Draft
Do Not Quote or Cite
External Review Draft No 1
April 1980
Air Quality Criteria
for Particulate Matter
and Sulfur Oxides
Volume IV
Health Effects
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
-------
Draft
Do Not Quote or Cite
External Review Draft No. 1
April 1980
Air Quality Criteria
for Particulate Matter
and Sulfur Oxides
Volume IV
Health Effects
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 to Volume IV
Volume IV of this Criteria Document addresses the effects of sulfur
oxides and particulate matter on health. To understand these effects, however,
one must first appreciate the characteristics of these substances as they
occur in the environment. This prerequisite information may be found in
Volume II, which covers chemical and physical properties, analytical and
measurement techniques, sources and emissions, environmental concentrations
and exposures, and atmospheric transmission.
This volume begins its assessment of health effects by examining
respiratory deposition and biological fate of inhaled aerosols and sulfur
dioxide (Chapter 11). The respiratory system is the principal route of
exposure to airborne particles and gaseous sulfur oxides, viz. SCL. Such
exposure is a function of physicochemical properties of the pollutants as well
as anatomical and physiological features of the exposed organism. Moreover,
exposure consists not only of the inhalation and deposition of substances, but
their movement to other organs, biological transformation, or removal from the
body.
Chapter 12 assesses jjn vitro and j_n vivo studies of toxic effects of
sulfur oxides and particulate matter. In vitro studies focus on specific
mechanisms whereas j_n vivo studies examine morphological and physiological
responses of whole organisms after chronic or acute exposures.
Although animal toxicological studies provide essential information on
the basic mechanisms of the health effects of sulfur oxides and particulate
matter, they are, of course, limited to subjects other than humans. Controlled
ill
-------
human studies, discussed in Chapter 13, provide an important perspective on
the health effects of these pollutants by exposing humans under controlled
laboratory conditions. It has thus been possible to evaluate respiratory and
other responses of humans to a number of specific forms of sulfur oxides and
particulate matter. Human studies are limited, however, to relatively short-
term exposure regimens. For information on long-term exposures, epidemiological
studies must be used.
Chapter 14 evaluates evidence relating certain health indices in selected
populations exposed to ambient conditions. In contrast to controlled experiments
discussed in the two previous chapters, epidemiological studies do not examine
variables under the control of the investigator. That is, they must deal with
variations in pollution as they occur in the real world. Evaluation of such
studies is complicated by differences in study design and conduct, selection
of variables, assessment of pollution exposure, assessment of health status,
and suitability of statistical techniques. Such studies necessarily include
possible confounding variables, but have the advantage of direct relevance to
other human exposures.
The progression from i_n vitro and j_n vivo animal studies to human laboratory
studies to epidemiological studies reflects the trade-offs that must be made
in any analysis of the health effects of environmental pollutants. The more
specific the conditions of exposure and experimental manipulation, the less
general are the results thus obtained; and the more general the conditions of
study, the less precise are the findings that result. Taken as a whole,
however, these various types of studies provide a basis for formulating
conclusions regarding the health effects of sulfur oxides and particulate
matter.
iv
-------
CONTENTS
11. RESPIRATORY DEPOSITION AND BIOLOGICAL FATE OF INHALED AEROSOLS
AND S0? 11-1
11.1 INTRODUCTION 11-1
11.1.1 General Considerations 11~1
11.1.2 Aerosol and S0? Characteristics 11-4
11.1.3 The Respirator^ Tract 11-9
11.1.4 Respiration 11-15
11.2 DEPOSITION IN MAN AND EXPERIMENTAL ANIMALS 11-18
11.2.1 Insoluble and Hydrophobic Solid Particles 11-18
11.2.2 Soluble, Deliquescent, and Hygroscopic Particles . 11-42
11.2.3 Surface Coated Particles 11-44
11.2.4 Gas Deposition 11-45
11.3 TRANSFORMATIONS AND CLEARANCE FROM THE RESPIRATORY TRACT . 11-59
11.3.1 Deposited Particulate Material 11-60
11.3.2 Absorbed S0? 11-74
11.3.3 Particles ahd S09 Mixtures 11-79
11.4 DISCUSSION AND SUMMARY / 11-79
11.5 REFERENCES 11-83
-------
LIST OF FIGURES
Number Page
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 11-10
11-2 Representation of five major mechanisms of deposition of inhaled
airborne particles in the respiratory tract 11-19
11-3 Total and regional deposition fractions in the human respiratory
tract for various sizes of inhaled3airborne spherical particles
with physical density of one ug/cm as calculated by the ICRP Task
Group on Lung Dynamics for breathing rate of 15 breaths per minute
(BPM) and a tidal volume (TV) of 750 ml 11-26
11-4 Total and regional deposition fractions in the human respiratory
tract for various sizes of inhaled.,airborne spherical particles
with physical density of one g/cm as calculated by the ICRP Task
Group on Lung Dynamics for a breathing rate of 15 breaths per minute
(BPM) and a tidal volume (TV) of 1450 ml 11-27
11-5 The range of regional deposition fractions for log-normally
distributed spherical aerosols in human nose breathing at 15
BPM and 1450 ml TV. Geometric standard deviation ranges between
1.2 and 4.5; particle physical density is one g/cm so that MMD =
MMAD 11-28
11-6 Selected data reported for the deposition in the entire respiratory
tract of monodisperse aerosols inhaled through the nose by people
are compared with predicted values calculated by the ICRP Task
Group on Lung Dynamics 11-31
11-7 Selected data reported for the deposition in the respiratory tract
of monodisperse aerosols inhaled through the mouth by people are
compared with predicted values calculated by the ICRP Task Group on
Lung Dynamics 11-32
11-8 Selected data reported for the deposition fraction of monodisperse
aerosols in the human nasopharyngeal (NP) region of the respiratory
tract are plotted against the characteristic term (D Q, where Q
is the average inspiratory flow in 1/min) that contrBfs inertial
impaction; for reference, the calculated value is shown for 15 BPM
at 1450 ml TV 11-33
-------
11-9 Selected data reported for tracheobronchial (TB) deposition of
monodisperse aerosols inhaled through the mouth by people are
compared with predicted values calculated by the 1CRP Task Group
on Lung Dynamics 11-34
11-10 Selected data reported for pulmonary (P) deposition of monodisperse
aerosols inhaled through the mouth by people are compared with
predicted values calculated for tidal volumes (TV) of 750 ml and
1450 ml by the ICRP Task Group on Lung Dynamics 11-35
11-11 Deposition of inhaled^polydisperse aerosols of lanthanum oxide
(radiolabeled with La) in beagle dogs exposed in a nose-only
exposure apparatus showing (a) the deposition fraction in the total
dog, (b) the deposition fraction in the tracheobronchial region,
(c) the deposition fraction in the nasopharyngeal region, and (d)
the deposition fraction in the pulmonary region 11-39
11-12 Deposition of inhaled monodisperse aerosols of fused alumino-
silicate spheres in small rodents showing the deposition in the
nasopharyngeal (nasal) region, the tracheo-bronchial (T-B) region,
the pulmonary region and in the total respiratory tract 11-41
11-13 Single exponential model, fit by weighted least-squares, of the
buildup (based on text Equation 10) and retention (based on text
Equation 12) of zinc in rat lungs 11-69
11-14 Example of the use of the sum of exponential models for describing
models for describing lung uptake during inhalation exposure
(Equation 14) and retention (clearance phase) after exposure ends
(Equation 16) for three lung compartments with half-lives 50 d,
350 d, and 500 d, and twenty-day exposure rates of 1.4 mg/d (E,),
1.7 mg/d (E9), and 2.1 mg/d (E-,), respectively . 11-71
c* *j
11-15 Example of the use of the power function model for describing lung
uptake during inhalation exposure (text Equation 18) and retention
(clearance phase) after exposure ends (text Equation 19) for a
twenty-day exposure at 8.5 mg/d (E) 11-73
11-16 Model of the multicompartmental deposition, clearance, retention,
translocation, and excretion of inhaled particulate material in the
respiratory tract and tissues of the body; the numbered circles
represent the transfer rate constants 11-75
11-17 Multicomponent model of the deposition, clearance, retention,
translocation and excretion of an example sparingly soluble
metallic compound ( CeCl_ continued in CsCl particles) inhaled
by man or experimental animals; the rate constants are based upon
first order kinetics as in text Equation 11 11-76
11-18 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 11-77
vii
-------
LIST OF TABLES
Number
11-1 Summary of the respiratory deposition and clearance of inhaled
aerosols.
11-82
-------
CONTENTS
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 Potential Mutagenic Effects of Sulfite + S0? 12-5
12.2.1.3 Metabolism of Sulfur Dioxide 12-6
12.2.1.3.1 Integrated metabolism 12-6
12.2.1.3.2 Sulfite oxidase 12-11
12.2.1.4 Activation and Inhibitation of Enzymes by Bisul-
fite 12-14
12.2.2 Mortality 12-15
12.2.3 Tumorogenesis in Animals Exposed to S0? or S0? and
Benzo(a)pyrene 12-16
12.2.4 Morphological Alterations 12-19
12.2.5 Alterations in Pulmonary Function 12-30
12. 2. 6 Effects on Host Defenses 12-39
12. 3 EFFECTS ON PARTICULATE MATTER 12-43
12.3.1 Mortality 12-45
12.3.2 Morphological Alterations 12-46
12.3.3 Alterations in Pulmonary Function 12-48
12. 3. 3.1 Acute Exposure Effects 12-48
12.3.3.2 Chronic Exposure Effects 12-66
12.3.4 Alteration in Host Defense 12-70
12.3.4.1 Mucociliary Clearance 12-70
12.3.4.2 Alveolar Macrophages 12-74
12.3.4.3 Interaction with Infectious Agents 12-80
12.3.4.4 Immune Suppression 12-83
12.4 INTERACTION OF SULFUR DIOXIDE AND OTHER POLLUTANTS 12-88
12.4.1 Sulfur Dioxide and Particulate Matter 12-88
12.4.1.1 Acute Exposure Effects 12-88
12.4.1.2 Chronic Exposure Effects 12-91
12.4.2 Interaction with Ozone 12-100
12. 5 CARCINOGENESIS AND MUTAGENESIS 12-104
12.5.1 Airborne Particulate Matter 12-106
12.5.1.1 In vitro studies 12-106
12.5.1.2 In vivo studies 12-109
12.5.2 Sulfur Oxides 12-114
12. 5.3 Metals 12-117
12. 6 CONCLUSIONS 12-124
12.6.1 Sulfur Dioxide 12-124
12.6.2 Particulate Matter 12-128
12.6.3 Interactions of Gases and Particles 12-132
12.7 REFERENCES 12-135
APPENDIX A 12A-1
1x
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LIST OF TABLES
Table Page
12-1. Potential Mutagenic Effects of S02/Bisulfate 12-7
12-2. Lethal Effects of S02 on Animals 12-17
12-3. Tumorigenesis in animals exposed to SC^ or SC^ and
benzo(a)pyrene 12-20
12-4. Effects of sulfur dioxide on lung morphology 12-21
12-5. Effects of sulfur dioxide on pulmonary function 12-40
12-6. Effects of sulfur dioxide on host defense 12-44
12-7. Effects of particulate matter on lung morphology 12-49
12-8. Respiratory response of guinea pigs exposed for 1 hour to
particles in the Amdur et al. studies 12-50
12-9. Effects of acute exposure to particulate matter on pulmonary
function 12-67
12-10. Effects of chronic exposure to particulate matter on pulmonary
function 12-69
12-11. Effects of sulfuric acid on muociliary clearance 12-73
12-12. Effects of metals and other particles on host defense mechanisms. 12-86
12-13. Effects of acute exposure to sulfur dioxide in combination with
particulate matter 12-92
12-14. Pollutant concentrations for chronic exposure of dogs 12-95
12-15. Effects of chronic exposure to sulfur oxides and particulate
matter 12-101
12-16. Effects of interaction of sulfur oxides and ozone 12-105
-------
LIST OF FIGURES
FIGURE Page
12-1. An integrated scheme for metabolism of sulfur dioxide in
mammals 12-9
12-2. Mitotic count after S02 exposure up to 6 weeks 12-24
12-3. Histogram areas covered by PAS sensitive material 12-26
12-4. Increase in goblet cells after exposure to S0? 12-27
12-5. Dose-response curves 12-36
12-6. Mean number and standard error of alveolar cells 12-79
-------
CONTENTS
13. CONTROLLED HUMAN STUDIES 13-1
13.1 INTRODUCTION 13-1
13.2 SULFUR DIOXIDE 13-2
13.2.1 Subjective Reports 13-3
13.2.2 Sensory Effects 13-4
13.2.2.1 Odor Perception Threshold 13-4
13.2.2.2 Sensitivity of the Dark-Adapted Eye 13-7
13.2.2.3 Interruption of Alpha Rhythm 13-8
13.2.3 Respiratory and Related Effects 13-9
13.2.3.1 Water Solubility 13-17
13.2.3.2 Nasal Versus Oral Exposure 13-17
13.2.3.3 Subject Activity Level 13-18
13.2.3.4 Temporal Parameters 13-20
13.2.3.5 Mucociliary Transport 13-22
13.2.3.6 Health Status 13-25
13.3 PARTICULATE MATTER 13-26
13.4 SULFUR DIOXIDE AND OZONE 13-30
13.5 SULFURIC ACID AND SULFATES 13-33
13.5.1 Sensory Effects 13-33
13.5.2 Respiratory and Related Effects 13-37
13.6 SUMMARY 13-42
13. 7 REFERENCES 13-47
-------
LIST OF TABLES
Table
13-1 Sensory effects of S0? I3"5
13-2 Pulmonary effects of SCL 13-1Q
13-3 Pulmonary effects of aerosols 13-27
13-4 Pulmonary effects of S0~ and other air pollutants 13-34
13-5 Sensory effects of sulfaric acid and sulfates 13-35
13-6 Pulmonary effects of sulfuric acid 13-43
XTM
-------
CONTENTS
14. EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF ATMOSPHERIC
CONCENTRATIONS OF SULFUR DIOXIDE AND PARTICULATE MATTER ON
HUMAN HEALTH 14-1
14.1 INTRODUCTION 14-1
14. 2 AIR QUALITY MEASUREMENT CONSIDERATIONS 14-15
14.2.1 British Approaches 14-15
14.2.1.1 British S02 Measurements 14-15
14.2.1.2 Daily smoke measurements of the United
kingdom national survey 14-22
14. 2. 2 American Approaches 14-26
14. 2. 2.1 American SO^ measurements 14-26
14.2.2.2 American high volume TSP sampling measurements. 14-30
14. 3 AIR POLLUTION AND MORTALITY 14-34
14. 3.1 Introduction 14-34
14.3.2 Acute episodes 14-36
14.3.3 Mortality associated with short-term variations
in pol lution 14-49
14.3.4 Cross-sectional studies of mortality 14-69
14. 3. 5 Lung cancer mortal ity 14-87
14.3.6 Summary for mortality studies 14-89
14.4 MORBIDITY ASSOCIATED WITH SHORT-TERM POLLUTION EXPOSURES 14-92
14.4.1 Introduction 14-92
14.4.2 Episodes 14-98
14.4.3 Panel studies of acute respiratory disease (ARD) 14-106
14.4.4 Aggravation of asthmatic symptoms 14-114
14.4.5 Hospital/clinical admission studies and absence
studies 14-114
14.4.6 Pulmonary function studies 14-114
14.5 MORBIDITY ASSOCIATED WITH LONG-TERM POLLUTION EXPOSURES 14-127
14. 5.1 Introduction 14-127
14.5.2 Chronic respiratory disease prevalence studies 14-130
14.5.3 Other respiratory disease/symptom prevalence
studies 14-158
14.5.4 Pulmonary function studies 14-177
14.5.5 Studies combining respiratory disease symptoms
with pulmonary function 14-189
14. 6 SUMMARY AND CONCLUSIONS 14-199
14.6.1 American summary of chapter contents 14-199
14.6.1.1 Health effects of acute exposure to S0~ and
Particulate Matter 14-205
14.6.1.2 Health effects of chronic exposure to S0? and
particulate matter 14-206
14.6.1.3 Health effects of atmospheric sulfates 14-207
14.6.1.4 Respirable particulates effects 14-207
xiv
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14.6.2 Methodological factors impacting interpretation of
results 14-208
14.6.3 Quantitative dose-response relationships defined by
community health studies 14-214
14.6.3.1 Review articles and commentary (1974-1978) 14-216
14.6.3.2 Major evaluative documents (1978) 14-227
14. 7 REFERENCES 14-252
APPENDICES
APPENDIX A A-l
APPENDIX B (To be added later) B-l
APPENDIX C C-l
xv
-------
LIST OF TABLES
Number Page
14-1 Summary of evaluation of sources, magnitudes, and directional
biases of errors associated with British SCL measurements 14-19
14-2 Summary of evaluation of sources, magnitudes, and directional
biases of errors associated with British Smoke (particulate)
measurements 14-24
14-3 Summary of evaluation of sources, magnitudes, and directional
biases of errors associated with American SCL measurements 14-29
14-4 Summary of evaluation of sources, magnitudes, and directional
biases of errors associated with total suspended particulate
(TSP) measurements 14-32
14-5 Excess deaths and pollutant concentrations during severe air
pollution episodes in London (1948-75) 14-40
14-6 Acute air pollution episodes in the United States 14-43
14-7 Other acute air pollution episodes 14-47
14-8 Mean deviation of daily mortality from 15 day moving average,
by level of smoke (London, November 1, 1958-January 31, 1959 14-55
14-9 Mean deviation of daily mortality from 15 day moving average,
by level of SOp (London, November 1, 1958-January 31, 1959) 14-55
14-10 Mean deviation of daily mortality from 15 day moving average,
by level of smoke (London, 1958 to 1960) 14-57
14-11 Mean deviation of daily mortality from 15 day moving average,
by level of SOp (London, 1958-1959 14-57
14-12 Minima temperature data for London (Croydon) 14-61
14-13 Pollution and temperature data for London, December 1958 14-63
14-14 Average deviation of daily mortality from normal, by level
of smoke shade (CoH), (New York, 1960 to 1964, October
through March) 14-67
14-15 Average deviation of daily mortality from normal, by level
of S02 (New York, 1960 to 1964, October through March) 14-67
14-16 Qualitative association of geographic differences in mortality
with residence in areas of heavy air pollution 14-70
14-17 Average annual death rates per 1000 population from all causes
according to economic and particulate levels, and age: white
males, 50-69 years of age, Buffalo and environs, 1959-1961 14-74
14-18 Average annual death rates per 1000 population from all causes
according to economic, particulate and SO levels 14-75
14-19 Comparison of arithmetic and geometric means of TSP data--
Buffalo study, 1961-1963 14-78
14-20 Comparison of arithmetic and geometric means of sulfur data--
Buffalo study, 1961-1963 14-79
14-21 Summary of evidence for mortality effects of acute exposure to
particulate matter and SOp (non-episodic) 14-90
14-22 Summary of evidence for mortality effects of chronic exposure to
particulate matter and S0? 14-91
14-23 Qualitative studies of air pollution and acute respiratory
disease 14-93
xvi
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14-24 Chicago mean annual levels of pollutants in areas, 12/69-11/70.. 14-110
14-25 Acute respiratory illness among families living in two metropolitan
areas 14-111
14-26 Smoking-adjusted, acute respiratory disease attack rates 14-112
14-27 Average deviation of respiratory and cardiac morbidity from
15-day moving average, by S02 level (London, 1958-1960) 14-118
14-28 Average deviation of respiratory and cardiac morbidity from
15-day moving average, by smoke level (BS) (London,
1958-1960) 14-118
14-29 Summary of evidence for morbidity effects of acute exposure
to SOp and particulates 14-125
14-30 Qualitative studies of air pollution and prevalence of
chronic respiratory symptoms and pulmonary function declines 14-131
14-31 Prevalence ratios for persistent cough and phlegm standardized
for age and smoking, by air pollution indices 14-137
14-32 The prevalence (%) of respiratory symptoms and diseases by low
and high smoke pollution in boys and girls 14-144
14-33 The prevalence (%) of respiratory symptoms and diseases by low
and high SO- pollution in boys and girls 14-145
14-34 Summary of associations (±) of pollution with health data 14-146
14-35 Chronic prevalence rates and pollution levels in four Utah
communities , 1970 14-154
14-36 CRD prevalence rates for Chicago recruits 14-157
14-37 Frequency of lower respiratory tract of children in Britain
by pollution levels 14-161
14-38 Four-year reported rates of one or more episodes of
LRD among white and black children by community
exposure Southeastern U. S. 1971 14-169
14-39 Estimated pollutant exposure levels in Charlotte,
North Carolina (intermediate exposure and Birmingham,
Alabama (high exposure) 1960-1971 14-171
14-40 Pollution levels, Berlin, New Hampshire, during three study
periods 14-192
14-40a Summary of long-term exposure studies of pulmonary function
deficits and chronic respiratory disease 14-196
14-41 Summary table - acute exposure effects 14-201
14-42 Summary table - chronic exposure effects 14-203
14-43 Summary of dose-response relationships for effects of particles
and S0? and health 14-217
14-44 Expected health effects of air pollution on selected population.. 14-218
14-45 Particulate and sulfur dioxide levels and effects on health 14-222
14-46 Summary of effects of sulfur dioxide and particulates on
human health—long term effects 14-225
14-47 NRC/National Academy of Sciences health effects and dose/response
relationships for particulates and sulfur dioxide 14-228
14-48 Exposure-effect relationships of sulfur dioxide, smoke;
and total suspended particulates: Effects of short-term
exposures • 14-233
14-49 Exposure-effect relationships of sulfur dioxide, smoke, and
total suspended particulates: Effects of long-term exposures 14-234
14-50 Expected effects of air pollutants on health in selected
segments of the population: Effects of short-term exposures 14-235
xvn
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14-51 Expected effects of air pollutants on health in selected segments
of the population: Effects of long-term exposures 14-236
14-52 Guidelines for exposure limits consistent with the protection
of publ ic health 14-237
14-53 Summary of evidence for health effects of acute exposure to
S02 and particulates 14-240
14-54 Summary of evidence for health effects of chronic exposure
to SOp and particulate matter 14-241
14-55 Epidemiologic studies suggesting an effect of particulate air
pollution at concentrations at or near the U.S. ambient air
quality standard and comments by Shy on the reviews of them
by Hoi 1 and et al 14-247
xvi ii
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LIST OF FIGURES
Number Page
14-1 A comparison of lead dioxide and hydrogen peroxide methods
for sulfur dioxide showing wide variations between simultaneous
measurements 14-17
14-2 Daily air pollution and deaths, London, 1952 14-38
14-3 Residual mortality as a function of S0? for the New York-
New Jersey Metropolitan area, 1962 to 1966 14-53
14-4 Effect on bronchitic patients of high pollution levels
(January 1954) 14-99
14-5 Locations of air monitoring stations in Birmingham, Alabama,
from which air quality data employed in Hammer study were
obtained 14-174
14-5A Acute dose-response relationships from selected studies 14-231
14-5B Chronic dose-response relationships from selected studies 14-231
14-6 Locations of air monitoring stations in Charlotte, N.C. from
which air quality data employed in Hammer study were obtained 14-175
14-8 Comparison of interpretations of studies evaluated by Holland
et al. (1979), WHO (1979), and other reviews such as those
in the NRC/NAS documents and the present chapter 14-245
xix
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Terms and Symbols Used in Respiratory Physiology
A. General
X
X
%x
X/Y%
t
anat
max
B.
1.
V
F
2.
I
E
A
T
D
B
STPO
BTPS
ATPO
ATPS
L
Pressures in general
Dash above any symbol indicates a mean value
Dot above any symbol indicates a time derivative
Two dots above any symbol indicate the second time derivative
Percent sign preceding a symbol indicates percentage of the
predicted normal value
Percent sign after a symbol indicates a ratio function with
the ratio function with the ratio expressed as a percentage.
Both components of the ratio must be designated; e.g.,
FEV,/FEV% = 100 X FEV,/FVC
Frequency of any event in time, e.g., respiratory frequency: the
number of breathing cycles per unit of time
Time
Anatomical
Maximum
Gas Phase Symbols
Primary
Qualifying
Gas volume in general. Pressure, temperature, and percent
saturation with water vapor must be stated
Fractional concentration in dry gas phase
Inspired
Expired
Alveolar
Tidal
Dead Space
Barometric
Standard temperature and pressure, dry. These are the conditions
of a volume of gas at 0°C, at 760 torr, without water vapor
Body temperature (37°C), barometric pressure (at sea level = 760
torr), and saturated with water vapor
Ambient temperature, pressure, dry
Ambient temperature and pressure, saturated with water vapor
Lung
C.
1.
0
C
s
Blood Phase Symbols
Primary
Volume flow of blood
Concentration in blood phase
Saturation in blood phase
xx
-------
2. Qualifying
b
a
v
v
c
Blood in general
Arterial. Exact location to be specified in text when term is used
Venous. Exact location to be specified in text when term is used
Mixed venous
Capillary. Exact location to be specified in text when term is used
Pulmonary end-capillary
D. Pulmonary Function
1. Lung volumes (expressed as BTPS)
RV
ERV
Vr
IRV
VL
1C
IVC
VC
FRC
TLC
RV/TLC%
Vc
that can be inspired from the end-tidal
maximum volume measured on inspiration
VD
VD
anat
Residual volume: volume of air remaining in the lungs after
maximum exhalation
Expiratory reserve volume: maximum volume of air that can
be exhaled from the end-tidal volume
Tidal Volume: volume of gas that is inspired or expired
during one ventilatory cycle
Inspiratory reserve volume: maximum volume that can be inspired
from an end-tidal inspiratory level
Volume of the lung, including the conducting airways. Conditions
of measurement must be stated
Inspiratory capacity: volume
expiratory volume
Inspiratory vital capacity:
after a full expiration
Vital capacity: volume measured on complete expiration after the
deepest inspiration, but without respect to the effort involved
Functional residual capacity: volume of gas remaining in the lungs
and airways at the end of a resting tidal expiration
Total lung capacity: volume of gas in the lung and airways after
as much gas as possible has been inhaled
Residual volume to total lung capacity ratio, expressed as a percent
Physiological dead space: calculated volume (BPTS), which accounts
for the difference between the presures of CO- in expired gas and
arterial blood. Physiological dead space reflects the combination
of anatomical dead space and alveolar dead space, the volume of the
latter increasing with the importance of the nonuniformity of the
ventilation/perfusion ratio in the lung
Volume of the anatomic dead space (BTPS)
The alveolar dead-space volume (BTPS)
Forced respiratory maneuvers (expressed as BTPS)
Forced vital capacity: The volume of gas expired after full
inspiration, and with expiration performed as rapidly and
completely as possible
Forced inspiratory vital capacity: maximal volume of air inspired
after a maximum expiration, and with inspiration performed as rapidly
and completely as possible
Denotes the volume of gas that is exhaled in a given time interval
during the execution of a forced vital capacity
Ratio of timed forced expiratory volume to forced vital capacity,
expressed as a percentage
2.
FVC
FIVC
FEV.
FEVt/FVC%
xxi
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PEF
Vmax
xx%
Vmax
xx%TLC
FEF
Peak expiratory flow (liters/min or liters/sec)
Maximum expiratory flow (instantaneous) qualified by the volume
expressed as percent of the FVC that has been
: VmaXyr^ is the maximum expiratory flow after
been exhaled and 25% remains to be exhaled)
flow (instantaneous) qualified by the volume
expressed as percent of the TLC that remains
Vmax.no/T| - is the maximum expiratory
the TLtrrefrtains in the lung)
at which measured,
exhaled. (Example
75% of the FVC has
Maximum expiratory
at which measured,
in the lung. (Example:
flow when 40 percent of
x-y
FEF,
FEF
2-1-2L
25%-75%
MVV
FET
MIF
Forced expiratory flow between two designated volume points in the
FVC. These points may be designated as absolute volumes starting
from the full inspiratory point or by designating the percent of
FVC exhaled
Forced expiratory flow between 200 ml and 1,200 ml of the FVC;
formerly called maximum expiratory flow
Forced expiratory flow during the middle half of the FVC; formerly
called maximum midexpiratory flow
Maximum voluntary ventilation: maximum volume of air that can be
breathed per min by a subject breathing quickly and as deeply as
possible. The time of measurement of this tiring lung function
test is usually between 12 and 30 sec, but the test result is given
in liters (BTPS)Xmin
Forced expiratory time required to exhale a specifed FVC, e.g.,
FETqry is the time required to deliver the first 95% of the
FVC, rET9t-
-------
Pleura! pressure: the pressure between the visceral and parietal
pleura relative to atmospheric pressure, in cm H?0
Palv Alveolar pressure
PL Transpulmonary pressure: transpulmonary pressure, PL = Palv - Ppl,
measurement conditions to be defined
PstL Static recoil pressure of the lung; transpulmonary pressure measured
under static conditions
Pbs Pressure at the body surface
Pes Esophageal pressure used to estimate Ppl
PW Transthoracic pressure: pressure difference between parietal
pleural surface and body surface. Transthoracic in the sense
used means "across the wall." Pw + Ppl - Pbs
Ptm Transmural pressure pertaining to an airway or blood vessel
Prs Transrespiratory pressure: pressure across the respiratory
system. Prs + Palv - Pbs = PL + Pw
(b) Flow-pressure relationships
R Flow resistance: the ratio of the flow-resistive components of
pressure to simultaneous flow in cm H20/liter per sec
Raw Airway resistance calculated from pressure difference between
airway opening (Pao) and alveoli (Palv) divided by the airflow,
cm H^O/liter/sec
RL Total pulmonary resistance includes the frictional resistance of
the lungs and air passages. It equals the sum of airway resistance
and lung tissue resistance. It is measured by relating flow-dependent
transpulmcnary pressure to airflow at the mouth
Rrs Total respiratory resistance includes the sum of airway resistance,
lung tissue resistance, and chest wall resistance. It is measured
by relating flow dependent transrespiratory pressure to airflow at
the mouth.
Rus Resistance of the airways on the upstream (alveolar) side of the
point in the airways where intraluminal pressure equals Ppl
(equal pressure point), measured during maximum expiratory flow
Rds Resistance of the airways on the downstream (mouth) side of the
point in the airways where intraluminal pressure equals Ppl,
measured during maximum expiratory flow
Gaw Airway conductance, reciprocal of Raw
Gaw/VL Specific conductance expressed per liter of lung volume at which
Gaw is measured
(c) Volume-pressure relationships
C Compliance: the slope of a static volume-pressure curve at a
point, or the linear approximation of a nearly straight portion
of such a curve expressed in liter/cm H^O or ml/cm H^O
Cdyn Dynamic compliance: the ratio of the tidal volume to the
tidal volume to the change in intrapleural pressure between
the points of zero flow at the extremes of tidal volume in
liter/cm H?0 or ml/cm hLO
Static compliance, value for compliance determined on the
basis of measurements made during periods of cessation of
airflow
xxm
-------
C/VL
E
Pst
W
Specific compliance: compliance divided by the lung volume
at which it is determined, usually FRC
Elastance: the reciprocal of compliance; expressed in cm
HpO/liter or cm H2/ml
Static components of pressure
Work of breathing: the energy required for breathing movements
5. Diffusing Capacity
DL
Diffusing capacity of the lung: Amount of gas (02> CO, CCL)
commonly expressed as ml gas (STPD) diffusing between alveolar
gas and pulmonary capillary blood per torr mean gas pressure
difference per min. Total resistance to diffusion for oxygen
1 _...,,.„ 1
and CO
includes resistance to diffusion of the
;o
DM
6
Vc
DL/VA
p OMU ^ p.
the gas across theualveolar-capillary membrane, through plasma
in the capillary, and across the red cell membrane (I/DM), and
the resistance to diffusion within the red cell arising from
the chemical reaction between the gas and hemoglobin, (1/6V ),
1 . 1 + 1
"DlT DM 6Vc
The diffusing capacity of the pulmonary membrane
The rate of gas uptake by 1 ml of normal whole blood per min
for a partial pressure of 1 torr
Average volume of blood in the capillary bed in milliliters
Diffusion per unit of alveolar volume. DL is expressed STPD,
and VA is expressed in liters (BTPS)
according to the formulation
6. Respiratory Gases
Pa>
PA'
Sa
02
PA-Pa
Ca-Cv
Arterial tension of gas x, torr (mm Hg)
Alveolar tension of gas x, torr (mm Hg)
Arterial oxygen saturation (percent)
Concentration: for example, CaCQp is the concentration of
oxygen in a blood sample, including both oxygen combined with
hemoglobin and physically dissolved oxygen, ordinarily expressed
at ml Op (STPD)/100 ml blood, or mmole Op/liter
Alveolar-arterial gas pressure difference: the difference in
partial pressure of a gas (e.g., Op or Np) in the alveolar
gas spaces and that in the systemic arterial blood,
measured in torr. For oxygen, as an example,
PA - Pa
Also symbolixed AaDnp
Arterial-venous concentration difference. For oxygen, as an
example, CaQ2 - CV
'02
XXIV
-------
7. Pulmonary shunts
6s
Shunt: vascular connection between circulatory pathways so
that venous blood is diverted into vessels containing arterialized
blood (right-to-left shunt, venous admixture) or vice versa
(left-to-right shunt). Right-to-left shunt within the lung,
heart, or large vessels due to malformations are more important
in respiratory physiology. Flow from left to right through a
shunt should be marked with a negative sign.
E. Pulmonary Dysfunction
1. Altered breathing
dysanea
hyperventilation
hypoventhetion
An unpleasant subjective feeling of difficult or labored breathing
An alveolar ventilation that is excessive relative to the
simultaneous metabolic rate. As a result the alveolar
is significantly reduced below the normal for the altitude
ilveolar ventilation that is small relative to the
AfiC
simultaneous metabolic rate so
significantly above the normal
that alveolar Prn?
for the altitude^
rises
2. Altered blood gases
hypoxia
hypoxernia
hypocapnie
hyparcapnia
Any state in which the oxygen in the lung, blood, and/or tissues
is abnormally low compared with that of normal resting person
breathing air at sea level
A state in which the oxygen pressure and/or concentration in
arterial blood is lower than its normal value at sea level.
Normal oxygen pressures at seal level are 85-100 torr in
arterial blood. In adult humans the normal oxygen concentra-
tion is 17-23 ml 02/100 ml arterial blood
Any state in which the systemic arterial carbon dioxide
pressure is significantly below 40 torr, as in hyperventilation
Any state in which the
is significantly above
tion is inadequate for
or during C09 inhalation
systemic arterial carbon dioxide pressure
40 torr. May occur when alveolar ventila-
a given metabolic rate (hypoventilation)
3. Altered acid-base balance
acidemia
alkelemia
base excess (BE)
Any state of systemic arterial plasma in which the pH is
significantly less than the normal value, 7.41 ± 0.02 in
adult man at rest
Any state of systemic arterial plasma in which the pH is
significantly greater than the normal value, 7.41 ± 0.02
in adult man at rest
Base excess: A measure of metabolic alkalosis or metabolic
acidosis (negative values of base excess) expressed as the
rnEq of strong acid or strong alkali required to titrate a
sample of 1 liter of blood to a pH of 7.40. The titration
is made with the blood sample kept at 37°C, oxygenated, and
equilibrated to PCQ2 of 40 torr
xxv
-------
acidosis
alkelosis
The result of any process that by itself adds excess C0?
(respiratory acidosis) or nonvolatile acids (metabolic acidosis)
to arterial blood. Acidemia does not necessarily result, because
compensating mechanisms (increase of HCO~ in respiratory acidosis,
increase of ventilation and consequently; decrease of arterial CO,
in metabolic acidosis) may intervene to restore plasma pH to norm*
The result of any process that, by itself, diminishes acids
(respiratory alkalosis) or increases bases (metabolic alkalosis)
in arterial blood. Alkalemia does not necessarily result, because
compensating mechanisms may intervene to restore plasma pH to normal
chronic respira-
tory failure
obstructive
ventilatory
defect
restrictive
ventilatory
defect
impairment
disability
n
4. Other
pulmonary
insufficiency
acute respiratory
failure
Altered function of the lung,
that usually include dyspnea
which produces clinical symptoms
Rapidly occurring hypoxemia, hypercabia, or both caused by a
disorder of the respiratory system. The duration of the illness
and the values of arterial oxygen tension and arterial carbon
dioxide tension used as criteria for this term should be given.
The term acute ventilatory failure should be used only when the
arterial carbon dioxide tension is increased. The term pulmonary
failure has been used to indicate respiratory failure specifically
caused by disorders of the lung
Chronic hypoxemia or hypercapnia caused by a disorder of the
respiratory system. The duration of the condition and the
values of arterial oxygen tension and arterial carbon dioxide
tension used as criteria for this term should be given
Slowing of air flow during forced ventilatory maneuvers
Reduction of vital capacity not explainable by airflow obstruction
A measurable degree of anatomic or functional abnormality that
may or may not have clinical significance. Permanent impairment
is that which persists for some period of time, e.g., one year
after maximum medical rehabilitation has been achieved
A legally or administratively determined state in which a patient's
ability to engage in a specific activity under certain circum-
stances is reduced or absent because of physical or mental
impairment. Other factors, such as age, education, and customary
way of making a livelihood, are^ considered in evaluating disability.
Permanent disability exists when no substantial improvement of
the patient's ability to engage in the specific activity can
be expected
xxvi
-------
REFERENCES
1. (Pappenheirner Committee) Standardization of definitions and symbols in
respiratory physiology, Fed. Proc. 1950, 9, 602.
2. Glossary on respiration and gas exchange, J. Appl. Physio!., 1973, 34, 549.
3. Mead, J. and Milic-Emili, J.: Theory and methodology in respiratory mumanics
with glossary of symbols, in Handbook of Physiology-Respiration I. pp. 363-364
4. Hyatt, R. E.: Dynamic lung volumes, in Handbook of Physiology-Respiration II.
p. 1366.
5. Clinical spirometry (ACCP Committee), Dis Chest, 1963, 43, 214.
6. Gandevia, B. , and Hugh-Jones, P.: Terminology for measurements of ventilatory
capacity: A report to the Thoracic Society, Thorax, 1957, 12, 290.
7. Pulmonary terms and symbols: A report of the ACCP-ATS Joint Committee on
Pulmonary Nomenclature, Chest, 1975, 67, 583.
xxvn
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CONTRIBUTORS AND REVIEWERS
Mr. John Acquavella
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
Dr. Roy E. Albert
Institute of Environmental Medicine
New York University Medical Center
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Dr. Martin Alexander
Department of Agronomy
Cornell University
Ithaca, New York 14850
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Environmental Sciences Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
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Department of Botany
University of Florida
Gainesville, Florida 32611
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Strategies and Air Standards Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
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Strategies and Air Standards Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
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Monitoring and Data Analysis Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
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Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
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Environmental Sciences Research Laboratory
U.S. Environmental Protection Agency
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Environmental Division
U. S. Department of Energy
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Industrial Environmental Research Laboratory
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Environmental Criteria and Assessment Office
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Environmental Sciences Research Laboratory
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Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
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Health Effects Research Laboratory
U.S. Environmental Protection Agency
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Department of Environmental Medicine
University of Washington
Seattle, Washington 98195
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New York State Department of Environmental Conservation
Division of Air Resources
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Midwest Research Institute
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xx ix
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School of Forest Resources
North Carolina State University
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Monitoring and Data Analysis Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
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Environmental Criteria and Assessment Office
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Environmental Sciences Research Laboratory
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Environmental Sciences Research Laboratory
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School of Public Health
Harvard University
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xxx
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Department of Energy and Environment
Brookhaven National Laboratory
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Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
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School of Public Health
Harvard University
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New York Department of Environmental Conservation
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Environmental Monitoring Systems Laboratory
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Department of Environmental Health
University of Washington
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Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
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New York Department of Environmental Conservation
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Health Effects Research Laboratory
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Environmental Criteria and Assessment Office
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xxx i
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Health Effects Research Laboratory
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Health Effects Research Laboratory
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Environmental Criteria and Assessment Office
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Ministry of Agriculture
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Environmental Monitoring Systems Laboratory
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Health Effects Research Laboratory
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Environmental Monitoring Systems Laboratory
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xxx ii
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Health Effects Research Laboratory
U.S. Environmental Protection Agency
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Environmental Sciences Research Laboratory
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Department of Energy and Environment
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University of Michigan
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Health Effects Research Laboratory
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University of California
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xxxm
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Health Effects Research Laboratory
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CAPITA
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Argonne National Laboratory
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Biospherics, Inc.
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xxxv
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xxxvn
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xxxvm
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xxxix
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U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
Dr. William H. Zoller
Chemistry Department
University of Maryland
College Park, Maryland 20742
We wish to thank everyone who contributed their efforts to the preparation of
this document, including the following staff members of the Environmental
Criteria and Assessment Office, U.S. Environmental Protection Agency, Research
Triangle Park, North Carolina:
Mrs. Dela Bates
Ms. Hope Brown
Ms. Diane Chappell
Ms. Deborah Doerr
Ms. Mary El ing
Ms. Bettie Haley
Mr. Allen Hoyt
Ms. Susan Nobs
Ms. Evelynne Rash
Ms. Connie van Oosten
Ms. Donna Wicker
The final draft of this document will cite the many persons outside of the
Environmental Criteria and Assessment Office who have assisted in its pre-
paration.
xlii
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11. RESPIRATORY DEPOSITION AND BIOLOGICAL FATE
OF INHALED AEROSOLS AND S02*
11.1 INTRODUCTION
11.1.1 General Considerations
The respiratory airways system is the major route for exposure of people
to airborne particles (aerosols) and S02 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 complicated by
interactions that may occur between the particles, the S0? gas, other gases
such as biologically endogenous ammonia, and the water vapor present in the
airways.
In inhalation toxicology, specific terminology is applied to these pro-
cesses. The term deposition refers specifically to the removal of inhaled
particles or gas by the respiratory tract and to the initial regional pattern of
these deposited materials. The term clearance refers to the subsequent trans-
location (movement of material in the lung to other organs), transformation, and
removal of deposited particles from the respiratory tract or from the body. It can
also refer to the removal of reaction products formed from SO-- The temporal
distribution of uncleared deposited particulate materials or gas and reaction
products is called retention. At the end of a brief aerosol or gas exposure,
*Report prepared with support of the Office of Health and Environmental Research
of the U.S. Department of Energy (DOE) under contract with the University of
California, Davis.
11-1
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these three concepts may be described by the relationship:
RETENTION (t) = DEPOSITION - CLEARANCE (t) (1)
where (t) refers to a function of time after deposition occurs (Raabe, 1979).
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, hygro-
scopicity or deliquescence, chemical composition, gas diffusivity, and related
reactions. The geometry of the respiratory airways from nose and mouth to the
lung parenchyma also influences aerosol deposition; the important morphometric
parameters include the diameters, lengths, and branching angles of airway
segments. Physiological factors that affect deposition include breathing
patterns, air flow dynamics in the respiratory tract, and variations of rela-
tive humidity and temperature within the airways. With this information,
theoretical models of regional deposition have been developed to predict the
fate of inhaled aerosols of various types. Carefully collected data from
experiments with human volunteers provide a basis for testing these theo-
retical predictions.
The current state of knowledge concerning the quantification of the
deposition of inhaled aerosols for both man and experimental animals is fairly
well established. Important questions to be resolved concern the deposition
of inhaled S02, especially with respect to gas-particle interaction and the
extent of synergism between SO- and particulate materials with respect to
deposition and toxicological effects. However, the fundamental factors
associated with these processes have been recognized for over 20 years in that
the deposition in the deep lung during inhalation and, concomitantly. the
potential for biological response to S0? may be enhanced by the presence in
11-2
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the atmosphere of certain aerosols emitted from both natural and man-made
sources. Therefore one should consider the deposition, clearance, trans-
location, and biological response of inhaled SO- in conjunction with the
aerosols that are present in some in the environment.
Clearance from the respiratory tract depends on many factors, including
site of deposition, chemical composition and properties of the deposited
particles, S02 reaction products, mucociliary transport in the tracheobronchial
tree, macrophage phagocytosis in the deep lung, and pulmonary lymph and blood
flow.
Translocation of sulfur compounds or other materials from the lung to
other organs is important, since the lung can be the portal of entry for toxic
agents that have effects on other organs of the body. Hence, multicompartment
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 SO- 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. In particular, air pollution experiments that use small rodents
must be interpreted with respect to important differences between human and
rodent airways, breathing patterns, flow dynamics, regional deposition, and
subsequent clearance. Emphasis in the following discussion will be on the
deposition and clearance that occur in the human airways, but selected com-
parisons are made with other mammalian species to clarify differences that may
affect health impact analyses of experimental data.
11-3
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11.1.2 Aerosol and SO- Characteristics
An aerosol may be defined as a relatively stable suspension of small
liquid or solid particles in a gaseous medium. Airborne particulate materials
in the environment are aerosols. Aerosols containing potentially toxic com-
ponents consist of particles 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.
Another important property, physical density, may vary with particle size and
particle type (Raabe et al., 1975). Also, the concentration of of toxic
components in particles may be different for different sized particles
(Natusch et al., 1974). 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
composition, toxic potential, and physical density should not be expected to
describe adequately general aerosol behavior in the atmosphere and may be
seriously misleading concerning specific aerosol toxicity, especially when
particles are found in combination with S0? gas.
It is essential for evaluation of the possible health effects associated
with their inhalation that the physical and chemical properties of aerosols
and gases be appropriately characterized. These properties then can provide
predictive information concerning deposition and other important dosimetric
factors that need to be considered if biological responses are to be fully
understood.
If particles in an aerosol are s^r-oth and spherical or nearly spherical,
their physical sizes can be conveniently described in terms of their respective
geometric diameters. Aerosols of solids rarely contain smooth, spherical
11-4
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particles, however; 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).
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 (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 (related to the diffusion coef-
ficient) (Fuchs, 1964) (see Section 11.2.1). When particles are inhaled,
their aerodynamic properties, combined with various aspects of respiratory
mechanics, determine their fractional deposition and the deposition location
in the respiratory tract (Phalen and Raabe, 1974; Morrow, 1964a, 1974; Lippmann
et a!., 1971; Hamilton and Walton, 1961).
In order to avoid the complications associated with the effects of parti-
cle 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
11-5
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equivalent diameter (Dae). defined by Hatch and Gross (1964) as "the diameter
of a unit density sphere having the same ..ettling speed (under gravity) as the
particle in question of whatever shape and density." Raabe (1976) has recom-
mended the use of an aerodynamic resist nee diameter (D ), defined more
dr
directly with terms used in physics to describe the inertial properties of a
particle. The relationship between these two aerodynamic diameters is given
by:
DV[pC(D)]
D = ——— = D C(D ) (2)
ar / ae ae
with D the aerodynamic (equivalent unit density sphere) diameter and C(D ),
the (Cunningham) slip correction associated with a unit density (p*=l g/cm )
sphere of diameter D. . The slip correction, C(D), a function of physical
QC
size D, is a semi empirical factor that corrects the Stokes1 Law of viscous
resistance for the effect of "slip" between the air molecules when the aerosol
particles are almost as small as or smaller than the mean free path of air
molecules. Both of these aerodynamic diameters have been widely used in the
inhalation toxicology literature. It is probably not crucial to the general
properties of inhaled particles to differentiate between or be unduly concerned
with these two definitions, since their difference is only 0.08 urn or less
over all sizes under normal conditions at sea level. Hence, the term aero-
dynamic diameter can be used to refer to either or both of these two defi-
nitions. Particle characteristics described in terms of physical diameter can
also be described in terms of aerodynamic diameter.
Since not all particles in an aerosol are of the same physical or aero-
dynamic size, the distribution of sizes must be described. If either the
11-6
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physical diameter (D) or the projected aerodynamic diameter is used to charac-
terize particles, the distribution of particle sizes in a mixed aerosol is
most conveniently described as a probability density function f(D) [f(D or
d r
f(Dae)L with
/ f(D)dD = 1 (3)
o
One such generally useful function, the log-normal 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). Photochemically generated aerosols
create small nucleated particles that are generally smaller than 0.1 urn (the
nuclei mode) while combustion and other particle generation processes usually
yield relatively coarse particles larger than 2 urn. Another mode usually
exists between 0.1 urn and 2 urn because of the great stability of particles in
this range (see Chapters 3 and 5).
Since aerosols rarely consist of particles of a single size, they must be
described in terms of parameters of size distribution functions. It has
become customary in the absence of detailed data and for the sake of general-
ization to describe aerosols in terms of their geometric mean or median
diameter and the geometric standard deviation (a ) 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 og, or the count
median aerodynamic diameter (CMAD) and og if aerodynamic sizes have been
measured. Numerically, half the particles in an aerosol have physical sizes
11-7
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less than the CMD and half are 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 (physical) diameter (HMD) or »ass median
aerodynamic diameter (MMAD) and o is usually preferred in describing aerosols
1n inhalation toxicology research. Half the mass of particles in an aerosol
is associated with particles smaller than the HMD and half with larger particles,
Likewise, half the mass of particles is associated with particles whose aero-
dynamic 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 yielding the activity
median diameter (AMD) or activity median aerodynamic diameter (AMAD). Inter-
relationships among these various ways to express the diameter of the aerosol
have been examined for the log normal 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 con-
ditions (e.g., wind velocity or state of turbulence) affect the aerodynamics
of aerosol particles. Another property that affects particle behavior is
electrostatic charge. Environmental aerosols normally have some electrostatic
charge distribution.
The concentration of environmental aerosols or gases affects inhalation
deposition and particle dynamics. The number of particles per unit volume of
gas (#/cm ) provides information indicative of the coagulation rate for an
aerosol. The mass concentration (mg/m or ug/m ) or concentration of a spe-
cific potentially toxic species (mg of constituent/m ) provides information
11-8
-------
needed to calculate inhalation exposure levels. For SO-, the concentration
may be expressed in parts per million (ppm) or in mass concentrations (mg/m3);
each 1 ppm of S02 equals 2.62 mg/m3 (2620 ug/m3).
Sulfur dioxide gas is a rapidly diffusing reactive gas that 1s readily
soluble in water and body fluids (Aharonson, 1976). Through normal and catalyst
nediated oxidation processes in air S02 gas is slowly oxidized to form H2$04,
leading to sulfate salts. Since NH3 is formed in natural biological processes
including endogenously in the airways, (NH4)2$04 and NH4HS04 are important
products of S02 oxidation (Charlson et al., 1978). Specific instrumental and
chemical techniques are available for SCL and other sulfur containing compound:
in aerosol-gas mixtures.
11.1.3 The Respiratory Tract
To evaluate the regional deposition of inhaled aerosols and sulfur dioxide,
the normal dimensions of each anatomical section of the respiratory tract from
nasal cavity to the parenchyma of the lung are needed (Figure 11-1). With
these measurements, predictive models of the deposition of inhaled particles
and gases have been devised. Although differences exist among individuals,
and variability occurs during the breathing cycle of any given individual
(Marshall and Holden, 1963), general descriptions of the anatomical features
of the respiratory tract and airflow characteristics are quite satisfactory
for general predictive models of deposition.
Morphometric measurements of the airways have been made by (a) preparation
of corrosive casts of the airspaces (Tompsett, 1970; Frank and Yaeder, 1966;
Phalen et al., 1973; Raabe et al., H76-); (b) direct measurements ui vivo,
such as by endoscopy, radiography, (Nadel , et al., 1967; Adams r-^t-a+rT '1942;
Yeh, et al., 1975), or at autopsy (Berg, et al., 1949); or (c) two-dimensional
11-9
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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
(adapted from Raabe, 1970).
11-10
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measurements of cross-sectional cuts of tissue either by direct observation or
with the aid of light and electron microscopy (Weibel and Elias, 1967; Nagashi,
$1td^ L^ilL^A^g1—-
1972; Hansen .*W4, ( 1074; Hansen et al , 1975; Hansen and Ampaya, 1975).
The respiratory tract 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. For consideration of the
mechanisms associated with deposition and clearance of inhaled aerosols, the
respiratory tract can be divided into three functional regions: (1) naso-
pharynx (NP), 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 conduct-
ing 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 parenchymal airspaces of the lung, including the
respiratory bronchioles, alveolar ducts, alveolar sacs, atria, and alveoli
(i.e., the gas-exchange region). Although the anatomical and physiological
divisions between these regions are gradual and difficult to distinguish, the
formal separation of the ciliated from the unciliated regions has useful
applications, particularly when considering particle clearance.
The NP consists primarily of hollow portions of the nose and throat. 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 the
direction of the pharynx. The turbinates are shelf-like projections of bone
11-11
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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 elevated mucosal folds that partially
obstruct the airway. The distance from the epiglottis to below the larynx is
5 to 7 cm, with a vertical diameter of 3.6 to 4.4 cm (Snyder, 1975). Females
have smaller laryngeal regions than do males.
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 conductive airway ducts (Tenney and Bartlett, 1967). The trachea
divides into two major bronchi. 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., 1976b).
The lungs consist of two major parts, the left and right lungs, connected
to 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. Each lobe is
served by a bronchus from one of the two major bronchi. 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., 1976b).
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).
The pulmonary, gas-exchange region of the lung begins with the partially
alveolated respiratory bronchioles. Pulmonary branching proceeds through a
11-12
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few levels of respiratory bronchioles to completely alveolated ducts (Smith
and Boyden, 1949; Whimster et al., 1970; Krahl, 1963) and alveolar sacs
(Tenney and Remmers, 1963; Rattle, 1961b; Machlin, 1950; Frasier 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 respiratory zone are coated with a
complex aqueous liquid containing several biochemically specialized substances,
including pulmonary surfactants (Green, 1974).
Several researchers have measured the conductive airways of the lung.
Weibel (1963) used a corrosion cast of the human lung prepared by Liebow and
co-workers (1947) to make detailed measurements of unbroken segments to the
tenth branching; he could not measure further. He used these measurements in
conjunction with histological data (Weibel and Elias, 1967) on the human
alveolar acinus to develop a consistent model of airway number and dimensions.
Horsfield (1972), Horsfield and Gumming (1968), Horsfield and Gumming (1967),
Horsfield et al. (1971), and Parker et al. (1971) also measured casts of the
human conductive airways. Raabe et al. (1976 ) used an i_n situ method (Phalen
et al., 1973) to measure the conductive airways of several mammalian species,
including man, dog, rat, and hamster. They used casts prepared at autopsy
under conditions simulating end inspiration (Raabe, 1979). These replica
casts purportedly were more faithful reproductions of the normal airway
orientation than were those obtained with excised lungs. After determining
the lengths, diameters, and branching angles for selected segments from trachea
to terminal bronchioles, Raabe and co-workers (1976b) performed extensive
measurements on the conductive airways of man and experimental animals. They
demonstrated that the number of airway branches in the human TB region from
11-13
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trachea to terminal bronchiole can range from 11 to 22. They also showed that
different lobes have different average numbers of branches to terminal, with
the apical or upper lobes tending to have fewer branches than the other lobes.
These measurements reveal the diversity of branching angles, airway segment
lengths and diameters, and branching patterns in mammalian species. Other
factors, such as airway closure, changes in caliber during breathing, bronch-
motor tone and constrictions can alter these dimensions (Slonim and Hamilton,
1971; Hinshaw, 1969).
The number of alveoli increases after birth until late childhood, reaching
a maximum of about 300 million (Charnock and Doeshuk, 1973; Davies and Reid,
1970; Dunnill, 1962). Schreider and Raabe (1980) made acinus measurements of
casts of the respiratory airways. Although the alveolus usually assumes an
irregular shape because of the thin walls and close packing, alveolar size is
usually described as the equivalent spherical diameter. Reported diameters
range from 150 to 300 pm for man (Weibel, 1963; Davies, 1961; Crosfill and
Widdicombe, 1961; Kliment, 1973; Von Hayek, 1960). The alveolar dimensions
vary with degree of inflation (D'Angelo, 1972, Forrest, 1970) and hydrostatic
pressure (Glazier et al., 1966, 1967).
The total surface area of the alveoli in adult man was reported by Von
2 ?
Hayek (1960) as 35 m in expiration and 100 m in deep inspiration. Weibel
iy
(1963) estimated a surface area of 70 m for a human lung at three-quarters
2
capacity. This compares with 45.5 m for 16 kg dogs (Tenny and Remmers, 1963)
2
and 1.1 m for guinea pigs (Schreider, 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
11-14
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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 estimation of
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 gener-
ation 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).
11.1.4 Respiration
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 inhaled soluble, deliquescent,
and hygroscopic aerosols will depend in part on the relative humidity in the
airways, since the growth of such particles (with concomitant increase in
aerodynamic size) will directly affect both the site and extent of inhalation
deposition.
The relative humidity of inhaled air probably reaches near saturation in
the nose (Verzar et al., 1953). Since the human nose is a relatively simple
and short passageway, tranquil diffusion alone cannot account for rapid humidi-
fication. Rather, convective mixing must play a role, suggesting a mechanism
for enhancing S0? collection in the nose. The lower temperature of inhaled
11-15
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air increases the effectiveness of nasal humidification by convective mixing.
Unlike humidity, the temperature of the inhaled air may not reach body tempera-
ture until relatively deep in the lung. Deal et al. (1979a, b, c) measured
retrocardiac and retrotracheal temperatures under different ambient tempera-
tures and found airway cooling associated with breathing cool air. Raabe et
al. (1976b) 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 tempera-
ture of exhaled air at the nose of a dog averaged only 31°C (Raabe and Yeh,
1976a).
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 inertia! and diffusional deposition processes
(Altshuler et al., 1967). The total air remaining in the lungs at the end of
normal expiration [functional residual capacity (FRC)] affects the relative
mixing of inhaled particles and, when compared with total lung capacity (TLC),
is indicative of the extent of aerosol penetration into the lung (West, 1974;
Luft, 1958). Weibel (1972) developed relationships relating human lung capacity
to body weight, and Guyton (1947a, b) and Stahl (1967) developed interspecies
relationships describing respiratory volumes and patterns. An important
difference between man and rodents is that small rodents breathe by inhaling
shallowly and rapidly (for rats about 1.5 ml TV at 100 breaths per minute).
The inspiratory capacity (1C), the maximum volume of air that can be
inhaled after a given normal expiration, is contrasted to the vital capacity
(VC), 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
11-16
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airways (from nose to terminal bronchioles) at end expiration is considered to
occupy the respiratory dead space (VD). since the conductive airways are not
Involved in gas exchange (Paiva, 1973; Paiva and Paiva-Verentennicoff, 1972;
Palmes, 1973).
Gas flow dynamics within the upper airways may be expected to be turbulent
1n 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 introduces an important air
flow disturbance that can influence trachea! 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 laminar or bulk flow and uniform velocity profiles, are
usually incorporated into analytic descriptions.
Representative values for normal human respiratory parameters (Snyder,
1975) are frequently used for deposition and dosimetric prediction although it
is understood that these values may not describe any particular person. 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. For a young adult
2
weighing 70 kg with a height of 175 cm and a body surface area of 1.8 m ,
Snyder (1975) assumed a breathing rate of 12 breaths per minute with minute
volume of 7.5 liters/minute. Morrow et al. (1966) assumed three sets of
11-17
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representative tidal volumes, 750 ml at rest, 1450 ml during moderate activity,
and 2150 ml during strenuous exercise with 15 breaths per minute for deposition
calculations.
11.2 DEPOSITION IN MAN AND EXPERIMENTAL ANIMALS
11.2.1 Insoluble and Hydrophobic Solid Particles
The behavior of inhaled airborne particles in the respiratory airways and
their alternative fate of either deposition or exhalation depend upon aerosol
mechanics under the given physiological and anatomical condition (Yeh et al.,
1976; DuBois and Rogers, 1968). To understand the basic physiological and
anatomical factors influencing deposition, initial consideration must be given
to nonreactive stable spherical particles whose physical properties do not
vary during the breathing cycle. When deposition measurements and calculations
are confirmed for these ideal insoluble particles, it is possible to develop
an understanding of the more complex behavior of hygroscopic and deliquescent
particles.
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 trans-
ferred to unexhaled lung air (Engel et al., 1973; Davies, 1972; Altshuler,
1961). Deposition increases with duration of breath holding and depth of
breathing (Palmes et al., 1973; Palmes et al., 1967; 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
11-18
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I
VO
INTERCEPTIONV
ELECTROSTATIC
ATTRACTION
GRAVITATIONAL
SETTLING
IMPACTION
BROWN! AN
DIFFUSION
FIGURE 11-2. Representation of five major mechanisms of deposition of inhaled airborne particles in the
respiratory tract (from Raabe, 1979).
-------
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 doubled the inhalation deposition 1n 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 j_n vitro
studies (Chan et al., 1978). However, 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 charge-to-size ratio (and associated electrical mobility) of an aerosol
particle determines the extent to which the mechanism may play a role in
deposition. Hence, the role of this mechanism may depend on particle source,
age, and special electrical phenomena in the environment. 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
This process would have a zero probability if the particles were only points
rather than extended bodies. 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 negligible role in the
inhalation deposition of most environmental aerosols.
11-20
-------
Impaction dominates deposition of particles larger than 3 urn D in the
3 r
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 into the surface of the airway. Impaction at
an airway branch has been likened to impaction at the bend of a tube, providing
theoretical estimates of the impaction probability (P.) (Johnston and Muir,
1973; Yen, 1974; Cheng and Wang, 1975). Aerodynamic separation of this type
is satisfactorily characterized in terms of the particle aerodynamic diameter.
If impaction in the airways is likened to collection of aerosols in a round-jet
impactor, the 50 percent collection efficiency would occur at a particle
aerodynamic diameter of 18 urn D for the human trachael bifurcation for a
or
volumetric flow rate of 45 liter/minute and would have little effect on
particles smaller than 6 urn D . However, the airflow in the trachea and
O i
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 turbi-
nates would be expected to collect some particles as small as 1 or 2 um Dflr by
impaction. Hence, impaction is an important process affecting the inhalation
deposition in the human airways of environmental aerosol particles greater
than 1 um in aerodynamic diameter.
11-21
-------
Gravitational settling occurs because of the influence of the earth's
gravity on small particles. Deposition of particles by this mechanism can
occur in all airways except those very few that are vertical. The probability
of gravitational deposition (P ) is usually estimated with equations describing
gravitational settling of particles in an inclined cylindrical tube of diameter
(d) under laminar flow conditions (Wang, 1975; Heyder and Gebhart, 1977).
This deposition depends on the particle concentration distribution in the
airway segments, the incline angle with respect to gravity, and the aerodynamic
resistance diameter (D ) of the particle. Deposition by gravitational settling
Q i
is therefore characterized in terms of the particle aerodynamic 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
G I
environmental aerosols in the distal region of the bronchial airways. Settling
plays an equally important role in the pulmonary deposition and is responsible
for part of the deposition of particles in this region during mouth breathing.
Deposition by diffusion results from the random (Brownian) motion of very
small particles caused by bombardment of the gas molecules in air. The magni-
tude of this motion can be described by the diffusion coefficient for a given
physical particle diameter. Since larger particles have relatively small
diffusional mobility compared with inertia, diffusion primarily affects depo-
sition of particles with physical diameters smaller than 1 urn. For a 0.5 urn
particle with a physical density of about 1 g/cm3, the influences of inertia!
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
11-22
-------
approximately Poisueille, the probability of deposition by diffusion (PQ)
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 it might overestimate deposition in lung segments where
there is minimal mixing between branches and laminar flow between segments.
It is important to note that the diffusivity, electrical mobility, and
interception potential of a particle depend on its physical size, while the
inertial properties of settling and impaction depend on its aerodynamic diam-
eter. 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 um D , it is convenient to use 0.5 um
sr
as the boundary between two regions. 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 0.5 um and 1 um D (the equivalent sizes for a spherical
u i
particle with physical diameter 0.5 um and D with density 3 g/cm , respec-
a r
tively). Of course, a comparison of deposition probabilities is desirable
between the aerodynamic diameter and physical diameter of submicrometer pa"-
tides.
Thus, it is possible to use the available information concerning breathing
patterns and respiratory physiology, the anatomical and geometrical characteris-
tics of the airways, and the physical behavior of insoluble spherical particles
to develop theoretical models of regional deposition (Landahl, 1963; Findeisen,
1935; Beeckmans, 1965; Landahl et al., 1951). In these models, deposition of
inhaled aerosols in a given region of the respiratory tract or in the entire
11-23
-------
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 inhalation. For example,
pulmonary deposition (sometimes called alveolar deposition) 1s 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 nasopharyngeal and tracheobronchial
regions of the respiratory airways.
The theoretical probability of deposition can be calculated as the dif-
ference between unity and the product of the probabilities of transmission
through a given duct or series of ducts. Hence, the probability of deposition
for a monodisperse aerosol of a given particle size for the combination of
impaction, settling, and diffusion for a single segment region is given by:
P = 1 - (1 - PT)(1 - Ps)(l - PD) (4)
where P is the combined deposition probability, P, is the impaction deposition
probability, P$ is the settling deposition probability, and PQ is the diffusion
deposition probability.
Most model calculations treat the various mechanisms of deposition as
independently occurring phenomena. However, such processes as Brownian dif-
fusion and gravitational settling will interfere with each other when their
effects are of comparable magnitude, and that interference can reduce the
combined deposition to less than the sum of the separate depositions (Goldberg
et al., 1978). Taulbee and Yu (1975a) have developed a theoretical deposition
11-24
-------
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.
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 a!.,
1966). Although the purpose of these models was to determine radiation exposure
from inhaled radioactive aerosols, the ICRP aerosol deposition and clearance
models are broadly applicable to environmental aerosols. The ICRP Task Group
used the anatomical model and general methods of Findeisen (1935) and Landahl
(1950, 1963) for calculating deposition in the tracheobronchial and pulmonary
regions. The Gormley-Kennedy (1949) equation for cylindrical tubes was used
for calculating diffusional deposition. Particles were assumed to be insoluble,
stable, and spherical with physical densities of 1 g/cm . Regional deposition
was calculated for a breathing rate of 15 breaths per minute (BPM) for three
tidal volumes (TV): (a) TV 750 ml, at rest (Figure 11-3), (b) TV 1450 ml,
moderate activity (Figure 11-4), and (c) TV 2150 ml, fairly strenuous activity.
The ICRP Task Group used the calculated deposition fractions for individual
particle sizes to predict deposition of log-normally distributed aerosols
consisting of unit density spherical particles with geometric standard devia-
tions (o ) as high as 4.5. When the results were expressed in terms of the
mass median diameter (MMD) for these various sized distributions of unit
density of aerosols (equivalent to the MMAD), the loci of the expected depo-
sition values spanned relatively narrow limits (Figure 11-5).
The ICRP Task Group on Lung Dynamics (Morrow et al., 1966) compared the
calculated regional and total deposition fractions for inhaled particles with
the available human data. Those data were primarily total deposition values
11-25
-------
O\
M m
I5BPM
750 ml TV
i i i liiti
0.01 O.I 1.0 100
DIAMETER OF SPHERICAL PARTICLE WITH DENSITY EQUAL TO ONE
100.0
FIGURE 11-3. Total and regional deposition fractions in the human respiratory tract for various sizes of
inhaled airborne spherical particles with physical density of one g/cm as calculated by the ICRP Task
Group on Lung Dynamics (Morrow et al., 1966) for hreathing rate of 15 breaths per minute (BPM) and a
tidal volume (TV) of 750 ml (from Raabe, 1979).
-------
N>
•vl
I5BPM
1450 ml TV
0.01 O.I 1.0 100
DIAMETER OF SPHERICAL PARTICLE. WITH DENSITY EOUAL TO ONE
1000
FIGURE 11-4. Total and regional deposition fractions in the human respiratory tract for various si/cs of
inhaled airborne spherical particles with physical density of one g/cm as calculated by the ICRP Task Group
on Lung Dynamics (Morrow et al., 1956) for a breathing rate of 15 breaths per minute (BPM) and a tidal volume
(TV) of 1450 ml (from Raabe, 1979).
-------
0.01
l O.I 0.5 1.0 5 10 50 ICD
MASS MEDIAN DlAVITER-W'CRDfo
FIGURE 11-5. The range of regional deposition fractions (shaded areas) for
log-normally distributed spherical aerosols in human nose breathing at 15 BPM
and 1450 ml TV. Geometric standard deviation ranges between 1.2 and 4.5;
particle physical density is one g/cm so that MMD = MMAD (Morrow et
al., 1966)
11-28
-------
for polydisperse and sometimes unstable aerosols (Morrow, 1970b; 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; Landahl and Hermann, 1948). Since then, the deposition 1n humans
of monodisperse insoluble, stable aerosols of different sizes has been measured
under different breathing conditions. The most extensive of these studies are
those of Lippmann and Albert, (1969), Heyder et al. (1975), 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 and 1971b), and Foord et al. (1976), among others (Pavia et al.,
1977; Muir and Davies, 1967; Taulbee et al., 1978; Hounam, 1971; Heyder, 1971;
Heyder and Davies, 1971; Fry and Black, 1973.)
These human deposition data have been collected from volunteers inhaling
test aerosols through either mouthpieces or nose tubes. Differences between
those artificially controlled inhalations and normal, spontaneous mouth breathing
or nose breathing are possible. Also, the particular breathing rate (BPM),
respiratory functional residual capacity (FRC), and tidal volume (TV) used in
the experiments affect deposition.
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 (Heyder et al., 1975). By tagging the test aerosols with radio-
labels, investigators can separate deposition by region, beginning with either
nasopharyngeal deposition for nose breathing or pharyngeal deposition for
mouth breathing (Albert et al., 1967a). The measurement of clearance of the
radiolabeled aerosol from the thorax can be used to separate early clearance,
11-29
-------
indicative of tr^cheobronchial (TB) deposition, from more slowly cleared
pulmonary (P) deposition (Lippmann and Albert, 1969).
Selected portions of the available data on total and regional aerosol
deposition have been compared with the calculated deposition values of the
ICRP Task Group on Lung Dynamics (Morrow et al., 1966) (Figures 11-6 to 11-10).
In these comparisons, the predicted values either agree well with or represent
the upper limit of the observed deposition values. The greatest overall
discrepancy between actual and calculated values occurs for particles smaller
than 0.2 urn; fractional pulmonary deposition measured for those particles
during mouth breathing is about 0.1 to 0.2, compared with the predicted 0.3 to
0.6. However, actual data for these smaller particles are based on few experi-
ments.
The most extensive and generally useful comparison of the effects of
respiratory parameters on aerosol deposition have been conducted by Heyder and
coworkers (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 urn and 4.0
urn in diameter, Heyder et al. (1975) measured only total respiratory depo-
sition during either nose or mouth breathing. They sequentially maintained a
given tidal volume and tested different selected breathing rates, inspiratory
flow rates, and particle sizes. They then maintained a fixed breathing rate
and studied deposition at different tidal volumes and inspiratory flow rates.
Likewise, they held respiratory flow rates constant and measured deposition at
different tidal volumes and breathing rates. They demonstrated several
important features of aerosol deposition in the human respiratory airways.
With volumetric flow rate held at 15 liter/minute, the particle size yielding
11-30
-------
I
to
o
V-
o
<
oc
u.
z
o
CO
o
OL
LJ
Q
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
O.I
0
0
TOTAL DEPOSITION FOR NASAL BREATHING
O M/VLTONI, 1500ml J?BPM(I972)
O HEYDER, 1000 ml I3BPM(I975)
A GEORGE, 350-76O ™1 (4 BPM (1967 )
• SHANTY, 1150 ml 18 BPM( 1974)
U th
JL
i i I i t i I
TV 750 ml
JL
JL
t i i i I
| 0.2 0.3 0.5 0.7 1.0 2.0 30 5.0 7.0
PHYSICAL DIAMETER |- AERODYNAMIC DIAMETER, D0r t^m)-
10.0
FIGURE 11-6. Selected data (Giacomelli-Maltoni et al., 1972; Heyder et al., 1975; George and Breslin, 1967;
Shanty, 1974) reported for the deposition in the entire respiratory tract of monodisperse aerosols inhaled
through the nose by people are compared with predicted values calculated by the ICRP Task Group on Lung Dynamics
(Morrow et al., 1966) (from Raabe, 1979).
-------
CJ
ro
1.0
0.9
z 0.8
o
P 0.7
o
g 0.6
U.
