth et al.,
1980). Average particle sizes of the silica preparations were 0.012, 0.8, 1.5, and 1.9 urn.
The silica particles were from different suppliers; the crystalline structures could have
differed also. Mice were injected intravenously. The smaller particles tended to depress the
humoral immune response to a greater extent.
12.4 INTERACTION OF SULFUR DIOXIDE AND OTHER POLLUTANTS
12.4.1 Sulfur Dioxide and Particulate Matter
Although man breathes a multitide of chemicals in various mixtures at various dose-rates,
most animal toxicological and controlled human exposures are conducted with single chemicals.
This simplifies the research and permits an improved estimate of cause-effect relationships,
but it prohibits evaluation of the effects of pollutant mixtures which may be additive,
synergistic, or antagonistic with respect to the individual pollutants. However, some inter-
action studies which elucidate the complexity of toxicological interrelationships have been
conducted. Some of this work utilized pollutant combinations that would favor the conversion
of the primary pollutant to a secondary pollutant (i.e., S02 altered to H2$04, etc.). Other
research was directed at evaluating the influence of several pollutants when delivered in
combination or in sequence.
XRD12B/A 12-53 2-5-81
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12.4.1.1 Acute Exposure Effects—The question of the possible effect of aerosols on the
response to S0? is a critical problem in air pollution toxicology (Amdur, 1975). The
phenomenon has been investigated in simple model systems of SOp alone or in combination with
an aerosol of a single chemical. The typical bioassay system has been the comparison of the
increase in pulmonary flow resistance in guinea pigs produced by a given concentration of SC^
alone with that produced in the presence of the aerosol. The aerosols used in many of these
studies were "inert" in the sense that they did not produce an alteration in flow resistance
when they were given alone.
The initial simple prototype aerosol used was sodium chloride (NaCl) at concentrations of
10 mg/m and 4 mg/m (Amdur, 1961). These experiments with guinea pigs indicated-that the
response to a given concentration of SO, was potentiated by 10 mg/m sodium chloride. For
3
example, a concentration of 5.24 mg/m (2 ppm) SO- alone produced an increase of 20 percent in
pulmonary flow resistance; when the sodium chloride was present, the increase was 55 percent.
The potentiation did not occur until the latter part of a 1 hr exposure. When the
concentration of sodium chloride was reduced to 4 mg/m , the potentiation was greatly reduced.
Examination of post-exposure data indicated that the response to the combination resembled the
response to a more irritant aerosol. The length of recovery was related to the concentration
of SO-, and the presence of the aerosol delayed recovery to control values. The chamber
relative humidities were below 70 percent; but on entering the high humidity of the
respiratory tract, the sodium chloride would absorb water to become a droplet capable of
dissolving SO-, thus favoring the production of HLSO.. Sodium chloride does not catalyze the
oxidation of S02 to sulfuric acid.
Experiments by McJilton et al. (1973) indicate the importance of ambient relative
humidity and the solubility of SO, in the sodium chloride droplet. They examined the effect
3 3
of 1 mg/m NaCl on the response to 2.62 mg/m (1 ppm) SO- at low (<40 percent) and high (>80
percent) relative humidity. An increase in pulmonary flow resistance in guinea pigs was the
criterion of response. As would have been predicted from the earlier work, no increase was
observed with this sodium chloride concentration at low relative humidity. At high relative
humidity, the potentiation was marked and was evident during both the early and late parts of
the 1 hr exposure. The rapid onset indicates the formation of an irritant aerosol in the
exposure chamber under conditions of high humidity. As would have been predicted, no
conversion to sulfate was found, but the droplets were acid with an estimated pH of 4.
Presumably, this was sulfurous acid. (See the discussion of the effect of relative humidity
on sulfate and nitrate aerosols above and on human exposure experiments in Chapter 13).
Amdur and Underbill (1968) studied the effect of aerosols of soluble salts of metals
shown to convert SO- to sulfuric acid using the Mead-Amdur method. Manganous chloride,
ferrous sulfate, and sodium orthovanadate caused a three-fold increase in the resistance to
flow over that of 2.62 mg/m (1 ppm) SO- alone. The potentiation was evident during the first
10 min as well as during the remainder of the 1 hr exposure. Chamber relative humidity was 50
XRD12B/A 12-54 2-5-81
-------
percent, indicating that high humidity was not necessary for the formation of an irritant
aerosol in the chamber when the catalyzing metals were present. Analysis of the collected
aerosol indicated the presence of sulfate, presumably as sulfuric acid (Amdur, 1973). These
analyses indicated that at an S02 concentration of 0.52 mg/m (0.2 ppm) about 0.08 mg sulfuric
acid was formed. When this amount of sulfuric acid was administered with 0.52 mg/m3 (0.2 ppm)
S02, the increase in flow resistance duplicated the increase observed with the iron and vana-
dium aerosols (Amdur, 1974). This suggests that sulfuric acid formation is the most likely
mechanism of potentiation for the aerosols of these metals. Amdur et al. (1978a) have
reported that a 1 hr exposure to 0.4 mg/m copper sulfate also potentiated the response to
0.94 mg/m (0.36 ppm) SO^- It is not certain whether this is mediated through the formation
of sulfuric acid or through the formation of a sulfite complex. The increased resistance to
flow from exposure to 0.79 to 0.84 mg/m3 (0.3 to 0.32 ppm) S00 with ammonium sulfate (0.9
3 3 3
mg/m ), ammonium bisulfate (0.9 mg/m ), or sodium sulfate (0.9 mg/m ) was purely additive. It
should be pointed out that these salts have not been tested under conditions of high relative
humidity.
Amdur and Underbill (1968) also examined the effect of a variety of solid aerosols
(carbon, iron oxide, manganese dioxide, and fly ash) which do not catalyze the conversion of
S0? to HpSO.. None of these potentiated the increased resistance to flow when compared to S0?
(Table 12-11).
12.4.1.2 Chronic Exposure Effects—Animals were exposed continuously to various combinations
of S02, sulfuric acid (0.5 to 3.4 urn, HMD), and fly ash (3.5 to 5.9 urn, MMD). The fly ash had
been collected downstream from electrostatic precipitators of coal-burning electric generating
plants (Alarie et al., 1975). Monkeys were exposed for 18 mo and guinea pigs for 12 mo. For
monkeys, exposures were to S02, H2$04 + fly ash, S02 + H2$04, or S02 + H2$04 + fly ash.
Guinea pigs received either 0.9 mg/m3 H2$04 (0.49 |jm MMD) or 0.08 mg/m3 H2$04 (0.54 or 2.23 urn
MMD) + 0.45 mg/m fly ash (3.5 or 5.31 (jrn MMD). In monkeys, a battery of hematological and
pulmonary function (tidal volume, respiratory rate, minute volume, dynamic compliance, pul-
monary flow resistance, work of breathing, distribution of ventilation, CO diffusing capacity,
and arterial blood gases) tests were applied at various times during exposure, but no signifi-
cant effects were attributed to the exposures. Similar methods (except for distribution of
ventilation and CO diffusing capacity) were used with guinea pigs, and again no significant
3 3
effects were observed. At the end of the exposure to 2.59 mg/m (0.99 ppm) S02 + 0.93 mg/m
H-SO. (0.5 |jm MMD, a 1.5 to 3.8), the lungs of monkeys had morphological alterations in the
bronchial mucosa (focal goblet cell hypertrophy and occasional hyperplasia and focal squamous
metaplasia). Monkeys exposed to 2.65 mg/m3 (1.01 ppm) S02 + 0.88 mg/m H2S04 (0.54 urn MMD, og
1.5 to 3.8) + 0.41 mg/m3 fly ash (4.1 pm MMD, a 1.8 to 2.8) had similar alterations. Thus,
fly ash did not enhance the effect. Monkeys which received 0.99 mg/m H2$04 (0.64 |jm MMD, og
1.5 to 3.0) + 0.55 mg/m3 fly ash (5.34 pm MMD, a 1.8 to 2.2) had slight alterations in the
y
mucosa of the bronchi and respiratory bronchioles. Focal areas of erosion and epithelial
XRD12B/A 12-55 2-5-81
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SOX12C/A 11 1-30-81
TABLE 12-11. EFFECTS OF ACUTE EXPOSURE TO SULFUR DIOXIDE IN COMBINATION WITH PARTICULATE HATTER
i
en
CTl
5.24
and
Concentration Duration
mg/m3 (2 ppm) S02, 10 mg/ms 1 hr
4 mg/m3 Nad
Species Results
Guinea pig 5.24 mg/m3 (2 ppm) S02 alone produced an increase
of 20% in pulmonary flow resistance; with NaCl at
10 mg/m3 the increase was 55% and the potentiation
did not occur until the latter part of the exposure.
At 4 mg/m3 NaCl, the potentiation was greatly
reduced.
Reference
Amdur, 1961
2.62 mg/m3 (1 ppm) S02, 1 mg/m3 1 hr
NaCl at low (40 %) and high (SOX)
relative humidity (RH)
2.62 mg/m3 (1 ppm) S02, an 1 hr
aerosol of soluble salts
(manganous chloride, ferrous
sulfate, and sodium orthovana-
date) 50% RH
0.94 mg/m3 (0.36 ppm) S02, 1 hr
0.4 mg/m3 copper sulfate
0.79 to 0.84 mg/m3 (0.3 to 1 hr
0.32 ppm) S02 and 0.9 mg/m3
ammonium bisulfate, or 0.9
ng/m3 sodium sulfate
Guinea pig No increase in pulmonary flow resistance at low RH.
At high RH, the potentiation was marked and evident
during both early and late parts of the exposure.
Guinea pig Presence of soluble salt increased pulmonary flow
resistance about 3-fold. The potentiation was
evident early in the exposure.
Guinea pig Potentiated pulmonary flow resistance.
Guinea pig The effect on pulmonary flow resistance was
additive.
McJilton et al., 1973
Amdur and
Underhill, 1968
Amdur et al., 1978a
Amdur et al., 1978a
-------
hypertrophy and hyperplasia were observed. The other groups of monkeys had no remarkable
morphological changes. All monkeys exposed to fly ash displayed no
morphological alterations, although presence of the fly ash was easily observed. Guinea pigs
experienced no morphological effects which could be attributed to pollutant exposure.
In a previous study, Alarie et al. (1973bc) found no effects on pulmonary function,
hematology, or morphology of monkeys or guinea pigs exposed to approximately 0.56 mg/m3 fly
ash in combination with 3 concentrations of S02 (0.28, 2.62, or 13.1 mg/m3; 0.11, 1, or 5
ppm). Monkeys were exposed continuously for 78 wk and guinea pigs continuously for 52 wk.
Lewis et al. (1969, 1973) investigated the effects of S02 and H2$0. in normal dogs and in
dogs which had been previously exposed for 191 days to 48.9 mg/m (26 ppm) N02> Dogs
identically treated with N02 had morphological changes in the lung, and one of the animals had
striking bullous emphysema. Sulfur oxide exposures were for 21 hr/day for a maximum of 620
days to 13.4 mg/m (5.1 ppm) S02, to 0.89 mg/m3 H2$04 (90 percent < 0.5 urn in diameter), or to
a combination of the two. These concentrations were averaged over time, and when the animals
were examined at 225 days, the concentration of H2$04 was lower (0.76 mg/m3 H2$04 in the H2$04
group and 0.84 mg/m H2$04 in the H2$04 + S02 group). After 225 days of exposure (Lewis et
al., 1969), dogs receiving H2$04 had a significantly lower diffusing capacity for CO than
those that did not receive HLSO^.. In the S02-exposed animals, pulmonary compliance was
reduced (p < 0.05), and pulmonary resistance was increased (p < 0.05) compared to animals that
did not receive SO,,. Dogs not pre-exposed to NO- which received SO- + H2S04 had a smaller
residual volume (p < 0.01) than all other dogs.
These dogs were also examined after 620 days of exposure (Lewis et al., 1973). At 3, 7,
19 or 20.5 mo of exposure, sulfur oxides did not markedly affect hematological indices (number
of erythrocytes and leukocytes, hemoglobin concentration, hematocrit, mean corpuscular hemo-
globulin value, mean corpuscular volume, and mean corpuscular hemoglobin concentration).
There were no morphological changes that could be clearly identified as resulting from sulfur
oxide exposure. However, pulmonary function was altered. Generally, the animals pre-exposed
to N0? were more resistant to the sulfur oxides. Sulfur dioxide did not produce any signifi-
cant effects except for an increase in mean nitrogen washouts. Sulfuric acid caused a
significant (p < 0.05) decrease in diffusing capacity for CO, residual volume, and net lung
volume (inflated) with an increase in total expiratory resistance. There was also a
significant (p = 0.1) decrease in total lung capacity, inspiratory capacity, and functional
residual capacity. Total lung weight and heart weight were also decreased. Other measure-
ments (other lung volumes, dynamic and static compliance, and N2 washout) were not signifi-
cantly affected. These alterations of diffusing capacity for CO and lung volumes are inter-
preted as a loss of functional parenchyma, and, along with the increase in total pulmonary
resistance, are in the direction expected for animals that develop obstructive pulmonary
effects. Although the standard histological techniques used did not detect morphological
effects, it is conceivable that the pulmonary function effects preceeded measurable structural
alterations.
XRD12B/A 12-57 2-5-81
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Female beagle dogs were .exposed 16 hr/day for 68 mo to raw or photochemical ly reacted
auto exhaust, oxides of sulfur or nitrogen, or their combinations. A description of the expo-
sure groups is given in Table 12-12. More than 90 percent of the particles were <0.5 urn in
diameter. They were examined after 18 (Vaughn et al., 1969), 36 (Lewis et al., 1973), and 61
mo (Lewis et al., 1974) of exposure and 32 to 36 mo (Hyde et al., 1978; Orthoefer et al.,
1976) after the 68 mo exposure ceased. A monograph describing the entire study and results is
available (Stara et al., 1980). Only those results pertaining to sulfur oxides will be de-
scribed here.
Typical hematological examinations (except for differential counts) were made approxi-
mately every 6 mo (Stara et al., 1980). The SO group had no major differences from control.
However, in the presence of auto exhaust (with or without irradiation), SO did cause some
significant elevations in hematocrit and hemoglobin concentration. Clinical chemistries were
unchanged during or approximately 1 1/2 yr after exposure (Stara et al., 1980). Although
cardiovascular function was also assessed after 4 yr of exposure and 3 yr after exposure
ceased, no significant changes which could be attributed to SO were found (Stara et al.,
1980).
A variety of other parameters were examined during or immediately after exposure (Stara
et al., 1980). SO caused no significant effect on visual evoked brain potentials.
After 18 (Vaughn et al., 1969) or 36 mo (Lewis et al., 1974) of exposure, no significant
changes in pulmonary function were observed. A variety of alterations were found using
analysis of variance after 61 mo (Lewis et al., 1974) of exposure, but only those significant
results related to sulfur oxides will be discussed in detail here. Residual volumes were
increased in dogs receiving R + SO (see Table 12-12 for abbreviations) compared to those
receiving I + SO , SO , and CA. Residual volumes of the SO group were lower than those of
A A X
the CA group. When x analyses were applied to the data of the number of dogs/group having
alterations as judged by clinical criteria, additional significant differences were found.
More dogs of the I + SO group had higher total expiratory resistance than their controls (CA
and SO ). The ratio of residual volume to total lung capacity was higher in animals exposed
to R + SO compared to those receiving clean air (CA). This change was interpreted as pul-
monary hyperinflation. Although other lung volumes, compliance, resistance, diffusing capa-
city for CO, N2 washout, peak expiratory flow, and maximum breathing capacity were also
measured, sulfur oxides had no effects.
Two years after exposure ceased, pulmonary function measurements were made again (Stara
et al. , 1980). These measurements were made in a different laboratory than those made during
exposure, but consistency among measurements of the control group and another set of dogs of
similar age at the new laboratory indicated that this difference did not cause a major impact
of the findings. Animals in the R, R + SO , and I + SO groups had an increased PaC09
/> X 4-
(p < 0.05) compared to controls. These groups and the SO group had a greater dead space
volume compared to controls. Respiratory frequency was increased in the SO group. Although
XRD12B/A 12-58 2-5-81
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TABLE 12-12. POLLUTANT CONCENTRATIONS FOR CHRONIC EXPOSURE OF DOGS (Hyde et al., 1978)
Atmosphere
CO
Pollutant Concentration, mg/m
HC
(as CH4) N0£
NO
OX
(as 0) S0
Control Air (CA)C
Nonirradiated auto
exhaust (R)
112.1
18.0
0.09
1.78
Irradiated auto
exhaust (I)
108.6
15.6
1.77
0.23
0.39
S02 + H2S04(SOX)C
1.10
0.09
en
vo
Nonirradiated auto
exhaust + SO, +
H,SO. (R + S6j
113.1
17.9
0.09
1.86
1.27
0.09
Irradiated auto
exhaust + SO, + H-SO.
(I + S0x) ^ i
109.0
15.6
1.68
0.23
0.39
1.10
0.11
Nitrogen oxides, 1
(NO, high)
1.21
0.31
Nitrogen oxides, 2
(NO high)
0.27
2.05
Abbreviations in parentheses
3>90% of H_SO. particles were < 0.5 urn in diameter (optical sizing)
-------
DLCO was unchanged, the ratio, of Dl_co to total lung capacity was decreased in all pollutant-
exposed dogs. Vital capacity was not changed. For the S0x group compared to control, total
lung capacity and residual volume were significantly increased. But, there was no change in
functional residual volume; respiratory, pulmonary, and chest wall resistance were not
affected; and quasistatic chest wall compliance was decreased. There was a greater change in
dynamic compliance with increasing breathing frequency in dogs exposed to S0x- When the
pulmonary function values at the end of exposure were compared directly to those values 2 yr
after exposure ceased, the following observations were made in the S0x group: residual
volume, total lung capacity, vital capacity, inspiratory capacity, and functional residual
capacity, DLCO and the ratio of DLCO to total lung capacity increased. The magnitudes of
these changes were greater than changes in controls, in most cases. From evaluation of all
the data, the authors state that functional loss continues following termination of the
exposure and the damage caused by SO was primarily to the parenchyma. They also state that
the combination of auto exhaust and SO "did not appear to augment specific functional losses
caused by single species of pollutants."
Thirty-two to 36 mo (Hyde et al., 1978) after exposure ceased, the lungs of the beagles
were examined using morphologic (light, scanning electron and transmission electron micros-
copy) and morphometric techniques. Only the results for sulfur oxide combinations will be
described in detail. In the SO group, lung weight, total lung capacity, and the displaced
volume of the processed right lung were significantly increased over the controls (CA). In
the most severely affected SO dogs, the air spaces enlarged and the number and size of inter-
alveolar pores increased. Only the high NO- dogs had a greater degree of air space enlarge-
ment. The SO animals had a loss of cilia in the conducting airways without squamous cell
metaplasia; nonciliated bronchiolar cell hyperplasia; and loss of interalveolar septa in
alveolar ducts. When SO was combined with R, cilia were also lost, but squamous cell meta-
plasia occurred. Exposure to R + SO and I + SO produced nonciliated bronchiolar cell hyper-
plasia and an increase in interalveolar pores and alveolar air space enlargement. The
enlargement of the distal air spaces was centered on respiratory bronchioles and alveolar
ducts and was associated with an apparent loss of interalveolar septa in all animals receiving
S02 and H-SO.. The authors consider these changes to be analogous to an incipient stage of
human proximal acinar (centrilobular) emphysema. The important observation from these experi-
ments is that mixtures of SO- and HLSO., representing an interacting gas-aerosol system simi-
lar to that in urban atmospheres, produced anatomic alterations at concentrations lower than
either SO- or H-SO. aerosols alone.
In a monograph (Stara et al., 1980) describing all the dog studies, the morphological and
functional changes are compared. In the SO group the changes in pulmonary function corre-
lated well with the morphological effects. Since the changes in pulmonary function were pro-
gressive over the post-exposure period, it is likely that morphological changes were also
progressive.
XRD12B/A 12-60 2-5-81
-------
*
Biochemical analyses were performed on these dogs at the time of sacrifice, 2.5 to 3 yr
after exposure ceased. Hydroxyproline concentration (used as an index of collagen content)
and prolyl hydroxylase activity (the rate-limiting enzyme in collagen synthesis) were measured
(Orthoefer et al., 1976). No significant changes in hydroxyproline were found. The SO and I
+ SOX groups had significantly elevated prolyl hydroxylase activity compared to the R, R +
SOX, and CA groups. While it is remarkable that effects on prolyl hydroxylase remained 2.5 -
3 yr post-exposure, it is not possible to interpret further these results. No significant
alterations were observed in brain, heart, lung or liver lipids amongst the experimental
groups (Stara et al., 1980).
Zarkower (1972) reported mixed effects on the immune system of mice exposed to 5.24 mg/m
(2 ppm) S02 and 0.56 mg/m carbon (1.8 to 2.2 \im, MMD), alone and in combination for 100 hr/wk
for up to 192 days. Animals were immunized with aerosols of bacteria (Escherichia coli) at
various times during exposure. After 102 days of exposure, there were no statistically signifi-
cant changes. Sulfur dioxide exposure caused an increase (p < 0.05) in serum antibody titer
at 135 days and a decrease (p < 0.01) at 192 days. Carbon and carbon + S02 produced an equiva-
lent decrease (p < 0.01) in antibody titer at 192 days (but not at 135 days) which appeared to
be a greater decrease than that found in the SO^-exposed mice. In the spleen, exposure to S02
caused an increase (p < 0.01) in the number of antibody-producing cells at 135 days and a
decrease (p < 0.01) in number at 192 days. In the mediastinal lymph nodes (which drain the
lung), S0? caused no such changes. Carbon + S0?, but not carbon alone, caused an increase
(p < 0.01) in the number of antibody-producing cells in the mediastinal lymph nodes and a
decrease (p >0.05) in the spleen at 135 days. After 192 days of exposure to carbon or carbon
+ S0?, the number of antibody producing spleen cells decreased (p <0.01). The immunosuppres-
sion in these 2 groups was roughly equivalent and appeared to be more severe than that in the
S0_ alone group. In the mediastinal lymph nodes, only carbon + S0? caused immunoenhancement
(p < 0.05). Thus, for the pulmonary immune system, only exposure to the combination of S0«
and carbon caused significant effects. After 192 days, the systemic immune system was
affected in all 3 exposure groups. It appeared that carbon and carbon + SO,, caused equivalent
effects and that both regimens were more effective than SO.,.
Fenters et al. (1979) showed that exposure for 3 hr/day, 5 days/wk for up to 20 wk to a
mixture of 1.4 mg/ny3 H?SO. plus 1.5 mg/m carbon (0.4 (jm, mean particle diameter) or to 1.5
mg/m3 carbon only (0.3 \im, mean particle diameter) also altered the immune system of mice.
Serum immunoglobulins (Ig) decreased, with the exception of IgM which was increased after 1 wk
of exposure to either carbon or H2SO. + carbon. After 1 wk, some Ig classes decreased in both
exposure groups, but after 4 or 12 wk of exposure, alterations were observed only in the H2S04
+ carbon group. Results for Ig were mixed at 20 wk. In the carbon group, the number of
specific antibody-producing spleen cells was increased at 4 wk, unchanged at 12 wk, and
decreased at 20 wk. A similar trend was observed in the H2$04 + carbon group, but only the
immunosuppression at 20 wk was significant. In examining other host defense systems, no
XRD12B/A 12-61 2-5-81
-------
alterations of alveolar macrophage viability or cell numbers were observed. After 4 and 12 wk
of exposure, pulmonary bactericidal activity was increased in both exposure groups. By 20 wk
of exposure, values were not significantly different from controls. Using the infectivity
model with influenza Ap/Taiwan virus, a 20-, but not a 4-, wk exposure to H2$04 + carbon
increased mortality.
Morphological changes were observed in these mice (Renters et al., 1979) using scanning
electron microscopy after 12 wk of carbon exposure. In the external nares, there was excess
sloughing of squamous cells. In the trachea, the number of mucous cells appeared to increase;
dying cells were present, and microvilli were lost. No alterations of the bronchi were seen.
The alveoli had some areas of congestion with thickening, loss of interalveolar septa, and
enlarged pores. After 20 wk of exposure, damage was similar, but to a lesser degree. Mice
exposed to the mixture of HUSO, and carbon showed 'equivalent effects, but the damage was
somewhat more severe than that seen in the carbon only group.
The influence of HUSO, and carbon on the trachea of hamsters was investigated by Schiff
3
et al. (1979). Animals were exposed for 3 hr to 1.1 mg/m HUSO. (0.12 urn, mean size) and/or
3
1.5 mg/m carbon (0.3 urn, mean size) and were examined either immediately, or 24, 48, or 72 hr
later. Carbon caused no change in ciliary beat frequency. Sulfuric acid exposure, however,
caused depression in this frequency at all time periods. The combination of HUSO, and carbon
produced similar effects, but recovery had occurred by 48 hr post-exposure. Using light
microscopy, the percentage of normal tracheal epithelium was determined. Up to 48 hr after
exposure, the combination of HUSO, and carbon resulted in more tissue destruction than either
pollutant alone, although the single pollutants did cause some damage. Morphological altera-
tions of all pollutant exposure groups were observed using light and scanning electron
microscopy (see Table 12-13).
12.4.2 Interaction with Ozone
3
Cavender et al. (1977) exposed rats and guinea pigs to sulfuric acid aerosols (10 mg/m ,
1 urn MMD), 3.9 mg/m (2 ppm) ozone, or a combination of the two for 6 hr/day for 2 or 7 days;
they then measured the ratio of lung to body weight and examined the lungs histologically. No
synergism was observed between the ozone and sulfuric acid treatments. The histological
lesions were those ascribed to ozone alone. This same group (Cavender, 1978) exposed rats and
guinea pigs to sulfuric acid aerosols (10 mg/m , 50 percent equivalent aerodynamic diameter,
0.83 urn, o = 1.66), 1.02 mg/m (0.52 ppm) ozone, or a combination of the two for 6 hr/day, 5
days/wk for 6 mo. The histological alterations were those due to ozone alone.
Last and Cross (1978) found synergistic effects of a continuous exposure of sulfuric acid
aerosol (1 mg/m ) and ozone (0.78 to 0.98 mg/m or 0.4 to 0.5 ppm) when administered simultan-
eously to rats for 3 days. Glycoprotein synthesis was stimulated in tracheal ring explants
measured ex vivo. Ozone alone caused a decreased glycoprotein secretion; sulfuric acid was
3
relatively inactive, requiring concentrations in excess of 100 mg/m to produce changes in
XRD12B/A 12-62 2-5-81
-------
SOX12C/A 12 2-5-81
TABLE 12-13. EFFECTS OF CHRONIC EXPOSURE TO SULFUR OXIDES AND PARTICULATE MATTER
Concentration
Duration
Species
Results
Reference
ro
i
ci
to
Various combinations of S02, IB mo,
H2S04 (0.5 to 3.4 Mm, HMO), continuous
and fly ash (3.5 to 5.9 Mm,
MMD): S02l H2S04 + fly ash,
S02 + H2S04, S02 + H2S04 +
fly ash
0.9 mg/m3 H2S04 (0.49 MM, 12 mo,
HMD); 0.08 mg/m3 H2SO« continuous
(0.54 or 2.23 Mm. MMD) +
0.45 mg/m3 fly ash (3.5
or 5.31 Mm. MMO)
Approximately 0.56 mg/m3 fly 78 wk,
ash in combination with S02 at continuous
0.28, 2.62, or 13.1 mg/m3 (0.11,
1, or 5 ppm).
Approximately 0.56 mg/m3 fly ash
in combination with S02 at
0.28, 2.62, or 13.1 mg/m3
(0.11, 1, or 5 ppm)
13.4 mg/m3 (5.1 ppm) S02, or
0.89 mg/m3 H2S04 (90X <0.5
urn in diameter), or to a
combination of the two
52 wk.
continuous
21 hr/day, 620 days
Monkey No significant effects on hematology or pulmonary
function tests during exposure. At end of exposure
to 0.99 ppm S02 + 0.93 mg/m3 H2S04 (0.5 pm, MMD)
lungs had morphologica'i alterations in the bronchial
mucosa. Exposure to 1.01 upm S02 +0.88 mg/m3 H-SO.
(0.54 Mm, MMD) + 0.41 mg/m fly ash (4,1 Mm, MMD} hid
similar alterations, thus fly ash did not enhance
effect. Exnosure to 0.99 mg/m3 H.SO. (0.64 \w, MMD)
+ 0.55 mg/m3 fly as (5.34 \>m, MMD} hid slight
alterations.
Guinea pig No significant effects on hematology, pulmonary
function, or morphology.
Monkey No effects on pulmonary function, hematology,
or morphology.
Guinea pig No effects on pulmonary function, hematology,
or morphology.
Dog After 225 days, dogs receiving H2S04 had a lower
diffusing capacity for CO than those that did not
receive H2S04. In the S02-exposed group, pulmonary
compliance was reduced and pulmonary resistance was
increased compared to dogs that did not receive S02.
Dogs not pre-exposed to N02 who received S02 + H2S04
had a smaller residual volume than all other dogs.
After 620 days, pulmonary function was altered from
sulfur oxide exposure but no hematological or
morphological changes occurred. S02 did not produce
any effects except for an increase in mean nitrogen
washout. H2S04 decreased diffusing capacity
for CO, residual volume, and net lung volume and
increase in total expiratory resistance.
Total lung capacity, inspiratory capacity functional
residual capacity were decreased. Total lung weight
and heart rate were also decreased.
Alarie et al. , 1975
Alarie et al., 1975
Alarie et al., 1973b
Alarie et al., 1973b
Lewis et al., 1969, 1973
-------
SOX12C/A 13 2-5-81
TABLE 12-13 (continued).
Concentration
Duration
Species
Results
Reference
(see Table 12-12)
16 hr/day, 68 mo
Dog
cr>
-p.
5.24 mg/m3 (2 ppm) S02, or 0.56
mg/m3 carbon (1.8 to 2.2 urn,
HMD), or in combination
1.4 mq/m3 H2SO< plus 1.5
mg/m3 carbon (0.4 urn, mean
particle diameter), or 1.5
mg/m3 carbon only (0.3 urn,
mean particle diameter)
1.1 mg/m3 H2S04 (0.12 urn, mean
size), or 1.5 mg/m3 carbon (0.3
urn, mean size), or in combination
100 hr/wk, 192 days
House
3 hr/day, 5 day/wk,
20 wk
3 hr
House
Hamster
After 18 or 36 mo exposure no changes in pulmonary
function. Residual volumes increased in dogs
receiving R + SO compared to I + SO , SO , and CA.
Residual volumesxof the SO group were lower than of
the CA group. Hore dogs of the I + SO had higher
total expiratory resistance than their controls
(CA and SO ). The ratio of residual volume to total
lung capacity was higher in R + SO than CA. 32 to 36
mo after exposure ceased, the SO group had lung
weight, total lung capacity, and displaced
volume of the processed right lung increased over
controls (CA). SO dogs had loss of cilia in the
conducting airways. SO + R had loss of cilia
and squamous metaplasia. Exposure to R + S0x
and I + SO produced nonciliated bronchiolar
cell hyperjhasia and an increase in interalveolar
pores and alveolar air space enlargement.
For the pulmonary immune system, only exposure to
the combination caused significant effects. After
192 days, the systemic immune system was affected
in all 3 exposure groups; carbon and carbon + S02
were more effective than S02, although S02 did
cause significant effects.
Altered the immune system. Morphological changes
observed; more severe with carbon only exposure.
Carbon caused no change in ciliary beat frequency.
Ciliary beat frequency was depressed after
H2SOH exposure. The combination produced similar
effects, but recovery had occurred by 48 hr post-
exposure. Up to 48 hr after exposure H2SO« +
carbon resulted in more tissue destruction than
either pollutant alone.
Lewis et al., 1969,
1973
Zarkower, 1972
Renters et al., 1979
Schiff et al., 1979
-------
*
glycoprotein secretion. The lung DMA, RNA, and protein content increased in the group exposed
to ozone and sulfuric acid aerosols, while the ozone-exposed group had only a small increase
and the sulfuric acid group had none.
Grose et al. (1980) investigated the interaction of H-SO. and 03 on ciliary beat fre-
quency in the trachea of hamsters. A 2 hr exposure to 0.88 mg/m3 H2$04 (0.23 pm, VMD) signi-
ficantly depressed ciliary beat frequency. By 72 hr after exposure, recovery had occurred.
Hamsters exposed to 0.196 mg/m (0.1 ppm) 03 for 3 hr were not significantly affected.
However, when animals were exposed in sequence, first to 0_ and then to H2S04> ciliary beat
frequency was decreased significantly, but to a lesser extent than that caused by H2$04 alone.
Analysis showed that antagonism (p < 0.05) occurred in this sequential exposure.
Gardner et al. (1977a) found that the sequence of exposure to sulfuric acid aerosols and
ozone altered the response of mice to airborne infections. Mice were exposed alone or in
sequence to 0.196 mg/m (0.1 ppm) ozone for 3 hr and to 0.9 mg/m sulfuric acid aerosol (VMC
0.23 urn ± 2.4 SD, geometric) for 2 hr. When given alone, neither pollutant caused a
statistically significant increase in the mortality to a subsequent infection with S.
pyogenes. When the pollutants were given sequentially, a significant increase in mortality
occurred only when ozone was given immediately before exposure to sulfuric acid, and the
response was additive. The reverse procedure had no effect on mortality due to S. pyogenes
infections. Because photochemical oxidants and sulfur oxides often co-exist in polluted air,
these studies are of very practical importance. The question of the temporal sequence has
been poorly investigated. Simple mechanisms to predict this additive response sequence are
not apparent. Thus, the results are opposite those of the Grose et al. (1980) study described
above with the tracheal model which showed that sequential exposure to 0, and H_S04 had an
antagonisitic effect. The reasons for this difference are not known. However, the infecti-
vity model is thought to reflect alveolar level effects (Gardner and Graham, 1977). whereas
the ciliary beat frequency model is a measure of effects at the level of the trachea. In
addition different animal species were used. These findings also indicate the complexity of
interaction effects and the need to exercise care in extrapolating the effects of pollutants
from one parameter to another (see Table 12-14).
12.5 CARCINOGENESIS AND MUTAGENESIS OF SULFUR COMPOUNDS AND ATMOSPHERIC
PARTICLES
Attempts have been made for several decades to correlate various indices of particulate
air pollution with the development of cancer in man. In many cases a positive association has
been found between increased community air pollution and cancer of the lungs and/or gastro-
intestinal tract. This knowledge has led to suspicions concerning the chemical nature of that
portion or portions of airborne particulate matter which may be contributing to an excess of
human cancer. At least three classes of potential etiologic agents have been studied in this
regard: organic matter (including polycyclic hydrocarbons) which is adsorbed to suspended
particles; sulfur oxides; and trace metals.
XRD12B/A 12-65 2-5-81
-------
SOX12C/A 14 2-5-81
TABLE 12-14. EFFECTS OF INTERACTION OF SULFUR OXIDES AND OZONE
Concentration
Duration
Species
Results
Reference
ro
i
en
10 mg/ma (1 yin, HMD) H2S04
aerosol, or 3.9 mg/m3 (2 ppm)
03, or combination of the two
10 mg/m3 (50% equivalent aero-
dynamic diameter, 0.83 put, o =
1.66) H2S04 aerosol, or 1.029
mg/m3 (0.52 ppm) 03, or com-
bination of the two
1 mg/m3 H2S04 aerosol and
0.78 to 0.98 mg/m3 (0.4 to
0.5 ppm) 03
0.196 mg/m3 (0.1 ppm) 03;
0.9 mg/m3 H2S04 aerosol (VMC
0.23 pm ± 2.4 SO, geometric)
exposed alone or in sequence
0.196 mg/m3 (0.1 ppm) 03;
0.88 mg/m3 H2SO« aerosol (0.23
urn, VMD) exposed alone or In
sequence
6 hr/day, 2 or 7
days
6 hr/day, S day/wk,
6 mo
3 days,
continuous
3 hr, 03;
2 hr, H2SO«
3 hr, 03;
2 hr. H2SO«
Rat and No synergism in effect on ratio of lung to body
Guinea pig weight. Histological lesions were those ascribed
to 03 alone.
Rat and Morphological alterations due to 03 alone.
Guinea pig
Rat Synergistic effects. Glycoprotein synthesis was
stimulated in trachea! ring explants; lung DNA,
RNA, and protein content increased.
Mouse In response to airborne infections a significant
increase in mortality only when 03 was given
immediately before exposure to H2S04, and the
response was additive.
Hamster H2S04 depressed ciliary beat frequency.
By 72 hr after exposure, recovery had occurred.
03 exposure had no effect. Sequential 03 then
H2S04 exposure decreased ciliary beat frequency
significantly but to a lesser extent than that
caused by H2S04 alone.
Cavender et al., 1977
Cavender et al., 1978
Last and Cross, 1978
Gardner et al., 1977a
Grose et al., 1980
-------
*
Test systems for the bioassay of potential mutagens and carcinogens are diverse, ranging
from the measurement of chemically-induced reverse mutations in bacteria to the frank pro-
duction of carcinomas by administration to mammals. However, it is commonly believed that
fundamental similarities exist between the molecular mechanisms of both mutagenesis and
carcinogenesis. This assumption is based on the theory that chemical interaction with DNA
and/or other critical cellular macromolecules initiates a mutagenic or carcinogenic trans-
formation.
Because of the relationship between molecular events involved in mutagenesis and
carcinogenesis (Miller, 1978), the demonstration of mutagenic activity for a substance is
generally taken as strong presumptive evidence for the existence of carcinogenic activity.
Therefore, it is believed that an investigation of the mutagenicity of a substance may be
predictive of its carcinogenic potential, and may serve as an early warning of a possible
threat to human health in cases where positive results are obtained.
12.5.1 Airborne Particulate Matter
12.5.1.1 In Vitro Mutagenesis Assays of Particulate Matter—Organic material associated with
airborne particles has been investigated to a limited extent for mutagenic and carcinogenic
potential. In these studies, particulate material is experimentally limited to that which is
retained by the filter medium used (glass fiber, paper...etc.). Organic compounds associated
with aqueous particles cannot effectively be trapped, and thus there is no information on the
biological effect or nature of these compounds. The particles that have created most interest
are those with a carbonaceous core. These particles, because of their large surface area,
adsorb many organic compounds some of which are known to be mutagenic and carcinogenic, such
as benzo(a)pyrene. Because of the small size (0.2-0.3 ^m mean diameter) of many of the
particles, they can be deposited in the respiratory regions of the lung where the adsorbed
organic material can desorb into the alveolar fluid and enter the associated tissue. The
ability of soluble proteins to leach mutagens off particulates has been demonstrated using
horse serum and coal fly ash (Crisp et al., 1978).
A number of studies were conducted with fractionated extracts of particulate matter from
urban air in order to obtain information on the chemical nature of the mutagens present
(Dehnen et al., 1977; Teranishi et al., 1978; Miller and Alefheim, 1980; Tokiwa et al., 1980).
Estimates have been made as to the relative mutagenicity of each extract; however, due to the
possible interaction among the many compounds present in any fraction of the extracts the only
conclusion that can be drawn is that both the polar and neutral fraction contain significant
portions of the total mutagenic activity. The polar fraction contained direct acting
mutagens. Some could be chemical derivatives of polycyclic aromatic hydrocarbon (PAH)
compounds. At present the identity of compounds which are acting as direct mutagens is
uncertain.
In a similar manner as in studies with airborne particulate matter, mutagens were
extracted from particles emitted from a coal powered electric plant (Crisp et al., 1978;
XRD12B/A
12-67 2-5-81
-------
Kubitschek et al., 1979), gasoline engines (Wang et al., 1978), and light-duty and heavy-duty
diesel engines (Huisingh et al., 1977). The extracts obtained from all sources were direct
acting frame-shift mutagens. Only in the heavy duty diesel engine study was fractionation
carried out on the crude extract. A review of diesel engine particulate matter is available
(Santodonato, 1978).
The Salmonel la assay has been used in an attempt to define air quality by measuring the
mutagenic potential of airborne particulates. Tokiwa et al. (1977) compared ths number of
revertants per ^ig of particulate matter collected in the industrial area of Ohmata with that
collected in the residential area of Fukuoka, Japan. In a similar manner Pitts et al. (1978)
compared eight urban samples in the California South Coast Basin with one collected in a rural
area of the San Bernadino mountains. In both cases the mutagenic activity was less in the
residential and rural areas compared to that observed in the urban areas. Also, mutagenic
potential was determined in a quantitative manner for a variety of air samples collected in
Chicago (Commoner et al., 1978). In order to rank samples, the inverse of the minimum
quantity of particulate matter needed to obtain a significant Ames assay result was
calculated. Again, mutagenic potential was correlated with urban pollution and prevailing
concentration gradients from sources of pollution.
Caution must be exercised when comparing in a quantitative manner results of Ames assays
on complex environmental mixtures. Indirect mutagenesis is extremely difficult to quantitate,
since microsomal oxidation to non-reactive as well as reactive compounds occurs. Mixtures of
direct and indirect mutagens may not produce an additive result. For any valid comparison
there has to be nearly complete separation of these two types of mutagens (Commoner et al.,
1978). Also, the effects on mutagenesis of synergism and antagonism among compounds in
complex mixtures has not been adequately investigated. In the case of complex mixtures
obtained from tar-sand, the mutagenic activity of the known mutagen, 2-aminoanthracene, was
greatly inhibited by interaction with the mixture (Shahin and Fournier, 1978). For these
reasons a quantitative assessment of air quality is not readily obtainable with the use of the
Ames Salmonel la mutagenicity assay.
The data obtained with mammalian cell transformation assays support the conclusions
derived from the Ames Salmonella assays. There appears to be a variety of biologically active
agents present in the extracts of airborne particulate matter, and these agents are of both a
polar and nonpolar nature. The identity of these compounds is unknown; however, the activity
present is greater than that which could be accounted for by the PAH present in the samples.
Even though the cells transformed by extracts of particulate matter formed tumors when
injected into newborn mice, it is presently unclear how the process of transformation in
virus-infected cells relates to the process of chemical carcinogenesis. Hence, cell transfor-
mation assays should be considered in the same way as Ames assays; that is, as only an
indicator of the presence of biologically active compounds.
XRD12B/A 12-68 2-5-81
-------
*
The dominant lethal assay of Epstein et al. (1972) is the only short term j_n vivo assay
performed on airborne participate extracts. The water soluble and benzene soluble fractions
produced no fetal deaths or preimplantation losses beyond control limits. On the other hand,
the oxygenated fraction showed significant fetal deaths and decreased total implants.
12.5.1.2. Tumorigenesis of Participate Extracts—It was realized as early as the 1930's that
increasing amounts of particulate matter in the air may correlate with the increasing rate of
human lung cancer. Some of the earliest i_n vivo experiments dealt with the repeated exposure
of mice to clouds of soot, followed by autopsy examination for tumors at the end of their
natural lifespan. A number of different kinds of soot have been chosen for these studies due
to their significant contribution to airborne particulate matter. Upon bioassay of soot from
chimneys (Campbell, 1939; Seelig and Benignus, 1938), motor exhaust (Campbell, 1939), and air-
borne particulate matter collected in the vicinity of a factory and roadway (McDonald and
Woodhouse, 1942), a slight increase over control in the number of lung tumors was observed.
Only in the case where road dust from a freshly tarred road was used were there significant
increases, with 57 percent of the experimental and 8 percent of the control group having lung
tumors (Campbell, 1934). However, when five years later dust from the same road, which had
not been retarred, was again tested only 8 percent of the experimental group and 1.4 percent
of the control group developed lung tumors (Campbell, 1942). In a recent study with lifetime
exposure of rats to automotive exhaust, no tumors were detected in the lungs of the treated
animals. Although these studies have all attempted to demonstrate the potential of airborne
particulate matter to cause lung tumors, the results obtained are ambiguous due to the low
tumor incidence and the small size of the animal groups.
Among the various compounds associated with airborne particles, PAH have received the
greatest attention with regard to carcinogenic potential. PAH were the first compounds ever
shown to be associated with carcinogenesis. To this day, carcinogenic PAH are still distin-
guished by several unique features: (a) several compounds of this class are among the most
potent animal carcinogens known to exist, producing tumors by single exposures to microgram
quantities; (b) they act both at the site of application and at organs distant from the site
of absorption; and (c) their effects have been demonstrated in nearly every tissue and species
tested, regardless of the route of administration. The most widely studied PAH, benzo(a)-
pyrene, is ubiquitous in the environment and produces in animals tumors which closely resemble
human carcinomas.
The production of lung tumors with airborne particulates has been extremely difficult.
However, organic extracts of airborne particulates readily cause tumors when injected subcu-
taneously into mice. As early as 1942 sarcomas were produced in mice using the benzene
extracts of particulate matter collected from an urban area (Leiter and Shear, 1942; Leiter
and Shimkin, 1942). In these initial studies the tumor incidence was low, with only 8 percent
of the mice developing tumors by the end of the study; however, none of the control mice had
sarcomas. In one later study, the tumor incidence was as high as 61 percent when particles
XRD12B/A 12-69 2-5-81
-------
were collected in the vicinity, of a petrochemical plant (Rigdon and Neal, 1971). Even in this
case of high tumor production, no increase in the incidence of tumors over the spontaneous
rate was observed in any organ of the animal distant to the site of injection. Only when neo-
natal mice were injected subcutaneously with particulate extracts did tumors appear distant
from the injection site (Epstein et al., 1966), with a very high incidence of hepatomas (83
percent) and multiple pulmonary adenomas (67 percent). Remote tumor formation after sub-
cutaneous injection of neonatal mice was confirmed with both the crude extract of particles
collected in New York City and subfractions of this extract; the predominant tumors were again
hepatomas (Asahina et al., 1972).
The carcinogenic nature of extracts of particulate matter has also been demonstrated by
studies involving skin painting on the backs of mice. With repeated application (three times
per week for the life of the animal) of the benzene extract of particulates collected in the
Los Angeles area, papillomas were formed which subsequently progressed to carcinomas (Kotin et
al., 1954). Papillomas first appeared after 465 days, and at the time the data were presented
42 percent of the mice had developed tumors. Although papillomas and carcinomas of the skin
were the most commonly observed tumors, lung tumors have also been noted after skin applica-
tion (Clemo et al., 1955). Among the different methods of administering particulate extracts
to the mouse for bioassay, skin painting yields the highest tumor incidence, with greater than
90 percent of the surviving animals in some cases developing tumors.
In subsequent studies, the phenomenon of two-stage tumorigenesis was used to characterize
further the biological activity in airborne particulates. In two-stage tumorigenesis an
initiator is an agent (usually a carcinogen) which, when applied in a single dose to the skin
of a mouse does not produce tumors at the applied concentration, but predisposes the skin so
that later repeated application of a promoter (an agent that by itself will not produce tumors)
will cause the formation of tumors. A complete carcinogen is one which, if applied in suffi-
cient concentration, can produce tumors by itself. Extracts of airborne particles from
Detroit were fractionated, and the fractions examined for complete carcinogenicity and tumor
initiating and promoting activity (Stern, 1968; Wynder and Hoffman, 1962). Only the whole
extract and the aromatic fraction proved to be a complete carcinogen, while the insoluble,
acidic, aliphatic and oxygenated fractions produced no tumors (there was insufficient basic
fraction to perform the assay).
In order to examine the aromatic fraction for initiating activity, this fraction was
applied to the backs of mice in a sub-tumorigenic dose followed by repeated application of the
known promoter croton oil. Tumor initiating activity corresponded in a general way to the
benzo(a)pyrene content of the fraction. The other fractions of the particulate extract were
not tested for initiating activity. It should be noted that an initiator does not necessarily
have to be a complete carcinogen, although most if not all complete carcinogens will initiate
if applied at a low dose where their complete carcinogenic action is not apparent. For this
reason it is possible that some of the fractions could have initiating activity even though
XRD12B/A 12-70 2-5-81
-------
they did not act as complet> .carcinogens when first tested. However, the relevance of two-
stage carcinogenesis to environmentally-caused cancer is not known.
Several contributing sources of airborne particulate matter, gasoline and diesel engines
and the soot from coal and oil burning furnaces, have been examined individually and shown to
produce tumors. Extracts of particulates from gasoline engines show carcinogenic activity
when painted on the backs of mice (Brune, 1977; Wynder and Hoffman, 1965) and when injected
subcutaneously (Pott et al., 1977). Extracts from diesel engines have shown tumorigem'c
activity in some studies but not in others; the same holds true for extracts of chimney soot
where activity was shown in some instances (Campbell, 1939) while not in others (Mittler and
Nicholson, 1957). The discrepancies among these results could be due to qualitative and/or
quantitative differences in the nature of the organic compounds adsorbed to the particles or
difference in assay systems. Differences may have existed in the operating parameters of the
generating source, or variations in particulate collection procedures. With diesel engines
the mode of operation (the load under which the engine was run), the type of fuel and the
temperature at which the particles were collected all affect the biological activity of the
sample. With soot collected from chimneys, an important consideration is the temperature at
which the particulate matter is collected. The organic material on particulates is generated
in the gaseous phase while condensation on nuclei occurs at lower temperatures. Unless
particles are collected under similar conditions, disparities will exist in their chemical
composition and biological activity. Taken together, it is nevertheless apparent that all the
major types of airborne particulate matter contain adsorbed compounds which are carcinogenic
to animals and may contribute in some degree to the incidence of human cancer associated with
exposure to urban particulate matter.