^ 0.5
o
t 0.4
CO
g 0.3
LJ
0 0.2
0.!
0
0,
TOTAL DEPOSITION FOR MOUTH BREATHING
T
T
T
T 1—I I I I
1=ICRP-DEPOSITION AFTER NP REGION (1966)
O MALTONI, lOOOTnl I2BPM(I972)
• ALTSHULER, 500^1 I5BPM(I957)
1000 ml 15 BPMCI975)
760ml II BPM(I967)
1000 ml IO-I5BPMII976)
II4O ml I8BPM( 1974)
XT'
O HErDER,
A GEORGE,
O FOORD,
• SHANTY,
A LIPPMANN, -1400ml |4BPM(I969)
TV!450m1
TV 750 ml
i a i
0.2 0.3
PHYSICAL DIAMETER
0.7 1.0 2.0 30 5.0 7.0
— AERODYNAMIC DIAMETER, D0f f pm) -
10.
FIGURE 11-7. Selected data (Giacomel1i-Maltoni et al., 1972; Altshuler et al., 1957; Heyder et al., 1975;
George and Breslin, 1967; Foord et al., 1976; Shanty, 1974; and Lippmann and Albert, 1969) reported for the
deposition in the respiratory tract of monodisperse aerosols inhaled through the mouth by people are compared
with predicted values calculated by the ICRP Task Group on Lung Dynamics (Morrow et al., 1966) (from Raabe, 1979).
-------
i
OJ
OJ
NASOPHARYNGEAL(NP) DEPOSITION
AERODYNAMIC DIAMETERfDor(,im) FOR TV 1450 ml AND15BPM
0.7 1.0 1.5 2.0 3.0 4.0 50 60 80 fO.O
ICRPU966)
It MOUNAM U9TI)
A UPPMANN (1970)
I • • • •
4000 10000
(//mln)
FIGURE 11-8. Selected data (Hounam et al., 1971; Lippmann, 1970 ) reported for the deposition fraction of
monodisperse aerosols in the?human nasopharyngeal (NP) region of the respiratory tract are plotted against
the characteristic term (D Q, where Q is the average inspiratory flow in 1/min) that controls inertial
impaction; for reference, ?fie calculated value (Morrow et al., 1966) is shown for 15 BPM at 1450 ml TV
(from Raabe, 1979).
-------
TRACHEOBRONCHIAL (TB) DEPOSITION
1.0'
0.9
z °-8
£0.7
o
g 0.6
L-
z 0.5
o
b 0.4
CO
8 0.3
LJ
0 0.2
O.I
0
I I ITT
I I I I I I
— ICRP (1966)
OFOORD, 1000 ml 10 BPW
• FOORD, 1000 ml 15 BPW j
ALIPPMANN', »i600 ml I4BPW/-
TV 750cm3
TV 1450 ml
1.0
5.0 10.0
AERODYNAMIC DIAMETER, D
Qr
FIGURE 11-9. Selected data (Foord et a!., 1976; Lippmann and Albert, 1969)
reported for tracheobronchial (TB) depositionjtof monodisperse aerosols inhaled
through the mouth by people are compared with predicted values calculated by
the ICRP Task Group on Lung Dynamics^Morrow et al., 1966) (from Raabe, 1979).
11-34
-------
I
U)
en
1.0
0.9 h
0.8
PULMONARY (P) DEPOSITION FOR MOUTH BREATHING
I I
ICRP -FOR PflRITCLES EVTEWW5
ALTSHULER, 500 ml 13 BPM (1967 )
( »9G6)
A GEORGE,
0 FOORO.
SMANTY
A UPPMONN,
760 ml II BPMU967)
lOOOtnl IS BPM (1976)
IBBPM(t974)
1400ml
0.2 0.3 0.5
PHYSICAL DIAMETER
0.7 1.0 2.0 30
— AERODYNAMIC DIAMETER,
50 7.0 10.0
11-10.
Selected data (AHshuler et al 1967 George .n- Bresl In
-------
the lowest deposition changed from 0.66 urn at TV 250 ml to 0.46 urn at TV 2000
ml. Breathing at TV 1000 ml changed this minimum deposition size from 0.58 urn
at 30 BPM to 0.46 urn at 3.75 BPM. Hence, the particle size of minimum depo-
sition 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 urn D went from 0.08
O T
to 0.4, an increase of a factor of 5.
When Heyder et al. (1975) kept the breathing frequency constant while
changing the flow rate, the deposition for particles smaller than 1 urn remained
essentially unchanged, indicating that inertial impaction was of little impor-
tance in the deposition of submicrometer aerosols. On the other hand, the
deposition of particles larger than 1 urn D was enhanced at high flow rates,
O I
indicating the influence of inertial impaction on the deposition of larger
particles.
Alveolar and total deposition of particles for mouth breathing was
evaluated by Heyder et al. (1980) as a function of their aerodynamic diameter
for two breathing patterns. 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 a decrease of the particle size for maximum alveolar deposition
from 4 mm to 3.2 mm as the mean residence time increased. With this mean
flowrate particles smaller than about 2.3 mm aerodynamic diameter were
exclusively deposited in the alveolar region, indicating their inertia was not
sufficiently 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 aero-
dynamic diameter smaller than about 1.5 mm were exclusively deposited in the
alveolar region of the respiratory tract. From the data of Heyder et al.
11-36
-------
(1980) it can also be seen that alveolar deposition and the particle size for
maximum deposition decrease as the mean flow rate increases. In the above
studies the maximum of alveolar deposition was shifted from 3.5 wn to 3 mm in
aerodynamic diameter.
Considering the limitations of the models used by the ICRP Task Group on
Lung Dynamics (Morrow et al., 1966) and the inherent variability between
individuals, their results for deposition of insoluble hydrophobic particles
provide generally useful guidance for environmental assessment purposes,
especially since they do not underestimate deposition fraction for the chosen
respiratory conditions. These models may represent other breathing conditions
as well, considering that individuals can exhibit differences in deposition
depending on the physiological parameters and the influence of cigarette
smoking and lung disease alterations (Lippmann, 1977).
When aerosols are inhaled through the nose the relatively efficient
filtration action of the nasopharyngeal region eliminates the passage of
particles larger than 10 urn D to the lung and markedly limits the pulmonary
a I
deposition of particles between 2 urn D,,. and 10 um D,^ (Figures 11-3-11-5).
Q I G l
An active person breathing at 15 BPM and a tidal volume of 1450 ml (Figure
11-4) would be expected to deposit in the deep lung about 35 percent, 25
percent, 10 percent, and close to 0 percent of inhaled aerosols of unit
density spherical particles of 0.2 um, 1.0 m, 5.0 um, and 10 um, respectively,
during nose breathing. Likewise, the tracheobronchial deposition would be
expected to be about 2 percent, 3 percent, 6 percent, and 0 percent for these
sizes, respectively.
Mouth breathing markedly alters the deposition of inhaled particles in
humans (Lippmann, 1977; Miller et al., 1979; Heyder et al., 1980) in that
11-37
-------
larger particles can enter both the tracheobronchial region (Figure 11-9) and
the pulmonary region (Figure 11-10). The deposition in the deep lung would be
expected to be about 35 percent, 30 percent, 55 percent, and 10 percent for
inhaled aerosols of unit density spherical particles of 0.2 urn, 1 urn, 5 urn,
and 10 urn, respectively, for a person breathing at 15 BPM with a tidal volume
of 1450 ml. This demonstrates the greater importance of the pulmonary
depositions of larger particles during mouth breathing. In addition, some
larger particles that normally are all collected in the nasopharyngeal region
during nose breathing may pass the glottis and deposit in the upper part of
the tracheobronchial tree during mouth breathing (Figure 11-9; Morrow et al.,
1966; and Lippmann, 1977). Lippmann (1977) calculated that about 10 percent
of particles as large as 15 urn unit density spheres might enter the tracheo-
bronchial tree during mouth breathing (Q = 30 liter/minute). The rest and
larger particles are deposited in the mouth and oral pharynx. Miller et al.
(1979) used this finding in suggesting that an "inhalable" particle sampling
procedure consider particles as large as 15 urn aerodynamic diameter, capable
of penetrating to the tracheobronchial region.
Since much information concerning inhalation toxicology is collected with
beagles or small rodents, it is important to consider the comparative regional
deposition in these experimental animals. Cuddihy et al. (1973) measured the
regional deposition of polydisperse 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 ranged from 0.42 urn
u I
to 6.6 m with geometric standard deviation o = 1.8. These results are
summarized in Figure 11-11 and compared with the Task Group Values for man
with TV 1450 ml, integrated to account for a a = 1.8.
11-38
-------
LO-
CI
UJ
t 0.5-
00
S. o
o >-
K C 02-
0.10
l I I I i t
DC; ?ra£
noc- .'t y-
ooc ,'e-/J
.I 02
ACTIVITY
10 2
i^3CDr-NAWlC Dl-WE TE R («
i i i r^
5 10
0>0
OOJ
tf?
£ tr
o
UJ
t OC.^n
I? 1
o
»-
u
B
05 LO
ACTIVITY
00
I.O-
z
o
5
z
o
a Q2
z
o
S oio-
a
z
o
.03
05 10
ACTIVITY MEDIAN AEcOOYNAMiC
01
\
0.5 10 S ICO
ACTIVITY MEDIAN AERODYNAMIC DIAMETER (,.m.
FIGURE 11-11. Deposition of inhaled polydisperse aerosols of lanthanum oxide
(radiolabeled with 140La) in beagle dogs exposed in a nose-only exposure
apparatus showing (a) the deposition fraction in the total dog, (b) the deposition
fraction in the tracheobronchial region, (c) the deposition fraction in the
nasopharyngeal region, and (d) the deposition fraction in the pulmonary region
(from Cuddihy et al., 1973). The dashed lines indicate the range of observed
values.
11-39
-------
Raabe et al. (1977) have measured the regional deposition of 0.1 um to
3.15 m D, monodisperse aerosols in rats (TV about 2 ml, 70 BPM) and Syrian
or
hamsters (TV about 0.8 ml at about 40 BPM). Their results are summarized in
Figure 11-12. The deposition of particles 3 urn D or less 1n small rodents
Is about one-half the ICRP (Morrow et al., 1966) estimates for humans, although
some comparable deposition values have been reported for humans by Heyder et
al. (1975). The distributions among the respiratory regions during nose
breathing follow a pattern that is very similar to human regional deposition
during nose breathing. The use of rodents or dogs in inhalation toxicology
research for extrapolation to humans does not seem to entail significant
problems associated with differences in regional deposition of inhaled aerosols
based on particle sizes less than 3 urn D__ for inert insoluble particles
a r
during nose breathing.
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 3.15 um
and 2.19 um Dar particles than for smaller particles. In addition, Raabe et
al. (1977) showed that these differences in relative lobar deposition were
related to the geometric mean number of airway bifurcations between trachea
11-40
-------
r 1 1
RAT HAMSTER
N-P A A
T-B n o
P o
RAABE, et ol. (1977)
O.I 0.2 0.3
PHYSICAL DIAMETER
0.7 1.0 2.0 3.0
AERODYNAMIC DIAMETER •
Dor(/im)
5.0
FIGURE 11-12. Deposition of inhaled monodisperse aerosols of fused aluminosi1icate spheres in small rodents
showing the deposition in the nasnpharynqeal (nasal) region, the tracheo-bronchia1 (T-B) region, the pulmonary
region and in the total respiratory tract based upon Raahe et al. (1977).
-------
and terminal bronchioles in each lobe for rats and hamsters. Since similar
morphometric differences occur in human lungs, nonuniform lobar deposition
should also occur. Schlesinger et al. (1977) found nonuniform deposition 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 lobular deposition and the reported incidence of bronchogenic carcinoma
in different human lung lobes.
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 consist of deli-
quescent or hygroscopic particles that may grow in the humid respiratory
airways. That growth will affect deposition (Scherer et al., 1979). 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. However, 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.
Perron (1977) has described the factors affecting soluble particle growth
in the airways during breathing. Basically, his results suggest that particles
1 urn in aerodynamic diameter will increase by a factor of three to four in
aerodynamic diameter during passage through the airways. Nasopharyngeal,
tracheobronchial, and pulmonary deposition of the enlarged particles would be
greater than the deposition expected for the original particle size. Submi-
cronic particles, including those as small as 0.05 urn, will grow by a factor
11-42
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of two in physical diameter, with relatively little effect on deposition;
particles smaller than 0.3 urn Dar may even have some reduced pulmonary depo-
sition with growth because of reduced diffusivity.
Acid sulfates and sulfuric acid formed by the oxidation of S02 1n the
environment may be reduced in acidity by naturally occurring ammonia (NH3) to
form ammonium sulfate (NH4)2$04 and ammonium bisulfate (NH4HS04). Larson et
al. (1977) made short-term measurements that suggest that endogenously gener-
ated ammonia (NI-L) gas in the human airways may rapidly and completely neutra-
lize sulfuric acid aerosols in the concentrations that are normally
encountered in the ambient environment. Further, it is useful to note that
ammonia is generated from food and excreta in inhalation chambers used to
expose experimental animals to sulfuric acid (I-LSO.) so that some neutrali-
zation of sulfuric acid in these test atmospheres may also occur.
Because of SO- oxidation, most environmental aerosols have a major ammo-
nium sulfate (NH4)~S04 or NHLHSO- constituent and possibly some hygroscopic
H~SO., especially in the submicrometer size range. Growth of these particles
will occur in the respiratory airways during breathing. 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 wale""
equal to 26 times its original particle volume. Also, the increased size will
enhance losses by inertia! mechanisms, including impaction in the upper airways
A 1 urn D particle of H2$04 or (NH4)2$04 may grow to nearly 3 urn Dar 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 urn Dar particle,
with the net result that pulmonary deposition is reduced (see Figure 11-3).
Particle growth in the airways may be a protective mechanism, since (a) the
11-43
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deposition in the upper airways is probably less potentially harmful than in
the pulmonary regions; and (b) 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^,
(NH4)HSO., H?SO., organic compounds including polynuclear aromatic hydrocarbons
(PAH), and small particles of other sparingly soluble materials. Some surface
growth due to water adsorption may occur in the airways but 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.
Important examples of coated particles are the fly ash, soot, or other
residual solid particle aerosols released to the environment by fossil fuel
combustion. 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
compunds 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 SCL can adsorb to the particle
surfaces or finer aerosols can aggregate 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
pm D and to particle surface for smaller particles. In either case the
11-44
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fractional 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 a!., 1976). Therefore, the
growth of such surface-coated particles in the airways should be expected to
be much less than for pure deliquescent 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 composed of a deli-
quescent 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 morphology 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 SO-.
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 critically 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
11-45
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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., 1974). 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.
The amount of a gas acting on a given area of the respiratory tract is
reflected by the airway concentration at that level. In general, the more
soluble a gas is the higher it is removed in the respiratory tract. However,
the resultant tissue dose and observed toxicity do not necessarily correlate
with this removal. The gas must first come in contact with the mucous or
surfactant layer lining the airway, depending upon which level of the respi-
ratory tract the gas has reached. Chemical reactions with components in these
layers can occur, thereby increasing the total absorption of the gas, but can
also reduce the amount of the gas penetrating to the tissue. Thus, knowledge
of the biochemical composition of the mucous and surfactant layers is needed
to identify components of these fluids which may react with the gas, influenc-
ing deposition and the resulting toxicity
Various reviews are available on the physical and chemical properties of
bronchial secretions (Barton and Lourenco, 1973; Charman et al., 1974) on the
structure and function of tracheobronchial mucosa (Kilburn, 1967). on the
surface lining of lung alveoli (Rattle, 1965), and on the chemical mechanisms
of action of gases, such as 03 and N02, in biological systems (Menzel , 1976).
Although respiratory surface area differs greatly among various vertebrate
species, the amount of surfactant correlates well with the amount of dipalmitoy'
lecithin in lung parenchyma and with alveolar surface area (Clements et al ,
mo
•19-&9). Dipalmitoyl lecithin has been found to constitute 90-95 percent of
11-46
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recoverable lipid (Balis et a!., we-; Hurst et al., 1973). Thus, the alveolar
region is normally lined with saturated lecithin and is mostly free of other
lipids, proteins and carbohydrates. Ecanow et al. (1967) suggested a possible
role of alveolar surfactants in the uptake of inhaled gas related to the
formation upon inspiration of micelles which can readily solubilize non-polar
gases or inhaled anaesthetics. With release of pressure during expiration,
the micelles return to the subphase, disaggregate, and release the anaesthetic
or molecular gases for absorption by the blood stream.
Physicochemical properties of a gas relevant to respiratory tract depo-
sition 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. 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 SO- 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 effectively increases the diffusion coeffi-
cient. 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, knowledge on the biochemical mechanisms of action
of a given gas may enable one or more of these compartments to be ignored.
11-47
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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 pressure gradient and is termed convection. Molecular
diffusion due to local concentration gradients 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 turbu-
lence 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.
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.
The complex anatomical structure of the nose is well suited for
humidification, regulation of temperature, and removal of many particles and
gases. The air deflecting channels of the posterior 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. This
results in turbulence and eddies which continue as the air traverses the
passages around the turbinates. Proctor and Swift (1971) studied the flow of
11-48
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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.
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 bifur-
cating 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 turbu-
lent air enters the trachea and is directed against its ventral wall imparting
additional turbulence over that associated with the corrugated walls and
length of the trachea.
11-49
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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 transitional. 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. 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 veloci-
ties 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
bifurcation, 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 turbu-
lent eddies are localized in the core.
11-50
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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
l/»in 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.
Diffusion in the lung normally involves at least three gases and the
governing laws are Stefan-Maxwell equations rather than the more familar
Pick's law (Hirschfelder et al., 1954). In a multicomponent mixture, the
transfer of one component is a function of its own concentration as well as of
the concentration of the other components; in the binary case diffusivity is
dependent on the total pressure and temperature of the mixture, the molecular
weights of the two species and is independent of the composition of the
If $7
mixture. Toor (-1-951-) showed that a ternary gas mixture may exhibit one of the
following phenomena: 1) diffusion barrier - when a component gas diffusion
rate is zero even though its concentration gradient is not zero, 2) osmotic
diffusion - when a component gas diffusion rate is not zero even though its
concentration gradient is zero, and 3) reverse diffusion - when a component
gas diffuses against the gradient of its concentration. An exact solution to
the Stefan-Maxell equation is extremely difficult to obtain and in respiratory
physiology, diffusion in the lung has always been assumed mathematically to be
binary. Chang et al. (1975) used a simple gas film model to examine differ-
ences between binary and ternary diffusion. Their results indicate that for
air breathing under normal conditions, gas transport diffusion problems in the
lungs may be examined using binary laws. However, significant errors may
occur if binary laws are used to examine diffusion involving gases, such as
helium, or high pressures.
11-51
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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 function 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 determine the value. Various
functional forms have been proposed in the studies cited above for an appro-
priate expression for the effective axial diffusion coefficient.
Utilizing two dimensionless parameters, Wilson and Lin (1970) showed that
pure convection is the dominant mechanism of gas transport through the 7th
generation of branching in the human lung. Based upon their analyses they
suggested that roughly between generations 8 and 12 Taylor laminar diffusivity
(Taylor, 1953) for parabolic flow in a straight tube would apply. For this
type of diffusion, radial diffusion and axial convection are coupled to pro-
duce an effective block flow with axial diffusion. Block flow convection with
axial diffusion dominates in generations beyond the 12th. Turbulent pipe flow
diffusivity (Taylor, 1954) has been used in the case where flow is turbulent
11-52
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over part of the bronchial tree (Davidson and Fitz-Gerald, 1974; Pedley,
1970).
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 algebraic 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 concentration profiles due to Taylor's mechanism in individual
airways. Using an average standard deviation of airway lengths based upon the
data of Weibel (1963) and various flow theory limiting values, Yu (1975)
demonstrated that Taylor diffusion is everywhere in the tracheobronchial 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 Gumming (1967) to con-
struct 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
11-53
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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 tracheo-
bronchial 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).
As computational models of gas transport, such as that of Pack et al.
(1977), become more refined to include effective diffusion, fluctuating lung
dimensions, etc., one can obtain a better understanding of the effects of
various factors affecting the transport and removal in the lung of gases, such
as SO-. The deposition of SO,, in the respiratory tract depends upon the
transfer of the gas from the air to the liquid coating or mucus membrane
surfaces of the airways and subsequent reaction of the sulfite anion with
constituents of body fluids or cells. Since SO- dissolves readily in water at
or near neutral pH, the moist walls of the airways should readily collect SO-
and diffusion to the surface of the airways from inhaled air should be an
irreversible and efficient process (Balchum et al. , 1960). The rate at which
SO- comes in contact with the walls of the airways is therefore controlled by
the diffusion (Aharonson, 1976).
The theoretical diffusivity of SO- at body temperature (sea level) is
2
0.20 cm /sec. This diffusivity in combination with high solubility in body
fluids is responsible for high deposition in the nasopharyngeal region and
upper airways. Frank et al. (1969) surgically isolated the upper airways of
anesthetized dogs with separate connections for the nose and mouth. Sulfur
dioxide labeled with 35S was passed through this isolated nasopharyngeal
11-54
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region for 5 min, and nearly complete removal was observed for concentrations
of 2.62 mg/m to 131 mg/m (1 to 50 ppm) at a flow rate of 3.5 liter/minute
through the nose. Uptake of the mouth averaged more than 95 percent at 3.5
liter/minute with SO^ levels of 2.62 mg/m3 and 26.2 mg/m3 (1 and 10 ppm).
Strandberg (1964) made similar measurements for rabbits with trachea! cannulas
He observed 95 percent absorption in the respiratory tract at 524 mg SO^/mg
(200 ppm) but at 0.13 mg SO./m (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 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 SO- 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
11-55
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pressure of the vapor. Their analysis for acetone, ether, ozone, and
sulfur dioxide showed the. 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 (1970) there was a 32-fold
increase in the amount of S0~ 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 concentration dependent, as the data of Strandberg (1964)
suggests, increasing airflow rate may increase uptake due to higher
levels of SOp being present along the center of the inspired airstream
for the same input levels.
The deposition and clearance of sulfur dioxide also has been
studied in jm vitro and model systems. In a model of the tracheobron-
chial airways lined with a simulated airway fluid (bovine serum albumin
dissolved in saline), it was observed that S02 was primarily absorbed in
the upper third of the simulated airway with only a small fraction of
the SO- 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 con-
centration 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 SO-, but
11-56
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in its transit through the nose the expired air acquired SO- 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 SO- during the first 15 minutes
after cessation of the SO- exposure.
Melville (1970) exposed humans to SO- levels ranging from 4 mg/m to 9
mg/m (1.5 ppm to 3.4 ppm) for periods up to 10 min. Extraction of SO- during
nose breathing was significantly greater (p < 0.01) than during mouth breathing
(85% versus 70%, respectively) and was independent of the inspired concen-
tration of S02. Andersen et al. (1974) found that at least 99% of 65.5 mg
3
S02/m (25.0 ppm) was absorbed in the nose of subjects during inspiration.
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 aerosol particles and can partici-
pate in a variety of surface interactions. Surface absorption related to
temperature and gaseous vapor pressure occurs if residence sites for the gas
molecules are present on the particles. Such physical adsorption can be
described by the Longmuir 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 (Natusch,
1978). In addition aerosols of liquid droplets can collect and carry volatile
11-57
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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.
Since SO- is found in the gas phase in various environmental aerosols,
the reactions that occur between SO- and aerosols, and the gas-to-particle
conversions that may occur, can greatly influence the regional deposition of
biologically active chemical species. Since SO- is highly soluble in water,
droplet aerosols, including those formed by delinquescent particles, will
collect dissolved SO- and can carry the resulting sulfurous acid deep into the
lung. The presence of certain sulfite species formed by such reactions in
environmental aerosols has been suggested (Eatough et al., 1978). SO- is also
known to be converted to sulfate by reactions catalyzed by some aerosols,
including those containing iron or manganese. The simple adsorption of SO- to
aerosol surfaces by chemical reaction may lead to the aerosol's acting as a
vector for transporting SO- to the deep lung. These types of S0--aerosol
behaviors are apparently responsible for the so-called synergism in biological
response found in experiments using SO- in combination with certain aerosols
(Goetz, 1960; Frank et al., 1962). However, in a study in which rabbits were
exposed to a mixture of SO- and carbon particles that adsorbed SO- on their
surface, the presence of carbon particles in the SO- mixture did not affect
absorption in the respiratory tract to any appreciable extent (Dalhamn and
Strandberg, 1963).
The deposition of the aerosol and gaseous fractions of the sulfur species
can be predicted from the properties of these fractions. Hence, the problem
of estimating deposition (and subsequent biological effects) requires an
11-58
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understanding of the proportion of sulfur species associated with the aerosol
fraction and their chemical properties. Since these reactions are dynamic
processes, the rate and mechanics of the gas-particle chemical reactions,
especially as they may occur in the airways, must be understood.
11.3 TRANSFORMATIONS AND CLEARANCE FROM THE RESPIRATORY TRACT
Particulate material deposited in the respiratory tract may eventually be
cleared by the tracheobronchial ciliary mucus conveyor or nasal mucus flow to
the throat and is either expectorated or swallowed. Other deposited material
may be cleared by either the lymphatic system or transfer to the blood. SO-
probably reacts rapidly with biological constituents to produce S-sulfonate
(Gunnison, 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 are soluble in body fluids, their deposition in the nasal turbi-
nates with subsequent absorption into the blood may be more important than
pulmonary deposition, and total deposition of soluble particles may be more
important than regional deposition. For relatively inert and insoluble parti-
cles, deposition in the pulmonary region, where they may be tenaciously retained,
would be more hazardous. The deposition by dissolution of SO, in the naso-
pharyngeal region may be protective, since it probably involves less serious
biological effects than deposition in the bronchial or pulmonary airways.
Mouth breathing would eliminate the nasal absorption and increase the S02
levels entering the lung. If the particles or SO- 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.
11-59
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11.3.1 Depor ,ted Particulate Material
Because clearance from the three respiratory tract regions (NP, TB, and
P) is physiologically and temporally different, by region of deposition and
characteristic chemical classes of particles (i.e., by relative solubility in
body fluids) (Morrow et al., 1966). 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 relative importance of clearance mechanisms
in different mammalian species.
Particle deposition in the nasopharyngeal (NP) region is limited primarily
to the larger particles deposited by inertia! impaction. Deposition of various
aerosol particles may lead to specific biological effects associated with this
region. For particles that do not quickly dissolve or that 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; Proctor and Wagner, 1965 and 1967; Proctor et al.,
1973).
The posterior portions of the human nose, including the nasal turbinates,
have mucociliary clearance averaging 4 to 6 mm/min with considerable variation
a^cj. 1$&qu,
-------
Group (Morrow et al., 1966) adopted a 4-minute half-time for physical
clearance from the human NP region by mucociliary transport to the throat and
subsequent swallowing.
Soluble particles or droplets are readily assimilated by the mucous
membranes of the NP region directly into the blood. Solubility is graded frorr,
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
conductive airways, particles of various sizes can be deposited. If deposited
in sufficient quantity over a sufficiently long period, some of these particles
can lead to biological responses in the bronchial airways (Ulmer, 1967; Nadel
et al., 1967). 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. In mouth breathing of aerosols, such as during
smoking or under physical exertion, the beneficial filtering of large particles
in the NP region 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 has
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 expectoration or swallowing and
passage through the gastrointestinal tract. Mucus flow influences the ciliary
mucus conveyor (Van As and Webster, 1972; Besarab and Litt, 1970; Oadaian Jt74fj
11-61
-------
The rate of mucus movement is slowest in the finer, more distal airways
and greatest in the major bronchi and trachea. In addition, coughing can
accelerate tracheobronchial clearance by the mucociliary conveyor. The size
distribution of particles affects their distribution in the tracheobronchial
tree. The clearance of small particles, usually deposited deep in the lung,
is slower than for larger particles, which tend to deposit in the larger
airways (Albert et al., 1967b; Albert et al., 1973; Camner et al., 1971;
Luchsinger et al. , 1968).
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., 1972a, 1972b, Camner et al. 1973a, 1973b; Albert
et al., 1967b). Material with slow dissolution rates in the TB compartment
will usually not persist for 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 e-t-aT;1972a; LaBelle et al., 1966; Bohning et al., 1975; Albert et
i /}
al., 1974; Thomson^1973^
Particles smaller than about 10 urn D are deposited to some extent in
Q T*
the pulmonary region of the lung upon inhalation (Figures 3, 4, and 10),
although the deposition of particles much smaller than 0.01 pm 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 (Blank et al.,
11-62
-------
1969; Balis et al., 1971; Rattle, 1961b; Kott et al., 1974; Henderson et al.,
1975). There are no ciliated cells in the epithelium of this region, and flow
of liquid from pulmonary airspaces into the tracheobronchial region is minimal
in humans (unlike murine species; Gross et al., 1966). Insoluble materials
that deposit in the human pulmonary region are usually retained for extended
periods.
A description of the clearance of particles from the pulmonary region
should characterize particle distribution and redistribution. Usually,
relatively insoluble particles are rapidly phagocytized by pulmonary macro-
phages (LaBelle and Brieger, 1961; Sanders and Adee, 1968; Green, 1971; Green,
1974; Ferin, 1965; Camner et al., 1973a; Camner et al., 1974; Camner et al.,
1973b; Chapman and Hibbs, 1977). Smaller particles may not be as efficiently
or rapidly collected as larger particles (Hahn et al., 1977); some particles
may enter the alveolar interstitium by pinocytosis (Strecker, 1967). Chemo-
toxic processes have been identified in phagocytosis (Metzger, 1968), and some
particles may be cytotoxic to macrophage cells (Allison et al., 1967). Migra-
tion and grouping of macrophages laden with particles can lead to redistri-
bution of evenly dispersed particles into clumps and focal aggregations of
particles in the deep lung. Some 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 pulmonary interstitium (Strecker, 1967), impeding mechanical redistri-
bution or removal (Felicetti et al., 1975). Only the very smallest particles
(smaller than 10 nm in physical diameter) can readily diffuse through pores
directly into the blood, passing intact through the air-to-blood cellular
11-63
-------
barrier of the gas-exchange regions of the lung (Raabe et al., 1978a; Raabe et
al., 1978b; Gross, 1954; Raabe, 1979).
Another possible clearance route for migrating particles and particle-laden
macrophages is the p'/imonary lymph drainage system with translocation 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) studied the pulmonary clearance of extremely insoluble
95
and inert particles 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 UO. (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 acci-
dentally inhaled, relatively insoluble 239PuCL (plutonium 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. Pulmonary
clearance half-times as long as 1000 days have been reported for extremely
insoluble particles of plutonium 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.
11-64
-------
Because of the slow clearance by the various mechanical pathways, dis-
solution and associated 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 properties at the normal lung fluid pH of about 7.4 (Kanapilly,
1977). Raabe et al. (1978a) suggested that the apparent dissolution of highly
insoluble PuO- actually may be due to fragmentation into particles small
enough to move readily into the blood, rather than to true dissolution.
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 material, the time required to dissolve half the
mass of (monodisperse) particles of initial physical diameter (D ) is given
by:
= 0.618 a pD /or k (5)
with p the physical density of the particles and a and a the volume and
surface shape factors, respectively (for spherical particles a$/av = 6).
The particles would be expected to be completely dissolved at a time, tf,
given by:
tf = 3av p D0/ask (6)
11-65
-------
Mercer (1967) also calculated the expected dissolution half-time for poly-
disperse particles when their mass median (physical) diameter in the
lung is known:
Tl/2 = °'6 °v
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) = M/MQ =
where f1 = (l-f2), 0 = agKt/avp(MMD) and f-l, f2, A^ and \2 are functions of
the geometric standard deviations as defined by Mercer (1967). Therefore, for
dissolution-controlled pulmonary clearance, smaller particles will exhibit
proportionately 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.
Since respiratory tract clearance may begin immediately after the initial
deposition, the dynamics of retention can become quite complicated when addi-
tional deposition is superimposed on clearance phenomena. Extended or chronic
11-66
-------
exposures are the rule for environmental aerosols, and particulate material
may accumulate in some portions of the lung (Davies, 1963; Walkenhorst, 1967;
Davies, 1964a; Einbrodt, 1967).
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 a!., 1970; Luchsinger et al.,
1968; Aldas et al., 1971; Ferin, 1967; Barclay et al., 1938; Morrow et al ,
1967a; Morrow et al., 1967b; Friberg and Holma, 1961; Holma, 1967, Kaufman and
Gamsus, 1974). The lung burden or respiratory tract burden can be represented
by an appropriate retention function with time as the independent variable
(Morrow, 1970a; Morrow, 1970b). For models based on simple first-order kinetics
the lung burden (y) at a given time during exposure is controlled by the
instantaneous equation (Raabe, 1967):
- E - V
where E is the instantaneous deposition rate of particulate material deposited
in the lung per unit time during an inhalation exposure and X, is the fraction
of material in the lung cleared from the lung per unit time. For an exposure
that lasts a time t , the lung burden from the exposure is given by:
'Ve
ye = (E - Ee l e)/\1 (10)
where E is the average exposure rate. After the exposure ends, the clearance
is governed by:
dy_ _ A,y (11)
dt "
11-67
-------
and the lung burden is given by:
-At
y = ye e i (12)
where y is the lung ourden at the end of the exposure period (t ). Hoi linger et
al. (1979) used this simple model to describe the deposition and clearance of
inhaled submicronic ZnO in rats (Figure 11-13) where the concentration of zinc
(as Zn) in the lungs (as described by Equations 10 and 12) is superimposed on
the natural background concentration of zinc in lung tissue. The normally
' ~1
insoluble zinc has only a 4.8-hour dissolution half-time (A, = 0.21 h ) for
this aerosol. Of course, environmental aerosol exposures continue so that a
steady state lung burden may be expressed by:
yss = EAi d3)
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, as given in
Equations 10 and 12, the lung burden during exposure is given by:
n n -At
y = Z y. = Z (E. - E.e 1 e)/i (14)
e i=l n i=l 1 1
where the subscript i is the index associated with each of the n different
clearance compartments. The steady state value for environmental aerosols is:
11-68
-------
(O
1000
800
LJ 600
! 500
£ 400
X
ui 300
tr
0 200
c
M
i 100
60
60
50
- EXPOSURE PERIOD
r
T
i—r
T
CLEARANCE PERIOD
LUNG I DotoVofuc+SE
Controls
>
Base Level 114±3(SE)
JL
JL
JL
L
-20 -10 -10 -5
0 5 10 15 20 25 30
TIME (HOURS) POST EXPOSURE
35 40 45 50
FIGURE 11-13. Single exponential model, fit by weighted least-squares, of the buildup (based on text equation 10)
and retention (based on text Equation 12) of zinc in rat lungs (data from Hoi linger et al. 1979).
-------
yss = !Ei/Ai (15)
1=1
Likewise, the retention, when exposure ends, is given by (Raabe, 1967):
n -A.t
y
= I (y,e 1 ) (16)
where each of the X. values translates to a clearance rate for each of the
compartments given by half-time T,^ = 1n 2/Ai (Figure 11-14).
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). In such a model, the pulmonary region is
treated as one complex, well-mixed pool into which material is added and
removed during exposure, as given by the instantaneous equation:
dy_
dt = E - Apy/t [y = 0 at t = 0] (17)
where y is the total lung burden at a given time (t), E is the average deposi-
tion rate of inhaled particulate material in the lung, and A 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 arbi-
trary; time is taken as zero only at the beginning of the inhalation exposure,
11-70
-------
100.0-3
NxE|r l.4mg/doy
\Ti=50d
» •»
EXPOSURE \
PHASE
te=20doys
0 200 400 600 800
TIME, days
1000
1200
MOO
FIGURE 11-14. Example of the use of the sum of exponential models for describing lung uptake during inhalation
exposure (Equation 14) and retention (clearance phase) after exposure ends (Equation 16) for three lung
compartments with half-lives 50 d, 350 d, and 500 d, and twenty-day exposure rates of 1.4 mq/d (Ej). 1.7 mq/d (E?),
and 2.1 mq/d (E3), rpspectively (from Raabe, 1979).
-------
when the lung burden is nil. Thus, during an exposure lasting until time (te),
the pulmonary burden (yfi) is given by (Raabe, 1967):
ye = Ete/(\p + i) (18)
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 ends is given by (Raabe, 1967):
y = ye te*p t Xp = At P [t = te + tp] (19)
where time (t) is reckoned from the beginning of exposure and is equal to
the sum of the exposure time (t ) and the time after exposure (t ). This
model is illustrated in Figure 11-15.
Deposited particulate material cleared from the lung is usually trans-
formed 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 toxi-
cants after deposition in the lung could define the probable target organs and
indicate potential pathogenesis of resulting disease.
Multicompartmental models that describe biological behavior can become
extremely complex. Each toxicant or component of aerosol particles deposited
11-72
-------
100.0 F
I
*»J
OJ
en
E
u. -
o -J
LU CC
Q LU
CD
O O
c
o
CL
LU
O
100 1,000
TIME^doys
lopoo 100,000
FIGURE 11-15 Example of the use of the power function model for describing lung uptake during inhalation exposure
(text Equation 18) and retention (clearance phase) after exposure ends (text Equation 19) for a twenty-day exposure
at 8.5 mq/d (E) (adapted from Raabe 1967).
-------
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 (Figure 11-16) shows 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.
A more specific model of the systemic metabolism of inhaled aerosols is
144
shown (Figure 11-17) for cerium trichloride ( CeCU) contained in particles
of cesium chloride (CsCl) with a MMAD of about 2 urn (Boecker and Cuddihy,
3 i
1974). The resultant pattern of combined uptake and retention in various
organs after inhalation exposure is illustrated in Figure 11-18. In this
case, the exposure is acute; the fate of relatively insoluble materials in
chronically inhaled environmental aerosols may involve more complex relation-
ships.
11.3.2 Absorbed S02
S02 coming in contact with the fluids lining the airways (pH 7 4) should
dissolve into the aqueous fluid and form some bisulfite (HSO,-) and considerable
2~
sulfite (S03 ) anions. Because of the chemical reactivity of these anions,
various reactions are possible, leading to the oxidation of sulfite to sulfate.
Clearance of sulfite from the respiratory tract may involve several
intermediate chemical reactions and transformations. Gunnison (1971) has
identified S-sulfonate in blood as a reaction product of inhaled SO-. The
reaction rate is rapid, if not nearly instantaneous, so that there is no
11-74
-------
FTPURF 11-16 Model of the multicompartmental deposition, clearance, retention
tJanslocation and excretion of inhaled particulate material in the respiratory
tract and Ussues of the body; the numbered circles represent the transfer
rate constants (from Cuddihy, 1969).
11-75
-------
Re&pifQtory Environment
5
•t;
^ £
0.65
I
Cow
>C'1-
[ff^r *
N
re
> c
b
c
0
39
70
7?
4 1
3*
2«
So''
02-
-i »•
•^
-OOOOi
-OOOOi
- Oi
O.O4-
fccet
Oi —
-oo4_:
~^*~
-0000:
Tronsfer Ro»e Con»1or.!s
Eiprettvd 0» Free lion o?
Comporlmtnlol Content
per Doy
FIGURE 11-17. Multicomponent model of the deposition, clearance retention,
U^slocation and excretion of an example sparingly soluble metallic compound
( CeCl3 continued in CsCl particles) inhaled by man or experimental animals;
the rate constants are based upon first order kinetics as in text Equation 11
(from Boecker and Cuddihy, 1974).
11-76
-------
•00
0'
J-.
DAYS POST-INHALATION EXPOSURE
*oc
FIGURE 11-18. Example of the organ retention of an inhaled sparingly soluble
metallic compound assuming a single acute exposure demonstrating the trans-
location from lung and build-up and clearance from other organs (from Boecker
and Cuddihy, 1974).
11-77
-------
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.
Potentially detrimental reactions are most likely to be of biological concern
when they occur in the pulmonary and bronchial regions of the lung.
Desorption from the upper respiratory tract may be expected whenever the
partial pressure of SO- on mucosal surfaces exceeds that of the air flowing
by. Desorption of SO- 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 S02
in the lungs of dogs that apparently was carried by the blood after nasal
deposition. In human subjects breathing 42.2 mg/m (16.1 ppm) through a mask
for 30 minutes, 12% of the SO- 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 SO- 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 SO- on tracheobronchial clearance in 9 healthy, nonsmoking
adults was studied by Wolff et al. (1975). Technetium Tc 99m albumin aerosol
(3 |jm MMAD, o = 1.6) was inhaled as a bolus under controlled conditions. A
three hour exposure to 13.1 mg S02/m (5.0 ppm) had no significant effect on
mucociliary clearance in resting subjects, 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 S0-/m3 (5.0 ppm) and
65.5 mg S02/m (25.0 ppm), but not 2.62 mg S0-/m3 (1.0 ppm), was observed by
Andersen et al. (1974). Decreases were greatest in the anterior nose and in
11-78
-------
subjects with initially slow mucus flow rates. Newhouse et al. (1978)
assessed the effect of oral exposure to SCL on bronchial clearance of a radio-
active aerosol (3 urn MMAD) in healthy nonsmoking males and females who exer-
cised 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 SOp/m (5.0 ppm), clearance was increased.
11.3.3 Particles and SO- Mixtures
The presence of adsorbed SO- or other sulfur compounds on aerosol sur-
faces 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 particles may also undergo reaction with
sulfite or other species upon contact with body fluids.
The formation of sulfate anions by oxidation of SO- 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 mate-
rials, 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 and
diffusional dilution into body fluids.
11.4 DISCUSSION AND SUMMARY
When aerosols or S0? are inhaled by man or experimental animals, different
fractions of the inhaled materials deposit by a variety of mechanisms in
various locations in the respiratory tract. Particle size distribution,
particle chemical properties, S02 diffusivity, respiratory tract anatomy, and
airflow patterns all influence the deposition. The predicted regional
11-79
-------
deposition percentages for man given by the Task Group on Lung Dynamics are in
reasonable agreement with available experimental measurements and provide
useful general guidelines for estimating particle deposition for environmental
assessment. Nose breathing and mouth breathing provide somewhat contrasting
deposition patterns. During nose breathing nearly all particles larger than 8
urn in aerodynamic diameter are usually collected in the nasopharyngeal region,
while this natural filtration can be circumvented during mouth breathing so
that some particles as large as 15 urn aerodynamic diameter may enter the
tracheobronchial region. After deposition, the inhaled material will be
translocated by processes that depend on the character of the particles and
their site of deposition. If the material is quite soluble in body fluids, it
will readily enter the bloodstream. Relatively insoluble material that lands
on ciliated epithelium, either in the nasopharyngeal 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 lymphatic drainage. Some material from the
pulmonary region may enter the TB region and be cleared by the mucociliary
conveyor.
Both deposition and retention play roles in determining the effects of
inhaled particulate toxicants and SO-. Everyone is environmentally exposed to
a variety of dusts, fumes, sprays, mists, smoke, photochemical particles, and
combustion aerosols, as well as SCL and other potentially toxic gases. The
particle size distribution and chemical and physical composition of airborne
particulate material require special attention in toxicological evaluations
11-80
-------
since a wide variety of physicochemical properties may be encountered in both
experimental and ambient inhalation exposures. Sulfur dioxide may deposit
directly in the airways or enter into a variety of gas-to-particle conversions
or gas-particle chemical and physical reactions. SO- must be considered with
aerosol behavior in the atmosphere and during inhalation deposition, as well
as in relation to respiratory responses.
The three functional regions (NP, TB, and P) of the respiratory airways
can each be characterized by major mechanisms of deposition and clearance
(Table 11-1). 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.
11-81
-------
TABLE 11-1. SUMMARY OF THE RESPIRATORY DEPOSITION AND CLEARANCE
OF INHALED AEROSOLS (FROM RAABE, 1979)
REGION DEPOSITION CLEARANCE
IMPACTION MUCOCILIARY
NP DIFFUSION SNEEZING
NASOPHARYNGEAL INTERCEPTION BLOWING
ATTRACTION DISSOLUTION
IMPACTION MUCOCILIARY
DIFFUSION COUGHING
TB SETTLING DISSOLUTION
TRACHEOBRONCHIAL INTERCEPTION
ATTRACTION
DIFFUSION DISSOLUTION
P SETTLING PHAGOCYTOSIS
PULMONARY ATTRACTION LYMPH FLOW
INTERCEPTION
11-82
-------
11. RESPIRABLE AEROSOL SAMPLING
A fundamental principle in inhalation toxicology is that it is the deposi-
tion of inhaled particulate materials in sensitive regions of the respiratory
tract or subsequent transformations and translocations to sensitive organs or
cells that leads to potentially deleterious biological responses. Particles
(or gases) that deposit neither in sensitive regions of the airways nor in
regions conducive to translocation to sensitive organs are cleared with rela-
tively low probability of causing injury or disease (Morrow, 1964-). For
example, large insoluble particles that deposit almost exclusively in the nose
are prevented from reaching the lung during nose breathing and are less likely
to lead to injury than smaller particles having appreciable lung deposition.
This principle was early observed in coal mining in Europe; it was found
that the air concentration of dust in mines didn't necessarily correlate to
the incidence of respiratory disease. However, a meaningful comparison was
possible when samples were aerodynamically fractionated to provide a separate
measure of the respirable dust levels. This led to the use of "respirable"
dust samples in the coal mining industry (Walton, 1954). Further, the
repeated practice of collecting respirable dust samples is necessary, since
there is variability in the aerodynamic size distribution of dust depending on
age and source.
On this basis the principle of "respirable" dust sampling was developed
(Lippmann, 1970b). In this context the word "respirable" means broadly "fit
to be breathed." The objective is to collect samples that have been purposely
biased in favor of the smaller, more respirable sizes. Only the smaller size
fraction is measured to yield the "respirable" aerosol concentration. No
specific "cut-size" was defined, since it is clear that there is no size for
ll-82a
-------
which all particles smaller are respirable and all larger are not. Instead,
weighting functions were defined that simulated the size classification
normally afforded by the human naso-pharyngeal deposition during nose
breathing. Another factor involved in describing a respirable fraction was
the availability of a simple instrument that would provide a practical means
for collection of these size-classified samples.
Two weighting functions have been generally used as criteria for respir-
-------
o.
w
c
111
o_
BMRC curve
LASL curve
0 2 4 6 8 10
Diom unit density sphere —
FIGURED /H9
Respirable aerosol sampling criteria for penetration of
repirable aerosols through a size-classifier to provide for
collection of particles that have the greatest potential for
pulmonary deposition if inhaled (from Raabe,1979).
ll-82c
-------
efficiently deposited in the pulmonary region during mouth breathing (Fig. &
fl-3
than during nose breathing (Fig.^-) are weighted more than would be justified
by the ICRP Task Group nose breathing models.
It is important to note that the "respirable" dust sample is thus not
intended to be a measure of the lung deposition but only a measure of aerosol
concentration for particles that are the primary candidates for lung deposi-
tion. Clearly, the respirable dust sample is only biologically relevant for
aerosols whose upper respiratory deposition is not expected to be of major
health impact. Soluble aerosols of toxic substances can enter the blood
directly from the nasal mucosa or the gastrointestinal tract during clearance
from the nose, and the deposition of particles as large as 100 ym or even
larger in the nose may be the .primary hazard for such aerosols.
ll-82d
-------
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ciliary activity. Pract. Otorhinolaryng. (Basel) 24:383, 1962.
Van Wijk, A. M., and H. S. Patterson. The percentage of particles of different
sizes removed from dust-laden air by breathing. J. Ind. Hyg. Toxicol.
22:31, 1940.
Verzar, F- J. Keith, and V. Parchet. Temperatur und feuchtigkeit der luft in
den atemwegen. Pflugers Archiv. 25J7:400, 1953.
Von Hayek, H. The Human Lung. Hafner Publishing Co. Inc., New York, 1960.
11-103
-------
Waligora, S. J., Jr. Pulmonary retention of zirconium oxide ( Nb) in man and
beagle dogs. Health Phys. 20:89, 1971.
Walkenhorst, W. Untersuchungen an einem nach teilchengrossen geordneten
mischstaub im atembarden korngrossenboreich. In: Inhaled Particles and
Vapours II. C. N. Davies, ed., Pergamon Press, Oxford, 1967. p. 563.
Walton, W. H. Theory of size classification of airborne dust clouds by
elutriation. Brit. J. Appl. Phys. Suppl. 3:529, 1954.
Wang, C. S. Gravitational deposition from laminar flows in inclined channels.
J. Aerosol Sci. 6:19, 1975.
Wanner, A., J. A. Hirsch, D. E. Greeneltch, E. W. Swenson, and T. Fore.
Tracheal mucous velocity in beagles after chronic exposure to cigarette
smoke. Arch. Environ. Health. 27:370-371, 1973.
Washburn, E. W., Ed. National Research Council of the U.S.A. International
Critical Tables of Numerical Data, Physics, Chemistry and Technology.
Vol.3. New York: McGraw-Hill, 1928. 444pp.
Weibel, E. R. Morphometric estimation of pulmonary diffusion capacity. Resp.
Physio!. 14:26, 1972.
Weibel, E. R. Morphometry of the Human Lung. Academic Press. New York, 1963.
Weibel, E. R., and H. Elias. Introduction to stereologic principles. In:
Quantitative Methods in Morphology. E. R. Weibel, and H. Elias, eds.,
Springer-Verlag, Berlin, 1967. p. 89.
West, J. B. Observations on gas flow in the human bronchial tree. In:
Inhaled Particles and Vapours. C. N. Davies, ed. , Pergamon Press, Oxford,
1961. p. 3.
West, J. B. Observations on gas flow in the human bronchial tree, pp. 3-7.
In C. N. Davies, Ed. Inhaled Particles and Vapours. Proceedings of an
International Symposium organized by the British Occupational Hygiene
Society, 1960. New York: Pergamon Press, 1961.
West, J. B. Respiration Physiology-the essentials. Williams and Wilkins Co.,
Baltimore, Md., 1977, pp. 185.
West, J. B. Respiratory Physiology: the Essentials. Williams and Wilkins,
Philadelphia, 1974.
Whimster, W. F. The microanatomy of the alveolar duct system. Thorax 25:141,
1970. —
Whitby, K. T. The physical characteristics of sulfur aerosols Atmos. Environ
12:135, 1978.
11-104
-------
Additional References Recommended for Consideration in Chapter 11
Bar-Ziv, J., and G. M. Goldberg. Simple Siliceous pneumoconiosis in Negev
Bedouins. Arch. Environ. Health 29:121-126, 1974.
Brambilla, C., J. Abraham, E. Brambilla, K. Benirschke, and C. Bloor. Comparative
pathology of silicate pneumoconiosis. Am. J. Pathol. 96:149-170, 1979.
Camner, P. and K. Philipson. Human alveolar deposition of 4 urn Teflon particles.
Arch. Environ. Health 33(4):181-185, 1978.
Chan, L. T. and M. Lippman. Experimental measurements and empirical modeling
of the regional deposition of inhaled particles in humans. Am. Ind. Hyg.
Assoc. J., 1980. (in press)
Dejours, P. Oxygen Demand and Gas Exchange in Evolution of Respiratory Processes:
A Comparative Approach. Stephen C. Wood and Claude Lenfant, eds., Volume
13 of Lung Biology in Health and Disease (executive editor: Claude
Lenfant). Marcelu Dekker, Inc. New York, 1980. pp. 1-49.
Heyder, J. , J. Gebhart, and W. Stahlhofen. Inhalation of Aerosols: Particle
Deposition and Retention. In: Generation of Aerosols and Facilities for
Exposure Experiments. K. Willeke, ed., Ann Arbor Science Publishers,
Inc., 1980.
Hyde, D. M., N. E. Robinson, J. F. Gillespie, and W. S. Tyler. Morphomety of
the distal air spaces in lungs of aging dogs. J. Appl. Physiol. 43(1):86-91,
1977.
Lippman, M., D. B. Yeates, and R. E. Albert. Deposition, Retention and Clearance
of Inhaled Particles. Br. J. Ind. Med., 1980. (in press)
Richards, D. W. Pulmonary Changes Due to Aging. In: Handbook of Physiology
Respiration (Volume II). W. 0. Fenn and H. Rahn, eds., American Physiological
Society. Washington, DC, 1965. pp. 1525-1529.
Sherwin, R. P., M. L. Barman, and J. L. Abraham. Silicate Pneumoconiosis of
Farm Workers. Laboratory Investigations 40(5):576-582, 1979.
Stauffer, D. Scaling Theory for Aerosol Deposition in the Lungs of Different
Mammals. J. Aerosol Sci. 6:223-225, 1975.
Weibel, E. R. Morphometrics of the lung. In: Handbook of Physiology Respiration
(Volume I). W. 0. Fenn and H. Rahn, eds. American Physiological Society,
Washington, DC, 1964. pp. 285-307.
Weibel, E. R. Oxygen Demand and Size of Respiratory Structures in Mammals.
In: Evolution of Respiratory Processes: A Comparative Approach. Steven
C7 Wood and Claude Lenfant, eds., Volume 13 of Lung Biology In Health and
Disease (executive editor Claude Lenfant). Marcel Dekker, Inc., 1980.
-------
11. RESPIRABLE AEROSOL SAMPLING
A fundamental principle in inhalation toxicology is that it is the deposi-"
tion of inhaled participate materials in sensitive regions of the respiratory
tract or subsequent transformations and translocations to sensitr^organs or
cells that leads to potentially deleterious biological responses. Particles
(or gases) that deposit neither in sensitive regions of the airways nor in
regions conducive to translocation to sensitive organs/are cleared with rela-
tively low probability of causing injury or disease^(Morrow, 1964). For
example, large insoluble particles that deposit/almost exclusively in the nose
are prevented from reaching the lung during ifose breathing and are less likely
to lead to injury than smaller particles/having appreciable lung deposition.
This principle was early observed /in coal mining in Europe; it was found
that the air concentration of dust ;fn mines didn't necessarily correlate to
the incidence of respiratory disease. However, a meaningful comparison was
possible when samples were ae|7bdynamically fractionated to provide a separate
measure of the respirable d-dst levels. This led to the use of "respirable"
dust samples in the coal/mining industry (Walton, 1954). Further, the
/
repeated practice of jebllecting respirable dust samples is necessary, since
there is variability in the aerodynamic size distribution of dust depending on
ity
age and source./'
/
On this basis the principle of "respirable" dust sampling was developed
(Lippmann,/1970b). In this context the word "respirable" means broadly "fit
to be b/eathed." The objective is to collect samples that have been purposely
biased in favor of the smaller, more respirable sizes. Only the smaller size
fraction is measured to yield the "respirable" aerosol concentration. No
specific "cut-size" was defined, since it is clear that there is no size for
ll-82a
-------
Missing reference page 11-105 from first printing
Chapter 11 - PM/SO
/>
Wilson, T. A., and K. Lin. Convection and diffusion in the airways and the
design of the bronchial tree. In: Airway Dynamics Physiology and
Pharmacology. A. Bouhuys, editor. Springfield, 111. Thomas 1970.
pp. 5-19.
Wolff, R. K., M. Dolovich, C. M. Rossman, and M. T. Newhouse. Sulfur dioxide
and tracheobronchial clearance in man. Arch. Environ. Health 30:52.1-527,
1975. ~
Yeh, H. C. Use of a heat transfer analogy for a mathematical model of
respiratory tract deposition. Bull. Math. Biol, 35:105, 1974.
Yeh, H. C,, A. J. Hulbert, R. F. Phalen, D. J. Velasquez, and T. D. Harris. A
steroradiographic technique and its application to the evaluation of lung
casts. Invest. Radiol. 10:351, 1975.
Yeh, H. C. , R. F. Phalen, and 0. G. Raabe. Factors influencing the deposition of
inhaled particles. Environ. Health Persp. 15:147, 1976.
Yus C. P. An equation of gas transport in the lung. Resp. Physiof. 23:257,
1975.
Yu, C. P. Precipitation of unipolarly charged particles in cylindrical and
spherical vessels. J. Aerosol Sci. 8:237, 1977.
Chapter 11 - PM/SO?
Errata
REFERENCE LIST CORRECTIONS
Page Par/Line Delete Insert
11-86 After ~ Clements, J. A., J. Nellenbogen,.
8th Ref. anc' H. J. Trahan, Pulmonary
surfactant and evolution of
the lungs. Science 169:
603-604, 1970.
11-93 After ~ Kawecki, J. M. Emmission of
llth Ref. Sulfur-Bearing Compounds
from Motor Vehicle and Air-
craft Engines, A Report to
Congress. EPA-600/9-78-028,
U. S. Env. Prot. Agency.
Aug. 1978.
11-96 After - Menzel, D. B. The role of
5th Ref. free radicals in the toxicity
of air pollutants (nitrogen
oxides and ozone). In:
Free Radicals in Biology,
Vol. II, Academic Press,
New York, 1976. pp. 181-202.
-------
12. TOXICOLOGICAL STUDIES
12.1 INTRODUCTION
This chapter describes j_n vitro and j_n vivo studies of sulfur oxides and
particulate matter. The toxic effects of sulfur oxides and of atmospheric
aerosols overlap because a major component of atmospheric aerosols are salts
of sulfuric acid (ammonium sulfate, sodium sulfate, zinc ammonium 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 (S02) 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 [(NH.^SOJ and
ammonium bisulfate (NhLHSO.) in the ambient air, the animal exposure chamber
atmosphere before inhalation, or to a lesser degree simultaneously upon
inhalation. Biological interaction can also occur, resulting in a situation
where the effect of a mixture of pollutants has additive, synergistic, or
antagonistic health effects compared to the effects of the single pollutants.
This chapter will also present brief discussions of the toxicology of
organic compounds so far detected as atmospheric particulates. Unfortunately,
our knowledge of the exact chemical nature and health effects of these
materials is incomplete. A more complete treatment of this subject can be
found in the health assessment document on polycyclic organic matter (POM).
A similar overview is provided for heavy metals. Individual documents and
275-283
reviews have covered this topic in more detail.
12-1
-------
Because of the relative toxicity of various particles and their
interaction with S0?, this Chapter should be taken as a whole and not as
artificially segregated major topics. Discussions of the deposition and
clearance are limited; the reader, therefore, should be familiar with the
content of Chapter 11 which presents this subject in detail.
12.2 EFFECTS OF SULFUR DIOXIDE
12.2.1 Biochemistry of Sulfur Dioxide
Much of the discussion under 12.2.1 relates to i_n vitro experiments, ^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
culture 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
present, the effect would not be observed. In addition, the dosimetric
relationships of j_n vitro studies to i_n vivo studies are not defined.
Therefore, effective concentrations cannot be extrapolated from j_n vitro to
j_n vivo studies. For the above reasons, there is some controversy as to whether
these iji vitro reactions can be extrapolated to mechanisms of toxicity.
Nonetheless, sound jln vitro investigations can show whether a given pollutant
has the potential of altering a given target. I_n vitro studies are best used
to provide guidance for j_n vivo investigations or when j_n vivo results have
been observed. In the latter case, the relatively simplified _i_n vitro system
can sometimes elucidate the potential mechanisms of toxicity. To these ends,
they can be useful.
Knowledge of the chemistry of sulfurous acid and S02 is necessary to
understand the physiological and toxicological properties of SO,. Sulfur
12-2
-------
dioxide is the gaseous anhydride of sulfurous acid. It dissolves readily in
water; and at physiological pH near neutrality, hydrated S02 readily dis-
sociates to form bisulfite and sulfite ions as illustrated by Equations 12-1
and 12-2. The rate of hydration of S02 is very rapid; the rate constant of
hydration, k^ is 3.4 x 10 M*1 sec"1, and the rate constant of the reverse
reaction is 2 x 10 M"1 sec"1 at 20°C (Equation 12-1).1 The dissociation
constants of sulfurous acid are 1.37 and 6.25 (in dilute salt solutions),1 so
at pH 7.4 sulfite ions are present at about 14 times those of bisulfite, but
in rapid equilibrium. Hence, SOp can be treated as bisulfite/sulfite and
conversely.
S02 + H20 ^ H2S03 12-1
H+ + HSO~ ^ ^ 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-- The
chemical reactions of bisulfite with biological molecules are discussed in
detail in Appendix I. Briefly, there are three important reactions: sulfonation,
autoxidation, and addition to cytosine.
Sulfonation results from the nucleophilic attack of bisulfite on
disulfides:
RSSR' «• HSO, N RSSO," * R'SH
3 -s; 3 12-3
12-3
-------
This reaction is also known as sulfitolysis. The products of the reaction are
S-sulfonates (RSSO-") and thiols (R'SH). Direct evidence for the formation of
plasma S-sulfonates has been found. 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) and nondiffusable (nondialyzable or protein) S-sulfonates.
The exact molecular species has not been determined. 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
(see Appendix I, Section 1.0).
Similar reversible nucleophilic addition of bisulfite to a variety of
biologically important molecules has been reported (see Appendix I). The
toxicologies! 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 SCL.
Autoxidation of bisulfite occurs through a multistep chain reaction (see
Appendix I, Section 2.0). These reactions may be important because they
produce hydroxyl (-OH) and superoxide (-02~) 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 radiation. Autoxidation of
bisulfite could lead to increased concentrations of these reactive chemical
species within the cell and could hypothetically lead to similar adverse
12-4
-------
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. (See Appendix I,
Section 3.0.) No direct evidence has been presented to support peroxidation
of cellular lipids as a mechanism of toxicity of S02.
Bisulfite addition to cytosine can result in deamination to form uracil.
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; transamination also requires high sulfite and amine
concentrations. The decomposition of the cytosine-sulfite adduct is the rate
limiting step in both reactions.
12.2.1.2 Potential Mutagenic Effects of Sulfite and SO,,—At the present time,
no clear evidence exists for mutagenicity caused by S02 or sulfite. However,
because of the reactivity of sulfite with cytosine, the potential mutagenic
properties of sulfite and S02 have been examined. Such experiments are detailed
in Appendix I, Section 6.0. To date, microbial experiments with high concentrations
of sulfite in acid solutions i_n vitro have produced mutations. These conditions
would be similar to those favoring deamination of cytosine. Experiments
conducted at low concentrations and neutral pH are less convincing. For
example, the microbial assays were not done with strains of Salmonella known
to be sensitive to mutagens (Ames Assays). Negative experiments have been
reported when insects (Drosophila) and mammals (mice) were exposed. Cytotoxicity,
rather than mutagenicity, appears when cultured animal and human cells are
12-5
-------
exposed to sulfite. (See Table 12-1 for summary; details in Appendix I,
Section 6.0.)
12.2.1.3 Metabolism of Sulfur Dioxide
12.2.1.3.1 Integrated Metabolism. There are several studies of the metabolism
of exogenously supplied S02, sulfite, or bisulfite. Quantitative differences
exist between inhaled and ingested S02 with regard to the rate of clearance of
69
the key intermediary in sulfite metabolism, plasma S-sulfonates, but no
qualitative differences exist in the metabolism of inhaled S02 and injected or
ingested bisulfite or sulfite. The importance of the appearance of plasma
S-sulfonates lies in tneir potential ability to serve as a circulating poe1 of
sulfite molecules. Plasma S-sulfonates represent both protein-bound and small
molecular weight thiol-bound forms of sulfite (Reaction 1 in Figure 12-1).
Continuous inhalation of 26.2 mg/m (10 ppm) S02 resulted in the attainment of
38 ± 15 nmole of plasma S-sulfonates/ml in rabbits after about 4 days.69 The
clearance of plasma S-sulfonates generated by either inhalation of S0? 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.69 The
mechanism for this quantitative difference in clearance rates has not yet been
found. An integrated scheme is shown in Figure 12-1.
Inhaled S02 quickly penetrates the nasal mucosa and airways as shown by
the rapid appearance of 35S in the venous blood of dogs inhaling 35S02.44 A
significant fraction of the blood 35S was probably in the form of plasma
S-sulfonates (RSS03). Gunnison and Palmes69 have shown that this compound
accumulates on long-term inhalation of S02 as well as on ingestion or injection
of sulfite solutions in rabbits. These researchers suggest that tissue or
12-6
-------
TABLE 12-1. POTENTIAL HUT4GENIC EFFECTS OF S02/BISULFITE
Concentration SO.
•4
1310 mg/m3
(500 ppm)
Bisulfite
0.9 M HSOl
pH 5.0 J
3 H HSO~
pH 5-6 J
1 M HSO"
pH 5.2 J
5 x 10"3 M HSO"
pH 3.6
0.04 or 0.08 M
Organise
Phage T4-R11 System
Phage T4-R11
Systeit
E. coll K12 &
K15
S. cerevlslae
D. »elanogaster
Hela cells
(Hunan)
End Point
GC+AT or
deamlnatlon of
cysodne
deanlnatlon of
cytocine
GC+AT or
deanl nation of cytoclne
Point Mutation
Point Mutation
Cytotoxiclty
Response Conoents Reference
S-je^-nd
201
i Poor dose Hayatsu and.Blura
response Ilda et al.
+ Mukal et al.203
+ Doranga.and
DupuyZD4
May not be Valencia et «1.205
bioavallsble
«• Thowpson and Pace
13.1 - 105 ng/n
(5 - 40 ppm x 3 «1n)
House flbroblasts &
Peritoneal aacrophages
Nulsen «t al
208
-------
TABLE 12-1. POTENTIAL MUTAGENIC EFFECTS OF S02/BISULFITE
Concentration SO.
1310 mg/m3
(500 pp*0
Bisulfite
0.9 M
pH 5.0
3 M
pH 5-6
1 M
pH 5.2
5 x 10 " 3 M
pH 3.6
0.04 or 0.06 M
Organise
Phage T4-R11 System
Phage T4-R11
System
E. coll K12 &
K15
S. cerevlsiae
D. melanogaster
Hela cells
(Human)
End Point
GOAT or
dean i nation of
cysocine /''
deaml nation of _,,,--^
cytoclne- /-'''
GOAT of
deam'lnatlon of cytoclne
Point Mutation
Point Mutation
Cytotoxicfty
Response ^.- Comments Reference
.,---'' Drake
± Poor dose Hayatsu and^Niura
response Sida et al.
+ Mukal et al.203
norland
May not be Valencia et al.205
bioavallable
207
+ Thompson and Pace
13.1 - 105 nq/wT
(5 - 40 ppM x 3 Din)
Mouse flbroblasts &
Peritoneal aacrophages
Nulsen et al.
208
-------
TABLE 12-1. (Continued)
Concentration SO. Bisulfite
14.9 mg/m3
0.0001H
0.01N
0.0001M
0. 0040H
^ 0.0025M
ro
Organism
Human lymphocytes
Human lymphocytes
House oocytes
Ewe oocytes
Cow oocytes
End Point
Point Hutation
Chromosomal aberrations
Cytotoxicity
Inhibition of mitosis
Inhibition of meiosis
Inhibition of meiosis
Inhibition of meiosis
Response Comments Reference
.
Kikigawiiqand
+ -S+wHor
* Dose related Harman et al
response
+ Observed Jagiello et
fuzziness of
+ chromosomes may be
due to Cytotoxicity
+
• J- i Z. O
213
al.212
CD
-------
ro
i
10
Liver
SO.
HSO!
•SO
-?
^
Plasma \
Proteins ^ \
4 >1
Low Molecular ]
Weight Oisulflde /
Intracellular
Pool
RSSR * SO
Intracellular Pool
in Organs
G5H or RSH
NAOPH
NADP*
RSH * SOI2
-2 5 J
RSH * RSOj ^ MS"
Sulflte
0x1dase
HSO
Metabolism
Sul fated GlycomHno^lycans
and Glycoprotelns _^ Urinary
Complex
7 Sulfates
Kidney
^
~'
^ Urinary SOj2
Figure 12 1. An integrative scheme for metabolism of sulfur dioxide in mammals.
-------
plasma sulfhydryl compounds can react with plasma S-sulfonates to reverse the
reaction, leading to the establishment of an intracellular pool of sulfite.
Thus, intracellular concentrations of sulfite can occur over a prolonged
period after a single inhalation of SCL. Such a mechanism may explain the
observation that inhaled 35S02 leads to the presence of S in various other
organs in dogs besides the lung (e.g., the ovaries). Distribution of a
mobile source of sulfite through the blood is particularly important because
of the variety of reactions of S02, sulfite and bisulfite, and because of the
implication that toxic effects are also possible in nonpulmon'ry organs.
Frank et al.77 found exhaled S in the breath of dogs exposed to S02
through the surgically isolated head and upper airways. Presumably, the
35 35
breath S was in the form of S02 and could have occurred through nasal
absorption of S02 and distribution through the circulation. Breath S02 could
have come either from the desorption of hydrated S02 (bisulfite or sulfite) or
through reversal of the equilibrium of sulfite and plasma proteins with plasma
S-sulfonates. Since plasma S-sulfonates are the dominant form of exogenously
supplied S02 in the blood, the reversal of Reaction 1 (Figure 12-1) seems to
occur easily and rapidly during the early phases of exposure.
Most of the inhaled S02 is presumed to be detoxified by the sulfite
oxidase pathway in the liver, forming sulfate which is excreted in the urine
(Reaction 3, Figure 12-1). The dominance of this reaction has been supported
by studies of sulfite oxidase inhibition3 which are discussed below and by
the appearance of about 85 percent of the inhaled 35S02 as urinary sulfate in
44 Tt;
dogs. Once oxidized by sulfite oxidase, most of the inhaled "s derived
from S02 appears in the urine as 35S-sulfate.44 A small fraction (10 to 15
percent) of the urinary S was in the form of sulfuric acid esters and
12-10
-------
44
ethers. Sulfate arising from the oxidation of sulfite can enter the sulfate
pool and could be incorporated into sulfate macromolecules including
glycosaminoglycans and glycoproteins. These macromolecules are actively
synthesized by the respiratory mucosa and could account for the presence of
35 44
radiolabeled sulfur in the respiratory tract following inhalation of SO,,.
Most of the nondialyzable S detected by Yokoyama et al.44 was bound to the
crglobulin fraction of plasma. The chemical form of the S was not
44 3R
determined. Yokoyama et al. speculated that the S present in the
crglobulin fraction was in the form of sulfonated carbohydrates. The problem
69
is in need of further clarification. According to Gunnison and Palmes,
plasma S-sulfonated proteins may also have contained the S. 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.
Reductive cleavage of S-thiosulfates to a thiol and thiosulfate
(Reaction 4, Figure 12-1) has been reported. Thiosulfate can be reduced to
hydrosulfide (Reaction 5, Figure 12-1) by rhodonase and reduced lipoate or by
72-74
thiosulfate reductase and reduced glutathione.
12.2.1.3.2 Sulfite Oxidase. The biochemistry of sulfite oxidase will be
discussed because of its importance as a mechanism of detoxification of
sulfite. Genetic deficiency of sulfite oxidase occurs in humans.
42
Dietary factors can, however, alter the enzymatic activity. Sulfite oxidase
(EC 1.8.3.1) is a metallo-hemo protein with molybdenum and protoheme as the
•so 32~37 38 39~41
prosthetic groups. It exists in animals, bacteria, and plants.
In both plants and animals, the enzyme is located in the mitochondria.
Purified sulfite oxidase can utilize either cytochrome c or oxygen as the
12-11
-------
34 • i
electronic receptor. When coupled with cytochrome c to the mitochondria I
respiratory chain, sulfite oxidase reduces molecular oxygen to water (Equation
12-24), whereas during oxygen reduction, the product formed is hydrogen
peroxide (Equation 12-25).
SO'2V , 2 Cyt c (Fe3+)
12-24
S0~2' V 2 Cyt c (Fe2+) ' 1/2 0,
S0~2 + H20 + 02 -> S0~2+ H20£ 12-25
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 interaction of sulfite oxidase with the respira-
tory chain of the mitochondria, producing 1 mole of ATP/mole of su"!fite
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 problems. Cohen et al. suggested
that sulfite oxidase is the principal mechanism for detoxifying bisulfite and
S02- This is supported by a study which showed that dogs exposed to 35S02
excreted 80 to 90 percent of the inhaled 35S in the urine. Because sulfite
oxidase requires molybdenum, Cohen et al. were able to deplete rats of
sulfite oxidase by feeding them a low molybdenum diet and treating them with
100 ppm of sodium tungstate in drinking water. Tungsten competes with moly-
bdenum and essentially abolishes the activity of sulfite oxidase and xanthine
oxidase (EC 1.2.3.2), the two major molybdo-proteins of rat liver.
12-12
-------
Similar decreases were observed in the lung and other organs. The LD50 for
interperitoneally injected bisulfite was found to be 181 mg NaHSO,/kg in the
» J
sulfite oxidase deficient animals compared to 473 mg/kg in the nondeficient
rats.
A 0
The effect of inhaled SO,, on lethality was more complex. High levels
were used in all cases and two effects of inhaled S02 were observed. At 1,546
or 2,424 mg/m (590 or 925 ppm) SO- or less, the principal effect in control
animals was respiratory insufficiency resulting in death by asphyxiation. At
6,157 mg/m3 (2,350 ppm) S02 or greater (up to 1.3 x 106 mg/m3, 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
42
effect of bisulfite on the CNS has been suggested. Interperitoneally
42
injected bisulfite also produced CNS effects. Mortality was observed in
both the control and tungsten-treated animals exposed to greater than 1,554
mg/m (593 ppm) SO- for 4 hr. Most of the deaths occurred within 48 hr of
exposure, and no further mortality occurred during the subsequent 2 wk period.
Time before death, however, appeared to be much shorter for those rats treated
with tungsten than for control animals. To test this finding, rats were
exposed continuously to 1,546, 2,424, or 6,157 mg/m (590, 925, or 2,350 ppm)
S02. At 6,157 mg/m3 (2,350 ppm) and 2,424 mg/m3 (925 ppm), but not at 1,546
mg/m (590 ppm), a clear difference existed between the tungsten-treated
(i.e., deficient in sulfite oxidase) and control animals, with the
42
tungsten-treated animals dying earlier. Cohen et al. suggest that these
differences in survival times are due to the inability of the tungsten-treated
animals to detoxify inhaled S02 to sulfate. Of those animals exposed to 2,424
mg/m3 (925 ppm) S02, tungsten-treated animals died of seizures and
12-13
-------
prostration, whereas the control group succumbed to respiratory insufficiency.
The authors concluded that sulfite oxidase mainly alleviates acute systemic
toxicity due to bisulfite and has little or no effect on subacute or chronic
respiratory effects of SCL. The sulfite oxidase pathway in the rat lung is
capable of detoxifying bisulfite derived from inspired SO,, at the rate of 600
umole/day. The authors suggest that this is equivalent to 52.4 mg/m (20 ppm)
SCL in the atmosphere, assuming complete extraction of S02 by the rat lung.
The capacity of the rat (200 g) to oxidize bisulfite amounts to 150,000 umole
of bisulfite/day, which is theoretically equivalent to continuous exposure to
13,100 mg/m3 (5,000 ppm) S02- Since some rats exposed to 2,424 mg/m (925
ppm) S0? died (25 to 38 percent mortality), factors other than oxidation by
42
sulfite oxidase must be considered.
Attempts to induce higher levels of sulfite oxidase through pretreatment
42
of the animals with S02/bisulfite or phenobarbital failed. Since sulfite
oxidase is a mitochondria! enzyme with a long half-life, it is not likely that
phenobarbital or chronic exposure to SOp would result in adaptation through
induction of higher levels of sulfite oxidase.
12.2.1.4 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 and 2,3-diphosphoglyceric acid phosphatase.47 The mechanism by
which activation occurs is not known. Inhibition of several enzymes has been
reported; these include aryl sulfatase,47 choline sulfatase,48 rhodanase,38
49
and hydroxyl amine reductase. Malic dehydrogenase was inhibited by
micromolar concentrations of bisulfite (Ki = 5 uM).50"51 Other
52
dehydrogenases and flavoprotein oxidases are inhibited by bisulfite.
12-14
-------
Bisulfite effectively inhibits a number of other enzymes including potato
and rabbit muscle phosphorylase. Bisulfite inhibition was competitive with
respect to glucose-1-phosphate and inorganic phosphate, suggesting that the
bisulfite inhibition 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
p
enzymic reactions. Pyridine coenzyme-bisulfite adduct and
flavoenzyme-bisulfite adduct ' have been studied in detail, and these
adducts have been shown to be biologically inactive.
Despite all of the data obtained using j_n vitro systems on the inhibition
of enzymes by bisulfite/SOp, no inhibition or activation has been determined
In vivo with SO- exposure. Such inhibition may occur, but there has been no
concerted effort to search for inhibition of specific enzymes during S02
exposure.
12.2.2 Mortality
The acute lethal effects of SOp have been examined mostly in the older
literature and have been reviewed in the previous Air Quality Criteria
78
Document for Sulfur Oxides. In early studies, a number of different animal
species was examined for susceptibility to SOp. These data show that
mortality was not 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
CO
studies. Statistically significant mortality could be associated with
long-term exposure to S02 at 134 mg/m (51 ppm) or higher. The clinical signs
42
of S09 intoxication appear to vary with the dose rate. At concentrations
12-15
-------
below approximately 1,310 mg/m (500 ppm), mortality is associated with
respiratory insufficiency; above this concentration, mortality is ascribed to
central nervous disturbances producing seizures and paralysis of the
extremities. These clinical signs depend upon the presence and activity of
sulfite oxidase as discussed in Section 12.2.1.3.2 Injections of histamine or
230
adrenalectomy can increase the lethality of SO-.
Matsumura113'114 examined the effect of a 30-min exposure to several air
pollutants 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). The dyspneic attack of anaphylaxis was not affected by as much as
1,048 mg/m (400 ppm) S02.
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 SO,, are far in excess of those which occur
in the atmosphere due to pollution (Table 12-2).
12.2.3 Tumorogenesis in Animals Exposed to SO- or SO- and Benzo(a)pyrene
Tumorogenesis after exposure to SO- alone or to SO- and an aerosol of
*- ^^jUJ^^
benzq(a)pyrene has been examined. .Mice, were exposed/ito- 1,310 mg/m (500
dt**l^4^&&^ SV4/?*#" S0± ^^^-^^^ ^^^^^ ^C_^^/^>0^ ^-<-> ^
^S0,| for •5"-min/dayHFor 5 days/wk for lifetimes- . 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.
Primary pulmonary neoplasias increased in the males (n = 35) from 31 percent
in the control group to 54 percent in the S02-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
12-16
-------
TABLE 12-2. LETHAL EFFECTS OF SO, ON ANIMALS
09 Concentration
3
>: g/ra ppm
26.2
134
275
-1 , 310
1,598
2,392
3,086
5,175
9,165
13,236
5,782
6,571
7,205
786
10
51
105
610
913
1,178
1,975
3,498
5,052
2,207
2,508
2,750
300
Duration
6 hr/day x 5 day/wk
x 113 day
113 days
22 day
5 min/day x 5 day/wk
LJ .7 fi n ft -i i i-t- " j^ 7^
> X JOU flay^ ^e-^££-c^^t-
LTr.n 285.6 min
bO
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 . Reference
CO
Rat No mortality in excess of control Laskin et al.
No mortality in excess of control
64% mortality (treated-control)
Mice No increased mortality; tumor formation Peacock and Spence
c found
230
Mice IP injection of 200 to 300 mg histamine/mouse Leong et al
(Connaught Med. increased toxicity
Res. Lab. Strain)
230
Rat (Sprague- IP injection of 200 to 300 mg histamine/rat Leong, et al.
Dawley) or adrenal ectomy increased toxicity
230
Guinea Pig Leong, et al.
Guinea Pig Increased mortality Matsumura
due to anaphylaxis
from antigen challenge
to sensitized animals
-------
authors classified only tumors which invaded blood vessels as carcinoma. In
males, S02 did not affect the incidence of malignant tumors (2/35, 6 percent
in air group; 2/28, 7 percent in S02 group). However, in females, the
incidence of primary lung carcinoma increased from 0/30 in the controls to
4/30 (18 percent) in the S02-exposed mice. These were early studies and the
statistical analysis is vague. The significance of these increases,
therefore, is questionable. The investigators concluded that the increased
incidence of primary lung tumors was due to the initial inflammatory reaction
to SOp, followed by tolerance, which accelerated spontaneous tumor
development. They further state that this study does not "justify the
classification of SOp 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) 50^ for 6 hr/day, 5
3 3
days/wk for 534 exposure days or 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
CO CO
combination of the 2 regimens. When rats 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) S02 for 6 hr/day and 9.17 mg/m (3.5 ppm) S02 plus 10 mg/m3
benzo(a)pyrene for 1 hr/day and in 2/21 (9.5 percent) animals exposed to the
benzo(a)pyrene plus S02 for 1 hr/day. Renal metastasis also occurred.
Control rats exposed to air (n = 3) or to 26.2 mg/m3 (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.194 Exposure to air alone (n = 15)
or 26.2 mg/m (10 ppm) S02 (n = 15) for 6 hr/day caused no cancers (squamous
12-18
-------
cell carcinoma). A 1 hr/day exposure to 10 mg/m benzo(a)pyrene caused cancer
in 1/30 (3.3 percent) rats. A 6 hr/day exposure to 26.2 mg/m (10 ppm) SO-
plus a 1 hr/day exposure to 10 mg/m benzo(a)pyrene resulted in a cancer
incidence of 6.7 percent (2/30). When animals received a combination of 10
mg/m benzo(a)pyrene and 10.48 mg/m (4 ppm) S02, 4/45 (8.9 percent) of the
rats had cancer. The highest incidence (19.6 percent, 9/46) was found in
animals exposed for 6 hr/day to 26.2 mg/m (10 ppm) SO- plus a combination of
10 mg/m benzo(a)pyrene and 10.48 mg/m (4 ppm) S02 for 1 hr/day.
The biological significance of these studies (Table 12-3) is complex and
difficult to interpret, particularly since statistical analyses were not
reported in the publications. Few SOp exposure experiments have been carried
out for the near lifetime of the animal as in the early mouse study and the
194
subsequent rat study. 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
68 194
available for the colony of rats used, ' making the increased incidence by
the combined S0--benzo(a)pyrene treatment difficult to interpret. Tumor
formation may be a multistep process, requiring more than just the initiation
for expression. Thus, the potential co-carcinogenic activity of SO- may be
real and significant in terms of a human health hazard, but it is not
definitely proven by these experiments.
12.2.4 Morphological Alterations
Because of the high solubility of SO- in water, morphological and physio-
logical effects have been detected in the upper and lower airways (Table
12.4). At relatively high concentrations (used in most studies designed to
12-19
-------
TABLE 12-3. TUMOROGENESIS IN ANIMALS EXPOSED TO S02 OR S02 AND BENZO(a)PYRENE
Concentration
Duration
Species
Results
Reference
4310 mrjfm* (Ann ppj)
-------
TABLE 12-4. 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)
SO,
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 Gng**3 .
/#4'/
13.4 mg/m3 (5.12 pp«)
13.4 mg/m3 (5.1 ppm)
26.2 »g/m3 (10 ppm)
91.7 mg/m3 (35 ppn) (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 no, 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
•onkey
Dog
Mouse
Pig
Rat
Rat
QQ
Lungs of 15.0 mg/m3 (5.72 ppm) group, killed after Alarie et al.
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 ppn) 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
90 91
No remarkable morphologic alterations in the lung Alarie et al. '
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
goblet cells, IN
nasal cavity, disappearance of
•taplasia of the epithelium
Trachea) 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
Increased mitosis of goblet cells.
not lost by 5 wk post-exposure
Alteration
Alarie et al.90'91
Alarie et al.
92
Lewis et al
104
Giddens and Fairchild
80
Martin and Willoughby
81
Reid
,83
Lamb and Reid
,82
-------
detect morphological alterations), most of the inhaled SCL is removed by the
nasopharyngeal cavity. (See Chapter 11, Section 11.2.4 for an expanded
discussion of SCL absorption.) In rabbits, the concentration of inspired SC^
determines how much is removed in the nasopharyngeal cavity as opposed to the
79
bronchial and alveolar regions of the lung. 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 at concentrations in this 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 SG^, such as 0.13
mg/m3 (0.05 ppm), which is 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. 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 to 50 ppm) S02.77'101
80
Giddens and Fairchild pointed out that these differences in removal of
inspired S0£ could explain the apparent anomaly of little damage to the lower
respiratory tract at high SO,, concentrations. They undertook a study of the
effects of inhaled SO^ 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) $62 for a maximum of 72 hr. Pathological changes in the
nasal mucosa appeared after 24 hr of exposure and increased in severity after
12-22
-------
72 hr of exposure. Mice free of upper respiratory pathogens were
significantly less affected than the conventionally raised animals. Giddens
80
and Fairchild concluded that resident or acquired pathogens exacerbated the
morphological changes they had observed. Morphological alterations were,
however, qualitatively identical in both groups of animals. Cilia were lost
from the nasal mucosa; vacuolization appeared; and 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
81
were absent. Martin and Willoughby reported loss of cilia, disappearance of
goblet cells, and metaplasia of the epithelium of the nasal cavity of pigs
exposed to 91.7 mg/m (35 ppm) SO- for 1 to 6 wk. This study, however, was
marred by difficulties with the control of the S0?, rising on occasion to 262
mg/m (100 ppm), and with high relative humidity occurring during cleaning of
the pig pens.
82 83
Lamb and Reid and Reid attempted to use S02-exposed rats in a model
of human chronic bronchitis. They presented favorable arguments that
S02-induced bronchial hyperplasia is analogous to human chronic bronchitis.
Most of their studies have been carried out at high concentrations of SO-
(1,048 mg/m or 400 ppm S02 for 3 hr/day. 5 days/wk). Under these conditions,
the trachea! 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. Changes in the mitotic
index were observed (Figure 12-2). The effects of 502 were concentrated in
12-23
-------
o 4
I
Proiimal airways
Trachea
o
^__ Distal airways
HON-EXPOSED
ANIMALS
234
S02 exposure (weeks)
Figure 12-2. Mitotic count (four-hour period) after S02 exposure up
to six weeks. Mitoses represented as percentage of total nuclei.83
12-24
-------
the central airways, again suggesting that the solubility of SCL 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 this value returned to
the control level. The magnitude was proportional to the SCL concentration
(Figure 12-3). An elevation of the mitotic index occurred at concentrations
as low as 131 mg/m (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 mucous (Figure 12-4) resistant to
digestion by sialidase increased in numbers, and their distribution 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.
88
Alarie et al. 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) S02 for 1 yr.
The lungs of the guinea pigs exposed to 15.0 mg/m (5.72 ppm) and killed after
13 or 52 wk of exposure showed less spontaneous 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
88
disease during the exposure period. In these and other studies by Alarie
12-25
-------
SO 100 200 300
S02PPM
50 100 200 300
SO2PPM
Figure 12-3. Histogram area covered by PAS sen-
sitive material in tracheal epithelium of rats ex-
posed to 50, 100, 200, and 300 ppm of S02 on
eight rats at each concentration. 1,000 fields
(x20) were evaluated. Counts made with an auto-
mated image analyzer.83
12-26
-------
NORMAL
After ROE
50, EXPOSED
After RDE
Figure 12-4, Increase in goblet cells after expos-
ure to S02- Increase in goblet cells assessed by
comparison of left-hand diagrams; increase and
extension of goblet cells resistant to sialidase
(RDE) in right-hand pair.83
12-27
-------
90-92
and co-workers, light microscopic observations were limited to
conventional hematoxylin-eosin stained paraffin sections. The control group,
o
as well as those exposed to 0.34 and 2.64 mg/m (0.13 and 1.01 ppm), had
evidence of lung disease as shown by histocytic infiltration of the alveolar
walls. Tracheitis was also present in the above three groups, but not in the
15.0 mg/m3 (5.72 ppm) group. Hepatocyte vacuolation was observed in the
latter group. 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.
90 91
Subsequently these researchers ' exposed cynomolgus monkeys
continuously to 0.37, 1.7 or 3.35 mg/m3 (0.14, 0.64 or 1.28 ppm) S02 for 78 wk
but found no remarkable morphological alterations. Another group exposed to
12.3 mg/m (4.69 ppm) SO^ for 30 wk was accidentally exposed to concentrations
of S02 not higher than 2,620 mg/m (1,000 ppm) or lower than 524 mg/m3 (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 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
12-28
-------
bronchioles were plugged with proteinaceous material, macrophages, and
leukocytes. Bronchiectasis and bronchiolectasis were present in 8 of 9
animals. Vacuolation of hepatocytes was also observed, as with the guinea pig
group exposed to 15.0 mg/m (5.72 ppm) in the prior study.88
In a replication of this study, cynomolgus monkeys were exposed to 13.4
3 92
mg/m (5.12 ppm) S02 continuously for 18 mo. No alterations in lung
morphology were reported to be due to SO-. The morphological alterations
reported in the control group included lung mite infections and associated
"slight subacute bronchiolitis, alveolitis, and bronchitis." Pulmonary
88 90~92
function measurements were made in the above mentioned studies ' and are
described in Section 12.2.5.
The absence of S02~induced morphological alterations as reported by
Alarie et al.88'90"92 and Lewis et a!.104 who exposed dogs for 620 days (21
hr/day) to 13.4 mg/m (5.1 ppm) SOp is not in conflict with the broncho-
constriction induced by acute SO^ exposure reported by Amdur and her
qo go
co-workers at lower concentrations (see Section 12.2.5). Alarie et al.
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 concomitant changes in this physiological parameter (lung function)."
Further, the transient nature of the pulmonary function effects observed
during short-term exposures would be difficult 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 simple alteration of smooth
muscle tone as has been hypothesized, it might be morphologically
undetectable.
12-29
-------
Most of the studies in which the lungs of S02-exposed animals have been
examined center around tracheitis, bronchitis, ulceration, and mucosal hyper-
plasia (Table 12.4). The lowest concentrations at which these alterations
have been reported have been in the rat at 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
82 83
shorter durations of exposure is not known. ' The studies of Alarie et
al 88,90-92 are unfortunately flawed by the questionable health of the exposed
animals and the accidental exposure to high concentrations.
12.2.5 Alterations in Pulmonary Function
Changes in pulmonary function have been among the most sensitive and
fruitful areas of research in $02 toxicity. They have likewise been useful in
studying the effects of aerosols alone or in combination 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
94 95
flow resistance in guinea pigs has been developed by Amdur. ' Animals are
not anesthetized and breathe spontaneously, which allows sensitive measure-
ments of pulmonary function. (A complete description of this method appears
in Appendix I, section 7.2.1.)
The respiratory rate of mice has been used as an indication of pulmonary
pc
irritation by Alarie et al. Mice were exposed for 10 min to 0, 44.-5, 83.8,
162, 233, 322, 519, or 781 mg/m3 (0, 17, 32, 62, 89, 123, 198, or 298 ppm)
S02- About a 12 percent decrease was observed at 44.5 mg/m3 (17 ppm). The
respiratory rate decreased inversely to the logarithm of the concentration of
inspired SO,,. The decrease in respiratory rate, however, was transient,
12-30
-------
returning to nearly control levels within 10 min even at continued exposure to
781 mg/m (298 ppm) S02- 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 S02, being shortest
at highest concentrations. Mice exposed to 262 mg/m3 (100 ppm) S02 for 10 min
were allowed to recover in clean air prior to a subsequent 10 min exposure to
the same concentration. As the length of the recovery period was decreased
(from 12 min to 3 min), the effect of the subsequent S02 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 S02 exposure, the respiratory rate decreased at a rate comparable to
that following exposure to CBM alone. Thus, the refractory period associated
with S02 exposures appeared specific to S02 and not to CBM. When 262 to 328
mg/m (100 to 125 ppm) S02 was provided repeatedly for durations 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 S02 by
means of a trachea! 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
or
review by Alarie who suggests that stimulation and desensitization occur via
85
cholinergic nerve endings of the afferent trigeminal nerve. Alarie et al.
also suggest that SCL is hydrated to bisulfite and sulfite which react with a
receptor protein to form an S-thiosulfate and a thiol, cleaving an existing
12-31
-------
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.
Other investigators87'98"100'251 found that bronchoconstriction resulted
from both head-only and lung-only exposures in cats and dogs. When corrected
for the amount of S02 hypothesized to reach the lung, Amdur's study 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 502- At high concen-
trations of S02 or following long durations of exposure, the nasopharyngeal
receptors fatigue or become unresponsive, whereas the bronchial receptors do
87 251
not. Nadel et al. ' demonstrated the existence of a reflex arc by "cold
blocking" the vagus nerve. Chilling the vagus nerve prevents conduction of
nervous impulses and abolishes the bronchoconstriction produced by inhaled
S02> Intravenous injection of atropine, which blocks some vagal responses,
also prevents the SC^-induced effect. Sulfur dioxide-induced broncho-
constriction probably involves smooth muscle contraction. By acting on the
same smooth muscles, acetylcholine (which is the neurotransmitter of the
vagus) aerosols evoke bronchoconstrictive responses similar to those of
102
S02- Since the bronchoconstriction is dependent upon smooth muscle, which
is not likely to sustain constriction for long times, chronic exposures are
not likely to evoke sustained bronchoconstriction. Hypersecretion of mucus
and alteration of airway caliber are more likely chronic effects.
Exposure to S02 evokes an increase in resistance in guinea pigs which
persists for several hr and exhibits none of the tachyphylaxis found with
12-32
-------
_*. 98 99
other species. ' However, different techniques were used for these
*• 93
different species. Amdur, in a review of her data, reported that for a 1 hr
3 o
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 S02 that increased flow
resistance in guinea pigs. The response, a 12.8 percent increase (p < .001)
93
at these low levels of S02, was the average of 71 guinea pigs; the individual
data points were reported in other publications. '' 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) S02- In a more
130
recent study, Amdur et al. showed that a 1 hr exposure of guinea pigs to
0.84 mg/m (0.32 ppm) S02 caused a 12 percent increase in resistance (p <0.02)
and a non-statistically significant decrease in compliance. At
concentrations of S02 below 2.62 mg/m (1 ppm), the response of individual
animals varied considerably. ' ' Of 1,028 guinea pigs, 135 were
"sensitive", responding to low concentrations of S0« 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.93'170'274 On the other hand, Amdur et al.171 also
point out that some batches of animals may by chance not have a "sensitive"
individual. In this study, 3 groups of 10 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
qc
on data from earlier work, she concluded that 10 to 13 percent of the guinea
170 98 99
pig population is more responsive than the average. In cats and dogs,
on
the other hand, few were found to be sensitive to short-term (< 1 hr)
exposure to 52.4 mg/m3 (20 ppm) S02 (cats) or 18.3 mg/m (7 ppm) S02 (dogs).
12-33
-------
Even with the relatively small sample sizes used, some cats and dogs responded
and others did not.
Some of the problem of "sensitive" vs. "insensitive" 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 S02, 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 "sensitivity" or
"insensitivity" 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 "sensitive"
responders in each experiment. The total number of "sensitive" responders
will be small and variable because of the low incidence of "sensitive"
responders in the general animal population. A small, but variable, number of
"sensitive" 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 SC^, the matter is further complicated by comparisons between batches
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 "sensitivity" 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 "sensitive" animals would have been
12-34
-------
encountered. Further, the small number of animals has been studied in
different laboratories 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 "sensitivity" could be
detected. While the mechanism(s) responsible for "sensitivity" is not known,
the question of "sensitivity" is an important aspect deserving of further
study. A similar incidence of some 10 percent "sensitive" individuals in man
would have serious health policy implications.
79
Using Strandberg's data from the rabbit to correct for the
concentration of SCL hypothesized to reach the lung, Amdur was able to
normalize the concentration-response curve for S0?-induced bronchoconstriction
in the guinea pig resulting from nose-only exposures (Figure 12-5). A break
occurs in the concentration-response curve at about 52.4 mg/m (20 ppm) S02,
perhaps due to the poorer extraction of gaseous SO^ by the upper airways at
low concentrations. However, it should be recognized that SO- extraction data
for rabbits and dogs ' ' 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 suggests
that at concentrations of 1.05 to 1.31 mg/m (0.4 to 0.5 ppm) very little
removal of SO^ occurs in the upper airways. These data contrast with the
radiotracer studies in dogs. ' ' Others have required concentrations
greater than 18.3 mg/m3 (7 ppm) to evoke increases in flow resistance in
anesthetized cats98 and dogs.9 Differences in the sensitivity of the two
12-35
-------
• NORMAL X.NORMAL CONVERTED
ACANNULA TO "LUNG* CONCENTRATION
1'
u _
UJ
2
Uj
IT
u Ol
u
<005
ooi
^tr^r
OOI002 0-05 Ol O-2 0-5 I 2
S02 RPM
Figure 12-5. Dose-response curves.
50oo 20 so) ooo
12-36
-------
models may lie in the use of anesthesia, in the use of different species, or
in a different incidence of "sensitive" 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
102
al. found an increased bronchial reactivity to aerosols of acetylcholine, a
potent bronchoconstrictive agent. Acetylcholine is also the endogenous neuro-
muscular transmitter which can cause bronchoconstriction. Bronchoconstriction
was determined by esophageal pressure concomitant with tidal volume. Greatest
response occurred at 5.24 mg/m (2 ppm), although 2.62 mg/m (1 ppm) also
caused an effect. The effect of 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 and that bronchial reactivity is susceptible
to other physiological modifications.
Lee and Danner reported that exposure to SO* concentrations above 50
mg/m (19 ppm) for 1 hr caused an increase in tidal volume and a decrease in
respiratory rate in guinea pigs. When guinea pigs were exposed to 18 to 45
mg/m (7 to 17 ppm) S02, a general decrease in tidal volume and an increase in
respiratory rate were observed. The variability of these experiments was
extreme. The hemoglobin concentration in the blood rose as much as 40 percent
during the exposure, suggesting some extreme hemoconcentration phenomenon.
Inorganic sulfate concentrations also increased by as much as 100 percent
above pre-exposure values, but they were not corrected for hemoconcentration.
Animals chronically exposed to S02 have also been examined for
alterations in pulmonary function. Guinea pigs exposed continuously to 0.34,
2.64, or 15 mg/m3 (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
12-37
-------
present in all animals (including controls) except those exposed to the
ftft ^
highest concentration. Dogs exposed for 21 hr/day to 13.4 mg/m (5.1 ppm)
S02 for 225, but not 620, days demonstrated increased pulmonary flow
89
resistance and decreased lung compliance, after 620 days mean nitrogen
90*92
washouts were increased. Alarie and co-workers exposed cynomologus
monkeys continuously to 0.37, 1.7, 3.4, or 13.4 mg/m3 (0.14, 0.64, 1.28, or
5.12 ppm) SOp. 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) S02,
monkeys were inadvertently exposed to concentrations between 524 and 2,620
mg/m3 (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 12.2.4).
In summary, there are at least two sets of receptors responsible for
changes in respiratory function in animals acutely exposed to S0?. Decreases
in respiratory rate or increased resistance to flow are reliable end points.
Increased resistance to flow results from SO^ 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 S02- The reason for this is not known;
potential factors include species, strains, and experimental technique used.
Within the laboratory population, some individual animals are found to be more
sensitive than the average, but the mechanism for their sensitivity is not
known. While pulmonary function measurements in guinea pigs appear to be
highly sensitive to acute S02 exposures, chronic S02 exposure has not been
proven to have a similar effect, although chronic studies with guinea pigs are
12-38
-------
Unclear because of disease in the control group. In other chronic studies,
pulmonary function of monkeys was unchanged at S02 concentrations up to 13.4
mg/m (5.12 ppm), but dogs were affected by 225, but not 620, days of exposure
to 13.4 mg/m (5.1 ppm). High levels of SCL 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
Sl^-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 SOp is not likely to cause a permanent alteration in
bronchial tone. Unfortunately, investigations of the reactivity of the
airways after chronic exposure to S0« have not appeared. We do not know if
chronic exposure to SOp causes an alteration in response to SG^ 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 SO^. (Table 12-5)
12.2.6 Effects on Host Defenses
Because alterations in particle removal could lead to increased suscepti-
bility to airborne microorganisms or increased residence times of other
non-viable particles, the effects of SOp on particle removal and engulfment,
as well as on integrated defenses against respiratory infection, have been
studied. The function of the cilia 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/m3 (1 or 3 ppm) S02 and graphite dust (mean diameter 1.5
urn, 1 mg/m3) for up to 119 consecutive days.105 Donkeys256 were exposed by
12-39
-------
TABLE 12-5. EFFECTS OF SULFUR DIOXIDE OH PULMONARY FUNCTION
Concentration
0.37, 1.7, 3.4. or 13.4 mg/m3
(0.14. 0.64, 1.28. or 5.12 pp»)
SO,
0.42 or 0.84 mg/m3 (0.16 or
0.32 ppn) SO,
0.52. 1.04. or 2.1 mg/m3 (0.2.
0.4, or 0.8 pp«i) S02
2.62, 5.24, 13.1. or 26.2 mg/m3
(1, 2, 5, or 10 ppM) SO,
13.4 mg/m3 (5.1 ppm) SO,
V 18 to 45 mg/m3 (7 to 17 ppa)
g SO,
0, 44.5, 83.8. 162. 233, 322,
Duration
72-78 wk, continuous
1 hr
1 hr
1 hr
21 hr/day. 225 and
620 days
1 hr
10 «1n
Species
CynoMologus
monkey
Guinea pig
Guinea pig
Dog
Dog
Guinea pig
Mouse
Results
No change
Increase in resistance
No significant Increase In airway resistance.
Increased bronchial reactivity to aerosols of
acetylchollne, a potent bronchoconstrictlve agent
Increased pulmnary 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
Respiratory rate decreased proportionally to the log
Reference
Al.rie et al.90'92
A^uret.l.124'130
Awdur et al.171
Isl-etal.102
Lewis et al.89
Lee and Danner
Alarle et al.85
519. or 781 mg/m3 (0, 17. 32,
62, 89. 123, 198, or 298 ppm)
SO,
>50 mg/m3 (>19 pp«) SO,
1 hr
Guinea pig
of the concentration; complete recovery within 30
Mln following all exposures. The tine for maximum
response was Inversely related to the log of the con-
centration, being shortest at highest concentrations
Increase In tidal volute and a decrease in respiratory Lee and Danner
rate
103
-------
nasal catheters to 68.1 to 1,868 mg/m3 (26 to 713 ppm) S02 for 30 min. Below
786 mg/m (300 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.
Ferin and Leach110 exposed rats to 0.26, 2.62, and 52.4 mg/m3 (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 (Ti02). The aerosol
was generated at about 15 mg/m (1.5 urn MMAD, a 3.3). These investigators
took the amount of Ti02 retained at 10 to 25 days as a measure of the
"integrated alveolar clearance". Low concentrations of S02 (0.26 mg/m3 or 0.1
ppm) accelerated clearance after 10 and 23 days, as did 2.62 mg/m (1 ppm) at
10 days but not afterwards until 25 days when clearance was decreased. Hirsch
et al. found that the tracheal mucous 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. The dogs were
examined by a broncho-fibroscope at the end of the exposures. No differences
in pulmonary function were reported. Confirmation of this study and
determination of the persistence of the decreased mucous flow at this low
level of S0? would be important to confirm in light of other data available.
It appears that 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.107' Using the infectivity model (see Section
12.3.4.3), Ehrlich178 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
12-41
-------
infections, however, are augmented by simultaneous or subsequent S02 exposure.
Mice were exposed to concentrations varying from 0 to 52.4 mg/m (0 to 20 ppm)
S02 continuously for 7 days.108 Mice breathing 18.3 to 26.2 mg/m3 (7 to 10
ppm) S0? began to experience an increase in pneumonia. The increase in lung
consolidation was significant at 65.5 mg/m3 (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
109
unaffected by S02 exposure. When these results were reanalyzed, 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
80
Giddens and Fairchild showed that mice with apparent respiratory infection
were more susceptible to the morphological effects of S02 (Section 12.2.4), a
rebound effect may be possible in which S02 and microbes 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.195 Exposure to the 2
highest concentrations increased j_n 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/m3 S02 (300 ppm)
for 6 hr/day on 10 consecutive days showed no changes in the lysosomal
enzymes, p-glucuronidase, p-galactosidase, and N-acetyl-p-glucosaminidase.112
Acid phosphatase activity was markedly increased. This is in agreement with
12-42
-------
Rylander's observation107 which suggests that SCL exposure (26.2 mg/m3 SO-, 10
ppm, for 6 hr/day, 5 days/wk for 4 wk) does not affect the bactericidal
activity of the lung. (Table 12.6)
12.3 EFFECTS OF PARTICIPATE 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 cause-effect relationships investigated. Sulfur dioxide is
often present in polluted atmospheres 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 atmosphere 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
elsewhere (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. The toxicities of the single components
are likely to be less than the combination which exists in the atmosphere,
although antagonistic interactions can also occur. For particles other than
12-43
-------
TABLE 12-6. 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 pm, 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
6 hr/day, 20 day
3 hr/day. 1-15 days
and 24 hr/day. 1-3 mo
7 days, continuous
6 hr/day for 20 days
30 min
6 hr/day, 10 days
continuous
Rat
1.5 hr/day, 5 day/wk Dog
Up to 119 days Rat
7 days continuous House
Guinea pig
Mouse
House
Rat
Donkey
Rat
Low concentrations (0.26 «g/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
jn 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.
Tracheal 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.
Bacterial clearance was not altered.
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.
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.
Ferrin and Leach
110
Kati and Laskin
195
111
106
Hirsch et al.
Fraser et al.
Lebowitz and
Fairchlld10*
Rylander107-192
Ehrlich178
Fairchild et al.
107
108
Did not affect the bactericidal activity of the lung. Rylander
Spiegelman et al.
256
Barry et al.
112
-------
^2^4' (NH.)?SO., anc' NH^HSO., no attempt will be made to be as inclusive as
documents for some of the individual components. Rather, an attempt will be
made in this section 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 section, 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 complete 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. Most of the
indirect effects through interaction with other pollutants have previously
been discussed for SOp. Some additional data implicating interactions between
S0? and particulate material, between S02 and ozone, and between ^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 compounds.
12.3.1 Mortality
The susceptibility of laboratory animals to sulfuric acid aerosols varies
considerably. Amdur 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
12-45
-------
response to sulfuric acid. The lethal concentration (LC) of 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 |jm being more toxic),
252
and the temperature (extreme cold increasing toxicity). In a recent study,
the LC50 (the concentration at which 50 percent of the animals die) in guinea
pigs for an 0.8 urn (MMAD) aerosol was 30 mg/m , whereas for a 0.4 um (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. The animals which 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.
Sulfuric 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
197
Alarie et al. investigated the effects of chronic H2S04 exposure.
Guinea pigs were exposed continuously for 52 wk to 0.1 mg/m3 H2SO. (2.78 um,
HMD) or to 0.08 mg/m H2S04 (0.84 um, MMD). Monkeys were exposed continuously
for 78 wk to 4.79 mg/m3 (0.73 um, MMD), 2.43 mg/m3 (3.6 um, MMD), 0.48 mg/m3
(0.54 Mm, MMD). or 0.38 mg/m3 (1.15 um, MMD). Sulfuric acid had no
significant hematological effects in either species. No microscopic lung
12-46
-------
alterations resulting from H^SO. exposure were observed in guinea pigs after
197 Q?
12 or 52 wk of exposure in this study or in a later study.
Morphological changes were evident in the lungs of monkeys. At the two
highest concentrations, there were changes (more prevalent in the 4.79 mg/m
H2$04 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 to
3 3
2.43 mg/m , but not to 4.79 mg/m HUSCL. However, particle size had an impact
at lower h^SO^ 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 thickening 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 ). 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 morphological effects of HpSO. alone.
104
Lewis et al. found no morphological changes after the dogs had been exposed
3
for 21 hr/day for 620 days to 0.89 mg/m H2S04 (90 percent <0.5 urn in
diameter).
Recently, Cockrell et al.118 and Ketels et al.120 studied the
morphological changes resulting from sulfuric acid aerosols. Cockrell et
al.118 examined the effects of 25 mg/m3 (1 urn, MMD, a 1.6) for 6 hr/day for 2
days in guinea pigs. Segmented alveolar hemorrhage, type 1 pneumocyte hyper-
plasia, and proliferation of pulmonary macrophages were reported. Ketels et
al.120 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
12-47
-------
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/m3, 10 daily exposures to 100 mg/m3, 20 daily exposures
to 50 mg/m3, or any one of these doses combined with 5 mg/m carbon particles.
The damage was judged to be proportional to the concentration (C), but not to
the product of concentration and time (T) of exposure or to the time of
exposure. (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 H,,$04 when
combined with other pollutants have been conducted. (See Section 12.4.1.2.
and Table 12-7)
12.3.3 Alterations in Pulmonary Function
12.3.3.1 Acute Exposure Effects—Generally, for short-term studies,
respiratory mechanics have been much more sensitive to H^SO. and some other
compounds than other parameters tested. Amdur has cautioned that her
94 95
method for measuring resistance ' 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 that, if
anything, this procedure increases rather than decreases the sensitivity of
the guinea pigs to inhaled irritants.
Using this method, Amdur and co-workers96'97'121"125'130'171'172 have
studied the effects of aerosols alone (see Table 12-8) or in combination with
S02- 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
12-48
-------
TABLE 12-7. EFFECTS OF PARTICIPATE MATTER ON LUNG MORPHOLOGY
Concentration
Duration
Species
Results
Reference
0.08 «Kj/n3 H,SO« (0.84 u*. MHO),
or 0.1 «g/m5 H2SO« (2.78 pit,
MMD1
0.38 mg/m3 (1.15 urn, HMD).
0.48 mg/m* (0.54 um. HMO),
2.43 nig/m3 (3.6 M™. HMO), or
4.79 mg/m3 (0.73 um.
0.89 mg/ms (90X <0.5 um in
diameter) H2S04 aerosol
»-•
i. 25 mg/m3 (1 pm. MMO. o 1.6)
*° H2SO, aerosol 9
50 mg/m3 H2SO«, or
100 mg/m3 H2SO«. 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 heaatological 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 ing/in3 (0.54 p"), but with larger size (1.15 UM,
0.38 mg/m3) hyperptasla 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.92-197
Alarie et al
197
Lewis et al
104
Cockrell et al.
118
Ketels et al
120
-------
TABLE 12-8. RESPIRATORY RESPONSE OF GUINEA PIGS EXPOSED FOR 1 HR TO PARTICLES
IN THE AMDUR et al. STUDIES
ro
i
in
o
Concentration
Compound mg/m3
H2S04 o.lO
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)?S04 0.50
* 2.14
1.02
9.54
NH4HS04 0.93
2.60
10.98
Particle
size, pm, MMD
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
172,173
172
172
64,125
125
125
125
125
172
172
172
172
125
125
125
125
125
130
130
123,130,170
130
130
130
130
-------
TABLE 12-8 (continued).
ro
i
in
Compound
Na2S04
ZnS04
ZnS04-
(NH4)2S04
CuS04
NaV04
FeS04
Fe203 (2hr)
MnCl2
Mn02
MnS04
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
0.70
1.00
11.70
21.00
1.00
9.70
4.00
Particle
size, pm, HMD**
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
0.076 (GMD)
0.076 (GMD)
Resistance
cm H20/ml/sec
% difference
from control
+2
+41*
+22*
+40*
+81*
+129*
+43*
+68*
+29*
+6
+32*
+9
+25*
+14*
+7a
+2a
-^
oa
+4a
-6a
-la
Compliance
ml/cm H20
% difference
from control Reference
-7 130
123,170
123,173
123
123,170
64,123
123,173
123
64,123,173
123,173
123
-11* 130
-15* 130
-11* 130
96
96
96,124
96,124
96
96
170
-------
TABLE 12-1. POTENTIAL MUTAGENIC EFFECTS OF S02/BISULFITE
Concentration SO.
4
1310 mg/m3
(500 ppm)
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 HSOl
pH 3.6 J
0.04 or 0.08 M
/
Organisn
Phage T4-R11 Systen
Phage T4-R11
Systen
E. coll K12 & //
K15 //
S. cerevtslae
D. nelanogaster
Hela cells
(Hunan)
End Point ^^
GC-»AT or /
deani natl on'of
cysocine'''
deami nation of
X cytocine
GC+AT or
deani nation of cytocine
Point Mutation
Point Mutation
Cytotoxiclty
^
Response Connents Reference
Sunne56o.nd
201
± Poor dose Hayatsu and.Miura
response I Ida et al.
+ Mukai et al.203
-»• * Doranga.and
Dupuy204
May not be Valencia et al.205
bioavallable
+ Thomson and Pace
13.1 - 105 ng/mj
(5 - 40 ppm n 3 nin)
Mouse flbroblasts &
Peritoneal nacrophages
Nulsen et al.
208
-------
TABLE 12-8 (continued).
Compound
Concentration
mg/ma
Particle
size, pm, HMD
Resistance
cm H20/ml/sec
% difference
from control
Compliance
ml/cm H20
% difference
from control
Reference
ro
Na2S04
ZnS04
ZnS04-
(NH4)2S04
CuS04
NaV04
FeS04
Fe203 (2hr)
MnCl2
2
Mn0
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
0.70
1.00
11.70
21.00
1.00
9.70
4.00
+9
+25*
+14*
-io
0
+4
-6
-I
-11*
-15*
-11*
123,173
123
123,170
64,123
123,173
123
64,123,173
123,173
123
130
130
130
96
70,96
96
124
96
96
170
-------
TABLE 12-8 (continued)
Resistance CompH
^
anc*^
cm H20/ml/sec nl/c^H^O
Concentration Particle % difference $xTffference
Compound mg/m3 S1-ze> pn)j mo from controi ^-'from control Reference
Open hearth 0.16 +lla ^/
dust 7.00 +6*''
Activated 8.70 / -3a
carbon
Spectographic 2.00 // +7a
carbon 8.00 / +i7a
/
»2 *p < 0.05 /
• /
tn /
a*». *. • . . . . x
96,124
96,124
96
96
96
Statistics not done
-------
Compound
TABLE 12-9 (continued)
Concentration
mg/m3
Particle
size, urn, MMD
Resistance
cm H20/ml/sec
% difference
from control
Compliance
ml/cm H20
% difference
from control
Reference
Open hearth
dust
Activated
carbon
Spectographic
carbon
0.16
7.00
8.70
2.00
8.00
0.037 (GMD) +lla
0.037 (GMD) +6a
-3a
+7a
+17a
0 96,124
-16 96,124
96
96
96
ro
i
en
ro
*p < 0.05
aStati sties not done
**Diameters are provided as mass median diameter (MMD) unless specified as geometric
median diameter by count (GMD).
-------
Additional References Recommended for Considerati^fKui Chapter 12
Costa, D. L. and M. 0. Amdur. Effect of oil jrrfsts on the im'tancy of sulfur
dioxides. II. Motor Oil. Am. Ind-^Hyg. Assoc. J. 40:809-815, 1979.
Costa, D. L., and M. 0. Amdur. Effect of oil mists on the irritancy of sulfur
dioxide. I. Mineral Oils arid Light Lubricating Oil. Am. Indust. Hyg.
Assoc. J. 40(8):680-685,/I979.
Costa, D. L., and M. O.^Afndur. Respiratory responses of guinea pigs to oil
mists. Am. Indusi. Hyg. Assoc. J. 40(8):673-679, 1979.
Schneider and Ca-Tkins. Sulfur dioxide induced lymphocyte defects in peripheral
blood cuKures. Environ. Res. 3:473-482, 1970.
-------
distensibility), tidal volume (the volume of air moved during normal
breathing), respiratory 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. (See Appendix I for a more detailed discussion of
methodology.)
The importance of particle size on the site of pulmonary deposition is
described in Chapter 11. The health effects impact of these factors is clear
125
from an early study. 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
y y
largest size (7 pm, 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 concentrations of 2
mg/m , the 0.8 urn particles were more effective than the 2.5 urn 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 differences 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
12-53
-------
0.8 pm particles caused narrowing of the smaller bronchi. While the results
of the experiments are reported in a straightforward concentration-response
curve, the physiological response producing the measurable effects is
obviously highly complex. Detailed understanding is lacking.
172
In a more recent investigation, Amdur et al. exposed guinea pigs for 1
hr to either 0.3 or 1 urn (MMD) H2S04 in concentrations ranging from 0.1 to 1
mg/m . The concentration-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 ^SO^ (1 pm), all
increases in resistance were 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 particle decreased compliance more than
the 1 urn particle. Animals were also examined for 30 min after exposure
ceased. At this time, after exposure to 0.1 mg/m HpSO. (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
155
earlier work with S02, Amdur et al. describe how the same amount of sulfur
when given as H2$04 produces 6 to 8 times the response observed when given as
so2.
253
Silbaugh et al. exposed Hartley guinea pigs for 1 hr to 1 urn (MMAD)
sulfuric acid aerosols at concentrations and relative humidities of 0 mg/m3
(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/m3 (80 percent RH), and
12-54
-------
48.3 mg/m (80 percent RH). Ten animals were exposed at each concentration
except for the 24.3 and 48.3 mg/m groups, which consisted of 9 and 8 animals,
respectively. 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 animals did not differ from controls, except for 1
animal exposed to 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 animals 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 values of total
pulmonary resistance and lower pre-exposure values of dynamic compliance.
These results suggest that the guinea pig reacts to acute sulfuric acid
exposure with an essentially all-or-^ine 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 consistent with
172
results published by Amdur et al. The presence of high pre-exposure
pulmonary resistance values in responsive animals is similar to the finding by
Amdur^54 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
12-55
-------
constrictive response observed in these studies differs markedly from the
125 172
graded response observed by Amdur et al. ' during similar exposures. The
reasons for these differences are unclear, but may be at least partially
related to differences in animal strains used in these studies and the studies
of Amdur and co-workers. These results indicate an absence of respiratory
function responses to environmental concentrations of sulfuric acid, but
suggest that sensitive subpopulations might exist.
Sackner et al. evaluated pulmonary function in anesthetized dogs
exposed either to approximately 18 mg/m HUSO^ for 7.5 min or to 4 mg/m ^SO^
for 4 hr immediately after exposure or 2 hr later. 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 significant changes were observed. The
pulmonary function (pulmonary resistance and dynamic compliance) of donkeys
was not affected by H2S04 exposure (1.51 mg/m3, 0.3 to 0.6 MMAD, 1 hr).222
Studies of the irritant potential of sulfate salts have shown that these
aerosols are not innocuous and evoke increased flow resistance similar to
sulfuric acid aerosols. The influence of particle size on the effects of zinc
ammonium sulfate has also been investigated by Amdur and Corn. 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
1 A/L
aerosol from the Donora, PA episode of 1948. Zinc ammonium sulfate is not
12-56
-------
a common species found in urban air. Four sizes of aerosols were
TT
'administered: 0.29, 0.51, 0.74, and 1.4 urn (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. 37-42) where no response
occurred.
Amdur et al.130 recently compared the effects of (NH4)2$04, 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/m3, 0.11
MMD) caused no significant effects on either resistance or compliance. At the
lowest concentrations used, (NH4)2$04 (0.5 mg/m3, 0.13 urn MMD), NH4HS04 (9.93
o o
mg/m , 0.13 urn MMD), and CuS04 (0.43 mg/m , 0.11 urn MMD) decreased compliance.
These concentrations of (NH4)2S04 and NH4HS04 also increased resistance. For
CuS04, the lowest concentration tested which caused an increase in resistance
was 2.05 mg/m (0.13 urn MMD). All of these compounds are less potent than
H2S04 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
12-57
-------
submicron aerosol and the sulfuric acid as a large aerosol, then zinc ammonium
sulfate would be more efficacious at the same concentration. Regardless of
the particle size, the equivalent amount of sulfur present as SC^ is much less
efficacious than if it were present as a sulfate salt or sulfuric acid. When
present as SCL, 2.62 mg/m3 (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 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 or irritant
potency is presented below.
Relative Irritant Potency of Sulfates In Guinea Pigs
Exposed for One Hour. '
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
Data are for 0.3 urn (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.
12-58
-------
126
Nadel et al. found that zinc ammonium sulfate (no concentration given)
*bnd 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
1 0-7
inhalation of sulfate salt aerosols. Charles and Menzel 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
128
lungs. The potency ranking of different sulfate salts in the release of
127 128
histamine from lung fragments ' was equivalent to that for increased
resistance to flow. Bronchoconstriction of the perfused lung occurred on
128
intratracheal injection of sulfate salts or histamine. 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. and Amdur, support the concept that an
intermediary release of histamine 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 equilibration with the
129
99.5 percent relative humidity of the respiratory tract. 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
12-59
-------
197 128
fragments. ' A recently published estimate of the dose of inhaled
129
ammonium sulfate needed to release histamine in the lung is in error.
Complete release of histamine (100 percent) occurred with 1 umole of ammonium
128
sulfate/lung and not 1 uM solution for the entire lung. 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 uj vivo, producing anaphylactic shock.
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. 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. found the rate of
35 -2
removal of SO. from the rat lung both i_n vivo and i_n vitro to be a
function of the cation associated with the salt and to follow the same order
of potency as reported by Amdur and co-workers 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.
196
Hackney has presented a preliminary summary of the effects of aerosols
of H2S04 and nitrate and sulfate salts on squirrel monkeys (Sairniri sciurens).
Monkeys were exposed (head-only) to aerosols at 2.5 mg/m3 of the respective
salts or sulfuric acid, 40 or 85 percent 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 respiratory
resistance was measured by the forced pressure oscillation technique at sine
12-60
-------
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).
196
Hackney reports that the measurement of resistance was frequency
dependent with changes in resistance appearing greater in the 10 Hz than the
20 Hz measurements. 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 exposures were at or near 2.5
mg/m . At low relative humidity (40 percent RH; MMAD 0.3 urn, o 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, a 2.3), 3 of 5 monkeys
had increased airway resistance by 1 hr. Zinc ammonium sulfate aerosols
produced increased resistance at low humidity (40 percent 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, o 1.6). Ammonium bisulfate (40 percent RH; MMAD 0.4
urn, a 1.8) also produced an effect at 2.7 mg/m .
3
1 Qfi
Data from exposures to sulfuric acid and NH4NO, 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 interpretation does not appear
to be altered by these two approaches, but it does point out the experimental
difficulties in interpretation of pulmonary function data from experimental
12-61
-------
animals. While H2$04 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.
196
Multiple contrast analysis of the above data showed that no
significant differences between baseline or control values could be found for
any exposure using data collected at 20 Hz. At 10 Hz, the data was more
variable, but significant differences indicative of increased airway
resistance could be found for animals exposed to ZnSO^, (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 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 " have noted a failure of ammonium sulfate
aerosols to alter cardiovascular and pulmonary function in dogs or trachea!
mucus velocity in sheep. Some of these reports are at variance with the
previously cited published reports, and no detail is presently available to
12-62
-------
evaluate this new evidence. No significant alterations in pulmonary
resistance and dynamic compliance were observed in donkeys exposed to 0.4 to
2.1 mg/m3 (NH4)2$04 (0.3 to 0.6 urn MMAD) for 1 hr.222
132
Larson and co-workers have proposed that breath ammonia is important
in neutralizing 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
129
length. 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 relation 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
132
important. Larson et al. have calculated the neutralization capacity of
the breath ammonia. Once the neutralization capacity 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
219
upper airways may be altered or the permeability of the lung may be
increased.134 Second, the chemical composition of the sulfate aerosol, if
other than sulfuric acid, may also alter the permeability of the lung to
sulfate.131'134'135 Third, the cation associated with the sulfate compound
may have pharmacological properties in itself. The permeability of the lung
12-63
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to sulfate ion presented as various sulfate salts is in the same relative
order as the irritant potential found for aerosols of the same sulfate
sans.130
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. Transport of sulfate would result in the
accumulation of 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, ' 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 detoxification step. The concept of breath
ammonia does not negate the histamine release hypothesis since ammonium
1 ?7
sulfate is active in the release of histamine in guinea pig lung fragments
128
and in rat lungs.
An important problem is the relation of these observations to human
effects. Unfortunately, histamine release by non-immune mediate reactions
such as the apparent ion exchange process due to sulfate interaction with mast
cell granules is poorly understood. 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
12-64
-------
128
perfused rat lung could be blocked by an H-l antihistamine. A number of
other inflammatory hormones, aside from histamine, mediate bronchial tone in
t
man. Slow reacting substance of anaphylaxis (SRS-A), 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.
One fact is clear from all of the studies so far reported. The
biological effect of sulfate compounds is highly dependent upon the chemical
composition 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 cationic species 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 also plays an important role in the toxicity.
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 NH,, even this rate of air flow may be
insufficient. The 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
12-65
-------
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 H-SO.. 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 SO^- 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 12-9)
12.3.3.2 Chronic Exposure Effects—The influence of chronic exposure to H^SO.
92 197
on pulmonary function was investigated by Alarie et al. ' Guinea pigs
exposed continuously to either 0.9 mg/m (0.49 urn, HMD), 0.1 mg/m3 (2.78 urn,
197 3 1Q7
HMD), or 0.08 mg/m (0.84 urn, MMD) for 52 wk had no significant changes
of pulmonary mechanics (including measurements of flow resistance, respiratory
rate, some lung volumes, and work of breathing) that could be attributed to
^SO^. However, cynomolgus monkeys exposed continuously and tested
periodically during 78 wk were affected by some treatment regimens.197
Monkeys exposed to 0.48 mg/m (0.54 urn, MMD) experienced an altered
distribution of ventilation (increased N2 washout) early in the exposure
period, but recovery occurred during exposure. Animals exposed to a similar
12-66
-------
TABLE 12-9. EFFECTS OF ACUTE EXPOSURE TO PARTICULATE MATTER ON PULMONARY FUNCTION*
Concentration
Duration
Species
Results
Reference
0 mg/ma (40 or 60% RH) 1.2 mg/m3 1 hr
(40% RH), 1.3 mg/m3 (80% RH).
14.6 mg/m3 (80% RH), 24.3 mg/m3
(80% RH). and 48.3 mg/m3 (80% RH)
1 M» (MMAD) HtS04 aerosol
0.8 - 1.51 mg/m* H2S04 1 hr
(0.3 - 0.6 \tm, MMAD) or
0.4 - 2.1 mg/m3 (NH4)2S04
(0.3 - 0.6 M*. MMAD)
2.5 mg/m* (NH4)2S04> 1 hr
ZnS04,(NH4)2S04, H2S04,
and NH4N03; 2.7 mg/m3
NH4HS04
Guinea pig Pulmonary function changes observed In one animal Sllbaugh et al.
(out of 10) exposed to 14.6 mq/m3, three animals
(out of 9) exposed to 24.3 mg/m3, and four animals
(out of 8) exposed to 48.3 mg/m3
253
Donkey No significant alterations In pulmonary resistance
and dynamic compliance
Schleslnger et al.
222
Monkey Increased airway resistance at high relative hiMldlty Hackney
for (NH4)2SO<, and low relative hualdity for
ZnS04 (NH4)2S04. NH4HS04 also increased resistance.
No significant effects with H2S04 or NH4NO,
196
-------
concentration (0.38 mg/m ) but a larger particle size (2.15 urn, HMD) 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, HMD) causing an onset sooner at 17 wk compared to 49 wk in
monkeys exposed to 4.79 mg/m3 H2$04 (0.73 urn, HMD). Beginning at approximatey
8 to 12 wk of exposure, 0.38 mg/m3 (2.15 urn, HMD), 2.43 mg/m (3.6 urn, HMD)
and 4.79 mg/m3 (0.73 urn, HMD) H2S04 increased respiratory rate. The only
alteration in arterial partial pressure of Q~ 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?SO. exposures. Morphological studies of these animals are described
in Section 12.3.2.
Chronic studies of dogs were performed by Lewis et al. ' The animals
were exposed for 21 hr/day for 225 or 620 days to 0.89 mg/m3 H2S04 (90 percent
< 0.5 urn in diameter) alone and in combination with S02 (see Section 12.4.1.2
89
for expanded discusion). After 225 days, dogs receiving H2S04 had a
significantly lower diffusing capacity for CO than animals that did not
10.4.
receive H2S04- After 620 days of exposure, CO diffusiong capacity was
still decreased (p < 0.05). In addition, residual volume and net lung volume
(inflated) were decreased (p < 0.05), and total expiratory resistance 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 12-10)
12-68
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TABLE 12-10. EFFECTS OF CHRONIC EXPOSURE TO PARTICULATE MATTER ON PULMONARY FUNCTION
Concentration
Duration
Species
Results
Reference
0.08 mg/m3 H,SO« (0.84 \m, HMO)
or 0.1 *g/MS H,SO« (2.78 M", H
HMD)
0.38 mg/m3 (1.15 \tm, HHO)
0.48 mg/m3 (0.54 MM, HMD)
2.43 mg/m3 (3.6 u". HMD)
4.79 mg/m3 (0.73 M«, MHO)
H.SO,
0.89 mg/m3 H,SO« (SOX
<0.5 p» In diameter)
52 wk, continuous
78 wk, continuous
Guinea pig No effects on pulmonary function.
Alarie et al.92'197
Monkey
21 hr/day, 225 or
620 days
Dog
Exposure to 0.48 mg/m3 altered distribution of
ventilation early in the exposure period, but
not later. Exposure to 2.43 or 4.79 mg/m3 altered
distribution of ventilation. Exposure to 0.38,
2.43, or 4.79 mg/m3 Increased respiratory rate.
Other pulmonary function parameters were not affected.
After 225 days lower CO diffusing capacity. After
620 days capacity-was still decreased, residual
volume and net lung volume were decreased, and
total expiratory resistance was increased; total
lung capacity, insplratory capacity, and functional
residual capacity were also decreased. Other
pulmonary function parameters were not affected.
Alarie et al.
197
Lewi, et al.89'104
ex
•o
-------
12.3.4 Alteration in Host Defenses
To protect itself against inhaled viable or non-viable particles, the
host has several mechanisms of defense. Particles which reach the gaseous
exchange regions of the lung can be phagocytized and killed (in the case of
microbes) by alveolar macrophages. Later these cells can be moved up to the
ciliated airways where they are cleared from the lung, along with other
particles that impact on the airways, by the mucociliary escalator. This very
brief description of clearance is expanded in Chapter 11.
218
12.3.4.1 Hucociliary Clearance—FairchiId et al. showed that 4 hr
exposures to 15 mg/m H2$04 (3.2 urn, CMD) after exposure to a nonviable radio-
labeled streptococcal aerosol reduced the rate of ciliary clearance of the
bacteria from the lungs and noses of mice. When mice received a 90 min
3
exposure to 15 mg/m H2SCL (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 effects were seen at concentrations of 1.5 mg/m (0.6 urn, CMD).
222
Schlesinger et al. demonstrated that 1 hr exposures to 0.3 to 0.6 urn
H2S04 mist at concentrations in the range of 0.19 to 1.36 mg/m produced
transient slowings of bronchial mucociliary particle clearance in 3 of 4
donkeys tested. In addition, 2 of the 4 animals developed persistently slowed
clearance after about 6 exposures. Similar exposures had no effects on
regional particle deposition or respiratory mechanics, and corresponding
•i
exposures to (NH4)2S04 up to 2 mg/m had no measurable effects. In subsequent
223
experiments, the 2 animals showing only transient responses and 2
previously unexposed animals were given daily 1 hr exposures, 5 days/wk, to
H2S04 at 0.1 mg/m . Within the first few wk of exposure, all 4 animals
12-70
-------
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. 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
279
clearance can have important implications. Lippmann et al. have conducted
similar experiments in human subjects which are reviewed in Chapter 13.
Trachea! mucociliary transport rates have been measured in several other
221
animal studies. Sackner et al. failed to find significant changes in
tracheal mucus velocity following short-term exposures to 14 mg/m (0.12 urn)
222
HpSO. in sheep. Similarly, Schlesinger et al. saw no effect on tracheal
transport in donkeys after 1 hr exposures to concentrations up to 1.4 mg/m
774
(0.3 to 0.6 urn MMAD) H2$04. On the other hand, Wolff et al. reported a
depression in tracheal transport rate in anesthesized dogs exposed for 1 hr to
1.0 mg/m3 (0.9 urn, MMAD, a 1.4) which persisted at 1 wk postexposure.
Recovery had occurred when the animals were examined again at 5 wk post
exposure. Following a 1 hr exposure to 0.5 mg/m H2S04, 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
12-71
-------
bronchi of individual humans in the Lippmann et al. 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
219
form which is then acidified by C02- In vitro studies have shown that
217
mucus is a sol in high pH solutions, while at lower pH it becomes viscous.
The H supplied by the H2SO. may stiffen the mucus and increase the efficiency
of removal. This is consistent with the increase in bronchial clearance rate
A ML. 7^, 3
(J* f s73$$s f*sffl -I Q"I TOO
observed in humans following exposure to 400 (gg/m-. Other studies ' have
shown that exposures to 0.9 to 1.1 mg/m HLSO. 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
181 182
details on these latter studies ' which were conducted 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 12-11)
Cadmium and nickel chlorides also disrupt the activity of the ciliated
epithelium. ' Tracheal rings have been isolated from hamsters and the
beat frequency and morphology of the ciliated epithelium have been observed.
Concentrations of CdCl2 as low as 6 uM i_n vitro resulted in decreased beat
12-72
-------
TABLE 12-11. EFFECTS OF SULFURIC ACID ON MUCOCILIARY CLEARANCE
Concentration
Duration
Species
Results
Reference
0.1 mg/m* H2S04
0.19 to 1.4 mg/m3 H2S04 (0.3
tc 0.6 UM. MMAO)
0.5 mg/m3 H,S04
1 hr/day, 5 day wk,
several MO
1 hr
1 hr
1.0 mg/ma H2S04 (0.9 u". MMAD, 1 hr
1.4 mg/m3 H2S04 (0.3 to 0.6 urn, 1 hr
MMAO)
1.5 mg/m3 H2S04 (0.6 UM, CMO) 90 Min
14 mg/m3 H2S04 (0.12 MI* MMAD) Short-ten*
15 mg/m3 H2S04 (3.2 u«, CMO) 4 hr
15 mg/m3 H2S04 (3.2 \m, CMO) 90 Min
Donkey Within the first few wk, all 4 aniMls developed
erratic bronchial Mucoclllary clearance rates,
either slower than or faster than those before
exposure. Those aninals never pre-exposed before
the 0.1 mg/m3 H2S04 had slowed clearance during
the second 3 MO of exposure.
Donkey Bronchial Mucoclllary clearance was slowed.
Dog Slight Increases In tracheal •ucoclllary transport
velocities Immediately and 1 day after exposure.
One wk later clearance was significantly decreased.
Dog Depression in tracheal Mucocillary transport rate
persisted at 1 wk post-exposure.
Donkey No effect on tracheal transport.
Mouse No significant effects.
Sheep No significant changes in tracheal •ucoclllary
transport rate
Mouse Exposure to H2S04 after exposure to a nonviable
streptococcal aerosol reduced the rate of ciliary
clearance of the bacteria fro* the lungs and nose.
Mouse Exposure to H2S04 4 days prior to bacterial aerosol.
Clearance of nonviable bacteria reduced in nose,
but not lungs.
Schleslnger et al.
223
Schleslnger et al.
Wolff et al.224
Wolff et al.224
222
Schleslnger et al.
71A
Falrchild et al. °
Sackner et al.221
218
222
Falrchild et al.'
Falrchild et al.
218
-------
frequency and degradation of the ciliated epithelium architecture. A prior
2-hr exposure i_n vivo to 2 urn aerosols of CdCl^ at 0.05 to 1.42 mg/m caused a
significant decrease in cilia beat frequency 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. 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 mg/m , Cd
was about 20 percent more effective than Ni in slowing cilia beat. (Table
12-12)
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
148
through removal of inhaled particles has been amply demonstrated.
005
Allison and Morgan have summarized the evidence that AM ingest both
toxic and non-toxic particles in the same manner. In the case of fibers,
??fi
ingestion appears more dependent upon the length of the fiber. Short
fibers of >5 urn are almost always ingested, while fibers >30 urn 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.225 This interaction is
12-74
-------
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
J>pC
lysosome to yield a secondary lysosome containing the particle. 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. examined the influence of HI vitro exposure to a variety
of particles on AM oxidant production (02~ and H^) 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
intermediate activity. Fugitive dusts and fly ash had the lowest activity.
149
Waters et al. 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 (VJD.,), or vanadium dioxide (VCL). Cytotoxicity was
directly proportional to the solubility of the vanadium compound: V^ > V,,03
> 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 V205, 21 ug
V/ml as V203, and 33 ug V/ml as VCL. When V205 was dissolved in the medium
prior to incubation with the AM, only about 9 ug 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 V205. Acid
12-75
-------
phosphatase, a lysosomal degradation enzyme necessary for digestion of phago-
cytized bacteria, was inhibited by 1 pg V/ml as VpOc, while the lysosomal
enzymes, lysozyme and p-glucuronidase, were not inhibited by concentrations as
high as 50 pg V/ml.
Alveolar macrophages exposed jm vitro for 20 hr to metallic salts were
also studied by Graham et al. 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 in vitro by low concentrations of CdC^
(2.2 x 10"5M) or NiCl2 (10"4M).163 Inhibition was proportional to the Hi"1"*" or
^ jr
Cd concentration and reached its maximum within 20 min. These studies
showed that the antibody dependent recognition system of AM was inhibited by
++ 4>^*
trace concentrations of Ni and Cd 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).
Aranyi et al. 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
12-76
-------
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 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 treatment,
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 MnCL-coated
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 intra-
cellular 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.
These results support the concept that the surface activity of particles
225
determines the toxicity of the particle.
Bingham and co-workers ' have examined the effects of Pb and Ni
inhalation on the number and type of AM present in the lungs of rats. In a
152
preliminary report, Bingham et al. showed that a 3 mo exposure to 0.01 or
0.15 mg/m3 Pb203 (0.18 urn, MMAD) decreased the number of AM/lung. The
specificity of this response was investigated in a subsequent study using
12-77
-------
soluble PbCl2 (0.1 mg/m3, 0.17 urn HMD) and NiCl2 (0.11 mg/m3, 0.32 urn HMD)
and insoluble Pb203 (0.15 mg/m , 0.15 urn MMD) and NiO (0.12 mg/m3, 0.25 urn
HMD) 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 (Figure 12-6). The number of AM was
depressed on inhalation of 0.15 mg/m Pb203 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 NiCU-exposed rats were
marked increases in mucus secretion and bronchial hyperplasia. No
morphological alterations were observed in those rats exposed to PbCl2 or
PbpO.,. 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. ' 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.
12-78
-------
i;
•vj
£
f»
^
"c
i.
^
*
10
9
NiO T
/ ,-\
6 r
y f
7 -
/
c /
b ~ .-x
5
4
3
2
1
n
I-''
T /I Contro/
- ! T , y / T
XV J*- " '
"M * ^
- V / ^^j
I^^I ^ T
/[ 1 1 1 I I t i 1 !
0 2 4 6 8 10 12 14 16 16
Doys of Exposure
Figure 12-6. Mean number and standard error of alveolar
cells washed from Jungs of rats after inhalation of oxides
of lead and nickel.
12-79
-------
These effects were not observed at 0.5 mg/m3 Cd, indicating that the minimum
effective dose may lie somewhere between these two concentrations.
Nickel chloride aerosols ' 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/m3 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/m3 Mn,0. reduced the number of AM which could be recovered by
188
lavage, but did not result in an influx of other cell types. The AM had a
reduced concentration of ATP and total protein and acid phosphatase activity.
Viability and phagocytic activity of AM were normal.
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. The observations of two
independent laboratories ' ' on NiCK aerosols are essentially in
agreement. (Table 12-12)
12.3.4.3 Interaction with Infectious Agents—Gardner and Ehrlich have
reviewed their groups' studies and presented new data on the effects of
aerosols on host defense mechanisms 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. ' Animals were placed in a head-only
exposure system for 2 hr and were given graded concentrations ranging from
0.075 to 1.94 mg/m3 Cd,154 from 0.1 to 0.67 mg/m3 Ni,155 or from 0.5 to 5
3 189
mg/m Mn. J In mice, these exposures to Cd and Ni chlorides and Mn.,0.
resulted in the deposition of 0.002 to 0.026 mg Cd,154 0.001 to 0.012 mg
Ni, or 0.005 to 0.042 mg Mn190 per g dry weight of lung respectively.
12-80
-------
Nickel clearance from the lungs of mice had a half-life of 3.4 days; while
190
Mn 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 CdClp,
NiC^, or MnCU 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 significant linear concentration
response. The lowest concentration tested at which a significant increase in
3 3
mortality was detected was 0.1 mg/m Cd or 0.5 mg/m Ni. Manganese, as
189
Mn20., was statistically estimated to produce a 10 percent increase in
3 176
mortality at 1.55 mg/m Mn, while MnClp required a higher concentration to
produce a measurable increase in mortality. Using a different infectivity
191 3
model, 3 or 4 days (3 hr/day) of exposure to 109 mg/m Mn02 (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 NiCl/, was complex. 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 CdCl2 and Mn were observed when the bacterial
challenge immediately followed exposure. The concentration-response curve of
Ni was very steep compared to Cd and Mn exposures. 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
12-81
-------
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.
The influence of a variety of sulfate species on host defense mechanisms
178
against infectious respiratory disease has been investigated by Ehrlich and
17Q
Ehrlich et al. 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
mg/m3 CdS04, 0.6 mg/m3 CuS04, 1.5 mg/m3 ZnS04, 2.2 mg/m3 A12(S04)3, 2.5 mg/m3
A1(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, Na2$04 at 4 mg/m3 S04, Fe2(S04)3 at 2.9 mg/m3 S04,
o
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/m or higher. However, ZnNO., 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. This is not unexpected as airway resistance
primarily detects alterations of the medium to large conducting airways, while
180
the infectivity model is hypothesized to reflect alveolar level changes.
The increased mortality of the infectivity model does seem to be a
measure of toxicity. When mice were exposed for 2 hr to 5.0 mg/m3 carbon
3
black or 2.5 mg/m iron oxide, no significant increases in mortality resulted
on subsequent exposure to airborne infection.
Death from S. pyogenes exposure in this infectivity model is due to
154 ^
septiceima. Septicemia occurs when the bacteria have grown to 10
organisms per lung. Removal and killing of the inhaled organisms will reduce
12-82
-------
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 control animals. Studies of tracheal 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. (Table 12-12)
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 NiClp depressed the
159
number of antibody-producing cells in the spleen. 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 NiClp aerosols (99 percent less
than 3 urn in diameter) was more effective in suppressing the primary immune
response. Graham et al. calculated that exposure to an aerosol of 0.25
mg/m 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
depression in the immune response. The lowest dose found to produce a similar
159
effect by injection was 208 ug Ni /mouse. 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
12-83
-------
the lung up to 4 days after exposure. Similar kinetics of removal have been
230
found using the isolated, ventilated, and perfused rat lung and human, rat,
231
and cat type II pneumocytes in culture.
Inhaled Cd also depresses the number of antibody producing cells and is
more potent than intramuscularly injected Cd. The highest intramuscular dose
of CdCl2 examined by Graham et al. was 11.81 ug Cd/g body weight (about 266
ug Cd/mouse), and it produced no immunosuppression. 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 CdCl2, a highly soluble salt. The inhalation dose
can be calculated on the same basis as that given above for Ni to be at a
maximum at 0.74 ug 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. ' Keller et al. found that
150 ug Cd given orally was required to produce imrnunosuppression.
For comparative purposes, the lowest inhalation exposure of CdCK found
3 3
to be immunosuppressive 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 ug/day and from water to be 160 ug/day. NiCl- was
found to be immunosuppressive at an inhalation exposure of 0.25 mg/m while
its TLV is 1 mg/m . The human exposure is estimated to be 2.36 ug/day from
229
inhalation and 600 ug/day from ingestion. 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 cytotoxicity to AM, depression of antibody production, and
12-84
-------
inhibition of antibody dependent aggregation reactions. All of these
mechanisms can help to explain the increased susceptibility 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
12-12)
12-85
-------
TABLE 12-12. EFFECTS OF METALS AND OTHER PARTICLES ON HOST DEFENSE MECHANISMS
Concentration
Duration
Species
Results
Reference
0.01 or 0.15 mg/m3 Pb,03
(0.18 urn, MMAD)
0.01 mg/m3 (0.17 pm. MMAD) PbCl2
or 0.11 mg/m* (0.32 urn. MHAO)
NiC12 or 0.15 mg/m3 (0.15 Mm.