12.5.2 Potential Mutagenic Effects of Sulfite and SO,,
Bisulfite addition to cytosine can result in deamination to form uracil (Shapiro, 1977;
Fishbein, 1976). The result would be a DNA conversion of GC to AT sites and could be
mutagenic. Transamination of cytosine can occur through reaction of an amine with cytosine-
sulfite adduct. Since the nucleus is rich in polyamines, transamination is a likely event.
Deamination of cytosine occurs most readily in high (1 M) concentrations of sulfite; trans-
amination also requires high sulfite and amine concentrations. The decomposition of the
cytosine-sulfite adduct is the rate limiting step in both reactions. At the present time, no
clear evidence exists for mutagenicity caused by SO^ or sulfite. However, because of the
reactivity of sulfite with cytosine, the potential mutagenic properties of sulfite and S0?
have been examined. Such experiments have recently been reviewed (Shapiro, 1977; Fishbein,
1976). To date, microbial experiments with high concentrations of sulfite in acid solutions
in vitro have produced mutations. These conditions would be similar to those favoring deamina-
~3
tion of cytosine. Experiments conducted at low concentrations (> 10 m sulfite) and neutral
pH (7-7.4) have not provided clear-cut evidence of mutagenesis. The microbial assays were not
done with strains of Salmonella known to be sensitive to mutagens (Ames Assays). Background
XRD12B/A 12-71 2-5-81
-------
mutation rates, mechanisms of. error-prone repair, and corrections for cytotoxicity were not
studied. Negative experiments have been reported when insects (Drosophila) (Valencia et al.,
1973) and mammals (mice) were exposed. Cytotoxicity, rather than mutagenicity, appears
when cultured animal and human cells (Thompson and Pace, 1962; Nulsen et al., 1974; Kikigawa
and lizuka, 1972; Schneider and Calkins, 1971; Timson, 1973) are exposed to sulfite. (See
Table 12-15 for summary.)
12.5.3 Tumorigenes is in Animals Exposed to SO^ or SO,, and Benzo(a)pyrene
Tumorigenesis after exposure to SCL alone or to SCL and an aerosol of benzo(a)pyrene has
been examined. Mice were exposed over their lifetimes in a 180 liter chamber into which 500
ppm S02 was introduced at a rate of 20 ml/min for 5 minutes, 5 days/week (Peacock and Spence,
1967). The concentration used cannot be calculated accurately from the paper. Thus, no con-
centration-related effects can be deduced from this study. Examinations for tumors of the
lung and other organs were undertaken only in mice that survived longer than 300 days, since
no primary lung tumors had been seen in younger mice. Only tumors greater than 1 mm were
recorded. Primary pulmonary neoplasias increased in the males (n = 35) from 31 percent in the
control group to 54 percent in the S0?-exposed group and in the females (n = 30) from 17 to 43
percent. The incidence of the next most common tumors in this strain of mice, hepatomas and
lymphomatoses, was not affected. The authors classified only tumors which invaded blood
vessels as carcinoma. In males, S0? did not affect the incidence of malignant tumors (2/35, 6
percent in air group; 2/28, 7 percent in S0? group). However, in females, the incidence of
primary lung carcinoma increased from 0/30 in the controls to 4/30 (18 percent) in the SO^-
exposed mice. These were early studies and the statistical analysis reported in the paper is
vague. Therefore, Hasselblad and Stead (1980) analyzed the data reported in the Peacock and
Spence (1967) study. A one-sided Fisher's exact test was used. In the males, the incidence
of primary lung carcinoma was not significantly affected by SO- (p = 0.604). However, for
females SO- increased the incidence of primary lung carcinoma (p = 0.056). The incidence of
lung adenomas was marginally increased in males (p = 0.065) and significantly increased in
females (p = 0.011). It, thus, appears that female mice of this strain were more susceptible.
The significance of these increases (Peacock and Spence, 1967), therefore, is questionable.
Peacock and Spence concluded that the increased incidence of primary lung tumors was due to
the initial inflammatory reaction to SO-, followed by tolerance, which accelerated spontaneous
tumor development. They further state that this study does not "justify the classification of
S0? as a chemical carcinogen as generally understood."
Lung tumors or other significant pathological effects were not observed in hamsters
exposed for 98 wk to 26.2 mg/m (10 ppm) SO, for 6 hr/day, 5 days/wk for 534 exposure days or
3 3
to 9.17 mg/m (3.5 ppm) S02 plus 10 mg/m benzo(a)pyrene for 1 hr/day, 5 days/wk for 494
exposure days or to a combination of the 2 regimens (Laskin et al., 1970). When rats (Laskin
et al., 1970) were exposed to the same regimen, however, lung squamous cell carcinoma was
found in 5/21 (23.8 percent) animals receiving the combined exposure of 26.2 mg/m (10 ppm)
XRD12B/A 12-72 2-5-81
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TABLE 12-15. POTENTIAL MUTAGENIC EFFECTS OF S02/BISULFITE
ro
i
oo
Concentration SO,
1310 mg/m3
(500 ppm)
13.1 - 105 mg/m3
(5 - 40 ppm x 3 min)
14.9 mg/m3
Bisulfite
0.9 M HSO"
pH 5.0 J
3 M HSO'
pH 5-6 J
1 M HSO"
pH 5.2 J
5 x 10~3 M HSOZ
pH 3.6 J
0.04 or 0.08 M
0.0001M
0.01H
0.0001H
0.0040H
0.0025M
Organism
Phage T4-R11 System
Phage T4-R11
System
E. coll K12 &
K15
S. cerevlsiae
D. melanogaster
Hela cells
(Human)
Mouse fibroblasts &
Peritoneal macrophages
Human lymphocytes
Human lymphocytes
Mouse oocytes
Ewe oocytes
Cow oocytes
End Point
GC^AT or
deami nation of
cysocine
deami nation of
cytosine
GC-»AT or
deami nation of cytosine
Point Mutation
Point Mutation
Cytotoxicity
Point Mutation
Chromosomal aberrations
Cytotoxicity
Inhibition of mitosis
Inhibition of meiosis
Inhibition of meiosis
Inhibition of meiosis
Response Comments
+
± Poor dose
response
+
•f
May not be
bioavailable
+
.
-
»
+ Dose related
response
+ Observed
fuzziness of
+ chromosomes may
be due to cyto-
+ toxicity
Reference
Summers and
Drake, 1971
Hayatsu and Miura,
1970,
lida et al. , 1974
Mukai et al. ,
1970
Dorange and
Dupuy, 1972
Valencia et al. ,
1973
Thompson and Pace,
1962
Nulsen et al. , 1974
Kikigawa and
lizuka, 1972
Harman et al . ,
1970
Jagiello et al. ,
1975
-------
*
S02 for 6 hr/day and 9.17 mg/m (3.5 ppm) S02 plus 10 mg/m benzo(a)pyrene for 1 hr/day and in
2/21 (9.5 percent) animals exposed to the benzo(a)pyrene plus SO, for 1 hr/day. Renal metasta-
3
sis also occurred. Control rats exposed to air (n = 3) or to 26.2 mg/m (10 ppm) S02 (n = 3)
had no tumors.
This study was subsequently extended to lifetime (exact time not specified) exposures (5
days/wk) of rats (Laskin et al., 1976). Exposure to air alone (n = 15) or to 26.2 mg/m (10
ppm) S09 (n = 15) for 6 hr/day caused no cancers (squamous cell carcinoma). A 1 hr/day expo-
3
sure to 10 mg/m benzo(a)pyrene caused cancer in 1/30 (3.3 percent) rats. A 6 hr/day exposure
3 3
to 26.2 mg/m (10 ppm) S00 plus a 1 hr/day exposure to 10 mg/m benzo(a)pyrene resulted in a
3
cancer incidence cf 6.7 percent (2/30). When animals received a combination of 10 mg/m benzo-
(a) pyrene and 10.48 mg/m (4 ppm) S00, 4/45 (8.9 percent) of the rats had cancer. The highest
3
incidence (19.6 percent, 9/46) was found in animals exposed for 6 hr/day to 26.2 mg/m (10 ppm)
S02 plus a combination of 10 mg/m benzo(a)pyrene and 10.48 mg/m (4 ppm) SOp for 1 hr/day.
The biological significance of these studies (Table 12-16) is complex and difficult to
interpret, particularly since statistical analyses were not reported in the publications.
Hasselblad and Stead (1980) analyzed the tumor incidence data of the later study (Laskin et
al., 1976) using a multiple probit approach. The cancer incidence increases due to S02 alone
and BaP alone were not statistically significant (p = 0.116 and p = 0.113, respectively).
However, the increase due to the combination of BaP and S0? was significant (p = 0.005). Few
S02 exposure experiments have been carried out for the near lifetime of the animal as in the
early mouse study (Peacock and Spence, 1967) and the subsequent rat study (Laskin et al.,
1976). Most work has centered around short-term acute studies in which the experimental
design and other aspects of the study would be inadequate to detect a low incidence of tumors.
The incidence of lung tumors increases as the animals age; but no historical control data are
available for the colony of rats used (Laskin et al., 1970; 1976), making the increased inci-
dence by the combined S0p-benzo(a)pyrene treatment difficult to interpret. Tumor formation
may be a multistep process, requiring more than just the initiation for expression. In order
to assure the biological and statistical validity of such tumorigenicity studies a careful
control of the diet is needed, along with detailed records of the incidence of tumors through-
out the life span of the animals. The absolute incidence of tumors, as well as the rate of
occurrence should be determined for a large number of control animals. Given the lack of
experimental details in the non-peer reviewed publication (Laskin et al., 1976) and the diffi-
culty of performing statistical analyses not done by the author, especially with the experi-
mental design used, it is not possible to come to a definitive conclusion about the results of
this study.
12.5.4 Effects of Trace Metals Found In Atmospheric Particles
Among the numerous trace metals found in the atmosphere, evidence of carcinogenicity in
experimental animals has been shown for at least nine (beryllium, cadmium, cobalt, chromium,
iron, nickel, lead, zinc, titanium). Limited evidence also points to compounds of molybdenum
XRD12B/A 12-74 2-5-81
-------
SOX12C/A 3 2-5-81
TABLE 12-16. TUMOROGENESIS IN ANIMALS EXPOSED TO S02 OR S02 AND BEN20(a)PYRENE
Concentration
Duration
Species
Results
Reference
(See Text for details)
5 min/days, 5 day/wk, Nice
lifetime
26.2 mg/m3 (10 ppm) S02 for 534
exposure days, or 1 hr exposure
<5 day/wk) to 9.17 mg/m3 (3.5
ppm) S02 + 10 mg/m3 benzo(a)-
pyrene for 494 exposure days, or
a combination of the 2 regimens
26.2 mg/m3 (10 ppm) S02 for 534
exposure days, or 1 hr exposure
(5 day/wk) to 9.17 mg/nr (3.5 ppm)
S02 + 10 mg/m3 benzo(a)pyrene
for 494 exposure days, or a com-
bination of the 2 r«gimens
6 hr/days, 5 day/wk,
98 wk
Hamster
6 hr/day,
98 wk
5 days/wk, Rat
26.2 mg/m3 (10 ppm) S02, or 10.5
mg/m3 (4 ppm) S02 * 10 mg/m3
benzo(a)pyrene, or a combination
of the 2 regimes
Lifetime (5 days/wk) Rat
Primary pulmonary neoplasias increased in the
males from 31 to 54% and in the females from 17
to 43%. Incidence of hepatomas and lymphomatoses
were not affected. Carcinoma incidence increased
in females from 0 to 18%; no change in carcinomas
in males
No lung tumors or other pathological effects
Peacock and Spence, 1967
Laskin et al., 1970
Lung squamous cell carcinoma: 5/21 (23.8%) animals
exposed to combined regimen of .26.2 mg/m3
(10 ppm) S02 for 6 hr/day and 9.17 mg/m3 (3.5 ppm)
S02 *• 10 mg/m3 benzo(a)pyrene for 1 hr/day; 2/21
(9.5%) animals exposed to benzo(a)pyrene + S02
for 1 hr/day; 0/3 in animals exposed to 26.2 mg/m3
(10 ppm) S02; and 0/3 in animals exposed to air
A 1 hr/day exposure to 10 mg/m3 benzo(a)pyrene
caused cancer in 1/30 (3.3%). A 6 hr/day expo-
sure to 26.2 mg/m3 (10 ppm) S02 + a 1 hr/day
exposure to 10 mg/m3 benzo(a)pyrene resulted in
squamous cell carcinoma incidence of 6.7% (2/30).
A combination of 10 mg/m3 benzo(a)pyrene and 10.5
mg/m3 (4 ppm) caused cancer in 4/45 (8.9%). Highest
incidence (19.6%, 9/46) found in exposure for 6 hr/
day to 26.2 mg/m3 (10 ppm) S02 + 10 mg/m3 benzo(a)-
pyrene and 10.5 mg/m3 (4 ppm) S02 for 1 hr/day. The
air control had an incidence of 0/15 and the 26.2 mg/m3
(10 ppm) SO2 exposure caused an incidence of 0/15.
Laskin et al., 1970
Laskin et al., 1976
-------
and manganese as possible tumorigens (Clemo and Miller, 1960). Moreover, three of these metals
(cadmium, chromium, nickel), in addition to arsenic, are implicated as human carcinogens.
Although trace metals are ubiquitous in the environment, their levels are generally so
low that it is difficult to predict the magnitude of carcinogenic risk in community settings.
This problem is compounded by the fact that clear dose-response relationships have not been
well-defined for most carcinogenic metals. For the present it is likely that the possible role
of trace metals in the production of cancer due to particulate air pollution will be limited
to qualitative judgments.
The topic of metal carcinogenesis has been extensively reviewed in recent years from
various perspectives (Furst, 1978; Furst and Haro, 1969; Sunderman, 1978; 1979). These sur-
veys generally conclude that with certain compounds tumors can be induced via a mechanism
which is apparently distinct from the phenomenon of so-called solid-state or foreign-body car-
cinogenesis. However, it is still debatable in many cases whether metal-induced tumors which
are associated with a particular route of administration (e.g., local sarcoma by subcutaneous
implantation) are indicative of true chemical carcinogenesis. While most carcinogenic metals
are active only in the form of organic and inorganic salts, for nickel and cadmium it appears
that both the pure elemental form as well as several of their salts are carcinogenic.
One of the most widely recognized and well-studied carcinogenic metals is nickel (Inter-
national Agency for Research on Cancer (IARC), 1973b; 1976b]. Sunderman (1979, 1978) indi-
cated that nickel subsulfide (Ni,S?) is probably the most potent carcinogenic metal studied to
date. Single intramuscular injections of 5 umol (1.2 mg) or 10 umol (2.5 mg) to Fischer rats
produced rhabdomyosarcomas in 77 percent and 93 percent of the treated animals, respectively.
Numerous investigators have confirmed that Ni.,S? produces local sarcomas following injection,
and one group has indicated that chronic inhalation of Ni,S2 in rats caused lung cancer (IARC,
1973b; 1976b). Several other forms of nickel have shown both positive and negative carcino-
genic activity. The chronic inhalation of nickel carbonyl (Ni(CO).) by rats at levels as low
as 0.03 mg/1 has produced pulmonary carcinomas (IARC, 1976b). In addition, Lau et al. (1972)
induced carcinomas and sarcomas in various organs, including liver and kidney, by multiple
intravenous injections of Ni(CO). to rats. Inhalation of elemental nickel powder has produced
equivocal results in mice, rats, and guinea pigs, and negative results in hamsters (IARC,
1976b). Single and repeated intramuscular injections of nickel powder induced local tumors in
rats and hamsters, although intravenous injections were either marginally effective (rat) or
ineffective (mouse, rabbit) (IARC, 1976b). A single intrapleural injection of nickel powder
(0.02 ml of a 0.06 percent suspension) did not produce neoplasms in mice; multiple intra-
pleural injections at high doses in rats were effective in the induction of local tumors
(IARC, 1976b).
The toxicology and carcinogenic potential of cadmium have been the subject of extensive
reviews in the past several years (IARC, 1976a; U.S. EPA, 1979; Towill et al., 1978). Cadmium
XRD12B/A 12-76 2-5-81
-------
is similar to nickel in that both the elemental form and several salts are carcinogenic, and
that oral administration is ineffective in producing tumors. The ability of cadmium to induce
tumors by inhalation exposure has not been adequately studied. However, single or repeated
injections (intramuscular, subcutaneous) of cadmium powder, cadmium chloride (CdCK), cadmium
oxide (CdO), cadmium sulfate (CdS04), or cadmium sulfide (CdS) to rodents frequently produces
local sarcomas (Furst and Haro, 1969; IARC, 1976b; Sunderman, 1979). A unique feature of the
action of cadmium is that single subcutaneous injections of CdCK to rodents (3.7 - 5.5 mg/kg
body weight) leads to a high incidence of interstitial cell (Leydig cell) tumors of the
testis. Stoner et al. (1976) recently reported that cadmium acetate did not cause a signifi-
cant increase in pulmonary tumor response in the strain A mouse bioassay system.
Chromium in the hexavalent (but not trivalent) state has produced tumors following inhala-
tion, implantation, and injection (IARC, 1973a; Towill et al., 1978). The inhalation of mixed
chromate dust failed to induce lung tumors in mice, rats, and rabbits, although pulmonary ade-
nomas developed in mice exposed by inhalation to calcium chromate (CaCrO.) dust (IARC, 1973a).
Local sarcomas in rats, mice, and rabbits have resulted from the intramuscular, subcutaneous,
intrapleural, intraosseous, and intraperitoneal injection of chromium powder and hexavalent
chromium compounds (IARC, 1973a; Sunderman, 1979). Several groups of investigators, however,
have failed to induce tumors by the parenteral administration of chromium compounds.
Although arsenic is recognized as a human carcinogen based upon epidemiological data,
there is little evidence to indicate carcinogenic activity in experimental animals (Furst and
Haro, 1969; Sunderman, 1979). In particular, the chromic administration of arsenous trioxide
(As-CU) in drinking water (34 mg/1) to rats failed to induce tumors (Furst and Haro, 1969).
However, others have reported that the subcutaneous injection of a sodium arsenite compound
led to an increase in the incidence of lymphocytic leukemias and malignant lymphomas in preg-
nant Swiss mice and their offspring (Sunderman, 1979).
Although not generally recognized as a human carcinogen, lead compounds have shown con-
siderable carcinogenic activity in rodents [IARC, 1972; U.S. Environmental Protection Agency
(U.S. EPA), 1977]. Several studies confirmed that renal carcinomas result from the oral and
parenteral administration of lead phosphate, lead acetate, or basic lead acetate to rats and
mice, but not to hamsters. In addition, tumors of the testis (Leydig cell), adrenals,
thyroid, pituitary and prostate have been found among rats fed lead acetate (3-4 mg/day for 18
months) (U.S. EPA, 1977). In a recent study using the strain A mouse pulmonary tumor bioassay
system, Stoner et al. (1976) reported that lead subacetate caused a statistically significant
increase in tumor formation. However, a dose-response relationship could not be demonstrated.
Beryllium salts have induced pulmonary cancers upon inhalation and osteosarcomas upon
intravenous injection in a variety of animal species (IARC, 1972). Aerosols of beryllium
sulfate (BeSO.) induced pulmonary carcinomas in all of a group of 43 rats (34 mg/m for 56
weeks), and in 2 of 10 Rhesus monkeys inhaling the compound at 35 mg/m for 8 years (IARC,
XRD12B/A 12-77 2-5-81
-------
1972). In addition, 3 of 20 monkeys developed pulmonary cancers after the intrabronchial
and/or bronchomural implantation of beryllium oxide (5 percent suspension in saline).
Numerous investigators found that the intravenous injection of zinc beryllium silicate or
beryllium oxide caused malignant bone tumors (osteosarcoma) in rabbits (IARC, 1972; Sunderman,
1979).
Evidence to support the carcinogenic potential of zinc and iron is limited. Zinc
compounds (ZnCK, ZnSO., ZnNO,) are carcinogenic only by intratesticular injection (Furst and
Haro, 1969; Sunderman, 1979). When evaluated in the strain A mouse pulmonary tumor bioassay
system, zinc acetate was found to be negative (Stoner et al., 1976). Iron-polysaccharide
complexes (e.g., iron-dextran) have commonly produced local sarcomas upon injection in mice,
rats, and rabbits (Furst and Haro, 1969; IARC, 1973c). In contrast to the sarcomagenic
properties of iron-dextran, ferric oxide (Fe?0,, hematite) produced no tumors in hamsters
(intratracheal instillation), guinea pigs (inhalation) or rats (subcutaneous implantation).
The carcinogenicity of titanium has not been fully investigated. Chronic studies with
mice involving the ingestion of a titanium salt in the drinking water gave negative results
(Furst and Haro. 1969). However, Furst and Haro (1969) succeeded in producing local sarcomas
and neoplasms in distant organs by the intramuscular injection of titanocene to rats and mice.
In addition, local fibrosarcomas developed in three out of 50 rats injected with titanium
dioxide.
Several groups of investigators have indicated that sarcomas can be produced by the
subcutaneous, intramuscular, or intraosseous injection of cobalt powder, to rabbits and rats
(Sunderman, 1979). Little additional data are available regarding the carcinogenic potential
of cobalt. Stoner et al. (1976) recently found that cobalt acetate had no effect on tumor in-
cidence in the strain A mouse pulmonary tumor bioassay system.
Selenium has recently received considerable attention as a potential carcinogen, and is
found in ambient air (IARC, 1975). Oral administration of sodium selenite and sodium selenate
to mice and rats has resulted in a wide range of neoplasmas including sarcomas, "lymphoma-
leukemias," mammary carcinomas, lung adenocarcinomas, and hepatic tumors (IARC, 1975).
Because selenium is an essential trace element, its role in the etiology of environmentally-
induced cancers remains unclear.
In an attempt to understand the fundamental biological activity of metals and its
relationship to carcinogenesis, numerous j_n vitro experiments have been conducted. Many of
these studies attempt to exploit the strong formal relationships between molecular events
involved in mutagenesis and carcinogenesis. In particular, the interaction of xenobiotics
with nucleic acids is believed to be a critical event in mutagenesis and/or cell
transformation. Cultures of mammalian cells and bacteria, as well as cell-free systems,
have been used to explore the potential mutagenicity/carcinogenicity of various metals.
Several biochemical studies have been completed which point to a possible direct action
on nucleic acids by metal cations as the basis for metal carcinogenesis. Murray and Feisel
XRD12B/A 12-78 2-5-81
-------
lie
(1976) prepared mixtures of synthetic polynucleotides and measured the changes in the melting
curves induced by the addition of carcinogenic and non-carcinogenic metal salts at a 10 M
concentration. Both cadmium chloride (CdC^) and manganese chloride (MnCU) induced
alterations in spectrophotometric measurements which were indicative of mispairing of nucleo-
tide bases.
More extensive studies have been conducted on the ability of metal salts to affect the
fidelity of DNA synthesis in a cell-free system (Loeb et al., 1977; Sirover and Loeb, 1976).
These investigators found a high correlation between metals which were mutagenic/carcinogenic
and the ability to increase the error frequency of deoxynucleotide incorporation. Nine metals
were scored as positive in this system at concentrations between 20 uM and 150 uM; silver,
beryllium, copper, cadmium, cobalt, chromium, manganese, nickel, and lead. Negative results
were obtained with barium, calcium, aluminum, iron, potassium, magnesium, sodium, rubidium,
strontium, and zinc. The authors concluded that the fidelity of DNA synthesis may have
potential application as a screening technique for mutagenic/carcinogenic metals.
The recent proliferation of j_n vitro cell transformation assays has resulted in further
confirmation of the carcinogenic/mutagenic action of several metals. The most noteworthy cell
transformation studies thus far with metals have been those employing primary cultures of
Syrian hamster embryo cells (Costa, 1979; DiPaolo and Casto. 1979; DiPaolo et al., 1978).
Morphological transformation has been obtained with salts of nickel, lead, cadmium, chromium,
beryllium, and arsenic. Salts of iron, titanium, tungstate, zinc, and aluminum displayed no
transforming properties. Unfortunately, there has not yet been an extensive validation of any
single test system for screening of potential metal carcinogens. Moreover, techniques are not
yet available to elucidate the molecular mechanism of metal-induced transformation, or to
explain how the physicochemical state of the metal affects its carcinogenic potential.
12.6 CONCLUSIONS
12.6.1 Sulfur Dioxide
Once inhaled, S0? appears to be converted to its hydrated forms, sulfurous acid,
bisulfite, and sulfite. The rate of absorption and removal of inhaled S0? varies with
species, but it is at least 80 percent of the inhaled amount.
The metabolism of S0? is predominantly to sulfate and is mediated by the enzyme sulfite
oxidase. Since sulfite oxidase is a molybdenum containing enzyme, dietary factors could
influence the function of the enzyme. No conclusive evidence has yet been reported. The
reaction of bisulfite with serum proteins to form S-thiosulfates is rapid. The S-thiosulfates
are remarkably long-lived (t 1/2 = 4.1 days in rabbits), supplying a circulating pool of
bisulfite which can reach all tissues. Since some circulating S-thiosulfates decompose to S0»
which is exhaled, S-thiosulfates can donate their bisulfite content to distal tissues.
An immediate effect of acute (5 1 hr) SO- inhalation is either a decrease in respiratory
rate or an increase in resistance to flow within the lung. The decrease in respiratory rate
depends on afferent conduction through the Vth or IXth cranial nerve following activation of
XRD12B/A 12-79 2-5-81
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receptors in the nose and upper airways. Nasal air flow is decreased. The response is
transient in nature and occurs at 44.5 mg/m (17 ppm) SO-. Lower concentrations were not
tested.
The increased resistance to flow on inhalation of S0~ is mediated through receptors in
the bronchial tree and persists during continued exposure. With this physiological parameter,
lower concentrations of S0? have been observed to cause reproducible changes in respiration.
The increased resistance to flow of air in the lung on SO- inhalation represents the
activation of an autonomic reflex arc through the vagus nerves. The same reflex arc occurs in
man. The reflex is cholinergic since atropine blocks the reflex, presumably at preganglionic
synapses. The guinea pig is the most sensitive animal for measuring airway resistance, with
significant changes in pulmonary resistance to air flow occurring on the inhalation of
concentrations as low as 0.42 mg/m (0.16 ppm) S0? for 1 hr. Chronic exposures have produced
alterations in pulmonary function in cynomolgus monkeys, but only at concentrations greater
than 13.1 mg/m (5 ppm). Dogs exposed to 13.4 mg/m (5.1 ppm) S02 for 21 hr/day for 225 days
had increased pulmonary flow resistance and decreased compliance. Lower concentrations were
not examined. It should be remembered that S0? appears to cause its immediate bronchocon-
strictive effect through action on airway smooth muscles, as evidenced by the antagonism of
the SOp-initiated bronchoconstriction by isoproterenol in man and animals. Since smooth
muscles adapt or fatigue during long-term stimulation, chronic exposure to S0? is not likely
to evidence bronchoconstriction equivalent to that occurring on short-term exposure.
Alterations in pulmonary function after chronic exposure to S0? are likely to occur through
other mechanisms, such as morphological changes in the airways or hypersecretion of mucus,
which will result in narrowing the airway. Concentration, rather than duration of exposure,
seems to be the most important parameter in determining responses to S0?, whether the response
is measured as a histopathological lesion or as a permanent alteration in respiration. There
is no theoretical hypothesis available at present to integrate the short-term effects observed
with 1 hr exposures and the effects of long-term exposures of several months.
In rats, histopathological effects of SO^ alone are confined to the bronchial epithelium,
with most of the effects occurring on the mucus secreting goblet cells. Goblet cell hyper-
trophy occurs on chronic exposure of rats, leading to the suggestion that S0? produces a
chronic bronchitis similar in many respects to that in man. Repeated exposure to a critical
concentration of SO,, (not less than 131 mg/m or 50 ppm) may be needed to produce the chronic
bronchitis. While SO^-produced chronic bronchitis in rats is similar to that in man and is a
useful model for the study of bronchitis, no evidence exists that chronic bronchitis is
produced in man from ambient concentrations of S0?.
The nasal mucosa of mice (particularly those with upper respiratory pathogens) was
3
altered by 72 hr exposure to 26.2 mg/m (10 ppm) S0«. Continous exposure to 0.37 to 3.35
3
mg/m (0.14 to 1.28 ppm) SOp for 78 wk did not cause any significant lung morphological
alterations in monkeys. The effects of near ambient concentrations of S0? on the morphology
and function of the nasal mucosa are not known.
XRD12B/A 12-80 2-5-81
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Some pulmonary host defense mechanisms are also affected by S0? exposure. After 10 and 23
days of exposure (7 hr/day, 5 days/wk) to 0.26 mg/m3 (0.1 ppm), clearance of particles from
the lower respiratory tract was accelerated in rats. At a higher concentration of S02 (2.62
mg/m , 1 ppm) there was an initial acceleration (at 10 days), followed by a slowing at 25
days. A 5 day (1.5 hr/day) exposure to 2.62 mg/m3 (1 ppm) reduced tracheal mucus flow in
dogs, but a longer exposure to this concentration caused no changes in ciliary beat frequency
of rats. These aberrations in tracheal clearance and mucus flow in several species are
consistent with the profound effects of higher concentrations of SO, on mucus glands in rats.
3
Antiviral defenses were altered by a 7 day continous exposure to 18.3 to 26.2 mg/m (7 to
10 ppm) SO- as evidenced by an increase in viral pneumonia. In this study, the combined
exposure to SO, and virus produced weight loss on exposure to concentrations as low as 9.43
3 1
mg/m (3.6 ppm) S02- Mice exposed to 13.1 mg/m (5 ppm) S02 for 3 hr/day for 1 to 15 days or
for 24 hr/day for 1 to 3 mo did not have increased susceptibility to bacterial lung disease.
A variety of changes in the humoral immune response of mice exposed for up to 196 days to 5.24
mg/m (2 ppm) have been reported.
Sulfur dioxide and bisulfite are mutagenic in microbial test systems (f_. coli and yeast
systems). The concentration of bisulfite was high (1m) and the pH low. The relevancy to
inhaled SO™ as a mutagen is not clear. A mechanism for the mutagenesis of SOp could be the
deamination of cytosine at high concentrations. Free radical reactions breaking glycosidic
bonds in DNA may be responsible at low concentrations. The potency of bisulfite in these j_n
vitro systems is moderate to weak when compared to agents such as nitrosamines or polycyclic
aromatic compounds. To date, experiments testing for mutagenicity or carcinogenicity by
bisulfite in mammals have been equivocal. On the basis of present evidence, one can not
decide whether or not bisulfite, and hence S0?, is a mutagen in mammals.
The influence of S0» on tumorigenesis has also been examined. Unfortunately, the two key
studies on tumorigenesis have not been replicated. Rats exposed (5 days/wk for 98 wk to a
lifetime) to 26.2 mg/m (10 ppm) SO, for 6 hr/day in combination with 9.2 or 10.5 mg/m (3.5
3
or 4 ppm) S0? plus 10 mg/m benzo(a)pyrene had an increased incidence of lung squamous cell
carcinoma. Hamsters were not affected. A reanalysis of the data shows that the increase in
tumors in rats due to S02 and benzo(a)pyrene is statistically significant. As a result of
these studies, the possibility exists that S02 may be a co-carcinogen in rats. The question
of carcinogenicity of SO, alone cannot be resolved at present. For the rat studies described
3
above, a total of 15 rats were exposed to 26.2 mg/m (10 ppm) S02 for 6 hr/day, 5 days/wk for
lifetimes, and none developed cancer. However, this sample size is small and would have a
very small probability of detecting a low cancer incidence. In a different study, mice were
exposed over their lifetimes to an indeterminable S02 concentration for 5 min/day, 5 days/wk.
This exposure increased the incidence of carcinoma in female, but not male, mice. Reanalysis
of the data showed the increased incidence of carcinoma in females was statistically signifi-
cant. The incidence of primary pulmonary neoplasias increased in both sexes. The investi-
gators for this mouse study state that although SO™ increased lung tumors, the results do "not
XRD12B/A 12-81 2-5-81
-------
justify the classification of. S02 as a chemical carcinogen as generally understood." Other
chronic SO- experiments have been conducted with several other animal species which included
lung morphology as an endpoint, but no lung tumors were reported. This does not negate the
positive studies, since they showed a species susceptibility to tumor development and were
conducted either at very high concentrations or in the presence of benzo(a)pyrene. The
general conclusion to be drawn from these studies is that SO- has not been proven to be a
carcinogen or co-carcinogen, but remains suspect.
12.6.2 Particulate Matter
The chemical and physical diversity of the particulate matter in the atmosphere presents
a severe limitation on the scope of the conclusions presented here. Most of the evidence for
adverse health effects of inhaled particles presented in this chapter relates to compounds
arising from sulfur oxides, e.g., sulfuric acid, ammonium sulfate, metal sulfates, and related
compounds. A brief treatment is presented for heavy metals and their compounds. A summary of
data related to organic material associated with particles is also presented, focusing pri-
marily on polycyclic organic compounds. Due to limitations of space, details dealt with in
other criteria documents or recent major reviews on specific elements and the broader aspects
of polycyclic organic compounds are presented by reference only. This chapter, then, should
not be taken as a summary of all of the data available on the health effects of atmospheric
particles, but rather as a selected summary related mostly to sulfur oxides. The reader
should refer to, and study, the more detailed reports before attempting to integrate the
present limited material into the generic problem of the effects of atmospheric particles.
Similarly, the subsequent section on the interactions between sulfur dioxide and particles
relates to a limited scope of the atmospheric particles.
All inhalation studies of particles available for review in this document were conducted
with particles which could be expected to be within the size range alveolar envelope of de-
position (>5 urn MMAD, depending upon the species exposed). Although particle deposition is
related to MMAD, the majority of studies did not report particle sizes as MMAD. A few j_n vitro
or intratracheal instillation studies have been performed which compared the effects of a wide
range of particles including those which occur in the atmospheric coarse mode particle sizes
(>2.5 urn Dae).
Reports disagree as to the potency of acute exposure to sulfate aerosols. Some investi-
gators contend that sulfuric acid is highly irritating, producing increases in pulmonary flow
resistance at low concentrations. The increased resistance to air flow in the lung was
directly proportional to the sulfate aerosol concentration inhaled. The bronchoconstriction
produced by zinc ammonium sulfate was similar in many properties to that produced by histamine
aerosols. Unlike SO^-initiated bronchoconstriction, intravenous atropine had no effect.
Inhaled or intravenous isoproterenol, however, blocked the zinc ammonium sulfate aerosol
bronchoconstriction. These data suggest that the zinc ammonium sulfate aerosol receptor and
presumably other sulfate receptors are not identical to the SO,, receptor. The two agents
XRD12B/A 12-82 2-5-81
-------
*
accordingly could act at separate sites in the lung. Histamine is implicated in the sulfate
aerosol action more clearly than in the bronchoconstricting action of S0?.
The lowest effective concentration producing bronchoconstriction so far reported was 0.1
mg/m H2$04 (1 hr) in the guinea pig. Particle size influenced the results in several ways
but the smaller sizes were generally more effective. Another study has observed an "all or
none" response (increased airway resistance) in guinea pigs exposed for 1 hr to 14.6, 24.3, or
48.3 mg/m H2S04. Exposure to lower concentrations (1.2 or 1.3 mg/m H-SO.) caused no effects.
Some of these conflicts may be due to differences in technique or in age or strain of guinea
pig. Large interindividual differences in dose-response curves are characteristic for inhaled
histamine. In man, dogs, cats, and guinea pigs, 100-fold differences in the bronchoconstric-
tive response to histamine have been observed. The individual dose-response curves are
remarkably reproducible. In dogs and guinea pigs the bronchoconstrictive response to
histamine fell within a single log-normal distribution, despite the large interindividual
differences in the dose of histamine required to elicit a specific response. These large
interindividual differences could represent differences in "susceptibility" of different
individuals, suggesting a small fraction of "susceptible" individuals; or they could represent
a very flat dose-response curve for a single population. Currently, the data favor a single
population hypothesis for histamine. The dose-response relationship for sulfate and sulfuric
acid aerosols is not adequate to differentiate between these two hypotheses. It is clear that
large interindividual differences in response to inhaled aerosols are a characteristic of the
biological response as measured by increased resistance to flow, regardless of the species
used, and are not an artifact of the exposure or measurement system.
Age may also play in important part in this response, since young guinea pigs are more
susceptible than older ones. For histamine sensitivity, age-dependence has been suggested as
an analog of juvenile asthma, but human airway sensitivity does not seem to follow the same
developmental pattern. Further research is needed to settle the question of special suscepti-
bility of young animals and children.
For the effects of 1 hr exposure of guinea pigs to sulfur oxides from one laboratory, an
apparent ranking of potency (for increased flow resistence) is as follows: H?SO. >
ZnS04(NH4)2S04 > Fe2(S04)3 > ZnS04 > (NH4)2S04 > NH4HS04, CuS04 > FeS04> Na2S04, MnS04- The
latter three caused no effects.
The toxicology of H?S04 is complicated by its partial concentration-dependent conversion
to (NH4)?SO. and NH4HS04 by ammonia in the breath or in the air of animal exposure chambers.
While this chemical reaction is stoichiometric, the actual concentrations of (NH4)2$04 and
NH.HSO. in the airways or chambers have not been measured definitively. Thus, comparing
results of H?SO. studies using animals to those using humans is confounded, particularly since
extensive neutralization would not be expected in the atmosphere of human exposure chambers.
One theory for the irritating action of sulfuric acid contends that sulfate salts can act to
promote release of histamine or other mediators of bronchoconstriction and is supported by
XRD12B/A 12-83 2-5-81
-------
*
biochemical and pharmacological evidence in 2 species. Anionic release of histamine may play
a role in the bronchial constriction as evidenced by the blockade with H-l antihistamines.
The effects of adrenergic agonists and antagonists suggest the involvement of tracheal smooth
muscle. Certainly, the clearance of sulfurous acid, bisulfite, sulfite, and sulfate from the
lung is influenced by the cations present in the aerosols inhaled simultaneously. Since
polluted air is such a complex mixture of these aerosols, the question of the toxicity of
ambient aerosols can not be approached on a simplistic basis by estimating toxicity from the
acidity or sulfate content alone.
Chronic exposure to HUSO, also produces changes in pulmonary function. Monkeys exposed to
3
0.48 mg/m H-SO. continously for 78 wk had altered distribution of ventilation early in the
3
exposure period. Higher concentrations (2.43 and 4.79 mg/m H?SO.) changed the distribution
of ventilation and increased respiratory rate, but caused no effects on other pulmonary
function measurements. A lower concentration (0.38 mg/m H,SO.) caused no effects. Morpho-
3
logical changes occurred at the lowest concentration tested (0.38 mg/m HLSO.). The effects
appeared to be related to size of the particle as well as to concentration. Major findings at
2.43 mg/m H^SO. included bronchiolar epithelial hyperplasia and thickening of the respiratory
bronchioles and alveolar walls. Guinea pigs exposed continously for 52 wk to 0.08 or 0.1
3 3
mg/m H?SO. had no effects on pulmonary function or morphology. Dogs which inhaled 0.89 mg/m
HpSO. for 620 days (21 hr/day) also had no morphological alterations. However, CO diffusing
capacity, residual volume, and net lung volume were decreased. Several other changes were
noted, including an increase in total expiratory resistance.
Sulfuric acid also alters mucociliary clearance which is responsible for clearing the
lung of viable or inanimate particles. These particles impact on the ciliated airways during
inhalation or reach this region as a result of alveolar clearance. A 1 hr exposure of dogs to
3 3
0.5 mg/m H-SO. increased tracheal mucocilary transport, whereas 1 mg/m H?SO. depressed this
rate. A 2 to 3 hr exposure to 0.9 to 1 mg/m H-SO. also decreased tracheal ciliary beat
3
frequency in hamsters. Lower concentrations (0.1 mg/m H-SO., 1 hr/day, 5 days/wk) caused
erratic bronchial mucociliary clearance rates in donkeys after several wk of exposure.
Continued exposure of the donkeys which had not received pre-exposures caused a persistent
slowing of bronchial clearance after about 3 mo of exposure. From these and other studies, it
appears that repeated exposures to low concentrations of H?SO. can slow mucociliary clearance.
This might imply increased lung residence times of materials that would ordinarily be cleared.
Other host defense parameters, e.g., resistance to bacterial infection, are not altered
by low concentrations of H?SO., but are affected by metal sulfates. The apparent relative
potency of various particles for increasing susceptibility to infectious (bacterial) respira-
tory disease has been determined in mice exposed for 3 hr: CdSO. > CuSO. > ZnNO~, ZnSO. >
O ^ O *f
A12(S04)3 > Zn(NH.)2(SO/.)2. At concentrations > 2.5 mg/m the following particles had no
significant effects in this model system: H2$04, (NH.)2SO., NH.HSO., Na2S04, Fe?(SO.)3,
Fe(NH4)2S04, NaN03, KN03> and NH4N03.
XRD12B/A 12-84 2-5-81
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It is evident that accurate estimates of the toxicity of complex aerosols occurring in
urban air based solely on their sulfate contents are inappropriate. The chemical composition
of the sulfate aerosols determines their relative toxicities. For pulmonary irritance, the
potency of a sulfate salt aerosol can be correlated with the permeability of the lung to that
specific sulfate salt. The metallic ions are also toxic. Since urban air contains sulfuric
acid, ammonium sulfate, and metallic sulfates in varying proportions, it is not possible to
extrapolate from the currently inadequate toxicological data on single compounds in animals to
man as he exists in a complex environment.
No data are available on the toxicity of secondary or complex atmospheric aerosols, since
only a very few published reports of animal studies have appeared. The problem is highly
complex because of the variability of aerosols from different urban localities and the compo-
sitional changes on collection. Toxicity can be approached, at present, only from estimates
of composition and toxicity of individual components. Using j_n vitro tests, metal
oxide-coated fly ash has measurable toxicity which can be ascribed to the insoluble oxides
when alveolar macrophages are exposed. The effects of soluble salts of Ni and Cd have major
differences. Nickel and Cd are removed from the lung with relative rapidity but may be stored
or bound to intracellular proteins to an extent which is sufficient for accumulation on
3 3
repeated short-term exposures. Two-hr exposures to both Ni (0.5 mg/m ) and Cd (0.1 mg/m )
aerosols impair the anti-bacterial defenses of the lung, leading to an increased sensitivity
to airborne pathogens in mice. Ciliary beat frequency in the trachea can be decreased by Cd
and Ni also. Humoral immunosuppression in mice has been reported after a 2-hr exposure to
0.19 mg/m3 CdCl2 or 0.25 mg/m3 NiCl2.
12.6.3 Combinations of Gases and Particles
Although man is exposed to a complex mixture of gases and particles, few animal studies
have been conducted with mixtures. The dissolution of SO- into liquid aerosols or the
sorption onto solid aerosols tends to increase the potency of SOp. The exact mechanism by
which potentiation occurs is still controversial. Sodium chloride and soluble salts
(manganous chloride, ferrous sulfate, or sodium orthovanadate) potentiated the effect
(increased flow resistance) of a 1-hr S02 exposure of guinea pigs. Hypothetically, these
particles favored the conversion of S02 to H-SO., thus increasing the response.
The effects of chronic exposure to a variety of mixtures of S02, H2S04, and fly ash were
examined in guinea pigs and monkeys. None of these studies showed effects on pulmonary
function. Morphological changes were observed in monkeys after an 18 mo continuous exposure
o 3
to 2.6 mg/m (0.99 ppm) S02 plus 0.88 mg/m H2$04; but the addition of fly ash did not
potentiate the response.
3 3
When dogs were exposed to S02 (13.4 mg/m , 5.1 ppm) and H2$04 (0.89 mg/m ) alone and in
combination for 21 hr/day for 620 days, no morphological changes were observed. Sulfur
dioxide did not cause any significant changes in pulmonary function except for an increase in
N? washout, but H?S04 caused a variety of changes which were interpreted as the development of
obstructive pulmonary disease.
XRD12B/A 12-85 2-5-81
-------
In another series of studies, dogs were exposed for 16 hr/day for 68 mo to raw or photo-
chemically reacted auto exhaust, oxides of sulfur or nitrogen, or their combinations. The
animals were examined periodically during exposure and at 32 to 36 mo after exposure ceased.
After 18 or 36 mo of exposure, no significant changes in pulmonary function were observed.
After 61 mo, a few functional alterations were observed in dogs exposed to SO (1.1 mg/m ,
3
0.42 ppm S02, and 0.09 mg/m H?SO.) alone and in combination with other pollutants. The
animals had been placed in clean air for 32 to 36 mo after exposure ceased, at which time the
S0x group had a variety of pulmonary functional and morphological alterations. These struc-
tural changes included a loss of cilia without squamous cell metaplasia, nonciliated bronchio-
lar hyperplasia, and a loss of interalveolar septa in alveolar ducts. The authors hypothe-
sized that these changes are analogous to an incipient stage of human proximal acinar
(centrilobular) emphysema. Since the pulmonary function changes were progressive during the
post-exposure period and they were correlated with the pathology, it can be hypothesized that
the morphological alterations were also progressive.
Combinations of carbon and H,SO. or SO, were investigated also. In mice exposed for 3
3 3
hr/day, 5 days/wk for up to 20 wk to a mixture of 1.4 mg/m KLSO. and 1.5 mg/m carbon or to
carbon only, morphological and immunological alterations were seen. In hamsters, a 3 hr
exposure to 1.1 mg/m +1.5 mg/m carbon depressed ciliary beat frequency, as did H-SO, alone.
Alterations of both the pulmonary and systemic immune systems were found in mice at various
3 3
lengths of exposure (100 hr/wk up to 192 days) to 5.2 mg/m (2 ppm) S0? and 0.56 mg/m carbon,
alone or in combination. Generally, carbon and carbon + S0? caused more extensive effects
than S02 alone.
When the interaction of 07 and H9SO. was studied, the morphological effects of a 6 mo
3 3
intermittent exposure of rats and guinea pigs to the mixture [10 mg/m H9SO. + 1.02 mg/m
3
(0.52 ppm) 0,] were attributed to 0, alone. However, combined exposure to 1 mg/m H?SO. and
0.78 to 0.98 (0.4 to 0.5 ppm) 0, resulted in synergistic effects on glycoprotein synthesis in
the trachea! and certain indices of lung biochemistry. Acute sequential exposure to first
3 3
0.196 mg/m (0.1 ppm) 03 and then 0.9 mg/m H-SO. caused additive effects on increased
susceptibility to infectious pulmonary disease and antagonistic effects on depression of
trachea ciliary beat frequency. From these studies, the interaction of 03 and H^SO. is quite
complex and appears to be dependent on the sequence of exposure as well as on the parameter
examined.
XRD12B/A 12-86 2-5-81
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lie
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13. CONTROLLED HUMAN STUDIES
13.1 INTRODUCTION
Evaluation of health effects induced by exposure to air pollutants requires that studies
be conducted under rigorously controlled conditions. Controlled studies provide a necessary
bridge between epidemiology and animal toxicology data. In general, such studies should pro-
vide situations which realistically simulate the exposures experienced by man in his normal
environment. However, the complexity and variability of the ambient environment is such that
most controlled studies initially have been designed to evaluate the effects of exposure to
single pollutants, and then later have been extended to the more complex mixtures of pol-
lutants actually present in the environment.
The high cost and minimal number of subjects who can be studied under controlled condi-
tions make it imperative that studies be conducted under stringent conditions in order to be
relevant to larger populations. Ideally the design of such controlled trials should include
normal individuals of both sexes and all age groups, subjects especially sensitive to some
particular pollutant, and individuals from populations suspected to be at special risk. Con-
sideration must also be given to the activity levels of the subjects, ambient environmental
conditions prevailing prior to the subjects' testing, and exposure variables that realistically
simulate ambient conditions, including such factors as temperature, humidity, duration of
exposure, and mode of exposure. Controlled studies also require proper experimental design
which should include purified air conditions, double blind exposure procedures (this cannot be
complied with when certain pollutants and some levels of these pollutants are being evaluated),
several concentrations of these pollutants should be employed in order to develop dose response
relationships, as well as comprehensive statistical treatment of the data obtained. In
addition, adequate (even duplicate) pollutant monitoring equipment with documentation of
quality control are needed. Proper attention must also be given to the presence of potential-
ly interfering pollutants inadvertently present or developing under certain conditions.
Ideally not only should physiological and biochemical evidence be obtained, but subjective
symptoms and/or changes in performance capability should also be assessed. Since the respira-
tory tract is the initial target of many air pollutants, proper and sensitive respiratory
function measurements are a primary requirement. Since diurnal patterns are known to occur in
physiological systems, experiments should be controlled as to time of day that they are con-
ducted. However, various biochemical systems may be affected if pollutants (or their reaction
products or substances absorbed on particulates) pass into the circulatory and other, systems.