MMAD) Pb203 or 0.12 mg/m3 (0.17
Mm, MMAO) NiO
0.05 to 1.42 mg/m* CdCl,
0.1 mg/» N1C12
!-•
ro
^Graded concentrations:
<* 0.075 to 1.94 mg/m3 CdCl2
0.1 to 0.67 mq/m3 N1C1,. or
0.5 to 5 mg/m3 Mn30«;
all aerosols (94-99*) <1.4 urn
in dia*eter
109 mg/m3 Mn02 (0.70 \tm, mean
diameter)
0.2 mg/m3 CdSO«, 0.6 mg/m3 CuS04,
1.5 mg/m3 ZnSO«, 2.2 mg/m3
A12(S04)3, or 3.6 mg/m3 MgS04
Ammonium sulfate at 5.3 mg/m3
S0«, NH«HSO«, at-6.7 mg/ni S04.
N02SO« at 4 mg/m* S0«, Fe2(SO«)2
at 2.9 mg/m3 S0«, or
Fe(NH4)2S04 at 2.5 mg/m3 S0«
3 mo
12 hr/day. 6 day/wk.
2 MO with PbC)2,
NiCl2, or NiO; con-
tinuously for 2 mo
with Pb203
2 hr
2 hr
2 hr
Rat
Rat
Hamster
Hamster
Mouse
3 hr/day
Mouse
3 hr
3 hr
Mouse
Mouse
Decreased the number of alveolar macrophages/lung. Bingham et al.
Exposure to Pb20,, but not PbCl,, resulted in a Bingham et al.
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 PbC)2 or Pb203.
Decreased ciliary beating frequency in trachea. Ada1 is et al.
Decreased ciliary beating frequency in trachea. Adalis et al.
The aerosols increased the mortality from the sub- Gardner et al.
sequent standard airborne streptococcal infection: Adkins et al.
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 Ma (getter,
mice received bacterial aerosol immediately after et al.
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 20X enhance- Ehrlich et al.
ment of bacterial-induced mortality over controls.
No significant alterations of host defense Ehrlich et al.
mechanisms.
152
153
157
156
154
155,189
178,179
178,179
-------
TABLE 12-12. (Continued)
Concentration
Duration
Species
Results
Reference
5,0 mg/m* carbon black or 2.5 2 hr
•g/ir iron oxide
0.19 mg/m3 CdCl, 2 hr
0.25 mg/m' NIC12
Mouse No significant increases In Mortality resulted on Gardner
subsequent exposure to airborne infection.
Mouse Decreased number of antibody-producing spleen cells Graham et al.
160
I
TO
-------
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 interaction 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 H-SO^, etc.). Other
research was directed at evaluating the influence of several pollutants when
delivered in combination or in sequence.
12.4.1.1 Acute Exposure Effects—The question of the possible effect of
aerosols on the response to S02 is a critical problem in air pollution
toxicology. The phenomenon has been investigated in simple model systems
of S02 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 S02 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 . These experiments with guinea pigs
indicated that the response to a given concentration of S02 was potentiated by
-------
3 3
10 mg/m sodium chloride. For example, a concentration of 5.24 mg/m (2 ppm)
S02 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 SOp, 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 S0« thus favoring the production of I^SO..
Sodium chloride does not catalyze the oxidation of S02 to sulfuric acid.
141
Experiments by McJilton et al. indicate the importance of ambient
relative humidity and the solubility of SO- in the sodium chloride droplet.
They examined the effect of 1 mg/m NaCl on the response to 2.62 mg/m (1 ppm)
S02 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
12-89
-------
sulfate and nitrate aerosols above and on human exposure experiments in
Chapter 13).
Amdur and Underhill studied the effect of aerosols of soluble salts of
metals shown to convert S02 to sulfuric acid. Manganous chloride, ferrous
sulfate, and sodium orthovanadate caused a threefold increase in the response
to S02 concentrations of 2.62 mg/m3 (1 ppm). 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 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
93
the presence of sulfate, presumably as sulfuric acid. 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/m (0.2 ppm) S02, the increase in flow resistance duplicated the
increase observed with the iron and vanadium aerosols. This suggests that
sulfuric acid formation is the most likely mechanism of potentiation for the
aerosols of these metals. Amdur et al. 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) S02. At the moment, it is not certain whether this is mediated through
the formation of sulfuric acid or through the formation of a sulfite complex.
The response to 0.79 to 0.84 mg/m (0.3 to 0.32 ppm) SO- with ammonium sulfate
(0.9 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.
96
Amdur and Underhill also examined the effec
aerosols (carbon, iron oxide, manganese dioxide, and fly ash) which do not
96
Amdur and Underhill also examined the effect of a variety of solid
12-90
-------
catalyze the conversion of SCL to H-SO.. None of these potentiated the
response to S02. (Table 12-13)
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) which
were collected downstream from electrostatic precipitators of coal-burning
92
electric generating plants). Monkeys were exposed for 18 mo and guinea pigs
for 12 mo. For monkeys, exposures were to S02, H2S04 + fly ash, S02 + H2$04,
or S02 + H2S04 + fly ash. Guinea pigs received either 0.9 mg/m3 HpS04 (0.49
pm MMD) or 0.08 mg/m3 H2$04 (0.54 or 2.23 urn HMD) + 0.45 mg/m3 fly ash
(3.5 or 5.31 urn HMD). In monkeys, a battery of hematological and pulmonary
function (tidal volume, respiratory rate, minute volume, dynamic compliance,
pulmonary 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 significant effects were attributed to the
exposures. Similar methods (except for distribution of ventilation and CO
diffusing capacity) were used with guinea pigs, but no significant effects
3
were observed. At the end of the exposure to 2.59 mg/m (0.99 ppm) SO,, + 0.93
mg/m H2$04 (0.5 urn 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/m3 H2S04 (0.54 urn MMD,
o 1.5 to 3.8) + 0.41 mg/m fly ash (4.1 urn MMD, a 1.8 to 2.8) had similar
alterations,."Thus, fly ash did not enhance the effect. Monkeys which received
0.99 mg/m3 H2S04 (0.64 urn MMD, a 1.5 to 3.0) + 0.55 mg/m3 fly ash (5.34 urn
MMD, a 1.8 to 2.2) had slight alterations in the mucosa of the bronchi and
12-91
-------
TABLE 12-13. EFFECTS OF ACUTE EXPOSURE TO SULFUR DIOXIDE IN COMBINATION WITH ("ARTICULATE HATTER
Concentration Duration
5.24 ug/m* (2 ppa) SO,. 10 Mg/M3 I hr
and 4 Kg/*3 NaCl
Species
Guinea pig
Results
5.24 Mg/M» (2 PPM) SO, alone
of 20X in pulMonary flow rei
produced an Increase
dstance; with NaCl at
Reference
A-dur97
ho
i
2.62 Mg/ar* (1 ppM) SO,, 1
NaCl at low (40 X) and high (80X)
relative huMidity (RH)
2.62 efl/K3 (1 ppn) SO,, an
aerosol of soluble salts
(•anganous chloride, ferrous
sulfate, and sodiDM orthovana-
date) 50% RH
0.94 wg/M3 (0.36 ppn) SO,,
0.4 ng/M3 copper sulfate
0.79 to 0.84 Mg/M3 (0.3 to
0.32 ppM) SO, and 0.9 Mg/M3
iuM blsulfate, or 0.9
sodluM sulfate
1 hr
1 hr
1 hr
1 hr
10 ng/Ma the increase was 55X and the potentialion
did not occur until the latter part of the exposure.
At 4 Mg/M3 NaCl, the potent(ation was greatly
reduced.
Guinea pig No increase In pulMonary flow resistance at low RH. McJIlton et al.
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 pulannary flow AMdur and «g
resistance about 3-fold. The potentiation was Underbill
evident early in the exposure.
141
Guinea pig Potentiated pulMonary flow resistance. AMdur et al
Guinea pig The effect on pulMonary flow resistance was AMdur et al
additive.
130
130
-------
respiratory bronchioles. Focal areas of erosion and epithelial 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.
199
In a previous study, Alarie et al. found no effects on pulmonary
function, hematology, or morphology of monkeys or guinea pigs exposed to
approximately 0.56 mg/m fly ash in combination with 3 concentrations of S02
(0.28, 2.62, or 13.1 mg/m ; 0.11, 1, or 5 ppm). Monkeys were exposed
continuously for 78 wk and guinea pigs for 52 wk.
89 104
Lewis et al. ' investigated the effects of S02 and H2S04 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/m H2SO. (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 HpSO. was lower (0.76 mg/m
H2S04 in the H2$04 group and 0.84 mg/m H2S04 in the H2S04 + S02 group).
89
After 225 days of exposure, dogs receiving HUSO, had a significantly lower
diffusing capacity for CO than those that did not receive H2SO.. 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 S0?. Dogs not pre-exposed to N02 which received S02 + H2SO. had a
smaller residual volume (p < 0.01) than all other dogs.
12-93
-------
These dogs were also examined after 620 days of exposure.104 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 hemoglobulin 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 significant 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 measurements (other lung volumes, dynamic and static
compliance, and N2 washout) were not significantly affected. These
alterations of diffusing capacity for CO and lung volumes are interpreted 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.
Beagle dogs were exposed 16 hr/day for 68 mo to raw or photochemically
reacted auto exhaust, oxides of sulfur or nitrogen, or their combinations. A
description of the exposure groups is given in Table 12-14. They were
examined after 18,186 36,104 and 61105 mo of exposure and 32 to 36 mo185'187
after the 68 mo exposure ceased.
12-94
-------
TABLE 12-14. POLLUTANT CONCENTRATIONS FOR CHRONIC EXPOSURE OF DOGS
185
Atmosphere
Pollutant Concentration, mg/m
CO
HC
(as CH) N0
NO
OX
(as 0) S0
Control Air (CA)'
Non irradiated auto
exhaust (R)
112.1
18.0
0.09
1.78
r\>
vo
tn
Irradiated auto
exhaust (I)
108.6
15.6
1.77
0.23
0.39
S02 + H2S04(SOy)
1.10
0.09
Nonirradiated auto
exhaust + S0_ +
HS0 (R + S6)
113.1
17.9
0.09
1.86
1.27
0.09
Irradiated auto
exhaust + SO, + H.SO.
(I + S0x) Z i
109.0
15.6
1.68
0.23
0.39
1.10
0.11
Nitrogen oxides, 1
(N02 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)
-------
After 18 or 36 mo of exposure, no significant changes in pulmonary
function were observed. A variety of alterations were found using analysis of
variance after 61 mo 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 + SOX (see Table 12-14 for abbreviations)
compared to those receiving I + SO SO , and CA. Residual volumes of the SO
A A "
2
group were lower than those of 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 air (CA). This change
was interpreted as pulmonary hyperinflation. Although other lung volumes,
compliance, resistance, diffusing capacity for CO, ^ washout, peak expiratory
flow, and maximum breathing capacity were also measured, sulfur oxides had no
effects.
18*5
Thirty-two to 36 mo after exposure ceased, the lungs of the beagles
were examined using morphologic (light, scanning electron and transmission
electron microscopy) 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 S0x dogs, the air spaces enlarged and the number and size of
interalveolar pores increased. Only the N02 high dogs had a greater degree of
air space enlargement. The SOX animals had a loss of cilia in the conducting
airways without squamous cell metaplasia, nonciliated bronchiolar cell hyper-
12-96
-------
plasia, and loss of interalveolar septa in alveolar ducts. When SO was
combined with R, cilia were also lost, but squamous cell metaplasia occurred.
Exposure to R + SO and I + SOX produced nonciliated bronchiolar cell
hyperplasia 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 S0~ and H^SO.. The
authors consider these changes to be analogous to an incipient stage of human
proximal acinar (centrilobular) emphysema.
Biochemical analyses were also performed on the lungs of these dogs at
187
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. No
significant changes in hydroxyproline were found. The SO and I + SO groups
had significantly elevated prolyl hydroxylase activity compared to the R, R +
SO , and CA groups.
^
Zarkower reported mixed effects on the immune system of mice exposed
o 3
to 5.24 mg/m (2 ppm) S02 and 0.56 mg/m carbon (1.8 to 2.2 urn, 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 significant changes.
Sulfur dioxide 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 equivalent 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
S0?-exposed mice. In the spleen, S02 caused an increase (p < 0.01) in the
12-97
-------
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),
SOp caused no such changes. Carbon + SO-, 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 + S02, the number of antibody
producing spleen cells decreased (p <0.01). The immunosuppression in these 2
groups was roughly equivalent and appeared to be more severe than that in the
SOp alone group. In the mediastinal lymph nodes, only carbon + S02 caused
immunoenhancement (p < 0.05). Thus, for the pulmonary immune system, only
exposure to the combination of S02 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 + S02 caused equivalent effects
and that both fag-i-mes were more effective than S02-
183
Renters et al. showed that exposure for 3 hr/day, 5 days/wk for up to
20 wk to a mixture of 1.4 mg/m HpSO^ plus 1.5 mg/m carbon (0.4 urn, mean
particle diameter) or to 1.5 mg/m carbon only (0.3 urn, mean particle
diameter) also altered the immune system of mice. Some classes of 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 H^SO. + 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 HUSO. + carbon group,
but only the immunosuppression at 20 wk was significant. In examining other
12-98
-------
*host defense systems, no 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 A2/Taiwan virus, a 20-, but not a 4-, wk exposure to H2SO. +
carbon increased mortality.
183
Morphological changes were observed in these mice 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 H2SO. and carbon showed equivalent effects, but
the damage was somewhat more severe than that seen in the carbon only group.
The influence of H2SO. and carbon on the trachea of hamsters was
182 3
investigated by Schiff et al. Animals were exposed for 3 hr to 1.1 mg/m
H2SO. (0.12 urn, mean size) and/or 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
H?SO. and carbon resulted in more tissue destruction than either pollutant
alone, although the single pollutants did cause some damage. Morphological
12-99
-------
alterations of all pollutant exposure groups were observed using light and
scanning electron microscopy, (see Table 12-15)
12.4.2 Interaction with Ozone
Cavender et al. exposed rats and guinea pigs to sulfuric acid aerosols
(10 rog/m3, 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 historically. No synergism was observed between the
ozone and sulfuric acid treatments. The histological lesions were those
119
ascribed to ozone alone. This same group exposed rats and guinea pigs to
sulfuric acid aerosols (10 mg/m , 50 percent equivalent aerodynamic diameter,
0.83 urn, a = 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.
144
Last and Cross 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 simultaneously to rats for 3 days. Glycoprotein
synthesis was stimulated in trachea! ring explants measured ex vivo. Ozone
alone caused a decreased glycoprotein secretion; sulfuric acid was relatively
inactive, requiring concentrations in excess of 100 mg/m to produce changes
in 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.
181
Grose et al. investigated the interaction of H-SO. and 0, on ciliary
beat frequency in the trachea of hamsters. A 2 hr exposure to 0.88 mg/m3
H2S04 (0.23 urn, VMD) significantly depressed ciliary beat frequency. By 72 hr
after exposure, recovery had occurred. Hamsters exposed to 0.196 mg/m3 (0.1
12-100
-------
TABLE 12-15. EFFECTS OF CHROMIC EXPOSURE TO SULFUR OXIDES AND PARTICULATE MATTER
Concentration
Various combinations of S02l
H2SO« (0.5 to 3.4 \m. HMD),
and fly ash (3.5 to 5.9 MM,
HMO): SO,, H2SO« + fly ash.
SO, * H2SO«. S02 + H2SO« +
fly ash
0.9 mg/m3 H2SO« (0.49 \im,
HMO); 0.08 mg/m3 H2S04
Duration
18 mo,
continuous
12 MO.
continuous
Species Results
Monkey No significant effects on heiutology or pulmonary
function tests during exposure. At end of exposure
to 0.99 pp» S02 + 0.93 mg/m3 H2S04 (O.S u». MMO)
lungs had Morphological alterations In the bronchial
Mucosa. Exposure to 1.01 DDM S02 + 0.88 mg/m3 H.SO.
(0.54 M«. MHO) + 0.41 Mg/m3 fly ash (4,1 MM, MMD) hid
similar alterations, thus fly ash did not enhance
effect. Exposure to 0.99 Mg/MJ H SO. (0.64 MM, MMO)
+ 0.55 mg/m fly as (5.34 M", MMO) hid slight
alterations.
Guinea pig No significant effects on hematology, pulMonary
function, or Morphology.
Reference
Alarie et al.92
Alarle et al.92
(0.54 or 2.23 p«. MMD) +
0.45 mg/m3 fly ash (3.5
or 5.31 M<*. HMO)
Approximately 0.56 mg/m3 fly
,_ ash In combination with S02 at
7* 0.28, 2.62, or 13.1 mg/m3 (0.11,
S 1. or 5 ppm).
i—
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 H2SO« (90X <0.5
MM in diameter), or to a
combination of the two
78 wk. Monkey
continuous
No effects on pulmonary function, hematology,
or morphology.
Alarle et al
199
52 wk,
continuous
Guinea pig No effects on pulmonary function, hematology,
or morphology.
Alarle et al.
199
21 hr/day, 620 days Dog
After 225 days, dogs receiving H2S04 had a lower
diffusing capacity for CO than those that did not
receive H2SO«. 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 SO, + H2S04
had a smaller residual volume than all other dogs.
After 620 days, pulmonary function was altered fro*
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.
Lewis et al.89'104
-------
TABLE 12-15 (continued).
Concentration
Duration
Species
Results
Reference
(see Table 12-»)
16 hr/day, 68 mo
Dog
5.24 *g/m3 (2 ppm) SO,, or 0.56
mg/m3 carbon (1.8 to 2.2 urn,
HMO), or In combination
1.4 mg/m3 H2SO, plus 1.5
mg/m3 carbon (0.4 pm, mean
particle diameter), or 1.5
mg/m3 carbon only (0.3 urn,
•can particle diameter)
1.1 mg/m3 H2SO« (0.12 urn. mean
size), or 1.5 mg/m3 carbon (0.3
pa. mean size), or in combination
100 hr/wk, 192 days Mouse
3 hr/day,
20 wk
3 hr
5 day/wk,
Mouse
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 volumes of the SO group Mere lower than of
the CA group. More dogs or the 1 + S0x had higher
total expiratory resistance than their controls
(CA and SO ). The ratio of residual volume to total
lung capacfty was higher in R + SO than CA. 32 to 36
mo after exposure ceased, the SO group had lung
weight, total lung capacity. andxdisplaced
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 + SO
and I + SO produced none 1 Hated bronchlolar
cell hyperplasla 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 + S0t
were more effective than S0t, 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
H,SO, 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.89'104
Zarkower
115
Renters et al.
183
Schiff et al
182
-------
ppm) 0., for 3 hr were not significantly affected. However, when animals were
exposed in sequence, first to 0, and then to HUSO., ciliary beat frequency was
decreased significantly, but to a lesser extent than that caused by H2SO.
alone. Analysis showed that antagonism (p < 0.05) occurred in this sequential
exposure.
145
Gardner et al. 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 Streptococcus
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 Streptococcus pyogenes infections. Because photo-
chemical 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
add'itive response sequence are not apparent. Thus, the results are opposite
181
those of the Grose et al. study described above with the trachea! model
which showed that sequential exposure to 03 and H2SO. had an antagonisitic
effect. The reasons for this difference are not known. However, the
180
infectivity model is thought to reflect alveolar level effects, 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
12-103
-------
in extrapolating the effects of pollutants from one parameter to another, (see
Table 12-16)
12.5 CARCINOGENESIS AND MUTAGENESIS
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 gastrointestinal 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.
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 production 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
transformation.
Because of the strong formal relationship between molecular events
involved in mutagenesis and carcinogenesis (Miller, 1978)323, 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
12-104
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TABLE 12-16. EFFECTS OF INTERACTION OF SULFUR OXIDES AND OZONE
Concentration
Duration
Species
Results
Reference
o
en
10 mg/m3 (1 u«, HMO) H2S04
aerosol, or 3.9 mg/m3 (2 ppm)
03, or combination of the two
10 mg/m3 (SOX equivalent aero-
dynamic diameter, 0.83 urn, a =
1.66) H4S04 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 M* ± 2.4 SO, geometric)
exposed alone or in sequence
0.196 mg/m3 (0.1 ppm) 03;
0.88 mg/m3 M2S04 aerosol (0.23
tim, VMO) exposed alone or In
sequence
6 hr/day, 2 or 7
days
6 hr/day, 5 day/wk,
6 mo
3 days,
continuous
3 hr. 03;
2 hr, H2S04
3 hr, 03;
2 hr, H2S04
Rat and
Guinea pig
Rat and
Guinea pig
Rat
House
Hamster
No synerglsM In effect on ratio of lung to body Calender et al.
weight. Hlstologlcal lesions were those ascribed
to 03 alone.
Morphological alterations due to 03 alone. Cavender et al.
143
119
Synerglstlc effects. Glycoprotein synthesis was Last and Cross
stimulated In tracheal ring explants; lung ONA,
RNA, and protein content Increased.
In response to airborne Infections a significant Gardner et al.
increase in Mortality only when Os was given
immediately before exposure to H2S04, and the
response was additive.
H2S04 depressed ciliary beat frequency. Grose et al.
By 72 hr after exposure, recovery had occurred.
03 exposure had no effect. Sequential 03 then
H2S04 exposure decreased ciliary beaUwtg frequency
significantly but to a lesser extent than that
caused by H2S04 alone.
144
1*4-
181
-------
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 studies—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.). Organics 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 urn mean diameter) of many of the particles,
they can be effectively drawn into the deep compartments 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).29°
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 (Teranishi, 1978; Miller and Alfheim,
1980; Dehnen and Tomingas, 1977; Tokiwa et al., i980).346»354»296.355
Estimates have been made as to the relative mutagenicity of each extract;
however, due to the possible interaction among the many compounds present in
12-106
-------
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. These studies also have confirmed in two ways that
polycyclic aromatic hydrocarbon (PAH) compounds are not the sole mutagens
present in particulate matter. First, the total mutagenic activity does not
co-fractionate with the PAH as evidenced by appreciable activity remaining in
the polar fraction. Second, the presence of mutagenic activity in the absence
of metabolic activation implicates non-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; Kubitshek and Venta, 1979),290>356 gasoline engines
(Wang et al., 1978), and light-duty and heavy-duty diesel engines
(Huisingh et al., 1978). The extracts obtained from all sources were
mutagenic to bacteria susceptible to frame-shift mutation, and no obligatory
requirement for metabolic activation was shown. Only in the heavy duty diesel
engine study was fractionation carried out on the crude extract. An extensive
review of diesel engine particulate matter is available (Santodonato et al.,
1978).332
The Ames assay has been used in an attempt to define air quality by
measuring the mutagenic potential of airborne particulates. Tokiwa et al.
(1977) compared the number of revertants per ug 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.
loo
v!978) compared eight urban samples in the California South Coast Basin
with one collected in a rural area of the San Bernadino mountains. In both
12-107
-------
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
294
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. Wind direction was then correlated with
mutagenic potential.
Caution must be exercised when comparing in a -quantitative manner results
of Arnes assays on complex environmental mixtures. Indirect mutagenesis is
extremely difficult to quantitate, since the detoxifying action of the
microsomal preparation makes the response of direct- and indirect-acting
mutagens non-additive. For any valid comparison there has to be nearly
294
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 ot
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 the above reasons a quantitative
assessment of air quality is not readily obtainable with the use of the Ames
Salmonella mutaqenicity 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 polycyclic aromatic
12-1OR
-------
hydrocarbons 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 as to how the process of transformation in
virus-infected cells relates to the process of chemical carcinogenesis.
Hence, cell transformation assays should be considered in the same way as Ames
assays; that is, as only an indicator of the presence of biologically active
compounds.
oqq
The dominant lethal assay of Epstein et al. (1972) is the only short
term j_n vivo assay performed on airborne particulate 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. Conclusions from these experiments are difficult to draw due to the
limited validation and sensitivity of this assay system.
12.5.1.2. In vivo studies--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 ui 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)288'335 motor exhaust (Campbell, 1939)288 and airborne particulate matter
collected in the vicinity of a factory and roadway (McDonald and Woodhouse,
ooo
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
12-109
-------
used were there significant increases, with 57 percent of the experimental
287
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
289
percent of the control group developed lung tumors (Campbell, 1942). In a
recent study with lifetime exposure of rats to automotive exhaust, there were
no tumors 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's
have received the greatest attention with regard to carcinogenic potential
331
(Santodonato et al., 1979) PAH's were the first compounds ever shown to be
associated with carcinogenesis. To this day, carcinogenic PAH's are still
distinguished 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 to 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 tumors in ani-
mals 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 subcutaneously into mice. As early as 1942
sarcomas were produced in mice using the benzene extracts of particulate
12-110
-------
matter collected from an urban area (Leiter and Shear, 1942; Leiter and
iiq oor)
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 particulates were collected in the
330
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 neonatal 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 subcutaneous injection of neonatal mice was confirmed with both the
crude extract of particulates collected in New York City and subfractions of
284
this extract; the predominant tumors were again hepatomas (Asahina, 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 application (Clemo et al.,
oqi
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.
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In subsequent studies, the phenomenon of two-stage tumorigenesis was used
to further characterize the biological activity in airborne particulates. In
two-stage tumorigenesis an initiator is an agent (usually a carcinogen)
applied in a single dose to the skin of a mouse which 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 sufficient concentration, can produce tumors by itself. Extracts
of airborne particulates from Detroit were fractionated, and the fractions
examined for complete carcinogenicity and tumor initiating and promoting
04? -ico
activity (Stern, 1968; Wynder and Hoffman, 1965). '-"^ 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-tumorigenie 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 they did
not act as complete carcinogens when first tested. However, the relevance of
two-stage carcinogenesis to environmentally-caused cancer is not known.
12-112
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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 jji vivo. Extracts of
particulates from gasoline engines show carcinogenic activity when painted on
the backs of mice (Brune, 1977; Wynder and Hoffman, 1962)286'353 and when
329
injected subcutaneously (Pott et al., 1977). Extracts from diesel engines
have shown tumorigenie activity in some studies but not in others; the same
holds true for extracts of chimney soot where activity was shown in some
288
instances (Campbell, 1939) while not in others (Mittler and Nicholson,
324
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 particulates. These differences may be a reflection of 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.
(A complete review of diesel particulate matter is provided by Santodonato et
332
al. 1978.) With soot collected from chimneys, an important consideration
is the temperature at which the particulate matter is collected. The organic
material on participates is generated in the gaseous phase and only after
cooling are they adsorbed onto the inert core. Unless particulates 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.
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12.5.2 Sulfur Oxides
Sulfur dioxide hydrates rapidly in the moist upper airways, to form
several ions. One of these, a bisulfite ion, effects the conversion reactions
of nucleic acids. In 1970 and 1974 Shapiro et al. (1970,1974)337'338 reported
that bisulfite ions mediated the conversion of one nucleic acid cycle to
another cycle. Compared with optimal conditions, 1 M bisulfite solution at pH
5 to 6, Shapiro (1977)337 noted that the same solution at the physiological pH
of 7 was only 1 percent as effective. In living cells the reaction could
change the nucleotide sequence of DNA possibly resulting in mutations.
Uncharacterized free radical reactions may also occur under physiological
conditions (Shapiro, 1977). Since free radical reactions do not depend on
high concentrations of bisulfite to obtain favorable equilibrium, they may be
of greater significance in biological systems. The evidence that bisulfite
reacts with model compounds (polycytidylic acid) and single- and possibly
double-stranded DNA has lead to the investigation of its genotoxic, mutagenic
and carcinogenic effects. This compound, however, has been considered
innocuous, and has a GRAS (generally recognized as safe) designation as a food
additive.
Mammalian |n vitro and i_n vivo systems were used to determine the ability
of bisulfite to cause chromosomal aberrations. Cultures of human lymphocytes
treated by bubbling S02 gas through the media (Schneider and Calkins, 1970)333
and cultures of human embryonic lung (Newell and Maxwell, 1974)325 and mouse,
cow, and ewe oocytes treated with bisulfite (Jagiello et al., 1975)314 showed
extensive chromosomal clumping after treatment. In severe cases of
chromosomal damage, the cell will not survive and hence a mutagenic or
carcinogenic transformation cannot occur. However, some cells showed only
12-114
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moderate damage, with inhibition of DNA synthesis, fragmentation of
chromosomes and inhibition of mitosis with damage to cells in anaphase. The
possibility exists that sublethal changes in chromosomes may produce adverse
effects on the cell which, particularly in the case of germ cells, may be
transmitted to future offspring. Although cells in culture are sensitive to
low concentrations of bisulfite, it has not been determined to what extent
bisulfite exists in the intact animal. Also, the ability of the dominant
lethal assay to detect mutagens has received only limited validation, and
hence the sensitivity of this assay is not known.
327 -
at
3 ' o_^ J&JT^' ^m^u^e^ry^ .Jrf dz-r?~ t/3/a P
Peacock and Spence (1967) exposed LX strain mice^to an atmosphere of
-5QO .ppm 50^ -five-days per weak, for two-yeaj&s-. The LX mice have a high
incidence of spontaneous tumors, with 31 percent of the males and 17 percent
of the females in the control group developing tumors of the lung by the end
of the experiment. The SOp treated group had a greater number of tumors, with
54 percent of the males and 43 percent of the females developing adenomas
and/or carcinomas. Due to the high spontaneous tumor incidence in these mice,
it was concluded that SOp elicited an inflammatory response, which accelerated
the development of spontaneous tumors.
A co-carcinogenic action has been ascribed to bisulfite because of the
enhancement of the carcinogenic potential of benzo(a)pyrene. Kuschner
(1968) allowed rats to inhale a mixture of S02 and benzo(a)pyrene for one
hour followed by six hours of exposure to either air or an SO^ atmosphere.
With this regimen, 18 percent and 50 percent , respectively, of the animals
developed tumors. Control animals receiving air or SO* alone were tumor
303
free. In a similar experiment von Nieding (1978) noted also that SCL
appeared to function as a cocarcinogen.
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The lack of evidence for mutagem'city/carcinogenicity of bisulfite in
mammalian i_n vivo systems may be due to the ability of mammals to rapidly bind
bisulfite followed by enzymatic oxidation to sulfate. In mammals bisulfite
can be regenerated by the reverse of the formation of S-sulfonates and the
resulting free bisulfite oxidized enzymatically to sulfate by sulfite oxidase.
Sulfite oxidase isolated from bovine liver has been extensively characterized
oqo
(Cohen and Fridovich, 1971). Approximately 80 percent of the reaction
proceeds without the formation of free radicals. However, a portion of the
reaction was inhibited by free radical scavengers, and the formation of the
free radicals was shown to be dependent on the enzyme and the bisulfite con-
centration. From what is known, mammals have a high capacity of detoxifying
bisulfite, but there is no assurance that reactions with plasma constituents
and sulfite oxidase are sufficiently complete to prevent reactions with ONA
and possible mutations. At present there has been no demonstration of genetic
damage attributable to jm vivo exposure to SCK or bisulfite. Sulfates have
not been shown to be carcinogenic, but there is some evidence that they can
augment the carcinogenic action of other compounds. Preliminary reports
indicate an increased tumor incidence when sulfuric acid aerosols are
administered along with benzo(a)pyrene (Lee and Duffield, 1977; Sellakumar,
1977). ' 4 In a novel theory of carcinogenesis, Hadler and Cook (1979)304
showed that Tris salts of sulfates induced transitory uncoupling of
mitochondria, with the speculated release of oncogenic mitochondrial genetic
material. The cocarcinogenic action of sulfate was not fully confirmed in
these laboratory studies, and at present only the inflammatory response, with
its implications for carcinogenesis, has been demonstrated with ambient air.
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In summary, sulfur dioxide, its oxidation products and their salts have
been shown to react with DMA and other biological molecules, and in some
instances to induce mutations in lower organisms. Although the potential for
similar mutagenic/carcinogenic interactions to occur in mammals cannot be
ruled out, it is apparent from the lack of genetic damage observed after
J£ vivo administration that the risk of direct carcinogenic action by these
compounds is small. The cocarcinogenic action, particularly by the inflam-
matory induction of a proliferative response, may be of greater significance.
However, the work in this area is in its infancy and hence only highly specu-
lative conclusions could be drawn.
12.5.3 Metals
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 and manganese as
possible tumorigens (Clemo and Miller, 1960; Cohen and Fridovich,
OTJO 793
1971).*^^' 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 judgements.
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The topic of metal carcinogenesis has been extensively reviewed in recent
years from various perspectives (Furst, 1977; Furst and Haro, 1969; Sunderman,
1978; Sunderman, xgyg).301.302.344.345 These surveys 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 carcinogenesis. 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 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 (IARC, 1973; IARC, 1976).306'307 Sunderman (1978, 1979)344'345
indicated 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 Ni3$2 produces local sarcomas following
injection, and one group has indicated that chronic inhalation of Ni3Sp in
rats caused lung cancer (IARC, 1973; IARC, 1976).306'307 Several other forms
of nickel have shown both positive and negative carcinogenic activity. The
chronic inhalation of nickel carbonyl (Ni(CO)4) by rats at levels as low as
0.03 mg/1 has produced pulmonary carcinomas which were believed to be
treatment-related (IARC, 1976).307 In addition, Lau et al. (1972)317 induced
carcinomas and sarcomas in various organs, including liver and kidney, by
12-118
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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, 1976). Single and repeated
intramuscular injections of nickel powder induced local tumors in rats and
hamsters, although intravenous injections were either marginally effective
007
(rat) or ineffective (mouse, rabbit) (IARC, 1976). A single intrapleural
injection of nickel powder (0.02 ml of a 0.06 percent suspension) did not
produce neoplasms in mice; multiple intrapleural injections at high doses in
rats were effective in the induction of local tumors (IARC, 1976).
The toxicology and carcinogenic potential of cadmium have been the
subject of extensive reviews in the past several years (IARC, 1976; USEPA,
1979; Towill et al., 1978).308>349.348 Cadmium 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 (CdC^), cadmium oxide (CdO), cadmium sulfate
(CdSO^), or cadmium sulfide (CdS) to rodents frequently produces local
sarcomas (Furst and Haro, 1969; IARC, 1976; Sunderman, 1979).302.308,344 A
unique feature of the action of cadmium is that single subcutaneous injections
of CdClp to rodents (3.7 - 5.5 mg/kg body weight) leads to a high incidence of
•34-5
interstitial cell (Leydig cell) tumors of the testis. Stoner et al. (1976)J0
recently reported that cadmium acetate did not cause a significant increase in
pulmonary tumor response in the strain A mouse bioassay system.
Chromium in the hexavalent (but not trivalent) state has produced tumors
following inhalation, implantation, and injection (IARC, 1973; Towill,
12-119
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•SflQ "1AQ
1978). ' The inhalation of mixed chromate dust failed to induce lung
tumors in mice, rats, and rabbits, although pulmonary adenomas developed in
309
mice exposed by inhalation to calcium chromate (CaCr04) dust (IARC, 1973).
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, 1973;
Sunderman, 1979).309'344 Several groups of investigators, however, have
failed to induce tumors by the paren teral administration of chromium
compounds.
Although arsenic is recognized as a human carcinogen based upon epidemio-
logical data, there is little evidence to indicate carcinogenic activity in
302 344
experimental animals (Furst and Haro, 1969; Sunderman, 1979). ' In
particular, the chromic administration of arsenous trioxide (As^O,) in
drinking water (34 mg/1) to rats failed to induce tumors (Furst and Haro,
302
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 pregnant Swiss mice and their offspring
(Sunderman, 1979).344
Although not generally recognized as a human carcinogen, lead compounds
have shown considerable carcinogenic activity in rodents (IARC, 1972;
Sunderman, 1979; USEPA, 1977).310'350 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) (USEPA, 1977).35° In a recent study using the strain A mouse
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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 osteo-
sarcomas upon intravenous injection in a variety of animal species (IARC,
1972). Aerosols of beryllium sulfate (BeS04) induced pulmonary carcinomas
in all of a group of 43 rats (34 mg/m for 56 weeks), and in two of ten Rhesus
monkeys inhaling the compound at 35 mg/m for eight years (IARC, 1972). In
addition, three of 20 monkeys developed pulmonary cancers after the intra-
bronchial and/or bronchomural implantation of pure 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
30? 344
intratesticular injection (Furst and Haro, 1969; Sunderman, 1979). '
When evaluated in the strain A mouse pulmonary tumor bioassay system, zinc
343
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,
on? -3-1 y
1969; IARC, 1973). u*»d" It is not clear whether this effect may have been
due to solid state carcinogenesis. In contrast to the sarcomagenic properties
of iron-dextran, ferric oxide (FepOj, hematite) produced no tumors in hamsters
(intratracheal instillation), guinea pigs (inhalation) or rats (subcutaneous
implantation).
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The carcinogenicity of titanium has not been fully investigated. Chronic
studies with mice involving the ingestion of a titanium salt in the drinking
302
water gave negative results (Furst and Haro, 1969). However, Furst and
Haro (1969)302 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
344
cobalt powder, to rabbits and rats (Sunderman, 1979). However, little
additional data are available regarding the carcinogenic potential of cobalt.
Stoner et al. (1976)343 recently found that cobalt acetate had no effect on
tumor incidence in the strain A mouse pulmonary tumor bioassay system.
Although selenium is not a metal, it 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 i_n vitro experiments have
been conducted. Many of these studies attempt to exploit the strong formal
relationships between molecular events involved in mutagenesis and carcino-
genesis. In particular, the interaction of xenobiotics with nucleic acids is
believed to be a critical event in mutagenesis and/or cell transformation.
12-122
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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
325
carcinogenesis. Murray and Feisel (1976) prepared mixtures of synthetic
polynucleotides and measured the changes in the mixing curves induced by the
addition of carcinogenic and non-carcinogenic metal salts at a 10 M
concentration. Both cadmium chloride (CdCU) and manganese chloride (MnClp)
induced alterations in spectrophotometric measurements which were indicative
of mispairing of nucleotide 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; Si rover 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 mM and
150 mM; 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 iji 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
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298
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, S02 appears to be converted to its hydrated forms,
sulfurous acid, bisulfite, and sulfite. The rate of absorption and removal of
inhaled S02 varies with soecies, but >&• at least 80 percent of the inhaled
to /ujfet4iu& 4s#u&-&01-* -^^ ^£K* sUtffz^&^'fi <2tei2£^
amount/(see Chapter ll for an expandea discussion on absorption).
The metabolism of S02 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, supplying a circulating pool of bisulfite which can
reach all tissues. Since some circulating S-thiosulfates decompose to SO-
which is exhaled, S-thiosulfates can donate their bisulfite content to distal
tissues. Sulfur dioxide and bisulfite are clearly mutagenic in microbial test
systems (Ames Salmonella and Yeast Systems). The mechanism for the
mutagenesis could be the deamination of cytosine at high concentrations. Free
radical reactions breaking glycosidic bonds in DNA may be responsible at low
12-124
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concentrations. The potency of bisulfite in these ^n vitro systems is
moderate to weak when compared to agents such as nitrosamines or polycyclic
aromatic compounds; but it is nonetheless positive. To date, experiments
testing for mutagenicity or carcinogenicity by bisulfite in nanvnals have been
equivocal. On the basis of present evidence, one can not decide whether or
not bisulfite, and hence SOp, is a mutagen in mammals.
The influence of S02 on tumorogenesis has also been examined. Rats
exposed (5 days/wk for 98 wk to a lifetime) to 26.2 mg/m (10 ppm) SOp for 6
hr/day in combination with 9.2 or 10.5 mg/m (3.5 or 4 ppm) SOp plus 10 mg/m
benzo(a)pyrene had an increased incidence of lung squanous cell carcinoma.
Hamsters were not affected. Statistical analyses were not performed,
preventing definite interpretation of the data. However, from these studies,
the possibility exists that SOp mav De a co-carcinogen in rats. The question
of carcinogenicity of SOp alone cannot be resolved at present. For the rat
studies described above, a total of 15 rats were exposed to 26.2 mg/m (10
ppm) SOp for 6 hr/day, 5 days/wk for lifetimes, and none developed cancer.
However, this sample size is small and would have a small probability of
detecting a low cancer incidence. In a different study, mice were^xposed f-e-r—
'
/dar-5-
-------
included lung morphology as an endpoint, but no lung tumors were reported.
This does not negate the positive studies since they showed a species
sensitivity to tumor development and were conducted either at very high
concentrations or in the presence of benzo(a)pyrene. Without statistical
analyses of the cancer incidence data, the general conclusion to be drawn from
these studies is that SCL has an unproven potential to act as a carcinogen or
a co-carcinogen in some animal species.
In rats, histopathological effects of S02 alone are confined to the
bronchial epithelium, with most of the effects occurring on the mucus
secreting goblet cells. Goblet cell hypertrophy occurs on chronic exposure of
rats, leading some to suggest that SOp 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. The nasal mucosa of mice (particularly those
with upper respiratory pathogens) was altered by 72 hr exposure to 26.2 mg/m
(10 ppm) SOp. Continous exposure to 0.37 to 3.35 mg/m (0.14 to 1.28 ppm) S02
for 78 wk did not cause any significant lung morphological alterations in
monkeys.
An immediate effect of acute (£ 1 hr) S02 inhalation is either a decrease
in respiratory rate or an increase in resistance to flow within the lung. The
decrease in respiratory rate is mediated by a vagal reflex through receptors
in the nose and upper airways. The response is transient in nature and occurs
2
at 44.5 mg/m (17 ppm). Lower concentrations were not tested. The increased
resistance to flow is mediated through receptors in the bronchial tree and
persists during continued exposure. With this physiological parameter, lower
concentrations of S02 have been observed to cause reproducible changes in
12-126
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respiration. The guinea pig is the most sensitive animal, having significant
changes at concentrations as low as 0.42 mg/m (0.16 ppm) SO^ for 1 hr.
Chronic exposures have produced alterations in pulmonary function in
cynomolgus monkeys, but only at concentrations greater than 13.1 mg/rn
o
(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 S02 appears to
cause its immediate bronchoconstrictive effect through action on airway smooth
muscles. Since smooth muscles adapt or fatigue during long-term stimulation,
chronic exposure to SOp is not likely to evidence bronchoconstriction equiva-
lent to that occurring on short-term exposure. Alterations in pulmonary
function after chronic exposure to S02 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 S02, 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 mo.
Some pulmonary host defense mechanisms are also affected by S02 exposure.
After 10 and 23 days of exposure (7 hr/day, 5 days/wk) to 0.26 mg/m (0.1
ppm), clearance of particles from the lower respiratory tract was accelerated
in rats. At a higher concentration (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/m (1 ppm) reduced tracheal mucous flow in dogs,
but a longer exposure to this concentration caused no changes in ciliary beat
12-127
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frequency of rats. Antiviral defenses were altered by a 7 day continous
exposure to 18.3 to 26.2 mg/m (7 to 10 ppm) S02 as evidenced by an increase
in viral pneumonia. In this study, the combined exposure to S02 and virus
produced weight loss at concentrations as low as 9.43 mg/m (3.6 ppm) S02-
Mice exposed to 13.1 mg/m3 (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.
12.6.2 Particulate Matter
The dissolution of SO- into liquid aerosols or the sorption onto solid
aerosols tends to increase the potency of S02- The exact mechanism by which
potentiation occurs is still controversial.
Reports disagree as to the potency of acute exposure to sulfate aerosols.
Some investigators contend that sulfuric acid is highly irritating, producing
increases in pulmonary flow resistance at low concentrations and linear
concentration responses. The lowest effective concentration so far reported
was 0.1 mg/m (1 hr) in the guinea pig. Particle size influenced the results
in several ways but the smaller sizes were generally more effective. Others
have 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/m3 H2S04. Exposure to
lower concentrations (1.2 or 1.3 mg/m ) caused no effects. Some of these
conflicts may be due to differences in technique, strain of animal, or species
of animal. Discrepancies are particularly marked in the potency of sulfate
salt aerosols, with older reports presenting significant alterations in
resistance to flow at low concentrations. The largest data base for the
effects of 1 hr exposure of guinea pigs to sulfur oxides comes from 1
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laboratory. This research has resulted in an apparent ranking of potency (for
increased flow resistence): H2$04 > ZnS04(NH4)2$04 > Fe2(S04)3 > ZnS04 >
(NH4)S04 > NH4HS04, CuS04 > FeS04> Na2S04, MnS04. The latter three caused no
effects.
The toxicology of H2$04 is complicated by its partial
concentration-dependent conversion to (NH4)2S04 and NH4HS04 by ammonia in the
breath or in the air of animal exposure chambers. While there is a
stoichiometry of this chemical reaction, the actual concentrations have not
been measured definitively. Thus, comparing results of H2S04 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 ifn'tiatiftg action of sulfuric acid contends that
sulfate salts can act to promote release of histamine or other mediators of
bronchoconstriction and is supported by 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 antihistamines and
adrenergic drugs. 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
alone.
Chronic exposure to H2S04 also produces changes in pulmonary function.
Monkeys exposed to 0.48 mg/m H2$04 continously for 78 wk had altered
distribution of ventilation early in the exposure period. Higher
concentrations (2.43 and 4.79 mg/m ) changed the distribution of ventilation
12-129
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and increased respiratory rate but caused no effects on other pulmonary
function measurements. A lower concentration (0.38 mg/m ) caused no effects.
Morphological changes occurred at the lowest concentration tested (0.38
mg/m3). The effects appeared to be related to size of the particle as well as
to concentration. Major findings at 2.43 mg/m H2S04 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
mg/m H2SO, had no effects on pulmonary function or morphology. Dogs which
inhaled 0.89 mg/m H2SO. 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 non-viable 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 0.5 mg/m H-SO. increased
trachea! mucocilary transport, whereas 1 mg/m H^SO. depressed this rate. A 2
to 3 hr exposure to 0.9 to 1 mg/m H2$04 also decreased trachea 1 ciliary beat
frequency in hamsters. Lower concentrations (0.1 mg/m HUSO., 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
low concentrations of H2$04 can slow mucociliary clearance. This might imply
increased lung residence times of materials that would ordinarily be cleared.
12-130
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Other host defense parameters, e.g., resistance to bacterial infection,
are not altered by low concentrations of ^SCL, but are affected by metal
sulfates. The apparent relative potency of various particles for increasing
susceptibility to infectious (bacterial) respiratory disease has been
determined in mice exposed for 3 hr: CdSO^ > CuS04 > ZnN03, ZnS04 > A1-(S04)3
> AKNH^CSO,)*. At concentrations > 2.5 mg/m the following particles had no
significant effects in this model system: H2$04, (NH4)S04, NH4HS04, Na,,S04,
Fe2(S04)3, Fe(NH4)2S04, NaN03, KN03, and NH4N03.
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 irritancies, which can be correlated with the permeability of
the lung to that specific sulfate salt. The metallic ions associated with
sulfate aerosols are also not without toxicity. 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 compositional changes on collection.
Toxicity can be approached, at present, only from estimates of composition and
toxicity of individual components. Fly ash has little toxicity when inhaled
at concentrations less than 100 mg/m , but it has definite toxicity at 200
mg/m3 or greater. Using i_n vitro tests, metal oxide-coated fly ash has
12-131
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measurable toxicity which can be ascribed to the insoluble oxides when
alveolar macrophages are exposed. The effects of soluble salts of Ni and Cd,
for example, 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 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 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/m CdCl2 or 0.25 mg/m
NiCl2.
12.6.3 Interactions of Gases and Particles
Although man is exposed to a complex mixture of gases and particles, few
animal studies have been conducted with mixtures. 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 SOp to
H-SO., thus increasing the response.
The effects of chronic exposure to a variety of mixtures of S02, H2$04,
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 to 2.6 mg/m (0.99 ppm) S0? plus
0.88 mg/m H2S04; but the addition of fly ash did not potentiate the response.
When dogs were exposed to S02 (13.4 mg/m3, 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
12-132
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in pulmonary function except for an increase in N~ washout, but H^SO. caused a
variety of changes which were interpreted as the development of obstructive
pulmonary disease.
In another series of studies, dogs were exposed for 16 hr/day for 68 mo
to raw or photochemically 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 , 0.42
/\
ppm $62, and 0.09 mg/m H^SO^) alone and in combination with other pollutants
in the study. The animals had been placed in clean air for 32 to 36 mo after
exposure ceased, at which time the SO group had a variety of morphological
A
alterations. These included a loss of cilia without squamous cell metaplasia,
nonciliated bronchiolar hyperplasia, and a loss of interalveolar septa in
alveolar ducts. The authors hypothesized that these changes are analogous to
an incipient stage of human proximal acinar (centrilobular) emphysema.
Combinations of carbon and HUSO, or SO- were investigated also. In mice
exposed for 3 hr/day, 5 days/wk for up to 20 wk to a mixture of 1.4 mg/m
FUSO. and 1.5 mg/m carbon or carbon only, morphological and immunological
alterations were seen in both groups. In hamsters, a 3 hr exposure to 1.1
3 3
mg/m + 1.5 mg/m carbon depressed ciliary beat frequency, as did ^SO^ alone.
Alterations of both the pulmonary and systemic immune systems were found in
mice at various lengths of exposure (100 hr/wk up to 192 days) to 5.2 mg/m (2
ppm) SO- and 0.56 mg/m carbon, alone and in combination. Generally, carbon
and carbon + S0? caused more extensive effects than SO- alone.
12-133
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When the interaction of 03 and H2$04 was studied, the morphological
effects to the mixture [10 mg/m H2$04 + 1.02 mg/m3 (0.52 ppm) 0,] of a 6 mo
intermittent exposure of rats and guinea pigs were attributed to 03 alone.
3
However, combined exposure to 1 mg/m H2$04 and 0.78 to 0.98 (0.4 to 0.5 ppm)
0, resulted in synergistic effects on glycoprotein synthesis in trachea and
certain indices of lung biochemistry. Acute sequential exposure to first
3 3
0.196 mg/m (0.1 ppm) 0, and then 0.9 mg/m H2$04 caused additive effects on
increased susceptibility to infectious pulmonary disease and antagonistic
effects on depression of tracheal ciliary beat frequency. From these studies,
the interaction of 03 and H2$04 is quite complex and appears to be dependent
on the sequence of exposure as well as on the parameter examined.
12-134
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333. Schneider, L K., and C. A. Calkins. Sulfur dioxide-induced lymphocyte
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Additional References Recommended for Consideration in Chapter 12
Costa, D. L. and M. 0. Amdur. Effect of oil mists on the irritancy of sulfur
dioxides. II. Motor Oil. Am. Ind. Hyg. Assoc. J. 40:809-815, 1979.
Costa, D. L., and M. 0. Amdur. Effect of oil mists on the irritancy of sulfur
dioxide. I. Mineral Oils and Light Lubricating Oil, Am. Indust, Hyg.
Assoc. J. 40(8):680-685, 1979.
Costa, D. L., and M. 0. Amdur. Respiratory responses of guinea pigs to oil
mists. Am. Indust. Hyg. Assoc. J. 40(8):673-679, 1979,
Schneider and Calkins. Sulfur dioxide induced lymphocyte defects in peripheral
blood cultures. Environ. Res. 3:473-482, 1970,
-------
APPENDIX I
1.0 SULFONATION BY SULFITE AND BISULFITE
Sulfite is a relatively strong nucleophile and can attack a number of
biological compounds by nucleophilic substitution or addition. Either sulfite
or bisulfite may be responsible for sulfonation. Nucleophilic substitution
•)
through sulfite attack is called sulfitolysis and has been reported for epoxide,
disulfide (Reaction 12-3), and thiamine (Reaction 12-4).4
RSSR' + HSO§ .« RSSOJ+R'SH
.^k.. -.. ./I
— CH2 N
S + HS05
12-4
The equilibrium constant for Reaction 12-3 with cysteine at 37°C and pH 7.75
_o
is 8.9 x 10 . If sulfite is incubated with rabbit plasma for 45 min,
nearly 100 percent of the added sulfite is present as S-sulfonates (R-S-SO^).
On this basis, Kaplan et al. calculated that chronic exposure to an
unspecified concentration of S02 would convert 0.16 percent of total plasma
12A-1
-------
proteins to S-sulfonates. The metabolic significance of this level of plasma
S-sulfonates is not yet clearly defined, although Kaplan et al. saw it as
toxic. On the other hand, Gunnison and Benton and Shapiro and Weisgras
concluded that 0.16 percent is a relatively low level of protein alteration
and that sulfitolysis is probably not metabolically significant. S-sulfonation
may serve as a vehicle for the widespread distribution and storage of bisulfite
in the body. (See Section 12.2.1.3.1).
Bisulfite adds in vitro to aldehydes (Reaction 12-5), ketones (including
p
sugars), conjugated alkenes, quinones, coumerins, the pyridine ring of NAD
(Reaction 12-6), the pyrazine ring of folic acid (Reaction 12-4), and the
isoalloxazine ring of flavine coenzymes (Reaction 12-7).
RCHO + HSOJ ,
10
?H
RCHSOJ
12-5
—NH-
SO
-2
OgS «w^^ H O
(V-
12-6
12-7
12A-2
-------
The ionic reaction of bisulfite with NAD and flavins i_n vitro has been
described by several authors. Bisulfite adds reversibly to the 4 position of
NAD with an equilibrium constant of 36 M at pH 7. The bisulfite adduct is
greatly stabilized in the presence of proteins since a stoichiometric reaction
of bisulfite at low concentrations occurs with protein bound NAD+. Enhancement
of the reaction of bisulfite with flavins bound to proteins has also been
observed. Two reaction mechanisms of bisulfite with NADH are discussed below.
The first is an ionic reaction in which bisulfite acts as a general acid
catalyst to hydrate the 5,6 unsaturation; this hydration reaction is rela-
tively slow. The second is a free radical oxidation of NADPH to the
pyridinium salt.
2.0 AUTOXIDATION OF SULFITE AND BISULFITE
Oxidation of sulfite to sulfate through the free radical chain mechanism
jj} vitro can be initiated by metal ions, ultraviolet irradiation, '
charge transfer complexes from the illuminated dyes, electrolytic gener-
17 17-22
ation of radicals or enzymatic reactions. These reactions are
important for their ability to generate free radicals. The autoxidation of
sulfite can be initiated by superoxide radical (-D- ), but is inhibited by
23 24
superoxide dismutase. ' This suggests that -Op radical is involved in
propagation as well as initiation. Thus, the reactive species generated
during the aerobic oxidation of sulfite includes -Op , *OH, and -SO^ . The
12-25
following scheme describes the sulfite oxygen chain reaction.
12A-3
-------
Initiation:
12~ 8
S032 * °2 * 'S°3~ + *°2~
Propagation:
12-9
•so3 + o2 - so5
S05" * SO]2 + S04" + SO;2 12-10
S04" + SO'2 - SO^2 + S03" 12-11
S04" + OH" •> SO^2 + -OH 12-12
•OH + S03"2 -» OH" + S03" 12-13
-02 + S03"2 + 2H+ -» 2-OH + S03" 12-14
Termination:
•OH + S03" * OH" + S03" 12"15
S03" + -02" -> 2H+ -> S03"+ H202 12-16
(H202 + S032 -» H20 + SO^2
S03 + H20 -^ S0^2+ 2H+) 12-17
Initiation (Reaction 12-8) is caused by metal ions, ultraviolet light or
enzymatic reactions. The chain is propagated by Reactions 12-9 through 12-14,
forming sulfate ion. Chain length of the reaction has been estimated at 30,000
moles/mole -02 in the xanthine-xanthine oxidase system and 300 moles/mole
•02 in the isolated chloroplast under illumination.15 The metal initiated
autoxidation of sulfite is inhibited by EDTA, organic acids, alcohols, thiols,
12A-4
-------
amines, and proteins that occur in cells and may act as radical scavengers
26 27
inhibiting autoxidation. ' Peroxidase initiated sulfite oxidation is not
25
inhibited by these scavengers, suggesting that in vivo the oxidation of
sulfite is catalyzed by enzymes. The non-enzymatic autoxidation outlined
above produces oxy- and sulfur oxide radicals that may be highly deleterious,
since they may cause lipid peroxidation. (See discussion below.)
Evidence for the formation of the highly reactive -OH and •()« species
22 28
has come mainly from studies of peroxidase catalyzed sulfite oxidation. '
In these studies, methional is used to scavenge hydroxyl free radicals generat-
29
ing ethylene as a characteristic oxidation product. Beauchamp and Fridovich
have demonstrated that *OH is responsible for ethylene formation from methional.
Methionine is rapidly oxidized to the sulfoxide (Reactions 12-18 and 12-19).
R-S-R + -OH -> R-S-R + OH 12-18
+ +
R-S-R + -OH -> R-S-R -»• R-S-H + H+
12-19
OH 0
In addition to methionine, tryptophan is also oxidized during the oxidation of
sulfite.
8 21
Co-oxidation of NADH and NADPH during sulfite oxidation has been reported, '
suggesting the following chain reaction:
12A-5
-------
SO ~ + Initiator -> -S03~ 12-20
_ p j.
NADH -S03~ -> NAD- + S03 + H 12-21
NAD- + 02 •* NAD+ + -02" 12-22
S0~2+ -0~ + 2H+ - -S0~2 + H202 12-23
The autoxidation of sulfite could deplete NADH and NADPH needed for metabolism,
but the amount of NADH or NADPH oxidized will not be significant at concen-
trations of S02 which occur in the ambient air.
3.0 BISULFITE-INITIATED LIPID PEROXIDATION
Kaplan et al.31 demonstrated that bisulfite (0.5 to 10 mM) initiates
peroxidation of aqueous emulsions of corn oil. Peroxidation was measured by
the formation of 2-thiobarbituric acid (TBA) reactive substances. Most likely,
these TBA reactive substances correspond to bicyclic peroxides formed during
the autoxidation of linolenic acid present in corn oil. The reaction was
inhibited by the addition of the phenolic antioxidant BHT (2,6-di-t-butyl-4,4-
hydroxymethyl phenol). Addition of manganous ion (10 to 10 M) also inhibited
the reaction. Therefore, autoxidation initiated by bisulfite seems to proceed
through some oxygenated intermediary. It is most probable that the reaction
proceeds through -OH or -02 (see Section 12.2.1.1). Kaplan et al. suggest that
peroxidation of cell membranes is a mechanism of inhaled S02 toxicity. This
hypothesis has not been supported by whole animal inhalation data.
4.0 POTENTIAL MUTAGENIC EFFECTS OF SULFITE
This section will review the biochemistry by bisulfite and sulfite.
While there is data suggesting a weak mutagenic effect uj vitro and in micro-
organisms, the question of mutagenesis ui vivo has not been demonstrated
in animals.
12A-6
-------
As pointed out in Section 3 above, alterations in DNA and RNA produced by
sulfite are detected only at high concentrations of sulfite, acid pH and i_n
vitro. Microbial systems validated for chemical mutagenesis have not been
used in these experiments. The biological viability of sulfite-induced alter-
ations in DNA remains an important unanswered question. If the alterations
were not transcribable, then cytotoxicity, rather than mutation, would be the
outcome. Further, the rapid metabolism of sulfite to sulfate j_n vivo might
preclude the accumulation of sufficient sulfite to react with DNA. This is
very important for the DNA contained in chromatin of higher organisms where
its reactivity towards sulfite is especially obscure. An additional factor,
so far not addressed experimentally, is the rate of DNA repair after sulfite
damage. Repair, without errors, may be sufficiently rapid to preclude trans-
cription of erroneous information. Lastly, if sulfite damage to DNA were
expressed as carcinogenesis, this would undoubtedly be a multistep process
involving many stages. It is still unknown how chemical carcinogens would
go through this process. However, the most conservative course would be
to avoid exposure to all mutagens, since there presently is no known way to
reverse carcinogenesis.
4.1 REACTIONS OF BISULFITE/SULFITE WITH DNA AND RNA AS RELATED TO MUTAGENESIS
The reactivity of bisulfite with nucleic acids and subsequent mutagenesis
induced by bisulfite have been reviewed by Shapiro and by Fishbein. The
deamination of cytosine to uracil in single-stranded, but not double-stranded,
CO
DNA is of interest (Reaction 12-26). This reaction also occurs in yeast
eg
RNA. The optimum conditions for both reactions are pH 5 and high bisulfite
concentrations on the order of 1M. Deamination results in the conversion of
GC to AT sites and could be mutagenic. GC to AT in DNA conversion has been
12A-7
-------
subsequently confirmed. (See the discussions on the effects of bisulfite on
cultured cells.) Decomposition of the uracil bisulfite complex is the rate
limiting step. The chemistry of this reaction is discussed in detail by
Shapiro.55 He calculated the rate of deamination of cytosine under physiological
conditions to evaluate the potential environmental genetic hazard. While it
is true that mammalian DNA is double-stranded, during the translational process
some regions of single-strandedness in the DNA may be susceptible to attack.
Double-strandedness does not completely prevent deamination of cytosine to
uracil and, therefore, the introduction of a point mutation. Using estimates
of the spontaneous mutation in man at 10 /gene/generation, ' or approxi-
_q 2 fil
mately 10 /base pair/generation assuming 10 base pairs to a genome, Shapiro
calculated that a concentration of 3 x 10 M bisulfite is sufficient to
double the spontaneous mutation rate. This estimate is probably high since
the deamination reaction is second order in bisulfite, whereas Shapiro cal-
culated the rate to be first order at low concentrations of bisulfite. In
doing as Shapiro assumes, other general acids or bases could substitute for
12-26
A
12A-8
-------
bisulfite in catalyzing the deamination step (Reaction 12-26). However,
Shapiro points out that double-strandedness markedly reduces the reactivity of
cytosine. The structure of DNA in eukaryotic chromatin and its reactivity
with bisulfite are not known.
Transamination can be carried out via the same chemical mechanism as
deamination (Reaction 12-27). The bisulfite adduct readily reacts with primary
amines, decomposing to the transaminated base. This reaction has been studied
in some detail. If transamination were to occur, then cross-linking of DNA
through reactions with other biopolymers containing free amine groups (lysyl
groups, for example) is theoretically possible. Thus far, it has been diffi-
cult to substantiate covalent cross-linking reactions resulting from this
reaction. Cross-linking of single-stranded MS2/phage has been observed.
Hi stones present in mammalian chromatin are rich in lysine and a DNA-histone
cross-link might occur jj} vivo. The biological consequences of such a
cross-link are not known at the present time.
NH, NHR'
RH? *,^X 12-27
NHR'
12A-9
-------
The very addition of sulfite to uracil and cytosine to form reversible
adducts could disrupt DMA function. Reaction of these bases with sulfite is
likely to reduce their hydrogen bonding with other bases, leading to disrup-
tion of the tertiary structure of the gene. Disruption of messenger RNA
function and translation could occur. The experiments reported to date are
not wholely convincing, but have been reviewed in detail by Shapiro.
5.0 FREE RADICAL REACTIONS WITH DMA
Sulfite catalyzed oxidation reactions are likely candidates as mechanisms
for sulfite/SO? damage to DMA at low concentrations of DMA. As discussed
above, the oxidation of sulfite produces a number of complex free radicals and
multistep chain reactions involving reactive oxygen and sulfur species such as
•SO,", -OH, -OOH, and -Q^. The effect of bisulfite-initiated free radical
CO
reactions on mutational events has been reviewed by Hayatsu. Sulfite also
initiates the free radical catalyzed autoxidation of unsaturated fatty acids.
It is possible that the combination of the oxygen and sulfur species generated
by bisulfite autoxidation or those generated by lipid peroxidation reactions
could damage DNA or RNA. While the deamination and transamination reactions
require considerable concentrations of bisulfite to achieve appreciable rates,
the free radical pathway need not consume or require large quantities of
bisulfite. Thus, free radical reactions could be carried out at trace concen-
trations which could result from environmental exposure to S0? or bisulfite.
If so, the free radical reaction initiated by bisulfite assumes greater theo-
retical interest, although direct evidence for this reaction j_n vivo is still
lacking.
6.0 EVIDENCE FOR SULFITE/S02 MUTAGENESIS
Studies on the genetic effects of bisulfite/S02 have taken two forms:
exposures at acidic pH and high bisulfite concentrations designed to
12A-10
-------
initiate cytosine deamination; and studies carried out at low bisulfite con-
centrations and/or neutral pH designed to investigate free radical or more
obscure reaction mechanisms.
In viruses, phage, bacteria, and yeasts, experiments carried out with
high concentrations of bisulfite support the conversion of GC to AT with
intact DNA and, therefore, cytosine deamination reactions. However, these
studies have not determined whether the cytosine deamination reaction
catalyzed by bisulfite can be carried out with double-stranded DNA in chroma-
_2 -3
tin. Studies with microorganisms are complicated since 10 to 10 M bisulfite
is a growth inhibitor. The inhibition of microbial growth is the principal
reason for the use of bisulfite in foodstuffs and particularly in oenology
Reactions with RNA and inhibition of protein synthesis by other means might
likewise occur.
The effects of SCL/bisulfite on plants have been well documented, but it
is not well established whether these toxic effects are due to inhibition of
photosynthesis or to mutations.
The picture of genetic effects of SOp/bisulfite becomes clouded when
considering the experiments on multicellular organisms or cultured mammalian
cells. In Drosophila (fruit flies), clear-cut mutagenesis has not been observed
in all studies. The results have been muddled by experimental design defects
such as the choice of the medium in which the bisulfite was presented to the
205
fruit flies. Reducing sugars in the growth medium could have decreased the
bioavailable bisulfite. No definite conclusion can be drawn at the present
time.
207-212
Experiments with cultured human and animal cells have been reported.
Cytotoxicity, but not clear-cut mutagenesis. was observed in most of these
12A-11
-------
studies. For example, human HeLa cells in culture showed decreased growth
when exposed to SO-,207 and mouse fibroblasts and peritoneal macrophages
?0ft
showed decreased cell viability. Human lymphocytes in culture showed
decreased growth, DNA synthesis, and mitotic index when exposed to either S02
or bisulfite solutions.210'211 No mutations or chromosomal breaks were
detected in these studies. Inhibition of meiosis has also been reported
with mouse, ewe, and cow oocytes exposed to low concentrations of
bisulfite.212 Some of the observed effects may be directly due to the
toxicity of S0?/bisulfite. For example, fuzziness and clumping of chromosomes
may represent stages of degeneration of dead cells.
In experiments to detect mutations directly, mice were either injected
213
with bisulfite or fed 1 percent sodium bisulfite in the diet. No effects
were found on the oocytes, and a reduced number of chromosomal abnormalities
212
was found in the livers of treated animals. In these experiments, only a
small number of animals were exposed to a single dose. The survey for
chromosomal abnormalities inappropriately used a model based upon regeneration
?1 ^
of liver cells following acute carbon tetrachloride intoxication. In the
host-mediated assay using rats and Saccharomyces cerevisiae, no effects were
observed.43'232
At the present time, the equivocal results of these assays leave open the
question of SCL-induced mutations in higher organisms.
7.0 TECHNICAL NOTES ON THE MEASUREMENT OF AIRWAY RESISTANCE AND LUNG- COMPLIANCE
IN EXPERIMENTAL ANIMALS
7.1 RESISTANCE AND COMPLIANCE
Sulfur dioxide inhalation initiates contraction of bronchoconstrictor
muscles in humans >233 and in a number of animal species.98'99'234'235 This
12A-12
-------
tubular narrowing will in turn inhibit air flow in and out of the lungs. The
measured degree of inhibition is called airway resistance. The reciprocal of
airway resistance is airway conductance. The actual resistance to air flow in
the lungs is due to friction between gas molecules in the gas stream and gas
poc
molecules along bronchial walls. Alterations in the cross-sectional area
of the trachea and larger bronchi account for major changes in resistance;
thus, resistance is a measurement that represents the central airways and is
237
not sensitive to peripheral changes in the lung. Other mechanical factors,
such as flow direction, volume history, lung tissue resistance, gas viscosity,
and lung volume, contribute directly or indirectly to the measurement of
236~238 239 24-f)
resistance. Humoral or pharmaceutical agents, ' mechanical
241 242 238 243
stimuli, respiratory heat exchange, and disease states ' also
influence resistance.
Compliance is a ratio of volume change in the lung and the pressure
required to overcome elastic resistance of the lung in order to attain the new
volume. (Compliance = volume change/pressure change.) This measurement
indicates the state or a change in the state of the parenchyma of the lung.
Lungs that are stiff (high elasticity) have a low compliance. Compliance is
decreased by constriction of alveolar duct smooth muscle, alveolar cellular
infiltration, edema, airway closure, pulmonary vascular congestion, fibrosis
236 237
of the lung, pneumonia and pulmonary distress syndrome in infants. '
Compliance is determined at periods of no air flow so that the value is
not influenced by frictional resistance. It can be measured in two ways.
Static compliance is computed by allowing the lung and thorax to inflate (or
deflate) to measured volumes in a stepwise fashion; the changes in volumes are
then related to the changes in pressures. Dynamic compliance is measured
during spontaneous breathing and is calculated at points when air is not
12A-13
-------
flowing, i.e., during pauses after inflation and deflation. Static compliance
equals dynamic compliance at normal tidal volumes (the volume of air moved
during normal breathing); however, physiological factors not necessarily
related to disease (such as lung volume and lung volume history) can alter the
compliance measurement. Dynamic compliance will also decrease with increased
breathing frequency or be frequency dependent if there is a non-uniform
236-238
distribution of ventilation in the lungs. It is probable that broncho-
constriction following the inhalation of irritants results in non-uniform
distribution of ventilation.
Computation of airway resistance and dynamic compliance requires
simultaneous measurement of intrapleural pressure (P_/i) and tidal volume (VT)
or flow (V). Assuming that inertial losses are small, the following relation-
ship occurs during normal breathing. Transpulmonary pressure (P-™) or the
pressure difference between the mouth and the intrapleural space at any given
time is:
PTP = v/R + -c7\T ">
where R is airway resistance and C is the compliance of the lung. Dynamic
compliance (Cdyr|) is determined during tidal breathing at points in time when
the flow is zero.
Cdyn = SPT; (Vins ' Vexp>/ <">
To compute resistance, P and V are measured during inspiration and during
expiration at points of equal lung volume on the assumption that at that time
12A-14
-------
inspiratory and expiratory compliance are equal. Equation I can then be
solved for total airway resistance (R).
P = V + V R (IV)
exp exp exp u '
C
assume V. = V
ins exp
C C
then
R = Ap = (P. - P ) (V)
-^ v ins expy v '
AV (V. - V )
v ins exp'
?37
Electrical subtraction is another method for calculating R. Signals
representing P-™ and V are displayed on the X and Y axis of an oscilloscope
and a signal proportional to the volume change is subtracted from the total
pressure signal. This is equivalent to subtracting the elastic component of
Pyp leaving only the resistive component. The electrical subtraction technique
allows separation of inspiratory and expiratory resistance and determination
of resistance at a specific flow rate as well as at any specified lung volume
over a small tidal range. Electrical subtraction has been programmed for
244
rapid computer analysis of airway resistance and dynamic compliance, greatly
enhancing accurate and uniform data collection.
These basic mechanical lung function tests, if correctly carried out, can
determine whether a response to a pollutant is located in the small airways
and parenchyma or in the central upper airways. However, when both resistance
and compliance change, it is more difficult to define the site of pulmonary
action.236'237
Methods used for obtaining intrapleural pressure and tidal volume or flow
from experimental animals are technically difficult and can impose various
12A-15
-------
artifacts on the final results. Measurement of VT or V requires the use of
either a whole body plethysmograph or a pneumotachograph flow meter. Intra-
pleural pressure is obtained by a fluid-filled catheter placed directly in the
intrapleural space or in the lower one-third of the thoracic esophagus. The
plethysmograph or pneumotachograph and the catheter are each connected to
calibrated pressure transducers that relay the signals to the recording equip-
ment. To ensure accuracy of resistance and compliance measurements, the
equipment should be tested over a range of frequencies to confirm compati-
bility with the animal signals and to rule out phase angle shifts in the
signal. For example, if the frequency response of the equipment is
inadequate, identical pressure signals would be artificially decreased or
increased at various breathing rates. Also, the P. signal from a small animal
breathing rapidly may be impeded as it travels through the long narrow
fluid-filled catheter, and the pulse would not match with the signal in the
plethysmograph. Thus, calculation of R and C , would yield erroneous or
misleading results.
7.2. ANIMAL PREPARATION FOR MEASUREMENT OF PULMONARY FUNCTION
7.2.1 Unanesthetized Guinea Pig
The following procedure was used to measure pulmonary function in guinea
pigs for all of the studies93"97'253 cited in Chapter 12. Guinea pigs were
lightly anesthetized with ether and a length of 0.03 I.D. polyethylene tubing
containing a wire stylet was pushed through the skin on the back into and out
of the chest cavity. The stylet was then removed and the catheter was filled
with heparinized saline. This intrapleural catheter was positioned so three
small holes were located inside the pleural cavity. The catheter was
connected to three-way stopcocks and regularly flushed with saline solution.
For the measurement of tidal volume, the guinea pig was placed in a body
12A-16
-------
plethysmograph with an airtight seal at the neck. (This method was originally
189
described by Amdur and Mead. ) In this procedure, the following factors may
influence the response of the animal to the pollutant and confound the
results: strain of guinea pig, age, existing disease, effects of residual
ether anaesthesia, extent of surgical trauma (catheter ± tracheostomy),
pneumothorax, volume of saline and heparin used to flush the catheter, and
irritability of the animal due to pain, confinement, fit of the neck seal or
noise in the room. In addition, the uniformity of conditions within the
exposure chamber, principally the temperature, humidity, and rate of flow, can
contribute to the degree of animal response.
7.2.2 Unanesthetized Monkey
Studies of pulmonary function in the monkey discussed in Chapter 12
were similar to those for guinea pigs. Disease-free animals were acclimated
to the procedure. Pulmonary function tests were conducted while the animal
was seated in a restraining chair wearing a face mask. A polyethylene
intrapleural catheter was inserted into the chest after subcutaneous
administration of 1 percent procaine hydrochloride. Transpulmonary pressure
was monitored between the intrapleural space and the face mask and airflow was
measured with a pneumotachograph in the face mask. All signals from the
animal were analyzed by a computer.
7.2.3 Anesthetized Dog and Anesthetized Cat
99
The dogs were anesthetized with sodium thiopental, and measurements
were taken while the animals were lying on their backs in a plethysmograph.
Tracheal and intrapleural catheters were inserted on the day of the
GO
experiment. The cats were anesthetized with I.P. pentobarbital sodium,
given I.V. gallamine triethiodide (a muscle relaxant), and placed on a
12A-17
-------
respirator. A tracheostomy and the insertion of an intrapleural catheter were
done on the day of the experiment.
Because of the extreme deviation from a normal physiological state, these
experiments might better be used to shed light on the mechanisms of S02 action
on the respiratory system rather than to assess the minimal effective concen-
tration.
7.3 GENERAL COMMENTS ON EXPERIMENTAL TECHNIQUES
Bronchoconstriction is dependent upon intact motor parasympathetic path-
ways in the human,87'246"248 cat87'126 and dog.249 Although bronchocon-
striction is under the control of the same neurological pathways in guinea
230 971
pigs, ' mucous secretory activity is more pronounced in the guinea pig
GO
than in the cat and may contribute to the sizeable difference seen in the
response to a given level of pollutant. There is wide variability in airway
response to SO- in the measurement of R and C . between different
Z dyn
45 98 99 234
species. ' ' ' Differences have been noted in airway responsiveness in
272
members of the same species tested on different days as well as between
239
individual animals tested on the same day. In order to normalize these
differences, it has become the practice to discuss response in terms of
percent change from control period values. Adequate numbers of animals in
each group and careful statistical analysis are required for understanding the
93 233
response of "reactors" ' in studies with such a high degree of variability
with so many confounding factors.
12A-18
-------
13. CONTROLLED HUMAN STUDIES
13.1 INTRODUCTION
Precise 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 provide situations which
realistically simulate the exposures experienced by man in his normal environ-
ment. 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 pollutants actually present in the environment.
The high cost and minimal number of subjects who can be studied under
controlled conditions make it imperative that studies be conducted under
stringent conditions in order to generalize to the entire population. 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 rrsk.
Consideration 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 (including purified air conditions) as well as comprehensive
statistical treatment of the data obtained. In addition, adequate
(even duplicate) pollutant monitoring equipment with documentation
13-1
-------
of quality control are needed. Proper attention must also be given to the
presence of potentially interfering pollutants inadvertently present or develop-
ing 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 respiratory tract
is the initial target of many air pollutants, proper and sensitive respiratory
function measurements are a primary requirement. However, various biochemical
systems may be secondarily affected if pollutants (or their reaction products
or substances absorbed on particulates) pass into the circulatory and other,
systems from the cellular level.
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
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 subsequent 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 the respiratory system have also been
reported varying from cough to altered mucociliary clearance. The following
sections address these various functional changes in greater detail. (See
Chapter 11 for more detailed discussion of S0? deposition).
13-2
-------
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 qualitative changes (coughing, rhinorrhea,
lacrimation) or asked to report whether they detect something in the air they
are breathing. Several studies have used such subjective reports as an indica-
tion of the effects of SO- on human subjects.
A number of early investigators exposed themselves to high concentrations
of SO- (>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 SO- 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 SO-, and 32 of whom were familiar with it. All of the subjects
already familiar with the gas seemed to detect it (either as SO- or as "some-
thing 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 SO,,; 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 S02 odor
that exposure was terminated. Above 5 ppm the odor was definitely detected by
all subjects.
13-3
-------
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; Nadel et al., 1965; Speizer and Frank, 1966a,b;
Melville, 1970; Weir and Bromberg, 1972, 1973; Lawther et al., 1975; Horvath
and Folinsbee, 1977), but the results seem to be quite variable at exposures
less than 5 to 10 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 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).
13.2.2.1 Odor Perception Threshold—In the Russian studies odor threshold is
typically determined 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 threshold concentration for the most
sensitive subject in a group of volunteers is defined as the threshold for
odor perception.
13-4
-------
TABLE 13-1. SENSORY EFFECTS OF SO,
Concentration
S0 (ppm)
Exposure
mins.
Effects
Reference
400
6.5
140, 210, 240
210, 240
1, 2, 5
3, 5, plus
V* 0.17 - 4.6
en
0.34 - 6.9
0.23
0.2 - 1.7
1 - 10
120
10 - 15
30
30
15
0.33
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 SO,, 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 cr-waves at levels above 0.2 ppm
Organoleptic effects at levels 2 ppm and above
Ogata, 1884
Lehman, 1893
Yamada, 1908
Yamada, 1908
Amdur et al. , 1953
Holmes,-19546^
Dubrovskaya, 1957
£dor Threshold^ 1968
Dubrovskaya, 1957
Shalamberidze, 1967
Bushtueva ot al., 13611
Greenwald, 1954
-------
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/m3 to 13 mg/m3 (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/m3 to 3.0 mg/m3; 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
2.5 mg/m3; 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/m3 to -2.9 mg/m ), and for the more sensitive of these persons it was
3 3
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 concen-
trations 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 test conditions could not perceive the 0.47 ppm
13-6
-------
level indicated. However, because of background 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 0.96 mg/m to 19.2 mg/m for 15 minutes before measuring
light sensitivity during dark adaptation. She reported that light sensitivity
was increased by sulfur dioxide concentrations of 0.96 mg/m to 1.8 mg/m
(0.34 ppm to 0.63 ppm), that the increase in sensitivity reached a 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 sensitivity 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/m3 to 7.2 mg/m (0.21 ppm to 2.5 ppm) caused slight increases in eye
sensitivity. Maximum sensitivity 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
13-7
-------
2.5 mg/m3 and 3.0 mg/m3 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 concentrations below the odor threshold.
Shalamberidze (1967) investigated the effects of S02 and NC^, singly and
in combination, on visual light sensitivity as determined by measures of dark
adaptation. According to this report, S02 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 reserva-
tions.
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 electro-
encephalogram 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.
Subjects with well defined o-rhythms studied in a silent and electrically
shielded chamber show a temporary attenuation of the o-rhythm each time they
are given a light signal. When the light is excluded, the a-rhythm returns to
normal. A concentration of test gas is determined 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
13-8
-------
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.
I1G>*>
Bushtueva e^t-ai. (19£&i) reported that 20-second exposures of six human
subjects to sulfur dioxide concentrations from 0.9 mg/m to 3 mg/m (-0.3 ppm
to -1.0 ppm) produced attenuation of the cr-wave lasting 2 to 6 seconds; at
concentrations of 3.0 mg/m to 5.0 mg/m (-1.0 ppm to 1.7 ppm) attenuation
lasted throughout the 20-second exposure. Exposures to 0.6 mg/m (-0.2 ppm)
did not cause attenuation of the cr-wave. The threshold for attenuation of the
crwave was the same as the odor theshold or the threshold of irritation of the
respiratory tract. In other experiments, Bushtueva demonstrated that electro-
cortical 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
A number of studies have documented the various respiratory and cardio-
vascular effects deriving from exposure to SO- (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 resting subjects breathing SO- 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 SO-. 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 SO, below 5 ppm. Nevertheless, these and other studies have documented a
variety of subjective and physiological effects under various conditions of
13-9
-------
13-2. IMHMONARY [FFFCTS OF SO-
Concentration
50^ (pp*)
1.0
3.0
5.0
9 - 60
1 - 8
--
.- 5. 10
V 20
o
1, 5. 13
1.3 - 00
1 - 45
2.'j, 5 0. 10.0
4 - 6
*lnlcr mi tlcul
Oral or
Duration of Nu**er of nasal Rest (R) or
exposure («ins) sulijccls exposure exercise (£)*
3 8-10 0 R * F
3 8-9 0 H • I
3 10 0 N
5 25 N - 0 R
10 14 Face mask R
10 -- N R
10 IB 0 - N R
10 6 0 K
10 12 0 N
10 8 - 1? Face Mask R
«
10 46 Face Mask R
10 15 0. N R
10 /OR
Exercise
Effects
Light exercise potentiates
effect of SO. MtF tnt
. . c su*
decreased
Airway resistance increased
Pulse rate, respiratory
increased; tidal volume
decreased
Could not duplicate Amdur's
results
No changes in pulse rate,
respiratory rate or tidal
vohme (5. 10 ppn) 2 sub-
jects had bronLhospasn
No changes in pulse rate,
respiratory rate. I'ulaonary
flow resistance increased at
5 and 13 p|>n
Bronchocunslric t ion
Decreased peak flow, decreased
expiratory c.i|i, icily above
1 . 6 ppn
SC decreased less with nasal
HPr.i Hi iny
Airway conductance decreased
rel lex vl lecl
Reference
Kreisnan et al .
1976
Nakanura, 1964
Awlur et al. ,
rale 1953
Hcllroy et al. ,
1954
I awl her. 1955
Frank et al. ,
1962
Sia and Pallle.
1957
TmM>no, 1961
Helvillo, 1970
Nadel, 1965
-------
13-2. (continued)
Concentration Duration of
SO. (ppm) exposure (mins)
15, 28 10
5 10
2.5 - 50 10
6.6 - 7.3 10
1.3-80 10
0.5. 1.0. 5.0 15
1. 5. 13 10 - 30
16.1 25
1.5, 15 30
1.1 - 3.6 30
•j 30
1 - 2~\ 60
1 60
Number of
subjects
8
5
5
variable
8 - 12
9
11
7
12
10
10
8 - 1?
-
Oral or
nasal
exposure
0
N
0
M
0
ON
Face mask
0
N
Face mask
0 - N
0
0
0
Mask, chamber
N
N
Rest (R) or
exercise (E)
R
R
R
R
R
R
R
R
R
R
I
R
R
Effects
Pulmonary flow resistance
increased less with nasal
breathing
MEF,-,. decreased less with
nasll inhalation
Increased respiratory and
inspiratory resistance
No changes in airway
resistance
Bronchoconslriction
MEFr-w. decreased at
Pulmonary flow resistance
increased at 5 and 13 ppm
but less during nasal
breathing '^r/^a^r"/ ^ "^^
,", // J /,j ^,~/^r st^Z
'&'*• jf&-Uf^Si&^3£&f,!&y£-
-------
13-2. (continued)
Concentration Duration of Number of
S0_ (ppm) exposure (mins) subjects
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
25.0 120
9
10
13
17
Exercise
8
4-12
9
4 - 8
15
11
10
15
Oral or
nasal Rest (R) or
exposure exercise (E)
0
Co. stimulus
ChSmber (N)
0
Chamber
Chamber
Chamber
Chamber
N
Chamber
Chamber
(l)ldl)
N
R
(0) R
R
R
E
E
E
E
R
E
E
R
Effects
No effect or MUCUS
transport
Deep breathing significantly
increased SRaw
At higher cone, of SO.
mucociliary activity
decreased
No pulmonary effects
No pulmonary effects
No pulmonary effects
Significant decrease in/^/yf }'
•fVC, FEV. ... MMFR, M£FR / '
Increase in nasal air flow
resistance; decrease in
nasal mucus flow
Insignificant changes in
R and P n2
e aO
MMFR decreased 8 5X increased
Iracheobronchial clearance
Increased nasal airfow
Reference
Wolff et al., 1975a
Lawther. 1975
Cralley, 1942
Bates and Hazucha, 1973;
"Hajuchj 3nd fiatet 1975 •
Bell et al. , 1977
Horvath and Follnsbee. 1977
Bedi et al. , 1979
Bates and Hazucha, 1973;
Ha/ucha and Bates, 1975
'—A&**(^*'
Andersen et al. , 1974
von Neiding et al., 1979
Newhouse et al. . 1978
Andersen et al. , 1974
resistance; decreased nasal
mucus (low
-------
13-2. (continued)
Concentration Duration of Number of
SO- (ppm) exposure (mins) 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
OJ
5 4.5 hours 32
(16 exposed)
Oral or
nasal
exposure
Oral
0
Chamber
Chamber
(N)
Chamber
Rest (R) or
exercise (E) Effects
R MMFR decreased 2.7% recovery ,
within 30 minutes ^3>^fJ^
-------
exposure to S02- Sim and Rattle (1957) performed extensive clinical studies
over a 10-month period on an unspecified number of (8 to 12) "healthy males
aged 18 to 45." SCL 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 S02 were said to be bronchoconstriction
(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 SOp) 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 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. 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 S02 on their pulmonary
physiology. The subjects inhaled 1 to 45 ppm S02 through a face mask for 10
minutes. Decreases in expiratory capacity and peak flow rate were proportional
to the concentration of S02- 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 S0? exposures.
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
13-14
-------
there was considerable variability in response 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 consequent to S02 exposure. Nine subjects inhaled through a mouth
piece S02 at concentrations of 0.5, 1.0, and 5 ppm for 15 minutes each, with
15-minute control periods interspersed. Maximum expiratory flow (MEF5Q~ vc)
was significantly lower after exposure to 1 ppm SOp (p <0.02) as well as 5 ppm
(p <0.01). Reichell (1972) found no significant changes in airway resistance
in normal subjects and patients with obstructive lung diseases exposed to 6.6
to 7.3 ppm SO-- Jaeger et al. (1979) exposed 40 normal non-smokers and 40
asthmatics (mild to moderate but with no recent exacerbations) subjects to 3
hours to 0.5 ppm SO-. Oral inhalation was forced by having the subjects wear
a nose clip. These resting subjects were also studied during exposure to
ambient air having an average SO- 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 had little
physiological importance. One normal and two asthmatic subjects exhibited
adverse reactions—the asthmatics requiring standard asthma medication. No
changes in pulmonary functions were observed during 60 minutes of exposure to
1 ppm S02 (McJilton et al., 1976).
Nadel et al. (1965) have helped elucidate the mechanism of bronchoconstric-
tion resulting from S02 exposure. They exposed seven subjects to 4 to 6 ppm
13-15
-------
SO- for 10 minutes via mouth in a closed plethysmograph. The mean decrease in
specific airway conductance was 39 percent (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,
Made! et al. concluded that the bronchoconstriction induced by S02 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 SO- 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 SC^ 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-aftd=Bnnd-, 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 sensitive 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 conditions, which
13-16
-------
raises the possibility of psychological factors contributing to this observed
sensitivity.
13.2.3.1 Water Solubility--Qne of the first points to note is that because of
its high solubility in water, S02 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 S02 on respiratory functions. These considerations will be
illustrated in the following sections (see Chapter 11).
13.2.3.2 Nasal Versus Oral Exposure—A number of studies have demonstrated
significant response differences between the nose and mouth as routes of
exposure to SO,,. Speizer and Frank (1966a), for example, compared the effects
of S02 (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 S0? 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 S02 (90 to 99 percent) in the inspired air was removed by
the nose. Similar results were obtained by Andersen et al. (1974) in a study that
will be described in detail below.
13-17
-------
Melville (1970) also compared oral and nasal routes of administration.
He used 15 subjects and exposed them (for 10 minutes) sequentially to 2.5, 5,
and 10 ppm SO-. 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 (SGflw): as the S02
concentration increased, SGau/ decreased (p <0.05). This was true regardless
oW
of administration route (for 2.5 ppm SOp), but the average decrease under oral
administration was greater (in 80 percent of subjects), than the decrease under
nasal administration (p <0.05). During exposure to 5 ppm S02 no significant
difference was observed in SG regardless of whether the 49 subjects breathed
aW
through mouth or nose.
Snell and Luchsinger (1969) also examined the differences between nasal
and oral exposure using SO- at 5 ppm. Five subjects' average maximum expiratory
flow (MEFr-y .,-) 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 SO- deposition.
13.2.3.3 Subject Activity Leve]--0ne 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
S02. At some level of ventilation, inhalation of air shifts from nasal to
mouth breathing. Studies under way (Horvath, personal communication) suggest
that subjects who are nasal breathers at rest move to mouth breathers when
ventilatory exchange is approximately 30 L/min. However, it should be
remembered that many individuals are always mouth breathers. Kreisman et al.
(1976), for example, reported that exercise may potentiate the effect of SO- on
respiratory function. In their study, subjects inhaled a mixture of S02 in
air for 3 minutes while exercising on a bicycle ergometer at a pace sufficient
13-18
-------
to double their resting minute ventilation rate. Eight subjects recieved 1
ppm S02 and nine subjects received 3 ppm. Those receiving 3 ppm showed a
significant (p <0.05) decrease in maximal expiratory flow (MEF^ /pj compared
to a control (untreated air) exposure. However, it is not clear that this
change differed significantly from the change in MEF. ,p.. occurring in
resting subjects. Bates and Hazucha (1973) and Hazucha and Bates (1975)
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 SO^. At 0.37 ppm SCL, Hazucha and Bates
(1975) observed no pulmonary function changes. Horvath and Folinsbee (1977)
and Bedi et al. (1979) exposed nine intermittently exercised subjects in
a chamber to 0.4 ppm SCL 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 resistance (SR=v) during exposure to S00 at 1 ppm. While
aw t
sitting quietly in an inhalation chamber, the same subjects had previously
shown no such increase after breathing concentrations of 1 to 3 ppm SO- for an
hour. As part of a series of experiments in this study, 17 subjects also
received 3 ppm S0~ by a mouthpiece and were instructed to talce 2, 4, 8, 16,
and 32 deep breaths at 5-minute intervals. Increases in SR due to SO^
were significantly greater after 16 (p <0.01) or 32 (p <0.001) deep breaths.
Burton et al. (1969), however, found no consistent effects in 10 subjects
exposed to S0? 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
13-19
-------
important consideration in reviewing the effects of SO,, on human subjects.
namely, temporal parameters.
13.2.3.4 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 SO- 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 S02-
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 SO- their
subjects' pulmonary resistance measures were just reaching their peaks, while
subjective reports of an odor of SO- had already subsided.
In a later study by Frank et al. (1964) the increase in pulmonary resistance
induced by S02 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
that percentage increases in specific airway conductance (SG ) were greatest
3W
during the first 5 minutes of up to 60 minutes of exposure to S0? by
mouth/nasal breathing. At 5 ppm, for example, he noted that SG decreased
9W
13-20
-------
significantly (p <0.05) within 5 minutes of exposure and stabilized slightly
above the values recorded under control conditions of no SO,.
Similar results were obtained by Lawther et al. (1975), who noted that
SRflw increased most 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 S02). In this last regard, similar findings
were reported by Gb'kenmeijer et al. (1973) for bronchitic patients exposed to
10 ppm S02. Respiratory effects were maximal at the end of a 3-minute
inhalation period, and recovery required 45 to 60 minutes.
Abe (1967) compared the temporal course of SOp exposures. 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). Effects of repeated exposures are noted
by Frank et al. (1964) and Tomono (1961).
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
concentrations (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
13-21
-------
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 administered on the third day of the study.
Significant (p <0.05 or less) decreases in forced expiratory flow (FEF25-75%^
and forced expiratory volume (FEV, Q) also occurred both within daily exposures
and across days (i.e., increasing concentrations), although the within-day
decrease in FEV, n was only significant on day 3 (at 25 ppm) (see Andersen et al.,
1974, Figure 7).
13.2.3.5 Mucociliary Transport—Grail ey (1942) investigated mucociliary clearance
when sophisticated 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 SOp 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 S0?
resulted in a 50 percent reduction in mucociliary transport and a 65 to 70
percent reduction at 50 to 55 ppm. Mucostatis in the anterior region of the
nose was observed in 14 of 15 subjects after 4 to 5 hours of exposure to 25
ppm S02 (Andersen et al., 1974). In addition, the mucus flow rate in the
anterior nose was reduced by 50 percent after 1 to 3 hours exposure to as
little as 1 ppm S02- At this concentration some subjects also had sporadic
mucostasis, although there were pronounced individual differences in these
measures even at baseline.
(177
Wolff and his co-workers (Wolff et al., 1975a, t^5b; Newhouse et al.,
1978) have also measured the rate of mucociliary transport. In Wolff et al.'s
(1975a) first study, nine subjects were exposed to 5 ppm SO- for 1 hour
while sitting quietly in an inhalation chamber and breathing through their
13-22
-------
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 S02 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. (1075b) 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 S0?
resulted in a significantly (p <0.05) greater rate of tracheobronchial muco-
ciliary clearance. This result contrasts with Andersen et al.'s findings (1974)
that nasal clearance rates were reduced by exposure to 5 ppm S0?. 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 SO- (5 ppm) or H2S04 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 approximately 70 to 75 percent of predicted maximum heart
rate was performed, followed by an additional 1.5 hours of rest exposure. The
13-23
-------
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 S0? 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 HpSO^ mist exposures. Tracheo-
bronchial clearance increased in both S02 (6 of 10 subjects) and H2$04 (5 of 10
subjects) exposures. The investigators 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 replicated 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 SO,,.
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), for example, noticed that
4 of 17 subjects caught colds within a week of their participation in a
study where mucostasis generally occurred during SOp 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
S02. It was unknown, however, whether this result reflected a direct effect
of S02 on the host, the rhinovirus, or both. In addition, the average incuba-
tion period was somewhat shorter for the group exposed to SO- (p <0.06).
13-24
-------
Virus shedding (a measure of infection determined from nasal washings) also
seemed to be somewhat decreased in the SOp exposed group, but not significantly
13.2.3.6 Health Status—Some studies have considered the preexisting health
status of subjects as a variable in assessing the physiological effects of
S02. 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 S02 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 SOp exposure.
Also, subjective complaints also appeared to be randomly distributed throughout
the course of the study and could not be related to S02 exposure 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 correla-
tions (p <0.001) between S02 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 a!., 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
13-25
-------
the relative importance of an individual's health status in determining his
physiological response to S02>
13.3. PARTICIPATE MATTER
One of the most 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 S02 in at least two distinct
ways: as a carrier of S02 and as a factor in chemical reactions resulting in
the conversion of S02 to other forms. In their carrier role, particles may
adsorb S02 and, depending on their size, solubility, and other characteristics,
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 SCL. In Nakamura 's (1964) study, 10 subjects
£ftf
were first exposed to NaCl aerosol (CMD = 0.95 umj/yestimate of MMAD =5.6 urn)
alone for 5 minutes, allowed to recover for 10 to 15 minutes, exposed to S02
alone at 9 to 60 ppm for 5 minutes, allowed 20 to 30 minutes to recover, and
then exposed to S02 and the NaCl aerosol together for 5 minutes. Airway
resistance was greater after the combination exposure than after exposure to
S02 alone (see Table 1 and Figure 4a, Nakamura, 1964). As noted, the combina-
tion condition always followed exposure to S02 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 S0? in combination with submicronic (0.22 \in
Misestimate of MMAD = 0.36 urn) particles of NaCl aerosol produced synergistic
13-26
-------
13-3. PULMONARY EFFECTS OF AEROSOLS
Duration of
Concentration exposure (mins)
SO, (1.6 - 5 ppm) 5
NSC1 0.22 urn HMD
SO, (9-60 ppm) 5
NSC1 (CMO = 0.95 urn)
S0« (0.5. 1.0 and 5.0 ppm) 15
Saline particles 7.0 urn
Ibid 30
^*
£SO, (1.1 - 3.6 ppm) - 30
^ N5C1 2.0 - 2.7 ug/ni
MHO = 0.25 urn
SO, (1-2. 4-7. 14-17 ppm) 30
N3C1 10-30 mg/nr
MMO 0.15 urn
SO, (1 ppm) - 60
NlCl 1 mg/mj
MMO 0.9 u og = 2.0 pm
Ibid 60
Ammonium tulfate 150
100 ug/nt
Ammonium bisulfate 150
85 ug/m aerosol size
distribution
0.4 urn (MMAO)
Number of
subjects
13
10
9
9
(asthmatics)
10
12
9
(asthmatics)
(normals)
5 (normal)
4 (ozone
sensitive)
6 (asthmatics)
16
Source
Mask
Mask
Oral
(Mask
(Exercise for
10 minutes)
Oral
Oral
Oral
Mask
Chamber
(exercise)
Chamber
(exercise)
Effects
Synergistic increases in
airway resistance with aerosol
Airway resistance greater after
exposure to aerosol than to
exposure to SO- alone
MEF,,j£ significantly greater
decreases in aerosol (NaCl)
condition
v M> v t,
significantly in aerosol
condition
No effect on pulmonary functions
Changes in pulmonary function
similar to changes due to SO-
alone not influenced by aerosol
Significant decreases in V ,-nv
• A IH3X jU*
and Vmax 75X
No pulmonary effects demon-
strated
No changes in pulmonary
functions
No changes in pulmonary
functions
Reference
Toyama. 1962
Nakamura, 1964
Snell and Luchslnger,
1969
Koenig et al., 1979
Burton et al. . 1969
Frank et al. . 1964
i
JLA^\
Koenig^ 1979
»~$-#jL^
Koenlg.^ 1979
Bell and Hackney. 1977;
Kleinman and Hackney,
Avol et al. . 1979
-------
increases in airway resistance in 13 subjects, even at levels as low as 1.6 to
5 ppm SO . There was also a linear relationship between SOp concentration and
percentage increase in airway resistance.
On the other hand, Burton et al. (1969) were unable to demonstrate comparable
effects in 10 subjects exposed to S02 (1.1 to 3.6 ppm) in combination with
NaCl aerosol (2.0 to 2.7 ug/m3; 0.25 urn MMD^estimate of 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 SOp 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 Rl (pulmonary flow resistance) noted to occur during SOp exposure
were intensified by the presence of sodium chloride particles. The NaCl
aerosols had a mean geometric diameter of 0.15 urn ^"estimate of MMAD =0.3 urn)
and a concentration of 10 to 30 mg/m ; SO- concentrations were 1 to 2, 4 to 7,
and 14 to 17 ppm. The subjects' response to the SO- exposures were as previously
noted in that Rl was not affected by the lower levels of S0? 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
S02 than under the combination condition. Addition of the NaCl aerosol resulted
in similar changes as observed to S02 alone. This effect was interesting in
that earlier work was cited suggesting that H2S04 may have been formed in the
droplets. (See discussion of similar animal studies in Chapter 12).
Snell and Luchsinger (1969) also compared the effects S02 alone and in
mixture with aerosols of either NaCl or distilled water. Nine subjects inhaled
13-28
-------
SOp at 0.5, 1, and 5 ppm alone and in combination with aerosols for 15-minute
periods separated by 15-minute control periods. For the saline aerosol condi-
tion, decreases in maximum expiratory flow rate (MEFcnv v-) were significant
(p <0.01) at all exposure levels (0.5, 1, and 5 ppm SO,,) (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 urn in diameter (see Figure 5,
Snell and Luchsinger, 1969). (See also Ulmer, 1974.) Koenig (1979) exposed
nine adolescent resting subjects (extrinsic asthmatics) for 60 minutes to
either filtered air, 1 ppm SO,, and 1 mg/m of sodium chloride droplet aerosol
or 1 mg/m of NaCl droplet aerosol (HMD 0.9 urn, unable to estimate MMAD, and
o of 2.0 urn). Exposure to SOp alone was not conducted. Oral breathing was
forced on all subjects. Total respiratory resistance (R-,-), maximal flow at 50
and 75 percent of expired vital capacity (partial flow volume). FEV, Q, and
functional residual 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
iTiaX
and V 7r
-------
during the exposures. Vma/ 50% and Vmax 75% decreased some 53 and 46 percent
respectively after the exercise. Significant changes in FEV1 Q and Ry were
also observed, suggesting that exercise and SC^-NaCl exposure resulted in
effects on both large as well as small airways.
As chemical interactants. particles such as aerosols of certain soluble
salts (e.g., ferrous iron, manganese, vanadium) may act as catalyst to convert SO.
to H?SO.. H?0 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 (03) 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 0, (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 03 and 0.37 ppm S0? for 2
hours. Temperature, humidity, concentrations and particle sizes 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 03 a 13 percent reduction was observed, while exposure
to the mixture of 0.37 ppm 03 and 0.37 ppm S02 resulted in a reduction of 37
13-30
-------
percent in this measure of pulmonary function. The effects resulting from 0-
and SO- 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 03 + SO- mixture
had greater detrimental on all pulmonary function measured than 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 decrements in
ffi ?^
FVC (40 percent) and FEV.^ (44 percent) in the first study (Bates and Hazucha^,
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 SO- and 0., exited from tubes separated by 8 inches (20
3 3
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 concentrated streams of SO- and 0- could have reacted
rapidly with each other and with ambient impurities like olefins, to form a
large number of H-SO. nuclei which grew by homogenous condensation, coagulation,
and absorption of NH3 during their 2-minute average residence time 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 SO- singly and
in combination for 2 hours in an inhalation chamber at 25°C and 45 percent RH.
13-31
-------
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 subjects showed significant decreases in maximum expiratory
flow, forced vital capacity, and inspiratory capacity. There were no signifi-
cant differences between the effects of CL alone and the combination of 0^ +
SCL. Although particulate matter was not present in the inlet air, it is not
known whether particles developed in the chamber at a later point.
Von Nieding et al. (1979) exposed 11 subjects to 03, NCL and SCL 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
A02' AC02' pHa' and tnoracic 9as volume (TGV). Airway resistance total (R )
p p
and AQ2 were altered in certain studies. a02 was decreased (7-8 torr) by
exposure to 5.0 ppm NCL 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 SCL and 0.1 ppm 0, or 5.0
ppm N02 and 0.1 ppm 0,. Airway resistance increased significantly [0.5 to 1.5
cm H20/(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 N02, 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 NC>2,
0.12 S02> and 0.025 03 (ppm) exposures. The expected increase in airway
13-32
-------
resistance was observed in the control study. Specific airway resistance (R.
x TGV) was significantly greater than in the control study following the
combined pollutant exposures. (See Table 13-4 for a summary of the pulmonary
effects of SOp and other air pollutants.)
13.5 SULFURIC ACID AND SULFATES
13.5.1 Sensory Effects
A number of studies have been directed toward determining threshold
concentrations of hLSO. 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 not given) which was sensed by odor
33 3
ranged from 0.6 mg/m to 0.85 mg/m (average 0.75 mg/m ). 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 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 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
13-33
-------
13-4. PULMONARY EFFECTS OF S02 AND OTHER AIR POLLUTANTS
Concentration
S02 (0. 37 ppm)
and
03 (0.37 pp«)
S02 (0.37 ppm)
and
03 (0.37 ppm)
V S02 (0.40 ppm)
and
0, (0.40 ppm
S02 (5 ppm)
and
N02 (5 ppm)
S0? (5 ppm)
NO- (5 ppm)
and
03 (0.1 ppm)
S02 (0.12 ppm)
N0? (0.06 ppm)
and
03 (0.025 ppm)
Duration of Number of
exposure (mins) subjects Source
120 8 Chamber
(exercise)
120 4 (normal) Chamber
4 (ozone (exercise)
sensitive)
4 (from Bates)
120 9 Chamber
(exercise)
120 11 Chamber
(exercise)
120 11 Chamber
(exercise)
120 1 1 Chamber
(exercise)
Effects
Decrease pulmonary functions
(in synergistic effect of
S0? on 03) FRC. FEVj n,
uurD IIP CD
ririr n ) "tr Hrny
Unable to confirm
synergistic effects
pulmonary decrement due
to 0, alone
Unable to confirm
synergistic effects
changes due to ozone
alone
No changes in Pa02> PaCQ2.
pHa or TGr -R.
increased
No changes in Pa02. PaC()2.
pHa or TGr -R. increased
No changes in pulmonary
functions
Reference
Hazucha and
Bates. 1973, 1975
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
-------
I
w
tn
13-5. SENSORY EFFECTS OF SULFURIC ACID AND SULFATES
Concentration Subjects Effects References
0.75 \ig/m 5 Threshold detected by odor Bushtueva, 1957, 1961
- increase in light sensitivity
- increase in optical chronaxie
1-3 pg/m 15 (exposed 5-15 *in) 3 mg/m detected by all subjects Amdur et al., 1952
-------
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 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 acid mist
at 0.7 mg/m . The combination of sulfur dioxide at 3 mg/m with sulfuric acid
mist at 0.7 mg/m resulted in an increase of approximately 60 percent in light
sensitivity. Exposures lasted for 4 1/2 minutes.
Bushtueva (1962) demonstrated that combinations of sulfur dioxide
3 3
at 0.50 mg/m (0.17 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.
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 concentra-
tions for combinations of the two were determined. Sulfuric acid mist (750
) increased optical chronaxie.
13-36
-------
13.5.2 Respiratory and Related Effects
Amdur et al. (1952) found respiratory changes in all subjects exposed for
15 minutes to HpSO^ aerosol at concentrations of 0.35 mg/m to 5 «g/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 HMD 1 urn. 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 in-
spiratory 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 . 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
H?SO. at 62 percent RH either via mask or 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 \im in size. The addition of water
13-37
-------
vapor to raise RH increased the mean particle size to 1.5 urn and intensified
irritant 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 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 (H^Op) aerosol mixtures, the latter of
which oxidizes SOp to form HpSO.. SOp concentrations ranged from 1 to 60 pptn;
3
the HO concentrations were 0.29 mg/m for particles of 4.6 |jm CMD (aotimatcd-
o c
MMAD = 13) and 0.33 mg/m3 for particles of 1.8 urn CMD (-estimated- MflAD = 5).
Airway resistance increased significantly in the combination (hLO- + 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 S0?
and H2S04 aerosols. They used an inadequate method to measure airway resistance.
They described the aerosols as having a 4.5 pm 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 ug/m . Measurements on these individuals continued for up to 3 hours
after exposure. The asthmatic patients represented a wide range of clinical
13-38
-------
status and treatment. Neither normal nor asthmatic individuals showed significant
alterations of lung volumes, distribution of ventilation, earoxlmetry, 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
HpSO^. 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 NHL 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 significant
changes. Two asthmatics, the extent of their disease state not given, exhibited
increases 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.
Lippmann et al. (1979) had 10 non-smokers inhale via nasal mask 0.5 urn
(a = 1.9) H2S04 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
13-39
-------
(assessed by body plethysmograph, partial forced expiratory maneuver, and
nitrogen washout) were measured before, and at 0.5, 2, and 4 hours post exposure.
99mTc-tagged monodispersed Fe203 aerosol (7.5 urn WAD, o = 1.1) was Inhaled
10 minutes before exposure for the determinations of lung retention of these
particles. Trachea! mucus transport rates (TMTR) and bronchial nucociliary
clearance were determined. No significant changes in respiratory mechanics or
TMTR were observed following H^SO^ exposure at any level. However, bronchial
mucociliary clearance halftime (TB,) was on the average markedly altered at
all concentrations of HpSO. inhaled. Bronchial clearance was increased (p
<0.02) following exposure to 100 ug/m ^SO^, while following exposure to
1,000 ug/m , it was significantly (p <0.03) reduced. Mucociliary transport in
the airways distal to the trachea was affected more by F^SO. 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
wr
(Schlesinger, et a!., 19680. 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.
Bell and Hackney (1977) presented preliminary data on a limited number of
subjects supporting a hypothesis that no adverse short-term (2.5 hours) effects
result from exposure to polydisperse ammonium sulfate particles in the respirable
size range (see Avol et al., 1979). Sixteen individuals were studied, each
being exposed from two to six times to ammonium sulfate. They exercised for
13-40
-------
the first 15 minutes of each half-hour. Ventilation volumes were approximately
double the resting volume during the four exercise periods. A battery of
pulmonary function measurements (FVC, FEVX Q) MMF, AN2> RV, TLC, CV/VC, CC/TLC
•nd IL) were administered to the subjects. Five normal and four "sensitive"
(i.e., sensitive to ozone exposures) subjects had 3 successive days of
exposures preceded by 2 days of purified air exposures. Ambient temperature
conditions were 88°F dry bulb and 40 and 85 percent relative humidity. Six
asthmatic subjects were studied at the lower humidity condition. Their first
day was a purified air exposure followed by 2 days in the ammonium sulfate
condition.
Kleinman and Hackney (1978) and Avol et al. (1979) further 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 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, FEFr0«£, FEF75%' TLC> Rv> de1ta nitrogen (AN.), closing volume, and
total respiratory resistance (R.) 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 exposure 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 pollutant) 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 bisulfate (NH^HSO.)
13-41
-------
and 85 pg/m for ammonium sulfate [(NH^KSO^]. The sulfate aerosol size
distribution was nominally 0.4 urn MMAD (a 2.5 to 3). There was some ammonia
(NHL) in the exposure chamber. Pulmonary functions were unaffected by exposure
to the two types of aerosol.
An interesting side observation was made on the asthmatics. On their
first day of exposure to NH.HSO. aerosol, they exhibited worse lung functions
in the pre-exposure measurements 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.)
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.
S02 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 S02> 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/m3 during dark adaptation.
13-42
-------
13-6. PULMONARY EFFECTS OF SULFURIC ACID
Duration of
Concentration exposure (mins)
0.35 - 5.0 mg/m3 H-SO. 15
MMO 1 pm £ *
3-39 Bg/m3 H.SO. 10 - 60
MMO 1-1.5 pfc
SO. (1-60 ppm) plus Variable
fCO. to form H.SO.
i-> aerosol
£ CMD 1.8 and 4.6 pm
u
H.SO. mist 3 120
f 1000 (jg/m
MMO 0.5 pm (og = 2.59)
H.SO. aerosol - 10
fo/100, 1000 ug/mj
MMO 0.1 pm
H,SO. (75 j.g/m3) 120
MMAD 0.48 - 0.81 pm
M.SO. (0, 100, .300. 60
6r 1,000 pg/mj
MMAD 0.5 pm
(og = 1.9)
Number of
subjects
15
Variable
10
6 normal
6 asthmatics
6 normal
6 asthmatics
10
Source
Mask (rest)
Mask (rest)
Chamber (rest)
(Rest)
Chamber
(exercise)
Oral
Chamber
(exercise)
Nasal
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
bronchoconslriction
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 pg/m .but * following
Reference
Amdur et al., 1952
Sim and Pattle, 1957
Toyama and Nakamura,
1964
Newhouse et al. , 1978
Sachner et al. . 1978
Kleinman and Hackney,
1978. Avol et al.. 1979
Lippmann et •!., 1979
clearance distal to trachea
more affected
-------
During light adaptation, the figures increase and decrease similarly but at
slightly higher levels of exposure. The alpha-wave has been found to be attenuated
by 0.9 to 3 mg/m SO- during 20 seconds of exposure.
Studies of the effects of S02 on the respiratory system of the body have
arrived at conflicting conclusions. Although one study found respiratory
effects after exposure to as little as 1 ppm S02, 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 S02 to which study subjects are exposed. In asthmatic
subjects, MMFR was significantly reduced after oral exposure to 0.5 ppm S02
for 3 hours. Although the bronchoconstrictive effects of exposure to S02 have
been found to be fairly consistent, subjects vary considerably in response to
exposures, and there are some especially sensitive subjects, possibly as much
as 10 percent of the population.
Because S02 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 no effect on
specific airway conductance, although higher levels had a dose-dependent
effect; that is. greater concentrations decreased SG more than lower concen-
aw
trations. The average decrease was greater after oral exposure than after
nasal administration.
The level of activity of the subjects tested affects the results because
the actual dose received is greater when subjects breathe through their mouth,
as during exercise. Just having subjects breathe deeply through the mouth
13-44
-------
significantly affected specific airway resistance during exposure to 1 ppm SO-
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 ninutes of
exposure. Recovery takes about 5 minutes in normal subjects, but »uch 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 SOp 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 SO- increased. Long exposures to 5 ppm SOp
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 SOp.
The interaction of S02 and particulate matter is an important factor in
Lunn's experimental studies. Airway resistance increased more after combined
exposure to S0« and sodium chloride than after exposure to SOp 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. MEFcQ^ was found to be significantly reduced after exposure
to a combination of saline aerosol and SOp. After exposure to combined hydrogen
peroxide and 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 concentrations (0.37 ppm) SOp 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
13-45
-------
levels of SOp and ozone combined with S02 or to ozone alone, but no synergistic
effect of the combined exposure.
Sulfuric acid and sulfates have been found to affect both sensory and
pulmonary function in study subjects. The odor threshold for sulfuric acid
3 3
aerosol has been set at 0.75 mg/m in one study and 3 mg/m in another. Light
sensitivity has been found to be consistently increased by 25 percent at 0.7
to 0.96 mg/m concentration of sulfuric acid mist (0.3 mg/m ). Optical chronaxie
has also been found to be increased after exposure of subjects to 750 um/m
sulfuric acid mist.
o
Respiratory effects from exposure to sulfuric acid mist (0.35 to 5 mg/m )
include increased respiratory rate and decreased maximal inspiratory and
expiratory flow rates and tidal volume. Several studies of the pulmonary
function of asthmatic and normal subjects suggested that pulmonary function
was not affected when the subjects were exposed to sulfuric acid. Mucociliary
clearance was affected by exposure to sulfuric acid, being significantly
increased after exposure to 100 um/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.
13-46
-------
Additional References Recommended for Consideration in Chapter 13
Anderson, L., G. R. Lundgvist, D. F. Proctor, and K. L. Swift. Human response
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EPA-600/1-79-032, U.S. Environmental Protection Agency, 1979.
Chaney, S., W. Blomquist, K. Muller, and P. Dewitt. Biochemical Effects of
Inhalation of Sulfuric Ackl Mist by Human Subjects While at Rest.
EPA-600/1-79-042, U.S. Environmental Protection Agency, 1979.
Coates, J. E. Lung Function: Assessment and Application in Medicine. Fourth
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Utell, J. J., A. T. Aquilina, W. J. Hall, D. M. Speers, R. G. Douglas, F. R.
Gibb, P. E. Morrow, and R. W. Hyde. Development of Airway Reactivity to
Nitrates in Subjects with Influenza. Am. Rev. Resp. Dis. 121:233-241,
1980.
-------
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13.7 REFERENCES
Abe, M. Effects of mixed N02, S02 on human pulmonary functions. Effects of
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Bates, D. V., and M. Hazucha. The short-term effects of ozone on the lung.
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pp. 507-540.
Bedi, J. F., L. J. Folinsbee, S. M. Horvath, and R. S. Ebenstein. Human
exposure to sulfur dioxide and ozone: Absence of a synergistic effect.
Arch. Environ. Health 34:233-239, 1979.
Bell and Hackney 1977.
13-47
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Bell, K. A., W. S. Linn, M. Hazucha, J. D. Hackney, and D. V. Bates.
Respiratory effects of exposure to ozone plus sulfur dioxide in Southern
Californians and Eastern Canadians. J. Am. Ind. Hyg. Assoc. 38:696-706,
1977.
Burton, G. G., Corn, M., Gee, J. B. L., Vassallo, D., and Thomas, A. Absence
of "synergistic response" to inhaled low concentration gas-aerosol mixtures
in healthy adult males. Presented at 9th Annual Air Pollution Medical
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Burton, G. G., M. Corn, J. B. Gee, C. Vasallo, and A. P. Thomas. Response of
healthy men to inhaled concentrations of gas-aerosol mixtures. Arch.
Environ. Health 18:681-692, 1969.
Bushtueva et al. 1960.
Bushtueva, D. A. New studies of the effect of sulfur dioxide and of sulfuric
acid aerosol on reflex activity of man. Jji: Limits of Allowable Concen-
trations of Atmospheric Pollutants. Book 5, B. S. Levine, translator,
U.S. Department of Commerce, Office of Technical Services, Washington, DC,
March 1962. pp. 86-92.
Bushtueva, K. A. The determination of the limit of allowable concentration of
sulfuric acid in atmospheric air. ^n: Limits of Allowable Concentrations
of Atmospheric Pollutants. Book 3, B. S. Levine, translator, U.S. Department
of Commerce, Office of Technical Services, Washington, DC, 1957. pp. 20-36.
Bushtueva, K. A. Threshold reflex effect of SO- and sulfuric acid aerosol
simultaneously present in the air. In: Limits of Allowable Concentrations
of Atmospheric Pollutants. Book 4, B~ S. Levine, translator, U.S. Department
of Commerce, Office of Technical Services, Washington, DC, January 1961.
pp. 72-79.
Cralley, L. V. The Effect of irritant gases upon the rate of ciliary activity.
J. Ind. Hyg. and Toxicol. 24:193-198, 1942.
Dubrovskaya, F- I. Hygienic evaluation of pollution of atmospheric air of a
large city with sulfur dioxide gas. In: Limits of Allowable Concentrations
of Atmospheric Pollutants. Book 3, B. S. Levine, translator, U.S. Department
of Commerce, Office of Technical Services, Washington, DC., 1957. pp. 37-51.
Frank, N. R. Studies on the effects of acute exposure to sulfur dioxide in
human subjects. Proc. R. Soc. Med. 57:1029-1033, 1964.
Frank, N. R., M. 0. Amdur, and J. L. Whittenberger. A comparison of the acute
effects of SO- administered alone or in combination with NaCl particles
on the respiratory mechanics of healthy adults. Int. J Air Water Pollut.
8:125-133, 1964.
Frank, N. R., M. 0. Amdur, J. Worcester, and J. L. Whittenberger.
Effects of acute controlled exposure to S0? on respiratory mechanics
in healthy male adults. J. Appl. Physiol. 17:252-258, 1962.
13-48
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Frank, R. , C. E. McJilton, and R. J. Charlson. Sulfur oxides and particles;
effects on pulmonary physiology in man and animals, ^n: Proceedings of
Conference on Health Effects of Air Pollution. National Research
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Office, Washington, DC.
Go'kenmeijer, J. D. M. , K. DeVries, and N. G. M. Orie. Response of the bronchial
tree to chemical stimuli. Rev. Inst. Hyg. Mines (Hasselt) 28:195-197,
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Greenwald, I. Effects of inhalation of low concentrations of sulfur
dioxide upon man and other mammals. Arch. Ind. Hyg. Occup. Med.
10:455-475, 1954.
Gunnison, A. F., and E. D. Palmes. S-Sulfanates in human plasma following
inhalation of sulfur dioxide. J. Am. Ind. Hyg. Assoc. 315:288-291, 1974.
Hazucha, M. , and D. V. Bates. Combined effect of ozone and sulphur dioxide on
human pulmonary function. Nature (London) 257:50-51, 1975.
Holmes, J. A., E. C. Franklin, and R. A. Gould. Report of the Selby Smelter
Commission. Bulletin 98, U.S. Department of the Interior, Bureau of Mines,
Washington, DC, 1915.
Horvath personal communication.
Horvath, S. M., and L. J. Folinsbee. Interactions of Two Air Pollutants,
Sulfur Dioxide and Ozone, on Lung Functions. Grant ARB-4-1266, California
Air Resources Board, Sacramento, CA, 1977.
Jaeger, M. J., D. Tribble, and H. J. Wittig. Effect of 0.5 ppm sulfur
dioxide on the respiratory function of normal and asthmatic
subjects. Lung 156:119-127, 1979.
Kisskalt, K. Uber den Einfluss der inhalation schwelfiger Sa'ure auf die
Entevickelung der Lungentuberculose: Ein Bietrag zum Studien der Gewer-
bekrankheiten. Z. Hyg. 48:269-279, 1904.
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In press, 1979.
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inhaled SO- and exercise on pulmonary function in asthmatic
adolescents. J. Allergy Clin. Immunol. 64:154, 1979.
Kreisman, H., C. A. Mitchell, H. R. Hosein, and A. Bouhuys. Effect of low
concentrations of sulfur dioxide on respiratory function in man. Lung
154:25-34, 1976.
13-49
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Lawther and Bond 1955.
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pulse rates in normal subjects. Lancet 2:745-748, 1955.
Lawther, P. J., A. J. MacFarlane, R. E. Waller, and A. G. F. Brooks. Pulmonary
function and sulphur dioxide, some preliminary findings. Environ. Res.
10:355-367, 1975.
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Arch. Hyg. 18:180-191, 1893.
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Mcllroy, M. B., R. Marshall, and R. V. Christie. Work of breathing in normal
subjects. Clin. Sci. 13:127-136, 1954.
McJilton, C. E., R. Frank, and R. J. Charlson. Influence of relative
humidity on functional effects of an inhaled S0?-aerosol mixture.
Am. Rev. Respir. Dis. 113:163-169, 1976. *
Melville, G. N. Changes in specific airway conductance in healthy volunteers
following nasal and oral inhalation of S09. West Indian Med. J. 19:231-235,
1970. *
Nadel, J. , H. Salem, B. Tamplin, and Y. Tokiwa. Mechanism of bronchoconstriction
during inhalation of sulfur dioxide. J. Appl. Physiol. 20:164-167, 1965.
Nadel, et al. Arch. Environ. Meth. 10:175-178, 1965.
Nakamura, K. Response of pulmonary airway resistance by interaction of aerosols
and gases in different physical and chemical nature. Nippon Eiseigaku Zasshi
19:38-49, 1964.
Newhouse, M. T., -M. Dolovich, G. Obminski, and R. K. Wolff. Effect of TLV
levels of S0? and H?SO. on bronchial clearance in exercising man. Arch.
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1884. -
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1978.
13-50
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Schlesinger, R. B., M. Lippmann, and R. E. Albert. Effects of Short-term
Exposures to Sulfuric Acid and Ammonium Sulfate. J. Am. Ind. Hyg. Assoc.
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resistance in health volunteers acutely exposed to SO, by mouth and by
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Speizer, F., and Frank, N. R. The Uptake and Release of SO, by the Human
Nose. Arch. Environ. Health 12:725-728, 1966b.
Tomono, Y. Effects of SO, on human pulmonary functions. Sangyo Igaku
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and sulfur dioxide to pulmonary airway resistance. Ind. Health 2:34-45,
1964.
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13-51
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Wolff et al. 1975a.
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13-52
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Chapter 14. Epidemiology Studies Corrigenda
Before listing specific minor errata (insertions/deletions) for text contained
in Chapter 14 of the April 1980, External Review Draft, several general comments
should be noted regarding planned reorganization and certain other major changes
to be made in the chapter. The chapter reorganization and other changes are
based in part on comments received both from within and outside EPA
and further technical information obtained since finalization and release of the
April, 1980, external review version of the chapter.
In regard to reorganization of the chapter, the present introduction (Section
14.1) discussing general epidemiology methodology considerations and the discussion
of air quality measurement considerations (Section 14.2) are to be retained,
with certain specific revisions noted later. Similarly, much of the later discussion
of caveats and limits contained in Section 14.6 is to be retained, again with certain
revisions as noted later. The materials between the above sections (dealing with
evaluation of specific studies), however, is to be reorganized using the following
format:
14.3 - Acute Exposure Effects
14.3.1 - Mortality
14.3.2 - Morbidity
Adults
Children
14.4 - Chronic Exposure Effects
14.4.1 - Mortality
14.4.2 - Morbidity
Adults
Children
Resequencing of the discussion of specific studies in the above manner both:
(1) better matches the presentation format followed for summary text and tables later
in Chapter 14 and in Volume I; and (2) better organizes discussion
of technical data related to development of health criteria for short-term (24-hour)
or long term (annual average) ambient air quality standards, respectively. Text on
-------
the bottom of pg. 14-14 is, therefore, to be revised to reflect the reorganization
of subsequent materials in Section 14.3 and 14.4, and to indicate that a new
Section 14.5 will contain integrative summary and interpretation discussion
materials of the type dealt with under the present Section 14.6.
Also, at the end of Section 14.1, following the above revisons of text at
the bottom of Pg. 14-14, new text to be inserted is to note that certain criteria
are to be followed, generally, in the selection of specific studies to be
discussed in detail under new Section 14.3 and 14.4. The criteria to be employed
in narrowing down the detailed discussion to potentially key studies are as
follows:
1. The studies have been peer-reviewed and published or are
"in press" to be published, such that final versions of the published reports
are (or can be made) publically available. Also, the results or analyses contained
in the published reports represent completed analyses of data, rather than "preliminary"
analyses subject to change before publication in "final" form.
2. The published information is sufficient to allow for reasonably clear
evaluation of the methodology employed in collection and analysis of
data leading to the results reported (or such information is satisfactorily
alternatively obtained or clarified).
3. Evidence exists for major confounding factors having been appropriately
controlled for or taken into account in the published analyses, e.g. especially
temperature in studies of acute effects and smoking, race, and socioeconomic
status in chronic exposure studies.
4. The published results, together with any alternatively obtained
information, appear to provide a reasonably clear potential basis by which to
define quantitative dose-effect or dose-response relationships for health
effects associated with sulfur oxides and particulate matter. Emphasis
is to be placed on studies yielding information on effects associated
with exposures below 1000 yg/m (24 hour average) that are most germane for
present criteria development purposes.
In addition to detailed discussion of studies meeting all of the above
criteria, certain other studies failing to meet one or more of the criteria may
also be considered or reviewed, based on their findings likely providing
important information bearing on the overall assessment of epidemiologic evidence
of significance for present purposes.
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Following the above modifications of introductory materials in Section 14.1,
the next section (14.2) on air quality measurement considerations is to be expanded
to include summary statements derived from Chapter 3 discussions of intercomparisons
between estimates of particulate matter levels obtained by various measurement
techniques. Thus, immediately before the start of Section 14.3 at the bottom of
Pg. 14-34, there is to be inserted a relatively brief summary discussion concerning
the main conclusions derived from Chapter 3 regarding intercomparisons of particulate
matter measurement data obtained by means of high-volume (TSP) sampling, British
smoke (BS), and other (e.g., the AISI) particulate measurement techniques. Note
will be made of the difficulties and limitations inherent in making such intercomparisons
and, based on this, the particulate matter measurement results employed in
particular studies discussed in Sections 14.3 and 14.4 are to be expressed there
only in terms of units appropriate for the specific measurement methodology
o
employed (e.g., in CoH units or yg/m of either BS or TSP). Only following
summarization of study results in terms of such original measurement units are
discussions of any potential interconversions between measurement units to be
included as part of later summary and conclusions materials in Section 14.5 and
elsewhere (e.g., Volume I).
No attempt will be made here to list myriad changes in sequencing of text
materials now under Sections 14.3 to 14.5 of the April, 1980, External Review
Draft necessary to accomplish the reorganization of materials into the new Sections
14.3 and 14.4 listed under the revised format outlined above. Rather, only
certain planned substantive content revisions (mainly large text deletions) of
existing materials -in Sections 14.3 to 14.5 of the April draft are summarized
below before presentation of more detailed lesser errata corrections for the
Chapter.
-3-
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On pg. 14-47, Table 14-7 is to be deleted along with revisions and reduction
in text at the bottom of pg. 14-46 and top of pg. 14-48, discussing the Osaka and
Rotterdam studies. The revisions are to note that the Biersteker and Watanabe
studies report data or information on quantitative dose-effect relationships, but
insufficient information was reported to allow for evaluation of the adequacy of
study design (especially in regard to adjustments made for temperature effects).
On pg. 14-51 to 14-52, the discussion of multiple regression studies by
Hodgson,158 Buechley,159'160 Lebowitz,170 and Lebowitz et al.171 is to be shortened
considerably. Note is to be made that these studies provide mainly qualitative
data on associations between sulfur oxides (SO ) or particulate matter (PM) and
A
observed mortality effects but generally do not provide clear data on quantitative
levels of SO or PM likely associated with such effects, with the exception of
X
the Beuchley studies ' finding significant increases in mortality when 24
hour mean S02 levels exceeded approximately
On pg. 14-56, 14-58, 14-59, the extensive quotation of material from Holland
et al. concerning the Martin studies ' is to be deleted. Also the rest of
the text on pg. 14-59 is to be deleted, along with the text concerning the detailed
additional analysis of mortality effects observed in the Martin studies6'11 that
runs from pg. 14-60 to 14-65. Similarly, the rest of the text on 14-65 and 14-66
(top) on further analysis of the 1975 London and 1975 Pittsburgh episodes is to
be deleted. The available reports or discussions of the 1975 London episodes do
not allow for more detailed analyses of the type indicated on pg. 14-65; and the
available report by Riggan et al. (1977)341 on the Pittsburgh episode contains
information only on preliminary analyses that remain to be more definitively
completed, peer-reviewed and published.
-4-
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On pg. 14-70 to 14-71, table 14-16 on qualitative mortality studies is to be
moved to the appendices and referred to in Chapter 14 text only briefly, in
I QQ
summary terms. Also, certain studies, such as those by Buck and Brown
19 20
Wicken and Buck, Burn and Pemberton, are to be added to qualitative studies
21 2"?
listed in Table 14-16. Comments on the Winkelstein studies and analyses
presented on pg. 14-73 to 14-81 would be especially valuable in order to resolve
whether to retain such detailed discussion of these results as important quantitative
findings or whether to simply list the Winkelstein results in a table of qualitative
findings.
On pg. 14-90, the summary table (14-21) is to be revised to show the 24 hour
particulate levels at which mortality effects were observed only in terms of the
original units (yg/m BS; CoH units) in which such data were reported (and not
possible comparable TSP units). On pg. 14-91, Table 14.22 is to be deleted.
On pg. 14-93 to 14-95, the Table (14.23) on qualitative studies of air
pollution and acute respiratory disease is to be moved to the Appendices and only
brief summary statements regarding the table kept in the main text of Chapter 14.
177 122 123
Comments on studies by Finklea et al. ' ' are to be deleted from the
table.
On pg. 14-96 and 14-97, text revisions are to be made that note the exclusion
from discussion in the April draft of studies carried out as part of the EPA
"CHESS" program. Also, in that connection, explanatory text will be inserted
stating that: (1) The manner in which CHESS program study results were reported
and interpreted in summary form in early 1970 publications and in more detail in
the 1974 "Sulfur Oxides Monograph" raised questions regarding possible inconsistencies
in data collection and analyses, as well as interpretation of the reported results;
-5-
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(2) Of particular concern were questions regarding the adequacy of air quality
data measurements (for TSP and SO^, as well as other pollutants) upon which key
quantitative conclusions were based regarding possible air pollution-health
effects relationships; (3) Many of the outstanding questions regarding the CHESS
studies remain to be clearly resolved and, until such time that they are, the
potential usefulness of such studies is extremely limited in terms of yielding
well-defined information on air pollution-health effects relationships as they
might pertain to development of health effects criteria; (4) Based on the above
considerations, CHESS program data sets and analyses will not be further discussed
in criteria document drafts, unless questions regarding accuracy of specific data
sets and their analyses have been satisfactorily resolved and reports on them
adequately peer reviewed.
On pg. 14-102, the last sentence on the page is to be amended to note that,
since measurements of air pollution and pulmonary function reported in the Stebbings
no p-i /-
et al. study and the Stebbings and Fogelman study were not initiated until
after the peak of the 1975 Pittsburgh episode, it is impossible to clearly relate
any health effects observed in those studies to specific S02 or PM levels. Consequently,
Op pi C
the rest of the detailed discussion of the Stebbings ' studies on pg. 14-103
and top, pg. 14-104, is to be deleted.
Also, on pg. 14-105 and 14-106, all text dealing with the Stebbings and
1QO
Hayes report on a 1971-1972 New York "CHESS" Program panel study is to be
deleted, as per statements made earlier concerning exclusion from discussion of
CHESS Program studies due to unresolved questions regarding their reported results
and interpretations. Similarly, the detailed text discussing the French et
al.306 New York ARD "CHESS" Program study is to be deleted from top, pg. 14-109
to top, pg. 14-133, including Tables 14-24 to 14-26 on pg. 14-110 to 14-112.
-6-
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On pg. 14-107 to 14-109, the discussion of the studies71' 205'210 by McCarroll
and associates is to be shortened (and reference to quantitative estimates of
pollutant levels associated with observed health effects deleted). Consideration
will be given to including brief summaries of those studies in an appropriate
table of qualitative studies.
On pg. 14-113, the detailed discussion of the Kalpalzanov et al. study is
to be deleted and its results only briefly summarized in an appropriate table of
qualitative studies.
On pg. 14-115 to 14-116, the discussions of the Kevany15 and Heinman54
72 73
and Sterling ' studies are to be deleted; the results of each are to be summarized
in an appropriate table of qualitative studies.
The discussion of the Fletcher et al. and Angel et al. studies on pg.
14-117, is to be moved to the new Section 14.4 on chronic exposure effects,
rather than remaining under the text on acute effects as presently situated. Note
will be made of difficulties in estimating quantitative levels of SO or PM
/\
associated with observed health effects, and other problems, which argue for
these studies to be included as part of an appropriate table of qualitative
studies.
The text on the Verma et al.65 study (bottom, pg. 14-120; top, 14-121) is to
be deleted and that study only mentioned briefly in an appropriate table of
qualitative studies. Also, on pg. 14-121, the discussion of the "Ministry of
CO
Pensions" study is to be moved to the new Section 14.4 on chronic effects; note
will be made of problems with air monitoring data used in that study and other
methodological problems which mitigate against useful quantitative information
being extracted for present criteria development purposes.
-7-
-------
On pg. 14-123, the Shephard et al.327' 328 discussion is to be deleted and
Iftfl
the Lebowitz et al. study results (including top pg. 14-124) briefly summarized
in a table of qualitative studies.
Table 14-29, on pg. 14-125 is to be revised as follows: (1) participate
matter measurement data will be expressed only in terms of BS or TSP as originally
reported, with a column being added for BS in the table headings along side the
TSP (yg/m3) heading; (2) "qualitative" studies will be deleted from the table,
including those by McCarroll et al.,205'206 Cassell et al.,208' 209 Greenburg et
al.,196 Stebbings et al.,216 Stebbings and Hayes,190 Heimann,54 and British
fi?
Ministry of Pensions.
On pg. 14-131 to 14-134, certain of the studies included in Table 14-30 as
yielding qualitative information on air pollution-health effects might be appropriately
deleted, except for ones providing data specifically elucidating associations
between health effects and SO or PM. Comments on which studies should be retained
J\
as meeting such criteria, and which should be deleted as useless for present
purposes, would be helpful.
The extensive discussion of the Irwig et al.98 and Melia et al.^new ref~ #342^
reports on the British school children study, on pg. 14-139 to 14-149 (top), is
to be deleted. Essentially no reference in the main body of Chapter 14 is to be
made to either the Irwig et al. or Melia et al. reports in view of the preliminary
nature of the analyses alluded to in the referenced papers and the lack of any
peer-reviewed published reports on "final" or completed analyses of the British
school children study.
On pg. 14-151 (top), the discussion of the study by Tsunetoshi et al.38 is
to be deleted and the results briefly summarized in a qualitative studies table.
-8-
-------
Similarly, the Suzuki et al. study discussion on pg. 14-151 (bottom) is to be
deleted and that study summarized in a qualitative studies table, as is also the
?1? ^17 ^1Q ^10
case for the Toyama et al., l£"3" Tani01* and YoshiiJ|y studies on pg. 14-152.
On pg. 14-152 to 14-158, all text is to be deleted regarding discussion of
91 9
the EPA "CHESS" studies reported by Chapman et al. ' for Utah "CRD" and Chicago
"CRD" prevalence rate data sets. Also, on pg. 14-158 (bottom) and 14-159 (top)
discussion of the Yoshida et al.176 is to be deleted and results of that study
briefly summarized in a qualitative studies table.
Comments focusing on the discussion and interpretation of the studies by
Rudnick182 and Douglas and Waller90 on pg. 14-159 to 14-163 would be highly
useful, as would comments on the Lunn et al. ' studies discussed on pg. 14-
1 ft? Qfl Qfi Q7
163 to 14-165. Rudnick , Douglas and Waller , and Lunn et al. °'y/ appear to
to provide at least some reasonably well-defined air quality data by which quantitative
health effects - SO /PM air pollution relationships might be delineated (they
J\
have been interpreted by leading experts in such a manner). This, together with
otherwise apparently sound methodological features, argue for these studies being
strongly considered as potential key studies in arriving at final conclusions
regarding the epidemiology data base for SO and PM.
/\
On pg. 14-165 to 14-177, all text is to be deleted regarding discussion of
CHESS studies reported by Hammer et al. and French et al. (on New York
"LRD" data), French et al.306 (on Utah "LRD" data), and Hammer113'257 (on Southeast
or Birmingham vs. Charlotte "LRD" data). This is in keeping with statements
presented earlier regarding exclusion of CHESS studies from consideration in view
of questions that remain to be resolved concerning data collection, analyses and
interpretation of results for CHESS Program studies. Of all the various CHESS
-9-
-------
studies to be deleted at this time, the Hammer113' 257 "Southeast LRD" study
appears to provide the most extensive and thorough data analyses potentially
leading to reliable quantitative estimates of air pollution (SO /PM)-health
/\
effects relationships. Also, there appears to be a reasonable possiblity of
resolving questions concerning the Hammer study within the time frame of
finalization of the present document. Comments on that study would, therefore,
be helpful in determining its possible future consideration for inclusion in the
criteria document as a potentially key quantitative study.
74-77
Comments focused on the Van der Lende et al. studies discussed on pg.
14-178 would also be quite useful, in view of its having been interpreted by a
number of experts as yielding important information on quantitative health effects
air pollution (SO /PM) relationships. Similarly, comments would be useful on the
/\
oo Q C
Becklake and Manfreda et al. studies as potentially finding lack of evidence
of health effects at S02 and TSP levels around 100 yg/m or less, as discussed on
pg. 14-178 and 14-179.
On pg. 14-179 (bottom) and pg. 14-180 (top), the discussion of the Kagawa et
010 9fiA
al. ' studies is to be deleted and, at most, briefly summarized within a
87
qualitative studies table. The same applies for the Zapletal et. al study
discussed at the top of pg. 14-180.
Comments would be especially valuable regarding the discussions on pg. 14-
180 to 14-186 regarding the studies by: Holland et al;101'102 Bennett et al.103;
rolley and Reid112; Ferris115; Mostardi and Leonard177; Mostardi and Martell258;
215
and Shy et al. (Cincinnati school children pulmonary function study). At
least some of these studies appear to provide potentially useful information by
which quantitative health effects - air pollution ,(SO /PM) relationships might
-10-
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be defined, whereas others may be sufficiently flawed methodologically
(e.g. in failure to control for smoking, etc.) so as to be rendered
essentially useless for present criteria development purposes.
On pg. 14-186 to 14-188, all of the text is to be deleted regarding
the "CHESS" studies reported on by Shy et al.215 (New York pulmonary
?! ^
function data) and Chapman et al . (Birmingham and Charlotte pulmonary
function data).
Comments would be useful regarding the Neri et al . ' studies,
discussed on pg. 14-189, as well as the other studies discussed on pg.
OQ
14-190 to 14-195. However, the discussion of Irwig et al. results, on
pg. 14-193 (bottom), is to be entirely deleted in view of the "preliminary"
nature of the results thus far reported.
On pg. 14-196 to 14-197, Table 14-40 is to be revised, including:
3 3
(1) addition of a column heading for BS (yg/m ) along side TSP (yg/m )
and listing of parti cul ate matter measurement data under only one of the
columns according to the original form or units reported for a given
1 09
study; and (2) deletion of CHESS Program studies (Goldberg et al . ,
House et al.,108 Nelson et al.,114 Hammer,113'257 Shy et al.,215 Chapman
99
et al. ) and qualitative studies (Kerrebijn et al . , Yoshida et
al . , ) consistent with deletions in text noted above. The present
Summary and Conclusions section (14.6) of Chapter 14, starting on pg.
14-199, is to be designated as Section 14.5 under the proposed chapter
reorganization format outlined on the first two pages of the present -
materials. Reflecting the planned format change, the first paragraph on
pg. 14-199 is to be appropriately revised to note under points (3) and
-11-
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(4) that acute and chronic exposure effects discussions appear under
Sections 14.3 and 14.4, respectively, of the newly reorganized chapter.
Point (5) at the end of the first paragraph is to be deleted.
On pg. 14-200, the last part of the last sentence of the first
paragraph (text starting with "--not for the purpose...") is to be
deleted as unnecessary. The next paragraph on pg. 14-200 is to be revised
to make reference to Table 14-41 as summarizing the results of key
studies discussed earlier in the chapter as providing valid information
on quantitative relationships between acute exposures to sulfur oxides
or particulate matter and mortality and morbility health effects.
Reference is also to be made to Table 14-42 as containing similar summarization
of key quantitative studies concerning chronic exposure effects.
Table 14-41, on pg. 14-201 and 14-202, is to be revised as follows:
(1) additional column headings for COH and BS measurement results in
3 3
yg/m are to be provided along side the TSP (ug/m ) heading; (2) results
for particulate matter measurements will be entered under one of the
three (BS; COH; TSP) columns only, as per the original units or form
reported for a given study; and (3) numerous deletions of entries from
the revised table are to be made. Such deletions are to include: (a)
the first four sets of entries designated as being for British, Dutch,
Japanese, and USA studies under episodic mortality; and (b) the morbidity
190
study entries for Stebbings and Hayes, McCc
et al.,208'209 and Stebbings and Fogleman.216
study entries for Stebbings and Hayes,190 McCarroll et al.,163 Cassell
-12-
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On pg. 14-203, changes analogous to the first two types listed above
for Table 14-41 are to also be made in Table 14-42. Entries are to be deleted
1 Rfi 1 K 18
from Table 14-42 for studies by Winkelstein,I0° Zeidberg and colleagues,10"
Hammer et al.,214 Goldberg et al.,109 House et al.,108 Nelson et al.,114
Hammer,113'257, Shy et al.,215 and Chapman et al.213
From pg. 14-205 to pg. 14-208 (top, before heading for Section 14.6.2),
all text for present Section 14.6.1.1 is to be deleted. The text under
Section 14.6.2 (pg. 14-208 to 14-214), however, is to remain, as is the text
under Section 14.6.3 (pg. 14-215 to pg. 14-251).
On pg. 14-245, Figure 14-8 is to be deleted and the differences between
301 312
evaluations of key studies between Holland et al. , WHO and other reviewers
briefly discussed only in new text inserted on pg. 12-244. Study results for the
Osaka (1962), Rotterdam (1960's), France (1973), Tokyo (1970), and Southeast
USA (1969-71) entries in the figure will not be discussed. The mistaken data
entry for "Chicago-(1972)M in the figure actually refers to Mostardi's177'258 studies
in Ohio (1972), and the entry in the key to the right for Apling et al., Waller
(1977-78) London is for Apling et al.; Weatherly and Waller (1977-78) London.
Discussion of differences in the reviewers' evaluations of study results will note
where the particular review "translated" original estimates of health effects-associated
particulate matter levels associated with health effects from original COH or
BS units to approximate corresponding TSP levels.
Lastly, at the end of Chapter 14, copies of summary tables now appearing
only in Volume I of the document (as Tables 1-19 to 1-22) are to be inserted to
summarize the evaluations of different reviews for key quantitative studies.