The above criteria need to be applied to any evaluation of clinically controlled studies.
However, due to particular restraints placed on investigators, no studies meet all of these
ideal requirements. Nonetheless, certain basic information may be derived from a number of
studies. This chapter provides an overview of controlled air pollutant exposure studies of
XD13A/A 13-1 2-14-81
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certain human health effects of sulfur compounds. It should be noted that laboratory studies
utilizing man have been limited to the evaluation of acute effects; thus the potential for
chronic health effects cannot be predicted from such exposures.
13.2 SULFUR DIOXIDE
Exposure of man to sulfur dioxide has been shown to induce a number of physiological
responses. Alterations in sensory system responses such as irritation of eyes and nose,
changes in odor perception, and dark adaptation have been reported. Various changes in
function of the respiratory system have also been reported. The following sections address
these various functional changes in greater detail. (See Chapter 11 for more detailed dis-
cussion of SO- deposition).
13.2.1 Subjective Reports
The perception of odor and the sensation of irritation in the eyes, nose, throat, or other
parts of the body are difficult to measure precisely. Thus subjects may be observed for quali-
tative changes (coughing, rhinorrhea, lacrimation) or asked to report whether they detect some-
thing in the air they are breathing. Several studies have used such subjective reports as an
indication of the effects of SO- on human subjects.
A number of early investigators exposed themselves to high concentrations of SOp (>500
ppm) and experienced coughing, irritation of the eyes and nose, and difficulty in breathing
(e.g., Ogata, 1884; Yamada, 1905; Kisskalt, 1904). In the course of investigating the effects
of S0? on industrial workers, Lehman (1893) and his associates experienced nasal irritation
during exposures of 10 to 15 minutes to 6.5 ppm SO-. Holmes et al. (1915 -- cited by Greenwald,
1954) carried out an extensive study of 60 subjects, 28 of whom were unaccustomed to breathing
SOp, and 32 of whom were familiar with it. All of the subjects already familiar with the gas
seemed to detect it (either as S0? or as "something foreign") at 3 ppm. But only 10 of 28
unaccustomed subjects detected something in the air at 3 ppm SO-. Few subjects found momentary
whiffs of 5 ppm disagreeable, although "Long-continued breathing of air containing slightly
more than 5 parts per million would probably cause discomfort to most people..." (Holmes et
al., 1915). Amdur et al. (1953) noted that during exposure to 1 to 2 ppm their subjects could
not usually detect the odor of S0?; even at 5 ppm most subjects could not smell the gas,
although they did complain of dryness in the throat. One subject, however, objected so
strongly to 5 ppm SO- odor that exposure was terminated. Above 5 ppm the odor was definitely
detected by all subjects.
A number of more recent studies have asked subjects to report their subjective experiences
(e.g., Greenwald, 1954; Tomono, 1961; Frank et al., 1962; Toyama and Nakamura, 1964; Speizer
and Frank, 1966a,b; Melville, 1970; Weir and Bromberg, 1972, 1973; Lawther etal., 1975;
Horvath and Folinsbee, 1977), but the results seem to be quite variable at exposures less than
5 ppm SOp. Also, Frank et al. (1962) have shown that subjective reports are in some situations
an unreliable indicator of physiological responses, since coughing and a sense of throat
XD13A/A 13-2 2-14-81
-------
irritation tended to subside in their subjects after a few minutes while other changes in
respiratory effects were still maximal.
13.2.2 Sensory Effects
Among the physiological functions that may reflect the effects of exposure to S0? are
certain sensory processes. These studies have investigated not only odor threshold but also
sensitivity of the dark-adapted eye to light and interruption of the alpha (a) rhythm in
electroencephalograms (see Table 13-1). Most of these investigations have been summarized by
Ryazanov (1962).
13-2-2-l Odor Perception Threshold—In the Russian studies odor threshold is typically deter-
mined in a well-ventilated chamber containing 2 orifices from which emerge 2 small streams of
gas, one being very pure air and the other other being a stream of the test gas. The subject
sits in front of the apparatus, sniffs both orifices, and points out the odorous one. This
experiment is repeated with the same concentration of test gas over a period of several days.
The experiment is performed with increasingly reduced concentrations until the subject, in the
majority of instances, denies the presence of an odor or gives erroneous answers. The thres-
hold concentration for the most sensitive subject in a group of volunteers is defined as the
threshold for odor perception.
Using the 2-orifice apparatus described above, Dubrovskaya (1957) conducted sulfur dioxide
odor perception threshold tests on 12 subjects. Sulfur dioxide concentrations of 0.5 mg/m to
3
13 mg/m (0.17 ppm to 4.6 ppm) were used in 530 threshold determinations. Six test subjects
sensed the odor of sulfur dioxide in the range 2.6 mg/m to 3.0 mg/m ; four subjects sensed
the odor in the range 1.6 mg/m to 2.0 mg/m ; one sensed the odor in the range 2.1 mg/m to
3 33
2.5 mg/m ; and one sensed the odor in the range 3.1 mg/m to 3.6 mg/m . Thus, the average
sulfur dioxide odor threshold concentration was 0.8 ppm to 1 ppm (~2.3 mg/m to ~2.9 mg/m ),
and for the more sensitive of these persons it was 0.5 ppm to 0.7 ppm (~1.5 mg/m to ~2.0
mg/m ). It should be noted, however, that most of the subjects were of an age at which odor
perception was presumed to be most sensitive.
Determination of sulfur dioxide odor thresholds (1968) conducted for the Manufacturing
Chemists' Association in the United States gave somewhat lower values than those cited above
(Arthur D. Little, Inc., 1968). The concentrations at which first one-half and then all of
the panel members could positively recognize the odor were reported to both be 0.47 ppm (1.3
mg/m ). The details of the test procedure are thoroughly discussed in the report, but one
important aspect is reiterated as a reminder that odor thresholds usually represent values
derived under ideally suited conditions and with trained individuals. The investigators, who
were highly qualified to judge on the basis of substantial experience with consumer evaluation
of known flavor and odor situations, derived threshold values under ideal conditions lower
than those which would be recognized by the majority of a population under ordinary atmospheric
conditions. This does not mean that normal individuals exposed to sulfur dioxide under ideal
XD13A/A 13-3 2-14-81
-------
* XD13A/B-1
TABLE 13-1. SENSORY EFFECTS OF SO,
Concentration
S02 (ppm)
400
6.5
140, 210, 240
210, 240
1, 2, 5
3, 5, plus
0.17 - 4.6
0.34 - 6.9
0.23
0.2 - 1.7
1-10
Exposure
mins.
120
10 - 15
30
30
-
"""
-
15
--
0.33
—
Effects
Dyspnea
Nasal irritation
Marked nasal irritation, sneezing
Eye irritation, lacrimation
All subjects detect odor above 5 ppm
Discomfort to all subjects exposed to 5 plus.
Some noted disagreeable odor at 5 ppm.
Average S02 odor threshold was 0.8 - 1.0 ppm
Positive recognition of SO. was 0.47 ppm
Light sensitivity increased at 0.34 - 0.63 ppm
and above.
Ocular sensitivity to light increased at SO.
levels of 0.23 ppm and above
Attenuation of a-waves at levels above 0.2 ppm
Orpanoleptic effects at levels 2 ppm and above
Reference
Ogata, 1884
Lehman, 1893
Yamada, 1905
Yamada, 1905
Amdur et al., 1953
Holmes, 1915 (see Green-
wald, 1954)
Dubrovskaya, 1957
Arthur D. Little, Inc.,
1968
Dubrovskaya, 1957
Snalamberidze, 1967
Bushtueva, 1962
Greenwald, 1954
U)
I
-------
*
test conditions could not perceive the 0.47 ppm level indicated. However, because of back-
ground odor and lack of awareness or concern with ambient odor conditions, such individuals in
an everyday situation would probably be less responsive to this low concentration.
13.2.2.2 Sensitivity of the Dark-Adapted Eye—The sensitivity of the eye to light while a
subject is in darkness increases with time. Several investigations have been made of the
effects of inhalation of sulfur oxides on this sensitivity. Typically, measurements of a
subject's normal sensitivity are taken in a dark, well-ventilated chamber in complete silence
(sudden stimuli, including noise, may affect the subject's response). Each subject is tested
once daily following preliminary stimulation at a high light level. Light sensitivity is
measured at 5-minute or 10-minute intervals, and a curve of increasing sensitivity to light is
established from measurements taken over a period of 7 to 10 days.
Dubrovskaya (1957) studied the effect of inhaling sulfur dioxide in concentrations from
33
0.96 mg/m to 19.2 mg/m for 15 minutes before measuring light sensitivity during dark adap-
tation. She reported that light sensitivity was increased by sulfur dioxide concentrations of
3 3
0.96 mg/m to 1.8 mg/m (0.34 ppm to 0.63 ppm), that the increase in sensitivity reached a
O Q
maximum at concentrations of 3.6 mg/m to 4.8 mg/m (1.3 ppm to 1.7 ppm), and that further
increases in the sulfur dioxide concentration resulted in progressive lowering of eye sensi-
tivity to light until at 19.2 mg/m the sensitivity was identical with that of the unexposed
subject.
In exposures during light adaptation, sulfur dioxide concentrations of 0.6 mg/m to 7.2
3
mg/m (0.21 ppm to 2.5 ppm) caused slight increases in eye sensitivity. Maximum sensitivity
3
was attained at 1.5 mg/m (0.52 ppm); at higher concentrations the increased sensitivity began
to abate. Two human subjects were used in these experiments. The odor threshold was between
33 33
2.5 mg/m and 3.0 mg/m for one subject and between 3.0 mg/m and 3.6 mg/m for the other, so
that changes in sensitivity to light during dark adaptations were caused by sulfur dioxide con-
centrations below the odor threshold.
Shalamberidze (1967) investigated the effects of S02 and N02, singly and in combination,
on visual light sensitivity as determined by measures of dark adaptation. According to this
report, S0? concentrations of 0.6 mg/m (0.23 ppm) and higher caused "a considerable increase
in the ocular sensitivity to light" (Shalamberidze, 1967, p. 11). So few details on methods
or results were presented, however, that this report cannot be accepted without reservations.
13.2.2.3 Interruption of Alpha Rhythm—The electroencephalogram is a composite record of the
electrical activity of the brain recorded as the difference in electrical potential between
two points on the head. In the adult, the electroencephalogram characteristically shows a
fairly uniform frequency from 8 cycles to 12 cycles per second in the posterior head regions
(alpha). Variations occur with age, the state of wakefulness and attentiveness, or as a result
of incoming sensory stimuli from exteroceptive or interoceptive receptors. The dominant
frequency (a) is inhibited or attenuated by eye opening and by mental activity.
XD13A/A 13-5 2-14-81
-------
Subjects with well defined orrhythms studied in a silent and electrically shielded chamber
show a temporary attenuation of the crrhythm each time they are given a light signal. When
the light is excluded, the crrhythm returns to normal. A concentration of test gas is deter-
mined which is so low that by itself it does not cause attenuation of the a-rhythm. A subject
breathes the gas at this concentration, and then he receives the light signal. After exposure
to this sequence (gas then light) several times (5 to 30 times in 1 day), a subject will show
attenuation before he receives the light signal; that is, he responds to the unperceived odor.
The unperceived odor thus becomes the conditioning stimulus and brings about the so-called
conditioned electrocortical reflex.
Bushtueva (1962) reported that 20-second exposures of six human subjects to sulfur dioxide
3 ?
concentrations from 0.9 mg/m to 3 mg/m (~0.3 ppm to ~1.0 ppm) produced attenuation of the
3 3
orwave lasting 2 to 6 seconds; at concentrations of 3.0 mg/m to 5.0 mg/m (-1.0 ppm to 1.7
3
ppm) attenuation lasted throughout the 20-second exposure. Exposures to 0.6 mg/m (~0.2 ppm)
did not cause attenuation of the crwave. The threshold for attenuation of the crwave was the
same as the odor theshold or the threshold of irritation of the respiratory tract. Bushtueva
further demonstrated that electrocortical conditioned reflexes could be developed with sulfur
dioxide at 0.6 mg/m (~0.2 ppm) but not with lesser concentrations of the mixture.
13.2.3 Respiratory and Related Effects
13.2.3.1 Respiratory Function—A number of studies have documented the various respiratory
and cardiovascular effects deriving from exposure to S0? (see Table 13-2). (See Chapters 11
and 12 for further discussion of respiratory effects of SO™.) One of the first clinical
studies of the effects of inhaling SO- was reported by Amdur et al. (1953). They had 14 rest-
ing subjects breathing S0? for 10 minutes through a face mask in concentrations ranging from 1
to 8 ppm. Pulse rate and respiration rate increased and tidal volume decreased during exposure
to as little as 1 ppm S0?. Several investigators attempted to replicate Amdur et al.'s (1953)
findings, including Mcllroy et al. (1954), Lawther (1955), and Frank et al. (1962). None was
able to find consistent respiratory or cardiovascular effects of S0? below 5 ppm. Nevertheless,
these and other studies have documented a variety of subjective and physiological effects under
various conditions of exposure to SO™. Sim and Rattle (1957) performed extensive clinical
studies over a 10-month period on an unspecified number (8 to 12) of "healthy males aged 18 to
45." S0? was administered either by face mask at concentrations ranging from 1.34 to 80 ppm
for 10 minutes or in an inhalation chamber at concentrations of 1.0 to 23.1 ppm for 60 minutes.
Regardless of exposure route, the only notable effects of S0? were stated to be bronchocon-
stric tion (increased resistance to air flow) and high-pitched chest rales at 49 ppm and
greater concentrations. They also reported that when ammonia (no value given) was also present
in the chamber (9.9 ppm S0?) the subjective impressions of bronchoconstriction disappeared.
Frank et al. (1962) examined the effects of acute (10 to 30 minute) exposures to SO™ via
mouth in 11 subjects. Each subject received approximately 1, 5, and 13 ppm of the gas in
XD13A/A 13-6 2-14-81
-------
* X013A/B-2
13-2. RESPIRATORY EFFECTS OF SO,
Oral or
Concentration Duration of Number of nasal Rest (R) or
SOg (ppm) exposure (rains) subjects exposure exercise (E)* Effects
1.0 3
3.0 3
5.0 3
9-60 5
1-8 10
10
5, 10 10
20 10
£l. 5, 13 10
1.3-80 10
1-45 10
CO
~-J 2.5, 5.0, 10.0 10
4-6 10
8-10 0 R * E
8-9 0 R + E
10 0 R
25 N - 0 R
14 Face mask R
— N R
18 0 - N R
60 R
12 0 R
8-12 Face Mask R
46 Face Mask R
15 0, N R
70 R
Light exercise potentiates
effect of SO. MEF.™
decreased '
Airway resistance increased
Pulse rate, respiratory
increased; tidal volume
rate decreased
Could not duplicate Amdur's
results
No changes in pulse rate,
respiratory rate or tidal
volume (5, 10 ppm) 2 sub-
jects had bronchospasm
No changes in pulse rate,
respiratory rate. Pulmonary
flow resistance increased at
5 and 13 ppm
Bronchoconstriction at the
higher concentrations
Decreased peak flow, decreased
expiratory capacity above
1.6 ppm
SG decreased less with nasal
Breathing
Airway conductance decreased
Reference
Kreisman et al. ,
1976
Nakamura, 1964
Anidur et al . ,
1953
Mcllroy et al.,
1954
Lawther, 1955
Frank et al.,
1962
Sim and Rattle,
1957
Tomono, 1961
Melville, 1970
Nadel et al., 1965
reflex effect
"Intermittent Exercise
-------
* XD13A/B-3
13-2. (continued)
Oral or
Concentration Duration of Number of nasal Rest (R) or
SO, (ppm) exposure (mins) subjects exposure exercise (E) Effects
15 28 10 80 R Pulmonary flow resistance
N increased less with nasal
breathing
5 10 5 0 R MEF50* decreased 1ess wUh
M nlstl inhalation
2,5 - 50 10 5 0 R Increased respiratory and
inspiratory resistance
1.3-80 10 8-12 Face mask R Bronchoconstriction
0.5, 1.0, 5.0 15 9 R MEF50~ decreased at
1 and 5 ppm
1, 3, D 10 7, 7, 7 0 R SR increased significantly
(21) it all cone for asthmatics;
Reference
. ri F b
1966*
Snell and
1969
Abe, 1967
Luchsinger,
Sim and Pattle, 1957
Snell and
1969
Sheppard,
Luchsinger,
et al . , 1980
_ 0.1, 0.25, 0.5
1. 5, 13
10
10 - 30
7, 6
11
CO
1
CO
16.1
1. 5, 15
1.1 - 3.6
5
25
30
30
30
7
12
10
10
Face mask
0 - N
0
0
0
R
R
R
E
only at 5 ppm for normals
and atopic subjects
SR significantly increased
fK the asthmatic group at
0.5 and 0.25 ppm SO, and
even at 0.1 in the two most
responsive subjects
Pulmonary flow resistance
increased at 5 and 13 ppm
but less during nasal
breathing; at 1 ppm, one
subject experienced 7% in-
crease in flow resistance,
another a 23% decrease
SO, almost completely
removal by nasal breathing
Increased in Rl at SO. levels
above 5 ppm
Deep breathing produced no
effects
HHFR decreased
Sheppard, et al., 1981
Frank et al., 1962
Speizer and Frank,
1966b
Frank et al., 1964
Burton et al., 1969
Newhouse et al., 1978
-------
* XD13A/B-4
13-2. (continued)
U)
I
ID
Concentration Duration of Number of
SO,, (ppm) exposure (mins) subjects
1-23 60
1 60
5 60
5-30 10
1 50
3
10, 15, 25. 50 60
•Intermittent
0.37 120
0.37 120
0.40 120
0. 75 120
1.0, 5.0 120
5.0 120
5.0 120
2!>.0 120
8-12
-
9
10
13
17
Exercise
8
4-12
9
4 - 8
15
11
10
15
Oral or
nasal Rest (R) or
exposure exercise (E)
Mask, chamber
N
N
0
CO. stimulus
Chamber (N)
0
Chamber
Chamber
Chamber
Chamber
N
Chamber
Chamber
(oral)
N
R
R
R
(0) R
R
R
E
E
E
E
R
E
E
R
Effects
Bronchoconstriction
No effects observed
No effect or mucus
transport
Deep breathing significantly
increased SR
aw
At higher cone, of SO,
mucociliary activity
decreased
No pulmonary effects
No pulmonary effects
No pulmonary effects
Significant decrease in
MEFR; FVC, FEV, „, MMFR
also decreased '
Increase in nasal air flow
resistance; decrease in
nasal mucus flow
Insignificant changes in
Re and KAQ
MMFR decreased 8.5% increased
tracheobronchial clearance
Reference
Sim and Pattle, 1957
McJilton, 1976
Wolff et al., 1975a
Lawther, 1975
Cralley, 1942
Bates and Hazucha, 1973;
Hazucha and Bates, 1975
Bell et al., 1977
Horvath and Folinsbee, 1977
Bedi et al. , 1979
Bates and Hazucha, 1973;
Andersen et al . , 1974
von Neiding et al., 1979
Newhouse et al . , 1978
Andersen et al . . 1974
resistance; decreased nasal
mucus flow
-------
* XD13A/B-5
13-2. (continued)
Concentration Duration of Number of
S02 (ppm) exposure (mins) subjects
0. 50 180 40
(normal subjects)
0.50 180 40 (asthmatics)
5 180* 10
0.3, 1.0 96 - 120 12 (normal)
and 3.0 Hours 7 (COPO)
1.0, 5.0 Up to 6 hrs/day 15
and 25.0
5 4.5 hours 32
(16 exposed)
Oral or
nasal
exposure
Oral
Oral
0
Chamber
Chamber
(N)
Chamber
Rest (R) or
exercise (E) Effects
R No pulmonary effects
R HMFR decreased 2.7X; recovery
within 30 minutes; 3 subjects
incurred delayed effects and
required medication.
E Increased tracheobronchial
clearance
R No difference in response
between groups. Slight
decrease in pulmonary
compliance but of ques-
tionable significance
R Significant decreases in
expiratory flow and FEV, „
decreased mucus flow
R Number of colds similar in
both groups but severity
less in SO. exposed subjects
Reference
Jaeger et al . , 1979
Jaeger et al., 1979
Wolff et al., 1975b
Weir and Bromberg, 1972
Andersen et al . , 1974
Andersen et al . , 1977
CO
I
-------
separate exposures at least 1 month apart. The only significant effects were a 39 percent
increase (p <0.01) in pulmonary flow resistance at 5 ppm and a 72 percent increase (p <0.001)
at 13 ppm. Only one subject showed a significant increase with I ppm S02 concentration, his
control resistance was the highest encountered. The recovery of some subjects was complete
within a few minutes. As in Sim and Rattle's study (1957), other cardiovascular or pulmonary
measures did not show any significant effects.
Tomono (1961) tested 46 men for the effects of SO- on their pulmonary physiology. The
subjects inhaled 1 to 45 ppm SO,, through a face mask for 10 minutes. Decreases in expiratory
capacity and peak flow rate were proportional to the concentration of S0?. Such effects were
detected at a concentration as low as 1.6 ppm. Slight increases in pulse and respiration
rates were observed in about 10 percent of the subjects but were not proportional to S02 expo-
sures. Nakamura (1964) exposed 10 subjects each to a different concentration of S02 (9 to 60
ppm) for 5 minutes. Airway resistance increased an average of 27 percent. Since each subject
was exposed to only one concentration of S02 and there was considerable variability in re-
sponse to the different concentrations, the significance of those isolated findings may be
questioned. No significant correlation between dosage and response was discovered. For
example, a subject had a 17 percent increase after exposure to 9 ppm, another 9 percent after
exposure to 16 ppm, another 75 percent after exposure to 4 ppm and another 22 percent after
exposure to 57 ppm.
Snell and Luchsinger (1969) also found significant decreases in pulmonary function con-
sequent to S02 exposure. Nine subjects inhaled through a mouth piece SOp at concentrations of
0.5, 1.0, and 5 ppm for 15 minutes each, with 15-minute control periods interspersed. Maximum
expiratory flow (MEF™^ ,.„) was significantly lower after exposure to 1 ppm S02 (p <0.02) as
well as 5 ppm (p <0.01). Reichel (1972) exposed 32 normal subjects continuously in a chamber
to 7.7 ppm S02 for 6 days. Intrathoracic gas volume and intrabronchial flow resistance was
not altered consequent to any of the 6 days of exposure. Airway resistance was measured in 16
of these subjects by inhalation of 3% acetylcholine chloride solution. The sensitivity re-
sponse to this challenge was not altered as a consequence of the exposure of S0?. Jaeger et
al. (1979) exposed 40 normal non-smokers and 40 asthmatics (mild to moderate but with no
recent exacerbations) subjects for 3 hours to 0.5 ppm SOp. Oral inhalation was forced by
having the subjects wear a nose clip. These resting subjects were also studied during expo-
sure to ambient air having an average S02 content of 0.005 ppm. Three pulmonary function
tests (VC, FEV-, and MMFR) were performed at intervals during the exposure and a more intensive
series of tests were made prior to and after the exposure. The only significant (p <0.04)
effect observed was a 2.7 percent decrease in MMFR in the asthmatic subjects. This minimal
change was stated to have little physiological importance. One normal and two asthmatic sub-
jects exhibited adverse reactions—the asthmatics requiring standard asthma medication.
Nadel et al. (1965) have helped elucidate the mechanism of bronchoconstriction resulting
from S0? exposure. They exposed seven subjects to 4 to 6 ppm S02 for 10 minutes via mouth in
a closed plethysmograph. The mean decrease in specific airway conductance was 39 percent
XD13A/A 13-11 2-14-81
-------
(p <0.001). Injecting the subjects with 1.2 to 1.8 mg atropine sulfate 20 minutes before S02
inhalation resulted in only a 3 percent (p >0.20) decrement in specific airway conductance/
thoracic gas volume. However, atropine did not affect the coughing or sensation of irritation
in the pharynx or substernal area. From this and other evidence, Nadel et al. concluded that
the bronchoconstriction induced by S0? depends on changes in smooth muscle tone mediated by
parasympathetic motor pathways. Thus, when sensory receptors in the tracheobronchial region
are irritated by a substance such as S0?, a reflexive bronchospasm may be triggered.
Apart from fairly consistent bronchoconstriction effects, a common element in these and
other reports of the effects of S02 has been the notable variability among subjects in their
responses to such exposures. In Frank et al.'s study (1962), for example, 9 of 11 subjects
showed no effects at 1 ppm, but 1 subject showed a significant (p <0.01) decrease in pulmonary
flow resistance, whereas the remaining subject showed a significant (p <0.01) increase. Sim
and Rattle (1957) reported that they themselves appeared to be exceptionally sensitive to S02
encountered in the course of their research. They experienced persistent and uncomfortable
spells of coughing and wheezing upon contact with the gas. Other investigators (e.g., Burton
et al., 1969; Frank, 1964; Nadel et al, 1965; Lawther, 1955; Lawther et al., 1975; Jaeger et
al., 1979) have reported "hyper-reactors" among their subjects. Indeed, some investigators
have suggested that about 10 percent of the total population is made up of especially sensi-
tive persons (Amdur, 1973, 1974; Horvath and Folinsbee, 1977). However, in at least one
instance (Andersen et al., 1974), a subject's response was exaggerated even under control con-
ditions, which raises the possibility of psychological factors contributing to this observed
sensitivity.
13.2.3.2 Water Solubility—One of the first points to note is that because of its high solu-
bility in water, S0? is readily absorbed when it comes in contact with the moist surfaces of
the nose and upper respiratory passages (Frank et al., 1973). This has a number of important
implications for the analysis of the effects of SO- on respiratory functions. These consider-
ations will be illustrated in the following sections (see Chapter 11).
13.2.3.3 Nasal Versus Oral Exposure—A number of studies have demonstrated significant re-
sponse differences between the nose and mouth as routes of exposure to S0?. Speizer and Frank
(1966a), for example, compared the effects of SOp (10-minute exposures at 15 and 28 ppm) in
eight subjects breathing the gas either by nose or by mouth. The subjects coughed less and
reported less irritation of the throat and chest when breathing through their noses. Also,
pulmonary flow resistance increased less during nasal exposure than during oral exposure.
A second study by the same investigators (Speizer and Frank, 1966b) refined their
analysis of these effects, using seven subjects and a specially designed face mask. Air was
sampled at various points, including: (1) within the face mask before being inspired, (2)
within the subject's nose, and (3) within the subject's oropharynx. Exposures lasted 25 to 30
minutes. The average concentration of SO- within the mask was 16.1 ppm; within the oropharynx
the concentration was too low for the investigators' equipment to measure. Thus, essentially
all of the SO- (90 to 99 percent) in the inspired air was removed by the nose. Similar
XD13A/A 13-12 2-14-81
-------
results were obtained by Andersen et al. (1974) in a study that will be described in detail
later.
Melville (1970) also compared oral and nasal routes of administration. He used 15 sub-
jects and exposed them (for 10 minutes) sequentially to 2.5, 5, and 10 ppm S02. More SO^ was
cleared per minute with nose breathing than with mouth breathing. There was a clear dose-
dependent response reflected in measures of the subjects' specific airway conductance (SG ):
oW
as the S0? concentration increased, SG decreased (p <0.05). This was true regardless of
^ aW
administration route (for 2.5 ppm S02), but the average decrease under oral administration was
greater (in 80 percent of subjects), than the decrease under nasal administration (p <0.05).
During a 1-hour exposure to 5 ppm SO, no significant difference was observed in SG regard-
£. aw
less of whether the 49 subjects breathed through mouth or nose.
Snell and Luchsinger (1969) also examined the differences between nasal and oral exposure
using S02 at 5 ppm. Five subjects' average maximum expiratory flow (MEF™*, vc) was 10 percent
lower following oral exposure than following nasal exposure. This difference, however, was
not statistically significant. See Chapter 11 for further discussion of S02 deposition.
13.2.3.4 Subject Activity Level—One of the practical implications of the above findings is
that vigorous activity, such as heavy exercise or work, may significantly affect the actual
dose received by a person during exposure to SO,,. At some level of ventilation, inhalation of
air shifts from nasal to mouth breathing. Studies under way (Horvath, Ph.D. theses, personal
communication) suggest that subjects who are nasal breathers at rest move to oral-nasal
breathers when ventilatory exchange is approximately 30 L/min. However, it should be
remembered that many individuals are always mouth breathers. Saiben et al. (1978) studied 63
subjects while they exercised at increasing work loads. Incomplete information was obtained
on 13 subjects. Ten subjects breathed through the mouth at all work loads while five never
opened their mouths. In the remaining 35 subjects, the highest ventilation volume attained
with nasal breathing was 40.2 liters per minute. Determination of the shift to oral breathing
was obtained by a subjective observation by an observer. In a second study using 10 subjects,
ventilation was more precisely (but still not a completely adequate technique) determined by
movements of the rib cage. The mean value of ventilation at the point of shift to oral
breathing was 44.2 liters/min. It should be noted that there remains the possibility that
some air continues to enter the lungs through the nose, but the volume definitely is reduced
(Horvath, personal communication).
Kreisman et al. (1976), for example, reported that exercise may potentiate the effect of
S02 on respiratory function. In their study, subjects inhaled a mixture of SO,, in air for 3
minutes while exercising on a bicycle ergometer at a pace sufficient to double their resting
minute ventilation rate. Eight subjects recieved 1 ppm SOp and nine subjects received 3 ppm.
Those receiving 3 ppm showed a significant (p <0.05) decrease in maximal expiratory flow
(MEF.p.0, ,DN) compared to a control (untreated air) exposure. However, it is not clear that
- \ r )
this change differed significantly from the change in MEF,,^, ,„.. occurring in resting subjects.
XD13A/A 13-13 2-14-81
-------
Bates and Hazucha (1973) reported significant decreases in FVC (10 percent), FEV1 Q (10%), MMFR
(10%), and MEFR (23%) in 4 subjects (who exercised intermittently during the exposure) exposed
in a chamber containing 0.75 ppm S02- At 0.37 ppm S02, Hazucha and Bates (1975) observed no
significant pulmonary function changes. Horvath and Folinsbee (1977) and Bedi et al. (1979)
exposed nine intermittently exercised subjects in a chamber to 0.4 ppm S02 and found no
pulmonary function changes.
Lawther et al. (1975) have demonstrated that simply instructing 12 subjects to take 25
deep breaths by mouth resulted in a significant (p <0.001) increase in specific airway resis-
tance (SRaw) during exposure to S02 at 1 ppm. While sitting quietly in an inhalation chamber,
the same subjects had previously shown no such increase after breathing concentrations of 1 to
3 ppm S02 for an hour. As part of a series of experiments in this study, 17 subjects also
received 3 ppm S02 by a mouthpiece and were instructed to take 2, 4, 8, 16, and 32 deep breaths
at 5-minute intervals. Increases in SR due to S09 were significantly greater after 16 (p
3W c.
<0.01) or 32 (p <0.001) deep breaths.
Burton et al. (1969), however, found no consistent effects in 10 subjects exposed to S02
at 1.1 to 3.6 ppm for 30 minutes, regardless of whether the subjects breathed normally or at a
forced hyperventilation rate of up to 2.5 L/sec. One (other) difference between these two
studies was the duration of exposure. Burton et al. (1969) exposed their subjects for 30
minutes, whereas, Lawther et al. (1975) maintained exposures for an hour. This raises another
important consideration in reviewing the effects of S02 on human subjects, namely, temporal
parameters.
Sheppard et al. (1981), using 13 non-smoking mild asthmatic volunteers (10 men, 3 women,
20 to 30 years of age), demonstrated that moderate exercise increases the bronchomotor effect
of S0? at concentrations of 0.5, 0.25, and 0.1 ppm. In seven subjects with mild asthma, inha-
lation of 0.50 and 0.25 ppm of S02 during the performance of moderate exercise significantly
increased SRaw, whereas neither inhalation of 0.50 ppm of S02 at rest nor inhalation of humidi-
fied, filtered air during exercise had any effect on SRaw. Inhalation of 0.50 ppm during
exercise significantly increased SRaw in all seven subjects (p < 0.05), and three developed
wheezing and shortness of breath. During the corresponding period of exercise alone and during
inhalation of 0.50 ppm at rest, SRaw did not increase in any subject. After inhalation of
0.50 ppm of S02 during exercise, SRaw was significantly greater than after exersise alone or
inhalation of 0.50 ppm of S02 at rest (p < 0.05). Inhalation of 0.25 ppm during exercise
significantly increased SRaw in three of the seven subjects, and the increase in SRaw for the
group was significant (p < 0.05). No subject developed wheezing or shortness of breath.
During the corresponding period of exercise alone, SRaw did not increase in any subject. In
the two most responsive subjects, inhalation of 0.10 ppm of S02 as well as 0.25 and 0.50 ppm
significantly increased SRaw, and there appeared to be a dose-response relationship.
In the second set of studies, in all six subjects, inhalation of 1 ppm of S02 dramatically
increased SRaw, both when it was delivered during exercise and during eucapnic hyperventilation.
XD13A/A 13-14 2-14-81
-------
*
In every case, the increase in SRaw was accompanied by dyspnea and audible wheezing. The
magnitude of the increase in SRaw was the same when the subjects inhaled SOp while they exer-
cised or while they performed eucapnic hyperventilation at the same minute ventilation.
The bronchoconstriction produced by inhalation of 0.50 ppm of S02 during exercise was
gradual in onset. Immediately after exercise, SRaw did not differ significantly from baseline
values. It then increased over the first 3.5 tnin, reached a plateau, and gradually returned
to baseline values by 30 min after exposure. A similar time course was seen in those subjects
who developed bronchoconstriction after exposure to 0.25 and 0.10 ppm of SO,,.
13.2.3.5 Temporal Parameters—Early studies (e.g., Lehman, 1893) suggested that workers
chronically exposed to relatively high concentrations of S02 were less conscious of its
presence in the atmosphere than persons not as familiar with the gas. However, Holmes et al.'s
data (1915) indicated that subjects already accustomed to S02 could detect its odor at lower
concentrations than could persons unaccustomed to it. Nevertheless, it would seem plausible
that "self-selection" would tend to reduce the number of relatively sensitive persons among
the population of workers chronically in contact with supra-threshold levels of SO,,.
As previously noted, a study by Frank et al. (1962) has indicated that subjective reports
are not a reliable indicator of physiological responses in any event. After 5 to 10 minutes
of exposure to either 5 or 13 ppm S0? their subjects' pulmonary resistance measures were just
reaching their peaks, while subjective reports of an odor of S0? had already subsided.
In a later study by Frank et al. (1964) the increase in pulmonary resistance induced by
S0? peaked at about 10 minutes and then gradually decreased over the next 15 minutes. This
finding corresponds closely to Sim and Rattle's (1957) report that, if lung resistance
increased at all in individual subjects, the increase occurred within the first 10 minutes.
Similar short-term responses (within 5 to 10 minutes after the start of exposure) have
been recorded by other investigators. Melville (1970) found in 49 subjects that percentage
decreases in specific airway conductance (SG ) were greatest during the first 5 minutes of up
aW
to 60 minutes of exposure to S02 by mouth/nasal breathing. At 5 ppm, for example, he noted
that SG decreased significantly (p <0.05) within 5 minutes of exposure and stabilized
clW
slightly above the values recorded under control conditions of no SO,,.
Similar results were obtained by Lawther et al. (1975), who noted that SR increased most
QW
during the first 5 minutes of exposure. Recovery to baseline levels generally required about
5 minutes, although 3 "S02 sensitive" subjects out of a total of 14 took 10 to 65 minutes to
recover from higher exposure levels (up to 30 ppm SO,,). In this last regard, similar findings
were reported by Gb'kenmeijer et al. (1973) for bronchitic patients exposed to 10 ppm SO,,.
Respiratory effects were maximal at the end of a 3-minute inhalation period, and recovery
following removal to clean environment required 45 to 60 minutes.
Abe (1967) compared the temporal course of S02 exposur.es. His five mouth-breathing
subjects were given 2.5 or 5.0 ppm SO,,. He reported immediate significant (p <0.05) increases
in expiratory resistance (42 percent) and inspiratory resistance (25 percent).
XD13A/A 13-15 2-14-81
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*
Longer term effects (over a period of hours) have been reported by Andersen et al. (1974),
who investigated nasal mucus flow rates as well as airway resistance and subjective responses.
Nasal mucociliary flow was measured by placing a radioactivity labeled resin particle on the
superior surface of the inferior turbinate and tracking its position with a si it-collimator
detector. A total of 15 subjects were exposed via an inhalation chamber to increasing concen-
trations (1, 5, and 25 ppm) of S02 for approximately 6 hours per day over 3 consecutive days.
Baseline measurements were made under conditions of filtered air on a day prior to experimental
exposures. This study found a number of effects reaching their maximum after 1 to 6 hours of
exposure. Nasal cross-sectional airway area generally decreased throughout the 6-hour daily
trials, but the decreases were only significant (p <0.05) at 1 ppm and 5 ppm, since there was
an overall drop in this measure (approaching a "floor level") by the time 25 ppm was adminis-
tered on the third day of the study. Nasal airflow resistance increased significantly (P
<0.05) with the 6-hour exposure to each concentration (1, 5, 25 ppm SO-). Significant (p <0.05
or less) decreases in forced expiratory flow (FEFpryra,) and forced expiratory volume (FEV. „)
also occurred both within daily exposures and across days (i.e., increasing concentrations),
although the within-day decrease in FEV-, Q was only significant on day 3 (at 25 ppm) (see
Andersen et al., 1974, Figure 7).
13.2.3.6 Mucociliary Transport--Cralley (1942) investigated mucociliary clearance when sophis-
ticated radioactive measurement techniques were not available. A drop of red dye was placed
in the active ciliary region of the inferior meatus of a volunteer subject. The rate of mucus
clearance was reflected in the time between the dye's introduction and its appearance in the
expelled mucus. Exposure to S0» at 10 to 15 ppm for 60 minutes produced only a small decrease
in the rate of mucus removal. A 30- to 60-minute exposure to 25 ppm SOp resulted in a 50
percent reduction in mucociliary transport and a 65 to 70 percent reduction at 50 to 55 ppm.
Mucositis in the anterior region of the nose was observed in 14 of 15 subjects after 4 to 5
hours of exposure on successive days to 1, 5, and 25 ppm S0? (Andersen et al., 1974). There
appeared to be no carry-over effect from the previous days exposure. Mucous flow rates on the
first day of exposure (to 1 ppm) tended to be lower but were not significantly lower than those
observed on the control day (0 ppm). Mucus flow rates were significantly lower on the second
day (5 ppm) and were further decreased on the third day (25 ppm) of exposure. The subjects
noted discomfort only on the second and third day exposures. At these concentrations some
subjects also had sporadic mucostasis, although there were pronounced individual differences
in these measures even at baseline. Andersen et al. (1974) calculated the cross-sectional area
of the nasal airways. A significant decrease (0.02
-------
exposed to 5 ppm SCL for 1 hour while sitting quietly in an inhalation chamber and breathing
through their mouths. Mucociliary clearance was assessed by having the subjects first inhale
a radioactively tagged aerosol and then monitoring its subsequent tracheobronchial deposition
and retention during S0? exposure. No significant effects were found in mucociliary clearance,
except for a small transient change (p <0.05) after 1 hour of exposure.
In their second study, Wolff et al. (1975b) used similar methods to compare subjects while
resting or exercising. Exercise was performed on a bicycle ergometer for 0.5 hour at a pace
to yield heart rates 70 to 75 percent of estimated maximum values. Exposure in this study
lasted for 2.5 to 3 hours. The combination of exercise and exposure (via mouth) to 5 ppm SO^
resulted in a significantly (p <0.05) greater rate of tracheobronchial mucociliary clearance.
This result contrasts with Andersen et al.'s findings (1974) that nasal clearance rates were
reduced by exposure to 5 ppm S0?. However, the difference between the two studies can probably
be explained on the basis of dose. Dose to the lung will be much lower than to the nose
because of the absorption of S02 onto upper airway mucosal surfaces. Therefore, lung effects
could be typical of lower concentrations and increases might be anticipated as seen for low
levels of HpSO,. Of course, the two studies focused on different regions of the respiratory
tract (tracheobronchial versus nasal), but this in itself provides no cogent account for these
contrasting effects. Both of these investigators replicated their findings in later studies
[Andersen et al., (1977) and Newhouse et al., (1978)]. Extension of these studies was made by
Newhouse et al. (1978) whose 10 subjects breathed either S0? (5 ppm) or HUSO, mist (1 mg/m )
delivered as an aerosol of 0.58 urn MMAD. An aerosol containing a 0.025 percent solution of
mTc-albumen was inhaled prior to pollutant exposure. The bolus technique (exposure to
short-term peak concentrations) employed achieved deposition of the aerosol, primarily in the
large airways. One-half hour later the subjects were exposed to the pollutants. They
immediately exercised for the next 0.5 hour. A total of 20 minutes of exercise at approxi-
mately 70 to 75 percent of predicted maximum heart rate was performed, followed by an addi-
tional 1.5 hours of rest exposure. The subjects breathed through the mouth to eliminate nasal
ventilation and absorption of pollutants. Pulmonary function tests conducted at the end of 2
hours' exposure to SO™ indicated no changes in FVC or FEV, Q but maximum mid-expiratory flow
rate (MMFR) decreased 8.5 percent, possibly due to a reflex bronchoconstriction. No pulmonary
changes were found consequent to the H»SO. mist exposures. Tracheobronchial clearance
increased in both S0? (6 of 10 subjects) and H?SO» (5 of 10 subjects) exposures. The investi-
gators did not present their data in a manner which would provide information as to the
relationship between clearance rates and MMFR. It should be noted that even these data are in
contrast to the replicated observations by Andersen et al. (1977), who showed a slowing of
nasal clearance on exposure to 5 ppm S0?.
Mucociliary transport is a significant aspect of the respiratory system's defense against
airborne agents. A disturbance in this function might have important implications for a number
of health effects, such as susceptibility to cold-virus infections. Andersen et al. (1974),
XD13A/A 13-17 2-14-81
-------
for example, noticed that 4 of 17 subjects caught colds within a week of their participation
in a study where mucostasis generally occurred during S0? exposure. Andersen et al. (1977)
followed up this observation by inoculating volunteers with a strain of rhinovirus (RV3). The
basic design of the study and reactions of the subjects are shown in a table (Andersen et al.,
1977, p. 121). Although there was no difference in the number of colds that developed in the
two groups of subjects (all nose breathers), cold symptoms were judged (under a double-blind
procedure) to be less severe (p <0.05) in the group exposed to SO^. It was unknown, however,
whether this result reflected a direct effect of S02 on the host, the rhinovirus, or both. In
addition, the average incubation period was somewhat shorter for the group exposed to S02 (p
<0.06). Virus shedding (a measure of infection determined from nasal washings) also seemed to
be somewhat decreased in the S02 exposed group, but not significantly.
13.2.3.7 Health Status—Some studies have considered the preexisting health status of subjects
as a variable in assessing the physiological effects of SO™. Weir and Bromberg, for example,
conducted separate studies on 12 healthy subjects (Weir and Bromberg, 1972) and on 7 smokers
who showed early signs of chronic obstructive pulmonary disease (Weir and Bromberg, 1973).
The subjects were exposed to 0, 0.3, 1, and 3 ppm SOp in an inhalation chamber for 96 or 120
hours (smokers or nonsmokers, respectively), with several days separating each trial. The
individual variablity among the smokers in their daily lung functions was so great that no
effects could be attributed to SO,, exposure. Also, subjective complaints also appeared to be
randomly distributed throughout the course of the study and could not be related to S02 expo-
sure levels.
Gunnison and Palmes (1974) compared heavy smokers (7) and non-smokers (13) with respect
to blood plasma levels of S-sulfonate after exposure to 0.3, 1.0, 3.0, 4.2, and 6.0 ppm SO,,.
Both groups showed highly significant correlations (p <0.001) between SO,, concentrations and
S-sulfonate levels. But there was no significant differentiation between the two groups of
subjects in this regard.
Several other studies of SO,, (e.g., Snell and Luchsinger, 1969; Andersen et al., 1974;
Gokenmeijer et al., 1973; Burton et al., 1968, 1969) have included asthmatic patients or
smokers, but have not provided even qualitative ratings of their health status. This alone
would make it difficult to compare the results of different studies using "healthy" or
"impaired" subjects. Morever, the great individual variability among both normal and impaired
persons in these studies makes it difficult to reach any conclusions about the relative
importance of an individual's health status in determining his physiological response to SO,,.
13.3. PARTICULATE MATTER
One of the significant factors influencing physiological responses to S0? is the presence
of particulate matter in the atmosphere (Amdur, 1969) (see Table 13-3). Particulate matter
interacts with SO,, in at least two distinct ways: as a carrier of SO,, and as a factor in
chemical reactions resulting in the conversion of SO,, to other forms. In their carrier role,
particles may adsorb S02 and, depending on their size, solubility, and other characteristics,
XD13A/A 13-18 2-14-81
-------
13-3. PULMONARV EFFECTS OF AEROSOLS
CO
i—»
ID
Duration of
Concentration exposure (mins)
SO, (1.6-5 ppm) 5
NaCl 0.22 pm HMD
SO, (9-60 ppm) 5
N3C1 (CMD = 0.95 MID)
SO, (0.5, 1.0 and 5.0 ppm) IS
Saline particles 7.0 M«I
High cone, aerosol
(1 Mm/or each)
Low cone, aerosol
(0.1 mg/m3 each)
NaHSO. 16*
NH.HSO,
(NB )JO
H2s642 *
S02 (1 ppm) 30
NaCl 1 mg/m3
MMD 0.9 M og = 2.0 Mm
SO- (1.1 - 3.6 ppm) , 30
NSC1 2.0-2.7 Mg/m
MMD = 0.25 Mm
SO, (1-2, 4-7, 14-17 ppm) 30
NSC1 10-30 mg/mj
MMD 0.15 Mm
S02 (1 ppm) 60
NaCl 1 mg/m3
MMD 0.9 M og = 2.0 Mm
SO, (Ippm) - 120
NRC1 1 mg/mj
MMD 0.9 M og = 2.0 Mm
Mixture of: SO, 120
(0.37 ppm); 0, £
(0.37 ppm) ana ,
H-SO, (100 Mg/nr)
MMD 0.5 Mm, og = 3.0
Ammonium tulfate 150
100 Mg/m
Ammonium bisulfate 150
85 M9/m aerosol size
distribution
0.4 Mm (MMAD)
Number of
subjects
13
10
9
16 normals
17 asthmatics
8
(asthmatics)
10
12
9
(asthmatics)
(normals)
19 (normal)
5 (normal)
4 (ozone
sensitive)
6 (asthmatics)
16
Source
Mask
Mask
Oral
Oral
Mask
(exercise for
10 minutes)
Oral
Oral
Oral
Mask
Chamber
(exercise)
Chamber
(exercise)
Chamber
(exercise)
Effects Reference
Synergistic increases in Toyama, 1962
airway resistance with aerosol
Airway resistance greater after Nakamura, 1964
exposure to aerosol than to
exposure to S02 alone
MEF,™ significantly greater Snell and Luchsinger,
diseases in aerosol (NaCl) 1969
condition
SG induced by carbachol was Utcll et al., 1981
Significantly potentiated
in asthmatics breathing H,SO,
and NH.HSO. at 1 mg/m each. 3
Low sulfate exposure (0.1 mg/m )
produced no changes in SG ;
however, the two most respon-
sive asthmatics to high HjSO.
dose via inhalation exhibited
a potential effect to the
lower acid exposure
'max 50%- 'max 75%- Koenigetal.. 1981
FEV, 0 and RT decrease
significantly in aerosol
condition
No effect on pulmonary functions Burton et al., 1969
Changes in pulmonary function Frank et al., 1964
similar to changes due to SO,
alone not influenced by aerosol
Significant decreases in V eg* Koenig et al., 1980
and V . ,„
max 75%
No pulmonary effects demon- Morgan et al . , 1977
strated
Small but statistically signif- Kleinman et al., 1981
icant decrements in FEV,
and slight increases in the
incidence of clinical symptoms
No changes in pulmonary Bell and Hackney, 1977
functions
No changes in pulmonary Kleinman and Hackney, :
functions Avol et al., 1979
•Rest
-------
transport it deep into the respiratory system (see Chapter 11, Section 11.2 for more detailed
discussion of deposition.)
This point is illustrated by the results of studies by Nakamura (1964) and Toyama (1962),
who reported that sodium chloride (NaCl) aerosol potentiated the response of human subjects to
S02. In Nakamura's (1964) study, 10 subjects were first exposed to NaCl aerosol (CMD = 0.95
urn; Horvath's estimate MMAD =5.6 |jm) alone for 5 minutes, allowed to recover for 10 to 15
minutes, exposed to S0? alone at 9 to 60 ppm for 5 minutes, allowed 20 to 30 minutes to
recover, and then exposed to SOp and the NaCl aerosol together for 5 minutes. Airway
resistance was greater after the combination exposure than after exposure to 862 alone (see
Table 1 and Figure 4a, Nakamura, 1964). As noted, the combination condition always followed
exposure to SOp alone, thus raising the possibility that the effects of the latter exposure
were confounded. However, on average, the subjects' airway resistance measures returned to
only 4 percent above their pre-exposure control levels, thus making it more likely that the
reported effects were independent of preceding conditions.