-13-
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The tables will be the same as present Tables 1-19, 1-20, and 1-21, except
for those modifications discussed for those tables earlier, under present
corrigenda materials for Chapter 1. Appropriate text will also be inserted
to discuss the reviewers' evaluations summarized in the tables and definite
statements made regarding which studies appear to be generally viewed as
being valid and conclusions that can appropriately be drawn based on those
study results.
-14-
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14. EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF ATMOSPHERIC CONCENTRATIONS
OF SULFUR DIOXIDE AND PARTICULATE MATTER ON HUMAN HEALTH
14.1 INTRODUCTION
In the preceding chapters of this volume (Chapters 11, 12, and 13),
Information was assessed regarding the uptake, deposition, and absorption of
sulfur oxides and particulate matter and various health effects demonstrated
to be associated with these pollutants by means of animal toxicology and human
clinical studies. Such studies offer the advantage of being able to study
biological processes specifically associated with particular pollutant
exposures under highly controlled laboratory conditions.
The animal toxicology studies are particularly valuable in providing both
qualitative characterization of the full ranges of health effects caused in
mammalian species by SOp and particulate matter exposures and information on
the mechanisms of action underlying such effects. However, considerable
caution must be applied in extrapolating quantitative dose-effect relationships
defined in animal studies to humans.
Of course, some such definition of quantitative dose-effect relationships
can be more directly ascertained by means of human clinical studies. Such
studies, however, are also somewhat limited, in terms of the kinds of health
effects potentially characterized by them. More specifically, only the effects
of short-term (a few hours) exposures or perhaps a few repeated short exposures
are typically investigated in such studies. Also, the nature of the effects
studied are generally limited to detection of onset of relatively transient
changes in pulmonary or cardiac functions and, at times, related physiological
or biochemical parameters. In addition, restrictions arising from human rights
14-1
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considerations often result in limitations that preclude thorough investigation
of health effects experienced by the most sensitive members of the population.
Community health (epidemiology) studies offer several advantages that go
beyond what can be determined by animal toxicology or human clinical studies,
in that health effects of both short- and long-term pollutant exposures (including
the presence of other pollutants) can be studied and sensitive members of
populations at special risk for particular effects identified. In addition,
epidemiology evaluations are not limited to the study of more or less transient
physiological or biochemical effects but also include investigation of both
acute and chronic disease effects induced by SO and particulate matter pollution
A
and associated human mortality as well. Information from epidemiology studies,
then, together with the results from animal and human clinical studies, help
to provide more complete understanding of the health effects of environmental
air pollutants such as sulfur oxides and particulate matter.
Before proceeding with evaluations of epidemiology studies in this chapter,
certain methodological considerations should be discussed as background for
the critical review that follows. Epidemiology is the study of the etiology
and natural history of disease in populations. Epidemiologic studies examine:
(1) the distribution of diseases in populations and their subgroups; (2) the
interplay of agent, host, and external environment; and (3) epidemics or
changes in the homoeostasis in populations. As such, epidemiologic studies
are important in understanding air pollution. They can be conducted in clinical
settings or among populations in communities (or subcommunities) to examine
the relationship between air pollution concentrations and health effects.
Such relationships may be found to be spurious (accidental), indirect (occurring
in the same place and/or time), or direct (such as when subclinical or clinical
14-2
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disease nearly always follows exposure). The consistency of a relationship in
different times and places and the strength of that relationship will generally
determine the likelihood of the relationship being causal. The tendency for
certain events to occur together (dose and response or stimuli and response)
93*i 937 93ft 94? 9A4
also strengthens the conviction that the relationship may be causal. '•''
A. B. Hill added the concepts of the specificity of results and the demonstration
of a biological gradient as other patterns of results highly indicative of
likely causal relationships existing.
There are, however, complications associated with estimating dose and
measuring effects by means of community health studies. For example, certain
competing risks, such as cigarette smoking and occupational exposures must be
identified and taken into account in experimental design and statistical
analyses of study results. Other confounding factors, such as socio-economic
status, race, and weather, must also be evaluated. In all studies, the researcher
accepts the exposures as they occur. Exposures are not subject to manipulation,
although ambient levels change during the course of a study. It is always
difficult to evaluate the long-term effect of large fluctuations in the levels
of air pollution around a given mean value compared to small fluctuations
around the same mean.
Population studies involve the comparisons of groups of people residing
in different areas (spatial) or the change in certain measurements in the
groups over time (temporal). There is no guarantee that the populations
residing in different areas are anything like each other and lifelong exposure
is usually not considered. There are always possible errors and biases,
effects of response rate, effects of perception, and various methodological
problems of both a measurement and a statistical nature.
14-3
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Many epidemiological studies of the health effects of air pollutants rely
on descriptive methods. When possible, covariables and confounding variables
are described, and occasionally used in analysis. Health indices nay use
available data such as mortality statistics. Analytical approaches are more
likely to involve the collection of a greater amount of data on individuals
and more reliance on statistical analysis. They usually provide information
on other key variables in addition to the specific dependent and independent
variables (health indices and exposure levels, respectively). They usually
test specific hypotheses, searching for associations between occurrence of
particular diseases and potential causal agents. Prospective studies are
those which start with risk or causative factors and proceed to the disease.
They usually employ standardized statistical measurements and have better
contro,! of other variables. Retrospective studies (like case-control studies)
i
start with the disease and examine risk or causative factors. They encounter
difficulties in (1) ascertaining cases (a group of individuals who meet certain
criteria for the presence of a certain disease process) and controls, (2)
obtaining pertinent records, and (3) obtaining data on and measuring of risk
factors. Such studies, however, at times lack the best probability estimates
of risk. Epidemiological studies in the clinical setting, for example, involve
the use of clinical techniques on patient populations to assess the effect of the
249
environment on cases and controls.
3t/'z
Health risks may be evaluated, according to Lowrance (1976), in four
steps: identifying health effects; quantifying these effects at various
concentrations of pollutant; estimating the number of people exposed at those
concentrations; and calculating overall health risks associated with the given
degree of concentration. In this regard, it is more difficult to determine
the health effects of specific amounts of sulfur oxides emitted by specific
14-4
-------
sources, or suspended particulate matter of specific types emitted by specific
sources than it is to demonstrate a health effect of pollution in general. In
addition, acute, readily detectable effects and chronic and often delayed
effects due to cumulative exposures must be of concern. Also, there are
limits to relating the varieties of effects to combinations of pollutants,
isolating of the effects of individual pollutants, and isolating of air
pollution effects from other causal contributing factors.
Making valid observations of air pollution exposures are probably the
most difficult aspects of community studies. To make observation even more
difficult, there is lack of consistency in the measurement techniques used
over time in the United States and in other countries. (See Chapters 2, 3,
and 5.) No completely satisfactory methods, for example, have been devised
for deriving equivalency relationships among data for smoke, CoHs, or high-volume
results, although some efforts have been made (see Chapter 3). Also, the
specific measure of particulate air pollution (BS, TSP, CoH, etc.) most relevant
to health effects is not yet clearly established. Few particles greater than
15 urn in aerodynamic equivalent diameter appear to reach the lower respiratory
tract; but the possible significance of larger particles still needs exploration.
The relative importance of individual physical/chemical characteristics of
fine and coarse mode aerosols needs further exploration. (See Chapters 2, 6,
and 11).
In studying the health effects of particulate matter, one difficulty is
the variety of ways in which particulate pollution has been measured. Most of
the measurements of particulate matter made in Great Britain and on the European
continent have used the British Standard Smoke (BS) method. This is a nongravi-
metric method, using the light reflectance from a stained filter paper. The
reflectance is calibrated against a standard Coal Smoke and given in ug/m .
14-5
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In essence it measures the blackness of the spot. The interpretation of
standard smoke measurements is influenced by the relative prevalence of black
and white, grey, or other colored particulates. This method collects the
smaller particle sizes that can penetrate into and be deposited deeply in the
lung. Comparisons have been made in Great Britain between British Standard
Smoke and total suspended particulates (TSP) as measured by the high-volume
sampling methods; and TSP values have been found to generally be consistently
3
higher than BS values at BS levels below 500 ug/m , reflecting the fact that
high-volume samplers collect particles over a wider range of sizes. Some of
these particles are not likely to penetrate into the lung, but can be deposited
in the upper airways—nose and pharynx—where they can have an effect either
directly or secondarily when swallowed. From certain British data and other
analyses discussed in Chapter 3, a correction factor can be applied to "covert"
British Smoke data to total suspended particulates as measured by the high-volume
method, the measure of particulate pollution in many studies in the United
States. Other studies, especially in New York, have measured coefficients of
haze (CoH). Only limited information currently exists, however, regarding the
relating of this measure to TSP measurements.
There are very few pollutants which have been measured over long periods
of time in a great number of cities. This shortage of data is associated with
two related problems. First, to the extent that the variation in the available
air pollution data does not reflect the variation of all mortality- or morbidity-
inducing pollutants, the estimates of the effect of sulfur oxides and partic-
ulate matter may be biased. Ambient air pollution represents a complex mix of
materials, which makes the identification of the causative agent, or agents,
difficult. Thus, sulfur oxides or particulate matter levels may represent
indices of pollutant mixes containing other toxic agents more directly associated
with health effects found to vary with SO and particulate matter air concentrations
14-6
-------
A third feature of many pollution data sets is significant colinearity.
In general, places which have high particulate levels also tend to have high
SO- levels. Although this does not limit our ability to find a "pollution"
effect, it does limit an effort to partition the effect among the various
pollutants being considered. With coal burning, for example, concentrations
of S02 and particulate matter tend to fluctuate together, making it difficult
to separate the relative contribution of each pollutant to any effects seen.
An additional difficulty in relating air quality to health is the possi-
bility of a lag between an initiating exposure and its effect. The latency
between the initiating insult and the detection of cancer is often many years
and some health effects of air pollution may be subject to similar delayed
response. On the other hand, a high concentration of sulfur oxides or partic-
ulate matter may immediately initiate some responses. In reality, time lag is
a complex problem involving the weighted average of exposures in various time
periods. However, almost all studies use limited data on lagged exposure and
most use only current air quality to proxy the previous exposures. In serial
measurement studies, the failure to consider the appropriate lagged exposures
will probably result in biasing the estimated effect toward zero.
Many observational studies have estimated exposures from data obtained at
monitoring sites used to represent large areas, 2 to 5 km in radius. Thus,
measurements at these sites may not correspond to exposure for some individuals
in the area respresented. The estimate of exposure is even less representative
for persons working in other areas or significantly exposed at work. In
addition, most persons spend more time indoors where the air pollution mix can
be quite different.
14-7
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In serial measurement studies, the average exposure in the community may
not equal the ambient air quality at the monitoring site. However, if a
change in air quality at the monitoring site corresponds to a proportional
change in the community exposure, the monitored air quality can be used as a
surrogate for actual exposure. Cross-sectional studies present a different
problem when using data from a central monitoring site to measure exposure.
The relationship between community exposure and central station ambient air
quality may change from community to community. When many monitoring sites
have been selected to monitor sources, it is possible that the dependence
between community exposure and monitored ambient air quality is a function of
the air quality.
Many studies have found that meteorological factors help determine ambient
pollutant levels. Many studies have found that meteorological factors affect
health. There is obviously a complex interaction between meteorological
conditions and air pollutant levels in space and time. The meteorological
variables which have been shown to be critical include: temperature, relative
humidity, wind speed (and direction), precipitation, and the adiabatic lapse
rate. Also included are barometric pressure, solar radiation, and other
meteorological indices. Studies in which the meteorological variables are not
considered along with the pollutant levels or exposures are usually judged to
be lacking in critical information or in environmental factors which may
influence the health indices (as well as the factors which may influence the
pollutant levels themselves). Occupational exposure to pollutants can certainly
have a major effect on the host, and possibly on the host's family. Interactions
may also occur between the occupational pollutant exposure and the ambient
pollutant exposure. Thus, studies of acute and/or chronic effects of the
14-8
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S02/TSP complex should consider the occupational exposure effects as well.
Lifelong exposure to other pollutants from any source will influence chronic
diseases. Housing ventilation, filtration, the generation of pollutants in
Indoor environments, and temperature and humidity conditions 1n those environ-
ments will all have a relative role in the influence on human health. As
such, they play a significant role in the effects of the SO./TSP complex on
the health indices. The status of the host and the host's history and genetic
makeup will influence the ways the pollutants may have an effect and on what
indices.
In addition to the SO^/TSP exposure variables, and the health indices
(the independent and dependent variables, respectively), there are many
variables which may act as either covariables or intervening, confounding, or
spurious variables. In addition, there are temporal and spatial factors which
must be considered. Covariables are those factors which also help determine
occurrence of and variation in the dependent variable or the independent
variables. Intervening variables are those factors through which an independent
variable may have an effect on a dependent variable. Confounding variables
are those factors which, because of their direct or indirect relation to
either dependent or independent variables, have a tendency to confound the
picture unless they are taken into account. Spurious variables are those
factors which happen to be totally unrelated variables that fluctuate in time
or space in a parallel fashion to either the dependent or independent variable,
and thus may be associated with either one due to the influence of variable
tijne or the variable space (or similar variables).
It is important to eventually determine some form of quantitative relation
between the exposure dose and the health effect response. This will differ
14-9
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with regard to type of response and will always have a time component as an
additional dimension. Some attempts have been made to do this for health
245
status as a whole.
The quantification of dose-response relationships will yield a family of
curves specific for different health effects and specific for factors of age,
sex, etc., as well as for the addition of other environmental variables. This
hypothetical family of curves might show that a given increase in exposure
amount may increase the frequency of some effects, whereas those same amounts
may not increase other health effects. Susceptible populations may not only
have a curve that is higher than that for nonsusceptible populations, but it
may have a different shape. Extrapolation of dose-response curves is a form
of theoretical model building or hypothesis generation. Extrapolation does
not provide the empirical evidence of effect at any given level.
Dose-response curves could be utilized as sets of damage functions for
pollutants to be applied to the dose estimates for all segments of the popula-
tion. Data gaps may require judgments and assumptions to be used in order to
derive estimates of relationships occurring within those gaps. Although only
estimates, they may be useful to suggest what changes in dosage may lead to a
relative change of effects in the population exposed. Absolute change estimates
may be more speculative. Certainly in a qualitative sense, one would continue
to expect decreases in overall risk for those effects with decreasing pollutant
levels.
Demographic and anthropomorphic measures are usually covariables. Disease
occurs differentially in males and females, and at different ages. Disease
may occur differentially in different race or ethnic groups independent of
social status. Height and weight (body mass) have been shown to be highly
14-10
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pertinent in terms of functional characteristics such as lung volume and
pulmonary flows.
Smoking should be a key variable in the examination of the effects of
pollutants on the health indices. Other behavioral variables which may influence
the status of the host or susceptibility to certain diseases include: alcohol
consumption, diet, exposures in recreational activities and hobbies, exercise,
other recreation and other activities including vehicular driving.
Biological factors in the host which will influence the effect of pollu-
tion on the health indices include: resistance, susceptibility, immunity,
present disease of the type being studied, and co-morbidity. Often these are
not measured or measurable. Co-morbidity and present disease, however, should
be known and considered. Familiar factors, including genetic factors, and
exposure to microbes that can produce acute illness, also play a role in the
status of the host, and thus, the potential pollutant effects.
Social economic status and cultural factors will also influence the host,
not only in terms of the possibility of an effect of a pollutant on a host,
but also the perception of the effect and the medical care received by the
host. In comparing different areas, socio-cultural differences are often
critical.
The MRC questionnaire or variations thereof has come to be the most
commonly utilized tool to derive health indicators of respiratory disease.
Such questionnaires generally include information on demographic variables,
anthropomorphic variables, acute and chronic respiratory disease history, and
may also seek information on family respiratory history, occupational exposure
249
histories, and residential histories. Standardized questionnaires have
become the tool of choice. Some inter-observer variability with the MRC
14-11
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questionnaire, however, has been noted; and variations have been noted with
self-administration of the questionnaires. Nevertheless, comparisons of
interviewer- and self-administered questionnaires have generally found good
agreement, (c.f. Wiggins, 1974; Lebowitz, 1980).
Questionnaires to derive information on acute changes (diaries) have been
developed. The period of recall is considered critical. Such diaries have
been utilized most effectively in conjunction with medical practices, house
visits, phone calls, and pulmonary function testing. Frequent monitoring and
follow-up with direct contact (visits or calls) are considered necessary.
Motivated and understanding subjects have improved the amount and quality of
234 249
the response. '
The most commonly used pulmonary function tests in epidemiological studies
are peak flow and spirometry. The peak expiratory flow rate (PEF or PEFR) is
the maximum flow rate during a maximum expiratory flow volume (MEFV maneuver).
The instrument in general usage is the Wright peak flow meter. It is used
often to measure serial changes. It predominately shows large changes in
upper airway function. It has a great deal of variability and poor ability to
be calibrated. However, it is a useful adjunct of acute studies; it is not
234 249
otherwise generally suggested. '
Spirometry tests normally measure the forced vital capacity (FVC) and the
forced expiratory volume (FEV). They are the simplest, most repeatable,
valid, and among the most discriminating tests reflecting mechanics of
234 249
breathing. ' The subject must be coached through the MEFV maneuver.
Other tests have been used occasionally. These are more complex and are
used in specialized studies to look at different properties of lung
mechanics.234'249
14-12
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Observational studies of the health effects of air pollution are sometimes
viewed as natural experiments in which the exposure to pollutants varies over
groups or over time. However, this view overlooks the effects of other factors
influencing mortality or morbidity which may also vary over the study units.
These factors are typically not subject to control by the investigator.
Ideally, the influence of such variables is minimal and can be quantified. In
231
practice, this ideal is not always achieved.
Cross-sectional prospective studies compare health index differences to
air pollution levels during the same time period across several locations.
Such studies attempt to relate differences in community health indices to
differences in air quality across communities. The adjustment for concomitant
variables such as age, personal habits, and occupation is the most sensitive
part of the analysis of cross-sectional data. Retrospective studies start
with the disease and seek risk or causative factors. They encounter difficulties:
(1) in ascertaining cases (a group of individuals who meet certain criteria
for the presence of a certain disease process) and controls; (2) in terms of
the inadequacy of the records utilized; (3) in obtaining and measuring risk
factors; and (4) in the lack of true probability estimates of risk. Prospective
studies are those which start with risk or causative factors and proceed to
the disease. They usually employ standardized statistical measurements and
have better control of other variables.
Randomization cannot be used in all cases to avoid selection effects.
The influence of extraneous factors is sometimes partially controlled by
studying population groups which are as similar as possible and which are
exposed to similar environmental conditions except for air pollution level.
Typically, investigators also use some method of adjustment to correct observed
14-13
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associations between sulfur oxides or particulates and the health measures for
differences between populations or over time in these extraneous factors. The
adequacy of these adjustments depends entirely on the selection of factors and
their interrelationships. Moreover, the degree of success in adjusting for
selection effects is unknown. Therefore, replication and reanalysis of studies
are essential to establish a pattern of association while minimizing selection
effects.
Although there have been many literature reviews on S0x and particulate
matter effects>245-248,251,301,304,107, 311, 313,314 thgy do not a]1 su1t the
purposes of an air quality criteria document. A more exhaustive and less
personal review assessment than appears in some is necessary. As a starting
point in the present assessment, important information discussed in Chapter 3
is summarized regarding critical appraisal of SCL and particulate matter air
quality measurements employed in community health epidemiology studies evaluated
in this chapter. Then, the ensuing discussion of epidemiology (community
health) studies is subdivided into three main subsections: Section 14.3 deals
with mortality studies; Section 14.4 discusses studies relating morbidity to
short-term pollutant exposures; and Section 14.5 discusses morbidity associated
with long-term studies. Within each of these chapter subsections, a number of
different health end points are discussed. For example, under the mortality
section, studies of effects of acute air pollution episodes on deaths and
death rates are delineated, as well as studies on long-term mortality trends.
Under both the long- and short-term morbidity sections, studies are discussed
which deal with health end points such as chronic bronchitis, respiratory
diseases, pulmonary function, and aggravation of cardio-pulmonary symptoms.
The main focus of this chapter is to describe the studies used and consider
the interpretation of individual study results.
14-14
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14.2 AIR QUALITY MEASUREMENT CONSIDERATIONS
The critical assessment contained in Chapter 3 of this document regarding
practical applications of measurement approaches employed in Great Britain and
the United States for determinations of air concentrations of oxides of sulfur
and particulate matter are concisely summarized here as background Information
important for the ensuing discussion of community epidemiology studies. The
information presented in part concerns published information on the relative
specificity, sensitivity, accuracy, precision, and reliability of the methods
discussed when used under optimum conditions in the hands of technically-expert
analysts. Much more emphasis, however, is placed on evaluation of results
actually obtained in the course of practical applications of the measurement
methods, often by less technically-skilled personnel. That evaluation draws
mainly upon published commentary on quality control assessments for the different
applications. Also, the major focus here is on British and American air
measurement approaches most widely used in acquiring S02 and particulate
matter data utilized in published quantitative community health studies of
interest later.
14.2.1 British Approaches .•??,•
14.2.1.1 British SO^ Measurements—As noted earlier, the lead dioxide gauge
was used extensively in Britain during the years prior to 1960. However, use
of the hydrogen peroxide method was gradually interspersed with the lead
dioxide gauge during the course of the 1950s, often being coupled in tandem,
as it were, with the apparatus for smoke measurements. Much of the early
(1950s) British epidemiology data discussed later in this chapter has been
related to S0? measurements obtained by the hydrogen peroxide method, especially
where 24-hr S0? values are used. Nevertheless, it is useful to compare the
14-15
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results obtained with the two methods, since some British air quality data of
historical interest are derived from the lead dioxide method.
In 1962, as part of the establishment of the British National Air Pollution
Survey, a working party was set up to compare the lead dioxide gauge with the
hydrogen peroxide method, which was then chosen as the standard method for use
&/
-------
v>
tu
E
X
O
5
o
u
S
7
> 6
$ B
§
8 4
*n _
O **
r 2
REGRESSION LINE
95* CONFIDENCE LIMITS
• • : i s*T\ l *
\: : wf::. ' ".'-'
'
I i ! ' V '
0 100 200 300 400 BOO 600 700
CONCENTRATION OF SO2 BY THE HYDROGEN PEROXIDE METHOD pg/m3
Figure 14-1 A comparison of lead dioxide and hydrogen peroxide methods for
sulfur dioxide showing wide variations between simultaneous
measurements. The solid line is the regression line, and the
dotted lines are the 95 percent confidence limits. From WSL
14-17
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In other words, estimates of SO,, levels derived from lead dioxide
sulfation rate measurements, especially 24-hr estimates, can only be roughly
compared with S02 estimates obtained by the hydrogen peroxide method at other
geographic sites or at later times at the same location(s). Also, from the
data in Figure 14-1, comparisons between sulfation rate readings may only be
meaningful when such readings differ by the equivalent of about 180 ug/m of
SOp. Some of the types and magnitudes of errors encountered in the British
application of lead dioxide gauges to measure S02 levels are summarized in
Table 14-1. As shown in Table 14-1, several problems (e.g., humidity and
temperature effects) result in the lead dioxide method being essentially
useless for 24-hr, measurements and in their otherwise having a rather large
(±180 ug/m 20) error band associated with them.
Based on some of the above problems, when the National Survey began in
1961 it was recognized that the lead dioxide method could not provide the
24-hour SOp measurements necessary for correlation with mortality and
morbidity effects investigated by epidemiology studies. The hydrogen peroxide
method for S02 was, therefore, adopted as being more valid than the old lead
dioxide gauge sulfation method. Because many of the staff making the
measurements would be the same people who had been servicing particle deposit
gauges and the lead candles without detailed technical knowledge of the
£{/,£•
analyses, however, an Instruction Manual (IM) issued by WSL in 1966 had to be
quite detailed and clearly readable by people with no training in analytical
techniques.
As mentioned above, the lead peroxide method was selected because its
sensitivity, reliability and precision were demonstrated to be much better
than that obtained in comparison to the lead dioxide method. More
14-18
-------
TABU M-1. SUWARY or CVALUATIM or SOURCES. WWHTWK. <•*
ASSOCIATED WITH BRITISH SOj MEASUREMENTS
TIM
period
Beasui se»nt
o»thod
Reported
of erro'
Direction and a»gn1t«da of
reported error
British SOj data
lead Dioxide Humidity (RH)
Teeperature (T)
Wind spaed (WS)
19H-1MO
(British National
Air Pel. Survey)
Hydrogen
Peroxide
Reectlen rote Increase* with RH.
Rcectlon rate Increoses 2X
per 5* rise.
Reaction rate Increases
with WS.
(Overall
Siting of Senate line
Intake:
a. too near boiler chlemyt 50 - 100 pf/ar overostleatlon.
b. too near vegetation 50 - .70 percent undorestleatlon.
Saaplo line Adsorption:
a. Good care t cleaning 10 ug/eT vaderestlaetlon. .
b. Averoge care 20-25 ug/n low froo 50 ug/B .
c. Poor car* (Insects, dirt) Probable greater underestleatlon.
Flow Meter Problem*:
a. Dally norawl condition*
b. B-port onlt with only
one weekly flow roadlng
Allowoble Filter Clean
leakage
Poor Cleap Care ft Tochnloue
t 3 percent variation.
t S percent variation.
1-2 percent enderoatleatlon.
S-10 percent «ndere*t1oat1en.
Crede • Classware Usage 2-5
laproper Alkalinity Buffering S-10 ug/ai' underestlMtloo.
40 ug/er low froa 50 pg/e
C02 In Deelnerallted In
Ataeipnarlc Aanonl*
eonthly Man.
tu
<80
oii on 101 «f
er aaeiilef 1n orfean areas.
^/m low on
on Ind. days t 40
lav tvntnly •!•••<• Man In
country areas.
error In d»tor«inat1o«.
THratlon Error:
a. Moroni-sharp color »5
change of Indicator et
pH 4.5 .
b. Gradual color change of *10 »»/•* error In determination.
Indicator at pH 4.5 .
c. Rounding off to 0.1 •! *5 Kt/"J error 1n eetnrolnetlen.
of alkali voluot added.
evaporation of reagent:
<15 vt/m everestlewtloB,
'especially In suaer anntnt.
Variable positive blot, eopoclally In aoaw.
Variable positive bias, especially In tMswr.
Variable positive blM. isnder high wind cond.
Con be s* to i 180 u»V
OccMlanel (prob. rare) poeltlvo blao.
Occasional (prob. rare) negative bias.
Possible general 10 pg/ta3 nogetlve b1a
Occasional 40-501 negative bias.
Likely rare 50-90S negative bias.
•vjgllglble 1a»ect. fritmit tM av«c1s1en
of data.
•SX negative bios en Mgh SO.-tS «qre.
•9 positive bios on low $0*1$ days.
Nagllglble 1se
of deu.
likely occMle
ct.
el
od tl* precision
nefetiv* bias.
Negligible *_v. .
Occasional 5-10 pg/er negative blea. fc
Occasional negative bios of up to BOX.
>» Mfe net. bias ea> 101 of saewr
~sss9les In ur*>en area*.
Occasional neq. bias In coentrv eroes-
•p to BO •»/• dally data k ep to 1001
eonthly even In suaaer.
Pisie»« t S **/• precis Ion of *Ma.
* 10 (Pf/a* precision level. c
Added t S pa/ej precis la* error.0
13-100X pea. bias for SO. data <1M > .
7.5-1M pos. bias for SO* of 100-700 (**•».,
J.»-7.5X pos. bias for $0- of 2OO-400 »•/•I*.
O.25X pos. bias for S0 dlta >400 ug/o .
Teetteratvre and Pressure:
a. Corrections • nereis I
b. large AP at filter
n tmderettlMtlen.
101 underestimation.
eonorel V nog. bias In SO, data.
Occasional - tlOX negative bias 1n SO, dot*.
*0ata free 1W5-1W0 eott clearly lopacteel.
^Oate froe 196«-19C7 eatt clearly Impacted.
e*t <50 ufl/«J -ncertalnty due to these two errors Is - 7 ug/-3 or 14*. Thet It. *W of the date ere wltMn 14* end 5X ere >tM In error.
-------
specifically, the British Standard for sulfur dioxide determination by the
hydrogen peroxide method states that replicate determinations can be expected
to be within ±20 ug/m3 for concentrations up to 500 mg/m and within ±4 percent
for concentrations above 500 ug/m ; and an OECD Working Parting stated the
accuracy of the method to be ±10% at levels >100 ug/m3. However, as summarized
in Table 14-1, numerous sources of errors have been encountered in the practical
application of the method in collecting data for the British National Survey
over the past 15-20 years.
Certain of the sources of error listed in Table 14-1, it can be seen,
resulted in relatively small errors, whereas others produced errors ranging up
to 50-100% in magnitude. Also, some errors appear to have been restricted to
affecting data from only limited locations (usually unspecified as to specific
names of localities) or during only limited time periods. Many of these types
of errors appear to have been detected fairly quickly and steps taken to
successfully correct or minimize them. Still other sources of errors exist
(e.g., those from reagent evaporation), which have likely affected essentially
all British National Survey S02 data. Some of these appear to remain uncorrected
to this date, in some cases more than 10 or 15 years after they were first
detected and brought to the attention of Warren Spring Laboratory officials
responsible for overseeing quality control for the entire National Air Pollution
Survey. See Chapter 3 for a more detailed discussion of each type of error.
Taking the above information into account for present purposes, it would
be extremely difficult to determine precisely which errors affected particular
National Survey data sets employed in British epidemiology and other studies
discussed later in this chapter. That would likely require a thorough examina-
tion, on a time- and site-specific basis, of records detailing information on
14-20
-------
how each pertinent data set was collected and WSL quality control assessment
reports for the data sets. Alternatively, in later evaluations of British
epidemiology studies one could accept the following overall evaluation and set
of conclusions by the WSL (1975) regarding British National Survey air pollution
data (emphases added):
The actual degree of accuracy attained in the Survey is not known.
Input data are scrutinized by WSL staff, and subjected to computer
checks, and any reflectances, titres, or air flows which are abnor-
mally high or low or show unusually abrupt changes from one day to
the next are queried and data known to be invalid are excluded from
the annual summary tables. Such checks can however eliminate only
some of the gross errors. More information will become available on
accuracy when current (1974) plans to institute additional quality
control, e.g., on reagent solutions, are put into operation.
However, although the accuracy of the Survey data cannot at present
be quantified, many of the errors discussed in the previous para-
graphs will cancel out when data are averaged over periods of a few
months or a year, or for groups of sites. The remainder tend to
show up as anomalies when data are compared with past or subsequent
data at the same site or with data from other sites; anomalies of
this kind have been commented upon throughout the Reports. Members
of Warren Spring Laboratory staff have devoted a large effort over
the years to site visiting and checking on procedures. It is their
experience that the vast majority of the instruments are maintained
and operated with reasonable care^and accuracy. The Laboratory is
therefore confident that the accuracy is sufficient for the type of
data analyses carried out in the present series of reports.
Presumably, it is the opinion of the WSL and British epidemiologists that the
accuracy of the survey data is also sufficient to meet the original objectives
of the Survey, ie. to assess the benefits accruing from the Clean Air Act of
1956, which requires use of the survey air quality data along with community
health endpoint evaluations in order to define quantitative air pollution/health
effects relationships. That this presumption is likely correct is further
attested to by the long history of reliance on these data by British epidemio-
logists, such as in the making of statements regarding such quantitative relation
ships in innumerable journal articles and reviews appearing during the past
twenty years, up to and Including the very recent review by Holland et al. (1979)
14-21
-------
14.2.1.2 Dally Smoke Measurements of the United Kingdom National Survey—The
general technique for the British Smoke shade (BS) measurement 1s described in
detail in Chapter 2, and a detailed critical assessment of the measurement
procedure is provided in Chapter 3 to allow for evaluation of the precision,
accuracy, and reliability of the measurements. Also, details of the BS
measurements are provided by an Instruction Manual (IM) issued by (Warren
Spring Laboratory in 1966. At the start of the National Survey in 1961 (WSL,
1961) it was recognized: "The daily instrument, while comparatively simple in
design and operation gives reliable results TT\ good hands* and seemed the best
choice for the National Survey." WSL circulated the specifications of the
apparatus and methods to all the cooperating organizations as careful, uniform
work was essential if the results from the different sites throughout the
country were to be comparable. However, WSL found that detailed instructions
were necessary as most of the Local Authority staff making the measurements
had no training in analytical techniques. These methods were reviewed by an
O.E.C.D. Working Party and a report "Methods of Measuring Air Pollution"
(OECD, 1964) was prepared, which was accepted into the British Standards
Specification 1747, Parts 2 and 3. The Manual of Instruction (WSL, 1966)
incorporated the improvements in techniques, "but apparatus and procedures are
specified in much greater detail to assist operation by observers with no
technical knowledge."*
Partly due to the lack of analytical training of survey monitoring site
operators, and other factors as well, various errors were encountered in
carrying out BS measurements for the National Survey.
'Underline added for present emphasis.
14-22
-------
Table 14-2 summarizes information discussed in Chapter 3 on the sources,
magnitudes and directional biases of errors associated with British smoke
measurements during the past 30 to 40 years. For example, prior to 1961, the
use of weights for sealing purposes led to highly variable errors 1n BS
measurements due to leakage at filter clamps, and steps were taken to require
screw-down clamps as standard procedure as part of the later British National
Survey work implemented after 1961. It is not clear to what extent any specific
British BS data sets from the 1950s may have been affected by the clamp leakage
problem, but one must assume that such errors could not have often been very
large or serious and that the WSL took appropriate steps to eliminate or
invalidate any data in gross error as they were detected via their quality
control efforts in the late 1950s. Analogously, there is evidence that WSL
did take steps to inform users of pre-1961 BS data of errors arising from (1)
comparing reflectance on filters to photographs of painted stains and (2) use
of reflectance readings below 25 percent, where the stain was too dark to use
the Clark-Owens DSIR curve. However, it also appears that only a few investigators
(e.g., Commins and Waller, 1970) took steps to go back and correct published
reports based on the affected pre-1961 data and to publish revised analyses
taking into account corrections for the pre-1961 data errors.
Probably of much greater concern than the pre-1961 BS measurement errors
are those encountered after the establishment and initial implementation of
the British National Survey in 1961. These include certain errors, e.g., the
"computer error of 1961-1964," which were eventually detected by WSL and
resulted in steps being taken to correct affected BS data in National Survey
data banks. It is clear, however, that whereas users of the affected data may
have been informed of such errors by WSL, virtually none of them have taken
14-23
-------
TABLE 14-2. SUMMARY OF EVALUATION OF SOURCES, MAGNITUDES, AND DIRECTIONAL BIASES OF ERRORS
ASSOCIATED WITH BRITISH SMOKE (PARTICULATE) MEASUREMENTS
Time
period
Measurement
method
Reported source
of error
Direction and magnitude
of reported error
Likely general Impact
on published BS data
1944-1950s
Pre-1961
Smoke filter
1961-1964
1964-1980
Leakage at clamp.
Weights used to make the
seal.
Highly variable under-
estimation of BS levels.
Depending upon observer
and value of R.
Comparing reflectance to
photographs of painted
standard stains.
Reflectance (R) below 25%, 50-100% underestimation.
stain too dark with use
of Clark-Owens DSIR curve.
Computer not following
proper calibration curve.
Clamp correction factor
for other than 1-inch
clamp.
Flow rate - normal 1 day.
Flow by 8-port with 1
reading per week.
Variability of reading
reflectance.
Averaging reflectance
Instead.of averaging
mass/cm .
Use of coarse side of
filter facing upstream.
<80% underestimation at low
R 1f not corrected by WSL
(See Moulds.1961) and
discussion of clamp size
correction factor.
Uncertain; derivation
cannot be verified.
Possible +20%.
+3% variation.
r!0% underestimation.
+10% overestlmation.
+2 units of R
Highly variable under-
estimation due to non-
linearity of R.
6-15% underestimation.
Probable widespread highly
variable negative bias.
Probable widespread relatively
small negative bias.
Occasional 50-100% negative
bias in some data sets.
Negligible for BS <~100 ug/"»3-
Increasing negative bias up to 80%
as BS values increase over 100
Possible underestimate for 2-inch
and 4-Inch clamps
Possible overestimate for 1/2-Inch
and 10 rm clamps.
Presumed ± 3% precision level.
10% negative bias on high BS days.
10% positive bias on low BS days.
Error Increases with BS level fro»-±10%
at 50 ug/KT up to ±20% at 400 ftg/m .
Probable small negative bias at low
BS levels, could be large at high BS.
Occasional negative bias of 6-15%.
-------
TABLE 14-2 (continued).
Time
period
Measurement
method
Reported source
of error
Direction and magnitude
of reported error
Likely general Impact
on published BS data
Reading of wrong side of
stained filter.
Leakage at filter clamp
a. Normal, with good care
b. With Inadequate care.
c. Careless loading where
uneven stains are
produced.
Use of wrong clamp size
a. Stain too light R>90%.
b. Stain too dark R<25%.
50-75% underestimation.
1-2% underestimation.
2-8% underestimation.
10-20% underestimation.
i
ro
in
Highly variable over-
estimation.
Highly variable under-
estimation.
Occasional negative bias
of 50-75%.
General 1-2% negative bias.
Occasional 2-8% negative bias
Occasional 10-20% negative bi
Data usage not recommended.
Data usage not recommended.
-------
steps to (1) alert recipients of publications containing analyses based on the
affected data of the likely inaccuracies or ranges of error Involved; (2) to
reanalyze the study results based on the affected data sets; or (3) to reissue
or publish anew any revised analyses. In fact, even some Warren Spring Laboratory
quality control literature prepared and published during the 1960s or 1970s
and still in use may contain incorrect information and recommended standard
procedures for BS measurements based on analyses "contaminated" by computer
errors or other problems summarized in Table 14-2 and discussed in more detail
in Chapter 3.
In regard to determining which British BS data sets and related epide-
miology studies are affected by different post-1961 National Survey errors, it
is again presently very difficult, as was the case with British S02 measurements,
to specify with any confidence the nature and magnitude of specific errors
impacting particular studies. This would probably require thorough examination
of records and WSL quality control reports concerning each of the pertinent
data sets. On the other hand one can project that certain data sets and
British epidemiology studies were almost certainly affected by some subset of
BS measurement errors and these are taken into account in evaluating such
studies later this Chapter. For example, published reports o^ the "Ministry
fe*- %
of Pensions" (1965) and Douglas and Waller (1966) studies contain specific
reference to usage of National Survey data from the 1961-64 period and,
therefore, the results of those studies should be reevaluated in light of
measurement errors reported by the WSL for that period.
14.2.2 American Approaches
14.2.2.1 American SO,, Measurements—Turning to American measurement approaches,
different types of measurement methods for a given pollutant were adopted by
14-26
-------
various local, state, and federal agencies in establishing or expanding air
quality monitoring systems that proliferated across the United States during
the 1950s and 1960s. Rather than discuss methods used for S02 measurements by
all of the different American air monitoring systems, main emphasis 1s placed
here on the discussion of only certain key American applications of measurement
methods for S0x that are of crucial importance for later discussions of quanti-
tative relationships between health effects and atmospheric levels of sulfur
dioxide. These include mainly applications of SO^ measurement methods as
employed in the EPA "CHESS Program" as the single largest attempt to define
quantitative relationships between air pollution and health effects.
In regard to sulfur oxides measurement approaches used in the United States,
lead dioxide or other "sulfation rate" measurement methods were, as in Britain,
widely employed prior to the early 1960s for assessing SO- air levels. However,
probably to a somewhat greater extent than in Britain, sulfation rate measurement
techniques continued to be used later into the mid or late 1960s by some
monitoring programs in the United States or in connection with certain community
health epidemiology studies, as discussed later in this chapter. As shortcomings
of the "sulfation" methods became more widely recognized, however, their use
was generally abandoned and more specific methods for the measurement of SOp
or other sulfur oxide compounds were adopted, as was done in Britain. The
hydrogen peroxide acidimetric method (see OECD, 1965) selected for use in the
British National Air Pollution Survey, however, was not very widely adopted in
the United States for S02 measurements. Rather, versions of West-Gaeke (1956)
colorimetric procedures were much more widely used in the USA. Conductivity
measurements for S02 (Adams et al., 1971). based on an acidimetric method
adaptation often used in automatic instruments and most suitable for measuring
14-27
-------
periods of around 24 hours, later began to be applied in the operation of some
American air monitoring networks in the 1970s.
The West-Gaeke method was the method mainly employed in the EPA "CHESS
Program" for determining SOp air levels for inclusion in analyses of community
health end point data in "CHESS" epidemiology studies. The application of
that method in the CHESS Program was accordingly most thoroughly discussed in
Chapter 3. The types of errors in measurement associated with CHESS SOp data
are summarized in Table 14-3, along with notation of some factors affecting
earlier sulfation methods. Much of the information on the former subject is
. /j
derived from a 1976 Congressional Investigative Report (IR; which contained a
thorough evaluation of EPA CHESS Program air quality measurements and other
aspects of the Program.
Looking at the types of errors associated with earlier American use of
sulfation rate lead dioxide methods, similar effects of temperature, humidity,
etc. , as affected analogous British SOp methods are seen to apply here to
American data as well.
Turning to American applications of SOp measurements since the widespread
abandonment of sulfur dioxide sulfation rate methods in the mid to late 1960s,
several different types of errors were identified as being associated with EPA
CHESS Program SOp measurements via a thorough evaluation of the CHESS Program,
irt
as reported in the IR (1976). As can be seen, the magnitudes of some errors
in CHESS SOp measurements spanned about the same range as those seen for
British National Survey SOp measurements and, at times, derived from analogous
sources of error, e.g., evaporation or other loss of reagents. In the case of
the American CHESS Program data, however, the specific overall impact of the
various detected errors on particular CHESS data sets appears to have been
/»?
more definitively defined by the work of the IR (1976); more specifically, it
14-28
-------
1944-1968
TABLE 14-3. SUMMARY OF EVALUATION OF SOURCES. MAGNITUDES, AND DIRECTIONAL BIASES OF ERRORS
ASSOCIATED WITH AMERICAN SO. MEASUREMENTS
T1M
period
Measurement^
method
Reported source
of error
Direction and Magnitude
of reported error
Likely general Impact on American SO. data
Lead dioxide.
Humidity (RH).
Temperature (T).
Wlndspeed (WS).
Saturation of Reagent
(sulfatlon plate mainly).
Reaction rate Increases with RH.
Reaction rate Increases 2X per 5°
rise.
Reaction rate Increases with WS.
Variable underestimation beyond
pt. where 15X of PbO, on plate
reacted. J
Variable positive bias, especially 1n summer.
Variable positive bias, especially In sumer.
Variable positive bias, especially In summer.
Possible large negative bias, especially for 30-
day samples for summer Monthly readings.
t
ro
vo
1969-1975
(EPA CHESS
PROGRAM)
West-Gaeke
Pararosanallne.
(Overall Errors).
Spillage of reagent
during shlpnent.
T1*e delay for reagent-
50. complex.
Concentration dependence
of sampling method.
18X of total volume SOX of tine;
occasional total loss
SO, losses of 1.0, 5, 25, and
75X at 20, 30, 40, and 50°C,
respectively.
Underestimation of unspecified
Magnitude at dally SO, >200
Generally wide ± error band associated with data.
Possible negative bias up to >100X. mainly 1n
summer, with 30-day reading.
Half of SO
mean of
0, data likely negatively biased by
17X; some up to 100X.
Usually small (
-------
appears that the CHESS data generally tended to be somewhat negatively biased
in comparison to other local or state S0? data from monitoring sites proximal
in
to the CHESS sites, with the local and state data judged by the IR (1976) to
be reasonably accurate and reliable. The specific magnitude of the negative
bias for particular years of CHESS data is summarized in Table 14-3, and
appears to have been around 30-40% in some circumstances and up to around 100%
in other cases.
14.2.2.2 American High-Volume TSP Sampling Measurements
As discussed earlier, the hi-volume TSP sampler, since its development in
the early 1950s, has been the instrument most commonly used in United States
for measurement of atmospheric particulate matter; and high-volume TSP readings
have most typically been used in American epidemiology study evaluations of
associated air pollution-health effects relationships. In contrast, other
particulate matter measurement approaches (e.g., the coefficient of haze
method) saw only relatively limited application during the 1950s and early
1960s in certain American locations and were infrequently used in estimating
quantitative relationships between airborne particulate matter and health or
welfare effects. Accordingly, major emphasis is placed below on the critical
appraisal of certain key applications of hi-volume TSP measurements in the
United States. As before, in discussing American applications for measurement
of oxides of sulfur, the present summarization focuses most heavily on evaluation
of applications of TSP measurement methods employed as part of the EPA "CHESS
Program," as the single most extensive and comprehensive use of such methods
as part of American community health epidemiology studies. Much of the information
is derived from the 1976 Congressional Investigative Report (IR), which included
a thorough analysis of EPA CHESS Program TSP measurements and comments regarding
certain local or state TSP measurements.
14-30
-------
The main sources, directions and magnitudes of errors identified as
possibly affecting American TSP measurements are summarized in Table 14-4. In
addition to various sources of minor errors inherent to the basic TSP sampling
method, certain other nuances of procedures included in the Federal Reference
Method (40 CFR 50, Appendix B) may have resulted in the introduction of an
additional slight negative bias in TSP data obtained by American researchers.
This, more specifically, pertains to the manner in which flow rate calculations
are made upon which final TSP concentration determinations are based.
The Federal Reference procedure calls for the averaging of the initial
and final recorded airflow rates. However, as described in Appendix 3-A of
Chapter 3, the uncontrolled flow rate drops more rapidly at the start of the
run than at the end of the run. Therefore, a linear approximation leads to an
0^^^ (ia&tet&Zlter &~£d£?d£*j£s*'
overestimate of the/^flgw rate, which will reduce the jnea^uped value. Consequently,
all TSP data computed in this manner have a slight negative bias which is
likely usually of the order of 5 percent; on occassion, however, under circumstances
3
where the flow rate may have fallen below 40 ft /min, larger errors (up to
approximately 15 percent) may have been introduced. Assuming that monitoring
site operators in the United States adhere to the recommended Federal Reference
Method procedures, then this type of bias is likely inherent in essentially
all American TSP data collected without flow rate control or recording.
Despite such problems, it can be seen that the maximum range of uncertainty
derived from the various errors associated with American TSP measurements is
generally less than 20 percent in either a positive or negative direction on a
random (±) basis.
14-31
-------
Time
period
TABLE 14-4. SUMMARY OF EVALUATION OF SOURCES, MAGNITUDES, AND DIRECTIONAL BIASES OF ERRORS
ASSOCIATED WITH AMERICAN TOTAL SUSPENDED PARTICULATE (TSP) MEASUREMENTS
Measurement
method
Reported source
of error
Direction and Magnitude
of reported error
Likely general Impact
on published TSP data
1954-1980
Staplex HI Vol TSP
i
oo
ro
Tim* Off (Due to power
failure).
Weighing error.
Flow Measurement (with
control).
Flow Measurement (without
control)
a. Constant TSP—Average
of flows.
1. Low TSP level.
2. High TSP level.
b. Rising TSP-Average of
flows.
c. Falling TSP-Average of
flows.
Aerosol evaporation on
standing.
Condensation of water vapor.
Foreign bodies on filter
(Insects).
Windblown dust Into filter
during off-mode.
Wind speed effect on pene-
tration of dust Into the
HI-Vol shelter.
Wind direction effect due to
HI-Vol Asymmetry
Artifact formation, NO,
SO' 3
Variable underestimation.
±2X random variation.
12X random variation.
2X underestimation.
5-10X underestimation.
10-20X underestimation
10-20X overestlmatlon.
1-2X underestimation.
5X overestlmatlon.
Generally small over-
estimation.
Generally small over-
estimation.
Less penetration at high
wlndspeed.
Higher penetration when
normal to sides.
5-10 ug/m overestlmatlon.
Negligible Impact, rare negative bla*.
Negligible Impact.
Negligible Impact.
Negligible Impact.
Possible 5-lot negative bias.
Possible 10-20X negative bias.
Possible 10-20* positive bias.
Probable negligible Impact.
Possible 5X positive bias.
Possible 5* positive bias.
Occasional (rare) positive bias.
Occasional (rare) negative bias.
Probable Increase 1n random (i) error.
Occasional positive bias.
-------
TABLE 14-4 (continued).
T1M
ptrlod
Measurement
Method1'
Reported source
of error
Direction and Magnitude
of reported error
Likely general Impact
on published TSP data
1969-1975
(EPA CHESS
PrograM).
Fed. Reference
Method Standard
HI-Vol Sampler
Loss of sampling Material
In field.
Loss of sampling Material
1n Mailing.
Evaporation of organic sub-
stances.
Vlndflow velocity and
asytmetry.
(Overall errors).
No specific estimate of
Magnitude of error; but
would be underestlMatlon.
Reported 4-25X apparent
loss; MBX. likely due to
crustal (sand, etc.)
fall-off froM selected
Utah saMplIng sites.
No specific estlMate of error
Magnitude, but not likely to
exceed 5X underestlMatlon.
No specific estlMate of error
Magnitude; but Most likely to
Increase randoM variation or
SMall underestlMatlon.
Probable slight negative bias
In Utah winter data. No known iMpact
on other CHESS TSP data.
Probable general small <10X negative bias;
occasional 25% negative bias.
Probable slight negative bias
of <5X for TSP data fro* urban/
Industrial areas.
Negligible iMpact or slight
negative bias.
Generally <10X negative bias;
occasional 10 to 3OX negative bias.
i .
u> As suMMarlzed by Congressional Investigative Report (IR).
-------
Errors in addition to general TSP measurement errors reported by the 1976
Congressional Committee Investigative Report (IR, 1976) to affect CHESS Program
TSP measurements during 1969-1975 are broken out and listed seperately in
Table 3-5. Some of those errors (e.g., loss of sample materials 1n filter
removal from the field monitoring apparatus) were reported by the IR (1976) as
likely affecting only very restricted CHESS data sets. Others, e.g., errors
due to loss of sample in mailing, appear to have been more widespread and
presumably impacted on many CHESS data sets. It is interesting to note,
however, that the IR (1976) concluded that the net effect of all of the errors
was to introduce, in general, a slight negative bias of 10 to 30 percent into
CHESS TSP data, which is not much beyond the range of different types of
errors (e.g., linear flow corrections) more generally associated with American
applications of TSP measurements. Section IV C 3 of the IR (1976) further
concluded that:
"...the TSP data were by far the best quality data taken in the
CHESS monitoring program. Differences measured between High and Low
sites are probably reasonable estimates of the differences of TSP
exposures as received by populations in these areas."
It appears reasonable to concur with the IR (1976) and, accordingly, to
accept CHESS TSP measurements as reasonable estimates of TSP exposures of
CHESS Program community health study populations, taking into account that
J^
such data may by biased low by no more than 10 or. at mojt. 30 percent.
14.3 AIR POLLUTION AND MORTALITY
14.3.1 Introduction
Mortality represents the ultimate end point of many disease processes.
Estimates of mortality rates are generally fairly accurate in most places for
most time periods. On the other hand, mortality rate is not necessarily a
14-34
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sensitive indicator of the effect of pollution at any given place or time,
since it may be related to various lengths and types of exposures. Also,
recorded cause of death may or may not be accurate, necessitating additional
care in assessing reports of pollution-associated increases in cause-specific
mortality. Daily mortality varies greatly and its relationship to fluctuations
in ambient air levels may be fortuitous or may represent a trend that started
anywhere in the past (days, weeks, or years earlier). Despite the above
problems, numerous studies have attempted to determine possible relationships
between air pollution, including elevated levels of SO and particulate matter,
and documented increases in mortality rates.
Studies of mortality tend to fall into three broad categories: (1)
episode studies examining the effects of very high pollution levels lasting,
at most, for a few days; (2) studies in which short-term fluctuations in
pollution and mortality are monitored over more extended time-periods for a
particular population, and (3) cross-sectional studies in which mortality and
pollution are compared across different geographic areas. The earliest mortality
studies had limited estimates of pollution, and the numbers of deaths were
compared with those from other periods of time with the hope that similar
conditions prevailed except for air pollution. Often the differences are
large enough to be convincing in spite of the lack of complete information on
other pertinent data.
Short-term effects studies are usually limited to a well-defined population
that 1s followed through time. Since the period of time is relatively short,
it is usually safe to assume that the population has remained constant with
respect to age and composition. These studies are very sensitive to temporal
14-35
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variables such as influenza cycles, ambient temperature and other meteorologic
factors, season, day of the week, and even holidays. Confidence can be best
placed in those studies of this type where the contributions of such factors
are either controlled for or otherwise properly adjusted for or taken Into
account.
Long-term studies usually compare mortality rates over long periods of
time such as one to twenty years. The comparisons are usually cross-sectional,
that is, between geographic areas. Temporal factors are less important, but
the demographic characteristics of the study areas are critical. Among the
more important factors are age, race or ethnic differences, sex, socioeconomic
status, in-out migration, smoking habits, and general health care. The location
of monitoring sites in each area is also extremely important in long-term
studies. If the monitors in some geographic areas are in industrial locations
while the monitors in other areas are in residential locations, the differences
that are ascribed to ambient air pollution may actually represent other
differences between industrial and residential locations.
14.3.2 Acute Episodes
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.I
An intense fog covered the Meuse Valley from Liege to Huy ' from
December 1 to 5, 1930, and was accompanied by an anticyclonic high pressure
area with low winds and large amounts of fine particulate matter. Sixty
deaths associated with the fog occurred among residents of the Valley on
14-36
-------
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 complications associated with fog-induced Injuries.
The death rate in the area was 10.5 times normal. The illnesses abated rapidly
when the fog dispersed.
149
A similar but smaller event occurred in Donora, Pennsylvania. Donora
was blanketed by a dense fog during late October 1948, which adversely affected
43 percent of the population. Twenty persons died during or shortly after the
fog, and 10 percent of the population was classified as being severely affected.
No pollution measurements were made during the incident but the investigators
concluded that no single chemical agent was responsible. Sulfur dioxide, its
oxidation products and particulate matter were undoubtedly significant
contaminants. During subsequent inversion periods, presumably not as severe
as the one in October 1948, daily averages of sulfur dioxide as high as 0.4
ppm (~1140 |jg/m ) were recorded.
2 202-204
A pollution episode also occurred on December 5 to 9, 1952 in London. '
Monitoring sites near the center of the fog averaged 1.98 mg/m British Smoke
(BS) with an average maximum of 2.65 mg/m ; the maximum BS reported was 4.46
mg/m for a 48 hr sample. The corresponding mean values for S02 were 0.91
ppm, 1.26 ppm and 1.34 ppm. Four thousand excess deaths were noted during the
fog. As shown in Figure 14-2, the death rate began to rise within 24 hours of
the beginning of the pollution episode and fell abruptly to slightly elevated
levels when the fog abated. Most deaths occurred among people with pre-existing
disease, including bronchitis (tenfold increase in deaths) and coronary heart
disease (threefold increase). It has been noted that influenza present in
London at the time may have also influenced the reported death rate.
14-37
-------
/ ? J 4 5 6 7 6 9 10 II 12 a 14 15
DECEMBER 1952
Figure 14-2. Daily air pollution and deaths, London, 1952203
14-38
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11-14
Excess mortality in London during lesser episodes was assessed by
various statistical techniques for comparing observed and expected mortality.
The expected mortality rates were estimated from the mean number of deaths
occurring during the same dates over a number of years, from observed deaths
during previous or subsequent weeks, or by deviation from 15-day moving
averages of daily mortality. Aerometric data obtained for the various studies
are not entirely comparable; thus the study results only allow for crude
comparison. It has also been noted that the published concentration levels
may not be representative of the acutual exposures of all of the affected
312
population.
The information on mortality and maximum 24-hr pollution measurements for
BS and SO,, are presented in Table 14-5. The maximum 24-hr concentrations of
S02 during the 1952 and 1962 episodes were almost identical, and 1962 maximum
TSP measurements were 75 percent of the 1952 maximum, but far more deaths
occurred in 1952. This raises questions concerning the influence of factors
other than pollutant levels. The maximum smoke concentration recorded in 1952
was the highest ever observed and yet is believed to have underestimated the
actual concentration, because the filter became completely saturated and
additional deposition had little effect on the intensity of the black spot
produced on the instrument's filter tape. In 1962, publicity about the
hazards of episodic conditions may have motivated the population, particularly
the elderly, to avoid exposure as much as possible. Interpretation of the
other data in Table 14-5, however, argue against this possibility. In 1956,
the memory of the 1952 episode should still have been clear and, therefore, at
least as many precautions should have been taken. However, more excess deaths
occurred in 1956 than in 1962, even though concentrations were less than those
14-39
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TABLE 14-5. EXCESS DEATHS AND POLLUTANT CONCENTRATIONS DURING SEVERE
AIR POLLUTION EPISODES IN LONDON (1948-75)2,3,219-221,301
Maximum 24-hr pollutant
concentration, pg/m3
Duration, Estimated Smoke S02
Date days excess deaths (BS) (H202 titration)
Nov. 1948 6 750 2780 2150
Dec. 1952 4 4000 4460 3830
Jan. 1956 4 1000 2830 1430
Dec. 1957 4 750 2417 3335
Jan. 1959 6 250 1723 1850
Dec. 1962 5 700 3144 3834
Dec. 1975 2 100-200 546 994
14-40
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measured in 1962. Thus, the influence of publicity on minimizing exposure is
only one possibility. A second possibility is that influenza in 1952 may have
increased mortality. A third possibility is that the composition of air
pollution changed between 1952 and 1962 as a result of the 1956 British Clean
Air Act. The act limited the combustion of high-volatile coal for domestic
heating and thereby affected the amount of tars in the atmosphere. Such
alterations in the composition of air pollutants could have delayed or altered
the atmospheric transformation of S02 to more toxic materials.
Regardless of whether any of the above explanations apply, one clear
conclusion from the major London episodes is that increases in mortality are
associated with severe increases in air pollution. During the most severe
episodes, maximum 24-hour concentrations exceeded 1400 ug/m (0.5 ppm) for S02
and 1700 ug/m for smoke (BS). A less severe episode in 1975, resulting in
•
100-200 estimated excess deaths, had maximum 24-hour concentrations of about
994 ug/rn (0.35 ppm) for S02 and about 546 ug/ni for smoke ..-. jt has
been suggested that mortality levels during this episode may have been
affected by a concurrently occurring physician's strike in London; but the
strike referred to actually occurred the week before the air pollution episode.
Thus, one would have to assert that it was the return of the physicians to
work that may have contributed to the observed increases in mortality as an
alternative to the induction of mortality by the elevations in air pollution.
Q
One study, by Gore and Shaddick, has associated sharp increases in
mortality with four milder episodes of high air pollution between 1954 and
1956 in London. Using a 7-day moving average of deaths, the authors concluded
that significant increases in the number of deaths occurred when 24-hour mean
BS concentrations exceeded 2000 ug/m and the 24-hour mean S02 concentration
was at least 1150 ug/m3 (0.4 ppm).
14-41
-------
The data from the London air pollution episodes do not clearly delineate
the effects of specific pollutants acting alone or in combination. However,
during these periods characterized by heavy fog, low wind speed and high
humidity, the conditions for the formation of secondary pollutants may have
been better than usual. One of these conditions could be the presence of
impurities in the particulate matter that could serve as catalysts for the
reactions that form secondary pollutants, such as the transformation of sulfates
from sulfur dioxide (SO^). Holland et al. (1979) draw attention to iron as
an impurity in coal as possibly being involved in catalyzing atmospheric
conversions of certain sulfur compounds to more toxic forms. The concentrations
of sulfates were not recorded, but according to current knowledge they could
have likely been very significant components of the pollution, related both to
the particulate matter and the precursor SOp. In addition, the effects of low
temperatures may have been important.
Episodes of acute air pollution have also occurred in the United States,
but no single event has reached the proportions of the major London episodes.
Studies have been consistent, however, in showing that increases in total
mortality, and in some cases cause-specific mortality and morbidity, were
associated with the major episode in Donora in 1948 and, also, with episodes
in New York City. " In these studies, increases in mortality have generally
been related to 24-hour mean S02 concentrations above 1000 pg/m3 (Table 14-6),
together with measured particulate matter above 5.0 coefficient of haze units
(CoHs). Ingram and Golden154 estimated that 5.0 to 6.0 CoHs was approximately
equivalent to 570 to 720 ug/m3 of BS as monitored in England.
The estimates of excess mortality reported from the five New York episodes
were derived by comparing daily deaths during periods of high air pollution
14-42
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TABLE 14-6. ACUTE AIR POLLUTION EPISODES IN THE UNITED STATES
24 Hour
pollutant concentrations*
Location
Donora, Pa.
Detroit
New York City
New York City
»-•
•f New York City
5 New York City
New York City
Date
Oct. 1948
Sept. 1952
Nov. 1953
Dec. 1962
Jan 1963
Jan-Feb 1963
Feb. -Mar. 1964
Reference
(149)
(230)
(151)
(150)
(150)
(153)
(153)
Estimated
excess deaths
20
t infant mort.
200
90
7
" f
405-647C
50
S02, max particulates,
ug/m3a
max:
>1140 (0.4 ppm)
2620 (1.0 ppm)
1000 - 1500
Max (1 hour)
2288 (0.86 ppm)
1890 (0.72 ppm)
1830 (0.7 ppm)
1570 (0.6 ppm)
1570 (0.6 ppm)
CoHsb
___
5.0
6.5
6.0
7.0
5.0
ug/m3 TSP
— — —
>200
570
800
720
880
570
^Conversions: ,
1 ppm S02 = 2620 ug/m
b5-6 CoH = 370-720 ug/m3 TSP
clnfluenza outbreak also present
-------
with daily deaths for the same period in the years immediately before or
following the episode ' or by calculating daily deviations from a 15-day
moving average of daily deaths. The number of deaths in New York City was
reviewed for excess mortality in relation to the air pollution episode of
November 1953 by Greenburg et al. Excess deaths were related to elevated
concentrations of sulfur dioxide and suspended particles. Average daily smoke
shade (particulate matter) measured in Central Park was in excess of 5.0 CoH
units (568 ug/m3 TSP), while the S02 rose during the episode from the typical
3 3
New York City 24 hr average of between 400 ug/m to 532 ug/m (0.15 to 0.20
ppm) to 24 hour averages of 1000 to 1500, and reached a maximum level of 2288
ug/m (0.86 ppm), which was probably a half-hour value. For this episode,
there was a lag effect and excess deaths were distributed among all age groups.
The number of deaths, although not showing the marked rise seen in some of the
London episodes, was above average for comparable periods before and immediately
after the incident. For the period November 15 to 24, 1953, the average
number of deaths per day was 244, whereas during the 3 years preceding and
following 1953, the average was 224 deaths per day for the same calendar
period.
A later New York City episode (1962) was also studied by Greenburg et
al., but they did not discern any excess mortality. McCarroll and Bradley
and McCarroll, however, did find evidence of excess mortality arising from
acute episodes in New York City in November and December of 1962, January and
February of 1963, and February and March of 1964. In their studies, those
workers compared 24-hour average levels of various pollutants with New York
City mortality figures, employing daily deviations from 15-day moving averages.
Pertinent air quality measurements were performed at a single station in lower
Manhattan, and fluctuations in the values at this station were known to correlate
14-44
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well with those at another station 6.5 miles away. Excess deaths during the
v
first episode peaked on December 1, 1962 one day after the daily average for
sulfur dioxide concentrations peaked at 1886 ug/m3 (0.72 ppm) and smoke shade
levels peaked at 6.5 CoH units (800 ug/m TSP) during a period of atmospheric
inversion and low ground-wind speed. The increased death rates were shared by
the 45 to 64 age group and those over 65. A later episode, occuring around
January 7, 1963, was associated with an SO. concentration above 1834 ug/m
(0.7 ppm) and a smoke shade value of 6.0 CoH units (720 ug/m TSP). Some days
did not have excess mortality. During another episode between January 29 and
February 13, 1963 a peak death rate was apparently superimposed upon an elevated
death rate average due to the presence of influenza virus in the community;
daily pollutant levels averaged about 1570 ug/m (0.6 ppm) for SO. and 6.0 for
CoH units (720 ug/m TSP). A fourth episode of excess mortality (April 1963)
did not show sharp increases in air pollution. A fifth episode (February to
March 1964) again showed simultaneous increases in air pollution and mortality.
S02 was over 1570 ug/m (0.6 ppm) and TSP was 570 ug/m (5 CoH).
Severe air pollution also encompassed the New York City area during
the Thanksgiving weekend, November 23 to 25, 1966. The maximum 24-hour average
of hourly SO. values, as measured by electroconductivity, was 1,340 ug/m (0.51
ppm) on November 23, and 1,230 and 1,020 ug/m (0.47 and 0.41 ppm) on the 24th
3
and 25th. The maximum hourly concentration was 2,670 ug/m (1.02 ppm). Smoke
shade values were above 5 CoHs (570 ug/m TSP) on the 3 days. The average
number of daily deaths during the 7 days of the air pollution episode was 261
compared with the expected value of 237 for control periods in 6 surrounding
years.229
14-45
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230
In Detroit a rise in infant mortality and deaths in cancer patients
occurred over a 3-day period in September, 1952, accompanied by a rise in the
3-day mean suspended particulate matter above 200 ug/m and an Instantaneous
S02 maximum of 2,620 ug/m (1.0 ppm). This is not believed to be related to
cold temperatures that often characterized the London episodes.
Direct, precise comparisons of the pollution data from the London and
United States episodes, it has been asserted, cannot be made because of
differences in the methods used for measuring air pollution concentrations.
However, even rough comparisons accomplished by interconversion of BS, CoH,
and TSP (by means of the approaches discussed in Chapter 3) suggest that the
pollution must have been much greater in London. This is consistent with the
respective health findings indicating that, in a population of approximately
the same size, the estimated number of excess deaths was much higher in London.
than in New York. Of course, these differences may have also been caused by a
number of factors, including the accuracy with which the air measurements used
reflected exposure for the total population, and the fact that the concomitantly
occurring pollutants may have been quite different and might have acted together
to increase the impact on human health. It is known also that acute episodes
of excessive mortality have not been associated with all days of high pollution
in New York or London.152'163
Investigations in Rotterdam (Brasser et al.302; Joosting303; Biersteker315)
indicate that a positive association exists between air pollution and total
mortality as shown in Table 14-7. Biersteker315 found excess mortality to be
associated with 24 hour smoke and S02 levels of approximately 500 ug/m3 (OECD
2
smoke) and 1000 ug/m (sulfur dioxide method), respectively. Brasser et
al. found similar relationships when the S02 value of 500 ug/m3 per 24
14-46
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TABLE 14-7. OTHER ACUTE AIR POLLUTION EPISODES
24 Hour mean
pollutant concentrations
Location
Osaka
Rotterdam
Date
Dec. 1962
varies
Reference
100
232
Estimated
excess deaths
60
varies
S°2/3a
ug/m3
262
300-500
TSP
(ug/m3)
1000
d
JParticulates to S02 ratio of 1:3-1:4 (303)
-fc.
I
-------
hours is surpassed for a few days. This effect may begin to occur at lower
concentrations, somewhere between 300 and 500 ug/m3 S02 (0.11 to 0.19 ppm) per
24 hours, based on S0? measurements made with the hydrogen peroxide titrimetric
method.232'302 The Rotterdam episodes of January to February 1959 and December
1962 have also been discussed by Joosting. Particulate levels are generally
low in Rotterdam. On comparing particulate and S02 concentrations, Joosting
has characterized the ratio of particulates to S02 as low (1:1), moderate
(1:1.5 to 1:2), and high (1:3 to 1:4). Rotterdam is in the last category,
whereas London is in the first.
Watanabe100 (Table 14-7) found 60 excess deaths (about 20 percent) associated
with a 1962 air pollution episode in Osaka, Japan, in which the 24-hour mean
SOp concentration exceeded 260 ug/m (0.1 ppm) together with concentrations of
3
TSP greater than 1000 ug/m , both measured at a central station. Low temperatures
312
may have been partly responsible for these effects.
When a marked increase in air pollution is associated with a sudden
dramatic 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
. pop
considered as another possible cause of the death rate increase. On the
other hand, the consistency of the above associations between S02 and particulate
matter elevations and increases in mortality render it extremely unlikely that
weather changes alone provide an adequate explanation for all such observations.
This view is further reinforced by (1) the fact that at least some episodes
(e.g., the 1952 Detroit one) were not accompanied by sharp falls in temperature;
and (2) other weather changes of similar magnitudes to those accompanying the
14-48
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above pollution episodes are not usually associated with such dramatic
increases in mortality in the absence of greatly increased levels of S0?,
particulate matter, or other pollutants.
143.3 Mortality Associated with Short-term Variations in Pollution
A number of investigators have reported on relationships in the
United States between mortality and daily variations in air pollution during
non-episodic periods.155-160,170,171
Schimmel and Greenburg used more than 500,000 death certificates for
New York City in a study of daily mortality from January 1, 1963 to December 31,
1968. The study attempted to relate fluctuations in mortality to daily S02
and smoke shade, after adjusting for weather and other temporal factors, and
recognized the problems of auto- and cross-correlation. The authors concluded:
"...that with a high degree of probability a certain portion of deaths would
not have occurred at the time they did, in the absence of air pollution." By
using their fully adjusted model, their estimate of excess deaths was 18.2 per
day. Pollution estimates only came from a single station (Harlem), where SO-
averaged 0.17 ppm (450 ug/m ) for the study, while smoke shade averaged 2.1
3
CoH units (203 ug/m TSP). The authors attributed approximately 20 percent of
the excess deaths to SO- and 80 percent to smoke shade, but it has been noted
that this represents stretching interpretation of the epidemiologic data to a
point of precision beyond that allowed by existing techniques. Schimmel
155
and Greenburg also performed cause-specific analyses for ten different
cause categories. Estimated excess deaths were high in both the respiratory
disease category and the coronary heart disease category. The linear regression
model of Schimmel and Greenburg assumes that excess deaths rise in proportion
to the increase of the S0? or smoke shade levels over the range of values they
studied.
14-49
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Schimmel and Murawski ' expanded the death certificate data to
include information through 1972. Using a revised model, they revised their
estimate of premature deaths to be 2.8 percent (about 7 deaths per day) and
stated that the lower estimates were "...explained by a fuller correction for
seasonal trends and temperature effects." They found a colinearity of temperature
and SOp, but a curvilinear term for temperature may be more appropriate due to
the known increase in mortality at extreme temperatures. They estimated the
percent excesses attributed to SOp and to smoke shade. Based on separate
analyses for the years 1963 to 1966, 1967 to 1969, and 1970 to 1972 the authors
concluded that the reduction in SOp levels had not resulted in decreased
estimated premature deaths due to SOp. They further stated that "the SOp
association with mortality is not really a measurement of SOp effects but,
rather, SOp is to be viewed as an index of the effects of the more volatile
components of combustion activity."
187
Schimmel has presented additional data and analyses for the 14-year
period of 1963 to 1976, leading to results and conclusions similar to those
derived from the earlier papers by Schimmel and Murawski. '
184~5§§ 301 312
Several reviews " • •*" have been critical of the findings and
interpretations reported in the above Schimmel papers.1 Some of the
same criticism may also apply to certain other studies of the short-term
effects of air pollution on mortality. With particular reference to the
Schimmel papers, various reviewers noted that large standard errors for reported
S02 effects, and others, complicate interpretation of the Schimmel findings.
Also, it was pointed out, it is not particularly surprising that some weak,
but statistically significant, relationships were found (especially in the
earlier Schimmel papers) in view of the enormous numbers of regression analyses
14-50
-------
carried out and the consequent likelihood that at least a few statistically
significant associations would be found by chance alone. Conversely, it was
18^
noted ? that, because of considerations not taken into account In SchirmneVs
later papers, one cannot rule out a possible significant contribution of SO,,
to mortality levels observed in New York City—although Schimmel and his
&foity£<*' «e*~
colleagues failad to find any significant^assrociations between
S02 levels and decreasing- mortality rates over the same time- span. One factor
that may strongly limit the potential for Schimmel 's statistical approach (to
convincingly demonstrate significant associations, or lack thereof, between
various air pollution parameters and mortality) was his use of air quality
data from a single monitoring site in New York City. Thus, the crucial air
quality measurement data imputs, upon which virtually all of the rest of his
analyses very heavily depend, may not have adequately represented exposures
312
for the entire New York City population studied.
158
Hodgson used multiple regression methods to examine the relationship
between deaths and air pollution concentrations in New York City. He concluded
that much of the variation in deaths could be explained by the ambient concen-
trations of S0? or particulate matter (as measured in CoHs) but the monthly
average data used provided no useful quantitative information.
159
Multiple regression analyses were used also by Buechley to relate
daily deaths in the New York/New Jersey metropolitan area from 1962 to 1966 to
concentrations of S0? measured at a single monitoring station. For this
analysis, the data were adjusted for season, temperature, day of week, and an
Influenza epidemic. Beuchley's results have been interpreted to indicate that
on days on which the 24-hour mean SO- concentration exceeded 500 ug/m (0.19
ppm), deaths were 2 percent higher than expected; on days when the 24-hour
14-51
-------
mean S0? concentration was 30 ug/m (0.01 ppm) or less, deaths were 1.5 percent
less than expected (see Figure 14-3). The authors indicated that measurement
of particulate matter (CoHs) did as well as S02 in predicting deaths, but no
data were given. Extension of the analysis through 1972 gave Indications
of the importance of temperature and influenza regarding short-term variations
in the number of deaths. The extended analysis again indicated the association
between pollution and deaths but gave no additional information on the relative
significance of SOp or particulate matter.
Lebowitz studied relationships between air pollution exposure and
mortality in New York (1962 to 1965), Philadelphia (1963 to 1964), and Los Angeles
(1962 to 1965), and Lebowitz et al. performed similar studies in Tokyo
(1966 to 1969). These investigators developed a model in which higher air
pollution concentrations (one standard deviation above season mean) were
treated as stimuli; deaths, using various lag periods were treated as responses
to these stimuli. Although no definitive levels were reported, significant
relationships between periods of heavy pollution and increases in the number
of deaths were found in each area studied. New York winter pollutant averages
were 484 ug/m3 (.182 ppm) S02 and 150 ug/m3 TSP (2.12 CoH). Philadelphia
winter average TSP was 100 |jg/m (1.6 CoH). Los Angeles winter average S02
was 390 pg/m (.148 ppm). Adverse temperature and humidity changes were shown
to be very important as well, but did not account for all mortality increases
more directly attributable to or closely associated with increases in air
pollution.
A number of reports have investigated relationships between mortality and
5-14
air pollution in England during periods with no unusual air pollution episodes.
For most of these studies, 15-day moving averages were constructed and the
effects of pollution were assessed in terms of daily deviations from these
14-52
-------
47 D«y»
42
£ «i
u
t-
DC
0
£
_l -1
LU
CC -2
-
-
-
232
Days
-
120
Days j
-" - •
13U
Days
210
Days
-
Days
275
Days
""
-
1B4
203
99
Jays
114
Day*
.
-
-.
— —
— "
10
30 60 BO 140 200 300 400 SOO 650 1.000 UOO
Figure 14-3. Residual Mortality as a Function of S0? for the ic.q
New York - New Jersey Metropolitan area, 1962 to 1966
14-53
-------
baselines. Increases in daily deaths during the winter of 1958-59 were found
to be associated with concentrations of BS >750 ug/m3 and SOp >660 ug/m (0.25
ppm). Increases in daily deaths were not associated with pollutants at
14
lower concentrations. Similar studies in Sheffield were not as consistent.
Increases in deaths were associated with very high concentrations of pollutants,
but 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 particulates at levels near present 24 hour air quality
standards are those of Martin and Bradley and Martin. The first of these
studies related daily mortality from all causes and from bronchitis and pneumonia
to the level of S0? 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 S0~. Neither
temperature nor humidity was significantly correlated with mortality.
Though the authors emphasized the relationship between change in pollution
level and change in number of deaths, an influenza epidemic occurring during
part of the study may have influenced part of their results. The authors,
however, provided the number of deaths, smoke levels, and S02 levels from
November 1, 1958 to February 28, 1959 in the published report on the study. A
further analysis of these data was performed by Ware et al.304 but excludes
the month of February, in which an epidemic of Type A influenza also had a
significant influence on daily mortality. For the remaining 92 days, the
deviation of daily mortality from the 15-day moving average (truncated at each
end of the series) was computed, and the average of these deviations is given
for intervals for smoke level in Table 14-8 and S02 level in Table 14-9.
14-54
-------
TABLE 14-8. MEAN DEVIATION OF DAILY MORTALITY FROM 15 DAY MOVING AVERAGE,
BY LEVEL OF SMOKE (LONDON, NOVEMBER 1, 1958 - JANUARY 31, 1959)
Smoke level, Number Mean
ug/m BS of Days Deviation
100-199 6 -17.84
200-299 14 -11.63
300-399 16 -10.31
400-499 19 -5.57
500-599 9 18.46
600-699 6 18.80
700-799 7 5.31
800-1199 10 17.17
1200+ 5 31.37
TABLE 14-9. MEAN DEVIATION OF DAILY MORTALITY FROM 15 DAY MOVING AVERAGE,
BY LEVEL OF S02 (LONDON, NOVEMBER 1, 1958 - JANUARY 31, 1959)
SO, level ,
3
ug/m BS
100-199
200-299
300-399
400-499
500+
Number
of Days
16
28
22
12
9
Mean
Deviation
-11.38
-10.78
8.50
13.45
21.25
14-55
-------
These tables suggest 500-600 ug/m BS and 300-400 ug/m3 S02 as levels
above which increased mortality is seen, although this is not intended to
suggest a threshold for response. In fact, the data suggest a gradient of
mortality over the entire range of air quality seen. Although temperature and
humidity were not correlated with daily mortality, both pollution level and
daily mortality increased throughout the period of study, and the possibility
of other extraneous seasonal variables contributing to this association cannot
be ignored. On the other hand, it has been suggested that the use of
15-day moving averages may underestimate the magnitude of effects associated
with some episodes of high air pollution and, thusly, even more marked increases
in mortality might be attributable to the increases in S02 and particulate
matter.
A similar analysis was carried out by Martin 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. Tables 14-10
and Table 14-11 show Martin's results 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 mean deviation was positive in every
group. Bronchitis mortality was also significantly, though less strongly,
correlated with pollution level, but pneumonia mortality was not correlated
with pollution.
Holland et al. (1979) discuss the above findings on mortality as follows
(ejnphasis added):
The nearest approach to an episode of high pollution in London
in the last 10 years has been one lasting about two days, on December
15-16, 1975. On that occasion, the 24-hour average concentration of
smokg (BS) rose to 546 ug/m , and that of sulfur dioxide to 994
ug/m . A comparison of the crude weekly totals of deaths for the
14-56
-------
TABLE 14-10. MEAN DEVIATION OF DAILY MORTALITY FROM 15 DAY MOVING AVERAGE,
BY LEVEL OF SMOKE (LONDON, 1958 to 1960)
Smoke level ,
pg/m BS
500-599
600-699
700-799
800-1199
1200+
Number
of Days
9
6
9
8
7
Mean
Deviation
5.2
13.0
9.2
15.6
40.0
TABLE 14-11. MEAN DEVIATION OF DAILY MORTALITY FROM 15 DAY MOVING AVERAGE,
BY LEVEL OF S02 (LONDON, 1958 to 1960)
S05 level, Number Mean
3
pg/m of Days Deviation
400-499 9 9.0
500-599 6 11.6
600-799 9 16.0
800-899 6 19.2
900+ 5 39.6
14-57
-------
weeks around that time shows an excess of 100 to 200 in the week of
the fog; but, as in a number of the other episodes, there was also a
fall in temperature that may have been a contributory factor (11,
12). Relationships between short-term changes in mortality and low
temperatures have been recognized for many years, having been demonstrated
in London data as far back as the nineteenth century (13, 14).
In addition to studies of the major episodes of high pollution,
attention has also been paid to day-to-day variations 1n mortality
in London since 1952. Gore and Shaddick (15) calculated seven-day
moving averages of deaths in the inner area (County of London) only,
over winter periods from 1954 to 1956, and they found sharp increases
in association with four foggy periods. Their own assessment was
that the increases in deaths were particularly marked when pollution
(as 24-hour averages) exceeded 2000 ug/m smoke (BS), with 0.4 ppm
(1149 ug/m ) sulfur dioxide. This was a very conservative judgment,
and there were increases in deaths in their series with^smoke and
sulfur dioxide concentrations of the order of 1000 ug/m and 750
ug/m , respectively. Such changes may, in part, have been attributable
to other associated environmental conditions, such as cold weather
(that is, within minimum temperatures falling below freezing point),
but, ajs i_n other studies of the kind, there i_s m> satisfactory way
of distinguishing the effects o_f these factors. It is important in
trying to elucidate the influence of temperature independent of
other meteorologic variables to compare like with like. Thus, cold
Januarys should be compared with warm Januarys, and cold Julys with
warm Julys. Most work has shown an association between respiratory
disease and cold weather (e.g., see reference 16).
The main series of studies on day-to-day variations in deaths
in Greater London is that by Martin and colleagues. In most of
their studies, 15-day moving averages have been calculated and the
short-term effects of pollution have been assessed in terms of
deviation from these. (The moving average for each day refers to
the average number of deaths for the day in question, together with
seven days on each side of it.) The general seasonal trends and the
direct effects of epidemics (notably of influenza) are eliminated in
this way, although there is a risk of underestimating the magnitude
of effects associated with some episodes of high pollution. In the
winter of 1958-1959, when there were many days with high pollution,
Martin and Bradley (17) reported a marked association between daily
deviations in deaths, and concentrations of smoke or sulfur dioxide.
These increases in deaths were consistently related to day-to-day
increases in concentrations of the pollutants, and the authors
originally assessed their results in terms of the increments in
pollution only. They also showed that there were significant correlations
between deviations in deaths and the actual concentrations of pollutants
on the same day. No correlation technique such as this, however,
can show the full impact of pollution. The effects are sometimes
dalayed by about one day, but since there is no uniformity in any
such lag effects during a winter season, it cannot be dealt with
simply by introducing a one (or more) day lag between the pollution
and mortality figures.
14-58
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Martin and Bradley displayed their results in detail in tabular
form, so that days with elevated pollution could be linked with
changes in mortality in the most appropriate way. Subsequently,
increases in deaths (of 20 or more on a total of the order of 200-400
per day) were considered to be associated with 24-hour mean concen-
trations of smoke (BS) >750 ug/m and S02 >0.25 ppm (710 ug/m )
(18). It was not possible then, by this technique, to detect
variations in daily deaths at lower concentrations, and this finding
has not been contradicted HI any way by subsequent events. Indeed,
with a general decline in pollution levels in London such that
24-hour (BS} smoke concentrations are now seldom, if ever, as high
as 750 ug/m , there jjs still ITO evidence o_f associations of any
day-to-day variation jjn mortality with relatively minor peaks i_n
pollution.
301
Not mentioned by Holland et al. (1979) in their above analysis is the
fact that Martin and his colleagues reported that they found no significant
association between excess mortality and temperature. As stated by Martin and
Bradley in discussing their findings for the winter of 1958 to 1959 (emphasis
added):
Temperature is the climatic factor most frequently considered
to have an association with fog mortality. Russell (1924, 1926)
drew attention to the importance of cold weather as a factor in
increasing mortality rates during fogs, but his investigations were
based on weekly means and his results are not, therefore, applicable
to the immediate effects of individual incidents. By itself, unless
well below freezing point, temperature appears to have comparatively
little immediate effect on winter mortality and this i_s exemplified
by the low correlation coeficient (-0.030) which was found during
the winter of 1958-59. A range of 30-38°F j_s characteristic £f most
winter fogs and temperatures consistently below 30°F are the exception.
At the other extreme several fogs each associated with a mortality
peak were found in November and December. 1958, with temperatures
substantially over 38°F. As yet details have not been collected of
a sufficient number of incidents to estimate mathematically the
effect of temperature on fog mortality, but apart from the exceptional
incidents with very low temperatures H appears on present information
to have a comparatively minor influence.
See Appendix 14-B for more detailed review of literature on associations
between mortality and temperature.
Also overlooked by Holland et al. (1979) in their above analysis is
the fact that other tests (beside correlation techniques) of possible associations
14-59
-------
between mortality, S02 and participate matter levels and temperature changes
can be utilized to assess results reported by Martin and colleagues. The
report by Martin and Bradley presents a daily mortality-BS-S02 data set in
tabular form. That detailed presentation of data allows for the validity of
some of the above blanket statements by Holland et al. to be evaluated
by means of certain nonparametric statistical tests.
Timing of Observations
The mortality data from Martin and Bradley are reported on the calendar
day of the date of death, that is 0001-2400. The S02 and smoke data for the
given day are an average for seven Greater London stations obtained from the
24-hr collection values recorded from the bubblers and filters which were
turned off at 0900 the same day. The meteorological observations for London
(Croydon) give the maximum temperature between 0900 to 2100. The assignment
of the minimum temperature is less certain. As stated in the footnote of the
meteorological observations table "Minimum temperature night period 21-9 h.
and are entered to day of reading."
If strictly interpreted, the recorded daily minima may not be independent
since the temperature at 2400 may be the minimum on day 1 and the temperature
at 0100 may also be the minimum on day 2. That is, some of the minima in the
table could be 1 or 2 hours apart and other minima values could be 46 to 47
hours apart. With this timing uncertainty in mind, we can model these data as
follows.
The recorded minimum temperature recorded on day 1 influences the pollution
level recorded over the time period 0900, day 1 to 0900, day 2. Because
mortality from relatively low pollution levels would take a period of time to
occur, we expect the mortality on day 3 to be influenced by the pollution
14-60
-------
recorded on Day 2. Such a delay is not unreasonable since there is likely to
be a finite time from the stimulus which may lower resistance to a preexisting
low grade infection until the crisis stage is reached or for other fatal
effects to be manifested. In addition, respiratory patients in hospitals
might be placed in oxygen tents, with heroic measures taken to keep them alive
from day 2 to day 3.
A careful inspection of the mortality and temperature tables lead us to
the period December 8 to December 24, 1958 for the detailed study. This
choice was made because of the fact that daily mortality rates tended to
steadily increase over the winter period, November 1958 to February 1959.
This upward trend may have been caused by a combination of several of the
following factors:
1. Decreasing Temperatures : The monthly mean minima are shown in Table
14-12 with the corresponding average for the years 1931 to 1950. Note
that while temperatures in November and December were warmer than normal,
those in January and February were somewhat colder than normal.
TABLE 14-12.
MINIMA TEMPERATURE DATA FOR LONDON (Croydon)
Month
November 1958
December 1958
January 1959
February 1959
i
2. Presence of Influenza in
1958 to 1959
mean minima
40.6
38.1
31.5
34.7
London
1931 to 1950
average minima
40.1
37.0
36.1
35.7
Martin and Bradley report that an influenza epidemic occurred during this
winter period. The peak in mortality and peak in pollution occurred almost on
14-61
-------
the same days in February 1959; however, this may not have been happenstance
but indicitive of a true pollution effect of exacerbation of the preexisting
disease.
3. Cumulative Dosage Effect
A repeated dosage of pollution to a susceptible individual may serve to
lower the bodily resistance to such a point that an insult which might have
produced mild discomfort in November could produce a pulmonary crisis in
February. This would result in gradually increasing mortality trends over the
course of the winter, likely peaking in February along with peak pollution
levels and influenza effects.
By choosing December 1958, which was relatively warm, we avoid possible
temperature complications, the influence of the later influenza outbreak, and
the "sampling without replacement" problem as potential alternative explanations
for mortality effects varying as a function of S02 and particulate matter
pollution levels.
The pollution levels and minimum temperatures given in Table 14-13 were
all in the range where Holland et al. stated that no discernible mortality
(20 or more on a total of the order of 200-400 per day) effect should be
observed (that is, when BS < 760 ug/m , S02 < 0.18 ppm, T minimum > 33°F).
In order to establish the robustness of these pollution data during this
period, the day-to-day variation is evaluated by a sign-test. If we assume
that SO,, and BS are independent of each other, then during the 17-day period,
the 16 day-to-day changes should occur randomly. Therefore, one could expect
8 days when S02 and BS rise or fall together and 8 days when they do not rise
and fall together. As shown in Table 14-13, there are only 2 days of opposite
14-62
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TABLE 14-13. POLLUTION AND TEMPERATURE DATA FOR LONDON, DECEMBER 1958
Date
December
8th
9th
10th
llth
12th
13th
14th
15th
16th
17th
18th
19th
20th
21st
22nd
23rd
24th
Total deaths
(all causes)
307
305
288
285
308
291
289
334
343
319
307
284
297
256
297
311
296
Smoke BS
(ug/m3)
720
290
400
440
430
340
540
760
670
560
560
300
150
190
430
520
430
Minimum
S09 temperature
(ppm) (°F)
0.175
0.117
0.112
0.113
0.118
0.078
0.105
0.162
0.134
0.122
0.121
0.058
0.042
0.054
0.084
0.128
0.106
37
36
35
36
38
36
33
36
39
40
42
46
50
45
39
38
39
Heating
degrees
(60-T min)*
23
24
25
24
22
24
27
24
21
20
18
14
10
15
21
22
21
*Heating degrees are expressed in terms of 60°F—the minimum
temperature (°F) recorded for a given day at London (Croydon).
Tljis assumes that residential space heating is utilized proportionally
in relation to decreases in outside ambient temperature below 60°F.
14-63
-------
variation (Dec. 9-10 and Dec. 11-12). The chi-square test with 1-degree of
freedom is 2 (6)2/8 = 9 (P = 0.003), so one rejects the null-hypothesis of no
association and accepts the alternate hypothesis of BS - S02 association. The
averaging of air quality data from 7 monitoring stations apparently removes
the routine or expected experimental errors, and the average is robust as
expected. One can also perform the same test on smoke (Day 2) vs temperature
as heating degrees (Day 1) data, and SOp (Day 2) vs minimum temperature as
heating degrees (Day 1). Because of the one-day offset, we have 15 variations
with null expectations of 7.5 each. For BS there are only 2 days with opposite
2
variation, so that the chi-square test with 1-degree of freedom is 2 (5.5) /7.5 = 8
(P = 0.005) which demonstrates the close association of smoke (BS) with heating
degrees. Repeating the evaluation, but for SOp and temperature (heating
degrees), there are 4 days with opposite trend so that the chi-square with
1-degree of freedom is 2 (3.5) 77.5 = 3.26 (P = 0.07) which is on the edge of
statistical significance and highly suggestive of an association between S02
and temperature.
These evaluations show how the sign test can demonstrate an association
in cases where one expects, from prior knowledge, an association to exist.
Mortality Association with Temperature and Pollution
Because temperature is assumed to be offset from mortality by 2 days, we
have only 14 day-to-day changes and an expectation of 7 similar changes and 7
dissimilar changes if mortality Day 3 is independent of the minimum tempera-
ture Day 1. The data set gives a total of 4 opposite sign changes, so that
the chi-square test with 1 degree of freedom is 2 (3)2/7 = 2.57 (P = 0.13).
Note, if we test mortality Day 2 with temperature Day 1; P £ 0.50. Thus,
temperature does not appear to be statistically significantly related to
14-64
-------
mortality during the December, 1958, period studied. Performing similar
computations with both BS and SOp on Day 2 and mortality on Day 3, however,
there are 15 possible changes and only 3 were in the opposite direction,
o
leading to a chi-square test with 1-degree of freedom of 2 (4.5) 77.5 =5.4
(P = 0.02). Thus, it appears that mortality may be significantly associated
with increases in S02 and particulate matter at levels (190 - 520 ug/m BS;
150 - 375 Mg/m3 S02) below those stated by Holland et al.301 to be the lower
limits where mortality occurs. Furthermore, such mortality effects appear to
have occurred in the absence of any significant influence by temperature,
which was always above freezing and averaged approximately 39°F (minimum)
during the December period studied.
Similar thorough revaluations are being carried out for mortality data
from the 1975 London episode, when 100-200 excess deaths occurred and pollution
peaked for only 2 days, and also from a 1975 Pittsburgh episode, when 20
excess deaths were reported. Apparently, Holland et al. overlooked the
possible mortality effect in Pittsburgh, Pennsylvania, which was noted at the
82 301
end of a paper cited by them (Holland et al. reference 5-21). These
mortality effects associated with the Pittsburgh episode were described by
12
Riggan et al. (1976) and were also reported in a companion paper presented
341
at the 1977 Puerto Rico epidemiology symposium (Riggan et al., 1977) attended
by several of the authors of the Holland report. It is not implausible
that these excess deaths in Pittsburgh were related to the pollution levels,
because these pollution levels were similar to those found in London from
December 8-24, 1958. There exists another insidious similarity between the
London episodes and the Pittsburgh episode in 1975. As Holland et al. (1979)
aptly pointed out on page 556 of their report, sulfuric acid might be a
14-65
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component of crucial importance. The catalytic reaction of sulfur dioxide to
sulfuric acid on moist particulate materials might have been occurring in
London where iron is present as an impurity in coal (as noted by Holland et
al.310), and also in Pittsburgh where ferric oxide is likely present as "an
342
impurity" associated with steel making operations (see Sugden, 1967 ).
Consequently, more credence must be placed in the possibility that mortality
in air pollution episodes can and has occurred even under present day air
quality conditions in the United States and Britain.
222
Glasser and Greenburg 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 SO^ and bihourly smoke
shade (CoH) readings. The results are adequately summarized by the unadjusted
analysis, which is given in Table 14-14 and 14-15. This analysis suggests a
mortality effect for smoke shade above 3.0-4.0 CoH (350-400 ug/m TSP) and S02
above 786 ug/m with very distinct increases above 5 CoH (568 ug/m TSP) and
786 pg/m S02. In cross-tabulation of daily mortality by S0? and smoke shade
level, S02 appeared to be more strongly related to mortality and was used as
an index of pollution in some analyses. In a multiple regression analysis
with temperature and rainfall, S02 was more strongly associated with mortality
than either weather variable. This association persisted in analyses of
bimonthly periods. Although the observations are dependent, Glasser and
Greenburg computed standard errors for the mean deviations by assuming
independence. Most of these standard errors were near 2.0, though the entry
18.80 in Table 14-14 had a standard error of 4.3.
14-66
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TABLE 14-14. AVERAGE DEVIATION OF DAILY MORTALITY FROM NORMAL,
BY LEVEL OF SMOKE SHADE (CoH), (NEW YORK, 1960 to 1964, OCTOBER THROUGH MARCH)
Smoke shade
level, CoH
<1.0
1.0-1.9
2.0-2.9
3.0-3.9
4.0-4.9
5.0-5.9
6.0+
Number
of days
26
160
318
239
83
19
9
Mean
deviation
-2.79
-1.55
-2.37
1.48
2.52
18.80
17.18
TABLE 14-15. AVERAGE DEVIATION OF DAILY MORTALITY FROM NORMAL,
BY LEVEL OF S02 (NEW YORK, 1960 to 1964, OCTOBER THROUGH MARCH)
SO, level ,
(jg/m
<262
262-524
524-786
786-1048
>1048
Number
of days
112
311
172
66
80
Mean
deviation
-3.49
-3.08
1.78
9.42
11.86
14-67
-------
To analyze possible mortality effects of even lower levels of pollution,
even the 15-day moving average method is not sufficiently sensitive. Some
authors have argued that more sophisticated adjustment techniques are necessary
to ensure that seasonal and temperature effects are eliminated 1n adjusted
analyses.
Kevany et al. used partial correlation analysis to develop a relation-
ship between SO,, and smoke pollution in Dublin, Ireland, and specific mortality
data derived from death certificates between 1970 and 1973. Some forms of
mortality were reported to be occasionally correlated with SO. levels of 100
to 150 ug/m . The findings, however, were internally inconsistant and based
on truncated distributions of pollutant concentration estimates.
In summary, the results of the above studies of mortality associated with
short-term variations in air pollution collectively provide further evidence
for associations between excess mortality and marked elevations in atmospheric
concentrations of S0? and particulate matter. Again, however, as in the case
of the earlier discussion regarding acute pollution episode mortality effects,
it must be noted that in assessing various published results or the data sets
and analyses upon which the results are based, it is often difficult to
differentiate precisely the relative contributions to the observed excess
mortality rates of: (1) S02 or particulate matter, acting alone or in
combination; and (2) the possible effects of covarying changes in temperature,
other meteorological parameters or concurrent outbreaks of influenza or other
diseases.
Nevertheless, based on several methodologically sound studies which have
taken the latter factors into account, it appears to be possible to derive
credible, albeit rough, quantitative estimates of particulate matter and SO.
concentrations associated with the occurence of increased mortality in
14-68
-------
disparate geographic areas. Thus, for example, the studies of Martin and
Bradley and Martin strongly point toward notable increases in mortality in
London having occurred in association with repeated short-term exposures to
particulate matter levels exceeding approximately 500-600 ug/m BS and S0?
levels of 300 to 500 ug/m . Careful further analysis of their data, as detailed
above, suggests possible significant mortality effects at even lower levels of
BS and SO^, in the absence of significant temperature effects. In addition,
222
analysis of the Glasser and Greenburg study points toward increased mortality
in New York City, occurring in association with particulate matter levels
3 3
rising above approximately 350-400 ug/m TSP) and S02 above 524-786 ug/m .
14.3.4 Cross-Sectional Studies of Mortality
Numerous qualitative studies have been performed comparing 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 studies are summarized in Table 14-16. These are followed by a
discussion in more detail of other studies yielding better quantitative
information bearing on the present discussion.
199
Buck and Brown found a gradient of mortality from chronic respiratory
illness from 1955 to 1959 that coincided with areas of lowest-to-highest
pollution in 1962 in middle class areas. The pollution concentrations and
mortality were from different years. This study did not find a significant
relationship between smoking and mortality from lung cancer but the authors
estimated that increased mortality occurred with levels of over 200 ug/m BS
•3
and 200 ug/m S0?. Controlling for regional smoking and socio-economic
14-69
-------
TABLE 14-16.
QUALITATIVE ASSOCIATION OF GEOGRAPHIC DIFFERENCES IN MORTALITY
WITH RESEDENCE IN AREAS OF HEAVY AIR POLLUTION
Pemberton-aqd
Goldberg^"
Stocks
138,164-167
224-225
Gorham
Gore and Shaddick
-in • ii.2ZD
and Hewitt
Haastrom et al.
Zeidberg et al
Sprague et al.
16
17
Lepper et al.
227
Jacobs aa
Landoc
1950-1952 bronchitis mortality
rates in men 45 years of age
and older in county boroughs
of England and Wales
Bronchitis mortality, 1950-1953,
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 econimic 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
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 SOp concen-
tration, within a socioeconomic
status, without a consistent
mortality gradient between the
areas of intermediate and high
SO- concentration
Higher total and heart disease
mortality rates in industrial
area
14-70
-------
Morris et al.
24
Collins et al.
287
Beaker et al.
323
Toyama
330
Lindeberg
321
1960-72 mortality rates
compared to 1959-60 air
pollution levels
Death rates in children 0-14
years of age, 1958-1964,
1n relation to social and air
pollution indices in 83 county
boroughs of England and Wales
Thanksgiving 1966 Fog,
New York
Mortality in districts
of Tokyo
Deaths in Oslo winters
Mortality higher in smokers
with lower air pollution
exposures
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
Complaints of cough, phlegm,
wheezing, breathlessness, eye
irritation increased with in-
creasing air pollution
Bronchitis mortatliy associated
with dustfall (but not cardio-
vascular, pneumonia or cancer
mortality)
Average deaths per week, 1958-65
winter, correlated with pollution
14-71
-------
differences did not remove the high correlation between air pollution and
bronchitis mortality. That is, although Buck and Brown did not find a
relationship between smoking and lung cancer and bronchitis mortality, the
variation in smoking between regions was too small to differentiate the observed
. . .. .... 247,307
mortality differences. '
Wicken and Buck compared deaths from lung cancer and bronchitis (1952
to 1962) in areas of contrasting air pollution (1963) in northeast England.
Differences in death rates were associated with differences in exposure to
pollutants with high areas having annual BS of 160 ug/m (250 ug/m TSP) and
S02 of 115 ug/m . Because adjustments in analyses were made for smoking, age,
and social class, this study is generally considered to be a methodologically
304
sound study.
20
Burn and Pemberton studied total mortality and mortality from lung
cancer and bronchitis in three areas of differing pollutant concentrations in
Salford, England. Total mortality showed a gradient in the standardized
mortality ratio of between 90 and 106 with gradients in winter and summer for
S02 (340 to 715 and 450 to 680 ug/m , respectively) and British Smoke (145 to
255 and 170 to 270 ug/m, respectively). Since cigarette smoking, social
status and mobility were not examined, questions have been raised regarding
248 301
the validity of these reported associations. '
228
Watanabe and Kaneko studied 1965/1966 mortality rates in the Osaka,
area of Japan, stratified into 3 areas by degree of air pollution. Moving
averages and lags in mortality were utilized. A stepwise increase in total
mortality and deaths from circulatory disease was seen in areas of greater
pollution independent of temperature effects. The levels in the highest area
>2
were 300 ug/m3 TSP and 215 to 266 ug/m3 SO, (0.08 to 0.10 ppm).
14-72
-------
21-23
Winkelstein et al., studied total and cause-specific mortality in
Buffalo and Erie County, New York, for the years 1959 to 1961, in relation to
the air pollution levels. A network of 21 sampling stations provided data on
TSP, settleable solids, and oxides of sulfur for the period July 1961 to June
1963. Four areas were designated on the basis of the isopleth concentrations
of particulate matter, with the 2-year geometric mean concentrations of TSP in
the four areas being <80, 80 to 100, 100 to 135, and >135 pg/m3. Each area
was also divided into five economic groups. Chronic respiratory disease
mortality for white males 50 to 69 years old was about three times higher in
the high-pollution areas than in the low-pollution areas. The positive association
between TSP concentrations and total or chronic respiratory disease mortality
persisted across all economic groups. There was a positive association between
stomach cancer and 2-year geometric mean TSP in excess of 80 ug/m . Deaths
from cirrhosis of the liver also showed a positive association with TSP con-
centration for both white men and white women 50 years and older. Average
annual death rates, as they related to TSP concentration and economic level,
are shown in Table 14-17. Multiple probit analysis indicates the independent
effect of particulate matter on mortality.
Questions have been raised ' concerning the validity of the above
21-23
Winkelstein findings, because the study did not include smoking, occupation
or mobility data. However, these variables correlate significantly with
economic levels, which were controlled for in the analyses, somewhat minimizing
such shortcomings. In addition, Winkelstein conducted a follow-up
survey of smoking in adult women in Buffalo in 1963. He attempted to determine
the potential influence of smoking by residence. Among non-smoking women over
age 44, productive cough was positively correlated with residential suspended
particulate concentrations. Smokers with 5 or more years residence also had
14-73
-------
TABLE 14-17. AVERAGE ANNUAL DEATH RATES PER 1000 POPULATION
FROM ALL CAUSES ACCORDING TO ECONOMIC AND PARTICULATE LEVELS, AND
AGE: WHITE MALES, 50-69 YEARS OF AGE, BUFFALO AND ENVIRONS, 1959-1961
Particulate level
Economic
level
1 (low)
2
3
4
5 (high)
Total
1 (low)
—
24
(3663)
--
20
(6625)
17
(6335)
20
(16623)
2
36
(530)*
27
(9720)
24
(7684)
22
(7881)
21
(6394)
24
(32209)
3
41
(5281)
30
(6968)
26
(3954)
27
(2639)
20
(574)
31
(19416)
4 (high)
52
(1954)
36
(3185)
33
(1298)
--
--
40
(6437)
Total
43
(7765)
29
(23536)
25
(12936)
22
(17145)
19
(13303)
26
(74685)
21
Source: Winkelstein, et al.
*Population sizes given in parentheses
ANALYSIS TABLE USING ASYMPTOTIC CHI-SQUARES ESTIMATED BY PROBIT ANALYSIS
Effect
Participates
Linear effect
Nonlinear effect
Economic effects
Interactions
Asymptotic
chi-square
76.55
72.55
4.00
392.34
4.23
Degrees
of freedom
3
1
2
4
8
P-value
<.001
<.001
.135
<.001
.836
Source: V. Hasselblad (personal communication)
14-74
-------
TABLE 14-18. AVERAGE ANNUAL DEATH RATES PER 1000 POPULATION
FROM ALL CAUSES ACCORDING TO ECONOMIC,
PARTICULATE AND SO LEVELS
Economic
level
1 (low)
2
3
4
5 (high)
Part, low
S0x low
36
(530)*
26
(13,383)
24
(7,684)
21
(13,771)
19
(11,428)
Pol lution
Part, low
SO high
x s
(0)
(0)
(0)
19
(735)
16
(1,301)
Levels
Part, high
SO low
46
(4,413)
33
(2,245)
28
(4,189)
27
(2,639)
20
(574)
Part, high
SO high
J{
41
(2,822)
32
(7,908)
26
(1,063)
(0)
(0)
188
Source: Winkelstein et al.
*Population sizes given in parentheses
ANALYSIS TABLE USING ASYMPTOTIC CHI-SQUARES ESTIMATED BY PROBIT ANALYSIS
Effect
SO -particulate interaction
SO adjusted for participates
Participates adjusted for S0x
Economic
Other interactions
Asymptotic
chi-square
.55
3.26
43.36
406.84
4.95
Degrees
of freedom
1
1
1
4
7
P-value
.458
.071
<.001
<.001
.666
Source: V. Hasselblad (personal communication)
14-75
-------
positive correlations with residential TSP; both findings were independent of
socio-economic factors.305'307 This indicates the likely existence of effects
on health of residential pollution independent of smoking. Nevertheless, the
specific contribution of smoking to mortality effects observed in his early
studies21'23 could not be definitively determined, by this approach.
It has also been conjectured, (without presentation of convincing
supporting data), that Winkelstein's original findings might be simply
accounted for by higher mortality rates in high pollution areas being due to
greater proportions of residents in the high pollution areas coincidentally
also falling higher in the 50-69 age range studied than those in the low
pollution areas. This would, however, have to be an extraordinary coincidence
indeed for the same pattern of age bias to follow precisely the same dose-response
relationship patterns observed for pollution-mortality relationships shown in
Tables 14-17 and 14-18. Winkelstein also evaluated the possibility that
census tract population size (and thus density) could be positively correlated
with both air pollution levels and mortality rates. The total death rate for
white men ages 50 to 69 were computed for each of the four air pollution
levels in each group; it did not appear that the observed association of air
pollution and mortality was related to population size.
188
Winkelstein reanalyzed the same mortality data using two particulate
levels and two oxides of sulfur (SO )levels. The areas were split at 100
/\
3 2
ug/m for particulate matter and 0.45 mg/cm -30 days for S02> The mortality
rates (Table 14-18) show increases for particulate matter independent of
economic level; tests of significance calculated as in Table 14-17 show that
particles explain a highly significant increase in mortality. Probit analysis
indicates that SO adjusted for particulate matter had only borderline significance
/\
while particulate matter adjusted for SO was highly significant. The relative
14-76
-------
risk ratio of the high-particulate areas to the low-particulate (and low SO )
areas was between 1.15 and 1.29, for the economic levels (except for the
189
highest economic level). Winkelstein performed a similar analysis for
women (similar to Table 14-17). The same pattern of increasing mortality
rates across participate categories was found. The number of occupationally
exposed women can be assumed to be small at that time (1960) such that industrial
exposure was not the primary cause of increased mortality.
Taking into account all of the above analyses and information concerning
the Winklestein studies, it would appear that his finding on associations
between variations in mortality and geographic areas in terms of relative
levels of particulate matter or sulfur oxides are likely valid and cannot be
explained away in terms of possible confounding or covarying factors alone.
On the other hand, caution must be exercised in regard to uncritical, full
acceptance of the specific quantitative dose-response relationships implied by
the summarization of pertinent air quality data appearing in the published
Winkelstein reports without closer examination and analysis of the original
air quality data.
More specifically, conversion of Winkelsteins' air quality data from
2-year geometric means to annual arithmetic means is especially important in
order to allow for more direct comparison of his findings with results which
have more typically been reported in relation to annual average TSP concen-
trations expressed as arithmetic means. Conversion to arithmetic means of the
specific geometric means that served as the basis for Winkelstein's original
TSP pollution level groupings results in the values listed in the third vertical
column of Table 14-19. Similarly, conversion to arithmetic means of the
21-23
geometric means for pertinent SO air quality data reported by Winkelstein
/\
yields results as indicated in the third column of Table 14-20.
14-77
-------
TABLE 14-19. COMPARISON OF ARITHMETIC AND GEOMETRIC
MEANS OF TSP DATA - BUFFALO STUDY, 1961-1963
TSP Measurement 2-Year 2-Year With Flow
Original Grouping Geometric Mean Arithmetic Mean* Rate Correction
< 80 pg/m 75
76
78
80**
80-100 87
89
89
90
93
95
100-135 106
110
111
124
125
132
135
> 135 142
152
178
205
87
83
87
91
100
100
102
103
105
109
119
122
125
146
146
156
154
163
180
203
249
£ 100
115-125
~ 140-175
£ 180-285
21
*Modified from Winkelstein (1967) by E. Davis, personal communication to D. Mage
**In the original analysis, this station was included in the grouping
< 80 ug/m , 2-year geometric mean.
14-78
-------
TABLE 14-20. COMPARISON OF ARITHMETIC AND GEOMETRIC MEANS OF
OXIDES OF SULFUR DATA - BUFFALO STUDY, 1961-1963*
TSP Measurement
Original Grouping
2-yr geometric mean
Oxides of Sulfur
(mg/crri )**
2-Yr. Geometric Mean
Oxides of.Sulfur
(mg/cm )
2-Yr. Arithmetic Mean
Estimated §02
Level (ug/m"
< 80 ug/m 0.198
0.219
0.257
0.256
80-100 0.219
0.278
0.209
0.237
0.339
0.262
100-135 0.242
0.429
0.326
0.337
0.359
0.307
0.461
> 135 0.328
0.169
0.530
1.250
0.237
0.256
0.290
0.289
0.252
0.299
0.241
0.259
0.385
0.297
0.359
0.455
0.423
0.375
0.421
0.417
0.509
0.349
0.327
0.566
1.315
19
20
23
23
20
24
19
21
31
24
29
36
34
30
34
33
41
28
26
45
105
*Based on data from Winkelstein (1967).
21
'i
**Actually SO values shown here represent mg/cm readings per 30 days.
***Values stated here are likely underestimations of actual SO. concentrations due
to probable errors in measurement associated with use of "sDlfation rate"
analytical technique, as discussed briefly in accompanying text and in more
detail in Chapter 3.
14-79
-------
In addition to the above considerations, certain sources of measurement
error that would likely have affected the precision of the quantitative estimates
?1~?3
of TSP and SO levels employed by Winkelstein, have come to light in
J\
recent years. For example (as also discussed in Chapter 3), underestimation
of TSP concentrations likely occurred due to probable overestimation of flow
rates during sampling periods. This arises from the standard procedure,
employed by Americans, in taking an average of the flow rate readings obtained
at the start and end of a sampling period, rather than obtaining continuous
readings during the period and more accurately determining the flow rate by
integrating the area under the curve defined by the decreasing flow rate
readings over the sampling period. Precise estimation of the size of likely
resulting errors associated with specific American hi-vol TSP estimates determined
in the above manner is of course impossible but probably would not be more
than about 15 percent (see Appendix A of Chapter 3). Applying a 15 percent
maximum correction to the "arithmetic mean" TSP estimates in Table 14-19
results in annual average TSP values designated as being obtained "with flow
rate correction" in that table.
Analogously, it must be noted that the "sulfation" method used in deter-
21-23
mining the oxides of sulfur SO data reported by Winkelstein is not
specific for sulfur dioxide (S02). Also only approximate estimates can be
made of the proportion of S02 contributing to the reported SO data, as per
the values shown in the fourth column of Table 14-20. The interpretation is
further complicated because the basic SO and, therefore, these derived SO,
^ £
estimates likely were affected by the sensitivity of the sulfation technique
to variations in temperature and humidity. Thus, unless the latter were well
controlled within the monitoring sites, the net outcome would likely be that
14-80
-------
the values shown in Table 14-20 somewhat underestimate the actual oxides of
sulfur air levels (see Chapters 2 and 3 for a more detailed discussion of the
sulfation method). Regardless of the precise actual levels of either overall
oxides of sulfur or S02 as a subset, however, the matter of their possible
contribution to mortality (either alone or in combination with TSP) is more or
less moot because no statistically significant SO effects or SO -particulates
f\ XX
interactions are demonstrated by the probit analysis in Table 14-18.
25
Lave and Seskin, in another often-quoted study, obtained a positive
association for both men and women between bronchitis mortality in England and
smoke (BS) measurements. The positive association persisted when socioeconomic
or
factors were included in a multiple regression analysis. These investigators
then compared bi-weekly concentrations of air pollutants in 114 SMSAs in the
United States during 1964 with deaths from bronchitis. Regression analyses
showed significant positive relationships between mortality and suspended
particulate matter, even after adjustment for climate and the type of home
heating (both associated independently with mortality).
The bi-weekly high-volume TSP concentrations during the period covered by
the analyses ranged from 45 to 268 ug/m , with a mean of 118 ug/m . This
would suggest that biweekly mean TSP concentrations of 120 ug/m or higher
27
would be associated with excess bronchitis deaths. Lave and Seskin subsequently
published results of a time series analysis of air monitoring data from 25
SMSAs as they related to bronchitis mortality, lung cancer mortality, and
infant mortality during the years 1960 and 1969. In this analysis, each type
of mortality was related to air pollution concentration as indicated by the
annual mean concentration of TSP or sulfate.
14-81
-------
Again, TSP readings and suspended sulfate readings >120 >10 exceeded the
mean pollutant concentrations and, on the regression scale, were associated
with increased mortality. The time series analysis indicates that TSP has
about three times the explanatory power in the regression than does sulfate
and almost five times the explanatory power of SO^. Nitrates and N02 were not
significant in this analysis. The authors state that S02 and the nitrogen
compounds may be important acting together with the particulate matter.
Many questions can be raised about these study results. Cigarette smoking
was not considered in the analysis. There may also have been problems arising
from nonuniform distributions of samples or from other variables not included
in the analysis. Air pollution was measured only twice monthly at one or more
monitoring stations in each of 114 metropolitan areas. The regressions also
included some possible confounding by sex distributions, age distributions and
socioeconomic levels. Although this was an attempt to specify effects of
SO /TSP, effects of other pollutants cannot be subtracted. The greater effects
/N
of smoking were not included, nor were the effects of other exposures.
Potentially confounding are the choice of residential area related to the co-
and intervening variables and other community differences not measured. The
method is unable to relate pollution levels in cities to actual exposure of
individuals to air pollution attributed to the area of residence, especially
251
given the mobility of the U.S. population. Time series analysis also may
have systematic biases. Seasonal variation was not controlled. Problems with
geographic comparisons of mortality include: lack of information on covariables,
intervening variables and confounding factors; lack of specific exposure
histories and of specific causes of death; errors of omission and commission
in assigning deaths to places; inability to pinpoint effects of specific
14-82
-------
pollutants or to characterize dose-response relationships; Inability to
generalize. Considering all of the above problems with the Lave and Seskin
analyses, their reported findings and conclusions cannot be accepted as being
accurate or useful for present health criteria development purposes.
Four regression analyses are also reported by Lipfert. >253 The first
of these arises from analysis of 1969 mortality data from 60 U.S. cities using
a model much like one of Lave and Seskin1s; very similar coefficients are
obtained. The first two models differ only in that the first uses mortality
data from 60 SMSAs while the second uses mortality data from 60 U.S. cities.
The coefficient of sulfate (S04)is larger in~the second regression using
smaller geographic areas. The third model differs from the second in that
more cities are included and age of housing and birth rate are added as
independent variables, while smoking is added in the fourth. Though the
coefficient of TSP changes very little, the coefficient of sulfate is negative
in these regressions.
A regression analysis of 60 U.S. cities in 1970 was performed by Crocker
254
et al. In addition to variables used by other investigators, this model
includes variables for climate, education, availability of medical care and
nutritional habits. Although Crocker uses SO- and not SO. as a pollution
variable, neither pollutant contributes significantly to the regression. They
report a correlation between SOp and SO. of 0.74.
In evaluating regression analysis studies further, it should be noted
that the contribution of air pollutants to mortality can be summarized by
"elasticity". Elasticity is a dimensionless number that represents the expected
percent change in the dependent variable, mortality, associated with a 100
percent increase from the mean value in each of the independent variables.
14-83
-------
Elasticity is computed by multiplying each air pollutant regression coefficient
by the average value of that pollutant in the data set, adding these quantities
for all pollutants, and dividing by the average mortality over study units.
So long as the set of pollution variables chosen contains variables expressing
the association of air pollution with mortality, elasticity is relatively
insensitive to subset selection from a set of highly colinear pollutant
variables. Thus, elasticites can be viewed, at least approximately, as
measuring the total mortality effect of all pollutants included.
Elasticities for the nine regression analyses summarized above are as
pec
follows. The simplest model used by Lave and Seskin for the analysis of
the 1960 data had the largest elasticity (0.09). As other variables were
added, such as home heating fuel in the second regression, elasticity declined
(0.03). When occupation was added to the model for the first regression,
elasticity declined to 0.05. The first two Lipfert regressions use population
density, percent above age 65, percent nonwhite and percent with income below
$3000 as independent variables. Their elasticities were 0.10 and 0.09, respec-
tively. When birth rate and age of homes are added to the third or cigarette
smoking to the fourth, elasticity declines to 0.06 and 0.004, respectively. The
effect of cigarette smoking is especially notable. Finally, in the analysis
254
by Crocker et al. using several other independent variables, the elasticity
is nearly zero (0.004). These variables included measures of medical care,
diet, climate and cigarette smoking and could easily be defended as critically
important in any analysis controlling for other factors influencing mortality.
Though several authors have argued that the omission of smoking only adds
254
to error, Crocker et al. report a correlation of 0.23 between cigarette
consumption and sulfur dioxide in the six cities in their study. Certainly
14-84
-------
the two variables are not causally related, but both may reflect other
characteristics of the population.
255
Schwing and McDonald report on a study of 46 SMSAs (1959 to 1961) in
which 23 explanatory variables were used, including climate, socioeconomic,
occupational and smoking variables and eight air pollutants. This study
differs from others in that the investigators included all 23 variables in
their models. To counter the effects of severe colinearity, the authors used
two methods of analysis: ridge regression and constrained least squares, as
opposed to ordinary least squares. (The previously reported studies all used
ordinary least squares.)
Ridge regression is a numerical method for stabilizing estimates from
data that have several colinear variables. While the method does achieve
stability, it does so by selecting an arbitrary constant that has the effect
of shrinking each estimated coefficient toward zero. Though ridge regression
leads to smaller standard errors for the estimated coefficients, these coefficients
are no longer interpretable as partial regression coefficients, that is,
measures of the effects of changes in a single variable while other variables
are held fixed. As emphasized throughout this chapter, colinear data sets are
fundamentally insufficient to allow assignment of mortality effects to individual
members of a group of colinear independent variables.
255
Schwing and McDonald also used constrained least squares, constraining
the air pollution coefficients to positive values. This may be unreasonable
when eight air pollutants are studied simultaneously; for instance, respirable
sulfate as a fraction of total sulfate is not constant over different levels
of air quality (see Chapter 5). Schwing and McDonald report an elasticity of
0.022 from ridge regression and an elasticity of 0.045 from constrained least
14-85
-------
squares. These values are still an order of magnitude larger than that reported
by Crocker et al. (0.004).254 While Crocker et al. did not include data on
occupation, Schwing and McDonald did not include medical care.
While Lave and Seskin256 found associations between air quality and both
254
cardiovascular and cancer mortality, Crocker et al. found neither association.
Crocker et al. found an association between particulate level and pneumonia
mortality, while Lave and Seskin did not. In most analyses that can be compared,
Crocker et al. estimated air pollution effects smaller than those of Lave and
Seskin. This difference may be explained largely by the use of additional
independent variables in the models of Crocker et al.
In general, the regression analyses of cause-specific mortality show
inconsistencies across studies which highlight the sensitivities of these
analyses to the selection of independent variables. The colinearity of air
pollution variables, and other variables related to mortality, limits the
information to be gained from observational studies on the mortality effects
of pollutants at low concentrations.
In summary, many of the cross-sectional mortality studies reviewed above
either yielded only qualitative findings concerning air pollution mortality
relationships or, alternatively, suffer from methodological deficiencies which
make it impossible to accept their published findings regarding pertinent
quantitative dose-response relationships. Still, on the other hand, at least
TO 1QQ 21"23
some of the studies, such as those by Buck and associates ' and Winkelstein,
have yielded quantitative results not convincingly attributable to potentially
confounding or covarying factors and appear to be of use, when appropriately
interpreted in light of certain methodological considerations, in arriving at
quantitative estimates of air concentrations of TSP or SO associated with
increased mortality.
14-86
-------
14.3.5 Lung Cancer Mortality
Exposure to materials found in the ambient air may be associated with
increases in lung cancer under some circumstances. Cigarette smoking is the
uajor known cause of lung cancer, and occupational studies indicate that
significantly high risks of lung cancer are associated with exposure to ionizing
radiation, fibers, or specific metals. The interactions between smoking,
occupations, and ambient air exposure are not well understood.
A number of studies have reported on differences in lung cancer rates in
urban and rural areas. Higher rates are consistently found in urban
lift
areas even after removing the effects of cigarette smoking. Doll and Hill
found increased lung cancer deaths for urban dwellers that might have resulted
from increased air pollution. They reported that the effect of living in an
urban area was insignificant compared with the effect of smoking cigarettes.
The assumption is that the major difference has to do with the ambient air
pollutant exposures. This may not be the case, as there are many other factors
that differentiate urban and rural areas, such as: number of pollutants;
meteorological conditions; occupational and other exposures; and social and
cultural backgrounds. Unless all the differences between urban and rural
communities are controlled for, such comparisons run the risk of being fortuitous
The relationships of community size or population density, as indicators of
varying potential environmental stresses also show a consistent relationship
to lung cancer rates. Again, the impact is considerably less than is
the effect of smoking, and may be related to other urban-rural differences.
142-144
Some investigators have compared lung cancer rates for immigrants
from a specific country with rates for native born living in both countries.
Most of the data suggest that risk for the immigrant, controlling for smoking,
14-87
-------
is intermediate to the risk in the native and adopted countries. Considering
the long latent period for the development of many cancers, this suggests that
in some immigrants the effect of early exposure may develop after emigrating.
However, migration involves a time element, a change in place, and differential
host characteristics. These studies assume that the populations in the native
and adopted countries and factors other than pollutant exposures are similar.
Such assumptions are difficult to appraise, but are more often incorrect than
correct.
T26
Waller, after reviewing evidence from Britain, concluded that air
pollution either alone or in combination with other factors, may contribute
in a minor way to the development of lung cancer He also pointed out the
difficulties in assessing relationships between air pollution exposure and the
development of any chronic condition during a period of rapidly changing
concentrations of air pollution. For example, during the period 1954 to 1965,
the annual mean and peak concentrations of smoke in London decreased signifi-
cantly, as did the concentrations of potential carcinogens such as polycyclic
119
aromatic hydrocarbons, though no significant reduction in SO- was recorded.
197
Wynder and Gori reviewed information relating cancer to environmental
factors. They concluded that individuals were able to control many of the
factors related to cancer risk and thus individual lifestyles were far more
important risk factors for cancer than was air pollution.
Corn estimated relative dose of toxic materials inhaled from various
sources and concluded that the impact of the maximum quantity of air pollution
permitted by the ambient air quality standard was insignificant compared with
that of smoking one pack of cigarettes per day.
Benzo(a)pyrene is a known co-carcinogen and is the one constituent of
particulate matter most commonly monitored in ambient air as an index of
14-88
-------
potential carcinogenic hazard. Increases in total pollution exposure (dustfall,
SOp, trace elements, and polycyclic hydrocarbons) have been shown to be associated
in Japan with increased lung cancer rates in smokers but not in non-smokers.
Smoking also has been shown to increase the risk of lung cancer among asbestos
145 146
workers and uranium miners. There is, however, no evidence that the
concentrations of materials in the ambient air are sufficient to stimulate
similar smoking-associated increases.
1?5
A 1977 report from an international study group concluded that, although
data are not consistent and are affected by various types of indoor pollution,
the products of fossil fuel combustion (probably acting together with cigarette
smoke) are very likely responsible in large urban areas for approximately 5 to
10 cases of lung cancer per 100,000 males per year. On the other hand, from
307 308 312
the above discussion, and as noted by other reviewers, ' ' insufficient
qualitative or quantitative epidemiologic data presently exists to define
clear associations between cancer effects and exposures to atmospheric con-
centrations of either sulfur dioxide or particulate matter.
14.3.6 Summary for Mortality Studies
In the above discussion, numerous studies on associations between mortality
and acute, short-term, or chronic exposures to particulate matter and sulfur
oxides were critically evaluated. Many were evaluated as being flawed
methodologically or their results likely explainable in terms of confounding
or covarying factors to an extent that said findings are taken here as not
being useful in helping to develop quantitative health criteria for the effects
of atmospheric particulate matter and sulfur oxides. Several other studies,
however, were evaluated as being useful for such a purpose and are briefly
summarized in Tables 14-21 and 14-22. Note that the values listed in those
tables for 24-hr and annual average air concentrations, respectively, at
14-89
-------
TABLE 14.21. SUMMARY OF EVIDENCE FOR MORTALITY EFFECTS OF ACUTE EXPOSURE TO PARTICULATE MATTER AND SO,
(NON-EPISODIC)
24 Hour average pollutant
levels at which effects appear
Type
Daily
Daily
Daily
of study
Mortality
Mortality
Mortality
Reference
Martin
and Bradley11
Martin6
Glasser and
Greenburg222
Effects observed
Increases in daily
mortality
Increases in daily total
mortality above the 15-day
moving average
Increases in daily
mortality
TSP (ug/m3)
500-600
(300-500)*
500-600
350-400
S02 (ug/m3)
300-400
(200-300)*
400-500
524-786
o *From supplemental analysis given in this chapter.
-------
TABLE 14.22. SUMMARY OF EVIDENCE OF MORTALITY EFFECTS OF CHRONIC EXPOSURE TO PARTICULATE MATTER AND SO,
I
V£>
Annual average pollutant
levels at which effects appear
Type of study
Geographic Comparison
Geographic Comparison
(214 areas)
Geographic Comparison
Geographic Comparison
Geographic Comparison
Reference
Watanabe and
Kaneko228
Buck and Brown199
Wicken and Buck19
Winkelstein188
Burn and
Pemberton20
Effects observed
Increased mortality
Increased mortality
Increased chronic bronchitis
mortality
Increased mortality
Increased chronic bronchitis
and lung cancer
TSP (ug/m3)
300
200 BS
(300 TSP)**
160 BS
(260 TSP)**
125-140 TSP*
680 BS (winter)
270 BS (summer)
(350 TSP)**
so2 (Mg/m3)
215-266
200
115
not significant
715 (winter)
270 (summer)
* Two-year arithmetic mean with maximum possible flow correction, from Table 14.19.
**Estimated TSP from 100 BS = 200 TSP and 250 BS = 333 TSP (Holland et al. ).
-------
which effects appear represent the best estimate of TSP or S02 levels present
and associated with mortality effects demonstrated by particular studies,
taking into account various considerations discussed in the preceeding text
and Chapter 3. Thus, some of the estimates listed in the tables may differ
markedly from those appearing in the published versions of the listed studies.
14.4 MORBIDITY ASSOCIATED WITH SHORT-TERM POLLUTION EXPOSURES
14.4.1 Introduction
Morbidity studies of short-term air pollution exposures are much less
common in the epidemiologic literature than morbidity studies of 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. For ease of discussion
the studies to be discussed in this section are divided into six categories:
• Episodic morbidity
• Chronic heart and lung symptoms and patients
• Acute respiratory disease
• Aggravation of asthmatic symptoms
• Hospitalization-clinic admissions
• Absences data
• Pulmonary function
Difficulties in either the analysis or interpretation of these classes of
studies will be addressed separately as they appear in this section. Qualita-
tive studies are described only in summary form (Table 14-23). The key con-
clusions derived from such studies are that: (1) clear relationships or
associations exist between various health effects and elevated levels of S0?
and particulate matter, although the data in the studies do not allow for very
14-92
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TABLE 14-23
QUALITATIVE STUDIES OF AIR POLLUTION AND ACUTE
RESPIRATORY DISEASE
Study
Characteristics
Findings
Angel et al.
69
Attack rates of minor respiratory
illness among 85 London workers,
examined every 3 weeks, October
1962-May 1963.
Attack rates were associated
with weekly average smoke
and S02 concentrations.
Levy et al.
70
Schoettlin and
Landau288
Zeidberg et al.289
Cowan et al.290
Greenberg et al.291
Wei 11 et al.292
Carroll293
Hospital admissions for respira-
tory disease in Hamilton,
Ontario, correlated with
sulfur oxide/particulate air
pollution index.
137 asthmatics reporting attacks
on daily occurrence of asthma,
September-December, 1956, in
Los Angeles Basin.
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.
Increased hospital admissions on
heavy pollution days, except at
one hospital far removed from
major pollution sources.
Significantly more asthma on days
of heavier oxidant pollution.
No adjustment was made for
variations in temperature or season
Doubling of asthma attack rates
in persons living in more
polluted neighborhoods. No
adjustment for demographic or
social factors.
Significant association between
grain-dust 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.
14-93
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TABLE 14-23 (continued)
Study
Characteristics
Findings
Phelps294
Meyer295
Glasser et al.296
Chiaramonte
et al.297
Derrick57
Rao298
Goldstein and
Black58
"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.
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.
Disease primarily 1n 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.
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 in Harlem. In 1971 period,
50-90% increase in asthma
visits on 12 days of heaviest
pollution.
14-94
-------
TABLE 14-23 (continued)
Study
Characteristics
Findings
Finklea et al.117
Finklea
et al.122 123
Incidence of acute respiratory
disease, determined at 2-week
intervals, in parents of
nursery schoolchildren residing
in Chicago, December 1969-
November 1970.
Daily diaries kept by 50
asthmatics in each of three
New York City area communi-
ties, October 1970-May 1971.
Acute lower respiratory
illness rates were signifi-
cantly lower among families
living in neighborhoods
where air pollution had been
substantially decreased.
Rates were adjusted for social
class, smoking, residential
mobility, and season of year.
Cannot quantitate pollutant
exposures.
Temperature-adjusted attack
rates significantly correlated
with total particulates in two
of the communities. Increase
in relative risk from days of
light to heavy pollution was
relatively small. High turnover
in reporting panels.
'Reference 251
14-95
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precise quantitation of the specific air concentrations at which the health
effects occur; (2) the particular health effects observed with elevated S02
and particulate matter air levels range from temporary pulmonary function
decrements and biochemical changes to rather serious acute respiratory diseases
and exacerbation of preexisting disease processes; and (3) particular population
subgroups (e.g., the elderly, infirm, and children) are at special risk for
manifestation of deleterious health effects associated with short-term S02 and
particulate matter exposures.
Included in the further discussion below of quantitative studies of morbidity
associated with short-term exposures to airborne sulfur oxides and particulate
matter is a series of studies conducted by the U.S. Environmental Protection
Agency, most of which were the result of research conducted under the Community
Health and Environmental Surveillance (CHESS) Program,* an integrated set of
*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-650/1-74-004 (May 1974). The
controversy eventually led to the 1974 "CHESS Monograph" becoming the subject
of U.S. Congressional oversight hearings in 1976. Subcommittees 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 imple-
mented 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. 1257, 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.
14-96
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epidemiologic studies performed between 1969 and 1975. The health status of
volunteer participants was either ascertained during single contacts or followed
for time periods of up to nine months. These health measures were coordinated
with air pollution observations from the residential neighborhoods of the
study participants. Areas selected for study were chosen to represent pairs
or larger groups exhibiting a substantial pollution exposure range.
Approximately ten CHESS Program studies are cited and discussed in the
remainder of this chapter.113,117,122.123,212,213,214,215,297,306 Jhe rationale
for inclusion here of these studies, and qualifications regarding their use,
are set forth in Appendix A of this chapter. Generally the studies cited have
been included on the same basis as other non-CHESS studies, ie. in light of
their potential usefulness in yielding information on quantitative relation-
ships between health effects and air concentrations of sulfur oxides and
particulate matter. We have attempted to limit the discussion to studies
which have undergone peer review and have been published in the open scientific
literature apart from internal EPA reports.
Although the 1974 CHESS Monograph itself is not cited or relied upon in
this chapter, these considerations reflect the spirit of recommendation 3(b)
^(continued)
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.
14-97
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of the IR (1976) that the 1974 Monograph not be used as a source of specific
quantitative data or interpretations thereof to serve as the basis for regu-
latory decisions without explicit qualifications being provided.
14.4.2 Episodes
Several British studies have been published on health effects associated
with short-term exposures to sulfur oxides and particulate matter which appear
to provide useful information on quantitative dose-effect relationships.
59
Waller and Lawther, for example, reported that when smoke (BS) con-
centrations in London increased ten-fold 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
ug/m . S02 also increased [maximum about 2860 ug/m (1.0 ppm)] but H^SO. did
not, on the basis of washings from impactor slides. Most of the mass of
particulate matter was determined by microscopic studies to consist of particles
less than 1 urn in diameter.
52
Lawther 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." During the month of January
1954, an episode of relatively high pollution resulted in a sharp increase in
the number of patients whose condition worsened as 24-hour smoke (BS) increased
to about 400 pg/m (470 ug/m TSP) and 24-hour S02 increased to about 450
o
ug/m (0.15 ppm). Figure 14-4 shows graphically the effects of high pollution
levels observed in the 29 bronchitic patients studied in January 1954.
14-98
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wt or
aeon
woasc
tCTTCO
t
4
0
4
I
!
u
--MN
u
OS
O4
OS
02
Ol
o
I? It 19 2O 21
22
Figure 14-4.
EffectrOnj-Bronchitic Patients of High Pollution Levels (January
1954). ' (The figure represents the effect on bronchitic
patients of increased pollution levels; patients stated whether
they regarded their condition as "worse" or "better".)
14-99
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In the winter of 1955, the study was extended to include 180 patients in
the London area. The prevalence of 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 prevalence increased with increases in smoke (BS) to about 350
ug/m3 (425 ug/m3 TSP) and increases in S02 to about 300 ug/m . The data suggest
that during the winter months, SO,, 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 consistent 24-hour concentration
of less than 250 ug/m (325 ug/m TSP). The few short higher peaks in smoke
(BS) after this time had little effect on illness status. These investigators
state that the results are not indicative of causal relationships, but suggest
that the measurements of smoke (BS) and S0? are at least indicators of whatever
is the cause.
A later report by Lawther et al. 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 rela-
tion 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
author stated that, although exact relationships between the responses of
patients and the concentrations of smoke and SO^ could not be determined, the
minimum pollution leading to any significant response was about 500 ug/m
14-100
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(0.17 ppm) SOp, together with about 250 ug/m smoke (BS). Inspection of the
information provided in the report, however, could lead to the conclusion that
this is a conservative estimate. Some less consistent, but significant effect
3 247
may have been occurring with S02 concentrations of 250 ug/m or more. 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 response to
higher concentrations of pollution near the end of the winter. Although the
concentrations of smoke and SOp closely correlate, examination of the data
again suggests that often higher concentrations of SOp 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 SOp 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 SO-
pollution 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 declines in concentrations were from 342 ug/m BS to 129
ug/rn BS (225 ug/ni TSP) and from 299 ug/ni to 264 ug/ni S02. Lawther
et al. also emphasized that these responses may reflect the effects of brief
exposures to maximum concentrations several times greater than the 24-hour
average.
These studies among chronic bronchitis patients in London continued into
the 1970s as the frequency of periods of high pollution declined. There were
pen
no sharp increases reported in illness scores in the winter of 1969-70, nor
in the winter of 1974-75. 251
^
Fry et al. reported that home visits for respiratory throat disorders
increased from a normal level of about 85 to 150 per day for their clinic
patients during the air pollution episode in 1962. However, this rate represented
14-101
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only 2.4 illnesses per 1000 patients, with no deaths. In the 1952 episode of
comparable length, the illness rate was 9.5 per 1000 patients, and there were
two deaths. Perhaps their most significant of their observation was that
their bronchitis patients were affected but their asthmatic patients were not.
196
Greenburg et al. found during a New York episode that visits to emergency
rooms for cardiac or respiratory illness increased as CoHs approached 3.0 (260
3 3
ug/m ) and 24-hour S0? concentrations reached about 715 ug/m (0.25 ppm) as
air quality improved if the high levels of pollution had any immediate effect.
However, lung function deteriorated slightly over the study period as air
quality returned to more usual conditions, and therefore no immediate effect
could clearly be attributed to the air pollution levels observed although it
could not be ruled out the post-episode lung function deterioration might
reflect prolonged continuing effects of the pollution episode.
Results also obtained at Rotterdam have shown that when the S0? con-
3 3
centration rose for 3 to 4 days from about 300 ug/m to 500 ug/m (0.11 ppm to
0.19 ppm), the number of admissions into hospitals for respiratory tract
30?
"irritation" rose, especially in older individuals. In one episode in
312
December 1962 p. 69, local hospital admissions increased for cardrovascular
diseases for those 50 and older land mortality may have increased). Smoke was
about 500 ug/m3 (24 hour) and S02 was about 1000 ug/m3.
82
Stebbings et al. reported on the effects of an episode of high pollution
in Pittsburgh on pulmonary function measurements in schoolchildren. Forced
expiratory volume and forced vital capacity were measured in 270 fourth,
fifth, and sixth grade children attending six schools. Four of the schools
were in the high-pollution area in which 24-hour TSP levels had exceeded 700
3 3
ug/m and S02 levels had exceeded 300 ug/m (0.1 ppm). Measurements of air
pollution and pulmonary function were not initiated until after the peak of
14-102
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the episode had passed, but it was speculated that lung function would improve
as air quality improved if the high levels of pollution had any immediate
effect. However, lung function deteriorated slightly over the study period as
air quality returned to more usual conditions, and therefore no Immediate
effect could clearly be attributed to the pollution levels observed, although
it could not be ruled out the post-episode lung function deterioration might
reflect prolonged continuing effects of the pollution episode.
216
Stebbings and Fogleman, also reported on pulmonary function test
results on 224 parochial schoolchildren during and after the Pittsburgh air
pollution episode of November 1975, then reanalyzed to determine whether a
small subgroup of susceptible children could be defined. Individual regressions
of FEV y5 and FVC on time over the six-day study period were calculated, and
the distributions of individual slopes for the four exposed and two control
schools were compared. Excesses of strong upward trends in the exposed areas
would suggest effects of suspended particulate air pollution by indicating
significant improvement following the episode. A highly statistically significant
excess of strong upward trends in the FVC among exposed students was observed,
and was consistent by sex and by school within sex. Approximately 10 to 15
percent of the students appear susceptible to an average impairment of about
20 percent of the FVC. The findings are limited by the small number of subjects
with strong post-episode upward trends in the FVC, and by lack of validation
or replication of the study design, but do suggest that episode levels of
suspended particulates induce lung damage, and that this may occur only in a
small susceptible subgroup. Children with low baseline pulmonary function
values, a history of asthma, or with acute respiratory symptoms immediately
following the episode were not found to be especially susceptible to these
14-103
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effects of suspended participates. No effect of day-of-week, learning, or
other potential intervening effects (including regression toward the mean)
were noted.
Carnow et al. conducted a study specifically designed to Investigate
dose-effect relationships between air pollution and morbidity from respiratory
disease in patients during the late 1960s with chronic bronchitis, as they
related to air pollution exposure in Chicago. Patients, maintained daily
calendars of symptoms, grading the severty of their illness from 0 to 4. SCL
measurements were obtained from eight continuous monitors and from 20 additional
stations where 24-hour mean measurements were obtained 3 days a week. From
the data and the square mile grid covering the city, an index of exposure was
developed for patients based on the locations in which they spent most of
their daytime and nighttime hours. In patients over 55 years of age with
grades 3 and 4 bronchitis, increases in symptoms were associated with higher
SOp levels on the same day or on the previous day. Increased symptom rates
were reported when the 24-hour SO,, concentrations were 143 to 257 ug/m (0.05
to 0.09 ppm). However, the failure to include data on TSP levels, on
occupational exposures, or on smoking habits detracts from the value of this
study.307
173
Burrows et al. related the occurrence of symptoms recorded daily by
patients with chronic bronchitis to continuous monitoring data for gaseous
pollutants. No relationships were found, except for hydrocarbons, when data
were adjusted for season and daily temperature. It was concluded that 24-hour
concentrations of SOp played no major role in producing symptoms in people
with CRD but temperature probably did. This study was performed in similar
14-104
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patients in the same city and at about the same time as Carnow's, and the two
appear to cancel each other.
190
Stebbings and Hayes report on a study in New York during 1971-1972.
The authors studied the relationship between daily fluctuations in air pollution
levels and the aggravation of symptoms in over 300 elderly panelists in the
New York City Metropolitan area in 1971-72. Candidates for the study were
interviewed and questionnair information was used to classify them as well,
heart, lung, or heart-lung panelists. Eligible candidates had to reside
within 1.5 miles of a monitoring site and had to be 60 years of age or more.
Panelists were included in one of four groups identified as "well"; "lung"
(with respiratory symptoms); "heart" (with cardiac symptoms); and "heart-lung"
(with both respiratory and cardiac symptoms). The study lasted 34 weeks
during which time each panelist was asked to submit weekly diaries through the
mail indicating the days on which their symptoms were worse or better than
usual. Panelists who submitted diaries for fewer than 11 weeks were excluded
from the analyses, of which there were many. Symptoms about which information
was requested differed for each panel but together included the presence of
angina or chest pain, wheezing, cough and phlegm, shortness of breath and feet
swelling. Panelists also gave information on the presence of cough, colds or
sore throat, doctor visits and hospitalizations.
Air monitoring consisted of measuring 24-hour mean levels of SOp (West-Gaeke),
TSP, RSP, SS, SN, and NOp (Jacobs-Hochheiser method); the quantitative data
for S02 and NOp for individual days may be less than reliable. Weather data
used in the study included maximum and minimum daily temperatures and 24-hour
relative humidity.
14-105
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This report contained a discussion of the method then available for
analyzing the data collected and the probable effect of its inadequacies. The
authors concluded, however, that despite the qualification and limitations of
the methodology, the proportion of the respondents suffering more symptoms on
high pollution days than on low pollution days was sufficiently high that the
relationships could be detected in the panels as a whole.
Exacerbation of symptoms in the "well" panel was associated with elevated
levels of SCL, RSP, SS, and SN; a similar but weaker pattern was found for the
"lung" panel. Symptoms in the "heart" panel related only to SN and TSP.
Temperature showed a positive relationship to symptom rates in the "heart"
panel, but consistent relationships between temperature and symptoms were not
found in the "well," "lung," or "heart-lung" panels. The data suggested no
threshold for the effects, and no lesser susceptibility in the well panelist
than in the elderly panelist with chronic illness. The high and low ranges of
24-hour pollution concentrations from which the observations were developed
were TSP, <60 and >200 ug/m3; RSP, <30 and >60 ug/m3; SS, <6 and >12 ug/m3;
3 "3
SN, <2 and >8 ug/m ; and S02, <40 and >100 pg/m . The range for minimum
temperatures was between <20 and >50°F.
14.4.4 Panel Studies of Acute Respiratory Disease (ARD)
In addition to methodological problems similar to those mentioned for
chronic respiratory disease studies, lack of information on specific agents,
/
'and exposure to them, may pose a problem in correct classification of acute
respiratory diseases. Respiratory tract illnesses, especially in childhood,
are critical as both pathogenic and natural history events. Assessment by
questionnaire alone is difficult to validate and such history may be inconsistent.
On the other hand, definitions and criteria utilized in determining the presence
14-106
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and nature of acute respiratory illness are important, but not as critical, in
that any changes in symptomatology from a baseline (or lack of symptoms) may
indicate an acute event, although this does not imply that criteria (symptom,
duration and severity dependent) should not be utilized.