Toyama (1962) also reported that 5 minutes' exposure S02 in combination with submicronic
(0.22 (jm MMD; Horvath's estimate MMAD = 0.36 urn) particles of NaCl aerosol produced synergis-
tic increases in airway resistance in 13 subjects, even at levels as low as 1.6 to 5 ppm SOp.
There was also a linear relationship between S0? concentration and percentage increase in air-
way resistance.
On the other hand, Burton et al. (1969) were unable to demonstrate comparable effects in
10 subjects exposed to SO, (1.1 to 3.6 ppm) in combination with NaCl aerosol (2.0 to 2.7
3
mg/m ; 0.25 pro MMD; Horvath's estimate MMAD = 0.4 urn). There was, however, a great deal of
variability within and between subjects in this study, including one or two possible "hyper-
reactors" who did show effects below 3 ppm. Frank et al. (1964) studied 12 subjects who were
exposed to three conditions of S0? and NaCl aerosols. There were six subjects in each group,
but the same subjects were not evaluated under each of the three conditions. The purpose of
this study was to determine whether acute changes in respiratory dynamics R, (pulmonary flow
resistance) noted to occur during S02 exposure were intensified by the presence of sodium
chloride particles. The NaCl aerosols had a mean geometric diameter of 0.15 urn (Horvath's
estimate MMAD =0.3 urn) and a concentration of 10 to 30 mg/m ; S0? concentrations were 1 to 2,
4 to 7, and 14 to 17 ppm. The subjects' response to the S0? exposures were as previously
noted in that Rl was not affected by the lower levels of S02 and progressively increased at
the higher levels. The only statistically significant difference (p <0.05) between the
effects of the gas alone and the gas-aerosol mixture was a slightly greater average increase
in pulmonary flow resistance at 4 to 7 ppm SOp than under the combination condition. Addition
of the NaCl aerosol resulted in similar changes as observed to SO,, alone. This effect was
interesting in that earlier work was cited suggesting that HpSO. may have been formed in the
droplets. (See discussion of similar animal studies in Chapter 12).
XD13A/A 13-20 2-14-81
-------
Snell and Luchsinger (1969) also compared the effects S02 alone and in mixture with
aerosols of either NaCl or distilled water. Nine subjects inhaled S02 at 0.5, I, and 5 ppm
alone and in combination with aerosols for 15-minute periods separated by 15-minute control
periods. For the SO^ - saline aerosol exposure, decreases in maximum expiratory flow rate
(MEF50% vc) were significant (p <0.01) only at 5 ppm S02; whereas, the SOp - distilled water
aerosol exposure produced significant decreases (p <0.01) at all exposure levels (0.5, 1, and
5 ppm S02). (See Figures 3 and 4, Snell and Luchsinger, 1969.) The authors noted that the
size of the aerosol particles differed considerably, saline particles averaging around 7 urn in
diameter and water aerosols averaging less than 0.3 (jm in diameter (see Figure 5, Snell and
Luchsinger, 1969). (See also Ulmer, 1974.) Koenig et al. (1980) exposed nine adolescent
resting subjects (extrinsic asthmatics) for 60 minutes to either filtered air, 1 ppm SO, and 1
3 3
mg/m of sodium chloride droplet aerosol or 1 mg/m of NaCl droplet aerosol (HMD 0.9 pm,
unable to estimate MMAD, and a of 2.0 |jm). Exposure to SO,, alone was not performed. Oral
breathing was forced on all subjects. Total respiratory resistance (RT), maximal flow at 50
and 75 percent of expired vital capacity (partial flow volume), FEV, Q, and functional resi-
dual capacity were measured before, during (30 minutes), and after exposures. No significant
changes were found during exposures to filtered air or NaCl aerosol. Significant decreases (p
<0.025) were observed in V t-n
jects (normal, atopic and mild asthmatic) for 10 minutes to 0, 1, 3 and 5 ppm SO,,. The sub-
jects breathed these gases orally while their specific airway resistance (SR ) was measured
aW
in a body plethysmograph. Despite large inter-and intra-subject variability in these subjects
breathing clean air, it was found that asthmatic subjects SR increased significantly
3W
(0.05-0.025) at all concentrations of S02. Normal and atopic subjects had significant
increases in SR only while breathing 5 ppm S09. Some asthmatic subjects exhibited marked
aW c.
dyspnea requiring bronchodi lator therapy. The increased SR seen in either normal or mild
clW
asthmatic subjects were prevented by treatment with atropine confirming the involvement of
parasympathetic pathways in this response. Reichel (1972) exposed two groups of subjects with
obstructive bronchial disease to varying concentrations of SO, in his chamber. Patients with
3
minor obstructive disease were exposed continuously for 4 days to 10 mg/m S09 (n = 8), for 4
3 3
days to 4.7 mg/m (n = 4) and 5 subjects for 6 days to 0.75 mg/m (n = 5). Patients with
serious obstructive bronchial disease were also exposed--4 to 4.7 mg/m for 4 days and 4 to
2.6 mg/m for 6 days. Airway resistance was not influenced by such exposure. The details of
XD13A/A 13-21 2-14-81
-------
the measuring procedures were not adequately presented in his report. Koem'g et al. (1981)
exposed 8 adolescent extrinsic asthmatics to the same conditions as in her above study but had
them also undergo a 10-minute period of moderate exercise during the exposures. Vmax ^ and
Vmax 75«£ decreased 44 and 50 percent respectively from the baseline mean after the exercise.
Significant changes in FEV, _ and R, were observed, suggesting that exercise and SO^-NaCl
exposure resulted in effects on both large as well as small airways. The functional changes
seen after exercise with exposure to filtered air or NaCl droplet aerosol alone were not
statistically significant. Although V rnv was depressed in resting subjects (extrinsic
IT) 3 X
asthmatics) 8 percent (t = 2.83 p < 0.025) and 6 percent (t = 0.38, p = N.S), respectively,
in the 1980 and 1981 studies by Koenig et al., it should be mentioned that the latter change
was not significant after 30 minutes of exposure. In the 1980 study, all subjects (N = 9)
decreased in V 5Q^; however, in the 1981 study some of the eight subjects increased and
some decreased.
As chemical interactants, particles such as aerosols of certain soluble salts (e.g.,
ferrous iron, manganese, vanadium) may act as catalysts to convert S0~ to HUSO.. HpO from
atmospheric humidity or from physiological sources figures prominently in these reactions.
The following sections deal with common compounds of sulfur oxides and point up the influence
of a number of variables that affect human physiological response to these compounds.
13.4 SULFUR DIOXIDE AND OZONE
Sulfur dioxide and ozone (0,) may combine to form sulfuric acid on the warm, moist
surfaces of the respiratory tract. Studies have not yet demonstrated, however, that a true
synergistic bond exists between SO^ and 03 (see Chapters 6, 7, and 11).
Bates and Hazucha (1973) and Hazucha and Bates (1975) exposed eight volunteer male
subjects to a mixture of 0.37 ppm 0, and 0.37 ppm S02 for 2 hours. Temperature, humidity,
concentrations and particle sizes of ambient aerosols (if any) were not measured. Sulfur
dioxide alone had no detectable effect on lung function, while exposure to ozone alone
resulted in decrements in pulmonary function. The combination of gases resulted in more
severe (10 to 20% decrement) respiratory symptoms and pulmonary function changes than did
ozone alone. Using the maximal expiratory flow rate at 50 percent vital capacity as the most
sensitive indicator, it was evident that after 2 hours exposure to 0.37 ppm S02 no change
occurred. However, during exposure to 0.37 ppm 0, a 13 percent reduction was observed, while
exposure to the mixture of 0.37 ppm 0, and 0.37 ppm SO^ resulted in a reduction of 37 percent
in this measure of pulmonary function. The effects resulting from 0, and S0« in combination
were apparent in 0.5 hours, in contrast to a 2-hour time lag for exposure to 0~ alone.
Bell et al. (1977) attempted to replicate these studies alone with four normal and four
ozone-sensitive subjects. They showed that 0, + SOp mixture had greater detrimental effect on
all pulmonary function measured than did 0, alone. However, only some of these parameters
showed statistical significants decrement when compared to 0,. Four of Hazucha and Bates'
subjects were also studied by Bell et al. (1977). Two of these subjects had unusually large
XD13A/A 13-22 2-14-8
-------
decrements in FVC (40 percent) and FEV-j^ (44 percent) in the first study (Bates and Hazucha,
1973), while the other two had small but statistically significant decrements. None of the
subjects responded in a similar manner in the Bell study. Restrospective sampling of the
ambient air conditions utilizing particle samplers and chemical analysis in the chamber showed
that acid sulfate particles could have been 10- to 100-fold higher in Hazucha and Bates'
chamber and thus might have been responsible for the synergistic effects observed. In the
Montreal chamber, concentrated streams of S09 and 0., exited from tubes separated by 8 inches
3 i
(20 cm) under a fan which forced 167 ft /min (4.7 m /min) of air conditioned laboratory air
with SO^ and 0, through the chamber and out an exhaust line on the opposite wall. The concen-
trated streams of SO,, and 0., could have reacted rapidly with each other and with ambient
£» -j
impurities like olefins, to form a large number of H?SO. nuclei which grew by homogenous
condensation, coagulation, and absorption of NHL during their 2-minute average residence time
•J
in the chamber.
Horvath's group (Horvath and Folinsbee, 1977; Bedi et al., 1979) exposed nine young men
(18 to 27 years old) to 0.4 ppm 0, and 0.4 ppm S0? singly and in combination for 2 hours in an
inhalation chamber at 25°C and 45 percent RH. The subjects exercised intermittently for one-
half of the exposure period. A large number of pulmonary function tests were conducted before,
during, and after the exposure. Subjects exposed to filtered air or to 0.4 ppm SO- showed no
significant changes in pulmonary function. When exposed to either 0, or 03 plus SCL, the sub-
jects showed significant decreases in maximum expiratory flow, forced vital capacity, and
inspiratory capacity. There were no significant differences between the effects of 0, alone
and the combination of 03 + SO,,; thus, no synergistic effects were discernible in their
subjects. Although particulate matter was not present in the inlet air, it is not known
whether particles developed in the chamber at a later point.
The question of potential synergistic interaction between SO* and 03 remains unresolved.
Chamber studies were conducted by Kagawa and Tsuru (1979) exposing six subjects for 2 hours
with intermittent exercise (50 watts i.e. ventillation of 25 1/min) for periods of 15 minutes
exercise separated by periods of 15 minutes rest. The exposures were performed weekly in the
following sequence: filtered air, 0.15 ppm 03; filtered air, 0.15 ppm SO^; filtered air and
finally 0.15 ppm 03 - 0.15 ppm SO,,. Pulmonary function measurements were obtained prior to
exposure after 1 hour in the chamber and after leaving the chamber. Although a number of
pulmonary function tests were performed, they utilized change in specific airway conductance
(SG ) as the most sensitive test of change in function. They found a significant decrease
QW
in five of the six subjects (5/6) exposed to 03 alone. In three of the six young male subjects,
they found a significant enhanced decrease in SG after exposure to the combination pollutants
3W
compared to the decrease in SG in these subjects in 0, exposure. Two other subjects had
similar decreases in either 03 or Oj-SO,, exposure. They further suggest that the effect of the
two gases on SG is more than simply additive and results from a combined pollutant exposure.
3W
Subjective symptoms of cough and bronchial irritation were reported to occur in subjects
exposed to 03 or 0,-SO,,.
XD13A/A 13-23 2-14-81
-------
Von Nieding et al. (1979) exposed 11 subjects to 03> N02 and S02 singly and in various
combinations. The subjects were exposed for 2 hours with 1 hour devoted to exercise which
doubled their ventilation. The work periods were of 15 minute duration interspersed with
15-minute periods at rest. In the actual exposure experiments, no significant alterations
were observed for P. , P. , pH , and thoracic gas volume (Vtg). Airway resistance total
H02 HC02
(R+) and P. were altered in certain studies. P. was decreased (7-8 torr) by exposure to
"n "n
U2 02
5.0 ppm N02 but was not further decreased following exposures to 5.0 ppm N02 and 5.0 ppm S02
or 5.0 ppm N02, 5.0 ppm S02 and 0.1 ppm 03 or 5.0 ppm N02 and 0.1 ppm 03- Airway resistance
increased significantly [0.5 to 1.5 cm H?0/(L/s)] in the combination experiments to the same
extent as in the exposures to N02 alone. In the 1-hour post exposure period of the NO,,, S02,
and 03 experiment, Rt continued to increase. Subjects were also exposed to 0.06 N02> 0.12 S02,
and 0.025 03 (all in ppm). No changes in any of the measured parameters were observed. These
same subjects were challenged with a 1, 2, and 3 percent solution of acetylcholine following
control (filtered air) exposure and to the 5.0 N02> 5.0 S02, and 0.1 03 (ppm) as well as after
the 0.06 N02, 0.12 S02, and 0.025 0,, (ppm) exposures. The expected increase in airway
resistance was observed in the control study. Specific airway resistance (R x Vtg) was
3W
significantly greater than in the control study following the combined pollutant exposures.
(See Table 13-4 for a summary of the pulmonary effects of S0? and other air pollutants.)
Three groups of eight subjects, each of different ages (>30, >49 and between 30-40 years)
were exposed for 2 hours in a chamber on three successive days (Islam and Ulmer, 1979a). On
the first day, subjects breathed air and exercised intermittently (levels not given); on the
second day they were exposed at rest to 5.0 ppm S02, 5.0 ppm N02 and 0.1 ppm 03; on the third
day the environment was again 5.0 ppm S0?, 5.0 ppm N0? and 0.1 ppm 0., but the subjects exer-
cised intermittently during the exposure. Statistical evaluation of the data on the 11 lung
functions and the two blood parameters (P. and P. ) was not adequately performed. These
A02 C02
measurements were made before, immediately and 3 hours post exposure. Individual variability
was quite marked. The investigators concluded that in their healthy subjects no synergistic
effects occurred. However, since they did not systematically expose these subjects to the
individual components of their mixed pollutant environment, the conclusion can only be justi-
fied in that they apparently saw no consistent changes. There were some apparent changes in
certain indiviuals related to exercise (unknown level) and age but the data were not
adequately analyzed nor could they be from the information presented.
Islam and Ulmer (1979b) studied 15 young healthy males during chamber exposures to 0.9
•33 O
mg/m S02, 0.3 mg/m N02 and 0.15 mg/m 03. Ten subjects were exposed to 1 day of filtered
air and 4 successive days to the above gas mixture. Another group of 5 subjects were exposed
for 4 days to the pollutant mixture followed by 1 day to filtered air. Each exposure was 8
hours in duration. Following each exposure the subjects were challenged by an acetylcholine
p p
aerosol. Nine pulmonary function tests and four blood tests ( An , AGO,, Hb and lactate
U2 *
XD13A/A 13-24 2-14-81
-------
13-4. PULMONARY EFFECTS OF S02 AND OTHER AIR POLLUTANTS
CO
I
ro
en
Duration of
Concentration exposure (mins)
S02 (0.15 ppm) 120
and
03 (0.15 ppm)
S02 (0.37 ppm) 120
and
03 (0.37 ppm)
S02 (0.37 ppm) 120
and
03 (0.37 ppm)
S02 (0.40 ppm) 120
and
03 (0.40 ppm
S02 (5 ppm) 120
and
N02 (5 ppm)
S02 (5 ppm) 120
N02 (5 ppm)
and
03 (0. 1 ppm)
S02 (0.12 ppm) 120
N02 (0.06 ppm)
and
0, (0.025 ppm)
Mixture of: S02 (5 ppm) 120
N02 (5 ppm)
03 (0.1 ppm)
Mixture of: S02 8 hr/da for
(0.33 ppm) 4 successive
N02 (0. 16 ppm) days
03 (0.075 ppm)
Number of
subjects Source
6 E*
8 Chamber
(exercise)
4 (normal) Chamber
4 (ozone (exercise)
sensitive)
4 (from Bates)
9 Chamber
(exercise)
11 Chamber
(exercise)
11 Chamber
(exercise)
11 Chamber
(exercise)
8 Chamber
(exercise)
15 Chamber
(rest)
Effects
Significant enhanced
decrease in SGaw after
exposure to S02 - 03 in
comparison to 0, alone
Decrease pulmonary functions
(in synergistic effect of
S02 on Oj) FRC, FEV^ n,
HMFR, HEFR5Q%
Unable to confirm
synergistic effects
pulmonary decrement due
to 0, alone
Unable to confirm
synergistic effects
changes due to ozone
alone
No changes in PA , P^,-
pHa or TGr -R^j- 2
increased
No changes in PAQ , PACQ2,
pHa or TGr -Raw
increased
No changes in pulmonary
functions
Data not adequately analyzed
and could not be from the
data presented.
Statistical analysis of the
data not adequate
Reference
Kagawa et al . , 1979
Hazucha and
Bates, 1975
Bates and
Hazucha, 1973
Bell et al., 1977
Horvath and Folinsbee
1977;
Bedi et al. , 1979
von Nieding et al., 1979
von Nieding et al. , 1979
von Nieding et al. , 1979
Islam and Ulmer,
1979a
Islam and Ulmer,
1979b
*Exercise.
-------
*
dehydrogenase) were performed before and after the exposure. The study suffers from a
deficiency in statistical analysis of the data. No impairments of lung functions, blood gases
or blood chemistry were found. However, some of the subjects were said to have unusual
reponses.
13.5 SULFURIC ACID AND SULFATES
13.5.1 Sensory Effects
A number of studies have been directed toward determining threshold concentrations of
H2$04 for various sensory response (see Table 13-5). In a study with 10 test subjects,
Bushtueva (1957) found that the minimum concentration of sulfuric acid aerosol (particle size
33 3
not given) which was sensed by odor ranged from 0.6 mg/m to 0.85 mg/m (average 0.75 mg/m ).
3
In tests with five subjects (Bushtueva, 1961), a combination of sulfur dioxide at 1 mg/m
(0.35 ppm) and sulfuric acid mist at 0.4 mg/m was below the odor threshold. Amdur et al.
(1952) reported on 15 subjects (males and females) exposed for 5 to 15 minutes to various
concentrations of sulfuric acid mist the subjects breathed via a face mask. It was found that
3 3
1 mg/m was usually not detected, while 3 mg/m was detected by all subjects.
Bushtueva (1957) studied the effect of sulfuric acid mist on the light sensitivity of two
test subjects. Sensitivity was measured every 5 minutes during the first half-hour of each
test, then at 10-minute intervals thereafter. A control curve was established for each
subject by seven repeated tests, and then sulfuric acid aerosol was administered for 4 minutes
and for 9 minutes at the 15th and 60th minutes, respectively. With sulfuric acid mist of
undetermined particle size at a concentration of 0.6 mg/m , a just detectable increase in
light sensitivity occurred with the first exposure but not with the second. Concentrations in
3 3
the range of 0.7 mg/m to 0.96 mg/m brought about a well-defined increase in light
sensitivity. With 2.4 mg/m , increased sensitivity to light was elicited by the exposures at
both the 15th and 60th minutes of the test; normal sensitivity was restored in 40 to 50
minutes.
Bushtueva (1961) studied the effect of sulfur dioxide, sulfuric acid mist and
combinations of the two on sensitivity of the eye to light in three subjects. The combination
3 3
of sulfur dioxide at 0.65 mg/m (0.23 ppm) with sulfuric acid mist at 0.3 mg/m resulted in no
change in sensitivity of the eye to light. An increase of approximately 25 percent in light
sensitivity resulted from exposure to either sulfur dioxide at 3 mg/m (~1.0 ppm) or sulfuric
3 3
acid mist at 0.7 mg/m . The combination of sulfur dioxide at 3 mg/m with sulfuric acid mist
o
at 0.7 mg/m resulted in an increase of approximately 60 percent in light sensitivity.
Exposures lasted for 4 1/2 minutes.
•3
Bushtueva (1962) demonstrated that combinations of sulfur dioxide at 0.50 mg/m (0.17
3 3
ppm) with sulfuric acid mist at 0.15 mg/m or sulfur dioxide at 0.25 mg/m (0.087 ppm) with
sulfuric acid mist at 0.30 mg/m could produce electrocortical conditioned reflexes. There
are some uncertainties regarding this study.
XD13A/A 13-26 2-14-81
-------
XD13A/B-8
13-5. SENSORY EFFECTS OF SULFURIC ACID AND SULFATES
Concentration Subjects Effects References
0.75 mg/m3 5 Threshold detected by odor Bushtueva, 1957, 1961
- increase in light sensitivity
- increase in optical chronaxie
1-3 mg/m3 15 (exposed 5-15 min) 3 mg/m3 detected by all subjects Amdur et al., 1952
CO
ro
-------
Bushtueva (1961) studied the effects of different concentrations of sulfur dioxide,
sulfuric acid mist, and combinations of the two on the optical chronaxie of three subjects.
Optical chronaxie was determined in each test subject at 3-minute intervals as follows: at
the start and on the 3rd, 6th, 9th, 12th and 15th minutes. Between the 6th and 9th minutes
the subjects inhaled sulfur dioxide, sulfuric acid mist, or their combination for 2 minutes.
In each subject, the threshold concentrations of sulfur dioxide and sulfuric acid mist were
first determined independently, and then threshold concentrations for combinations of the two
were determined. Sulfuric acid mist (0.75 ug/m ) increased optical chronaxie.
13.5.2 Respiratory and Related Effects
Amdur et al. (1952) found respiratory changes in all subjects exposed for 15 minutes to
•3 O
H2$04 aerosol at concentrations of 0.35 mg/m to 5 mg/m . Vapors from an electrically heated
flask containing concentrated sulfuric acid were carried by compressed air into the main air
stream and then into a lucite mixing chamber, delivering a mist of MMD 1 um. The subjects
breathed through a pneumotachograph, permitting measurement of inspiratory and expiratory flow
rate. In 15 subjects, exposed to 0.35, 0.4, or 0.5 mg/m , the respiration rate increased
about 35 percent above control values, while the maximum inspiratory and expiratory flow rates
decreased about 20 percent. Tidal volume decreased about 28 percent in subjects exposed to
0.4 mg/m . These changes occurred within the first 3 minutes of exposure and were maintained
throughout the 15-minute exposure period. Lung function returned rapidly to baseline levels
after the exposure ended. The tidal volume rose above control values during the first minute
after termination of the exposure and then returned to preexposure levels. Breathing through
the same apparatus without the acid mist was done as a control, and no such changes were
observed. Some subjects showed a marked reaction to 5 mg/m , a level of acid mist perceptible
to all. Individual responses were much more varied at this level, the main effect being a
decrease in minute volume. The investigators suggest that bronchoconstriction may have been
the response to sulfuric acid.
The effect of breathing sulfuric acid mist at different relative humidities (RH) was
studied by Sim and Rattle (1957). Healthy males (variable number of subjects), 18 to 46 years
of age, breathed 3 to 39 mg/m concentrations of HUSO, at 62 percent RH either via mask or
3
exposure chamber. Subjects were also exposed in the chamber to 11.5 to 38 mg/m
concentrations at 91 percent RH. At the lower RH, particles were 1 um in size. The addition
of water vapor to raise RH increased the mean particle size to 1.5 |jm and intensified irritant
o
effects of exposure. For example, the irritancy of wet mist at 20.8 mg/m was much more
severe ("almost intolerable at the onset") than that of the dry mist at 39.4 mg/m ("well
tolerated by all"). Air flow resistance ranged from 43 to 150 percent above normal in
response to the wet mist, compared to increases ranging from 35.5 to 100 percent above normal
in response to the dry mist. Two subjects exposed to sulfuric acid mist developed bronchitic
symptoms but may have been previously exposed to other substances. Adding ammonia (quantity
XD13A/A 13-28 2-14-81
-------
*
not given) to the acid mist annulled its irritant properties. There was no consistent
evidence that the acid mist caused changes in respiratory functions or blood pressure, pulse
rate, or other cardiovascular functions.
Toyama and Nakamura (1964) investigated the synergistic effects of S02 in combination
with hydrogen peroxide (HJL) aerosol mixtures, the latter of which oxidizes S02 to form
H2S04- S02 concentrations ranged from 1 to 60 ppm; the KL02 concentrations were 0.29 mg/m
for particles of 4.6 urn CMD (Horvath estimated MMAD = 13) and 0.33 mg/m3 for particles of 1.8
urn CMD (Horvath estimated MMAD = 5). Airway resistance increased significantly in the combi-
nation (HLCL + S02) exposure, particularly for the group of 15 subjects inhaling the larger
particles (p <0.01). Toyama and Nakamura (1964) exposed subjects to a mixture of S02 and
H2SO^ aerosols. They used an inadequate method to measure airway resistance. They described
the aerosols as having a 4.5 urn diameter. They found a strong constricting effect on the
upper airways.
Sackner et al. (1978) studied normal resting young adults and seven asthmatic middle-aged
subjects who breathed, by mouth, either sodium chloride or sulfuric acid aerosols for 10
minutes at concentrations of 10, 100, and 1000 M9/m (0.1-0.2 MMAD). Measurements on these
individuals continued for up to 3 hours after exposure. The asthmatic patients represented a
wide range of clinical status and treatment. Neither normal nor asthmatic individuals showed
significant alterations of lung volumes, distribution of ventilation, earoximetry, dynamic
mechanics of breathing, oscillation mechanics of the chest-lung system, pulmonary capillary
blood flow, diffusing capacity, arterial oxygen saturation, oxygen uptake, or pulmonary tissue
volume. No delayed effects were observed during a follow-up period of a few weeks.
Kleinman and Hackney (1978) and Avol et al. (1979) reported on the pulmonary responses of
six normal and six asthmatic subjects exposed in an ambient environment of 88°F dry bulb and
40 percent relative humidity, and 94 ug/m H2SO.. The asthmatics had pulmonary function test
results which ranged widely from normal to abnormal. A sham exposure was followed by 2
consecutive days of acid exposure. Sufficient excess acid aerosol to neutralize the NH,
3
present (about 56 ug/m ammonia neutralization product) was added to the air to provide for
the desired acid concentration (75 ug/m ). The aerosol MMAD was approximately 0.48 to 0.81
urn. The effective exposure time was 2 hours, with the first 15 minutes of each half-hour
devoted to exercise which increased ventilation to twice the resting level. Only one subject
was exposed at a time to minimize the effects of ammonia neutralization. The normal subjects
showed no exposure-related changes. The lung functions of the asthmatics showed no signifi-
cant changes. Two asthmatics, the extent of their disease state not given, exhibited in-
creases in respiratory resistance on both exposure days. Nonetheless, it was concluded that
there were no convincing adverse short-term health effects of sulfuric acid. However, they
also noted the small size of their subject pool and recommended additional studies.
XD13A/A 13-29 2-14-81
-------
Utell et al. (1981) exposed 16 normal subjects and 17 asymptomatic asthmatics (all
subjects non-smokers) to acidic aerosols (MMAO = 0.5-1.0 |jm, o 1.5-2.2) for periods of 16
minutes. Several aerosol exposures were given each day in a double-blind random pattern. At
the beginning of each study, an approximate dose-response curve to inhaled carbachol was
obtained. All aerosols [NaHS04, (NH4)2S04; NH4HS04, H2S04, Nad] were given orally. The data
presented in the manuscript is incomplete, but what is available suggests that specific airway
conductance (SGaw) induced by carbachol was significantly potentiated (p <0.01) in asthmatics
3 3
breathing H2$04 and NH4HS04 (each 1 mg/m ). Low sulfate exposure (0.1 mg/m ) produced no
changes in SGaw, however; the two asthmatics most responsive to the high H-S04 dose via inhala-
tion exhibited a potential effect to the lower sulfuric acid exposure. No effects were noted
in the normal subjects. A more extensive presentation of the data obtained by these investi-
gators will be required before final decision of the effects of sulfates on asthmatics can be
determined.
Lippmann et al. (1980) had 10 non-smokers inhale via nasal mask 0.5 urn (a = 1.9) H,SO.
3 "
at 0 and approximately, 100, 300, and 1,000 ug/m for 1 hour. The exposures were random over
the 4 days of testing. Pulmonary functions (assessed by body plethysmograph, partial forced
expiratory maneuver, and nitrogen washout) were measured before, and at 0.5, 2, and 4 hours
post exposure. i"c-tagged monodispersed Fe^O, aerosol (7.5 urn MMAD, 0 =1.1) was inhaled
10 minutes before exposure for the determinations of lung retention of these particles.
Tracheal mucus transport rates (TMTR) and bronchial mucociliary clearance were determined. No
significant changes in respiratory mechanics or TMTR were observed following H2S04 exposure at
any level. However, bronchial mucociliary clearance halftime (TBjJ was on the average
markedly altered at all concentrations of H,SO., inhaled. Bronchial clearance was increased (p
3 3
<0.02) following exposure to 100 ug/m H2$04, while following exposure to 1,000 ug/nr , it was
significantly (p <0.03) reduced. Mucociliary transport in the airways distal to the trachea
was affected more by H2$04 exposure than was transport in the trachea. Out of ten subjects
four did not respond. "The alterations in bronchial clearance half-time were all transient,
which was consistent with the results seen earlier in similar inhalation tests on donkeys
(Schlesinger et al., 1978). However, when donkeys were repeatedly exposed to sulfuric acid at
comparable concentrations, four of six animals developed persistently slowed clearance, which
remained abnormal for at least several months (Schlesinger et al., 1978, 1979). Taken
together, these results suggest that at the concentrations employed persistent changes could
occur in mucociliary clearance in previously healthy individuals and exacerbate preexisting
respiratory disease.
Kleinman and Hackney (1978) and Avol et al. (1979) presented in greater detail the pre-
liminary findings reported by Bell and Hackney (1977). They evaluated the effects of various
sulfate compounds on normal subjects, ozone-sensitive subjects, and asthmatic subjects
(requiring medical treatment). The exposures were approximately 2.5 hours in duration, with
XD13A/A 13-30 2-14-81
-------
the subjects exercising the first 15 minutes of each half hour at a pace sufficient to double
their ventilation rates. Measurements of pulmonary functions, which included FVC, FEV,, MEFR,
^50%' ^75%' ^^> ^' delta nitrogen (AN,,), closing volume, and total respiratory re-
sistance (Rt) were made before and 2 hours after the work-rest regimen began. The ambient
conditions were 88°F dry bulb and either 40 or 85 percent relative humidity. Most of the expo-
sure studies were made on five to seven subjects. Four to five sensitive subjects and six
asthmatics completed the subject pool. Subjects were first exposed to a control (no pollut-
ant) environment and then to 2 or 3 consecutive days of the pollutants. The asthmatics were
not studied in the high humidity conditions, but were exposed to a higher concentration (up to
372 ug/m ) of (NH^SO^. Nominal exposure concentrations were 100 ug/m for ammonium bi-
sulfate (NH4HS04) and 85 ug/m for ammonium sulfate [(NH4)2S04~|. The sulfate aerosol size
distribution was nominally 0.4 urn MMAD (a 2.5 to 3). There was some ammonia (NH.,) in the
exposure chamber. Pulmonary functions were unaffected by exposure to the two types of aero-
sol.
An interesting side observation was made on the asthmatics. On their first day of
exposure to NH4HS04 aerosol, they exhibited worse lung functions in the pre-exposure measure-
ments than they had on a control day. Their functions improved consequent to the pollutant
exposure. Subsequent analysis of local ambient conditions showed that these subjects arrived
for their aerosol testing after a 3-day period of increased SO- and ozone levels during a
"mild air pollution episode." (See Table 13-6 for a summary of the pulmonary effects of
sulfuric acid.)
Kleinman et al. (1981) conducted studies in which 19 volunteers with normal pulmonary
function and no history of asthma were exposed on two separate days to clean air and to an
atmosphere mixture containing 03 (0.37 ppm), S02 (0.37 ppm), and H2$04 aerosol (100 ug/m ,
MMAD 0.5 urn; ag = 3.0). During this 2-hour period, the subjects alternatly exercised for 15
minutes, at a level calibrated to double minute ventillation, and rested for 15 minutes.
Statistical analysis of the group average data suggested that the mixture may have been
slightly more irritating to the subjects than 03 alone. A large percentage (13 of 19) of the
subjects exhibited small decrements in pulmonary function. The groups averaged FEV, g on the
exposure day was significantly depressed, 3.7 percent of the control value. One might expect
0, alone to depress FEV, Q by approximately 2.8 percent under similar exposure conditions.
Kerr et al. (1981) investigated the respiratory effects associated with exposure to low
levels of sulfuric acid (H2$04) aerosol. Twenty eight normal subjects were exposed for 4 hours
to 100 ug/m3 H2S04 aerosol of particle size 0.1 to 0.3 urn (HMD = 0.14 pm; ag = 2.9) in an
environmentally controlled exposure chamber. At one and three hours into the study on each
day, bicycle ergometer exercise was performed at a workload at 100 watts at 60 RPM for 15
minutes. Of the 28 subjects, 14 were nonsmokers and 14 were cigarette smokers. None of
the subjects complained of symptoms attributable to the exposure. Measurements of pulmonary
XD13A/A 13-31 2-14-81
-------
XD13A/B-9
13-6. PULMONARY EFFECTS OF SULFURIC ACID
OJ
I
oo
ro
Duration of
Concentration exposure (mins)
0.35 - 5.0 mg/m3 H,SO, 15
MMD 1 Mm
3-39 mg/m3 H,SO. 10 - 60
MMD 1-1.5 MA
SO. (1-60 ppm) plus Variable
H,0, to form H-SO.
alr&sol ' *
CMO 1.8 and 4.6 Mm
H.SO. mist , 120
(lOOO Mg/m
MMD 0.5 Mm (og = 2.59)
H,SO. aerosol , 10
10, 100, 1000 Mg/m
MMD 0.1 Mm
H,SO. (75 Mg/m3) 120
MMAD 0.48 - 0.81 Mm
H,SO. (0, 100, ,300, 60
Sr 1,000 Mg/m
MMAD 0.5 Mm
(og = 1.9)
H SO. - 240*
100 M9/»
MMD 0.14 Mm
og = 2.9
Number of
subjects
15
Variable
24
10
6 normal
6 asthmatics
6 normal
6 asthmatics
10
2fi normals
Source
Mask (rest)
Mask (rest)
Chamber (rest)
(Rest)
Chamber
(exercise)
Oral
Chamber
(exercise)
Nasal
Chamber
(exercise)
Effects
Respiratory rates increased,
max. insp. and expiratory
flow rates and tidal
decreased volumes
Longer particles due to "wet
mist" resulted in increased
flow resistance cough, rales
bronchoconstri cti on
Airway resistance
increased especially
with larger particles
No pulmonary function
changes but increased
tracheobronchial clearance
No pulmonary function
changes, no alterations
in gas transport
No pulmonary effects
in either group
No pulmonary function
effects
Broncial mucociliary
clearance t following
100 Mg/m ,but * following
1000 M9/m mucociliary
clearance distal to trachea
more affected
No pulmonary function effects
Reference
Amdur et al. , 1952
Sim and Rattle, 1957
Toyama and Nakamura,
1964
Newhouse et al. , 1978
Sachner et al . , 1978
Kleinman and Hackney,
1978; Avol et al., 1979
Lippmann et al. , 1980
Kerr et al., 1981
-------
*
function were obtained 2 hours into the exposure, immediately following exposure and 2 and 24
hours post-exposure. These measurements were compared with control values obtained at
comparable hours on the previous day when the subject breathed only filtered clean air in the
chamber. No significant differences in pulmonary function were observed either during the
exposure, immediately after exposure or 2 and 24 hours post-exposure.
13.6 SUMMARY
Human experimental studies of the health effects of exposure to pollutants in the ambient
environment require strict controls so that their findings can be generalized to the entire
population. Although no studies meet all the requirements for strict control, some basic
information can be garnered from many published studies.
SOp has been found to have effects on several physiologic functions. Through subjective
reports, the reliability of which has been questioned, a level of 5 ppm has been established
for detecting S0?, with considerable variation below that level. Several sensory processes
are affected by generally agreed-upon levels of concentration of S0?. The odor threshold
averages 0.8 to 1 ppm, with 0.47 ppm set in one study performed under ideal conditions. The
sensitivity of the eye to light increases at 0.34 to 0.63 ppm, is maximal at 1.3 to 1.7 ppm,
and decreases to normal by 19.2 mg/m during dark adaptation. During light adaptation, the
figures increase and decrease similarly but at slightly higher levels of exposure. The
3
alpha-wave has been found to be attenuated by 0.9 to 3 mg/m SOp during 20 seconds of exposure.
Studies of the effects of S0? on the respiratory system of the body have arrived at con-
flicting conclusions. Although one study found respiratory effects after exposure to as
little as 1 ppm SO,,, others could find no effect below 5 ppm. At the latter level, pulmonary
flow resistance increased 39 percent in one study. Respiratory effects have been found to be
proportional to the concentration of S0? to which study subjects are exposed. Although the
bronchoconstrictive effects of exposure to SOp have been found to be fairly consistent,
subjects vary considerably in response to exposures, and there are some especially sensitive
subjects, which may represent as much as 10 percent of the population. Recent studies have
shown that SR significantly increased in asthmatics at 0.5 and 0.25 ppm S09 and even at 0.1
ctW c.
ppm in some asthmatic subjects.
Because SO,, is readily water soluble, and nasal passages are high in humidity, the route
of exposure will affect the response of individuals. Subjects report less throat and chest
irritation when breathing through the nose, and pulmonary flow resistance increases less in
subjects who are nose breathing. Regardless of the route of exposure, 5 ppm S02 had limited
effects on specific airway conductance (airway bronchoconstriction), although higher levels
had a dose-dependent effect; that is, higher concentrations decreased SG more than lesser
9W
concentrations. The average decrease was greater after oral exposure than after nasal admini-
stration.
The level of activity of the subjects tested affects the results because the actual dose
delivered to lungs and airways is greater when subjects breathe through their mouth, as during
exercise. Just having subjects breathe deeply through the mouth significantly affected
XD13A/A 13-33 2-14-81
-------
specific airway resistance during exposure to 1 ppm S02 in one study, although another study
found no such effect. Respiratory effects of exposure either by nose or by mouth are greatest
after 5 to 10 minutes of exposure. Recovery takes about 5 minutes in normal subjects, but much
longer (10 to 60 minutes) in sensitive subjects and those who are asthmatic. Studies of nasal
mucus flow rates and airway resistance following about 6 hours of exposure to 1 and 5 ppm S0?
per day for 3 days found some effects maximal after 1 to 6 hours.
An early study found mucus clearance reduced increasingly as length and concentration of
exposure to S0? increased. Long exposures to 5 ppm S0? increased mucociliary clearance in one
study; a decrease had been found in nasal clearance rates in another study. Available studies
have not found a significant interaction of smoking with S02.
The interaction of S02 and particulate matter is an important factor in respiratory
effects studies. Airway resistance increased more after combined exposure to S02 and sodium
chloride than after exposure to S0? or sodium chloride alone in several studies although others
have failed to reach the same conclusion. This may have been due to formation of sulfuric
acid mist during the study. MEFrQc/ was found to be significantly reduced after exposure to a
combination of saline aerosol to 5 ppm S0?. After exposure to combined hydrogen peroxide and
0.5 to 5 ppm sulfur dioxide, airway resistance was found to be significantly increased. The
combination of SOp and ozone may have synergistic effects on lung function. At low concen-
trations (0.37 ppm) S02 had no effect on lung function, ozone impaired lung function, and the
combination impaired lung function even more. A similar study did not find the same results.
Other studies have found reductions in pulmonary function after exposure to low levels of S02
or ozone alone and in combination, with no synergistic effect observed with the combined
exposure. Japanese studies involving exposure to 0., alone and a combination of S02 (0.15 ppm)
and 03 (0.15 ppm) have observed a significant enhanced decrease in specific airway conductance
(SGaw) after exposure to the combination pollutants compared to the decrease in SGaw in these
subjects in 07 exposure. They suggest that the effect is synergestic and not just additive.
-------
*
demonstrated after exposure to sulfuric acid and sulfate salts at concentrations less than 0.1
3 1
mg/m . However, at higher concentrations (1.0 mg/m ) reduction in specific airway conductance
and FEV-^ have been observed after H2$04 and NH.HSO, exposures. Mucociliary clearance was
affected by exposure to sulfuric acid, being significantly increased after exposure to 100
3 3
|jm/m and significantly decreased after exposure to 1000 ug/m . Another study found no
pulmonary effect of exposure to sulfuric acid, ammonium bisulfate, and ammonium sulfate by
normal and asthmatic subjects.
XD13A/A 13-35 2-14-81
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*
ADDENDUM
Recent Abstract
Schlenker, E. , and M. Jaeger. Airway response of young and elderly subjects to 0.5 ppm
S02 and 0.5 ppm Oj. Physiologist 23:77, 1980a.
Ten elderly (73 ±7.7 years of age) and ten young (25.5 ± 4 years of age) were first
studied (presumably at rest) in a clean air environment and on the succeeding day were exposed
to the combined pollutants for 1 hr. A follow-up period of 3 hr was made on each day. No pul-
monary function changes were observed on either day in the old subjects. However, the young
subjects had a decrease in MMFR (5.23 to 4.65 L/sec) during the pollutant exposure. Recovery
to control levels was not complete in these young subjects in the following 3 hours in clean
air.
XD13A/A 13-36 2-14-81
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*
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14. EPIDEMIOLOGICAL STUDIES ON THE EFFECTS OF SULFUR
OXIDES AND PARTICULATE MATTER ON HUMAN HEALTH
14.1 INTRODUCTION
This chapter evaluates epidemiological literature concerning health effects associated
with ambient air exposures to sulfur oxides and particulate matter. The main focus of the
chapter is on: (1) the qualitative characterization of human health effects associated with
exposure to atmospheric sulfur dioxide (S0?), related sulfur compounds, and other particulate
matter (PM); (2) quantitative delineation of exposure/effect and exposure/response relation-
ships for the induction of such health effects; and (3) the identification of population groups
at special risk for experiencing the health effects at ambient exposure levels.
The epidemiological data discussed here both complement and extend information presented
as part of health effects analyses contained in preceding chapters (11,12,13) of this document.
Those chapters focus on information derived from animal toxicology and controlled human
exposure studies which offer the advantage of characterizing, under well-controlled laboratory
conditions, differential patterns of respiratory tract deposition and clearance of: S02; sul-
fates (SO.) and sulfuric acid (H?SO.); and other particulate matter of varying size and chemi-
cal composition. In addition, the animal toxicological studies provide evidence for notable
health effects occurring in mammalian species as the result of such respiratory tract deposition
of sulfur oxides and particulate matter, including: transient alterations in pulmonary
functions; altered mucociliary clearance and other respiratory tract defense mechanisms; and
increased susceptibility to infection and morphological damage seen especially after high level
or prolonged exposures. However, while such results from animal studies are highly suggestive
of analogous effects possibly being induced in human beings, caution must be exercised in
directly extrapolating the findings or associated dose-effect relationships to human health.
More direct delineation of quantitative dose-effect or dose-response relationships is possible
through controlled human exposure studies, but such studies also have important limitations.
For example, whereas controlled human exposure studies have demonstrated S0? or PM induction
of transient pulmonary function decrements, altered mucociliary clearance patterns, and symp-
tomatic effects consistent with animal toxicology study findings, observation of such effects
has generally been confined to conditions involving single or a few repeated short-term (<3
hrs) exposures but not prolonged chronic exposure conditions. Also left unanswered by con-
trolled human exposure studies are questions concerning whether or not more severe effects,
e.g., increased vulnerability to respiratory diseases or marked morphological damage, are
associated with either short-term or prolonged ambient exposure conditions.
Epidemiological studies, in contrast, offer several advantages beyond those of animal
toxicology or controlled human exposure studies. Health effects of both short- and long-term
pollutant exposures (including complex mixtures of pollutants) can be studied and sensitive
members of populations at special risk for particular effects at ambient air concentrations
SOX14G/A 14-1 2-14-81
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identified. Also, epidemiological evaluations allow for investigation of both acute and
chronic disease effects and associated human mortality. Epidemiological studies, then,
together with the results of controlled animal and human exposure studies, can significantly con-
tribute to more complete understanding of health effects of sulfur oxides and particulate matter,
especially in helping to characterize human health effects associated with those pollutants
under ambient conditions. Despite such advantages, however, important limitations do exist in
regard to the conduct, analyses, interpretation, and use of many of the available epidemio-
logical studies on the health impact of S0? and PM, as discussed next.
14.1.1 Methodological Considerations
As noted by Lowrence (1976), epidemiological and other types of studies employed in
generating information relevant to human risk assessment typically divide into four lines of
investigation. These involve making measurements aimed at: (1) defining exposure conditions;
(2) identifying adverse effects; (3) relating exposures to effects; and (4) estimating overall
risk.
In relation to accomplishing these goals, one important limitation of most of the epidemi-
ological studies reviewed here has been less-than-optimum characterization of community air
quality parameters used to estimate exposures of population groups to varying atmospheric con-
centrations of sulfur oxides and particulate matter. Such characterization of air quality has
generally involved relatively crude estimates of levels of pollutants present, allowing for
only limited qualitative statements to be made regarding exposure conditions--e.g. whether a
given site or time period had comparatively higher or lower atmospheric levels of SOp or PM
than some other site or time period. Only very rarely have the epidemiological studies relied
on measurement methods or practical field applications of those methods that permitted
reasonably precise determinations of variations in airborne levels of the pollutants of concern
so as to provide quantitative information on S0? or PM levels associated with observed health
effects. Even when reasonable quantification of community air quality parameters was achieved,
however, the use of such data in estimating actual population exposures has typically been
further constrained by factors such as siting of air sampling devices in relation to the study
population, frequency and duration of sampling periods, activity patterns of study population
members, and contributions of indoor air pollution to overall exposures of study groups.
These, and other limitations noted, arise in part from the fact that most of the presently-
reviewed epidemiological studies utilized air quality monitoring data obtained from sampling
networks originally established for purposes other than health-related research and, therefore,
not optimally designed to provide the specific types or quality of aerometric data ideally
needed for epidemiological assessment of health effects related to SCL and PM. Thus, the
aerometric data utilized thus far should generally be viewed as yielding, at best, only approx-
imate estimates of actual study population exposures.
Adequate characterization of health effects associated with various S0? and PM expo-
sure conditions has represented a second major type of problem for many of the epidemio-
logical studies evaluated in the present chapter. A variety of health endpoint measurements
SOX14G/A 14-2 2-14-81
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(mortality, morbidity, and indirect measures of morbidity) have been employed in such studies
and each have their own advantages and disadvantages, as has been discussed in detail in other
reviews (Hill, 1968; Speizer, 1969; Holland, 1970; Goldsmith and Friberg, 1977; Higgins, 1974;
Shy et al., 1978; NRC/NAS, 1978a; NRC/NAS, 1978b; Ferris, 1978; ATS, 1978; Macklen and Permutt,
1979; Fox et al., 1979). Some health outcome measurements have involved more or less direct
observations of signs and symptoms of disease states or objective indicators typically closely
associated with the occurrence of illnesses, e.g., patient visits to hospitals or clinics or
absenteeism from school or work. Direct quantification of health effects has also included
measurement of biochemical or physiological changes in study populations, as in the recording
of pulmonary function changes by spirometry methods. Indirect measures or indices of health
effects have also been used, e.g., in gathering information on frequency and duration of
respiratory illnesses by means of telephone interviews, written questionnaires, or self-
reported entries in diaries. The validity of such indirect measurements of health effects,
however, is heavily dependent on the ability and motivation of respondents to recall accurately
and report past or present health-related events; and this can be markedly influenced by
numerous extraneous factors such as age, cultural and educational background, instructions from
experimenters, sequencing of questions, and problems with interviewer variability and/or bias.
Confidence in the results obtained by either direct or indirect measurement methods is greatly
enhanced if possible interfering or biasing factors have been appropriately controlled for and,
especially for indirect health endpoint measurements, if results have been validated against
corroborating evidence such as physician or hospital records verifying reported health effect
occurrences.
Adequately relating observed health effects to specific parameters of ambient exposure
conditions is another objective that has been very difficult to achieve by epidemiological
studies reviewed below, such that relatively few allow for confident qualitative or quanti-
tative characterization of S0? or PM exposure/health effect relationships. For example, com-
peting risks, such as cigarette smoking and occupational exposures, may contribute to observed
health effects results and, therefore usually must be controlled for or taken into account in
order for much confidence to be placed in reported health effects/air pollution relationships;
however, numerous studies on SO* or PM effects have failed to control adequately for such
factors. Similarly, the possible effects of other covarying or confounding factors such as
socioeconomic status, race, and meteorological parameters have not always been adequately con-
trolled for or evaluated in relation to study results. Also, further complicating the evalu-
ation of the epidemiological data is the fact that exposure parameters are not subject to
experimenter control, with ambient levels of a given pollutant often widely varying over the
course of a study. This has made it extremely difficult to determine whether mean concen-
trations, peak concentrations, rapid fluctuations in levels, or other air quality factors are
most important as determinants of the reported health effects. In addition, significant
covariation between concentrations of S0?, PM, and other pollutants has often made it very
SOX14G/A 14-3 2-14-81
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difficult to distinguish among their relative contributions to the health effects demon-
strated.
Estimation of overall risk by means of epidemiology studies requires still further steps
beyond the delineation of exposure/effect relationships that define exposure conditions
(levels, durations, etc.) associated with the induction of specific health effects. That is,
estimation of risk also requires: (1) the identification of particular population groups
likely to manifest the health effects under exposure conditions of concern; and (2) ideally,
the determination of numbers or percentages of such individuals (responders) likely to be
affected at various exposure or dose levels. Delineation of the first variable, i.e., identi-
fication of population groups at special risk for being affected at lower exposure levels of
SOp and PM than other groups, has to some extent been accomplished through various epidemio-
logical studies reviewed here. However, epidemiological definition of precise quantitative
dose/response (or, more correctly, exposure/response) relationships, which define percentages
of population groups likely to manifest a given health effect at various levels or durations
of exposure to SO^ and PM, has been extremely difficult to achieve and is largely lacking at
this time.
Another limitation of the epidemiological information reviewed here concerns its useful-
ness in demonstrating cause/effect relationships versus merely establishing associations
between various health effects and S02 or PM (which may be non-causal in nature). The inter-
pretation of epidemiological data as an aid in inferring causal relationships between presumed
causal agents and associated effects has been the subject of discussion by several expert
committees or deliberative bodies faced with evaluation of controversial biomedical issues
during the past several decades (U.S. Surgeon General's Advisory Committee on Smoking and
Health, 1964; U.S. Senate Committee on Public Works, Subcommittee on Air and Water Pollution,
1968). Among the criteria selected by each group for determination of causality were many of
those advocated by A. B. Hill (1965), which included the following: (1) the strength of the
association; (2) the consistency of the association, as evidenced by its repeated observation
by different persons, in different places, circumstances and time; (3) specificity of the
association; (4) the temporal relationship of the association; (5) the coherence of the
association in being consistent with other known facts; (6) the existence of a biological
gradient, or dose-reponse curve, as revealed by the association; and (7) the biological plausi-
bility of the association. Hill further noted that strong support for likely causality
suggested by an association may be derived from experimental or semi-experimental evidence,
where manipulation of the presumed causative agent (its presense or absence, variability in
intensity, etc.) also affects the frequency or intensity of the associated effects.
It is important to note that Hill (1965) and the deliberative bodies or expert committees
alluded to above were careful to emphasize, regardless of the specific set of criteria selected
by each, that no one criterion was definitive by itself nor was it necessary that all be ful-
filled in order to support a determination of causality. Also, Hill and several of the groups
noted that statistical methods cannot establish proof of a causal relationship in an associ-
SOX14G/A 14-4 2-14-81
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ation nor does lack of "statistical significance" of an association according to arbitrarily
selected probability criteria necessarily negate the possibility of a causal relationship.
That is, as stated by the U.S. Surgeon Genera] Advisory Committee on Smoking and Health
(1964): "The causal significance of an association is a matter of judgment which goes beyond
any statement of statistical probability." Statistical findings, nevertheless, as well as
other types of observational and experimental information, are useful inputs in helping to
determine likely causal relationships.
14.1.2 Guidelines for Assessment of Epidemiological Studies
Taking into account the above methodological limitations, it appears to be possible to
delineate a reasonable set of guidelines by which to judge the relative scientific quality of
epidemiological studies and their findings reviewed in the present chapter. Such assessment
guidelines include consideration of the following questions:
1. Was the quality of the aerometric data used sufficient to allow for meaningful
characterization of geographic or temporal differences in study population pol-
lutant exposures?
2. Were the study populations well-defined and adequately selected so as to allow
for meaningful comparisons between study groups or meaningful temporal analyses
of health effects results?
3. Were the health endpoint measurements meaningful and reliable, including clear
definition of diagnostic criteria utilized and consistency in obtaining de-
pendent variable measurements?
4. Were the statistical analyses employed appropriate and properly performed and
interpreted, including accurate data handling and transfer at various steps of
analyses?
5. Were potentially confounding or covarying factors adequately controlled for or
taken into account in the study design and statistical analyses?
6. Are the reported findings internally consistent, biologically plausible, and
coherent in terms of being consistent with other known facts?
It is recognized that few, if any, epidemiological studies deal with each of the above
points in a completely ideal fashion; nevertheless, these guidelines provide benchmarks by
which to judge the relative quality of various studies and by which to select the best for
detailed discussion here.
Detailed critical analysis of the vast number of epidemiological studies on the health
effects of SCL and PM, especially in relation to each of the above questions, would represent
an undertaking beyond the scope or purpose of the present document. Of most importance for
present purposes are those studies which provide useful quantitative information on exposure/
effect or exposure/response relationships for health effects associated with ambient air
levels of SCL and PM likely to be encountered in the United States over the next 5-year
period. Accordingly, the following criteria were employed in selecting studies for detailed
discussion in the ensuing text:
1. Concentrations of both S0? and PM were reported, allowing for potential
evaluation of their separate or combined effects.
SOX14G/A 14-5 2-14-81
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2. Study results provide information on quantitative relationships between health
effects and ambient air S02 and PM levels of approximately 1000 (jg/m or less.
3. Important methodological considerations were adequately addressed, especially
(a) in controlling for likely potentially confounding factors and (b) in
carrying out data collection, analysis, and interpretation so as to minimize
errors or potential biases which could be reasonably expected to affect the
results.
4. The study results have been reported in the open literature or are in press,
typically after having undergone peer review.
In addition, some studies not meeting all of the above criteria are either briefly men-
tioned or discussed in the main chapter text below as appropriate in helping to elucidate par-
ticular points concerning the health effects of S02 and/or PM. Additional studies, including
those mainly providing only qualitative information on S0? and PM health effects are concisely
discussed in Appendices A and B.
As a starting point in the present assessment, important information discussed in Chap-
ters 2 and 3 is summarized with regard to physical and chemical properties of S0? and particu-
late matter indexed by air quality measurements employed in community health epidemiology
studies evaluated in this chapter. The ensuing discussion of community health studies is then
subdivided into two main subsections: Section 14.3 deals with studies of acute mortality and
morbidity effects most germane to development of health criteria for possible short-term
(e.g., 24 hr) ambient air standards; and Section 14.4 discusses studies of mortality and mor-
bidity effects associated with chronic exposures most pertinent for development of health cri-
teria for long-term (annual-average) ambient air standards. The last major chapter section
(14.5) attempts to provide an integrative summarization and interpretation of the overall pat-
tern of results evaluated in the preceding sections.
The extensive presently available epidemiological literature on the effects of occupa-
tional exposures to S0? and PM is not reviewed here for several reasons:
1. Such literature generally deals with the effects of exposures to S0? or PM
chemical species at levels many-fold higher than those encountered in the
ambient air by the general population.
2. Populations exposed occupationally mainly include healthy adults, self-
selected to some extent in terms of being better able to tolerate exposures
to S02 or PM substances than more susceptible workers seeking alternative
employment or other groups often at special risk among the general public
(e.g., the old, the chronically ill, young children, and asthmatics).
3. Extrapolation of observed occupational exposure/health effects relation-
ships (or lack thereof) to the general public (especially population groups
at special risk) could, therefore, be potentially misleading in terms of
demonstrating health effects among healthy workers at higher exposure
levels than would affect susceptible groups in the general population.
The occupational literature does, however, demonstrate well links between acute high
level or chronic lower level exposures to SCL or many different PM chemical species and a
variety of health effects, including: pulmonary function changes; respiratory tract diseases,
SOX14G/A 14-6 2-14-81
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morphological damage to the respiratory system; and, especially in the case of silica-related
compounds, certain heavy metals and organic PM species, induction of respiratory tract cancers
or many other types of carcinogenic and noncarcinogenic effects. The reader is referred to
National Institute of Occupational Safety and Health (NIOSH) criteria documents and other
pertinent reviews and assessments listed in Appendix C for information on health effects
associated with occupational airborne exposures to S0? and various PM species and recommended
or implemented occupational hygiene guidelines or standards aimed at protecting workers from
such effects.
14.2 AIR QUALITY MEASUREMENTS
Of key importance for the evaluation of epidemiological studies reviewed here is a clear
understanding of the physical and chemical properties of S0? and PM indexed by measurement
methods employed historically in collecting ambient air aerometric data utilized in those
studies. Such information on relevant air quality measurement methods and their limitations
is concisely summarized below as background for the critical evaluation of epidemiological
studies that follow. See Chapters 2 and 3 for more detailed discussion of measurement methods
and related information on physical and chemical properties of S0?.
14.2.1 Sulfur Oxides Measurements
Three main measurement methods or variations thereof have been employed in generating
data cited for sulfur dioxide (S0?) levels in epidemiological studies discussed below: (1)
sulfation rate (lead dioxide) methods; (2) hydrogen peroxide measurements and (3) the West-
Gaeke (pararosanaline) method.
Sulfation rate methods involve reaction of airborne sulfur compounds with lead dioxide in
a paste spread over an atmospherically-exposed plate or cylinder. Rates of reaction of sulfur
2
compounds with surface paste compounds are expressed in SO^/cm /day. However, the reactions
are not specific for S0?, and atmospheric concentrations of S0? or other sulfur compounds can-
not be accurately extrapolated from the results, which are markedly affected by factors such
as temperature and humidity. Lead dioxide gauges were widely used in the United Kingdom prior
to 1960 and provided aerometric data reported for SO™ in some pre~1960s British epidemio-
logical studies; sulfation rate methods were also used in certain American studies.
Use of the hydrogen peroxide method was gradually expanded in the United Kingdom during
the 1950s, often being coupled in tandem with apparatus for particulate matter (smoke) moni-
toring. The hydrogen peroxide method was adopted in the early 1960s as the standard S0?
method used in the National Survey of Air Pollution throughout the United Kingdom and, as an
OECD-recommended method, elsewhere in Europe. The method can yield reasonably accurate
estimates of atmospheric S02 concentrations expressed in (jg/rn ; but results obtained with
routine ambient air monitoring can be affected by factors such as temperature, presence of
atmospheric ammonia and titration errors. Very little quality assurance information exists on
sources and magnitudes of errors encountered in use of the method in obtaining S0? data
reported in specific British or other European epidemiological studies, making it difficult to
assess the accuracy and precision of reported S0~ values. Only in the case of the British
SOX14G/A 14-7 2-14-81
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National Survey has extensive quality assurance information been reported (Warren Spring Labora-
tory, 1961; 1962; 1966; 1967; 1975; 1977; OECD, 1964; Ellison, 1968) for S02 measurements made
in the United Kingdom and used in various British epidemiological studies.
The West-Gaeke (pararosanaline) method has been more widely employed in the United States
for measurement of SCL. The method involves absorption of S0? in potassium tetrachloromercu-
rate (TCM) solution, producing a chemical complex reacted with pararosanaline to form a red-
purple color measured colorimetrically. The method, suitable for sampling up to 24 hrs, is
specific for SCL if properly implemented to minimize interference by nitrogen or metal oxides,
but results can be affected by factors such as temperature variations and mishandling of
reagents. Only limited quality assurance information (Congressional Investigative Report,
1976) has been reported for some American S0? measurements by the West-Gaeke methods.
Measurement approaches for suspended sulfates and sulfuric acid, used mainly in the
United States, include turbidimetric and methylthymol blue methods. The former usually
involves collection of samples on sulfate-free glass fiber filters by means of high-volume PM
samplers. Sulfate is extracted and precipitated with barium chloride, and turbidity of the
suspension is determined spectrofluorometrically. However, the method does not differentiate
between sulfates and sulfuric acid, and secondary formation of such products from SO- in air
drawn through the filter can affect estimation of atmospheric sulfate levels. Similar collec-
tion procedures and limitations apply for the methylthymol blue method, which involves reac-
tion of extracted sulfate with barium chloride and complexing of the latter with methylthymol
blue. Inability to differentiate between sulfates and sulfuric acid limit these two methods
as specific measures of suspended sulfates, but their results can serve as rough indicators of
atmospheric levels of sulfur-oxide related PM.
14.2.2 Particulate Matter Measurements
To be of maximum value, epidemiological studies on PM effects must utilize air quality
measurement methods that provide meaningful data, not only regarding the mass or amount of
atmospheric PM, but also quantitative information related to size and chemical composition of
particles present. In actual practice, however, most epidemiological studies on PM effects
have relied on air quality data from air monitoring instruments of questionable sampling
accuracy and not specifically designed for health-related research. The resulting data thus
typically only provide limited information regarding mass, size or chemical properties of the
PM sampled.
Three main measurement approaches or variations thereof were used to obtain PM data
reported in epidemiological studies reviewed below: (1) the British Smokeshade light reflec-
tance method or variations used in the United Kingdom and elsewhere in Europe; (2) the Ameri-
can Society for Testing and Materials (ASTM) filter soiling method based on light transmit-
tance and used in the United States; and (3) the high-volume sampling method most widely
employed in the United States.
As discussed in Chapter 3, the British Smoke (BS) method and close variations of it in
routine use have typically employed standardized monitoring equipment with a D™ cut-point of
SOX14G/A 14-8 2-14-81
-------
= 4.5 urn at KPH (McFarland, 1979). Thus, regardless of whether or not larger coarse-mode
particles were present in the atmosphere during the sampling period, the BS method collected
predominantly small particles. The D5Q of the instrument may, however, shift at higher wind
speeds. The BS method neither directly measures the mass nor determines chemical composition
of collected particles. Rather, it primarily measures reflectance of light from a stain
formed by particles collected on filter paper, which is somewhat inefficient for collecting
very fine particles (Lui, 1978). The reflectance of light from the stain depends both on
density of the stain or amount of PM collected in a standard period of time and optical pro-
perties of the collected materials. Smoke particles composed of elemental carbon of the type
found in incomplete fossil fuel combustion products typically make the greatest contribution
to the darkness of the stain, especially in urban areas. Thus, the amount of elemental car-
bon, but not organic carbon, present in the stain tends to be most highly correlated with BS
reflectance readings. Other non-black, non-carbon particles also have optical properties such
that they can affect the reflectance readings (Pedace and Sansone, 1972).
Since highly variable relative proportions of atmospheric carbon and non-carbon PM can
exist from site to site or from one time to another at the same site, then the same absolute
BS reflectance reading can be associated with markedly different amounts (or mass) of parti-
cles collected or, even, carbon present. Site-specific calibrations of reflectance readings
against actual mass measurements obtained by collocated gravimetric monitoring devices are
therefore necessary in order to obtain approximate estimates of atmospheric concentrations of
PM based on the BS method. A single calibration curve relating mass or atmospheric concentra-
tion (in ug/m ) of particulate matter to BS reflectance readings obtained at a given site may
serve as a basis for crude estimates of PM (mainly small particle) levels at that site over
time, so long as the chemical composition and relative porportions of elemental carbon and
non-carbon PM do not markedly change.
As part of British National Survey and OECD work in the early 1960s, site-specific BS
mass calibration curves were determined for numerous urban areas in the United Kingdom and
Europe and efforts were made to interrelate such curves (or normalize them) against certain
standard curves. Two standard calibration curves were adopted: (1) a British standard smoke
curve that defines relationships between PM mass and BS refectance readings for London's
3
atmosphere in 1963, which was used to yield BS concentration estimates (in (jg/m ) reported in
many published British epidemic logical health studies; and (2) an international standard OECD
smoke curve, against which smoke reflectance measurements made elsewhere in Europe were com-
pared to yield smoke concentration estimates (in ug/m ) reported in various European epidemio-
logical studies on PM effects. Of crucial importance for evaluation of such studies is the
fact that the actual mass or smoke concentration present at a particular site may differ
markedly from the corresponding mass or concentration (in (jg/m ) associated with a given
reflectance reading on either of the two standard curves; and, great care must be applied in
interpreting exactly what any reported BS value in \ig/m means at all. Further complicating
interpretation of smoke data-used in most epidemiological studies is the lack of reporting of
SOX14G/A 14-9 2-14-81
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specific quality assurance information for the cited aerometric measurements. Such information
has only been reported in general terms for United Kingdom National Survey data utilized in
numerous British studies (Warren Spring Laboratory 1961, 1962, 1966, 1967, 1972, 1975; OECD
1964; Moulds, 1962; Ellison, 1968).
The ASTM or AISI light transmittance method is similar in approach to the British smoke
technique. The instrument has a D,-n cut-point of =5 urn and utilizes an air flow intake apparatus
similar to that used for the BS method, depositing collected material on a filter paper tape
periodically advanced to allow accumulation of another stain over a standard time period.
Opacity of the stain is determined by transmittance of light through the deposited material
and filter paper, with results expressed in terms of optical density or coefficient of haze
(CoHs) units per 1000 linear feet of air sampled (rather than mass units). Thus, CoHs read-
ings roughly index the soiling capacity of PM in the air and, like BS readings, are most
strongly affected by fine-mode elemental carbon particles. CoHs readings, however, are some-
what more markedly affected by non-carbon particles than BS measurements. The ASTM method
does not directly measure mass or determine chemical composition of the PM collected.
o
Attempts to ever relate CoHs to ug/m would require site-specific calibration of CoHs readings
against mass measurements determined by a collocated gravimetric device, but the accuracy of
such 'nass pstimates could b
-------
Numerous factors other than wind speed, as discussed in Chapter 3, can affect PM measurements
by hi-volume sampling techniques; however, quality assurance information for TSP measurements
reported in most American epidemic logical studies is largely lacking, except for extensive
information on U.S. Environmental Protection Agency CHESS Program data (Congressional Investi-
gative Report, 1976).
One consequence of the broader size range of particles sampled by the hi-vol method versus
the BS or ASTM methods are severe limitations on intercomparisons or conversions of PM
measurements by those methods to equivalent TSP units or vice versa. As shown by several
studies, no consistent relationship typically exists, for example, between BS and TSP measure-
ments taken at various sites or even during various seasons at the same site (Commins and
Waller, 1967; Lee, 1972; Ball and Hume, 1977; Holland et al., 1979). The one exception
appears to be that, during severe London air pollution episodes when low wind speed condi-
tions resulted in settling out of larger coarse-mode particles and fine-mode particles
markedly increased to constitute nearly 100 percent of the PM present, then TSP and BS levels
(in excess of = 500 |jg/m ) tended to converge as would be expected when both methods are
essentially sampling only fine-mode particles (Holland et al., 1979).
Taking into account the foregoing information on SOp and PM measurement methods and
factors affecting the quality of results obtained with routine field monitoring, aerometric
data cited in various epidemiological studies must generally be viewed as providing at best
only very approximate estimates of atmospheric levels of sulfur dioxide, other sulfur com-
pounds, or other PM associated with reported health effects. Further, to the extent that the
aerometric data cited are derived from use of techniques with limited specifity for the sub-
stance^) purportedly measured or the relative contributions of sulfur oxides or PM to
observed health effects cannot be distinguished from each other or from the effects of other
covarying pollutants, then the aerometric data and associated health effects reported might be
more appropriately viewed as relatively non-specific indicators of the effects of overall air
pollutant mixtures containing sulfur oxides and PM.
14.3 ACUTE SOx/PM EXPOSURE EFFECTS
14.3.1 Mortality
14.3.1.1 Acute Episode Studies—Detailed study of the human health effects associated with
episodes of severe air pollution spans a period of less than 50 years. The earliest reliable
documentation of such episodes describes an incident in the Meuse Valley of Belgium in 1930.
An intense fog covered the Meuse Valley from Liege to Huy (Firket, 1931) from December 1
to 5, 1930, and was accompanied by an anticyclonic high pressure area with low winds and large
amounts of PM. Sixty deaths associated with the fog occurred among residents of the Valley on
December 4 and 5. The people who died were sick for only a short time. Although there were
no other immediate deaths, several persons affected by the fog died much later from complica-
tions associated with fog-induced injuries. The death rate in the area was 10.5 times normal.
The illnesses abated rapidly when the fog dispersed.
A similar but smaller event later occurred in Donora, Pennsylvania (Shrenk et al., 1949':
Donora was blanketed by a dense fog during October 1948, which adversely affected 43 per v
SOX14G/A 14-11 »-i4-81
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of the population of approximately 10,000 people. Twenty persons, mostly adults with preexist-
ing cardiopulmonary diseases, died during or shortly after the fog due to cardiorespiratory
causes; and 10 percent of the population was classified as being severely affected. No pol-
lution measurements were made during the incident but SO™, its oxidation products, and PM were
undoubtedly significant contaminants. During subsequent inversion periods, presumably not as
severe in terms of pollutant elevations as the one in October 1948, daily averages of SO,, as
high as 0.4 ppm (-1140 (jg/m3) were recorded (NAPCA). Cioco and Thompson (1961) found in-
creased mortality rates and morbidity effects (e.g., heart disease, asthma, high blood pres-
sure, chronic bronchitis) during an 8-year follow-up period for Donora residents who had re-
ported acute illness during the 1948 episode in comparison to those reporting no acute ill-
ness.
As seen in Table 14-1, a series of episodes were documented in London between 1952-1975
(Ministry of Health, London, 1952; Martin and Bradley, 1960; Lawther, 1963; Clifton et al.,
1960; Wilkins, 1954; Wilkins, 1954; Logan, 1953; Waller, 1978; Apling et al., 1977; Holland et
al., 1979). Excess mortality reported during those episodes occurred mainly among the elderly
and chronically ill adults. Various factors have been discussed which might help explain some
of the excess mortality (Holland et al., 1979), including possible influences not only of
increased air pollution, but also of high humidity (fog) and low temperatures. Regardless of
the relative contributions of these different factors, one clear conclusion from these major
London episodes is that increases in mortality were associated with air pollution episodes
when concentrations of both S02 and BS exceeded 10QO ug/m3 (Rail, 1974; NAPCA, 1969; Goldsmith
and Friberg, 1977; Higgins, 1974; Shy et al., 1978; Holland et al., 1979; Higgins and Ferris,
1979; Speizer and Ferris, 1978; NRC/NAS, 1978a,b; WHO, 1979; Shy, 1979). The available data,
however, do not allow for clear delineation of the effects of specific pollutants acting alone
or in combination. Qualitative studies of milder episodes in the 1950's (Gore and Shaddick,
1958; Burgess and Shaddick, 1959) showed similar correlations of mortality with air pollution.
TABLE 14-1. EXCESS DEATHS AND POLLUTANT CONCENTRATIONS DURING SEVERE
AIR POLLUTION EPISODES IN LONDON (1948-75)
Maximum 24-hr pollutant
Date
Nov.
Dec.
Jan.
Dec.
Jan.
Dec.
Dec.
1948
1952
1956
1957
1959
1962
1975
Duration,
days
6
4
4
4
6
5
2
Deviation from
X of total
excess deaths
750
4000
1000
750
250
700
100-200**
concentration, ug/m3
Smoke
(BS)
2780
4460*
2830
2417
1723
3144
546
S02
(H202 titration)
2150
3830
1430
3335
1850
3834
994
*Note that peak and 24-hr BS levels were likely much higher than 4460
ug/m due to rapid saturation of filter paper by collected PM.
**Excess mortality during the 1975 London episode may be attributable in
part to a concurrently occurring strike affecting medical care.
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Episodes of acute air pollution have also occurred in the United States since the 1948
Donora episode, but no single event has reached the proportions of the major London episodes.
Some studies suggest however, that slight increases in excess deaths and morbidity were associ-
ated with severe episodes in New York City (see Table 14-2). The estimates of excess
mortality reported from the New York episodes were derived by comparing daily deaths during
periods of high air pollution with daily deaths for the same period in the years immediately
before or following the episode (Glasser and Greenburg, 1971) or by calculating daily devia-
tions from a 15-day moving average of daily deaths (McCarroll and Bradley, 1966). Studies of
the New York episodes listed in Table 14-2 controlled for meteorological variables and found
an independent influence of the pollutants (McCarroll and Bradley, 1966; Glasser and Greenburg
1971). During at least one of the episodes (December, 1962), the increased death rates were
predominantly in the 45 to 64 and 65 years and older age groups. During the episodes in
January, 1963, some days did not have an excess mortality. The episode between January and
February 1963 involved a peak death rate apparently superimposed upon an elevated death rate
average due to the present of influenza virus in the community. There was one other period of
excess mortality (April, 1963) which did not show sharp increases in air pollutants. The
above studies appear to yield a pattern of results indicative of small increases in mortality
o
among older adults occurring in New York City when S0? levels exceeded 1000 ug/m in the
presence of simultaneously elevated PM concentrations measured in the range of 5.0 to 7.0 CoH
units. The numbers of excess deaths detected; however, were very low in comparison to the
large total population of New York and the numbers of episode-related excess deaths observed
in London (vida supra). Direct, precise comparisons of the pollution data from the London and
New York episodes, as has been noted (Holland et al., 1979), cannot be made because of differ-
ences in methods used for measuring PM concentrations. However, even rough comparisons of the
results obtained by the different (BS, CoHs) approaches suggest that the pollution must have
typically been much greater in London.
When a marked increase in air pollution is associated with a sudden rise in the death
rate or illness rate that lasts for a few days and both return to normal shortly thereafter
(as documented in the above studies), a causal relationship is strongly suggested. Sudden
changes in weather, however, which may have caused the air pollution incidents, must also be
considered as another possible cause of the death rate increase. On the other hand, the con-
sistency of the above associations between S0? and particulate matter elevations and increases
in mortality render it extremely unlikely that weather changes alone provide an adequate expla-
nation for all such observations. This view is further reinforced by (1) the fact that at
least some episodes were not accompanied by sharp falls in temperature; and (2) other weather
changes of similar magnitudes to those accompanying the above pollution episodes are not
usually associated with such dramatic increases in mortality in the absence of greatly in-
creased levels of SOy, particulate matter, or other pollutants. In summary, the above London
episode studies appear to provide clear evidence for substantial increases in excess mortality
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TABLE 14-2. ACUTE AIR POLLUTION EPISODES IN NEW YORK CITY
Location
Date
Reference
Estimated
excess deaths
24 Hour
pollutant concentrations
S02, max participates,
|jg/m3 CoHs
New York City Dec. 1962
New York City Jan 1963
McCarroll and
Bradley, 1966
McCarroll and
Bradley, 1966
90
New York City Jan-Feb 1963 Glasser and Green-
burg, 1971
New York City Feb.-Mar. 1964 Glasser and Green-
burg, 1971
405-647**
50
1890 (0.72 ppm) 5-6.5
1830 (0.7 ppm) 6.0
1570 (0.6 ppm) 7.0
1570 (0.6 ppm) 5.0+
*Specific numbers of excess deaths not clearly reported in published paper.
**Influenza outbreak also present.
-------
when S0 exceeded 1000 (jg/m3 in the presence of PM over 1000 ng/m3 (BS). Certain of the New
2
York studies yield some evidence for small increases in excess mortality at simultaneous ele-
vations of 1000 (jg/m3 S02 and PM in the range of 5.0 - 7.0 CoHs.
14.3.1.2 Mortality Associated with Non-Episodic Variations in Pollution—A number of reports
have investigated relationships between mortality and air pollution in England during periods
with no unusual air pollution episodes (Weather ly and Waller, in press; Martin, 1964; Waller,
1969; Gore, 1958; Burgess, 1959; Scott, 1963; Martin, 1960; Riggan et al., 1975; Lawther,
1963; Clifton et al., 1960). For most of these studies, 15-day moving averages were construc-
ted and the effects of pollution were assessed in terms of daily deviations from these base-
lines. Increases in daily deaths during the winter of 1958-59 were found (Lawther, 1963) to
3 3
be associated with concentrations of BS >750 (jg/m and S02 >715 ug/m (0.25 ppm) during a long
(59-day) period of thick fog. Increases in daily deaths were not associated with pollutants
at lower concentrations during 1958-59; nor did they occur at similar pollutant levels during
the prior winter having only 8 days of fog. Similar studies in Sheffield (Clifton et al.,
1960) did not yield confirmatory results; that is, while- increases in deaths appeared to
possibly be associated with very high concentrations of pollutants, random variations in the
number of deaths were so large that firm conclusions could not be drawn.
Among the most important British studies bearing on acute health effects of sulfur oxides
and particulate matter at levels below 1000 ug/m are those of Martin and Bradley (1960) and
Martin (1964). The first of these studies related daily mortality from all causes and from
bronchitis and pneumonia to the level of S02 and smoke in London during the winter of 1958 to
1959. The authors found a considerable number of coincident peaks in pollution level and
daily mortality. The correlation of mortality from all causes with pollutants measured on the
log scale was 0.613 for smoke (BS) and 0.520 for S02- Martin and Bradley (1960) reported that
neither temperature nor humidity was significantly correlated with London mortality studied
during the winter of 1958-59, noting a very low correlation coefficient (r = -0.030) for tem-
perature and deaths for the entire 1958-59 winter and the occurrence of several peaks in
mortality during November and December, 1958, when temperatures were substantially over 38°F.
They further noted that a range of 30-38°F is characteristic of most winter fogs and tempera-
tures consistently below 30°F (when temperature effects on mortality can be expected) are the
exception.
Though the authors emphasized the relationship between change in pollution level and num-
ber of deaths and lack of meteorological effects, an influenza epidemic during part of the
study may have influenced some of the results. The authors, however, reported number of
deaths, smoke levels, and S02 levels from November 1, 1958 to February 28, 1959. A further
analysis of these data was performed by Ware et al. (1981) but excludes the month of February,
in which an epidemic of Type A influenza also significantly influenced daily mortality. For
the remaining 92 days, the deviations of daily mortality from the 15-daymoving average (trun-
cated at each end of the series) was computed and appeared to show a consistent and signifi-
cant trend of increasing mortality with increasing BS and S02. Change in mean deviations
SOX14G/A 14-15 2-14-81
-------
occurred between 500-600 ug/m3 BS and 300-400 ug/m3 S02 as levels above which small positive
increases in mortality over the moving average were seen, although this is not intended to
suggest a threshold for response. In fact, it is unclear at what level significant excess
mortality first occurred, but the analysis suggests that notable increases occurred somewhere
in the range of 500-1000 ug/m3 BS and S00 and most likely when both pollutants exceeded 750
3
ug/m . Although temperature and humidity were not correlated with daily mortality, both
pollution level and daily mortality increased throughout the period of study, and the possi-
bility of other extraneous seasonal variables contributing to this association cannot be
ignored.
An analysis similar to that used by Martin and Bradley (1960) was carried out by Martin
(1964) for the winter of 1959-60. This winter had fewer incidents of high pollution. The
significant positive correlation between mortality and pollution was, however, still present
although the coefficients were somewhat lower than in the previous year. The Martin (1964)
results were based on analyses combining high pollution days from 1958 to 1959 and 1959 to
1960, after excluding days on which pollution had fallen from a previously higher level. The
o
mean deviation was positive for every BS level above 500-600 ug/m and S09 level above 400-499
3
ug/m , but no clear threshold for significant increases in mortality could be clearly
delineated although the most marked increases occurred for BS levels over 1200 ug/m and S0?
3
levels exceeding 900 ug/m . Considerable covariation in levels of the two pollutants, however,
preclude attribution of the apparent mortality effects to either one alone. Bronchitis
mortality was also significantly, though less strongly, correlated with pollution level, but
pneumonia mortality was not correlated with pollution. Based on the above analyses, it
appears that small increases in mortality may have occurred in London during 1958 to 1960 in
3
association with covarying increases in BS and S09 levels in the range of 500-1000 ug/m ,
respectively. Holland et al. (1979), however, suggest that the increases in excess mortality
most clearly occurred when particulate levels exceeded 750 ug/m (BS) in the presence of S09
3
levels over 710 ug/m .
A number of investigators have also reported on relationships in the United States
between mortality and daily variations in air pollution during non-episodic periods (Greenburg
et al., 1967; Schimmel and Greenburg, 1972; Schimmel and Murawski, 1975; Schimmel and
Murawski, 1976; Hodgson, 1970; Buechley et al., 1975; Buechley, 1977; Lebowitz, 1973a,b).
These studies mainly provide, at most, qualitative evidence linking mortality effects to air
pollution (see Appendix A). For example, Hodgson (1970) used multiple regression methods to
examine the relationships between deaths and air pollution concentrations on a monthly basis
in New York City. His correlations between excess deaths and S0? or particulate matter (CoHs)
were significant. Buechley (1975, 1977) used similar models to relate daily deaths in the New
York/New Jersey metropolitan area (1962 through 1972) to SOp measured at a single monitoring
station; he showed significant correlation coefficiences as well, and showed a relation of
residual mortality to levels of S02> Lebowitz (1973a,b) utilized a stimulus-response model to
study daily air pollution exposures, meteorology, and daily mortality in New York (1962-1965),
SOX14G/A 14-16 2-14-81
-------
Philadelphia (1963-1964), Los Angeles (1962-1965), and Tokyo (1966-1969). Adverse temperature
and humidity changes were shown to be important, but cannot account for mortality increases
which were closely associated with increases of air pollution. In each case no specific pol-
lutant levels were clearly shown to be associated with significant increases in mortality.
In another study, possibly yielding useful quantitative information, Glasser and
Greenberg (1971) carried out an analysis of daily mortality in New York City during the 5 year
period 1960 to 1964, using only data from the months October through March. Deaths were
analyzed both as deviations from a 15-day moving average and as deviations from the 5-year
average for each day. Results from the two analyses were said to be qualitatively similar.
Twenty-four hour average pollution data were based on hourly S0? and bihourly smoke shade
(CoH) readings. The results are adequately summarized by the unadjusted analysis, which
suggests a trend in mortality over the full range of S00 and smoke shade (CoH) levels, with
3
marked positive mean deviations above 5.0-5.9 CoHs and S0? levels above 786-1048 ng/m .
Variations in the two pollutants, however, are markedly confounded due to their colinearity,
not allowing one to discern the relative contributions of each to reported excess mortality
effects. In cross-tabulation of daily mortality by S02 and smoke shade level, however, S02
was reported to be more strongly related to mortality and was used as an index of pollution in
some analyses; and, in a multiple regression analysis with temperature and rainfall, S0« was
reported to be more strongly associated with mortality than either weather variable. This
association persisted in analyses of bimonthly periods. Although the observations are
dependent, Glasser and Greenberg computed standard errors for the mean deviations by assuming
independence. As in the case of other New York non-episode mortality studies listed above
(e.g., Greenburg et al., 1967; Schimmel and Greenberg, 1972, etc.), the results of this study
are open to question on the basis of data from only a single monitoring station in central New
York having been used to generate exposure estimates for the entire metropolitan area, but
arguments can be made for those data possibly being reasonably representative for the entire
city under markedly elevated pollutant conditions (see Appendix A).
14.3.1.3 Morbidity—Morbidity studies of acute or short-term air pollution exposures are much
less common in the epidemiologic literature than morbidity studies of chronic or long-term air
pollution exposures. This reflects the dual complications of the difficulty of having
adequate estimates of pollution exposure as well as the statistical analytical problems of the
health data being collected. The main focus here is on studies providing information on
quantitative relationships or associations between ambient air concentrations of SO^ or parti-
culate matter and acute exposure morbidity health effects.
Several British studies have been published on health effects associated with acute or
short-term exposures of adults to sulfur oxides and particulate matter which appear to provide
useful information on quantitative dose-effect relationships.
Illness data were obtained in many of the early severe pollution episodes discussed
above; this information did little more than support the mortality results reported in those
SOX14G/A 14-17 2-14-81
-------
studies. There was evidence, however, that increases in illness occurred along with increases
in deaths, although the effects were less sudden. Waller and Lawther (1955), for example,
reported that when smoke (BS) concentrations in London increased tenfold during the course of
2 hours, there was a deterioration in the clinical condition of some patients with bronchitis
or asthma. On this day, peak smoke (BS) concentration may have reached 6500 |jg/m . SO,, also
increased to a maximum of about 2860 ug/m (1.0 ppm) but H2$04 did not, on the basis of
washings from impactor slides. Most of the mass of particulate matter was determined by micro-
scopic studies to consist of particles less than 1 |jm in diameter.
Lawther (1958) studied associations between daily variations in smoke and S0£ pollution
and the self-indicated health status in 29 British patients with chronic bronchitis. Patients
maintained diaries on which their daily condition was indicated in relation to their usual
condition. The alternatives were "better," "same," "worse," and "much worse." Figure 14-1
shows graphically the effects of high pollution levels observed in the 29 bronchitic patients
studied in January 1954. During the month of January 1954, an episode of relatively high pol-
lution resulted in a sharp increase in the number of patients whose condition worsened as
o
24-hour smoke (BS) increased from about 400 to 2000 |jg/m and 24-hour SO- increased from about
450 ug/m3 (0.15 ppm) to -1300 ug/m3 (0.20 ppm).
In the winter of 1955, the study was extended to include 180 patients in the London area.
The prevalence of exacerbation of preexisting illness was related more closely to pollution
than to temperature or humidity during the winter months, and the relationship disappeared
when the levels of pollution decreased in the spring. Actual numerical data are not given in
the report, but inspection of the figures indicate that exacerbation of illness increased as
smoke (BS) increased to about 300-350 ug/m and S0? to about 500-600 ug/m . The data suggest
that during the winter months, SOp was associated more closely with variations in health
status; however, in the spring of the year, when pollution concentrations were no longer
associated with health status, SO- continued to occur in intermittent peak concentrations as
high as those associated with increased illness during the winter. However, the association
between pollution and illness decreased when smoke (BS) concentrations fell to a fairly con-
o
sistent 24-hour concentration of less than 250 ug/m . The few short higher peaks in smoke
(BS) after this time had little effect on illness status. These investigators noted that
worsening of subjects' conditions were more likely associated with markedly higher short-term
peaks in pollution rather than the 24-hr average levels noted above and that the results are not
necessarily indicative of causal relationships, but rather that the measurements of smoke (BS)
and S0? may only be indicators of whatever is the cause.
A later report by Lawther et al. (1970) gave the results of further extension of these
studies into the winters of 1959-60 and 1964-65. The techniques used were similar except that
the patients now reported on health status in relation to the previous day rather than in
relation to usual conditions. These studies supported the results in previous years in that
the worsening of health status was associated clearly with increases in air pollution. The
authors stated that, although exact relationships between the responses of patients and the
SOX14G/A 14-18 2-14-81
-------
45
40
35
2.0
1.8
1.6
in*
*
O
1.0
0.8
0.6
0.4
{2 S
2 0^
u- oc
O uj
A
REL. HUMIDITY
TEMPERATURE
SMOKE
. so.
\
\
\
\
/ ••
I
I '
I __•_ • • .
100
90
80
70
60
0.5
0.4
°'3
0.2
0.1
0
16 17 18 19
JANUARY
20
21
22
(-
5
S
i
J
ui
ff
I
-------
concentrations of smoke and SOp could not be determined, the minimum pollution leading to any
significant response was about 500 ug/m3 (0.17 ppm) SOp, together with about 250 ug/m smoke
(BS). Lawther et al. (1970) also emphasized that these responses may reflect the effects of
brief exposures to maximum concentrations several times greater than the 24-hour average
(i.e., presumably in excess of 1000 ug/m3 for both BS and S02 levels). As in the earlier
studies, the results appear to relate more closely during the first part of the winter and, in
some instances, there was little reponse to higher concentrations of pollutants near the end
of the winter. Although the concentrations of smoke and S02 closely correlate, examination of
the data again suggests that often higher concentrations of S02 near the end of the winter,
occurring with generally lower concentrations of smoke, produced less response in the study
subjects than did the same concentrations of S0? earlier in the winter, when smoke was higher.
There was some evidence for a loss of interest by participants. When the association between
exacerbations and S02 concentrations were compared in the two winters, the impression was of a
slightly reduced and less consistent, but definite effect during the second winter. The
o o 33
declines in concentrations were from 342 ug/m to 129 ug/m BS and from 299 ug/m to 264 ug/m
SOp (Lawther et al., 1970). These studies among chronic bronchitis patients in London
continued into the 1970s as the frequency of periods of high pollution declined. There were
no sharp increases reported in illness scores in the winter of 1969-70 (Lawther, 1970) nor in
the winter of 1974-75 (Waller, 1971).
Martin (1964) examined applications for hospital admissions for the winter of 1958-59 and
found for men ages 45-79 (after adjustment for day of the week and correction for 15-day
moving average) significant correlations for both cardiovascular and respiratory conditions
with smoke (r = 0.46) and sulfur dioxide (r = 0.40). Analogous significant correlations were
found for the same male age group for such conditions in relation to both smoke (r = 0.41) and
SOp (r = 0.43) for the winter of 1959-60. The average deviations associated with increasing
SOp and smoke levels during both winters are summarized in Tables 14-3 and 14-4. As seen in
those tables, whereas no clear threshold for the onset of mean positive deviations across the
exposure ranges can be distinguished, very marked increments in the positive mean deviations
can be discerned starting at 800-899 ug/m3 for S02 and 1100-1510 ug/m3 for PM (BS). Presenta-
tion by the authors of their results separately in relation to SOp and BS (and the present
summarization in Tables 14-3 and 14-4) is not meant to imply that the relative individual
contributions of S02 and BS alone to the observed effects can be ascribed to the
concentrations listed, in view of considerable covariation in S0? and BS levels during the two
winters studied.
In addition to the above British and European studies, several American studies may
provide useful information on the effects of acute (24 hr) exposures to sulfur dioxide and
particulate matter.
For example, McCarroll and colleagues (Mountain et al., 1968; Thompson et al. "1970;
Cassell et al., 1969, 1972; Lebowitz et al., 1972; Lebowitz, 1977) demonstrated significant
SOX14G/A 14-20 2-14-81
-------
TABLE 14-3. AVERAGE DEVIATION OF RESPIRATORY AND
CARDIAC MORBIDITY FROM 15-DAY MOVING AVERAGE,
BY S02 LEVEL (LONDON, 1958-1960)
S02 level Number Mean
(|jg/m3) of days deviation
400-499 9 2.2
500-599 6 5.1
600-799 9 6.9
800-899 6 12.8
900-1280 5 12.8
TABLE 14-4. AVERAGE DEVIATION OF RESPIRATORY AND CARDIAC
MORBIDITY FROM 15-DAY MOVING AVERAGE,
BY SMOKE LEVEL (BS) (LONDON, 1958-1960)
Smoke level
(Ijg/m3, BS)
500-599
600-699
700-799
800-1099
1100-1510
Number
of days
9
6
9
8
7
Mean
deviation
3.2
-0.7
2.4
4.9
12.9
SOX14G/A 14-21 2-14-81
-------
multiple correlations between acute respiratory symptoms and air pollution, controlling for
season, weather, and social class, when seasonal SO, means in the range of 0.10-0.24 ppm
o ^
(-280-700 ug/m ) seasonal smoke shade means in the range of 1.56-3.15 CoHs. Initially,
multiple regression analyzes showed conflicting findings in that the pollutants were
occasionally absent from or negative in their regressions. This led to a separation of the
combined meteorological and air polluant conditions into categories of: (1) stormy weather
(low temperatures, occasional precipitation, high wind speed) when the pollutants were low;
(2) stagnation periods (low wind speed, moderate temperatures) when SOp and TSP were high; (3)
periods of change in pollutant levels during the fall through spring periods; and (4) high
photoxidant conditions in the summer. This analysis revealed significant correlations between
the pollutants and acute symptoms for 1800 individuals studied weekly in New York (1962-65)
during stagnation periods and significant correlations of the same acute respiratory symptoms
(predominately common colds) with meteorological conditions during stormy periods. They also
found a lag of one to three days in symptoms and corresponding increases in school absen-
teeism. Some individuals (mostly under the age of 10) were found to have reacted consistently
and frequently to increases in the pollutants, and their respiratory symptoms were of greater
duration and severity than "nonsensitive" individuals (Lebowitz et al., 1972). Those who were
sensitive during the first part of the period under study were found to be sensitive later on
in the study. The attack rates per person year were about double for the "sensitive", and
occurred predominately in the winter period. Additional qualitative studies demonstrating
effects of acute exposure to SOp and PM on the health of children and other sensitive groups,
e.g., asthmatics, are summarized in Appendix B.
In summary, studies on acute exposure effects tend to suggest that the elderly, those
with chronic cardiorespiratory diseases, children, and asthmatics may constitute populations
at risk for manifesting morbidity effects in response to acute exposure to elevated atmos-
pheric levels of sulfur dioxide and particulate matter. Lawther's studies in London, for
example, appear to demonstrate worsening of health status among bronchi tic patients to be
3
associated with acute 24-hr exposures to BS of 250-500 ug/m in the presence of S00 levels in
3
the range of 500-600 ug/m or peak 1-hr exposures to each of the pollutants at levels pre-
sumably in excess of 1000 ug/m . In contrast, no effects on bronchitics appeared to be
detectable at 24-hr BS levels below 250 ug/m in the presence of 24-hr SO, levels below 500
3
ug/m . Also, increased applications by adults aged 45-79 for admissions to London hospitals
for cardiac and respiratory morbidity most clearly occurred, based on Martin's studies, when
24-hr BS and SOp levels approached or exceeded 900-1000 ug/m ; and Martin's data suggest that
such effects may have occurred at somewhat lower levels down to 500 ug/m3 for both S0? and BS.
Insufficient epidemiological information exists, however, by which to determine specific
quantitative acute exposure levels at which the health of other sensitive groups, e.g.,
children and asthmatics, might be adversely affected.
SOX14G/A 14-22 2-14-81
-------
14.3.2 Chronic SO^/PM Exposure Effects
14.3.2.1 Mortality
Numerous studies have been performed comparing general or cause-specific mortality in
areas of lowest-to-highest pollution concentrations. Most of these studies do not account for
cigarette smoking, occupation, social status, and/or mobility differences between areas, thus
making it difficult to define accurately any quantitative relationships between mortality and
air pollution parameters. Many such qualitative studies are summarized in Appendix B.
Essentially no epidemic logical studies are presently well-accepted as providing valid quanti-
tative data relating respiratory disease mortality of chronic (annual average) exposures to
sulfur oxides or particulate matter.
Certain studies have more specifically attempted to relate lung cancer mortality to chronic
exposures to sulfur oxides, particulate matter undifferentiated by chemical composition, or
specific particulate matter chemical species. However, little or no clear epidemiological
evidence has been advanced to date to substantiate hypothesized links between S0? or other
sulfur oxides and cancer. Nor does there presently exist credible epidemiological evidence
linking increased cancer rates to elevations in PM as a class, i.e., undifferentiated as to
chemical content. Some epidemiological studies (e.g., of occupationally exposed workers)
do provide evidence of increased cancer risk associated with exposure to some types of parti-
culate matter, e.g., certain organic compounds or metals, often found in the fine- and coarse-
mode particulate fractions of many urban aerosols (see Appendix C). However, no well-accepted
basis currently exists by which to quantitatively define any consistent relationships con-
cerning relative contributions or levels of such PM components to possible carcinogenic
effects of PM pollution as a whole.
14.3.2.2 Morbidity
14.3.2.2.1 Respiratory effects in adults. Several extensive studies on associations between
air pollution and chronic respiratory disease have been conducted on European populations, but
few provide more than qualitative information on possible SOp or PM effects, as summarized in
Appendices A and B.
In one of the few English studies possibly yielding useful quantitative data, Lambert and
Reid (1970) surveyed nearly 10,000 British postal workers (age 35 to 59) for respiratory
symptoms indicated by response to a self-administered MRC questionnaire. Concurrent air
pollution data during 1965 were used to determine associations with symptoms where possible.
However, the areas from which such data were available included only about 30 percent of the
study group. Consequently, an index of pollution developed by Douglas and Waller in 1952,
from domestic coal consumption, was used as well. The areas covered by the index included 88
percent of the study group. The results summarized in Table 14-5, adjusted for age and
smoking habits but not as well for socioeconomic status, appeared to show relationships
between health effects and air pollution indices for both males and females. That is, a
greater prevalence of cough and phlegm was found to occur in more polluted areas, where annual
SOX14G/A 14-23 2-14-81
-------
mean BS concentrations exceeded 100 |jg/m and S02 150
tnan in areas where annual BS or
SOp concentrations were less than 100 tig/m (based on concentrations for the 30 percent of
study areas actually monitored). These investigators also developed data showing that smoking
was an important factor in acquiring chronic bronchitis and that the combined effect of
smoking and pollution exceeded the sum of the individual effects. However, failure to
consider socioeconomic status might have affected the results, (Holland et al., 1979),
although this is not very likely since the entire population consisted of a single
occupational group (Higgins, 1974; WHO, 1979).
TABLE 14-5 rrMVTOM-FKCVAUNCS RATIOS (rtWimXT COUCH AND FHUGM) STANDARDISED F0> AC! AND SMOKING IT A«-
INDICES
CMccnfntfea
(HC./CJB4
<100
M^ •• •• ••
IS»-
JOO+
y.»*fct
AUk. | Fcouki
nun
lll(M)
ll«(J7)
134 (M)
«
-- »
Sulphw dioiid*
MaUt
n an
9t an
120
9\an
»7
115 WO
FitWM I" iulic frf* <>»* oburved numben of tyaipiom-paiiiivc teipaadcr.li. Smoke uid uilphur dioud* conccnuaiwnt in bitcd on vilun M
mUmtU uu> ia Muck. IMS (>UlMnil Air PoUiMiM SuryeyX
From: Lambert and Reed, 1970.
Impairment of pulmonary function is likely to be one of the effects of exposure to air
pollution since the pulmonary system includes the tissues that receive the initial impact when
toxic materials are inhaled. Acute and chronic changes in function may be significant bio-
logical responses to air pollution exposure. A number of studies have been conducted in an
effort to relate pulmonary function changes to the presence of air pollutants in various
European, Japanese, and American communities. However, very few provide more than qualitative
evidence relating pulmonary function changes to elevations in SOp or PM (see Appendices A and
B).
A series of studies, reported on from the early 1960s to the mid-1970s were conducted by
Ferris, Anderson, and others. The initial study involved comparison of three areas within a
pulp-mill town in northern New Hampshire. In the original prevalence study (Ferris and
Anderson, 1962; Anderson et al., 1964), no association was found between questionnaire-
determined symptoms and lung function tests in the three areas with differing pollution levels
after standardizing for cigarette smoking. The authors discuss why residence is a limited
indicator for exposure (Anderson et al., 1964). The study was extended to compare Berlin,
New Hampshire, with the cleaner city of Chilliwack, British Columbia in Canada (Anderson and
Ferris, 1965). Sulfation rates (lead candle method) and dustfall rates were higher in Berlin
than in Chilliwack. The prevalence of chronic respiratory disease was greater in Berlin, but
the authors concluded that this difference was due to the interaction between age and smoking
habits within the respective populations. Higher levels of respiratory function in some
cigarette-smoking groups in the cleaner area were observed, but this difference could be due
to socioeconomic and ethnic differences as well as air pollution. Ethnic differences could
also have been a confounding factor (Higgins, 1974).
SOX14G/A
14-24
2-14-81
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The Berlin, New Hampshire, population was followed up in 1967 and again in 1973 (Ferris
et al., 1971, 1976). During the period between 1961 and 1976, all measured indicators of air
pollution fell. In the 1973 follow-up, sulfation rates nearly doubled from the 1967 level
(0.469 to 0.901 mg S03/100 cm2/day) while TSP values fell from 131 to 80 ug/m3. Only limited
data on SO,, was available (the mean of a series of 8-hr, samples for selected weeks) (WHO,
1979). During the 1961 to 1967 period, standardized respiratory symptom rates decreased and
there was an indication that lung function also improved. Between the period 1967 to 1973,
age-sex standardized respiratory symptom rates and age-sex-height standardized pulmonary
function levels were unchanged. Given that the same set of investigators, using the same
standardized procedures, conducted the symptom surveys and pulmonary function tests over the
entire course of these studies, it is unlikely that the observed improvements in Berlin were
due to variations in measurement procedures, but rather appear to be likely associated with
3
decreases in TSP levels from 180 to 131 ug/m . The relatively small changes observed, however,
argue for caution in placing much weight on these findings as quantitative indicators of
observed effect/no effect levels for TSP-induced health changes.
Becklake et al. (1979) used pulmonary spirometric and closing volume function tests (and
symptom reporting) in three areas of Montreal, Canada and did not find significant differences
in children or adults (other than in closing capacity) that were associated with TSP levels.
In the three areas studied, ambient SO, was reported to be 15, 123, and 59, and annual mean
3
high-volume TSP values were 84, 95, and 131 ug/m , respectively, for the low-, intermediate-,
and high-pollution areas, but there was a large overlap between areas. In a later report
(Aubry et al., 1979) discriminant analysis was utilized to control for smoking, after which
differences in health variables were not significant. This study, however, cannot be taken as
showing lack of effects at the listed S0? and TSP levels because the power of the study was
too low to expect an effect to be seen with the small number of subjects studied.
14.3.2.3 Respiratory Effects in Children—Several British studies have reported quantitative
relationships between respiratory disease incidence in children and elevations in sulfur
dioxide and particulate matter (BS). In one of the best known and frequently cited investi-
gations, Douglas and Waller (1966) studied a cohort of a national sample of children born in
the United Kingdom during the first week in March 1946. They prospectively examined the
occurrence of respiratory illness in the children in relation to the estimated intensity of
air pollution in the area of their residence. The areas in which the children lived were
assigned to one of four pollution groups on the basis of estimates derived from domestic coal
consumption in 1951-52. An effort to validate the index later, on the basis of measured smoke
(BS) and S0? measurements in 1962 and 1963, indicated that the categorization of study groups
by estimated pollution level was reasonably good. At the time of the 1962-63 measurements,
3
SO, varied from about 90 ug/m (0.03 ppm) in representative low-pollution areas sampled to
3
about 250 ug/m (0.09 ppm) in representative high-pollution areas actually sampled, as shown
in Table 14-6. Also, BS varied from about 67 ug/m to 205 ug/m in comparable areas.
Information on respiratory illness and symptoms was obtained from the children
t
SOX14G/A 14-25 2-14-81
-------
when they were 6, 7, and 11 and, if they had lived the first 11 years of their lives in the
same area, similar information was gathered when they were 15, 20, and 25 years of age. No
significant relationship was observed between upper respiratory tract infections and in-
creasing air pollution levels, in contrast to a highly significant and clear dose/response
relationship between increasing air pollution indices and lower respiratory tract infection
prevalence rates seen in Table 14-6, as indexed by virtually all of the health measures used.
It has been noted that: "Higher illness rates were noted in all higher pollution classes"
(NRC/NAS, 1978); and "Socio-economic status was important in the study but a relationship...
still existed within separate social classes" (WHO, 1979). These results appear to provide
qualitative evidence linking the occurrence of lower respiratory tract infection in children
under age 11 to long-term exposures to polluted air containing elevated levels of SO,, and PM.
TABLE 14-6. FREQUENCY OF LOWER RESPIRATORY TRACT INFECTIONS OF
CHILDREN IN BRITAIN BY POLLUTION LEVELS, %
1962-1963
Mean annual pollution level
Lower respiratory
tract infections
First attack in first 9 months
At least one attack in first two years
More than one attack in first two years:
Boys
Girls
Middle class
Manual working class
Admission to hospital in first five years:
Lower respiratory infection
Bronchitis
Pneumonia
Very low
Smoke: 67
S0£: 90
7.2
19.4
4.3
5.7
2.9
3.0
5.1
1.1
0.0
1.1
Low
132
133
11.4
24.2
7.9
8.1
7.7
4.0
10.8
2.3
0.9
1.4
Moderate
190
190
16.5
30.0
11.2
10.9
12.1
7.7
13.9
2.6
1.0
1.6
3
s , |jg/m
High
205
251
17.1
34.1
12.9
16.2
9.7
9.3
15.4
3.1
1.4
1.8
From Douglas and Waller (1966).
It is impossible, however, (based on the above reported results) to estimate specific
quantitative levels of S02 or PM that may be associated with the observed health effects in
the study. Douglas and Waller (1966) suggested that these children probably were exposed to
higher pollution concentrations in their early lives than suggested by the measurements made
in 1962-63 because of the improvement that followed the 1956 United Kingdom Clean Air Act.
Furthermore, attempting to retrospectively estimate past pollutant exposure levels from
limited (1-2 yrs) data following known or suspected marked changes in study area pollutant
SOX14G/A
14-26
2-14-81
-------
concentrations usually tends to invalidate or substantially decrease confidence in study
findings, at least concerning quantitative air pollution/health effects relationships. Thus,
fundamental deficiencies preclude the use of the aerometric data quantitatively, e.g., the
lack of data for all study areas and apparent failure to have used site-specific calibra-
tions for BS readings in all areas.
Further study of the Douglas and Waller population at 20 years of age indicated that in
the then now young adults, cigarette smoking had the greatest effect on respiratory symptom
prevalence, followed by a history of lower respiratory tract illness under 2 years of age. At
this time of their lives, social class and air pollution had little effect. The standardized
prevalence rate (percent), however, was higher among the group who had lived in high-pollution
areas (11.51) than in those who had lived in the low-pollution area (10.20) but the difference
was not significant. This study would appear to indicate that the effects of exposure to air
pollutants in high concentrations during the first 11 years of life had disappeared by age 20,
unless there was a history of lower respiratory illness before age 2. However, no specific
information is provided in the report to indicate the concentration of pollutants to which the
children were exposed after 1957 when they were 11 years old.
A final survey, when the study population was 25 years old, confirmed the observation made
5 years earlier. At this time, Kiernan et al. (1976) reported that smoking continued to have
the greatest effect on respiratory symptoms and lower respiratory illness. The association
with air pollution was again a positive one and stronger than had been observed 5 years
earlier, but was not statistically significant.
An association between air pollution and lower respiratory tract illness in children was
also observed by Lunn et al. (1967). These investigators studied respiratory illness in 5-
and 6-year-old schoolchildren living in four areas of Sheffield, England. Air pollution con-
centrations showed a gradient in 1964 across four study areas for mean 24-hour smoke (BS)
3 3
concentrations from 97 ug/m to 301 (jg/m and the same gradient for annual mean 24-hour S0?
33
concentrations from 123 ng/m to 275 ug/m . The following year, the annual concentrations of
smoke were about 20 percent lower and SCL about 10 percent higher, but the gradient was pre-
served for each pollutant. In high-pollution areas, individual 24-hour mean smoke concentra-
tions exceeded 500 (jg/m 30 to 45 times in 1964 and 0 to 15 times in 1965 for the lowest and
highest pollution areas, respectively. S0? exceeded 500 ug/m 11 to 32 times in 1964 and 0 to
23 times in 1965 for the lowest and highest pollution areas, respectively. Information on
respiratory symptoms and illness was obtained by questionnaires completed by the parents, by
physical examination, and by tests of pulmonary function (FEV~ ?I- and FVC). Socioeconomic
factors (SES) were considered in the analyses, but home heating systems were not. Although
certain differences in SES between areas were noted, the gradients between areas would exist
even when the groups were divided into social class, number of children in house, and so on
(1977). Positive associations were found between air pollution concentrations and both upper
and lower respiratory illness. Lower respiratory illness was 33 to 56 percent more frequent
SOX14G/A 14-27 2-14-81
-------
in the higher pollution areas than in the low-pollution area (p <0.005). Also, decrements in
lung function as measured by spirometry tests were closely associated with the occurrence of
respiratory disease symptoms.
The authors of the study (Lunn et al., 1967) highlighted the following points in dis-
cussing their results:
"The respiratory measurement findings showed no association with area, social
class, children in the house, and sharing of bedrooms, although Attercliffe, the
area of highest pollution, showed reduced F.E.V.n JC- and F.V.C. ratios. On the
other hand, very clear evidence of reduced F.E.V.Q?5 ratios emerged where there
was a past history of pneumonia and bronchitis, persistent or frequent cough, or
colds going to the chest. It must be stressed that these findings relate to first
year infant schoolchildren and that measurements were made during the summer term
when pollution levels were low and acute respiratory infections few and far
between. In other words, a pattern of respiratory disability had appeared at an
early age and was sufficiently established to persist although the factors of
pollution and infection were temporarily absent or at a low level."
In a second report, Lunn et al. (1970) gave results for 11-year-old children studied in
1963-64 that were similar to those provided earlier for the younger group. Upper and lower
respiratory illness occurred more frequently in children exposed to annual average 24-hour
mean smoke (BS) concentrations of 230 to 301 ug/m and 24-hour mean SO, concentrations of
o 33
181-275 ug/m than in children exposed to smoke (BS) at 97 ug/m and S02 at 123 ug/m . This
report also provided additional information obtained in 1968 on 68 percent of the children who
were 5 and 6 years in 1963-64. By 1968, tlie concentrations of smoke (BS) were only about
one-half of those measured in 1964, and S0» concentrations were about 10 to 15 percent below
those measured in 1964. By 1968 the pollution gradient no longer existed, so the combined
three higher pollution areas were compared with the single original low-pollution area. Lower
respiratory illness prevalence measured as "colds going to chest" was 27.9 percent in the low-
pollution area and 33.3 percent in the combined high-pollution areas, but the difference was
not statistically significant (p >0.05). (Ventilatory function results were similar.) Also,
the 9-year-old children had less respiratory illness than the 11-year-old group seen pre-
viously. Since 11-year-old children generally have less respiratory illness than do
9-year-olds, this represented an anomaly that the authors suggested may have been the result
of improved air quality. It should be noted that these Lunn et al. (1967, 1970) findings have
been widely accepted (Rail, 1974; Higgins, 1974; Holland and Bennett et al. , 1979; National
Research Council, 1978a; National Research Council, 1978b; WHO, 1979) as being valid, and, on
the basis of the results reported it appears that increased frequency of lower respiratory
symptoms and decreased lung function in children clearly occur with long-term exposures to
annual BS levels in the range of 230-301 ug/m3 and S02 levels of 181-275 ug/m3. Also, based
on the 1968 follow-up study results, it appears to be warranted to conclude that no observed
effect levels were demonstrated by the study for BS levels in the range of 48-169 ug/m and
o
SO- levels in the range of 94-253 ug/m .
SOX14G/A 14-28 2-14-81
-------
Rudnick (1978), as part of a well-designed and methodologically-sound study, collected
information by a self-administered questionnaire on respiratory symptoms and disease in 3805
children, 8 to 10 years old, living in three communities in Poland with differing air pol-
lution concentrations. The questionnaire sought information on respiratory symptoms and
symptoms of asthma during the previous 12 months. Mean pollutant concentrations in the higher
pollution area for the years 1974 and 1975 were 108 to 148 ug/m3 for S00 (OECD) and 150 to 227
.3 3
ug/m for smoke (OECD). The low pollution areas had SO, concentrations of 42 to 67 ug/m and
3
smoke concentrations of 53 to 82 ug/m . Most symptoms of respiratory illness in both boys and
girls occurred more frequently in the high pollution area but the differences were, in
general, nonsignificant. There was a higher prevalence of breathlessness, sinusitis and
asthma attacks in boys living in the high pollution area but only "runny nose in the last 12
months" occurred more frequently in girls in the same area. There were no significant differ-
ences between the frequencies of nonchronic cough, attacks of breathlessness, shortness of
breath, or multiple cases of pneumonia associated with the different pollution levels. These
results, however, cannot be taken as indicative of no-effect levels at above S0? and smoke
concentrations due to ambiguities concerning the measurement methods used, e.g., whether site-
specific calibrations were employed in generating the mass estimates for smoke rather than the
OECD standard curve, and given that at least some weak indications were reported for increased
symptomatology in the high pollution areas.
In the United States, a retrospective survey conducted by Hammer (1976, 1977) regarding
the frequency of lower respiratory illness in children was undertaken in 1971 in two south-
eastern cities, using similar questionnaire sampling as employed in certain other EPA "CHESS"
program studies (Hammer and Miller et al., 1976; French and Lowrimore, 1975). Data were
obtained by questionnaire from parents of about 10,000 children aged 1 to 12 years. The two
communities represent intermediate and high particulate exposures (annual averages of 74-112
3 3
ug/m and 133-169 ug/m TSP, respectively, for 1960 to 1971), with low annual average S09
3
exposures (<25 ug/m in both communities). The analysis of data indicated that in the high
exposure community (Birmingham) there was significantly increased respiratory disease over
that for the lower exposure community (Charlotte), based on statistically significant results
obtained on 10 of 17 measures of respiratory morbidity. This included more pneumonia and
croup among blacks and more lower respiratory disease, bronchitis and croup among whites in
Birmingham than in Charlotte. There was also a consistent trend for the association of more
illness and hospitalization with higher pollution to become stronger in older children. This
suggests that the effect increased with extended exposure. The investigators concluded that
differences in parental recall, questionnaire reliability, family size, crowding, or parental
smoking habits were not likely explanations for the excess morbidity in the high-pollution
areas, since these factors were not statistically significantly different between communities.
The results, therefore, were taken to be indicative of associations between increased lower
respiratory disease rates in children and exposure to moderately elevated particulate matter
SOX14G/A 14-29 2-14-81
-------
levels in the presence of low S02 levels. Asthma rates clustered in families, were higher in
male children and female parents, and were comparable to other studies. Significant increases
of lower respiratory disease were also reported for asthmatic children in the high exposure
community. The above aspects of the Hammer (1976, 1977) study appear to provide a basis for
arguing that it demonstrates, at least qualitatively, that significant respiratory effects in
children are associated with elevated particulate matter air concentrations in the presence of
very low levels of SCL.
Certain other aspects of the study, however, argue for caution in fully accepting its
reported findings and conclusions. The investigators assumed that cigarette-smoking for
children under age 13 in the South was minimal, equally distributed, and did not affect their
results. Also, although the response rates were excellent in both communities, they were
significantly lower in Charlotte (88 percent) than in Birmingham (95 percent) and signifi-
cantly lower for Blacks (84 percent) than for Whites (89 percent) within Charlotte. Such
small differences in response rates in absolute terms may be unlikely to have affected the
overall study results but the possibility cannot be completely discounted; nor can the
possible confounding effects of smoking be ruled out completely. Nor were the questionnaire
results checked for test-retest reliability to verify accuracy and consistency of parental
recall of illnesses for their children or validated against doctor or hospital records.
Furthermore, major reservations exist regarding the extent to which the reported air quality
data are accurate and adequately representative of the respective study population exposures;
most notably, exposures over much of the lifetimes of the older children (i.e., over 4 years
of age) were estimated using monitoring data from a single site or at best a few sites that
were not located directly in the residential areas being studied.*
In another American study, possible pulmonary function decrements were studied in
Cincinnati schoolchildren in 1967-1968 by Shy et al. (1973). Children from schools in an
industrial valley of Cincinnati were compared with children from schools in a non-industrial
river valley on the east side of the metropolitan area. Two each upper-middle white, lower-
middle white, and lower-middle black schools were selected from each valley. Air monitoring
stations within three blocks of the schools showed that 7-month average TSP values were from
18 to 32 ug/m higher in the industrial valley than in the non-industrial valley, but little
or no differences existed in corresponding levels for S09. Arithmetic averages over the 7
3
months of the study ranged for TSP from 96 to 114 ug/m in the more polluted industrial area
and from 77 to 82 ug/m in the cleaner areas. The 7-month average for S09 ranged from 39 to
3 3
51 ug/m in the polluted areas and from 40 to 45 ug/m in the clean areas. Ventilatory
function was measured as the forced expiratory volume at .75 second (FEV -,,-) on a Stead-Wells
*Note that the health effects results described here for the Hammer (1976; 1977) dissertation
study were based on analysis of unvalidated computerized data tapes. Recent realysis of the
data based on validated data tapes, however, has produced results very close to those reported
in the Hammer dissertation and the results are in the process of being prepared for peer review
and publication.
SOX14G/A 14-30 2-14-81
-------
water-filled spirometer once weekly on each child during each of the study months. The better
of two satisfactory forced expiratory maneuvers obtained on each test day was used for all com-
putations. Height, sex, and race were used to make adjusted FEV -,,- comparisons. The study
was confined to 394 second graders who participated in weekly measurements during November
1967, February 1968, and May 1968. These students represented 93 percent of second graders in
the classrooms selected. Mothers were interviewed to obtain socioeconomic data. The educa-
tional attainment of fathers was similar for corresponding schools in the industrial and non-
industrial valleys.
The Shy et al. (1975) data showed that average height adjusted FEV 75 in "clean" schools
exceeded that in "polluted" schools in all 3 months for lower-middle class whites and in 2 of
3 months for upper-middle whites. Blacks consistently had lower FEV 75 values, and a pol-
lution effect was seen among blacks during only one of three study periods. The absolute
differences in average FEV -,,. were roughly 40-120 ml (<10 percent) in most cases. A multi-
variate analysis of variance was applied which allowed for testing of community effects
adjusted for a possible month effect and for the covariates height, sex, race, and social
class. The dependent variable for each child was his vector of three monthly average FEV -,^
values. However, the authors reported that no association existed between acute exposures to
24-hr TSP levels and pulmonary function test results obtained on the same or following days,
making it difficult to ascribe the relatively weak observed differences in pulmonary function
between the study areas to the very small differences in annual average TSP levels in the
respective study areas.
In summary, one set of the above studies, by Lunn et al. (1967, 1970) in Sheffield,
England, provides clear evidence for significant pulmonary function decrements and increased
respiratory disease illnesses in children being associated with chronic exposure to SCL and PM
in the ambient air. Two American studies (Hammer, 1976, 1977; Shy et al., 1975) also provide
suggestive but controversial (mainly qualitative) evidence indicative of possible increases in
lower respiratory tract diseases and pulmonary function decrements in children being associat-
ed with elevations in ambient air PM in the absence of marked elevations in S0? levels.
14.5 CHAPTER SUMMARY AND CONCLUSIONS
Some of the epidemiological studies reviewed above appear to provide meaningful quantita-
tive information on health effects associated with ambient air exposures to PM and S0?.
Others, however, do not meet as fully the various objectives discussed earlier under Section
14.1.2 or ambiguity exists regarding clear interpretation of their reported results. Only
some of the study results can, therefore, be accepted with a relatively high degree of
certainty or confidence, whereas others may be seen as providing, at best, only suggestive
evidence for the reported associations between air pollutant parameters and health effects.
The main focus of the present section will be on summarizing results and conclusions derived
from selected key studies having a relatively high degree of certainty associated with their
findings.
SOX14G/A 14-31 2-14-81
-------
In general, the epidemiological studies reviewed above provide strong evidence for severe
health effects, such as mortality and respiratory diesease, being induced in certain popula-
tions at special risk by marked elevations at atmospheric levels of sulfur dioxide and parti-
culate matter. Those populations at special risk for such effects appear to include, mainly,
the elderly and adults with chronic pre-existing cardiac or respiratory diseases (e.g.,
bronchitics). Increased lower respiratory tract illnesses and more transient (likely
indicator) effects, e.g., decrements in pulmonary function, also appear to be associated for
children with lower chronic exposures to sulfur dioxide and PM. Also, some qualitative epi-
demiological evidence suggests that asthmatics may be a susceptible population at special risk
for experiencing pulmonary function decrements in response to elevations in SO,, and PM.
14.5.1 Health Effects Associated with Acute Exposures to Sulfur Oxides and Particulate Hatter
As noted earlier in the present chapter, it is widely accepted that increases in
mortality occur when either S09 or particulate matter levels increase beyond 24-hr levels of
3
1000 |jg/m . Such increased mortality, mainly in the elderly or chronically ill, may logically
also be most directly attributed to very high short-term peak levels in the pollutants, which
at times increased to several thousand ug/m during certain major pollution episodes.
Much more difficult to establish are to what extent significant increases in mortality
and morbidity are associated with exposures to S0? and/or particulate matter levels below 1000
3
ug/m . Concisely summarized in Table 14-7 are several key studies that appear to demonstrate
with a reasonably high degree of certainty, mortality and morbidity effects associated with
acute exposures (24 hrs) to these pollutants. The first two studies cited, by Martin and
Bradley (1960) and Martin (1964), deal with a relatively small body of data from London in the
late 1950s. No clear "threshhold" levels were revealed by their analyses regarding S0? or BS
levels at which significantly increased mortality began to occur. Based on their findings,
there appears to be little question that mortality in the elderly and chronically ill was
elevated in association with exposure to ambient air containing simultaneous S09 and BS levels
3
somewhere in the range of 500-1000 ug/m . Greatest certainty applies for levels in excess of
700-750 ug/m . Much less certainty is attached to lower estimates possibly derived from a
reanalysis of the same data set by Ware et al. (1981), which applies to mortality data from
very brief periods during the two London winters. It seems more likely that levels well in
excess of 500 ug/m BS and S02 are typically necessary in order to induce mortality among
highly susceptible elderly or chronically ill individuals.
Only very limited data exist by which to attempt to delineate any specific physical and
chemical properties of PM associated with the observed increases in mortality. Based on
information noted earlier (Section 14.2), it would seem that marked increases in small
particles to levels above 500-1000 ug/m appear to be most clearly associated with increased
mortality, based on the BS aerometric measurements reported, although contributions from
larger coarse-mode particles cannot be completely ruled out. Nor is it possible to state with
certainty specific PM chemical species associated with the increases in mortality. We do know
SOX14G/A 14-32 2-14-81
-------
TABLE 14-7. SUMMARY OF QUANTITATIVE CONCLUSIONS FROM EPIDEMIOLOGICAL STUDIES RELATING HEALTH
EFFECTS OF ACUTE EXPOSURE TO S02 AND PARTICULATE MATTER TO AMBIENT AIR LEVELS
Type of study
Mortality
Effects studied
Likely increases in daily
24-hr average pollutant level (pg/m )
particulate matter
CoH BS TSP S02
>1000 - >1000
Reference
Martin and
total mortality above a
15-day moving average during
winter 1958-59 among persons
with existing respiratory
or cardiac disease in London.
Bradley (1960)
CO
GO
Slight indication of likely
increases in daily total
mortality above a 15-day
moving average during winters
of 1958-59 and 1959-60 among
persons with existing respira-
tory or cardiac disease in
London.
750-1000
710-1000
Martin (1964)
Morbidity
Likely worsening of health
status among a group of
chronic bronchitis patients
250-500
500-600
Lawther et al.
(1958, 1970)
No apparent response or
worsening of health status
among a group of chronic
bronchitis patients
<250
<500
Lawther et al.
(1970, 1975)
-------
that large amounts of pollutants (e.g., elemental carbon, tarry organic matter, etc.) from
incomplete combustion of coal were present in the air, but no single component or combinations
of particulate pollutants can clearly be implicated. Nor can the relative contributions of
S02 or particulate matter be clearly separated based on these study results or possible inter-
active effects with increases in humidity (fog) completely ruled out; but temperature changes
do not appear to be important in explaining the mortality effects observed in Martin's studies.
A study by Glasser and Greenberg (1971), not listed in the table, similarly appears to
suggest, with less confidence, that slight mortality increases were associated with increases
in S02 above 786-1048 ug/m3 and in CoHs levels of 5.0-7.0. These latter levels likely corre-
spond to concentrations in excess of 570-720 pg/m3 BS equivalent units based on calibration
studies by Ingram alluded to above. Again specific particulate chemical species cannot be
clearly implicated nor the relative contributions of S02 and particulate matter separated. It
should be noted that, whatever, the causal agents, only very small increases in mortality may
have been detected at the above pollutant levels in New York City.
Similar analysis of Lawther morbidity studies listed in Table 14-7 suggests that acute
O
exposure to elevated 24 hr PM levels in the range of 250-500 ug/m (BS) in association with
24-hr S02 levels of 500-600 ug/m3 were likely associated with the induction of respiratory
disease symptoms in chronically ill London bronchitis patients. Again, little can be said,
however, in terms of specifying physical or chemical properties of PM associated with the
observed effects beyond the comments noted above in relation to Martin's studies on mortality.
In regard to chronic exposure effects of S0? and particulate matter, the best pertinent
epidemiclogical health studies are summarized in Table 14-8. The Lambert and Reid (1970) study
suggests that respiratory disease symptoms (cough and phlegm) are associated with long-term
(annual-average) exposures of adults to PM levels in the range of 100-200 ug/m (BS) or above
in association with S0? levels in the range of 150-200 ug/m or above. The studies by Ferris
et al. (1973, 1976) suggest that lung function decrements may occur in adults at TSP levels in
o
excess of 180 ug/m in the presence of relatively low estimated SCL level, whereas no effects
were observed by the same investigators at TSP levels below 130 g/m or by other investigators
(Holland and Stone, 1965; Deane et al., 1965; Comstock et al., 1973) at TSP levels in the range
of 70-163 ug/m , based on surveys of chest illness and symptoms prevalence. Other studies
listed in Table 14-8 suggest that significant respiratory effects occur in children in associ-
ation with long-term (annual average) PM levels in the range of 230-301 ug/m (BS) in associ-
3
ation with S09 levels of 181-275 ug/m . No effects were seen for children, however, at PM
"\ \
levels in the range of 48-169 ug/m (BS) or at S02 levels of 94-253 ug/m . One study, by
Hammer suggested possible respiratory effects in children at an annual average TSP level of
135-169 ug/m in the presence of very low S02 levels, but controversy and questions regarding
the conduct of the study, data analysis, and aerometric measurements cloud its interpretation.
SOX14G/A 14-34 2-14-81
-------
I
co
01
Cross-sectional
(5 cities)
TABLE 14-8. SUMMARY OF QUANTITATIVE CONCLUSIONS FROM EPIDEMIOLOGICAL STUDIES
RELATING HEALTH EFFECTS OF CHRONIC EXPOSURE TO S0? AND PARTICULATE
MATTER TO AMBIENT AIR LEVELS
Type of study
Cross-sectional
(4 areas)
Cross-sectional
(4 areas)
Cross-sectional
(4 areas)
Longitudinal
and cross-
sectional
Longitudinal
and cross-
sectional
3
Annual average pollutant levels (HQ/ro )
parti cul ate matter
Effects studied CoH BS TSP S02
Greater prevalence of cough - 100-200+ - 150-200+
and phlegm in areas of elevated
BS and S0? pollution, observed
in survey of 10,000 British
postal workers.
Likely increased frequency - 230-301 - 181-275
of lower respiratory symp-
toms and decreased lung
function in children
No observed effect on res- - 48-169 - 94-253
piratory symptoms and lung
function in children
Apparent improvement in - - 180
lung function of adults
in association with decreased
PM pollution in Berlin, N.H.
Apparent lack of effects - - 80-131
and symptoms , and no
apparent decrease in lung
function in adults
Reference
Lambert and Reid
(1970)
Lunn et al .
(1967)
Lunn et al .
(1970)
Ferris et al.
(1973, 1976)
Ferris et al .
(1973, 1976)
No apparent evidence of
increased symptom pre-
valence or chest illness
among telephone plant
workers
70-163
Holland and
Stone (1965)
Deane et al.
(1965)
Comstock et al.
(1973)
-------
Again, no specific particulate matter chemical species can clearly be implicated as
causal agents associated with the effects observed in those studies listed in Table 14-8. Nor
can potential contributions of relatively large inhalable coarse mode particles be ruled out
based on these study results; and, it should be remembered, that various occupational studies
listed in Appendix C at least qualitatively suggest that such sized particles of many
different types of chemical composition can be associated with significant pulmonary
decrements, respiratory tract pathology, and morphological damage.
It should also be noted that certain studies not listed in Tables 14-7 and 14-8 but
discussed in Sections 14.3 and 14.4, or Appendices A and B, suggest that respiratory effects
(usually pulmonary function decreases) may occur in association with lower annual average
exposure levels that those seen in Tables 14-7 and 14-8. Particular features of most of those
studies or ambiguities about their results, however, preclude acceptance of their findings
with much confidence at this time.
SOX14G/A 14-36 2-14-81
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in an air polluted area. Am. Rev. Respir. Dis. 107:400-409, 1973.
Zeidberg, L. D., R. A. Prindle, and E. Landau. The Nashville air pollution study. I. Sulfur
dioxide and bronchial asthma. A preliminary report. Am. Rev. Res. Dis. 84:489, 1961.
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Arch. Environ. Health 15:214-224, 1967.
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Appendix A - Chapter 14 PM/SOX
APPENDIX A
ANNOTATED COMMENTS ON COMMUNITY HEALTH
EPIDEMIOLOGICAL STUDIES NOT DISCUSSED IN
DETAIL IN MAIN TEXT OF CHAPTER 14.
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Appendix A - Chapter 14 PM/SOX
APPENDIX A
Numerous community health epidemiological studies have been cited during the
past 10 to 20 years as providing quantitative evidence for particular atmospheric
levels of sulfur oxides and/or particulate matter being associated with mortality
or morbidity effects. In the course of the present assessment, close examination
of such studies and published evaluations or reinterpretations of their findings
have led to the conclusion that methodological considerations or published
results reported for many of them substantially limit or preclude their usefulness
in helping to define quantitative air pollution/health effects relationships
especially at levels below 1000 ug/m . Based on this, many were excluded from
detailed discussion or consideration in the main text of Chapter 14 or mentioned
only briefly in support of certain points made in the chapter. Provided below
are annotated comments addressing limitations of various studies for helping
to quantify the health effects of sulfur oxides and particulate matter and
exposure levels at which such effects occur. Many of the studies listed,
however, do provide qualitative evidence helpful in characterizing sulfur
oxides and particulate matter health effects and are therefore cited as such
either in the main text of Chapter 14 or in tables summarizing qualitative
studies in Appendix B.
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Appendix A - Chapter 14 PM/SO
.X
A. STUDIES OF MORTALITY EFFECTS OF ACUTE EXPOSURES
1. British, European, and Japanese Studies
The following studies all concern early (1950s-60s) severe air pollution
episodes in England, when atmospheric concentrations of particulate matter
(BS) and sulfur dioxide markedly exceeded 1000 ng/m :
Burgess, S. E. , and C. W. Shaddick. Bronchitis and air pollution.
R. Soc. Health J. 79:10-24, 1959.
Clifton, M., D. Kerridge, J. Pemberton, W. Moulds, and J. K. Donoghue.
Morbidity and mortality from bronchitis in Sheffield in four
periods of severe pollution. Ijr. Proc. 1959 Int. Clean Air
Conf. London, National Society for Clean Air. 1960. p. 189.
Gore, A. T., and C. W. Shaddick. Atmospheric pollution and mortality
in the County of London. Br. J. Prev. Soc. Med. 12:104-113,
1958.
Logan, W. Mortality in the London fog incident. Lancet 1:336-338,
1953.
Scott, J. A. Fog and deaths in London, December 1952. Pub. Health
Rep. 68:474-479, 1953.
Scott, J. A. The London fog of December, 1962. Med. Off. 109:
250-252, 1963.
Ministry of Health. Mortality and Morbidity During the London Fog of
December 1952. London, Her Majesty's Stationery Office. 1954.
Wilkins, E. Air pollution and the London Fog of December, 1952. J.
Roy. Sanit. Inst. 64:1-21, 1954a.
Wilkins, E. Air pollution aspects of the London Fog of December,
1952. Roy. Meterol. Soc. J. 80:267-271, 1954b.
These studies are mainly useful in being indicative of mortality effects
occurring at BS/SOp levels well in excess of 1000 [jg/m and are widely accepted
as such, regardless of particular methodological flaws or limitations associated
with each.
Biersteker (1966) also reported the following study of a high pollution
episode in Rotterdam in December 1962:
Biersteker, K. Polluted Air Causes, Epidemiological Significance, and
Prevention of Atmospheric Pollution. Assen, Netherlands, Van
Gorcum and Co., pp. 21-23 (in Dutch), 1966.
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Appendix A - Chapter 14 PM/SOX
During the episode, 24-hr mean concentrations were recorded for participate
matter and sulfur dioxide at about 500 ug/m and 1000 \ig/m , respectively
(OECD smoke /sulfur dioxide methods), together with increased hospital admissions
for the elderly (over 50 years old) with cardiovascular diseases and weak
indications of increased mortality. However, these results were observed only
once in Rotterdam and could have been due to other causes and do not provide
evidence of a strongly convincing statistical relationship between observed
mortality and hospital admissions and the air pollution levels reported. Nor
is it possible to determine precisely what the reported smoke levels (in
(jg/m ) mean in terms of actual particulate matter mass present in Rotterdam at
the time.
A Japanese study, on relationships between mortality and air pollution in
Osaka was reported by Watanabe:
Watanabe, H. Health effects of air pollution in Osaka City. J. Osaka
Life Hyg. Assoc. 10:147-157(in Japanese), 1966.
Increases in mortality (about 20%) appeared to occur when daily concentrations
of particulate matter (as measured by a light scattering method) exceeded 1000
ug/m (4-day average) in association with S02 (probably sulfation method)
3
levels of 250 [iq/m . Low temperatures present may have contributed to the
effects and it is not possible to assess with confidence the statistical
relationship between observed mortality and the reported pollutant levels
which were apparently based on data from a single monitoring station. Nor is
it possible to interpret the exact meaning of the reported suspended particulate
matter measurement results as to how they might relate to fine-particulate
mode, inhalable coarse-mode, or total suspended particulates levels.
2. American Studies
The following series of studies, employing mainly regression analysis
techniques attempted to define relationships between daily mortality and
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variations in particulate matter and S02 in New York City during the periods
of the 1950s, 1960s, and 1970s:
Greenburg, L. , M. B. Jacobs, B. M. Droletti, F. Field, and M. M.
Braverman. Report of an air pollution incident in New York City,
November, 1953. Public Health Rep. 77:7-16, 1962.
Glasser, M., L. Greenburg, and F. Field. Mortality and Morbidity
During a Period of High Levels of Air Pollution, New York, November
23-25, 1966. Arch. Environ. Health 15:684-694, 1967.
Glasser, M., and L. Greenburg. Air pollution and mortality and weather,
New York city, 1960-64, Arch. Environ. Health 22:334-343, 1971.
Schimmel, N., and L. Greenburg. A study of the relationship of pollution
to mortality, New York City, 1963-1968. J. Air Pollut. Control
Assoc. 22:607-616, 1972.
Schimmel, H., and T. J. Murawski. The relation of air pollution to
mortality. J. Occup. Med. 18:316-333, 1976.
Among the disadvantages of these studies is the fact that only data from a
single air pollution station in Manhattan was used in attempting to correlate
changes in air pollution with mortality in the entire city, raising questions
regarding how representative those aerometric measurements are of exposures
for the entire study population. Goldstein and Landowitz (1977a,b) found that
most correlations between pollutant levels recorded at any two New York City
monitoring stations were <0.40 and concluded that use of aerometric data from
any single station generally did not adequately represent pollutant levels for
the entire city. A possible exception to this may occur during severe air
pollutant episodes when markedly increased pollutant levels at all stations
may tend to approach a common ceiling elevation. Lastly, many criticisms have
been advanced regarding specifics of the statistical approach employed (e.g.,
some correlations likely to be significant by chance alone from among a very
large number run) and some of the same and other investigators have since
reinterpreted these studies as generally not providing evidence of any association
between mortality and S0? levels and only very weak associations- with particulate
matter levels. Generally speaking, then, little evidence can be derived from
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Appendix A - Chapter 14 PM/SOX
these studies for excess mortality having been associated with either elevated
S02 or participate matter levels in New York City, with the possible exception
of during severe pollution episodes.
Several other American studies of New York or other United States cities
utilized primarily multiple regression analysis techniques that mainly allow
only for qualitative statements to be made regarding possible associations
between daily mortality and SCu or particulate matter levels. These studies
i nc1ude:
Buechley, R. W., W. B. Riggan, W. Hasselblad, and J. B. Van Bruggen.
SCL levels and perturbations in mortality. A study in New
York-New Jersey metropolis. Arch. Environ. Health 27:134-137,
1973.
Buechley, R. W. S02 Levels, 1967-1972 and Perturbations in Mortality.
Contract No. ES-5-2101. Report available from National Institute
of Environmental Health Sciences, Research Triangle Park, N.C.,
1977.
Hodgson, A., Jr. Short-term effects of air pollution on mortality
in New York City. Environ.•Sci. Technol. 4:589-597, 1970.
Lebowitz, M., P. Bendheim, G. Cristea, D. Markovitz, J. Misiaszek,
M. Staniec, and D. Van Wyck. The effect of air pollution and
weather on lung function in exercising children and adolescents.
Am. Rev. Respir. Dis. 109:262-273, 1974.
One other American study reported on possible mortality effects associated
with a 1975 episode in Pittsburgh, Pennsylvania:
Riggan, W. B., J. B. Van Bruggen, L. E. Truppi, and M. B. Hertz.
Mortality models: A policy tool. EPA-600/9-76-016, 196-198, 1976.
This report concerned an analysis of excess mortality associated with the same
air pollution episode studied by Stebbings et al. (1976). Only 20 excess
deaths were noted and these were associated with extremely high peak 1-hour
Q
air pollution concentrations over 1000 ug/m . Also, this report has not
undergone peer review.
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Appendix A - Chapter 14 PM/SOx
B. MORBIDITY EFFECTS AND ACUTE EXPOSURES
1. British, European, and Japanese Studies
Comments on certain individual acute exposure morbidity studies are as
follows for each.
FOR Carne, S. Air pollution study. Proc. R. Soc. Med.
57:30-34, 1964.
This study of general practicioners records of illness during the winter of
1962-63 in London provides evidence of morbidity effects among elderly patients
during the December, 1962, pollution episode when levels of smoke and SO^
3
markedly exceed 1000 g/m . However, the health effects results cannot be
reliably linked quantitatively to specific pollutant levels.
FOR: Angel, J. H., C. M. Fletcher, I. D. Hill, and C. M. Finker.
Respiratory illness in factory and office workers. Br. J. Dis.
Chest 59:66-80, 1965.
This study of acute respiratory illness attack and prevalence rates in a
working population of London correlated such rates with weekly peaks of pollu-
tion measured at several nearby sites. No clear conclusions were stated by
the authors regarding pollutant levels associated with notable illness increases.
Based on the reported data only some apparent increase seems to occur, generally,
when smoke and SOp levels exceed 1000 pg/m .
FOR: Gervois, M., G. Dubois, S. Gervois, J. M. Queta, A. Muller, and
C. Vorsin. Atmospheric pollution and acute respiratory disease.
Denoin and Quavrechoin epidemiological study. Rev. Epidemiol.
Sante Publique 25:195-207, 1977.
This article, in French, gives little methodology information and especially
about the quality of aerometry or health measurements. A positive association
was reported between pollution concentration and acute respiratory disease
within one town (Quavrechoin) but not another (Denoin), although there were no
clear differences in pollutant levels between the towns. Use of this study is
limited because of uncertainty about its validity and also because insufficient
information was given to allow conclusions to be drawn about quantitative
relationships.
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Appendix A - Chapter 14 PM/SO
FOR: Van der Lende, R. Epidemiology of Chronic Non-Specific Lung
Disease (Chronic Bronchitis). Assen, Royal Van Gorcum, and
Springfield, 111., Charles C. Thomas. 1969.
Van der Lende, R., J. P. M. de Kroon, G. J. Tammeling, B. F.
Visser, K. de Vries, J. Wever-Hess, and N. G. M. Orie. Prevalence
of chronic non-specific lung disease in a non-polluted and an
air polluted area of the Netherlands. In: Ecology of Chronic
Non-Specific Respiratory Diseases. Z. Brzezinski, J. Kopczynski,
and F. Sawicki, ed., Warsaw, Panstwowy Zaklad Wydownictw Lekarskick.
1972. p. 27-33.
Van der Lende, R., G. J. Temmeling, B. F. Visser, K. de Vries,
J. Wever-Hess, and N. G. M. Orie. Epidemiological investigations
in the Netherlands into the influence of smoking and atmospheric
pollution on respiratory symptoms and lung function disturbances.
Pneumonologie 149:119-126, 1973.
Van der Lende, R., C. Huygen, E. J. Jansen-Koster, S. Knijpstra,
R. Peset, B. F. Visser, E. H. E. Wolfs, and N. G. M. Orie. A
temporary decrease in ventilatory function of an urban population
during an acute increase in air pollution. Bull. Physiopathol.
Respir. 11:31-43, 1975.
Studies in the Netherlands reported by van der Lende and colleagues (van
der Lende et al., 1969, 1972, 1973, 1975) compared lung function in a large
population group in 1969 and again in 1972. In a more polluted area, age-,
health-, and smoking-adjusted FEV, n values in men increased from the first to
the second survey rather than decreasing with age as expected. This was
associated with a concurrent decrease in air pollution concentrations. The
investigators considered other possible causes of the improved pulmonary
function but concluded that the most plausible was the effect of reduced air
pollution, but little hard evidence was advanced to support this hypothesis.
In fact, the changes over time in PFT test results may be likely due to different
experimenters performing the tests from the earlier to later years.
2. American and Canadian Studies
Comments on several American (United States) and one Canadian acute
exposure morbidity studies are as follows for each.
FOR: Cassell, E. J., M. D. Lebowitz, I. M. Mountain, H. T. Lee, D.
J. Thompson, D. W. Wolter, and J. R. McCarroll. Air Pollution
Weather, and Illness in a New York Population. Arch Environ
Health 18:523-530, 1969.
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X
McCarroll, J. R., E. J. Cassell, W. T. Ingram, and D. Wolter.
I. Health and the Urban Environment. Am. J. Public Health
56:266-275, 1966.
Mountain, I. M., E. J. Cassell, D. W. Wolter, and J. D. Mountain.
Health and the Urban Environment. VII. Air Pollution and
Disease Symptoms in a Normal Population. Arch. Environ. Health
17:343-352, 1968.
Thompson, D. J., M. D. Lebowitz, E. J. Cassell, D. Wolter, and
J. McCarroll. Health and the Urban Environment. VIII. Air
Pollution, Weather, and the Common Cold. Am. J. Public Health
60(4):731-739, 1970.
These reports from the Cornell study gave results for correlations of
CoHs and S0? levels with numerous health endpoint measurements. Many of the
effects measured, such as tearing, are of modest health significance. Also,
numerous analyses are reported, predominantly multiple regression analysis;
and coefficients frequently change sign and magnitude as variables are added
and deleted, making it difficult or impossible to quantify health effects/air
pollution relationships from these qualitative studies.
FOR: Greenburg, L., F. F. Field, J. I. Reed, and C. L. Erhardt. Air
pollution and morbidity in New York City. J. Am. Med. Assoc.
182:161-164, 1962.
Greenburg, L., C. Erhardt, F. Field, J. I. Reid, and N. S.
Seriff. Intermittent air pollution episode in New York City,
1962. Public Health Rep. 78:1061-1064, 1963.
Greenburg, L., F. Field, J. I. Reed, and C. L. Erhardt. Asthma
and temperature change. An epidemiological study of emergency
clinic visits for asthma in three large New York Hospitals.
Arch. Environ. Health 8:642, 1964.
Peak pollution levels during these studies were often much higher than
1000 ug/m , especially when 1-hour values are considered. Also, methods of
analyses preclude clear quantitative statements on pollutant/health effect
relationships.
FOR: Carnow, B. W., M. H. Lepper, R. B. Shekelle, and J. Stamler.
Chicago air pollution study. Arch. Environ. Health 18:768-776,
1969.
No particulate matter concentrations were given, and individual exposures
to S0? were estimated from air pollution monitoring network data in combination
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with assumptions about individual activity patterns. Positive associations
between SCL levels and health effects were restricted to seriously ill elderly
patients over age 55 with grades 3 and 4 bronchitis. Subject attrition was
high during the course of the study.
FOR: Levy, D., M. Gent, and M. T. Newhouse. Relationship between
acute respiratory illness and air pollution levels in an industrial
city. Am. Rev. Respir. Dis. 116:167-175, 1977.
This Canadian study related hospital admissions records for acute respira-
tory conditions to changes in average weekly levels of an air pollution index
(combining CoH and SCL measurements) and found significant correlations even
after effects of temperature were taken into account. However, no clear
quantitative associations between specific CoH or SCL levels and increased
acute respiratory conditions could be deduced from the reported results.
FOR: Stebbings, J. H., D. C. Fogleman, K. E. McClain, and M. C.
Townsend. Effect of the Pittsburgh air pollution episode upon
pulmonary function in schoolchildren. J. Air Pollut. Control
Assoc. 26:547-553, 1976.
Stebbings, J. H., Jr., and D. G. Fogleman. Identifying a
Susceptible Subgroup: Effects of the Pittsburgh Air Pollution
Episode Upon Schoolchildren. Am. J. Epidemiol. 110:27-40,
1979.
Measurements of air pollution levels during the episode investigated in
these studies were made after highest levels of pollution had already past, as
were the health endpoints measured (mainly pulmonary function, e.g. FEV,
tests). Method of subject selection and lack of clear association of health
results to specific particulate matter (TSP) or S0? levels precludes quantitative
conclusions regarding health effects/air pollution relationships.
NOTE: Several published reports on EPA CHESS Program studies contain information
potentially bearing on acute exposure morbidity effects of sulfur oxides and
particulate matter. Most CHESS studies, however, provide information mainly
on chronic exposure morbidity effects and are discussed below under Section D.
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C. MORTALITY AND CHRONIC EXPOSURES
1. British, European, and Japanese Studies
Comments on several British studies earlier interpreted as ueilding
quantitative information on mortality relationships to particulate matter (BS)
and SO^ exposures are as follows for each.
FOR: Buck, S. F., and A. D. Brown. Mortality from Lung Cancer and
Bronchitis in Relation to Smoke and Sulfur Dioxide Concentration,
Population Density, and Social Index. Research Paper No. 7.
London, Tobacco Research Council. 1964.
This study attempted to relate standardized mortality ratios from 214
areas in the United Kingdom (1955-59) to daily smoke (BS) and S0? levels for
March, 1962. Several factors make it difficult to interpret or accept this
study's results, including: (1) pollution levels for 1962 do not provide an
adequate basis for quantitatively estimating what were probably much higher BS
and S0? levels possibly contributing to mortality occurring in 1955-59; (2) it
3
is not clear what the reported 1962 BS data in ug/m mean in terms of actual
mass indexed from the various U.K. areas, likely including many for which no
site-specific calibrations were carried out; (3) the 1962 BS levels calculated
were likely affected to an unknown extent by the computer error reported by
Warren Spring Laboratory for British National Survey BS data during 1961-64;
and (4) potential effects of differences in occupational exposure were not
taken into account.
FOR: Stocks, P. Air Pollution and Cancer Mortality in Liverpool
Hospital Region and North Walls. Inter. J. Air Pollut. 1:1-13,
1958.
Stocks, P. Cancer and bronchitis mortality in relation to
atmospheric deposit and smoke. Br. Med. J. 1:74, 1959.
Stocks, P. On the relations between atmospheric pollution in
urban and rural localities and mortality from cancer, bronchitis
and pneumonia with particular reference to 3:4-benzopyrene,
beryllium, molybdenum, vanadium, and arsenic. Br. J. Cancer
14:397-418, 1960.
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These studies on associations in the 1950s between standardized mortality
ratios for bronchitis, lung cancer, and other cancers and particulate matter
(BS) levels in 101 urban and rural areas of Wales and England provide no way
to clearly determine quantitative relationships between BS and mortality
effects. Interpretation of the BS aerometry data alone is clouded by ambiguities
regarding the actual mass of BS (in ng/m ) indexed by measurements reported
for various areas of England and Wales (i.e. were site-specific calibrations
o
used to make the jjg/m estimates?). Also, differences in smoking history were
not assessed as possibly accounting for reported urban-rural differences.
FOR: Wicken, A. J. , and S. F. Buck. Report on a study of environmental
factors associated with lung cancer and bronchitis deaths in
areas of northeast England. Research Paper No. 8. London,
Tobacco Research Council. 1964.
In this study of cancer and bronchitis in 12 areas of England, no actual
measurements of particulate matter (BS) or S0? were available except for 2
areas (North and South Eston) during 1963-1964 and an effort was made to
relate these levels to mortality during 1952-1962. Similar objections to
retrospective linking of later aerometry data to earlier mortality information
apply here as were stated above for the Buck and Brown (1964) study. Also
mortality differences for the two Easton areas may have been due as easily to
differences in study population age levels and smoking patterns as to any air
pollution gradient.
FOR: Lave, L. B., and B. P. Seskin. Air pollution and human health.
The quantitative effect, with an estimate of the dollar benefit
of pollution abatement is considered. Science 169:723-733,
1970.
Lave and Seskin (1970) attempted to demonstrate, by mathematical analyses
mainly involving regression analyses, relationships between BS measurements in
the United Kingdom and bronchitis mortality data once the effects of other
factors such as smoking and socioeconomic status (SES) are removed. This Lave
and Seskin (1970) study has been extensively critiqued in detail by others
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X
(Holland et al., 1979; Ware et al., 1980), who have noted, for example, difficul-
ties in justifying inclusion of smoking, SES, and air pollution levels in the
Lave and Seskin analyses as if they were completely independent variables and
the failure to make some direct allowance for smoking habits in the actual
analyses. Nor is there any basis to determine specific quantitative levels of
pollutants associated with mortality from the reported results.
2. American and Canadian Studies
Among published American reports on mortality associations with chronic
particulate matter and sulfur oxides exposures are the following regarding
results from the Nashville air pollution study:
Hagstrom, R. M., H. A. Sprague, and E. Landau. The Nashville air
pollution study. VII. Mortality from cancer in relation to air
pollution. Arch. Environ. Health 15:237-248, 1967.
Zeidberg, L. D. , R. A. Prindle, and E. Landau. The Nashville air
pollution study. I. Sulfur dioxide and bronchial asthma. A pre-
liminary report. Am. Rev. Res. Dis. 84:489, 1961.
Zeidberg, L. D., R. J. M. Horton, E. Landau, and V. Raymond. The
Nashville air pollution study. Mortality and diseases of the respiratory
system in relation to air pollution. Arch. Environ. Health 15:214-224,
1967.
One purpose of the Nashville study was to study relationships between air
pollution levels and mortality (total and respiratory disease specific) in
areas of the Nashville, TN, SMSA. Particulate matter and sulfur oxides measure-
ment obtained during 1958-1959 were related to dealths occurring during 1949-1960,
opening this study to criticisms regarding retrospective use of later aerometry
data in looking for links with earlier mortality. Also, data regarding smoking
habits and occupational exposures were not taken into account.
Two further publications by Lave and Seskin (1972, 1977) attempted to
extend their original U.K. analyses approach (Lave and Seskin, 1970) to metro-
politan statistical areas in the United States:
Lave, L. B., and B. P. Seskin. Air pollution, climate, and home
heating: Their effects on U.S. mortality rate? Am. J. Public
Health 62:909-916, 1972.
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Lave, L. B., and B. P. Seskin. Air Pollution and Human Health.
Baltimore, The Johns Hopkins University Press. 1977.
Similar comments as indicated above for the earlier Lave and Seskin (1970)
publication apply here. No clear information on quantitative relationships
between particulate matter or sulfur oxides levels and mortality can be derived
from these published analyses.
Another set of widely cited American mortality studies was conducted in
Buffalo, NY, by Winkelstein and associates:
Winkelstein, W., S. Kantor, E. Davis, C. Maneri, and W. Mosher. The
relationship of air pollution and economic status to total mortality
and selected respiratory system mortality in men. I. Suspended
particulates. Arch. Environ. Health 14:162-170, 1967.
Winkelstein, W., S. Kantor, E. Davis, C. Maneri, and W. Mosher. The
relationship of air pollution and economic status to total mortality
and selected respiratory system mortality in man. II. Oxides of
Sulfur. Arch. Environ. Health. 15:401-405, 1968.
Winkelstein, W., and S. Kantor. Stomach cancer. Arch. Environ.
Health 14:544-547, 1967.
Winkelstein, W. , and M. Gay. Suspended particulate air pollution.
Relationship to mortality from cirrhosis of the liver. Arch. Environ.
Health 22:174-177, 1971.
Numerous criticisms of these studies bave been discussed in detail by Holland
et al. (1979) and Ware et al. (1980). Among the more salient problems noted
were: (1) the use of 1961-1963 particulate matter and sulfur oxides measurement
data in trying to relate air pollution to mortality among the elderly during
1959-1961; (2) inadequate controls for possible age differences between study
groups that may have covaried with the air pollution gradient used; (3) lack
of information on lifetime, including occupational, exposures; and (4) failure
to correct for smoking habits. In a later presentation, Winkelstein (1972)
comments on several of these points and later attempts to correct for some of
them:
Winkelstein, W. Utility or futility of ordinary mortality statistics
in the study of air pollution effects. In: Proceedings of the
Sixth Berkeley Symposium on Mathematical Statistics and Probability.
L. LeCam, J. Newyman, and E. Scott, eds., University of California
Press, Berkeley, CA, 1972. pp. 539-554.
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y\
Still, this 1972 discussion does not lay to rest many of the different major
concerns regarding the Winkelstein Buffalo mortality findings.
D. MORBIDITY AND CHRONIC EXPOSURES
!• British, European and Japanese Studies
Comments on several British studies often cited as demonstrating morbidity
effects to be associated with chronic exposures of particulate matter (BS) and
sulfur oxides are as follows for each.
FOR: Burn, J. L., and J. Pemberton. Air pollution bronchitis and
lung cancer in Salford. Int. J. Air Water Pollut. 7:5-16,
1963.
This study demonstrates increases in sickness absences for bronchitis in
association with increases in BS levels, but failed to test for effects of
temperature decreases which covaried with the occurrence of pollution increases.
FOR: Ministry of Pensions and National Insurance. Report on an
Enquiry into the Incidence of Incapacity for Work. II. Incidence
of Incapacity for Work in Different Areas and Occupations.
London, Her Majesty's Stationery Office, 1965.
In this study, rates of illness, absences for diseases such as bronchitis
were related to smoke (BS) and S02 measurements from six areas of England,
Scotland and Wales in 1961-1962, yielding apparent correlations between bronchitis
and pollutant levels in some areas but not others. However, socioeconomic and
several other possible confounding factors were not taken into account. Also,
BS aerometry measurements were likely impacted by the computer error affecting
1961-1964 British National Survey BS data and one cannot determine what the
3
reported BS levels actually mean in terms of ng/m mass estimates in the
absence of information on site-specific mass calibrations.
FOR: Fletcher, C. M., R. Peto, C. M. Tinker, and F. E. Speizer. The
Natural History of Chronic Bronchitis and Emphysema (an eight
year study of early chronic obstructive lung disease in working
men in London). Oxford University Press, 1976.
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This latter study above did concern relationships between smoke (BS)
levels and morbidity effects. However, although certain apparent relationships
were detected, the authors (Fletcher et al, 1976) noted several factors which
complicate interpretation of their findings in such terms, and it is difficult
to link observed effects to quantitative levels of BS.
FOR: Holland, W. W., T. Halil, A. E. Bennett, and A. Elliot. Factors
influencing the onset of chronic respiratory disease. Br. Med.
J. 2:205-208, 1969.
Holland, W. W., T. Halil, A. E. Bennett, and A. Elliot. Indications
for measures to be taken in childhood to prevent chronic respiratory
disease. Milbank Mem. Fund Q. 47:215-227, 1969.
Bennett, A. E., W. W. Holland, T. Halil, and A. Elliot. Lung
function and air pollution. Chronic inflammation of the bronchi.
Prog. Respir. Res. 6:78-89, 1971.
These reports concern a study of pulmonary function in children living in
four areas of Kent, England. Differences in Black Smoke concentrations were
small and S02 concentrations were not given. Inconsistencies existed for
pulmonary function test results in relation to estimated air pollution gradients
across the different areas.
FOR: Holland, W. W., H. S. Kasap, J. R. T. Colley, and W. Cormack.
Respiratory symptoms and ventilatory function: A family study.
Br. J. Prev. Soc. Med. 23:77-84, 1969.
This study examined respiratory disease and pulmonary function in families
of Harrow, England (a suburb of London) during 1962-1965. During this period,
mean winter smoke levels declined in ug/m from 108 (1962-1963) to 72 (1964-1965) in
two "clean" areas and from 175 (1962-1963) to 73 (1964-1965) in two "dirty"
areas, but SO^ levels for the same areas, respectively, were higher in 1963-1964
and 1964-1965 for the "dirty" areas than the "clean" ones. The observed
differences in respiratory symptoms may have been related to earlier higher
pollutant levels.
FOR: Irwig, L., D. G. Altman, R. J. W. Gibson, and C. Du V. Florey.
Air Pollution: Methods to study its Relationship to Respiratory
Disease in British Schoolchildren. Proceedings of the Intermath
Symp on Recent Advances with Asses, of the Health Effects of
Environ. Pol., Luxembourg: Commission of the European Communities
Vol 1, 1975 pp. 289-300.
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Melia, R. J. W., C. Florey and A. V. Swan. The effect of
atmospheric smoke and sulfur dioxide on respiratory illness
among British schoolchildren: A preliminary report. Paper
presented at VIII Int. Scil. Meeting Int. Epidemiol. Assoc.,
Purerto Rico, 1977.
These are preliminary reports from a study not yet completed of children
in many areas of the United Kingdom. The results reported are not based on
final analyses of data and have not been subjected to peer review. Also,
aerometry data for BS measurements employed appear to be based on mass estimates
derived from calibration of reflectance readings for the British National
Survey standard curve (for London air in 1963) not necessarily accurately
reflecting actual BS mass levels in ug/m existing in non-London study areas.
FOR: Sawicki, F. Chronic non-specific respiratory disease in the
city of Cracow. X. Statistical analysis of air pollution by
suspended particulate matter and sulfur dioxide. Epidemiol.
Rev. 23:221, 1969.
Sawicki, F. Chronic non-specific respiratory disease in the
city of Cracow. XI. The cross-section study. Epidemiol. Rev.
23:242, 1969.
Sawicki, F. Air pollution and prevalence of non-specific
chronic respiratory disease. _In: Ecology of Chronic Non-Specific
Respiratory Diseases. Z. Brzezinski, J. Kopczynski, and F.
Sawicki. ed., Warsaw, Panstwowy Zaklad Wydawnictw Lekarskich.
1972. p. 3-13.
Sawicki, F. , and P. S. Lawrence, eds. Chronic Non-specific
Respiratory Disease in the City of Cracow--Report of a 5 year
Follow-up Study Among Adult Inhabitants of the City of Cracow.
National Institute of Hygiene, Warsaw, Poland, 1977.
A series of studies from Poland by Sawicki (1969, 1972, 1977) reported
higher prevalence rates of chronic bronchitis in males (all smoking categories)
and females (smokers and nonsmokers but not ex-smokers) in a high-pollution
community. However, many of the reported differences by air pollution gradient
disappeared when rates were adjusted for age, sex, and smoking habits. Also,
no consistent relationship was found between the chronic bronchitis prevalence
rate and length of residence in the high-pollution community. Several reviewers
(e.g., Holland et al., 1979) have taken this as being evidence indicating that
Sawicki's findings do not show a relationship between air pollution and bronchitis.
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In a repetition of this study in 1973, Sawicki and Lawrence (1977) found some
evidence suggesting a further relationship between the prevalence of chronic
bronchitis and air pollution levels. By 1973, annual smoke concentrations in
3 3
the high pollution area averaged 190 (jg/m (OECD) compared with 86 ug/m
(OECD) for the low-pollution area. Ambiguities exist regarding whether site-
specific calibrations were employed in generating the OECD smoke estimates.
S0? average annual concentrations were 114 and 46 ug/m , respectively, for the
high and low pollution areas. Both chronic bronchitis and asthma were more
prevalent in the high pollution area in males and females aged 31 to 50 and in
smokers. Chronic bronchitis was also more prevalent in female non-smokers in
the high pollution area in both 1968 and 1973. The investigators demonstrated
an interaction between air pollution and smoking. However, the authors concluded
that air pollution, in comparison to other factors, such as smoking, exerted a
relatively minor effect on the health of their study populations.
FOR: Petrilli, F. L., G. Agnese, and S. Kanitz. Epidemiologic
studies of air pollution effects in Genoa, Italy. Arch. Environ.
Health 12:733-740, 1966.
Petrilli et al. (1966) studied chronic respiratory illness, rhinitis,
influenza, and bronchopneumonia in several areas of Genoa, Italy, in relation
to air pollution concentrations, between 1954 and 1964. Respiratory illness
rates in non-smoking women over age 64 with a long residential history and no
industrial exposure history was strongly correlated with S0? concentrations
(Higgins and Ferris, 1978). These investigators found that all illness rates
were higher in industrial districts with higher annual mean pollution con-
centrations. However, differences in socioeconomic status between study areas
were not adequately controlled for and ambiguities exist regarding methodology
and interpretation of reported aerometric measurements.
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2. American and Canadian Studies
Numerous American and Canadian studies are often cited as showing
associations between morbidity and chronic exposures to particulate matter or
sulfur oxides. Comments on two Canadian studies as examples are as follows.
FOR: Aubrey, F. , G. W. Gibbs, and M. R. Becklake. Air Pollution and
Health in three urban communities. Arch. Environ. Health
34:360-368, Sept/Oct 1979.
This study of three communities in the Montreal area was marked by
relatively small air pollution differences between cities. Cough and phlegm
were weakly associated with air pollution concentration, but lung function was
not. Little meaningful quantitative information can be extracted from the
report.
FOR: Neri, L. C., J. S. Mandel, D. Hewitt, and D. Jurkowski. Chronic
obstructive pulmonary disease in two cities of contrasting air
quality. Can. Med. Assoc. J. 113:1043-1046, 1975.
This study compared the prevalence of symptomatic disease and the level
of pulmonary function in Sudbury, a mining community, and in Ottawa. Although
chronic bronchitis was more prevalent in Sudbury men, 58 percent of Sudbury
men had an occupational history suggesting high pollution exposure. Lung
function levels were lower for both men and women in Sudbury. Very high
periodic peak SO^ exposure levels (exceeding 1000 ug/m ) more likely account
for any pollutant effects than long-term chronic exposures to relatively low
annual average levels of SOp or annual mean particulate levels (which didn't
vary by much between Sudbury and Ottowa).
Two examples of recently published American studies possibly relevant for
present purposes are those by Bouhuys et al. (1978) and Manfreda et al. (1978).
Comments on each are as follows.
FOR: Bouhuys, A., G. J. Beck, and J. B. Schoenberg. Do present
levels of air pollution outdoors affect respiratory health?
Nature 276:466-471, 1978.
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Although the authors report that the two communities studied had very
different air pollution histories, concentrations during the study period were
actually very similar. Only a few associations were found with air pollution
concentration among several illness measures and lung function measurements
studied, perhaps not unexpectedly in view of the limitations of this study
regarding and pollution concentrations.
FOR: Manfreda, J., N. Nelson, and R. M. Cherniack. Prevalence of
respiratory abnormalities in a rural and an urban community.
Am. Rev. Respir. Dis. 117:215-226, 1978.
This was a qualitative study of urban-rural differences in two
communities with similar air pollution concentrations and provides no clean
quantitative information on the health effects of S02 or particulate matter.
Not included in the discussion in the main text of Chapter 14 concerning
quantitative studies of morbidity associated with acute or chronic exposures
to airborne sulfur oxides and particulate matter is a series of studies
conducted by the U. S. Environmental Protection Agency under the Community
Health and Environmental Surveillance System (CHESS) program, an integrated
set of epidemiological studies performed between 1969 and 1975. In those
studies, the health status of volunteer participants was either ascertained
during single contacts or followed for time periods of up to nine months.
Attempts were made to coordinate these health measures with air pollution
observations from the residential neighborhoods of the study participants in
an effort to derive information on quantatitive relationships between
morbidity effects and both acute and chronic exposures to sulfur oxides,
particulate matter and other air pollutants.
The results of approximately ten CHESS studies were published in summary
or review form in the early 1970's and were later presented in more detail in
a 1974 EPA monograph entitled "Health Consequences of Sulfur Oxides: A Report
from CHESS 1970-1971," U.S. EPA document No EPA-650/1-74-004 (May, 1974). The
manner in which the CHESS results were reported and interpreted in the 1974
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monograph raised questions regarding inconsistencies in data collection and
analyses, as well as possible mis- or overinterpretation of results, for CHESS
data sets discussed in the early published reports or the 1974 monograph.* Of
particular concern with regard to many of the studies was the adequacy of
aerometric data or other estimates of air quality parameters, as well as the
collection and analysis of health endpoint measurement data, upon which numerous
key conclusions were based regarding possible air pollution-health effects
relationships. Many questions regarding the validity of most CHESS study
findings published in the early 1970s still remain to be fully resolved. In
view of this, their potential usefulness in yielding information on quantitative
relationships between health effects and well-defined air concentrations of
sulfur oxides and particulate matter is extremely limited at this time; such
CHESS Program study results are, therefore, not included in the discussion in
the main chapter text concerning morbidity effects.
*The matter of misinterpretation or overinterpretation of data or results of analyses of data
collected as part of the CHESS Program contributed to considerable controversy regarding the
validity and accuracy of results of early CHESS studies, as interpreted and reported in a 1974
EPA monograph entitled "Health Consequences of Sulfur Oxides: A Report from CHESS" 1970-71,
U.S. EPA Document No. EPA-6550/1-74-004 (May 1974). The controversy eventually led to the 1974
"CHESS Monograph" becoming the subject of U.S. Congressional oversight hearings in 1976. Subcommi
of the U.S. House of Representatives Committee on Science and Technology produced a report on
the Monograph, other aspects of the CHESS Program, and EPA's air pollution research programs
generally—a report entitled "The Environmental Protection Agency's Research Program with Primary
Emphasis on the Community Health and Surveillance System (CHESS): An Investigative Report."
Of primary importance for the present discussion, that report, widely referred to either as
the "Brown Committee Report" or the "Investigative Report" (IR), contained various comments
regarding sources of error in CHESS Program air quality and health effects data and quality
control problems associated with such data collection and analysis. The I.R. also contained
various recommendations to be implemented by the Administrator of EPA pursuant to Section 10
of the Environmental Research, Development, and Demonstration Authorization Act of 1978 ("ERDDAA,"
P.L. 95-155, 91 Stat. 1275, November 8, 1977). ERDDAA also requires that EPA and the Agency's
Science Advisory Board report to Congress on the implementation of the IR recommendations.
One recommendation of the IR was that an addendum to the 1974 sulfur oxides monograph be
published, to be used in part to qualify the usefulness of the CHESS studies, and to apprise
the public of the controversy surrounding CHESS. An addendum has been published, and is available
from EPA, as announced in the Federal Register of April 2, 1980, 45 F.R. 21702. The addendum
is incorporated by reference in this document in partial qualification of the CHESS studies
cited herein, and is part of the public file (or docket) established for revision of this criteria
document. The addendum contains the full text of the IR, reports to Congress by EPA, on its
implementation of the IR recommendations, and a report to Congress by EPA's Science Advisory
Board on the same subject.
SOXGR3/G A-21 2-14-81
-------
Appendix A - Chapter 14 PM/SOX
Perhaps most controversial were studies discussed in a 1974 Monograph
reporting on certain of the CHESS studies, entitled: "Health Consequences of
Sulfur Oxides: A Report from CHESS, 1970-1971." Subcommittees of the House
Committee on Science and Technology of the U.S. Congress later produced a
report on the Monograph, the CHESS Program, and EPA's air pollution programs
in general—a report entitled: "The Environmental Protection Agency's Research
Program with Primary Emphasis on the Community Heal nth and Environmental
Surveillance System (CHESS): An Investigative Report." This report, cited in
the present criteria document as the Investigative Report or "IR (1976)," is a
comprehensive reference for qualifying the use of the CHESS Monograph, and the
CHESS studies generally. The full text of the IR (1976) is contained in an
Addendum to the CHESS Monograph, EPA-600/1-80-021, which is available from EPA
as noticed in the Federal Register on April 2, 1980, 45 FR 21702.
A proper evaluation of any CHESS study cited in this document should
include careful reference to the entire IR (1976). To put the evaluation of
problems associated with CHESS studies into perspective, the passage on General
Problems of Epidemiologic Investigations of Pollution Effects in Section VI of
the IR (1976) should be read. Based on considerations outlined in that passage,
critiques of specific CHESS studies in the 1974 monograph were presented by
the IR (1976). Those critiques which specifically address studies cited in
the present Chapter 14 or its appendices are reprinted verbatim on the following
pages.
SOXGR3/G A-22
2-14-81
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No.l, "Prevalence of chronic respiratory disease symptoms in adults
1970 survey of Salt Lake Basin Communities." Reported by Chapman et al.
APPENDIX A
\f
A RECAPITULATION OF THE AEROMETRIC AND METEOROLOGICAL
FINDINGS OF THE INVESTIGATION AS THEY RELATE TO SPECIFIC
SECTIONS OF THE CHESS MONOGRAPH AND THE HEALTH FINDINGS
A. INTRODUCTION
This section contains citations of errors and omissions found in a
careful review of the CHESS Monograph which show that the use of
aerometric and meteorological data in correlation with health effects
end point measurements can easily mislead the reader of the CHESS
document into inferences which are not wholly or even partially
supported by the data in the report. Page, paragraph, and figure
references are to the 1974 CHESS Monograph.
Since an important application of the aerometric data is to deter-
mine correlations with health effects, any errors or overusage of
aerometric data based upon estimates or improper measurements will
obviously reduce or negate the value of any health effects correlations
which are attempted. This misusage or overusage of aerometric data
will be particularly damaging as the extension of the conclusions i»
made in an attempt to discover possible threshold effects.
B. CRITIQUE
1. Prevalence of Chronic Respiratory Disease Symptoms in Adults:
1970 Survey of Salt Lake Basin Communities
Observed concentrations for only one year have been used to
crudely estimate concentrations of sulfur dioxide and suspended
sulfates relating to a 4-7 year exposure. The 1971 observed annual
average concentration of sulfur dioxide was used with the 1971
emission rate from the smelter to obtain a ratio that was then mul-
tiplied by emission rates for other years to estimate concentrations
for the other years. The. estimated sulfur dioxide concentrations
were then used in a regression equation based on a 1971 relationship
to estimate suspended sulfate concentrations. Possible changes in
meteorological conditions and mode of smelter operations were
neglected. Acknowledgment is not given in the discussion and sum-
mary that the critical concentrations relating to health effects are
nothing more than estimated concentrations.
It is questionable whether or not long-term exposures should have
been attempted for Magna, based on only one year's record of ob-
servations that are abnormal because of the smelter strike. It would
certainly have born approprintc to have mentioned that only es-
timated lonjj-terni data were available and indicated their degree of
uncertainty m the discussion and summary.
(85)
A-23
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86
Further, we find many errors on Page 2-37, Table 2.1.A. 14. It seems
tliat this table should have never been included in the report. Aside
from the misuse of the diffusion model (discussed in Chapter IV) this
table lists suspended sulfate values for Magna for the years 1940-1970,
that are not the same as listed in Table 2.1.A.16, on page 2-39. The
values are estimated by a simple ratio from the smelter emission rates,
but this is not explained. On page 2-39 a regression equation is used for
the same purpose. All of the sulfate concentrations under the heading
CHESS are estimated observations except those for the year 1971.
This has not been properly indicated, e.g. by the use of parentheses.
On pnges 2-37 emission rates are not sulfur dioxide rates as indicated
but emission rates in tons of sulfur per day. This means that the sulfur
dioxide emissions were twice the values listed. It also means that the
dispersion model estimates are incorrect. However, the listed estimated
concentrations in Magna and Kearns, which are based on a simple
ratio between observed concentrations in 1971 and some emission rate
for 1971, whatever it might be, are not changed.
Note that the regression equation for suspended sulfates, Salt
Lake City, (pages 2-39) which is:
SS=0.101(TSP)-3.65
is quite different thaa that which can be obtained from Table 2.1.4,
i.e.:
SS=0.065(TSP) + 1.93
S02 exposures were derived by multiplying the yearly smelter
emission of S02 by the ratio of the 1971 measured annual average
SO2 concentration to the 1971 SO, emission rate (193 tons/day).
Estimates of suspended sulfates were derived from the estimates of
S02, using the following regression equation for 1971:
SS=0.09(S02)+6.66
The annual TSP exposures were derived by multiplying the yearly
smelter production of copper by the ratio of the 1971 measured annual
arithmetic mean TSP concentration to the 1971 copper production
late (260,000 tons/year).
Smelter emissions of sulfur dioxide in the early 1940's were roughly
three times greater than they were after 1956 although copper pro-
duction has remained more or less constant. The method for estimating
suspended sulfate, which is based on sulfur dioxide estimates leads to
very high values in the 1940's whereas the total suspended particulate
are estimated lower in 1940 than in 1971. The procedure used produced
very high ratios between SS and TSP for the earlier years. For example,
the 1940 ratio (34.6/63) is 0.55. This ratio is so large that it is obviously
questionable.
The audacity of the estimates can be se^n in Figure 2.1.17. The
lowest value, which occurecl in 1971, is extrapolated all the way back to
1940, reaching unusually high annual average concentrations of more
than one part per million. Considering the effects of wind direction,
which would result in low concentrations much of the time because the
smelter stack plume would not be blowing toward the town, such an
annual average would result in short-period concentrations many times
A-24
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87
the annual average. It is questionable that such high concentrations
ever occurred. If they did, they would be well-remembered, and living
conditions in Magna would be different than in 1971. Such unreasonably
high estimates should have been further investigated before being
presented.
The grossness of the estimates made overrides other shortcomings
in this study pertaining to exposure that might be mentioned. How-
ever, more carefully made estimates would have required considerably
more work, including obtaining meteorological records and details of
smelter operations affecting plume behavior over the period of years
studied. Such a large effort may not have been worthwhile considering
the inexactness of some of the other aspects of the study. Nevertheless,
a study of this nature seems to call for actual observations, more ac-
curate estimates, or considerably less exactitude in its conclusions.
2. Frequency of Acute Lower Respiratory Disease in Children: Retro-
spective Survey of Salt Lake Basin Communities, 1967-1970
The same comments apply to this study as for the preceding study
on the prevalence of disease symptoms in adults. Inadequate recogni-
tion is given to the fact that only estimated concentration data are
being used in the discussion and summary.
3. Aggravation of Asthma by Air Pollutants: 1971 Salt Lake Basin
Studies
In this study, daily entries in a dairy were used to determine weekly
asthma attack rates. A statistical relationship was then determined
between the attack rates (weekly) and observed air pollution concen-
trations (averaged weekly). Participants lived within a 2-mile radius
of air monitoring stations.
Daily exposure of asthmatics in a community such as Magna, which
is close to the smelter, are poorly characterized by a single monitoring
station. On a given day, one side of the community could be much more
affected by the smelter stack plume than the other, and high concen-
trations from looping or fumigation might affect one neighborhood
but not others. The study inadequately assesses the effects of peak ex-
posures and episodes.
This report does not make clear that the minimum temperatures
used were from the Salt Lake City airport. The assumption seems to
have been made that temperature was uniform over the entire study
area. This is not true because of the differences in elevation and the
effects of the mountains, and the lake. Perhaps the differences were
not important, but they should have been considered. It is not clear
why days were stratified by minimum rather than mean temperature.
Minimum temperatures occur during the early morning when peo-
ple are generally indoors and perhaps in bed. When tempera-tures are
low, windows are generally closed. Also, lower minimum temperatures
are correlated with other meteorological phenomena that could also
affect asthma attack rates, e.g., lower humidity and lower wind speed.
Further there may be a correlation with wind direction. A lower than
average minimum temperature probably is also associated with a
strong temperature inversion which would be conducive to lofting
the smelter stack plume. Because of the many questions raised, the
findings pertaining to temperature merely suggest further study and
have no general application.
A-25
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88
Near the middle of the left hand column, page 2-89, the following
sentence appears. "The shut-down of operations by the strike was
aceompaniea by a pronounced improvement in air quality and a reduc-
tion in asthma attack rates that occurred sooner and were larger than
seasonal reductions observed in the more distant study communities
some 2 weeks later." Here there is a lack of appreciation of the natural
climatic differences that exit in the Salt Lake Basin. Some effects of
summer weather could easily be delayed two weeks before reaching
Ogden. The average date for the last killing frost in Ogden is about
May 6, whereas the average date of the last killing frost at Saltair
(the climatic station nearest to Magna with a long record) is about
April 12.
On Page 2-76 (near middle of page, right hand column) the smelter
is not "5 miles north of Magna."
On page 2-81 the first graph in Figure 2.4.1 is incorrectly drafted.
After the 17th week the broken line should be solid and the solid line
broken. The temperature curve should appear as in the graph for
the high exposure community.
Figure 2.4.2, page 2-81, shows a weakness in the argument that the
sulfur dioxide concentrations are responsible for the asthma attack
rate. In the High Exposure Community the attack rate starts up at
the 18th week as the sulfur dioxide concentrations approach zero, or
near zero, and remain very low for about six weeks. It is noted that
this same graph shows the highest S02 peak occurring at the 9th week,
which seems to begin about May 9. The graph on page 2-16 seems to
show the peak in April.
In Figure 2.4.4, page 2-82, with respect to the High Exposure
Community, it may be noted that the sulfate concentrations are not
particularly well-correlated with the sulfur dioxide concentrations
plotted in Figure 2.4.2, on the preceding page. The highest sulfate
reading occurs in the 3rd week, whereas the sulfur dioxide levels
build up to a peak in the 9th week.
On page 2-87, left hand column, it is stated that a threshold concen-
tration of 1.4 /ig/m* was calculated for suspended sulfates for the
higher temperature range. In Figure 2.4.4 all of the plotted concentra-
tions are greater than this value. Considering the background of
suspended sulfates generally observed, this low threshold value seems
to nave no practical significance.
The third paragraph that appears in the right hand column, page
2-89, probably applies to Magna, however, this is not made clear.
There is a possibility that the paragraph could be given broader
interpretation than actually intended since the last three sentences
seem to refer to conditions in urban areas generally. The paragraph
probably should have been divided into two separate paragraphs.
However, the main fault with the paragraph is that important con-
clusions are drawn that are not supported by information presented
elsewhere in the report. It snys "excess asthma attributable to sulfur
dioxide might be expected 5 to 10 percent of summer days", "total sus-
pended particulates could occur on up to 5 percent of summer days and
30 percent of fall and winter days", and "excesses due to suspended
sulfates are likely to occur on 10 percent of fall and winter days and
90 percent of summer days." Assuming that the stated relationships
A-26
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89
between concentrations and temperature are true, the report does
not explain how the percentages of days were obtained. Ihe study
covered only 26 weeks, but these conclusions apply to an entire year.
The percentages given seem to be rough estimates since they appear to
be given only to the nearest 5 or 10 percent. The percentages might
have been obtained from daily values for the minimum temperature,
pollutant concentrations and asthma attack rate; but it is not clear
now they were obtained.
Presumably daily average concentration levels of specific pollutants
were used in the construction of the "hockey stick" curves shown on
pages 2-86 and 2-88. The discussion implies that "24-hour levels"
were used, but the precise nature of the air quality data used in the
threshold analyses is not made clear.
There could be various reasons not explored by the study why the
thresholds for asthma attacks were lower on warmer days. One of
these is that there may be more plume looping on warmer days. This
might result in localized, short-period, high concentrations, but
relatively low average concentrations.
The validity of scientific work can be tested by the repeatability of
results. In this and the other CHESS studies there were factors
affecting asthma attack rates that were not considered and whose
effects are unknown. Such factors are: time spent outdoors, percentage
of time windows are open, temperature change, relative humidity, etc.
The incompleteness 01 the study and the lack of understanding of the
causes of the asthma attacks suggest that it might be repeated with
significantly different results.
Short-term exposures to concentrations much higher than average
annual or weekly concentrations could have occurred in the commu-
nities studied that were near large sources of air pollution such as
smelters. There exists the possibility that asthma attacks could be
triggered by brief-duration nigh concentrations. Such exposures could
have been determined only inadequately by the procedures used in
the study. The report does not make clear why more attention was
not devoted to peak concentrations.
4- Human Exposure to Air Pollutants in Five Rocky Mountain Com-
munities, 1940-1970
On pages 3-7 through 3-12 beginning with the second column]
paragraph near middle of page, which begins "By comparing . . .".
There is not a simple relationship between average daily pollutant
emissions and average annual pollutant concentrations because the
receptor area is often now downwind. Also, some consideration should
have been given to determining if the years for which data are available
were representative meteorologically.
(Page 3-11) Second paragraph, left hand side of page. Information
obtained during this investigation indicates that the ratio 1.63 ±0.21
should be 1.42±0.21. (The value 1.63 is the upper limit of this ratio.)
(Page 3-12) Emission ratios of particulate and sulfur dioxide for
1971 are omitted from this report. Therefore, it is not possible to
verify the ratios given here.
(Page 3-12) According to information obtained during this investi-
gation, the two values for TSP listed as 99.5 for the years 1971-70,
should be 98.1 for both years.
A-27
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No. 7, "Prevalence of chronic respiratory disease symptoms in military
recruits: Chicago induction center." Report by Chapman et al.212
92
ties where certain health effects were observed, the source of the
suspended sulfate is inadequately determined. The study findings are
much too incomplete to call for the stringent control of suspended
sulfates as has been done on page 3-51.
7. Prevalence of Chronic Respiratory Disease Symptoms in Military
Recruits: Chicago Induction Center (Paragraph 4.2)
Exposure estimates in this study are extremely crude. In the sum-
mary the following statement is made, "Available evidence indicates
that exposures lasting 12 years or more to ambient air pollution
characterized by elevated annual average levels of sulfur dioxide
(96 to 217 »jg/m3), suspended particulates (103 to 155 p$[m') and
suspended sulfates (14 Mg/m') were accompanied by significant in-
creases in the frequency of chronic respiratory disease symptoms."
The 96 Mg/m3 value is the average urban core value for 1969-70,
which ranges from 54 to 138 (ig/m3, whereas the 217 Mg/ma is an average
•value for five suburban communities for thq year 1969. Going back
12 years concentrations were much higher. During the period 1960
through 1965, the lowest value was 222, and there was a nigh of 344
in 1964. For the five suburban communities there was data only for
one other year. It averaged 183 jxg/m3. The 14 <*g/m3 concentration for
eulfates is for a period of 7 years, not 12 as stated. It basically repre-
sents data for the Chicago core area, with some scattered observations
from East Chicago and Hammond, Ind. The average concentrations
for the city should be somewhat less than in the core area. Use of the
core area value would generally result in an overestimate.
It is difficult to characterize exposures lasting 12 years for the entire
Chicago area. Either this should have been done in very general
terms, nonquantitatively, or a greater effort should have been made
to present more representative estimates.
The assumption is being made that sulfate observations made at a
central urban location in Chicago, averaged with a few observations
from East Chicago and Hammond, Ind. are generally representative of
the entire Chicago area.
(Page 4-8) Referring to the Chicago area the following statement is
made: "Each sampler location, identified by a station name in
Figure 4.1.2, represents the -central business-commercial district of
that particular area." This statement is not true. Practically all, if
not all the samplers are located on the roofs of school buildings in an
effort to obtain representative community values: They were not
located deliberately in business commercial districts and do not
slightly overestimate area-wide concentrations as suggested.
(Page 4-23) In reading this paper about th_ prevalence of chronic
respiratory disease symptoms in military recruits, questions arise about
the actual locations from which the men came and the local pollution
levels to which they might have been exposed. Some rural occupations
result in high exposures to dusts, plant allergens, etc.
(Pn?e 4-35) (Summary) The 12-year value for suspended sulfates
should be 16 micrograms per cubic meter, not 14, as stated. Also, it
appears that the concentrations of sulfur dioxide and suspended par-
ticulate are for only the period 1969-1970 and not for 12 years as
is stated. (See Table 4.1.A.6)
A-28
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No. 8, "Prospective Surveys of Acute Respiratory Disease in Volunteer
Families: Chicago Nursery School Study, 1969-1970." Report by Finklea et al.117
93
8. Prospective Surveys of Acute Respiratory Disease in Vflunteer Fam-
ilies: Chicago Nursery School Study, 1969-1970
On page 4-41, in Table 4.3.1, it is riot clear where the sulfur dioxule
data for the years 1959-63 come from. The Chicago network, which
would have provided community data, was not operating effectively
until 1964.
On the same page the suspended sulfate data are probably repre-
sentative for the core area but are high to be used as an average for the
city as a whole.
A serious weakness in this study is that the communities are ranked
Intermediate, High, and Highest according to a ranking that was
determined by suspended particulate values, whereas the most im-
portant finding pertains to sulfur dioxide. Referring back to Table
4.I.A.I, it can be seen that a considerably different ranking would have
resulted if the communities had been ranked according to sulfur
dioxide concentrations. In Table 4.3.1, it may be noted that during
the study that the "High" community had the lowest concentration
of sulfur dioxide.
Also note in Table 4.I.A.I that the Highest communities include-
GSA, which happens to be on the south edge of the Chicago Loop
area. This station probably contributed considerably to the high
concentration of sulfur dioxide attributed to the Highest community
during 1969-1970, yet it is very nonrepresentative of a nursery school.
Also, note that the Highest stations include Carver, which for some
reason ranks highest because of suspended particulate concentrations
whereas the sulfur dioxide concentrations are relatively low.
Sulfates are not considered in the summary of this study, which
seems to focus on sulfur dioxide without quantitative considerations of
suspended sulfate levels.
(rage 4-54) In the first paragraph of the Summary, the following
statement appears: "It is also possible that more recent lower air
pollution levels contributed to increased respiratory illness." On page
4-51 the following statement is found. "Acute respiratory morbidity
was significantly lower among families living in neighborhoods where
sulfur dioxide levels had been substantially decreased." These two
statements are contradictory and require clarification. The first
statement is remarkable. It can be interpreted to mean that some air
pollution is good for you. Did the authors intend to say this? Such an
important finding is inadequately supported by the contents of the
report.
9, Human Exposure to Air Pollution in Selected New York Metro-
politan Communities, 19^-1911
An overusage of estimated data can be found on page 5-19. The
following two statements appear: (Left hand column, middle para-
graph) "Measured values for suspended sulfates for 1956-1970 were
available from the Manhattan 121st Street Station, and these values-
were used for citywide values." (Lust paragraph on page) "The
observed annual rutios of suspended sulfiite to dustfull for New York
City were used to estimate the suspended sulfate levels in Queens and
Bronx."
A-29
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No 10 "Prevalence of Chronic Respiratory Disease Symptoms in Adults
212
1970 Survey of New York Communities." Report by Chapman et ai.
94
10. Prevalence of Chronic Respiratory Disease Symptoms in Adults:
1970 Survey of New York Communities
Three communities were compared: Riverhead, Long Island, a low
exposure community, Queens, an intermediate exposure community,
and the Bronx, a high exposure community. Parents of all children
attending certain elementary schools located within 1.5 miles of an
air monitoring station in each community were asked to participate
in the study. Each child was given a questionnaire to be filled out by
his parents and returned.
Regarding exposure, were the concentrations measured at the
monitoring stations generally representative? Assuming a person
remains reasonably near the station, in this case within lj| miles, and
breathes the outside air, the station measurements would be generally
representative for long-term average exposure. Maps of annual
concentrations which are for sulfur dioxide and suspended participate
matter, show reasonably uniform concentrations across the study
areas. However, as has been mentioned in the report (5.1) Human
Exposure to Air Pollution Selected New York Metropolitan Com-
munities, 1944-1971, by Thomas D. English, et al., the Queens Com-
munity lies about 1 mile west of the Jonn F. Kennedy International
Airport. The effect of this airport and the various other possible
:sources of air pollution that could have affected particular local
Areas were not determined.
The fact that the CHESS monitoring sites were the same as used
in the city air pollution control programs suggests that the sites
were picked and are being used because they seem to be generally
representative.
More important than the representativeness of the monitoring
site locations in this study is the proper interpretation of the effects
of the greatly reduced pollution levels during the period 1969-1971.
It is not meaningful to draw conclusions from sulfur dioxide exposures
ranging from 144 to 404 ng/m* and sulfate exposures ranging^ from
9-24 Mg/m3, as was done in this study. The implication is that nealth
effects can be caused by the lowest concentrations mentioned, and this
is not shown in the study. Also, it is stated that annual sulfur dioxide
levels of 50 to CO Mg/m3 (accompanied by annual average suspended
sulfate levels of about 14 >ig/m3 and annual arithmetic mean total
suspended participate levels of about 60 to 105 Mg/m3) could be assoc-
ciated with such effects. These are levels.that were measured in 1971,
whereas in the study there seems to have been no way to have differ-
entiated between the effects of pollution in 1971, or that might have
occurred during some earlier time. It is not reasonable to infer that
lower pollution levels are responsible for the observed health effects.
A-30
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No. 11, "Prospective Surveys of Acute Respiratory Desease in Volunteer
Families: 1970-1971 New York Studies." Reports by French et al,306
214
Hammer et al, and Chapman et al.
11. Prospective Surveys of Acute Respiratory Disease in Volunteer
Families: 1970-1971 New York Studies
In this study families were telephoned once every two weeks and
questioned about possible health effects. The families resided within
1 to 1.5 miles of the air monitoring stations. '•
In the discussion it is stated that acute lower respiratory disease
morbidity can be attributed to exposures to 2 to 3 years involving
annual average sulfur dioxide levels of 256 to 321 Mg/m (accompanied
by elevated annual average levels of total suspended particulate of
97 to 123 Mg/m8 and annual average suspended sulfate levels of
10 to 15 Mg/m8). These values are average values for the period 1966-
1970, a five year period, and not period of 2 to 3 years as indicated.
Also, they are the averages for the Bronx and Queens, respectively,
and therefore do not represent a range of concentrations that would
have occurred in any particular community, as implied. For example,
the sulfur dioxide concentrations in the Bronx ranged from 184 to
472 Mg/m3 and in the Queens from 131 to 420 Mg/m3, during the five
year period. Three year averages are 174 to 247 jig/m8, and two year
averages, lower still.
On page 5-16 the dustfall concentrations shown in Figure 5.1.21
seem to be greater than would be obtained from the data presented in
Figure 5.1.16.
On page 5-36 (Table 5.2.1) the values in this table seem to come
from Table 5.1.A.8. The values in the column headed 1949-58 are,
except for dustfall, for shorter time periods. For example, the values
for Queens come from data for the years 1956-58.
On page 5-45 (Summary) we find that since the concentration data
base comes from Table 5.1.A.8, the long term exposure values repre-
sent a period of less than 20 years.
Further, it is stated that there is a distinct possibility that in-
creased susceptibility to acute lower respiratory illness is maintained
or induced by exposures involving annual average sulfur dioxide
levels of 51 to 63 /jg/m3 (accompanied by annual average total sus-
pended particulate levels of 63 to 104 ^g/m3 and annual average sus-
pended sulfate levels of 13 to 14 jig/ms). The 51 to 63 Mg/m3, is a range
resulting from two different analyses of samples (see puge 5-53).
It represents uncertainty in measurement techniques rather than a
range of exposure as would be interpreted. These concentrations
and the suspended sulfate concentrations of 13 to 14 Mg/m3 happen to
have occurred in the Intermediate I and the Intermediate II com-
munities during 1971. This particular study as conducted could not
have differentiated between the effects of these levels of pollution
and the effects of higher levels that occurred earlier.
Only average annual concentrations were considered and not peak
or episode concentrations.
A-31
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No. 12, "Aggravation of Asthma by Air Pollutants: 1970-1971 New York
Studies." Reports by Finklea et al.
12. Aggravation of Asthma by Air Pollutants: 1970-1971 New York
Studies
Panelists who lived within a 1.5 mile radius of three monitoring
stations in communities identified as Low, Intermediate I, and Inter-
mediate II, because of their average air pollution concentrations,
recorded asthma attacks each day in a diary for a period lasting 32
weeks, October 1970-May 1971. From a statistical association between
asthma attack rates, 24-hour average concentrations from the moni-
toring stations, and daily minimum temperatures from airpdrts near
the study communities, it was concluded that 24-hour suspended
sulfate levels of 12 yg/m3 on cooler days (T^i,, equal to 30 to 50°)
and 7.3 Mg/ms on warmer days (Tmln greater than 50°F) were thresh-
olds for the induction of excessive asthma attacks. No firm evidence
could be found to associate elevations in sulfur dioxide (100 to 180
Mg/m* on 10 percent of days) with excessive asthma attack rates on
either cold or warmer days.
Regarding exposure levels, there is much less assurance that daily
average levels throughout a community would be more or less uni-
form than would be the case with annual average levels. More moni-
toring stations might have been operated, or mobile stations used,
to determine how pollution exposure varied from location to location.
The determination of such differences in air pollution concentrations
might have been important, but probably more important is that the
other factors (in addition to the observed air pollutants) that could
have caused or contributed to the asthma attacks were not examined.
It would not be worthwhile to refine the information on the distri-
bution of the air pollutants studied, unless a greater effort were made
to study all of the various possible causes of the asthma attacks more
thoroughly.
The study focused on the effects of minimum temperature. The
possible effects of other meteorological variables could also have been
explored. Of particular interest would be the effects of sudden, large
temperature changes.
It is not made clear why minimum instead of average, or even
maximum, temperatures were picked for correlation. Generally
there would be less actual exposure to minimum temperature, which
usually occurs about sunrise, than to warmer temperatures. Asth-
matics would generally be expected to protect themselves from colder
temperatures, staying indoors and keeping windows closed, whereas
on warmer days they might be more subject to exposure to outdoor
air with its assortment of possible allergens. There are diverse reasons
why temperature might be an important factor determining asthma
attack rates. No attempt was made in the study to provide an
explanation.
A-32
-------
It is expected that there would be noticeable temperature differences
between Riverhead (the Low community) and Queens (the Inter-
mediate I, community). Although it is stated that the temperatures
come from nearby airports, the temperature curves plotted in Figure
5.4.1 seem to be identical for both communities. It may be noted
that a different curve is plotted for the low community Figure 5.5.2.
(Figure 5.4.4) Although at a glance it appears that for the Inter-
mediate community that the "Attack Rate" and the "Suspended
Sulfate" curves are similar, close inspection shows that more often
than not, they are out of phase. Between the 2nd and 3rd week the
attack rate (AR) curve continues down as the suspended sulfate (SS)
curve starts up, between the 10th and llth week the AR-curve
continues down after the SS-curve starts up, between the 14th and
16th week the AR-curve goes up while the SS-curve continues down,
between the 19th and 20th week the AR-curve starts up while the SS-
curve continues down, and again on the 27th week the AR-curve
rises a week before an increase in the suspended sulfate concentrations.
In all, three of the five increases in attack rate precede, rather than
follow, increases in suspended sulfate concentrations.
IS. Frequency and Severity of Cardiopulmonary Symptoms in Adult
Panels. 1970-1971 New York Studies (Paragraph 5.5).
Symptom diaries were maintained daily for the 32-week period
October 8, 1970 through May 22, 1971, by four panels, depending
on state of health. The panelists were distributed in three communities
and lived within 1.5 miles of air pollution monitoring stations. It,
was concluded that elderly panelists in the low exposure community
reported higher symptom rates on days when sulfate levels exceeded
10 pg.ms. There seemed to be good evidence of a threshold effect
between 6 and 10 Mg'm8, with a greater morbidity excess on warmer
days.
Since suspended sulfates seem to be more uniformly distributed
than a pollutant such as sulfur dioxide, the concentrations determined
by monitoring should be generally representative of outdoor exposure
ard in most cases indoor and outdoor average exposures would be
expected to be similar. The question not answered by this study is
whether or not the panelists are also being exposed to some other
causative agent, or stress factor, that might nappen to correlate with
the sulfftte concentrations. It, and not the suspended sulfate con-
centrations, might be the cause of the observed health effects.
(Page 5-91) (Figure 5.5.3) The low value of sulfur dioxide that
began at the 19th week and continued until the 24th week are sus-
pected of not being true values. Near the end of the last paragraph
on the preceding page it is suggested that meteorological conditions
may have been responsible. A careful study of the meteorological
conditions and fuel usage would be necessary to determine if these
might have caused the persistent low concentrations. However, a
scanning of the daily local climatological data shows no obvious
reason for the reported low values.
Furthermore, the minimum temperature curve for the Low com-
munity in Figure 5.5.2 is not the same as given in Figure 5.4.1.
The New York Department of Air Resources also reported a large
drop in concentrations following the mid-winter peakjat the Queens
(Intermediate I) monitoring station, but reported values were never
as loiv, mid ft period of low values was not followed by a rise as shown
in tlio Figure. Further, the low values shown, which are about 25
n
-------
No. 14, "Ventilatory Function in School Children: 1970-1971 New York
Studies." Report by May et al.215
14. Ventilatory Function in School Children: 1970-1971 New York
Studies (Paragraph 5.6).
Pulmonary tests were made in three elementary schools in com-
munities with different air pollution levels, and there were four rounds
of testing, November-December 1970, January 1971, February-March
1971, and April 1971. The children lived within 1.5 miles of a particular
air monitoring station. The Queens monitoring station is on top of a
school where the testing was done. However, the Bronx station is on
top of a "court house in the center of a busy commercial area" (page
5-6) and may not be close to the school. For the Riverhead com-
munity it is not made clear whether or not the school and the monitor-
ing station are at the same location or near each other. It is assumed
that the schools in Riverhead and the Bronx were within 1% miles of
the monitoring stations, but this is not actually stated.
It was concluded that 9 or more years exposure to annual sulfur
dioxide levels of an estimated concentration of 131 to 435 itg/tn3
(accompanied by suspended particulate levels of about 75 to 200
Mg/m8) and suspended sulfate levels of about 5 to 25 Mg/m3 can be
associated with a small but significant impairment in Ventilatory
function. These values are from Table 5.6.2, and are the extreme high
and low values listed. There is an. implication here that the low con-
centrations, 131 Mg/m8 for sulfur dioxide and 5 ng/m* for suspended
sulfates represent threshold values. Actually they are only annual
average concentrations for the years 1969 and 1970. The observed
health effects may have been the result of exposure to much higher
concentrations in other years, or to some other cause.
A-34
-------
No. 15, "Ventilatory Function in School Children: 1967-68.
Testing in Cincinnati Neighborhoods. Reported by Shy et al.
15. Ventilatory Function in School Children: 1967-68 Testing in Cin-
cinnati Neighborhoods (Paragraph 6.1),
This study included a pair of public elementary schools in each of
six neighborhoods differing in socioeconomic level, race, or pollution
exposure. All children in one or two classrooms of the second grade of
the elementary schools were asked to participate in the study to achieve
sample sizes of 60 to 75 children in each-of the six study sectors.
Ventilatory performance as measured by a spirometer was obtained 12
times from each child: once weekly in the months of November 1967
and February and May 1968. The tests were administered on Tuesday
and Wednesday mornings.
Air monitoring stations were placed in locations within three blocks
of each school to provide samples representative of the air quality in
the neighborhood served by the school. No information is reported
on the distances of the homes of the children from the school. Ap-
parently it was assumed that the home environment and the school
environment were the same. Indoor soiling index and sulfur dioxide
observations were taken in the schools, but results are not reported.
It is reported that it was determined that indoor and outdoor sulfur
dioxide, soiling index, and suspended particulate levels measured
over the 24-hour or 4-hour period directly preceding pulmonary
function tests did not consistently correlate with the test values.
Details of this lack of correlation are not given, but it was concluded
that "ventilatory performance of children thus did not appear to be
acutely affected by variations in pollutant levels on the day of the
test." Possible exposures over intermediate periods, say three days or
one week, prior to testing were not considered. Conclusions seem to be
based on possible long-period exposures, probably over a lifetime.
Concentrations of sulfur dioxide were low (less than 52 ng/m?) in all
areas, so health effects were attributed to particulate pollutants
independent of atmospheric levels of gaseous sulfur dioxide.
Average sulfate levels during the period of the study were observed
to be between 8.9 and 10.1 itg/m*, in the polluted lower middle white
community, but previous average exposure was estimated to be 10.7
to 12.1 pg/m3, based on the National Air Surveillance Network station.
The average suspended sulfate level in the clean white sectors was 8.3
Mg/m3, a relative difference of 13 percent. (The largest differences in
area exposure were in the concentrations of suspended particulates.
Levels of total suspended particulates were J31 Mg/m* in polluted sec-
tors and 61 to 92 MgM3 io clean sectors.
In reading this paper one wonders about the psychological inter-
action between the children and the team members administering the
tests, who could anticipate the outcome of the experiment. The curves
for the black children in Figure 6.1.3, are particularly interesting.
A-35
-------
Appendix B - Chapter 14 PM/SO
APPENDIX B
Qualitative Community Health Epidemiology Studies of
Particulate Matter and Sulfur Oxides (PM/SO ) Morbidity Effects
Contents
Table B-l. Qualitative Studies of Morbidity Effects
Associated with Acute PM/SO Exposures
X
Table B-2. Qualitative Studies of Air Pollution and
Prevalence of Chronic Respiratory Symptoms and
Pulmonary Function Declines
Table B-3. Qualitative Association of Geographic Differences
in Mortality with Residence in Areas of Heavy Air
Pollution
SOXGR3/A B-l 2-14-81
-------
Appendix B - Chapter 14 PM/SO>
TABLE B-l. QUALITATIVE STUDIES OF MORBIDITY EFFECTS ASSOCIATED WITH ACUTE EXPOSURES
TO PARTICULATE MATTER AND SULFUR OXIDES
Study
Characteristics
Findings
Levy et al. (1977)
Zeidberg et al.
(1961)
Cowan et al.
(1963)
Greenberg et al.
(1964)
Wei 11 et al. (1964)
Carroll (1968)
Phelps (1965)
and Meyer (1976)
Glasser et al.
(1967)
Chiaramonte
et al. (1970)
Hospital admissions for respira-
tory disease in Hamilton,
Ontario, correlated with
sulfur oxide/particulate air
pollution index.
Study during 1 year of 49 adults
and 34 children with asthma in
Nashville, Tenn.
History of asthma, and skin tests
of University of Minnesota
students, in relation to dust
from nearby grain elevator.
New York City hospital emergency
room visits for asthma in -
month of September.
Retrospective study of emergency
room visits to New Orleans
Charity Hospital.
"Tokyo-Yokohama asthma" in
American servicemen stationed
in Japan after World War II.
Emergency room visits in seven
New York city hospitals during
the November 1966 air pollution
episode.
Emergency room visits at a
Brooklyn hospital during a
November 1966 air pollution
episode.
Increased hospital admissions on
heavy pollution days, except at
one hospital far removed from
major pollution sources.
Doubling of asthma attack rates
in persons living in more S02
polluted neighborhoods. No
adjustment for demographic or
social factors.
Significant association between
grain-dust particulate matter
exposure and asthma attacks.
Emergency room visits strongly
associated with onset of cold
weather but not with degrees of
air pollution during the one
month of study-
Periodic "epidemics" of asthma
in New Orleans could not be
traced to any common pollutant
exposure.
Disease primarily in smokers
attributed to allergic response
to atmospheric substances that
could not be characterized.
Patients improved after leaving
the area and were immediately
affected on return. Some had
long-term effects afterwards.
Increased emergency room visits
for asthma in three of seven
hospitals studied.
Statistically significant
increase in emergency room
visits for asthma and for
all respiratory diseases, con-
tinuing to 3 days after the
peak air pollution concen-
trations.
SOXGR3/A
B-2
2-14-81
-------
TABLE B-l (continued).
Appendix B - Chapter 14 PM/SO
Study
Characteristics
Findings
Derrick (1970)
Rao (1973)
Nighttime emergency room visits
for asthma in Brisbane,
Australia.
Pediatric emergency room visits
for asthma at Kings County
Hospital, Brooklyn, October
1970-March 1971.
Emergency room visits for
asthma at a hospital in
Harlem and in Brooklyn,
September-December 1970 and
September-December 1971.
Sulz et al. (1970) Hospitalizations for asthma
(1956-61) and for eczema (1951-61)
in Erie County NY. Attack rates
of patients stratified into air
pollution/social class categories.
Goldstein and
Black (1974)
Dohan and Taylor
(I960),
Dohan (1961)
and Ipsen et al.
(1969)
McCarroll et al.
(1967)
Mountain et al.
(1968)
Thompson et al.
(1970)
Cassell et al.
(1969, 1972)
Lebowitz et al.
(1972, 1977)
Ministry of Pen-
sions and National
Insurance (1965)
Weekly industrial absenteeism
rates in women RCA workers in
several locals, 1957-63.
Frequency of cough and eye
irritation in a New York
population living close to an
air monitoring station.
Negative correlation between
asthma visits with degrees
of smoke shade.
Negative correlation of asthma
visits with degrees of smoke
shade. Lack of temperature
adjustments. Considerable
distance of hospital district
from air monitoring stations.
Temperature adjusted asthma
rates positively correlated with
S02 values in Brooklyn but not
not in Harlem. In 1971 period,
50-90% increase in asthma
visits on 12 days of heaviest
pollution.
Area gradients in asthma and
eczema hospitalization rates,
adjusted for social class dif-
ferences, corresponded to the
air pollution gradient. Metero-
logical differences between areas
not analyzed.
Correlations with sulfation
explained by temperature
and season.
Maximal effect on cough fre-
quency occurred 1 or 2 days
after peak air pollution
concentrations, and cold
incidence and prevalence
correlates with S02 and Cons
levels independent of weather.
Incidence survey of worker in- Incapacity due to bronchitis
capacity from bronchitis and other correlated with winter concen-
illness in representative samples trations of smoke and S02 in
throughout Britain, 1961/1962. each of four 10-year age groups.
Socioeconomic and other
characteristics of the areas
may have contributed to the
associations.
SOXGR3/A
B-3
2-14-81
-------
TABLE B-l (continued).
Appendix B - Chapter 14 PM/SO>
Study
Characteristics
Findings
Lebowitz et al.
(1974)
Emerson (1973)
Carnow et al.
(1969)
Burrows et al.
(1968)
Kalpazanov et al
(1976)
Kevany et al.
(1975)
Sterling et al.
(1966, 1967)
Acute pulmonary function changes
in normal children in a copper
smelter town.
Weekly spirometry on bronchitis
patients in London, 1969-71.
Daily symptoms in chronic bron-
chitis patients in Chicago,
1960s.
Daily symptoms in chronic bron-
chitis patients in Chicago, 1960s.
Daily incidence of influenza in
Sofia, Bulgaria, 1972, 1974/75.
Cardio-respiratory hospital
admissions in Dublin, 1972-73.
Hospital admissions by disease
in Los Angeles with measures
of various pollutants.
Verma et al. (1969) NYC insurance workers'
absenteeism.
Burn and Pemberton Absenteeism among workers due to
(1963) bronchitis in Salford, England.
Heimann (1970)
Gregory (1970)
Acute morbidity and mortality in
Boston episodes, 1955-66.
Sickness abseenteeism for
Sheffield steelworkers in
1950s.
Pulmonary function decreased
with increasing air pollution
especially after exercise.
Temperature was controlled.
No correlation with air pollution
levels.
Patients over 55 with moderate-
severe bronchitis had increased
symptoms correlated with in-
creased S02 levels.
No relation of symptoms with
S02 when data were adjusted
for temperature and season.
Incidence was significantly
correlated with S02 and dust.
Low but significant correlations
between cardiovascular admissions
and S02/BS in winters.
Significant decrease of respira-
tory admissions with decreasing
S02, though S02 was low. Other
pollutants and weather may have
been more important.
Respiratory disease absenteeism
correlated with S02, controlled
for temperature and season.
Significantly correlated with S02.
Respiratory patient visits
higher, but mortality wasn't
during episodes.
Correlation of weekly absences
with SOx/TSP.
Gervois et al.
(1977)
Daily sickness absence of
French workers in 2 areas of
Northern France in winter
period.
Association found in
one town after adjusting
for temperature.
Monitoring method unknown.
SOXGR3/A
B-4
2-14-81
-------
Appendix'B - Chapter 14 PM/SO
TABLE B-l (continued).
Study
Characteristics
Findings
Lawther et al.
(1973, 1974a,b)
Ramsey (1976)
Stebbings et al.
(1976, 1979)
Day-to-day changes in ventilatory
function of a small group of
normal adult subjects and 2
bronchitics in London.
Pulmonary function in 7 male non-
smoking asthmatics (ages 19-21)
daily over 3 months.
Acute pulmonary function in
children after a pollution
episode in Pittsburgh.
After multiple regression
analysis to remove effects of
time trend, S02 concentrations
explained the largest
proportion of variance in peak
flow rates. Clearest
associations were shown after
exercise in periods of heavy pol-
lution. In some subjects it
was difficult to detect any
consistent effects of pollution.
Multiple regressions showed
significant correlation of some
tests in 5 subjects but weather
variables, but not with TSP or S02.
Continued decline seen during very
very short periods of study.
"Sensitive" subgroup defined by
improvement during period.
SOXGR3/A
B-5
2-14-81
-------
Appendix B - Chapter 14 PM/SOX
TABLE B-2. QUALITATIVE STUDIES OF AIR POLLUTION AND PREVALENCE OF CHRONIC
RESPIRATORY SYMPTOMS AND PULMONARY FUNCTION DECLINES
Study
Characteristics
Findings
Fairbairn and
Reid (1958)
Mork (1962)
Deane et al.
(1965)
Hoi land and Reid
(1965)
Cederlof (1966)
Hrubec et al.
(1973)
Bates et al.
(1962, 1966)
Bates (1967)
Comparison of respiratory illness
among British postmen living
in areas of heavy and light
pollution.
Questionnaire and ventilatory
function tests of male trans-
port workers 40-59 years of age
in Bergen, Norway and London,
England.
Questionnaire and ventilatory
function survey of outdoor
telephone workers 40-59 years
of age on the west coast of U.S.
Chronic respiratory symptom
prevalence in large panels of
twins in Sweden and in the
U.S. Index of air pollution
based on estimated residential
and occupational exposures
to S02, particulates, and CO.
Comparison of symptom prevalence,
work absences, and ventilatory
function in Canadian veterans
residing in 4 Canadian cities.
Sick leave, premature
retirement, and death
due to bronchitis or
pneumonia were closely
related to pollution
index based on visibility.
Greater frequency of
symptoms and lower
average peak flow rates
in London. Differences
were not explained by
smoking habits or socio-
economic factors.
No differences in symptom
prevalence between
San Francisco and
Los Angeles workers,
although particulate con-
centrations were approxi-
mately twice as high in
Los Angeles.
Increased prevalence of
respiratory symptoms,
adjusted for smoking and
age, a larger volume of
morning sputum and a lower
average ventilatory function
in London workers, and in
the English compared with
American workers.
Increased prevalence of
respiratory symptoms in
twins related to smoking,
alcohol consumption,
socioeconomic character-
istics, and urban residence,
but not to indices of air
pollution.
Lower prevalence of symptoms
and work absences and better
ventilatory function in
veterans living in the least
polluted city.
SOXGR3/A
B-6
2-14-81
-------
TABLE B-2 (Continued).
Appendix B - Chapter 14 PM/SO
Study
Characteristics
Findings
Bates (1973)
Yashizo
(1968)
Winkelstein and
Kantor (1969)
Ishikawa et al.
(1969)
Fujita et al.
(1969)
Reichel, (1970)
Ulmer et al. (1970)
10-year follow-up study of
Canadian veterans initially
evaluated in I960, and
followed at yearly intervals
with pulmonary function tests
and clinical evaluations.
Bronchitis survey of 7 areas of
Osaka, Japan, 1966, among
adults 40 years of age and over.
Survey of respiratory symptoms
in a random sample of white
women in Buffalo, New York.
Comparison of lungs obtained at
autopsy from residents of
St. Louis and Winnipeg.
Prevalence survey (Medical
Research Council questionnaire)
of post office employees in
Tokyo and adjacent areas, 1962
and re-surveyed in 1967.
Respiratory morbidity prevalence
surveys of random samples of
population in 3 areas of West
Germany with different degrees
of air pollution.
Least decline in pulmonary
function with age in veterans
from least polluted city.
Bronchitis rates, standardized
for sex, age, and smoking
were greater among men and
women in the more polluted
areas. Bronchitis rates
followed the air pollution
gradient.
In nonsmokers 45 years of age
and over, and among smokers
who did not change residence,
respiratory symptoms were
correlated with particulate
concentrations obtained in
the neighborhood of residence.
No association of symptom pre-
valence with S02 concentrations.
Autopsy sets, matched for age,
sex and race, showed more
emphysema in the more polluted
city. Autopsied groups may
not reflect prevalence of
disease in general population.
Two-fold increase over time in
prevalence of cough and sputum
production in same persons,
irrespective of smoking habits.
Change was attributed to
increasing degrees of air
pollution.
No differences in respiratory
morbidity, standardized for
age, sex, smoking habits,
and social conditions,
between populations living
in the different areas.
SOXGR3/A
B-7
2-14-81
-------
TABLE B-2 (Continued).
Appendix B - Chapter 14 PM/SO>
Study
Characteristics
Findings
Nobuhiro et al.
(1970)
Comstock et al.
(1973)
Speizer and
Ferris
(1973a,b)
Linn et al.
(1976)
Prindle et al.
(1963)
Watanabe (1965)
Anderson and
Larsen
(1966)
Chronic respiratory symptom
survey of high and low exposure
areas of Osaka and Ako City,
Japan.
Repeat survey in 1968/1969 of east
coast telephone workers and of
telephone workers in Tokyo.
Comparison of respiratory
symptoms and ventilatory
function in central city and
suburban Boston traffic police-
men.
Respiratory symptoms and function
in office working population
in Los Angeles and San Francisco,
1973.
Comparison of respiratory
disease and lung function
in residents of Seward and
New Florence, PA.
Peak flow rates in Japanese
school children residing in
Osaka.
Peak flow rates and school
absence rates in children 6-7
years of age from 3 towns in
British Columbia.
Higher prevalence of chronic
respiratory symptoms in more
polluted areas.
After adjustment for age and
smoking, no significant
association of respiratory
symptom prevalence with
place of residence.
Slight but insignificant
increase in symptoms pre-
valence among non-smokers
and smokers, but not
ex-smokers, from the central
city group. No group
differences in ventilatory
function.
No significant difference in
chronic respiratory symptom
prevalence between cities;
women in the more polluted
community more often reported
nonpersistent (<2 years)
production of cough and sputum.
Increased airway resistance in
inhabitants of more polluted
community. Differences in
occupation, smoking, and
socioeconomic level could
account for these differences.
Lower peak flow rates in
children from more polluted
communities. Improved peak
flow rates when air pollution
levels decreased.
Significant decrease in peak
flow rates in 2 towns
affected by Kraft pulp
mill emissions. No effect
on school absences.
Ethnic differences were
not studied.
SOXGR3/A
B-8
2-14-81
-------
TABLE B-2 (Continued).
Appendix B - Chapter 14 PM/SO
Study
Characteristics
Findings
Collins et al.
(1971)
Toyama et al.
(1966)
Tsunetoshi et al.
(1971)
Suzuki et al.
(1978)
Yoshida et al.
(1976)
Kagawa and Toyama
(1975)
Kagawa et al.
(1975)
Zaplatel et al.
(1973)
Holland et al.
(1969)
Col ley and
Holland (1967)
Death rates in children 0-14
years of age, 1958-1964,
in relation to social and air
pollution indices in 83 county
boroughs of England and Wales.
Respiratory symptoms and
spirometry in an agricultural
area of Japan, 1965, 678 subjects
ages 40-65, by smoking and sex.
Prevalence survey of chronic bron-
chitis in 9 areas of Osaka and
Hyogo Pref., Japan, in residents
ages 40 or more.
Prevalence survey of respiratory
symptoms in housewives ages 30
or over in Japan.
Prevalence of asthma in school-
children in areas of Japan.
Respiratory function of Tokyo
schoolchildren.
Pulmonary function in school-
children in Czechoslovakia.
Chronic bronchitis prevalence
in 2365 families in 2 London
suburbs, 1965.
Partial correlation analysis
suggested that indices of
domestic and industrial
pollution account for a
greater part of the area
differences in mortality
from bronchopneumonia and
all respiratory diseases
among children 0-1 year
of age.
Much lower prevalence rates and
and higher lung function than
elsewhere. S02<0.01 ppm,
mean TSP of 90
Multiple regression analysis
indicated increasing pre-
valence, adjusted for age, sex
and smoking, corresponding
to the area gradient of air
pollution.
Prevalence rates correlated
with various pollutants,
especially in older smokers.
Increased prevalence rates
in areas with higher sulfa-
tion rates.
Correlation seen with various
pollutants after controlling
for temperature.
Some children living in areas
of high air pollution had
functional abnormalities.
More symptoms in previously
polluted area in mothers and
in children, controlling
for smoking, social class, a
area of residence, place of
work, overcrowding, family
size and genetic factors.
SOXGR3/A
B-9
2-14-81
-------
TABLE B-2 (Continued).
Appendix B - Chapter 14 PM/SO>
Study
Characteristics
Findings
Holland et al.
(1969a,b)
Bennet et al.
(1973)
Col ley and Reid
(1970)
Ramaciotti et al.
(1977)
Bouhuys et al.
(1978)
Biersteker and
van Leeuwen
(1970a,b)
Prevalence of respiratory symptoms,
degrees of ventilatory function,
and past histories of respiratory
illness in more than 10,000 school
children 5-16 years of age re-
siding in 4 different areas of
northwest London, 1964/1965.
Greatest differences among areas
were found in degrees of air
pollution.
Respiratory disease prevalence
in more than 10,000 children
6-10 years old, England and
Wales, 1966.
Yoshii et al.
(1969)
Bronchitis symptoms and peak flow
in 1182 men in Geneva in relation
to S02, smoke and N0? at resi-
dence, smoking, and age, 1972-76.
Respiratory symptoms in an urban
and a rural Connecticut com-
munity, adjusting for sex, race,
age, smoking, occupation and
previous residence.
Peak flow rates in 935 school-
children living in 2 districts
of Rotterdam, one relatively
affluent and having good air
quality (40 ug of smoke per m3
and 120 ug of S02 per m3) and
the other less affluent, and
having 50% higher concentrations
of smoke and S02.
Chronic pharyngitis and histo-
pathological changes in 6th
grade children in 3 areas of
Yokkaichi, Japan.
Childhood smoking habits and
degree of air pollution were
found to have the greatest
- influence on respiratory
symptom prevalence and venti-
latory function. Social class,
family size, and past history
of respiratory disease also
contributed. All factors operated
independently and exerted their
effects additively.
Definite gradient of past
bronchitis and current cough
from lowest rates in rural
areas to highest rates in
the most heavily polluted areas.
Differences were more clear
in children of semi-skilled
and unskilled workers. No
effect on upper respiratory
ilIness rates.
Regression analysis showed
independent effect of S02,
smoke and N02 after con-
trolling for smoking and
age.
Communities had low concen-
trations of TSP and S02,
(<64 and 14 ug/m3, resp.)
No differences were found
among smokers. More asthma
in rural area.
No significant area differences
in peak flow, adjusted for
height and weight. Signifi-
cantly more childhood bronchitis
in more polluted district, but
differences were judged to be
due to poor living conditions,
because low pollution area of
of higher class residences.
Correlation of both with sulfation
rates seen.
SOXGR3/A
B-10
2-14-81
-------
TABLE B-2 (Continued).
Appendix B - Chapter 14 PM/SO
Study
Characteristics
Findings
Wailer et al.
(1974)
Hammer et al.
(1976)
Ventilatory function and respira-
tory symptom prevalence among
18-year-olds born in London
just before and after the smog
episode of 1952.
Retrospective survey of lower
respiratory illness in children
0-12 years of age living in 4
New York City area communities,
1969-1972.
Chapman et al.
(1973)
Retrospective survey of chronic
respiratory disease (CRD) rates
in elementary and high school
children living in four Utah
communities, 1970.
No differences were found between
the 2 groups. Both were exposed
to high degree of pollution during
the 1950s. History of lower
respiratory illness in childhood
had major influence on current
symptoms and ventilatory function.
Rates of total respiratory illness
croup, bronchitis, and other
chest infections were significantly
higher among black and white
children residing in communities
with heavier air pollution.
Differences in family size,
crowding, parental smoking,
and social class could not
explain the findings.
CRD prevalence rates reflected
community pollutant level
differences, with statistically
significant differences in CRD
rates between high and low
areas within sex and smoking
status groups. Communities
differed mainly in S02 levels,
in the presence of similar TSP
levels, suggesting qualitative
relationship between CRD effects
and elevated S02 levels.
Errors in aerometry measurements
around period of CRD rate
measurement and limitations
of retrospective estimation
of earlier exposure levels
preclude determination of
quantitative health effects/air
pollution relationships.
SOXGR3/A
B-ll
2-14-81
-------
Appendix B - Chapter 14 PM/SC^
Qualitative Community Health Epidemiology Studies of
Particulate Matter and Sulfur Oxides (PM/SO ) Mortality Effects
)\
Contents
Table B~3. Qualitative Association of Geographic Differences
in Mortality with Residence in Areas of Heavy Air
Pollution
SOXGR3/A B-12 2-14-81
-------
Appendix B - Chapter 14 PM/SO
TABLE B-3. QUALITATIVE ASSOCIATION OF GEOGRAPHIC DIFFERENCES IN MORTALITY
WITH RESIDENCE IN AREAS OF HEAVY AIR POLLUTION
Study
Characteristics
Findings
Pemberton and
Goldberg (1954)
1950-1952 bronchitis mortality
rates in men 45 years of age
and older in county boroughs
of England and Wales.
Stocks (1958, 1959, Bronchitis mortality, 1950-1953,
1960a,b)
Gorham (1958, 1959)
Gore and Shaddick
(1958) and
Hewitt (1956)
Hagstrom et al.
(1967) Zeidberg
et al. (1967)
Sprague and
Hagstrom (1969)
Lepper et al.
(1969)
Jacobs and
Landoc (1972)
Morris et al.
(1976)
in urban and rural areas of
Britian, with adjustments for
population density and social
index.
1950-1954 deaths, 53 counties
of England, Scotland, and
Wales.
Mortality in London, 1954-1958
and in 1950-1952, respectively.
1949-1960 deaths for each cause
in Nashville, Tenn., categor-
ized by census tract into 3
degrees of air pollution and
3 economic classes (levels
not accurately determined).
1964/1965 mortality rates in
Chicago census tracts strati-
fied by socioeconomic class and
S02 concentration.
1968/1970 mortality rates
in Charleston, S.C.,
industrial vs. non-indus-
trial areas.
1960-72 mortality rates
compared to 1959-60 air
pollution levels.
Sulfur oxide concentrations
(sulfation rates) were con-
sistently correlated with
bronchitis death rates in the
35 county boroughs analyzed.
Significant correlation of mor-
tality from bronchitis and
pneumonia among men, and from
bronchitis among females, with
smoke density.
Bronchitis mortality was strongly
correlated with acidity of
winter precipitation.
Duration of residence in London
significantly correlated with
bronchitis mortality, after
adjusting for social class.
Within the middle social class,
total respiratory disease
mortality, but not bronchitis
and emphysema mortality, were
significantly assoicated with
sulfation rates and social index.
White infant mortality rates
were significantly related to
sulfation rates.
Increased respiratory disease
death rates in areas of inter-
mediate and high S02 concen-
tration, within a socioeconomic
status, without a consistent
mortality gradient between the
areas of intermediate and high
S02 concentration.
Higher total and heart disease
mortality rates in industrial
area.
Mortality higher in smokers
with lower air pollution
exposures.
SOXGR3/A
B-13
2-14-81
-------
TABLE B-3 (Continued).
Appendix B - Chapter 14 PM/SO>
Study
Characteristics
Findings
Collins et al.
(1971)
Toyama (1964)
Death rates in children 0-14
years of age, 1958-1964,
in relation to social and air
pollution indices in 83 county
boroughs of England and Wales.
Mortality in districts
of Tokyo.
Lindeberg (1968) Deaths in Oslo winters.
US/Canada
Internat. Joint
Commission (1960)
Buck and Brown
(1964)
Winkelstein et al,
(1967),
Winkelstein and
Kantor (1967),
Winkelstein and
Gray (1971)
Zeidberg et al.
(1967)
Mortality, episodic and non-
episodic in Detroit and Windsor
(Canada in 3 areas, 1953.
Partial correlation analysis
suggested that indices of
domestic and industrial
pollution account for a
differences in mortality
from bronchopneumonia and
all respiratory diseases among
children 0-1 year of age.
Bronchitis mortatliy associated
with dustfall (but not cardio-
vascular, pneumonia or cancer
mortality).
Average deaths per week, 1958-65
winter, correlated with pollution.
Respiratory cancer and infant
mortality correlated with
episodic and non-episodic
levels of TSP and SO (as
did morbidity).
Bronchitis mortality in 214 areas Social index and S02 accounted
of Britain, 1955-1959, evaluated
with respect to S02, particulates,
social index, and population
density.
120 census tracts in Buffalo
stratified into 4 degrees of
particulate pollution and cross-
stratified into 5 economic
classes.
1949-1960 deaths for each cause
in Nashville, Tenn., categorized
by census tract into 3 degrees of
pollution and 3 economic classes.
for 36 percent of the variation
in bronchitis mortality within
county and noncounty boroughs
and in urban districts. Within
London boroughs, social index
was the most important factor.
Within an economic class,
death rates of white male 50-69
years of age, for all causes
and for chronic respiratory
disease corresponded to the
gradient of particulate, but
not S02 pollution.
Within the middle social class,
total respiratory disease
mortality, but not bronchitis
and emphysema mortality, were
significantly associated with
sulfation rates and social index.
White infant mortality rates
were significantly related to
sulfation rates.
SOXGR3/A
B-14
2-14-81
-------
Appendix B - Chapter 14 PM/SO
TABLE B-3 (Continued).
Study
Characteristics
Findings
Burn and Pemberton
(1963)
Wicken and Buck
(1964)
Kevany et al.
(1975)
Watanabe and Kaneko
(1971)
1950/59 deaths from all causes,
bronchitis and lung cancer in 3
polluted areas of Sal ford, U.K.
1952-62 deaths from bronchitis
and lung cancer in areas of
northeast England.
1970-73 deaths from various
causes in Dublin, Ireland.
1965-66 mortality by cause in 3
areas of Osaka, Japan.
The gradient of mortality from
all causes and from bronchitis
and lung cancer followed the
pollution gradient.
Differences in death rates
between areas were correlated
with their differences in air
pollution.
Partial correlation analysis
was significant for air
pollutants and some specific
causes of death.
A stepwise increase in circu-
latory mortality was related
to air pollution independent
of temperature.
SOXGR3/A
B-15
2-14-81
-------
Appendix C - Chapter 14 PM/SO
APPENDIX C
OCCUPATIONAL HEALTH STUDIES ON PARTICULATE
MATTER AND SULFUR OXIDES
SOXGR3/J C-l 2-16-81
-------
Appendix C - Chapter 14 PM/SO>
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Andersen, I., P. Camner, P. L. Jensen, K. Philipson, and D. F.
Proctor. A Comparison of Nasal and Tracheobronchial
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Anderson, I. B., G. R. Lundgvist, D. F. Proctor, and D. L.
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in a Smelter. II. Indices of Chest Disease. J.O.M.
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C-2 2-14-81
-------
Appendix C - Chapter 14 PM/SO
Balchum, 0. J. Environment in Relation to Respiratory Disease.
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1978. , «
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c_3 2-14-81
-------
Appendix C - Chapter 14 PM/SOX
Camner, P., P. Hellstrom, M. Lundborg, and X. Philipson. Lung
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D. Enarson, and S. Grzybowski. A Follow-Up Study of the
Grain Elevator Workers in the Port of Vancouver. Amer.
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Chan-Yeung, M., M. Schulzer, L. MacLean, E. Dorken, and S.
Grzybowski. Epidemiologic Health Survey of Grain Elevator
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1980.
0-4 2-14-81
-------
Appendix C - Chapter 14 PM/SOX
Crosbie, W. A., R. A. P. Cox, J. V. Lcblanc, and D. Cooper.
Survey of Respiratory Disease in Carbon Black Workers in
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Decoufle, P., and D. J. Wood. Mortality Patterns Among Workers
in a Gray Iron Foundry. Amer. J. Epidemiol. 109:667,
1979.
Decoufle, P., J. W. Lloyd, and L. G. Salvin. Causes of Death
Among Construction Machinery Operators. J.O.M. 19:
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Desman, J. A., D. J. Cotton, B. L. Graham, K. Y. Robert, F.
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Protection Agency, Research Triangle Park, NC, December 1979.
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2-14-81
C-5
-------
Appendix C - Chapter 14 PM/SO>
Ferris, B. G., Jr., F. E. Speizcr, J. D. Spengler, D. Dockery,
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C-6 2-14-81
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Appendix C - Chapter 14 PM/SOx
Hackney, J. D. , W. S. Linn, J. C. Mohlcr, E. E. Pedersen, P.
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C-7
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Appendix C - Chapter 14 PM/SOX
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C-8 2-14-81
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Appendix C - Chapter 14 PM/SOX
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Lowe, C. R., P. L. Pelmear, B. Campbell, R. A. N. Hitchens,
T. Khosla, and T. C. King. Bronchitis in Two Integrated
Steel Works. I. Ventilatory Capacity, Age, and Physique
of Non-Bronchitic Men. Br. J. Prev. Soc. Med., 22:1-11,
1968.
McEuen, D. D., and J. L. Abraham. Particulate Concentrations in
Pulmonary Alveolar Proteinosis. Environ. Res. 17:334-339,
1978.
Milham, S. Mortality in Aluminum Reduction Plant Workers. J.
Occup. Med., 21:475-480, 1979-
Mitchell, C. A., R. S. F. Schilling, and A. Bouhuys. Community
Studies of Lung Disease in Connecticut: Organization and
Methods. Am. Jour, of Epid. 103:212-225, 1976.
Morgan, W. K. C. Industrial Bronchitis. Brit. J. Ind. Med.
35:285-291, 1978.
Morgan, W. K. C. Magnetite Pneumoconiosis. J.O.M. 20:762-763,
1978.
Mushak, P., W. Galke, V. Hasselblad, and L. D. Grant. Health Assessment
Document for Arsenic (External Review Draft). U.S. Environmental
Protection Agency, Research Trianlge Park, NC, April 1980.
A W J M. Peters, D. H. Wegman, and L. J. Fine. Pulmo-
, A Wy' J'c«:on .n G^anite Dust Exposure: A Four-Year
Follow-up. Amer. Review Resp. Disease 115:769-776, 1977.
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Appendix C - Chapter 14 PM/SO,
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Beryllium. DHHS (NIOSH)
72-10268, U.S. Department of Health and Human Services, Washington, DC,
1972.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Coke Oven Emissions.
DHHS (NIOSH) 73-11016, U.S. Department of Health and Human Services,
Washington, DC, 1973.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Inorganic Mercury. DHHS
(NIOSH) 73-11024, U.S. Department of Health and Human Services,
Washington, DC, 1973.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Sulfur Dioxide. DHHS
(NIOSH) 74-111, U.S. Department of Health and Human Services, Washington,
DC, 1974.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Sulfuric Acid. DHHS
(NIOSH) 74-128, U.S. Department of Health and Human Services, Washington,
DC, 1974.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Ammonia. DHHS (NIOSH)
74-136, U.S. Department of Health and Human Services, Washington, DC,
1974.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Cotton Dust. DHHS
(NIOSH) 75-118, U.S. Department of Health and Human Services, Washington,
DC, 1975.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Inorganic Arsenic.
(Revised). DHHS (NIOSH) 75-149, U.S. Department of Health and Human
Services, Washington, DC, 1975.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Inorganic Fluoride. DHHS
(NIOSH) 76-103, U.S. Department of Health and Human Services, Washington
DC, 1973.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Zinc Oxide. DHHS (NIOSH)
76-104, U.S. Department of Health and Human Services, Washington DC
1974.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Chromium VI. DHHS
(NIOSH) 76-129, U.S. Department of Health and Human Services Washinaton
DC, 1976. M '
0-10 2-14-81
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Appendix C - Chapter 14 PM/SO^
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Nitric Acid. DHHS
(NIOSH) 76-141, U.S. Department of Health and Human Services, Washington,
DC, 1976.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Oxides of Nitrogen. DHHS
(NIOSH) 76-149, U.S. Department of Health and Human Services, Washington,
DC, 1976.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Cadmium. DHHS (NIOSH)
76-192, U.S. Department of Health and Human Services, Washington, DC,
1976.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Hydrogen Cyanide and
Cyanide Salts. DHHS (NIOSH) 77-108, U.S. Department of Health and Human
Services, Washington, DC, 1977.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Organotin Compounds.
DHHS (NIOSH) 77-115, U.S. Department of Health and Human Services,
Washington, DC, 1977.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Inorganic Nickel. DHHS
(NIOSH) 77-164, U.S. Department of Health and Human Services, Washington,
DC, 1977.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Asbestos. DHHS (NIOSH)
77-169, U.S. Department of Health and Human Services, Washington, DC,
1977.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Refined Petroleum
Solvents. DHHS (NIOSH) 77-192, U.S. Department of Health and Human
Services, Washington, DC, 1977.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Vanadium. DHHS (NIOSH)
77-222, U.S. Department of Health and Human Services, Washington, DC,
1977.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Tungsten and Cemented
Tungsten Carbide. DHHS (NIOSH) 77-227, U.S. Department of Health and
Human Services, Washington, DC, 1977.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Asphalt Fumes. DHHS
(NIOSH) 78-106, U.S. Department of Health and Human Services, Washington,
DC, 1978.
C-ll 2-14-81
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Appendix C - Chapter 14 PM/SOX
National Institute for Occupational Safety and Health. Criteria fora
recommended standard: Occupational Exposure to Coal Tar Products. DHHS
(NIOSH) 78-107, U.S. Department of Health and Human Services, Washington,
DC, 1978.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Inorganic Lead. DHHS
(NIOSH) 78-158, U.S. Department of Health and Human Services, Washington,
DC, 1978.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposures in Coal Gasification
Plants. DHHS (NIOSH) 78-191, U.S. Department of Health and Human
Services, Washington, DC, 1978.
National Institute for Occupational Safety and Health. Criteria for a
recommended standard: Occupational Exposure to Carbon Black. DHHS
(NIOSH) 78-204, U.S. Department of Health and Human Services, Washington,
DC, 1978.
°ffiCcDA°cfnn/RoeS-,e-Jarch and Deve1°Pment. Air Quality Criteria for Lead.
hPA-600/8-77-017, U.S. Environmental Protection Agency, Washington, DC,
December 1977.
Ogden, T. L. and J. L. Burkett. An Inhalable Dust Sample for
Measuring the Hazard from Total Airborne Particulate.
Ann. Occup. Hyg. 21:41-50, 1978.
Ogden, T. L. and J. L'. BurXett. The Human Head as a Dust Samp-
ler. In: Inhaled Particles IV. W- H. Walton, ed.
Pergamon Press, Oxford. 1977. p. 93'.''
Ohman, K. H. G. Prevention of Silica Exposure and Elimination
of Silicosis. AIHAJ 39^847-859, 1978.
Farobeck, P. S., and R. A. Jankowski. Assessment of the Respi-
rable Dust Levels in the Nation's Underground and Surface
Coal Mining Operations. AIHAJ 40:910-915, 1979.
Favia, D., and M. L. Thomson. The Fractional Deposition of In-
haled 2 and 5 pro Particles in the Alveolar and Tracheo-
bronchial Regions of the Healthy Human Lung. Ann. Occup.
Hyg. 19:109-114, 1976.
Pham, Q. T., R. Beigbeder, R. Deniau, P. Sadoul, and J. M. Mur.
Methodology of an Epidemiological Survey in the Iron-Ore
Mines of Lorraine. Research into the Long-term Effect of
Potentially Irritant Gases on the Pulmonary System. Amer.
Occup. Hyg. 19:33-35, 1976.
Plumlee, L., S. Coerr, H. L. Needleraan, and R. Albert. Panel
Discussion: Role of High Risk Groups in the Derivation of
Environmental Health Standards. Environ. Health Perspect.
29:155-159, 1979.
Reid, L. M. Introductory Remarks: Session on Disease Conditions
Predisposing Afflicted Individuals to the Toxic Effects of
Pollutants. Environ. Health Perspect. 29:127-129, 1979.
C-12 2-14-81
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Appendix C - Chapter 14 PM/SO>
Rencher, A. c., M. W. Carter, and D. W. McKee. A Retrospective
Epidemiological Study of Mortality at a Large Western
Copper Smelter. J.O.M. 19:754-58, 1977.
35:181-186. o 4- Arch- Environ. Health
Rockette, H.E. Cause Specific Mortality of Coal Miners. J.O.M.
19:795—801, 1977.
Roger, J., and K. A. Paton. Reading Chest Radiographs for Pneumo-
coniosis by Computer. Brit. J. Ind. Med. 32:267-272,
X 7 / W •
Rynbrandt, D., and J. Kleinerman. Nitrogen Dioxide and Pulmonary
Proteolytic Enzymes: Effect on Lung Tissue and Macro-
phages. Arch. Envr. Health. 32:165-73, 1977.
Sackner, M. A., M. Broudy, A. Friden, G. Villavicencio, and
M. A. Cohn. Effects of Breathing Nitrate and Sulfate Mi-
croaerosols for Four Hours on Pulmonary Function of Normal
Adults. Amer. Rev. Resp. Dis. 121:225, 1980 (Supplement).
Sackner, M. A., and D. Ford. Effects of Breathing NaCl and
Sulfate Aerosols in High Concentrations for 10 Minutes on
Pulmonary Function of Normal ,and Asthmatic Adults. Amer.
Rev. Resp. Dis. 121:255, 1980 (Supplement).
Sackner, M. A., B. Marchette, S. Birch, R. McDonald, and C. S.
Kim. Effects of Sodium Chloride and Sulfate Aerosols in
High Concentrations on Nasal Airflow Resistance and Nasal
Mucous Velocity of Normal Subjects and Patients with
Allergic Rhinitis. Amer. Rev. Resp. Dis. 121:254, 1980
(Supplement).
Santodonato, J. , P. Howard, D. Basu, S. Lande, J. K. Selkirk, and P. Sheehe.
Health Assessment Document for Polycyclic Organic Matter (Preprint).
EPA-600/9- 79-008, U.S. Environmental Protection Agency, Research Triangle
Park, NC, December 1979.
Saric, M., I. Kalacic, and A. Holetic. Follow-up of Ventilatory
Lung Function in a Group of Cement Workers. Brit. J. Ind.
Med. 33:18-24, 1976.
Saric, M., S. Lucic-Palaic, and R. J. M. Horton. Chronic Non-
specific Lung Disease and Alcohol Consumption. Environ.
Res. 14:14-21, 1977.
Schilling, R. S. F., A. D. Letal, S. L. Hui, G. J. Beck, J. B.
Schoenberg, and A. Bouhuys. Lung Function, Respiratory
Disease, and Smoking in Families. Am. Jour. Epid.
106:274-283, 1977.
C-13 2-14'81
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Appendix C - Chapter 14 PM/SOX
Seeker-Walker, R., P. Miller, R. Slavin, «. Paine, and M.
McCrate. The Effects of Air Pollution and Meteroiogic
Conditions on Daily Lung Function of Health Non-Smoking
Outdoor Workers. Amer. Rev. Resp. Dis. 121:258, 1980
(Supplement).
Severs, R. K. Air Pollution and Health. Texas Rep. Biol. Med.
33:45-83, 1975.
Sharratt, M. T. and F. J. Cerny. Pulmonary Function and Health
Status of Children in Two Cities of Diffemet Air Quality.
Arch. Envr. Health 34:114-119, 1979.
Shaw, D. T., N. Rajendran, and N. S. Liao. Theoretical Modeling
of Fine-Particle Deposition in 3-Dimensional Bronchial
Bifurcations. AIHAJ 39:195-201, 1978.
Sherwin, R. P., M. L. Barman, and J. L. Abraham. Silicate
Pneumoconiosis of Farm Workers. Lab. Invest. 40:576-582,
1979.
Smith, R. M., and V. D. Dinh. Changes in Forced Expiratory Flow
due to Air Pollution from Fireworks. Env. Res. 9:321-331,
1975.
Smith, J. T., J. M. Peters, J. C. Reading, and C. B. Castle.
Pulmonary Impairment from Chronic Exposure to Sulfur
Dioxide in a Smelter. Am. Rev. Resp. Dis. 116:31-39,
1977.
Smith, T. J., W. L. Wagner, and D. E. Moore. Chronic Sulfur
Dioxide Exposure in a Smelter. I. Exposure to S02 and
Dust: 1940-1974. J.O.M., 20:83-87, 1978.
Spengler, J. D., B. G. Ferris, D. W. Dockery, and F. E. Speizer.
Sulfur Dioxide and Nitrogen Dioxide Levels Inside and Out-
side Homes and the Implications on Health Effects Re-
search. Environ. Sci. Technol. 13:1276, 1979.
Stahlhofen, W., J. Gebhart, and J. Heyder. Experimental Determi-
nation of the Regional Deposition of Aerosol Particles in
the Human Respiratory Tract. AIHAJ 41:385-398a, 1980.
Stebbings, J.H. Panel Studies of Acute Health Effects of Air
Pollution. II. A Methodologic Study of Linear Regression
Analysis of Asthma Panel Data. Environ. Res. 17:10-32,
1978.
Sterling, T. D., S. V. Pollack, and J. Weinkam. Measuring the
Effect of Air Pollution on Urban Morbidity. Arch. En-
viron. Health 18:485-494, 1969.
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Appendix C - Chapter 14 PM/SOX
Strahilevitz, M., A. Strahilevitz, and J. E. Miller. Air Pollu-
tants and the Admission Rate of Psychiatric Patients.
Amer. J. Psychia. 136:2, 1979.
Stuart, B. O. Deposition and Clearance of Inhaled Particles.
Environ. Health Perspect. 16:41-53, 1976.
Sweet, D. V., W. E. Crouse, and J. V. Crable. Chemical and
Statistical Studies of Contaminants in Urban Lungs.
SIJAJ 39:515-26, 1978.
Sweet, D. V., W. E. Crouse, J. V. Crable, J. R. Carlberg, and
W. S. Lainhart. The Relationship of Total Dust, Free
Silica, and Trace Metal Concentrations to the Occupational
Respiratory Disease of Bituminous Coal Miners. AIHAJ
35:479-488, 1974.
Tabershaw, I. R. Oxides of Sulfur. J.O.M. 18:360-361, 1977.
Toca, F. M., C. L. Cheever, and C. M. Berry. Lead and Cadmium
Distribution in the Particulate Effluent from a Coal-
Fired Boiler. AIHAJ 34:396-403, 1973.
Utidjian, M. D., M. Corn, B. Dinman, P. F. Infante, P. Seminario.
Panel Discussion: Role of High Rish Groups in Standard
Deviation. Environ. Health Perspect. 29:161-173, 1979.
Valic, F., D. Beritic-Stahuljak, and B. Mark. A Pollow-Up Study
of Functional and Radiological Lung Changes in Carbon-
Black Exposure. Int. Arch. Occup., 34:51-63, 1975.
Vitek, J. Respirable Dust Sampling in Czechoslovak Coal Mines,
AIHAJ 38:247-252, 1977.
Walkonsky, P. M. Pulmonary Effects of Air Pollution. Current
Research. Arch. Envr. Health. 19:586-592, 1969.
Warner, C. G., G. M. Davies, J. G. Jones, and C. R. Lowe.
Bronchitis In Two Integrated Steel Works. II. Sulphur
Dioxide and Particulate Atmospheric Pollution In and
Around the Two Works.
Warren, C. P. W. Lung Disease in Farmers. Cand. Med. Assn. J.
116:391-394, 1977.
Whiting, W. B. Occupational Illnesses and Injuries of California
Agricultural Workers. J.O.M. 17:177-181, 1975.
Wolf, A. F. Occupational Diseases of the Lung. III. Pulmonary
Disease Due to Inhalation of Noxious Gases, Aerosols or
Fumes. Ann. Allergy. 35:165-171, 1975.
Yoshida, K., H. Oshima, and M. Imai. Air Pollution and Asthma in
Yokkaichi. Arch. Environ. Health 13:763-768, 1966.
2-14-81
C-15
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Appendix C - Chapter 14 PM/SO
Yu, C. P., P. Nicolaides, and T. T. Soong. Effect of Random
,i^ay Slzcs on Aerosol Deposition. AIHAJ 40:999-1005,
1979.
Zaidi, S. H. Some Aspects of Experimental Infective Pneumo-
coniosis. AIHAJ 38:239-245, 1977.
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