For acute conditions, the mode of assessment is more difficult than for
chronic conditions in that almost continuous monitoring is required. The use
of daily dairies is one mode of assessment, although not lacking in criticism.
Symptom information in daily dairies often suffers from errors of omission and
from the likelihood that the subjects would complete the dairy at the end of
the period of requested recall, which is likely to produce errors of commission.
Frequent interviews have been shown to minimize these errors. Gaps in information
are the most difficult problem in evaluating acute respiratory illness occurrence
in individuals. Meteorological factors are important, perhaps more important
than the pollutants. Other covariables and intervening variables of importance
include smoking, alcohol consumption, occupational exposures, housing, family
size, and structure. Although acute respiratory illnesses may be better
indicators of effects of pollutants, temporal analysis of such effects may
produce conflicting findings related to covariables, intervening variables,
the presence of endemic and epidemic infections, reporting biases, and the
249
environmental interactions of pollutants and weather.
McCarroll et al. studied daily symptoms (from weekly interviews) of
over 1800 individuals in three New York City housing projects between 1962 to
1965. This represents 35,400 person-weeks of data. They found that cough
frequency was related to SOp concentration but not particulate matter. In a
one
further report, McCarroll et al. showed several period of increased S02
with associated increases in respiratory and irritation symptoms. One episode
14-107
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(December 1962) saw a shart increase from 0.1 ppm to over 0.2 ppm in 2 days
accompanied by increased symptoms. During another episode S0? increased
slowly from 0.05 ppm to about 0.14 ppm over a 3-week period (October 1963)
with increased symptoms. A third episode occurred in March 1964, with levels
exceeding 0.3 ppm and increased symptoms (although there was some lag in
symptoms), and corresponding increases in school absenteeism.
pnr
McCarroll and colleagues also demonstrated increased prevalence rates
for common colds and cough in children and adults in 6-month periods surrounding
winter and summer controlling for smoking. However, these were often inconsistent
with S0~. Summer particulates (CoH) were positively correlated with respiratory
symptoms with some increase in prevalence rates for days with CoH above 1.50
significant for children. With inclusion of meteorological variables in
on?
multiple regression, the incidence rate of common colds was found significantly
independently related to S02 in some seasons. The prevalence rate of the
common cold was significantly related to CoH and meteorological variables,
one
especially in the spring of 1964 (R = 0.93), and "epidemic period."
?08 ?09
Cassell et al. ' showed two contrasting trends in the relationship
of pollutants to acute respiratory illness in winters, storms and air pollution
episodes, the former of which usually hiding the effect of the latter in most
207
analyses. Separated, the air pollutants (CO, COH, SOp) measured within a
quarter-mile of subjects correlated significantly with common cold incidence
and prevalence rates in winter (after controlling for weather variables). The
winters during this study had mean daily S02 levels of 0.17 ppm or greater,
207
mean daily COH of 2.20 or greater, and mean daily CO of 2.94 ppm or greater.
210
Individuals sensitive to the effects of air pollution and weather were delineated.
The young (under 10) reacted the greatest to high air pollution combined with
14-108
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low temperature. Reactions in sensitive individuals were also of greater
duration and severity. The reporting of acute illness varied proportionately
with social status but did not change the relationships mentioned; the different
social status groups *eing followed equivalently and simultaneously.
French et al. conducted an ARD study in the New York communites of
Bronx, Queens, and Riverhead in 1970-1971. Telephone interviewer made biweekly
calls to mothers of families enrolled in the study to inquire whether any
family member had developed upper or lower respiratory illness in the 2 weeks
and, if so, whether a doctor had been consulted and on how many days activity
was restricted. If an individual was reported to have both upper and lower
respiratory symptoms, the illness was classified as lower respiratory disease.
The major response variables were the number of respiratory illnesses per
hundred person-weeks of observation (the attack rate) and an arbitrary severity
score, which reflected physician visits, fever, and restricted activity.
Selected interviews were repeated a few days after the initial call and
concordant results were obtained in over 90 percent of those previously
reporting ARD and 98 percent of those previously denying ARD; this shows
reproducibility but not validity of reported illness. Total and lower respiratory
illness attack rates in Riverhead tended to be lower than in either Queens or
Bronx, is consistent with the pollution gradient. Based on NYC DAR levels in
3
1970, this would indicate more morbidity in areas with S02 of 160 ug/m (Queens)
O O
or more and 82 pg/m TSP or more (Queens) compared to 39 (jg/m TSP in (Riverhead).
See Appendix A for further discussion regarding the results and their
interpretation from this EPA CHESS Program study.
French et al. also reported on an ARD study in families of nursery
school children in Chicago for one year (12/69-11/70). A census was obtained
14-109
-------
on families agreeing to participate using a standardized questionnaire.
Migration, crowding and education were obtained and compared between areas.
Telephone interviews by trained interviewers were made fortnightly to the
mother or guardian concerning new respiratory illnesses and their symptoms,
and any medical consultation. Lower respiratory illnesses (LRI's) were
limited to chest colds with a persistant productive cough, croup,
bronchiolitis, or pneumonia. A sample of replies were compared to physicians'
records to validate reports. There were 2705 fathers, mothers and children
(ages 112) participating. Areas of relative pollution were grouped into two
categories (see Table 14-24). All families resided within 1 1/2 miles of an air
monitoring station. There was an increased attack rate of ARD in all family
members with 3 or more years residence in that area. Except for children
under 3, all family members in the high pollution areas had an excess risk of
acute LRI (Table 14-25). Upper respiratory illness (URI) rates were higher in
all family member in the high pollution areas. These higher ARD rates were
still significant after adjusting for family smoking (Table 14-26); The pollution
effect was independently significant. See Appendix A for further discussion
regarding the results of this EPA CHESS study and their interpretation.
TABLE 14-24. CHICAGO MEAN ANNUAL LEVELS OF POLLUTANTS IN AREAS, 12/69-11/70
LOW
HIGH
so2 (ug/m3)
57
106
TSP (ug/m3)
111
151
SS (ug/m3)
14.5
16.0
14-110
-------
TABLE 14-25 -Acute Reipintory Illneii Among Families Living
Two Metropolit»n Areas
r«mlly
Jt£ment
Chica|o
Fathers
Mothers
Older
tiblings
Nursery
sxhool
Children
Younger
tiblmgs
New York
Fathers
Mothers
School
children
Preschool
Children
Community
Pollution
[ipoiurt
Intermediate
Highest
Intermediate
Highest
Intermeddle
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Low
Intermediate (pooled)
Lo*
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
Low
Intermediate (pooled)
family
Cfcinftd
AUdreu
Dunnf
Previous
JSyr
No
No
Yes
Ye i
No
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
Ko
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
ln»oH»in|
Upper
Tract
1.00(2.59)'
1.21
1.27
1.20
1.00(3.96)
•l.*6
14
.24
.00(4.09)
.37
.14
.17
.00(7.57)
.12
.05
.21
.00(7.65)
.27
.16
.65
1.00(1.77)
0.95
0.8S
065
1.00(2.51)
091
1.04
0.63
1.00(2.60)
1.09
093
094
1.00(2.71)
1.26
1*£
1.19
ht»ehnn|
Lower
Tract
1.00(042)
2.29
1.10
0.90
.00(0 64)
.45
.53
.22
.00(0.63)
44
0.81
0.82
1.00(1.63)
1.30
1.25
1.53
1.00(2.64)
0.93
0.90
1.00
.00(1.66)
.39
.27
.35
ooa.Boi
.56
.67
.12
.00(325)
.23
.08
.21
.00(547)
.25
0.73
1.21
in
All Acirtt
ReipirJlory
hlnen
1.00(301)
1.36
1.2S
1 14
1.00(4 60;
1.46
1.19
1.28
1.00(4.73)
130
1.09
1.25
1.00(970)
1.15
1.09
1.24
1.00UO<9)
1.18
1.09
1.43
1.00(3.431
1 16
0.95
089
.00(4.31)
.18
.30
.20
.00(606!
.16
.00
.18
.00(8. IB.1
.25
0.98
1.15
'Figures In parentheses indicate base nte per 100 person weeks ot risk.
14-111
-------
TA
BLE 14-26 -Smoking
( family Segment
t
Mothers
Old;'
Nurvery school
Students
Younger
siblings
tie* Ys'k
fathers
Mothers
School
Children
Preschool
Children
•adjusted. Acute Respiratory
Community
Air Pollution
Exposure
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Intermediate
Highest
Low
Pooled
Intermediate
Low
Pooled
Intermediate
Low
Pooled
Intermediate
Low
Pooled
Intermediate
Disease Attack Rates*
Relative Risk of Acutt
Respiratory Illnet:
1.00(280)
1.33
1.00(476)
1.25
1.00(7.04)
1.18
1.00(035)
1.02
1.00 (9 <1)
137
1 00(1.58)
1.4}
1.000.72)
1.55
1.00(397)
1.09
1.00(6.12)
1.10
metropolitan Chicago
14-112
-------
All ARD diary studies experienced attrition over time and some
methodological problems plagued them. It is likely, however, that families
exposed to high levels of urban pollution experienced higher ARD attack rates
than did those less exposed.
A couple of studies have investigated relationships between the incidence
of acute respiratory disease and very high air pollution concentrations.
Kalpazanov et al. studied by regression analyses the relationship
between the daily number of newly reported cases of influenza during an
epidemic in Sofia, Bulgaria, and specific meteorologic or air pollution
factors. The number of new cases was taken from the official registration.
Sundays and Mondays were eliminated since it was shown that many Sunday
illnesses were not recorded until Monday. Aerometric samples were collected
daily from 8:00 a.m. until noon in the city center. Correlation coefficients
were developed for each factor for the day on which the illness was reported,
for the previous day, and for 2 days prior to the reporting of the illnesses.
Results indicated that the same-day measurements of air temperature,
visibility, S02, oxidants, cloudiness, and wind velocity all related to the
number of illnesses reported. Oxidants, however, showed a negative
correlation. On the day prior to the reporting of illnesses, only S0? was
related significantly (r = 0.6); 2 days prior to the reporting, nitric oxides,
formaldehyde, and oxidants were associated, oxidants again with a negative
correlation. The authors compared these results with those of an earlier 1972
influenza epidemic also in Sofia in which almost the same protocol was
followed. In 1972, but not in 1974-75, dust was associated with illness
reporting; a possible explanation of this was the much lower dust measurements
in 1974-75. Nitric oxides were also lower in 1974-75, while SOp was about
three times higher.
14-113
-------
14.4.4 Aggravation of Asthmatic Symptoms
Cohen et al. studied attack rates in 20 asthmatics over a period of 7
months and showed significant correlations between reported attack rates and
temperature as well as between reported attack rates and 24-hour mean air
pollution levels after the effect of temperature had been removed from the
analysis. Temperature showed by far the strongest association with attack
rates in multiple regression analyses. However, SO^, TSP, SS, SN, and soiling
index (CoHs) each explained a significant portion of the residual after the
effect of temperature had been removed. After temperature and any one pollutant
had been removed, none of the other pollutants explained a significant amount
of the variation in attack rates. Thus, the overall effect of air pollution
can be attributed to no specific pollutant. Significant 24-hour concentrations
3 3
were assessed as: TSP, 150 ug/m ; S0?, 200 ug/m (0.07 ppm); suspended sulfates
3 3
20 ug/m ; or suspended nitrates, 2.0 ug/m .
Kurata et al. found no associations between weekly mean concentrations
of S02, N02, 03, or CO and asthma symptoms. In this multifactorial study,
weekly mean concentrations of SO,, averaged less than 280 ug/m (0.10 ppm), but
3
occasional weekly highs reached 500 ug/m (0.17 ppm). It may be, however,
that asthma attacks would relate much more closely with daily means or daily
peaks than with weekly mean concentrations of pollution.
Many studies of asthma failed to evaluate many relevant factors, including
medication (steroids), humidity, exercise, daily temperature changes, other
pollutants, pollen, emotional factors, and exposure to smokers at home or
work.
14.4.5 Hospital/Clinical Admission Studies and Absence Studies
Visits to the emergency room provide a health outcome measure of a more
severe type than is generally provided by physician visits. Emergency room
records are frequently more complete, especially as to the acute episode, than
14-114
-------
are physician records. For these reasons, such disease outcomes have been
utilized in several studies of the acute health effects of air pollution.
Frequently, these studies have examined cause-specific reasons for the visits,
such as asthma. Most of these studies have been temporal in nature, although
some have compared of visits to hospitals in different regions of the city.
Data organization and analyses are usually similar to analyses of daily mortality.
Unfortunately, emergency room visits have the same problems with denominators
and reference populations as do other types of visits or medical records.
Also, it is difficult to relate spatio-temporal exposures to specific health
events or to the perceptions of those who come into the emergency room.
Finally, with the increased use of the emergency room as a family practice
center, fewer visits are associated with any acute exposure or attack.
Although hospital admissions have some of the same problems associated
with emergency room visits, more information is generally available from the
records. Hospital studies are limited, however, in terms of the finite number
of people that can be admitted.
During the winter of 1972 or 1973, Kevany studied 2364 admissions to
study hospitals. Data for cardiovascular disease and respiratory disease
admission rates showed very low (r <.30) but significant correlations for both
sexes between heart diseases and smoke or S0?. Insufficient exposure data
were provided.
54
Heimann studied the effect of short-term variations in pollutant levels
on the frequency of clinic visits for Boston patients with chronic respiratory
disease. These studies were conducted during periods of higher pollution in
1965 and 1966. Although indicated associations were less than in New York
during episodes, there was a positive association between pollution levels and
14-115
-------
clinic visits even though the maximum 24-hour geometric means from 20 stations
were 226 ug/m3 for high-volume TSP, 350 ug/m3 (0.12 ppm) for S02> and 2.2 for
CoHs.
17 T\
Sterling et al. ' used data from a medical insurance group to obtain
information on relationships between air pollution and hospital admission for
"relevant diseases" among about 10,000 individuals in California. Daily
pollution concentrations were given as the mean of the maximum and minimum
values of measurements taken at eight stations, 5 to 10 weeks apart, from
March to October. After allowing for the confounding effects of day-of-week,
deviation of stay, higher relevant admission rates occurred on those days
among the highest third of sulfur dioxide pollution than on those days among
the lowest third. The sulfur dioxide concentration mean for was about 45
ug/m (0.015 ppm); concentrations on the highest pollution day were not reported)
They also correlated with NO^, OX, TSP, but not with temperature or humidity.
Correlations were low and SOp/TSP concentrations were low. Consequently, one
of the other pollutants with which illness rates were associated (CO, N0?, or
03) may have been more significant. The indicated association for S0? may
have been caused by the interrelationships between pollutants. It is difficult
to state to what extent either SO or TSP were causally involved in producing
the health effects observed.
p
Illness data were obtained in many of the early s;evere pollution episodes. '
This information did little more than confirm the mortality results, though
there was some evidence that the increase in illness was not as large in
percentage terms as the increase in deaths, and the effects were not so sudden.
Martin examined hospital admissions for the winters of 1958 to 1959 and 1959
to 1960 and found, after adjustment for day of the week and correction for
15-day moving average, significant correlations for both
14-116
-------
cardiovascular and respiratory conditions with smoke and sulfur dioxide. The
average deviations by group are shown in Tables 14-27 and 14-28 and show more
irregularity than the mortality data.
274 69
Fletcher et al. and Angel et al. followed 1,136 working wen aged 30
to 59 in West London by surveys at 6-month intervals. The surveys included
collection and measurement of morning sputum volume and FEV.as well as data
from respiratory symptom questionnaires. Expected patterns of decline in lung
function with age occurred, and this was most rapid in cigarette smokers with
low lung function to start with. Another finding was a decrease in sputum
volume in men with constant smoking habits most consistently in the winter
samples. During six years of study, there was a decrease in mean sputum
volume during the first morning hour from about 1.5 ml to about 0.75 ml,
associated with a decrease in smoke (annual) from 140 ug/m (234 ug/m TSP) to
3
60 ug/m . Possible changes in cigarette tars, and in methods of smoking could
251
have influenced this result. During the winter of 1962 to 1963, they
intensively monitored a subsample of 87 men. The incidence and prevalence of
respiratory illnesses were associated with both BS and S0~, though the prevalence
was more related to smoke. Weekly concentrations were about 300 ug/m BS (370
ug/m3 TSP) and 400 |jg/m3 S02-
Studies of the acute effects of air pollutants and exacerbations in
chronic respiratory disease related to pollutant exposures have been conducted
by various investigators using absenteeism records. The use of these records
is complicated by the lack of shorter illnesses, the specific diseases (if
really present), the nature of the population under study, the absence of
weekend information, the absence of co-morbidity information, the absence of
covariable information (including smoking), and by such variables as day-of-week
14-117
-------
TABLE 14-27. AVERAGE DEVIATION OF RESPIRATORY AND
CARDIAC MORBIDITY FROM 15-DAY MOVING AVERAGE,
BY S02 LEVEL (LONDON, 1958-1960)
S09 Level
(pg/m3)
400-499
500-599
600-799
800-899
900+
TABLE
Smoke Level
(pgAi3, BS)
500-599
600-699
700-799
800-1099
1100+
Number
of days
9
6
9
6
5
Mean
Deviation
2.2
5.1
6.9
12.8
12.8
14-28. AVERAGE DEVIATION OF RESPIRATORY AND CARDIAC
MORBIDITY FROM 15-DAY MOVING AVERAGE,
BY SMOKE LEVEL (BS) (LONDON, 1958-1960)
Number
of days
9
6
9
8
7
Mean
Deviation
3.2
-0.7
2.4
4.9
12.9
14-118
-------
effects, season, holidays, etc. Nevertheless, these studies have been meaningful,
when appropriately done and when some of the shortcomings have been overcome.
Dohan and Taylor and Dohan studied relationships between 24-hour air
pollution concentrations (measured biweekly) and respiratory Illnesses lasting
more than 7 days in female workers in five United States cities. The workers,
all with one company, received insurance payments after the seventh day of
illness when a physician attested to the illness. Over a period of 3 years
(1957-1960), illness absence rates were related to measured concentration of
suspended particulate sulfate but not to TSP (range 100 to 190 ug/m ), benzene-
soluble organics or specific trace metals. Among the five cities the lowest
o
case rate was associated with mean 24-hour sulfate concentration of 7 ug/m
and the highest rate was associated with mean 24-hour sulfate concentrations
of 20 ug/m3.
68
Ipsen et al. studied employees from the same company but restricted
their investigations to one city and approximately 20,000 employees. As an
indication of illness frequency, the sum of dispensary visits during a particular
week was divided by the average working population. Air monitoring data were
obtained from the Department of Community Health Services of the City of
Philadelphia, Air Pollution Control Section. Data obtained included daily
measurements of TSP, suspended sulfates, and soiling index (CoHs), but not
SOp. Results indicated that periods of high particulate sulfate levels and
low temperatures were associated with high morbidity and that low sulfate
levels and high temperature were associated with low morbidity. No pollutant
had a notable effect over those of weather variables, but the sum of the air
pollutants, although actual concentrations were not reported, were said to be
positively correlated with prevalence measured on the same day, or with a lag
14-119
-------
of 7 days. This study did not consider the significant age differences,
smoking habits, or differences in weather and climate among these cities.
Gregory60 found that in the 1950's, sickness absences at a Sheffield
steelworks increased as monthly mean concentrations of smoke (BS) and SCL
increased. The monthly data provide little information relative to the actual
effective air pollution values. These original data were reviewed by Holland
et al. who concluded that rough judgment estimates of the concentrations
associated with increases in sickness absences were 24-hour means above 1,000
3 3
ug/m for smoke (BS) and above 850 ug/m (0.3 ppm) for SO^.
Gervois et al. made a comparison of sickness absence records of French
employees, with daily variations in smoke, S02, and temperature, for 89 days
during a winter season. Although pollution concentrations were similar in
each of two towns involved in the study, positive associations between pollution
and illness were obtained in only one. In this town, some association was
found after adjusting for temperature. Although the daily pollution data were
not given, the highest 24-hour mean values in the town with the positive
3
association were about 200 ug/m for both smoke and SO-. The mean values for
the 3-month period were 53 ug/m for smoke and 37 ug/m for S02; therefore, an
estimate of higher values associated with increased illness could be between
100 and 200 ug/m for both smoke and SOp.
Verma et al. reported that in a multiracial population of males and
females 16 to 64 years of age who worked for an insurance company in New York,
minimum respiratory disease absences occurred on hot days (maximum temperature
>76°F) when the 24-hour mean S02 levels were low (29 to 143 M9/m3; 0.01 to
0.05 ppm). Higher S02 levels increased absence rates. On cooler days (maximum
temperature <50°F), when S02 and suspended sulfates both were high, respiratory
14-120
-------
Illness absence rates were highest. Air pollution data for this study were
provided by the Department of Air Pollution Control of the City of New York
but information for particulates was not reported.
20
Burn and Pemberton found that incapacity for work due to bronchitis
among Sal ford, England, workers exceeded the expected number by a factor of
two when 24-hour mean smoke concentrations exceeded 1000 ug/m for 2 consecu-
tive days, thus relating bronchitis morbidity to smoke. It is possible,
however, that the episode conditions indicated by smoke concentrations above
1000 ug/m may have included sufficient S02 or derivatives (HpS04 or sulfates)
to produce the increased morbidity.
Additional information on the relationships between air pollution concen-
trations and absences from work has been reported from the British Ministry of
62
Pensions and National Insurance . This information indicates that sickness
absences (October 1961 to March 1962) for bronchitis, influenza, arthritis,
and rheumatism all occurred more frequently in high-pollution areas. Daily
pollution measurements were not provided, but data from five areas in Scotland
and around London showed correlations between bronchitis and pollution that
were stronger for S0? than for smoke. In these areas, the lowest bronchitis
inception rate appeared to be related to smoke levels between 100 and 200
3 3
ug/m and SOp between 150 and 250 ug/m (0.053 and 0.081 ppm). In South
Wales, however, more bronchitis appeared to be associated with lower pollutant
concentration, and lowest inception levels appeared to be less than the values
stated for the other study areas. The cause of the higher bronchitis rates in
South Wales is not clear.
14.4.6 Pulmonary Function Studies
7ft-ftl
Lawther et al. have reported on relationships between ventilatory
function measurements in four subjects and daily concentrations of smoke and
14-121
-------
S0? from 1960 to 1971. The tests performed daily included forced vital capacity:
forced expiratory volume, maximum midexpiratory flow, and peak expiratory flow
rates. During the period of study, 24-hour smoke concentrations ranged from
10 to 650 ug/m3, and 24-hour S02 ranged from 50 to 1500 ug/m3. Increases in
S02 were most consistently associated with poorer test results. However,
small decreases in function were associated with large increases in S02- Peak
flow rates in all subjects were related significantly with either smoke or S02
(p < 0.05), but were reduced by only 4 percent.
Emerson conducted weekly spirometric measurements on 18 patients with
chronic airway obstructions during 1969-1971 in London. They found them (FEV,
and MEFR) to correlate with changes in atmospheric conditions and with air
pollution. FEV, was more correlated with temperature. Average smoke (BS)
3
concentrations were 45 ug/m together with average SOp concentrations of 190
ug/m (0.07 ppm) pollution figures were averaged for 5-day periods while
operometric measures were made on specific days. Only one subject had significant
responses. This is a weak study ' although some authors consider it
to demonstrate levels of no effect.
83
Ramsey studied bronchoconstricting tendencies and pulmonary function on
a daily basis over a 3-month period in seven male, non-smoking asthmatics 19
to 21 years old. Three spirograms were produced each day at hourly intervals.
A Warren & Collins 13.5 liter respirometer was used. The three values were
averaged for FEV^^ Q, MEFR, MMFR, and flow rate. No information was provided
on the method and techniques for calibrating the instrument. Results were
analyzed by multiple regression, and values were considered significant only
when p < 0.001 (r > 0.42). Results showed that in three of the seven subjects,
one or more of the pulmonary function tests (MEFR, MMFR, flow rate, 10 to 25
14-122
-------
or 50 percent volume) was correlated with mean air temperature on the day of
the tests or on the previous day. Two subjects also showed correlation, each
in a single test parameter, with barometric pressure on the previous day, and
two showed positive, not negative, correlations between specific test results
and daily mean ozone concentrations. None of the test results showed significant
correlation with 24-hour TSP measurements that averaged 82.5 ± 35.5 ug/m
(maximum, 175 ug/m ), or 24-hour sulfate concentrations that averaged 3.2 ±
1.8 ug/m (maximum, 7.5 ug/m ). Protein (daily mean, 1.28 ± 0.7 ug/m ) and
total organics (average, 22.1 ± 9.8 ug/m ) also showed no significant correla-
tions with test results. The investigator concluded that temperature and
barometric pressure appear to be more instrumental in promoting tendencies to
asthmatics' dyspnea than do exposures to ambient air pollutants even when
levels of the pollutants exceed Federal air quality standards.
327 328
Shepherd et al. ' studied 10 respiratory patients for 3 months.
Several function measurements were negatively correlated with relative humidity
and CoH of 8 or more per day (1140 ug/m ). Lebowitz et al. tested pre- and
post exercise lung function in children 6 to 12 years of age in a smelter town
on 4 days with high temperature and varying S02/TSP (measured near the test
site), and in children 10 to 12 in an urban area on 4 days with high temperature
and varying TSP (measured nearby). A portable pneumotachygraph was used in
the latter study to measure FVC and FEV, Q and MMEF in the former study. The
two instruments were compared in a group of subjects and differences were less
than one percent. Results controlled for time of day, smoking, and respiratory
medical history, showed that exposures to high temperatures produced post
exercise decreases in FVC and FEV, Q that were related to the relative level
of pollution and temperature. In comparison, a nonexercise (cross-over)
14-123
-------
control group showed nonsignificant declines on high air pollution days.
During testing, outdoor temperatures were always above 86°F and relative
humidity was less than 30 percent. S02 ranged from <1 ppm to 5 ppm and absolute
TSP was unknown during testing in the smelter town. In the urban area, TSP on
3 3
high days averaged 106.7 ug/m and on low days averaged 98.3 ug/m ; suspended
sulfate was low and photo-oxidant levels were not known in absolute terms but
were considered equivalent. A control group who remained indoors in an air
conditioned building where pollution was low showed no significant differences
in pulmonary function (measured with the Collins 13.5 liter spirometer) that
could be related to the type or degree of exercise, day of week, or time of
day.
Summarized in Table 14-29 are the results of quantitative studies
reviewed above as providing information on associations between morbidity
effects and elevated levels of sulfur oxides and particulate matter.
Examination of the table reveals that several studies have shown worsening
of health status among bronchi tic patients and increased hospital admissions
to be associated with acute exposures to TSP and SOL levels as low as
200-350 and 300-500 ug/m3, respectively. Also, other study results
suggest that decreased pulmonary function and increased respiratory
symptoms in normal populations, as well as increased symptomatology in
asthmatic patients, may all be associated with somewhat lower levels of
TSP and S02 (between 150 to 250 ug/m3 and 250 to 300 ug/m3, respectively.)
14-124
-------
TABLE 14-29.• SUMMARY OF EVIDENCE FOR MORBIDITY EFFECTS OF ACUTE EXPOSURE TO SO, AND PARTICULATES
Type of Study
Morbidity
Acute- hospital
Acute-clinical
Acute- long.
(Daily - 3 yrs)
^ Acute- long.
ro 3
Ol
ER visits
Acute - children
Acute-clinical CB/AS
Acute-clinical CB
Acute-clinical CB
Acute-AS
Reference
Martin16
Lawther et al . 53
McCarroll
et al.2d5 206
Cassell et al.208 209
Greenberg et al. 19G
Stebbings et al.216
Waller and
Lawther59
Lawther et al. 52
Stebbings and
Hayes1 5o
Cohen et al.55
24-hour average pollutant levels
at which effects appear
Effects observed
Increases in hospital admissions
for cardiac or respiratory
illness
Worsening of health status among
195 bronchitics
Increased ARI daily inc/prev
Increased ARI average daily
inc/prev
Increased cardio-respiratory
visits
Decreased FEV\75
Increased symptoms in patients
in 2 hours
Decreased condition
Increased symptoms
Increased asthma attacks
TSP (|jg/m3)
500
250 BS
(344 TSP)
100 BS
(200 TSP)
145 BS
(245 TSP)
260 BS
(340 TSP)
700
6500 BS
(1° resp.)
400 BS
250-350 BS
200 (60 RSP)
12SS (8SN)
150 (20SS)
S02 (ug/m3)
400
300-500
372
452
715
300
2860
450
300
100
200
-------
TABLE 14-29 (continued).
Type of Study
Acute-clinical
visits
Absenteeism
Absenteeism
Reference
Heimann54
Gervois et al.61
British Ministry
24-hour average pollutant levels
at which effects appear
Effects observed
Increased visits by CRD
patients
Increased, male workers
Increased, male workers
TSP (ug/mj) I
226
100-200 BS
100-200 BS
™2 (M9'm /
350
100-200
150-250
Pension62
-------
14.5 MORBIDITY ASSOCIATED WITH LONG-TERM POLLUTION EXPOSURES
14.5.1 Introduction
Morbidity means the presence of any state of illness or disease. It may
represent acute disease or chronic disease. It may represent symptoms in one
organ system or in many. It may even represent temporal variations in symptoms
of a specific or a general nature. The incidence of morbidity represents the
new onset of morbidity, while the prevalence represents the presence of mor-
bidity. The incidence rate is usually the number of new cases over the number
of persons at risk in a given place during a given time. Prevalence rate is
the number of present cases over the number at risk in a given place for a
given period of time. Incidence and prevalence are usually obtained by
questionnarie. In general, morbidity is harder to ascertain than mortality,
but is usually a more sensitive indicator of health effects of ambient air
J.t/7 24O
pollutants. (Goldsmith, 1977: Lebowitz, 1973a, Speizer, 1969).
Studies of morbidity associated with long-term pollution exposures
represent the largest portion of epidemiologic air pollution studies. This is
true in part because it is easier to characterize long-term exposure (one or
more years) than short-term exposure (24 hours or less). For convenience the
studies are divided into six subcategories, based on the health end point:
(1) chronic bronchitis prevalence studies, (2) other respiratory disease/symptom
prevalence studies, (3) panel studies of acute respiratory disease, (4) pulmonary
function studies, (5) studies combining respiratory disease symptoms with
pulmonary function, and (6) hospitalization-clinic admission-absence studies.
Emergency room visits, hospital admissions, and physician visits represent
one measure of morbidity. They have been used frequently in examining the
14-127
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health effects of different levels of ambient air pollutants. Unfortunately,
appropriate denominators (the number of those at risk) are not generally
available in studies that use these measurements, and the populations so
described may be very specific sub-populations, presenting difficulties of
definition and preventing generalizations from the results.
Absenteeism from work or school due to specific morbidity is sometimes
used to determine the effects of pollutants. This method presents difficulties
in ascertaining of cases and of causes. Even more than hospital and physician
visits, absenteeism is directly related to the day of the week, the season,
and other social and behavioral factors. Absenteeism is also dependent on
interpretation by health or administrative personnel. Very often, absenteeism
is not examined unless it exceeds a certain number of days, and this seriously
limits it as a sensitive indicator of pollutant effects.
In the various types of epidemiologic studies, changes in some biological
function over time may be a good indicator of the effects of pollutants. Such
changes may include altered pulmonary function, alterated immunologic responses,
or altered biochemical activities or functions. These are usually quite
sensitive measures of biological activity, although they do not necessarily
represent meaningful stages of morbidity. Such measurements usually require
an expenditure of greater resources and greater cooperation on the part of
subjects or patients. Changes in function are measured in terms of percent
change over time or change in absolute function in individuals over time.
Morbidity studies typically employ one of three experimental design
strategies: spatial, temporal, or spatiotemporal. Spatial studies examine
health end point differences between communities (geographic areas) with
14-128
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differences in pollution exposure. Since it is impossible to find communities
with characteristics that are identical except for pollution exposure, it is
necessary to account for these differences. This can be done either by sub-
dividing the communities into similar subgroups or by adjusting for the
differences in the analysis. These differences typically include age, race or
ethnic group, sex, socioeconomic status, smoking habits, and general health
care. A critical examination of any spatial study must consider all factors
exerting an effect on the health end point. A study's credibility depends on
the adequacy with which it considers these factors.
Temporal studies associated with long-term pollution exposure axe less
common than spatial studies. A temporal study compares the changes of the
health end point through time with the changes in pollution. Each community
acts as its own control, making the factors critical to the spatial studies
much less important. Temporal factors such as temperature, season, other
meteorologic factors, and influenza cycles become critical. The appropriate
statistical analyses for such studies often have not been available at the
time of analysis. Studies should be judged on their ability to cope with
these factors and problems. Many long-term temporal studies are also spatial
studies, and thus offer a comparison of the two designs.
Common to both spatial and temporal designs is the problem of estimating
pollution exposure. The specificity of exposure assessment ranges from crude
indices such as coal combustion to sophisticated continuous monitors at several
locations. Unfortunately, even the most sophisticated devices have a history
of problems such as gross inaccuracies and non-specificity. More difficult is
the extrapolation from the measurements at a monitoring site to individual
14-129
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exposure levels. A major improvement in this characterization would be the
use of personal monitors. Although studies have been undertaken using these,
none have yet been published. Qualitative studies of morbidity associated
with long-term exposures to particulate matter or sulfur oxides are summarized
in Table 14-30. Studies yielding more quantitative information on the same
subject are discussed in more detail in the next several sections.
14.5.2 Chronic Respiratory Disease Prevalence Studies
Studies of the relationships between air pollution concentration and the
prevalence of chronic bronchitis have been reported from several countries.
Among the studies of morbidity, the chronic bronchitis indicator has most
consistently given positive associations. Nevertheless, there are a number of
problems encountered in attempts to interpret the data reported. These arise
from the fact that criteria for diagnosing chronic bronchitis are not con-
sistent around the world.
Historically, chronic bronchitis has been the most commonly utilized
representation of obstructive lung diseases and has most often been defined or
quantified in terms of answers to the British Medical Research Council's
Respiratory Questionnaire (BMRC), in one of its several versions. This
definition generally implies that the subject has a persistent cough and/or
phlegm, meaning cough and/or phlegm that occurs on most days for as many as 3
months of the year; in addition, the definition may require that the subject
has had these symptoms for at least 2 years. Although labelled "chronic
bronchitis," this illness differs from clinically diagnosed chronic bronchitis
in several respects. The clinical diagnosis may be made on the basis of the
presence of one or more criteria, including not only responses to that
question in a clinical setting, but also responses to questions about wheeze,
14-130
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TABLE 14-30. QUALITATIVE STUDIES OF AIR POLLUTION AND PREVALENCE OF CHRONIC
RESPIRATORY SYMPTOMS AND PULMONARY FUNCTION DECLINES
Study
Characteristics
Findings
Fairbairn and
Reid265
Mork
266
Deane et al.267
Cederlof,39
Hrubec et al.40
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
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
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. No
differences in symptom
prevalence between
San Francisco and
Los Angeles workers,
although particulate
concentrations were
approximately twice as
high in Los Angeles
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
14-131
-------
TABLE 14-30 QUALITATIVE STUDIES OF AIR POLLUTION AND PREVALENCE OF CHRONIC
RESPIRATORY SYMPTOMS AND PULMONARY FUNCTION DECLINES
Study
Characteristics
Findings
Bates et al.268-270
Bates271
Yashizo272
Winkelstein and
Kantor273
Jshikawa et al.275
Fujita et al.276
Comparison of symptom prevalence,
work absences, and ventilatory
function in Canadian veterans
residing in 4 Canadian cities
10-year follow-up study of
Canadian veterans initially
evaluated in 1960, 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 ove
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
Lower prevalence of symptoms
and work absences and better
ventilatory function in
veterans living in the lest
polluted city
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
14-132
-------
TABLE 14-30* QUALITATIVE STUDIES OF AIR POLLUTION AND PREVALENCE OF CHRONIC
RESPIRATORY SYMPTOMS AND PULMONARY FUNCTION DECLINES
Study
Characteristics
Findings
Reichel,277
Ulmer et al.278
Nobuhiro et al.279
Comstock et al.280
Speizer and
Ferris281-282
Linn et al.283
Prindle et al.284
Respiratory morbidity prevalence
surveys of random samples of
population in 3 areas of West
Germany with different degrees
of air pollution
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 poll ice-
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
No differences in respiratory
morbidity, standardized for
age, sex, smoking habits,
and social conditions,
between populations living
in the different areas
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
exsmokers, 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
14-133
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TABLE 14-30 . QUALITATIVE STUDIES OF AIR POLLUTION AND PREVALENCE OF CHRONIC
RESPIRATORY SYMPTOMS AND PULMONARY FUNCTION DECLINES
Study
Characteristics
Findings
Watanabe285
Anderson and
Larsen286
Collins et al.287
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
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
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
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
14-134
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shortness of breath, and attacks of wheeze with shortness of breath. The
clinician is also likely to use chest radiography results and/or pulmonary
function test abnormalities, as well as the results of physical examination,
in making a diagnosis. Although there is some correlation of persistent cough
and/or phlegm with these other symptoms, it is far from perfect, and nay even
be quite disparate. ' ' ' Nlso, although chronic bronchitis may be a
disease marked by mucus gland hyperplasia and other morphological changes, the
relationship of the morphological change with the symptoms and/or the
physiological changes are quite imperfect.
Criteria for inclusion and exclusion are pertinent in chronic bronchitis.
They are specifically relevant in studies of the incidence of disease, since
respiratory diseases have slow onsets in most cases (except possibly for
childhood asthma and bronchiectasis associated with childhood lower respiratory
tract illness). Chronic bronchitis often occurs in conjunction with emphysema
and/or asthma and must be differentiated from these other illnesses.
Methodological problems encountered in studies of chronic bronchitis
relate not only to difficulties of definition, but to perceptual differences
between observer and observed, sensitivity and specificity of measurements,
the lack of long-term exposure information, and the frequent lack of infor-
mation on other important variables. The occurrence of chronic bronchitis
has been related to occupation, smoking, socioeconomic status, and other
demographic characteristics as well as to ambient air pollution levels. Many
studies have failed to consider one or more of these factors, making inter-
pretation of results more difficult.
Several extensive studies on associations between air pollution and
chronic respiratory disease have been conducted on European populations.
14-135
-------
28
Lambert and Reid, for example, surveyed nearly 10,000 British postal workers
(age 35 to 59) for respiratory symptoms indicated by response to a self-
administered MRC questionnaire. Current air pollution data 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, adjusted for age and smoking habits but not socioeconomic
status (Table 14-31) show relationships for both males and females by both
pollution indices. One reasonable conclusion from the study may be that a
greater prevalence of cough and phlegm occurred in areas in which annual mean
3
smoke concentrations were 150 ug/m or more than in areas in which smoke
concentrations were 100 ug/m or less. 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. Failure to consider socioeconomic status might
have affected the results, but this is not very likely since the entire
248
population consisted of a single occupational group. '
pco
Holland and Reid surveyed respiratory symptoms, sputum production, and
lung function levels in post office employees in both central London and
peripheral towns. Over the age of 50, London men had more frequent and more
severe respiratory symptoms, produced more sputum, and had significantly lower
lung function tests. Socioeconomic factors were presumed the same, the
occupational exposures were homogeneous, and corrections were applied for
smoking. There were some physique differences in the rural areas and
14-136
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TABLE 14-31. PREVALENCE RATIOS FOR PERSISTENT COUGH AND PHLEGM
STANDARDIZED FOR AGE AND SMOKING, BY AIR POLLUTION INDICES
Smoke (BS)
annual mean,
pg/m3
<100
100-150
150-200
200+
SMOKE
Males
97
112
116
134
Females
93
120
116
129
SO,
Males
87
96
120
118
Females
103
110
115
120
Douglas and
Waller
Index
Very low
Low
Moderate
High
Males
88
91
117
118
Females
95
94
97
115
Source: Lambert and Reid, 1970
28
14-137
-------
allowances were made for these in the statistical evaluation. Unfortunately,
no quantitative air quality determinations accompanied these results.
302
However, Brasser et al. have furnished some applicable 24-hour average S02
3 3
values for London (St. Pancres), ie. 100 ug/m in summer and 500 pg/m in
winter, and Gloucester, Petersborough and Norwich, England, ie. 75 ug/m S02
and 200 ug/m3 S02, respectively, for summer and winter. Holland and Reid
concluded that the most likely cause of their observed difference in respiratory
morbidity between the men working in Central London and those in the three
rural areas was related to the differences in the local air pollution. These
ftfi 1fi? ?63
and other studies '* by Holland and coworkers demonstrate this gradient
between respiratory disease and air pollution as well as a gradient between
QC 1 CO
such disease and smoking. Lung function gradients were also seen ' indicat-
ing effects above 75 ug/m3 S02 and 200 ug/m3 TSP.247
89
Holland et al. studied the occurrence of chronic bronchitis in 2365
families in two areas of a London suburb that had different air pollution
concentrations. Area 1 was reported to have had far worse pollution than area
2 during the previous 10 years. Between 1962 and 1965, the particulate matter
(BS) dropped in area 1 from 108 to 72 ug/m , and the S02 first increased from
210 to 260 pg/m2 (0.08 to 0.10 ppm) and then decreased to 238 pg/m3 (0.08
ppm). In area 2, smoke decreased from 175 to 73 ug/m3 and S02 decreased from
279 to 193 |jg/m (0.10 to 0.07 ppm). Trained health visitors conducted
personal interviews, obtaining information on present and past respiratory
symptoms in parents and children, on social and environmental conditions of
the family, and on the parents' occupation and smoking habits.
Morning cough or phlegm was strongly associated with smoking in both fathers
and mothers. There was a weak social class gradient for symptoms within smoking
categories. There were no differences between area 1 and area 2 in
14-138
-------
the occurrence of symptoms in fathers. However, mothers and male and female
siblings all reported significantly more symptoms in area 1, the area with
presumed higher past BS and S02 (no specific data confirmed past levels) and
known higher present S02-
334
Colley and Holland studied the symptoms in all the members of the 2365
families in the London suburb. They attempted to assess the influence of
various factors: smoking, area of residence, place of work, overcrowding,
family size, social class and genetic factors. They showed that area of
residence was not as important for the prevalence of cough when compared to
home and occupational hazards, smoking and social class. In mothers, smoking
and area of residence were important; but social class was not. In children,
an effect of area of residence was demonstrated.
In addition to the above British studies, there exist several reports
concerning a long-term study on the effects of air pollutants on British
schoolchildren. Because the findings of this study appear to be important but
controversial, it is discussed in some detail here, since not all of the
results have yet appeared in the peer reviewed open scientific literature.
Considering that two authors of the report by Holland et al. (1979) are
also coauthors of these studies, Holland et al.'s own descriptions are used
where available. Holland et al. (1979) described these studies in a lengthy
paragraph on page 613 of their report:
One study in the United Kingdom concerned with exposure/response has
been presented in a preliminary communication (10).* It consisted
of data for primary schoolchildren aged 6-11 years in 10 areas in
England. The parents were asked about respiratory illnesses in the
14-139
-------
past year. The air pollution data, obtained from smoke (BS) and
sulfur dioxide samplers, were collected either at or within 0.8 km
(0.5 mi) of the schools. The results indicated a statistically
significant relationship between the frequency of colds going to the
chest during 1972-1973 and pollution measurements taken In November,
1973, after allowing for differences in the distributions of age,
sex, and social class between the areas. Although it was stated
that the relationship could be found for smoke (BS) levels from 10
to 130 ug/m , four factors cast doubt on so precise an interpre-
tation. First, smoking in the home was not considered; second,the
pollution measurements were taken after the period to which the
questionnaire related and in some areas smoke abatement orders
were being put into effect; third, the 10 areas in the analysis
were a non-randon sample of the set of 28 areas in the whole study;
and fourth, the findings were not replicated in the same study
using data collected two years later. A second report from this
longitudinal study using data collected in 1975 indicated no relation-
ship between symptoms and either smoke (BS) or sulfur dioxide
levels in the 19 areas with substantial pollution data for the period
to which the questionnaire related (28).*
After the (November 15, 1979) preliminary draft of this chapter 14 was
301
reviewed by Holland et al., their letter to the Administrator of the U.S.
Environmental Protection Agency dated January 11, 1980 stated:
The discussion of the study by Irwig and his colleagues (ref. 98)
(14-92) is incomplete as it fails to identify the fact that what is
quoted is a preliminary communication and the later definitive
.communication failed to substantiate the earlier results.-
The preliminary report presented data for primary schoolchildren
aged 6 to 11 years in ten areas in England. The parents were asked
about respiratory illnesses in the past year. The air pollution data,
obtained from British standard smoke and sulphur dioxide samplers,
were collected either at or within half a mile of the schools. The
results indicated a statistically significant relationship between
the frequency of colds going to the chest during 1972-73 and pollution
measurements taken in November 1973, after allowing for differences
in the distributions of age, sex, and social class between the areas.
"The above references (10) and (28) in the Holland et al. (1979) text refer to:
(10) Irwig L, Altman DG, Gibson ROW, Florey CduV. Air pollution: Methods to
study its relationship to respiratory disease in British schoolchildren. Pro-
ceedings of the International Symposium on Recent Advances in the Assessment of
the Health Effects of Environmental Pollution. Volume I. Luxembourg, Com-
m\ssion of the European Communities, 1975, pp. 289-300; and reference
(2*8) Melia RJW, Florey CduV, Swan AV: The effect of atmospheric smoke and sul-
fur dioxide on respiratory illness among British schoolchildren: A prelimi-
nary report. Paper given at the Vllth International Scientific Meeting of the
International Epidemiological Association, Puerto Rico, 1977.
14-140
-------
Although it was stated that the relationship could be found for
smoke (BS) levels from 10 to 130 ug/m , four factors cast doubt on
such an interpretation. First, smoking in the home was not con-
sidered; secondly, the pollution measurements were taker after the
period to which the questionnaire related, and in some areas smoke
abatement orders were being put into effect; thirdly, the ten areas
in the analysis were a non-random sample of the set of 28 areas in
the whole study; and fourth, the findings were not replicated in the
later study discussed below.
A second report from this longitudinal study of data collected in 1975
indicated no relationship between symptoms and either smoke or sulphur dioxide
levels in the 19 areas with substantial pollution data for the period to which
the questionnaire related. (Note: Reference 1 in the above quotation refers
to the Melia, Florey and Swan, 1977, paper read at the 1977 Puerto Rico meeting
footnoted on the prior page).
Some of the implications of these above-quoted descriptive passages are
that:
1. The Irwig paper was a "preliminary communication", and the Melia
paper was the "definitive communication" on the subject.
2. In the Irwig report, "smoking in the home was not considered",
but it was in the Melia report.
3. The Melia report "indicated no relationship between symptoms and
either smoke (BS) or sulfur dioxide levels".
However, the facts of these studies may be interpreted quite differently.
First, the Melia paper was perhaps just as "preliminary" as the Irwig
paper. In their own title of their paper cited in Holland et al. (1979),
14-141
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Melia et al. described it as "A preliminary report". Further, the pre-meeting
abstract of the paper states: "The results of Irwig in 1973 will be compared
with those from 1974 and 1975"... However, when the paper was presented in
September 1977, it stated at the end of the introduction: "Due to a problem
arising in the data processing, information collected in 1974 was not available
at the time of writing".
Consequently, it is hard to understand how the 1977 paper is definitive,
since the 1974 data have not been reported yet even in draft form, and neither
the 1975 paper nor the 1977 paper have passed the intense scrutiny of a peer
reviewed scientific journal.
Secondly, smoking was not considered in either the Melia paper or the
Irwig paper as confirmed by the authors' description of their "Method of Data
Collection". Melia, Florey, and Swan (1977) state:
No information on the smoking habits of members of the house-
hold or of the children themselves was obtained in the study.
Consequently, the possibility that the children themselves were already smok-
ing was not considered. The possible importance of smoking as a confounding
factor in these studies, however, is clouded by Holland et al. (1979) in
pointing out (page 604):
Since 1969, there have been many more surveys in children. In-
creasing numbers of investigators have realized that the young have
special advantages as subjects for the study of air pollution.
Under the age of nine years, they are unlikely to smoke cigarettes.
That is, since the Irwig and Melia studies were of schoolchildren "aged 6-11
years", perhaps a small proportion of the children over nine years old may
have begun smoking cigarettes, but probably the vast majority of those studied
did not; and this would lessen tremendously the likelihood that smoking may
have been an important confounder affecting the outcomes of the two studies.
If it were an important factor, however, then it would not be any more appropriate
14-142
-------
to assert that the later Melia findings somehow contradict the earlier Irwig
findings than to accept the initial Irwig findings for 1973 without hesitation.
The matter would simply remain an open question and, since it 1s possible that
more "smokers" were included among the low pollution area "control" populations,
smoking may have actually obscured even more significant results than those
reported in the two papers. Apropos to the latter point, it is interesting
that the Melia report actually did indicate a possible statistically significant
relationship between symptoms and air pollution, but the authors apparently
"corrected away" such significant differences.
Tables 14-32 and 14-33 from Melia, Florey, and Swan report the summary of
seven questions on respiratory disease and its symptoms for boys and girls in
areas of low and high smoke and SOp pollution. If there is no association of
air pollution with health, we would expect that out of the 28 comparisons
listed that 14 will show a positive association and 14 will show a negative
association . Instances of positive associations are indicated in the table
by (+) and cases of negative or inverse associations by (-). Because there were
equal numbers of boys reporting day or night cough independent of smoke (BS)
level a zero is placed in Tables 14-32 and 14-33 to indicate that it is neither
plus or minus within the significant figures reported by Melia, Florey. and
Swan (5.9 vs 5.9). The positive and negative associations seen are summarized
in Table 14-34.
Since Melia, Florey and Swan (1977) do not report the detailed results of
their regression analysis to allow for independent evaluation of the "effect
of the interfering factors" that they corrected for, it is difficult to under-
stand and reconcile their statement:
14-143
-------
TABLE 14-32
THE PREVALENCE (%) OF RESPIRATORY
HIGH SMOKE POLLUTION IN BOYS AND
Respiratory symptom
or disease
Morning cough
Day or night cough
Wheeze
Colds to Chest
Asthma
Bronchitis
Respiratory illness
No. of children
Boys
Low smoke
pollution
3.0
5.9
9.6
24.5
2.5
4.6
28.4
1064
SYMPTOMS AND
GIRLS. FROM
High smoke
pollution
4.0 (+)
5.9 (o)
10.0 (+)
21.9 (-)
1.6 (-)
4.2 (-)
25.7 (-)
867
DISEASES BY
MELIA ET AL.
Low smoke
pollution
1.4
3.2
6.5
18.7
1.1
3.3
22.5
1050
LOW AND
, (1977)
Girls
High smoke
pollution
5.7 (+)
8.7 (+)
7.8 (+)
19.7 (+)
0.5 (-)
3.8 (+)
24.1 (+)
873
"3
*Low smoke pollution: 12.0 - 34.9 ug/m
High smoke pollution: 35.0 - 73.0 |jg/m
(+) Positive association of symptom with air pollution increase
(-) Negative association of symptom with air pollution increase
(o) No association of symptom with air pollution increase
14-144
-------
TABLE 14-33
THE PREVALENCE (%) OF RESPIRATORY
HIGH S02 POLLUTION* IN BOYS AND
Respiratory symptom
or disease
Morning cough
Day or night cough
Wheeze
Colds to Chest
Asthma
Bronchitis
Respiratory illness
No. of children
Boys
Low S0.2.
pollution
3.3
6.2
8.6
21.7
2.6
4.0
25.6
1199
SYMPTOMS AND
GIRLS. FROM
High SO^
pollution
3.8 (+)
5.5 (-)
11.8 (+)
26.1 (+)
1.4 (-)
5.1 (+)
29.8 (+)
732
DISEASES BY
MELIA ET AL.
Low SO-aL
pollution
2.1
4.2
6.5
17.8
0.8
2.8
21.8
1181
LOW AND
(1977)
Girls
High SOa
pollution
5.4 (+)
8.1 (+)
8.0 (+)
21.3 (+)
0.9 (+)
4.7 (+)
25.5 (+)
742
*Low £6^ pollution: 19.0- 49.9 ug/iri
High SO^ pollution: 50.0 - 145.0 ug/m3
(+) Positive association of symptom with air pollution increase
(-) Negative association of symptom with air pollution increase
(o) No association of symptom with air pollution increase
14-145
-------
TABLE 14-34. SUMMARY OF ASSOCIATIONS (±) OF POLLUTION WITH HEALTH
DATA FROM MELIA, FLOREY AND SWAN (1977)
Respiratory symptom Smoke (BS) Sulphur dioxide (SOp)
or disease Boys Girls Boys Girls
Morning cough + + + +
Day or night cough 0 + " +
Wheeze + + + +
Colds to Chest - + + +
Asthma - - - +
Bronchitis - + + +
Respiratory illness - + + +
TOTAL (+) 2657
(+) Positive association of symptom with air pollution increase
(-) Negative association of symptom with air pollution increase
(o) No association of symptom with air pollution increase
14-146
-------
The prevalence in boys tended to decrease and that for girls to
increase with "increasing levels of smoke pollution, but conversely,
the prevalence in boys tended to increase and that for girls to
decrease with increasing levels of S0?.
Since all health question categories for girls showed an "uncorrected"
association with S02 (including asthma) and these associations were larger
than the associations with BS in 5 out of 7 cases it is hard to understand,
without carefully reviewing the regression analysis in it's entirety, how the
correction to the questionnaire responses could have been so overwhelming to
wipe out any associations for the girls.
The results for the boys in both cases, however, do not appear to be
significant, since we expect 3.5 plus and 3.5 minus in each case and the
2
chi-square with one-degree of freedom is 2 (1.5) 73.5 = 1.28; P > 0.25.
The chi-square with one-degree of freedom for the girls in regard to
2
smoke is computed as: 2 (2.5) /3.5 =3.57; P = 0.06. An alternate test of
the probability of obtaining 6 or more "heads" out of a total of 7 flips of an
honest coin (P of "heads" = P of "tails") is 1/16 or 0.0625. These values,
"on the edge of statistical significance," indicate that the association with
BS may not be unreasonable. However, for sulphur dioxide, the probability of
obtaining 7 out of 7 positive responses when no underlying association is
present is (1/2) or 1/128 (P = .008) which is clearly statistically significant.
If we combine the data for boys and girls, we expect a total of fourteen
positive and fourteen negative signs for the associations, if ino association
exists between health and air pollution. If we assume that the null association
for Boys and day or night cough with smoke is negative, then we have a total
of 20 positive responses and 8 negative responses.
14-147
-------
2
The chi-square sum with one-degree of freedom is 2 (6) 714 = 5.14 (P =
0.025) 50 the overall test for the children shows a statistically significant
association of air pollution and health.
Perhaps, if boys start smoking at an earlier age than girls, this might
explain the absence of observed associations of health effects for the boys
with atmospheric levels of BS. The lack of positive associations for the
boys, however, would in no way negate the finding of positive results for the
girls. Nor would any failure to find positive associations for one or another
of the groups studied by Melia in any way negate positive findings obtained by
Irvug at an earlier time and with different subjects.
Approaching the evaluation of the Ir>ig and Melia studies in the above
manner would be consistent with recommendations made by Holland et al. (1979)
which essentially hold that, when any study is performed with a group of
individuals at a certain period in their life while they are exposed to an atmosphere
of variable pollution levels, the results of the study must stand or fall on
its own merits. It is obviously impossible to repeat the study precisely.
Even if we go back to the same location at a later time and recapture the same
individuals, they will all be older and the pollution levels will be different.
Such changes of course were occurring between the time of the Iriviq and Melia
studies and Holland et al. even noted that "smoke abatement orders were being
put into effect."
Holland et al. (1980) also point out, in a discussion of the Van der
Lende study, that
Hypotheses are not strengthened or weakened, they are accepted
or rejected on the basis of available evidence.
14-148
-------
It is difficult for this statement to be reconciled with the statement
quoted previously from Holland et al. (1979) that doubt is cast on the 1973
findings of Irwig because
the findings were not replicated in the same study using data
collected two years later.
In fact, contrary to that assertion, we find that a careful examination of
results from Melia et al. (1977) suggests that there were likely observed
positive associations of respiratory symptoms-disease with air pollution,
which would make their findings consistent with Irwig et al. (1975).
29-31
A series of studies from Poland by Sawicki reported higher preva-
lence rates of chronic bronchitis in males (all smoking categories) and females
(smokers and nonsmokers but not ex-smokers) in a high-pollution community.
Rates were adjusted for age, sex, and smoking habits. The annual mean concen-
tration of particulate matter in the high-pollution area was 170 ug/m (BS)
3
compared with 90 ug/m (BS) in the low-pollution area. S02 concentrations
were 125 and 45 ug/m , respectively. During the heating season when more
smoke was emitted, the average concentrations of smoke for the high- and
low-pollution areas were 240 and 120 ug/m (BS) and, for SOp, 200 and 65
3
ug/m , respectively. No consistent relationship was found between the chronic
bronchitis prevalence rate and length of residence in the high-pollution
community. Some reviewers have taken this as being evidence indicating
that Sawicki's findings do not show a relationship between air pollution and
bronchitis, but other reviewers304'308'312'313'3143 have indicated that a
positive association appears to exist, and the present authors concur with
thts latter conclusion.
14-149
-------
181
A repetition of this study in 1973 also tended to confirm further the
relationship between the prevalence of chronic bronchitis and air pollution
levels. By 1973, annual smoke concentrations in the high pollution area
•J O
averaged 190 ug/m (BS) compared with 86 ug/m (BS) for the low-pollution
area. S09 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 investigator
demonstrated an interaction between air pollution and smoking. Between the
earlier study and 1973, the persistence of asthma and chronic bronchitis was
greater in males ages 31 to 50 in each smoking group in the high pollution
area. The incidence of asthma/chronic bronchitis was also greater in females
in several age groups in the high-pollution area.
32
Petrilli et al. 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 S02 concentrations.
These investigators found that all illness rates were higher in industrial
districts where annual mean pollution concentrations were >210 ug/m3 (0.008
ppm) for S02 and >190 ug/m for high volume mean TSP concentrations. Illness
rates rose in Genoa from 1954-1961 to 1962-1964 by 207 percent. Illness rates
were high also in a nonindustrial area where mean S0? was 100 ug/m (0.035
ppm) and TSP was 180 ug/m .
14-150
-------
In addition to the above European studies, several analogous investigations
have been reported for Japanese population study groups. For instance,
38
Tsunetoshi et al. performed a prevalence survey (MRC questionnaire) in nine
areas of Osaka and Hyogo prefectures, Japan. They studied about 30,000
Japanese over 40 years of age. Pulmonary function was measured by a spiro-
meter; maximum values were used. Multiple regression analysis indicated
increasing prevalence of chronic bronchitis (adjusted for sex and smoking)
related to the gradient of air pollution (sulfation rates and dustfall) in the
different areas. The prevalence ranged from 4 percent where the sulfation
2 3
rate was close to 1 mg/100 cm /day (about 80 ug/m S02) to 10 percent in areas
? 3
where the sulfation rate was about 3 mg/100 cm /day (240 ug/m S02). TSP
levels were not given.
183
Suzuki et al. reported on data collected in each of six study areas in
Japan. Information was obtained from about 400 housewives over 30 years of
age. The BMRC respiratory symptom questionnaire was administered once each
year between 1970 and 1974. The air pollutants monitored in each area included
S02, sulfur oxides, NO and N02, CO, TSP (high volume), and dustfall. The
prevalence of respiratory symptoms was associated with the annual arithmetic
means measured. The incidence of cough, phlegm, or persistent cough and
phlegm was higher among smokers and in the over-60 age group. These
respiratory symptoms were related to the concentrations of TSP (p <0.05) and
S02 (p <0.01) through 1972. S02 levels in 1971 were 94-97 ug/m3 (.036 to
.037 ppm) in the high areas. They decreased to 58-69 ug/m3 (.022 to .024 ppm) in
1974. TSP levels in 1971 in the high areas were between 206 and 434 ug/m
decreasing between 122 and 374 ug/m in 1974.
14-151
-------
Toyama et al. ' studied the prevalence of respiratory symptoms in
relation to S0?. Prevalence rates from 2.8 to 3.7 percent in males ages 40 to
59, after adjusting for age and smoking, were found in areas of a /ion-industrialized
rural town with SO^ concentrations of less than 30 ug/m (0.01 ppm) and TSP
o 312 318
concentrations of 106-341 ug/m (mean of 197). Tani ' performed a study
around a pulp mill and in controlled areas in Japan. A consistent relationship
was demonstrated between the prevalence of bronchitis and sulfation rates
(candle method). A prevalence of about 3 percent in both sexes, ages 40 to
2
59, were found in areas where the sulfation rate was around 0.6 mg/100 cm per
3
day (approximately 48 ug/m S02) compared to about 8 percent in areas where
2 3
the sulfation rate was 1.2 mg/100 cm per day (approximately 96 ug/m SOp).
No data were provided on TSP.
312 319
Yoshii ' noted an association between chronic pharyngitis accompanied
by histopathological changes at biopsy in Yokkaichi, Japan, in sixth grade
children. In heavily polluted districts, sulfation rates were much more than
2 3
1 mg/100 cm per day (>80 ug/m S02); in moderately polluted districts, they
2 3
ranged from 0.25 to 1.0 mg/100 cm per day (20 to 80 ug/m SOp); in the control
2 3
area it was less than 0.25 mg/100 cm per day (<20 ug/m SCO.
An EPA CHESS study on chronic respiratory disease (CRD) was reported on
212
by Chapman et al for populations studied in 1970 in four communities in
Utah (Salt Lake City, Ogden, Kearns, Magna) to assess the effects of smelter
emissions of sulfur oxides (SOp and suspended sulfates). Other pollutants
(TSP and nitrates) were estimated to be low to moderate; but concurrent trace
metal data were not collected. Questionnaire distribution to parents was
through elementary school children and by mail for high school students.
Response rates of 85 percent and 35 percent were found for child-carried
and mailed questionnaires, respectively. Although the 65 percent nonresponse
14-152
-------
rate to mailed questionnaires may have increased the possibility of serious
reporting bias, the authors indicated that similar inter-community CRD differences
were observed for both sets of parents. Respondents were excluded if they had
incomplete questionnaires, a residential change within the previous two years,
or occupational exposure to irritants such as coal dust, cutting oils, asbestos,
mine dust, smelter fumes, cotton dust and foundry dust. Subsequent analysis
showed that exclusion for occupational reasons results in a conservative
estimate of effects attributable to pollution. All races were included, but
the proportion of black respondents was trivial. No covariate measurements
were made to assess possible effects of religion or ethnic composition on
response patterns, although Salt Lake City has proportionately fewer Mormons
and Magna more Spanish Americans. Educational attainment was comparable,
however, in the four communities. CRD prevalence rates reflected pollution
levels faithfully in the different communities; and differences (2 to 7%) in
CRD rates between high and low areas were statistically significant within sex
and smoking status groups (Table 14-35). Relative risks were also different
statistically and air pollution had one-third the risk of smoking in mothers
and fathers (Table 14-35). Effects were additive.
Because of potential biasing factors, such as "CHESS" network air quality
measurement problems discussed in Chapter 3 and the IR (1976) and problems
in the use of dispersion modeling to make certain pollution estimates, several
reviews107'301'312'338 have questioned the validity of the reported findings
of the Utah CRD study, although one critique1 ultimately judged the reported
health effects differences between the study communities to be sound (see
Appendix A for this chapter). With regard to the CHESS air quality measurements,
however, the same report found that detected deficiencies in analyses were
14-153
-------
TABLE 14-35 Chronic Prevalence Rates and Pollution Levels in
Four Utah Cornmunities, 1870
Area I Smoking
Lou 3 areas
Kon-Smokers
Smokers
Magna
Kon-Smokers
Smokers
Source of Risk2*2
Prevalence Rate *
Mothers Fathers
4.16 3.00
15. BO 19.60
6.20 6. 81
22.25 26. BO
**
2 Relative
Mothers
1.00(4.16)
1. BO
1.25
6.Z5
0.33
Risk Ratios21
Fathers
1.00(2.00)
6.63
2.27
6. 93
0.35
2* 1S70 Local
TSP(vg/ms) Si
69-84 2.
70
Levels
Wvgtf.
,6-25.7
107.4
* Relative Prevalence^ Prevalence in specific group/Prevalence in non-smokers in
lou pollution area (baseline rates in parenthesis).
** Ratio of Relative Prevalence due to air pollution/Relative Prevalence due
to Bmoking.
14-154
-------
sufficient, especially for suspended sulfate estimates, such that the published
"CHESS" estimates were unacceptable as a basis for quantifying pollutant
health effects relationships. Fortunately, local air monitoring by the Utah
State Department of Health was available for some pertinent years and was
judged to be more accurate than "CHESS" estimates. Based on such local
data Magna was highest in S02, Ogden had the lowest S02 levels. Kearns and
Salt Lake City had exposures midway between Ogden and Magna. The 1970-71
local monitoring data for Magna can be contrasted to the other three "low"
pollution areas as shown in Table 14-35. Since the TSP levels were nearly
constant over time and similar across the four communities, they were unlikely
(alone) to be producing the differential health effects reported. Therefore,
observed differences in prevalence between the study communities appear to be
more likely associated with higher Magna SCL levels, acting either alone or in
combination with concurrently observed TSP levels. Precise quantisation of
the past or then current CHESS TSP or SCk levels associated with the health
effects observed in the Utah study, however, may not be possible, as concluded
elsewhere.107'312 On the other hand, to the extent that the 1970-71 local air
monitoring data may be representative of fairly stable SOp and TSP levels in
the study communities over many years, then the local monitoring values, or
more accurately, the corrected estimate values shown in Table 14-35 for Magna
might serve as rough pollution indices associated with CRD effects in smelter
areas similar to Magna.
212
Chapman et al. also reported on another CHESS study, involving military
recruits at the Chicago Induction Center from June 24, 1969, to February 20,
1970. Adult chronic respiratory disease (CRD) prevalence was determined by
means of a measured modified BMRC self-administered questionnaire that inquired
14-155
-------
whether the subject usually coughed and produced phlegm for at least 3 months
of the year.
A similar questionnaire had been validated for self-administration in a
1971 Japanese study, but validating data were not available for this survey;
still, it probably gave a reasonable good indication of the difference in
ranking of communities based on CRD prevalence. The questionnaire located the
subjects by their current residence, which was used to categorize recruits
into three groups: (1) Chicago proper, Gary. Hammond, Whiting, and East Chicago,
(2) other Chicago suburbs, and (3) other Illinois and Indiana areas. All
recruits living outside Illinois and Indiana were excluded, as were those not
living at their current address for at least 3 years. Symptom prevalence
rates for Chicago and its immediate suburbs were almost identical and were
consistently higher than the rates for other Illinois and Indiana areas for
both blacks and whites (Table 14-36). These differences persisted even after
adjustments were made for educational level of the recruits.
Questions have been raised ' regarding the ability to associate the
above reported "urban" health differences with specific air pollutants, especially
in view of problems associated with estimation of the air quality data upon
212
which published quantitative conclusions concerning study results were
based. Concerning the latter point, other applicable (NASN) aerometric data
for the greater Chicago area during the time of the study exists and is
summarized along with CRD prevalence results in Table 14-36. The annual
average arithmetic means for the 1969 NASN aerometric data suggest that Chicago
proper, East Chicago, and Hammond were highest in particulates, but the suburbs
may have been somewhat higher in SOp. For both pollutants it appears that the
other Illinois and Indiana areas were generally distinctly lower, although the
14-156
-------
TABLE 14-36. CRD PREVALENCE RATES FOR CHICAGO RECRUITS*
1 Annual Average
Chronic bronchitis prevalence, percent
Community
Other Illinois,
Indiana
Suburbs
Chicago
Bl
Nonsmokers
9.0
9.4
9.4
acks
Smokers
9.3
12.6
12.9
Whi
Nonsmokers
4.3
5.5
5.2
tes
Smokers
16.7
19.8
18.3
1969 NASN Levels
TSP
(pg/
42-95
72-150
129-172
3 S02
14-32
94-292
85-138
*Based on 1969-70 Chicago Inductee "CHESS" study reported by Chapman et al.'
14-157
-------
available data were quite sparse. Based on these limited aerometric data,
increased symptom rates would appear to be associated with both increased
particulates and increased SO^, but the data provide no basis
to distinguish the relative effects of the two pollutants. Use of these data
as estimates of SO or TSP chronic exposures associated with Increased morbidity
Pi p
effects reported by Chapman et al. for the Chicago CRD study must be qualified
somewhat, however, in view of the lack of more precise information on how
representative such data are for actual long-term exposures of the study
populations.
212
Placing the studies by Chapman et al. on United States "urban" and
"smelter-exposed" populations into a broader perspective also encompassing
other studies evaluated above, one finds that numerous studies have demonstrated
that higher chronic respiratory disease prevalence rates are associated with
elevated pollution levels in a number of locations around the world. These
not only include sites in the United States, but also in Great Britain, continental
European countries, and Japan. In addition, efforts have been made to utilize
reported air quality data available for the various study areas in order to
derive at least approximate estimates of ranges of ambient SO^ and particulate
matter air concentrations likely associated with the occurence of the chronic
respiratory disease effects documented by the various studies.
14.5.3 Other Respiratory Disease/Symptom Prevalence Studies
Yoshida et al. investigated the prevalence of bronchial asthma in
relation to the SO^ air pollution exposure among Japanese school children.
Precise data were not included in the published report, but inspection of the
figures indicates that in general the prevalence rate was between two and
three percent when S02 monitored by the lead candle sulfation rate method was
14-158
-------
2 3
between 0.5 and 1.0 mg 100 cm /day (40-80 ug/m ). For the most polluted area,
2 3
more than 1.5 mg S02/100 cm /day (110 to 120 ug/m ), the prevalence rate
exceeded five percent. In other respects (frequency of exacerbations of
illness, school absence record, and reaction to allergies), patients in the
high pollution area did not differ significantly from those in the low
pollution area.
182
Rudnick, 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 pollution concentrations. The question-
naire sought information on respiratory symptoms and symptoms of asthma during
the previous 12 months. Mean SO^ concentrations in the higher pollution area
for the years 1974 and 1975 were 108 to 148 ug/m3 for S02 and 150 to 227 ug/tn3
for smoke. The low pollution areas had S0? concentrations of 42 to 67 ug/m
3
and 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 differ-
ent pollution levels. While the above results are highly suggestive of at
least some SOp and TSP related health effects, difficulties in being able to
fully evaluate the statistical analyses upon which the reported findings are
based argue for caution in utilization of the reported findings.
14-159
-------
90
Douglas and Waller studied a cohort of a national sample of children
born in the United Kingdom during the first week in March 1946. They pro-
spectively examined the occurrence of respiratory illness in the children in
relation to the estimated intensity of air pollution 1n 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 S02 measurements in 1962 and 1963, indicated that the estimates
were reasonably good. At the time of the measurements, SOp varied from about
3 3
90 ug/m (0.03 ppm) in the low-pollution areas to about 250 ug/m (0.09 ppm)
in the high-pollution areas as shown in Table 14-37. Information on respiratory
illness and symptoms was obtained from the children 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 increasing air pollution levels, in contrast to a high significant
and close correlation between lower respiratory tract infection prevalence
rates and increasing air pollution level as seen in Table 14-37. In fact,
these relationships are very consistent for all of the measures listed.
The lowest concentration of smoke and sulfur dioxide were 67 ug/m and 90
ug/m , respectively. "Higher illness rates were noted in all higher pollution
classes;" and "Socio-economic status was important in the study but a
relationship.. .still existed within spearate social classes." Douglas and
90
Waller 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
14-160
-------
TABLE 14-37 Frequency of Lower Respiratory Tract Infections of
Children in Britain by Pollution Levels, %Q
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
Mean annual Pollution levels,
Very LowLowModerateHigh
Smoke: 67 132 190 205
S02: 90 133 190 251
7.2
19. M
5.7
2.9
3.0
5.1
1.1
0.0
1.1
11. «4 16.5
24.2 30.0
7.9 11.2
8.1
7.7
14.0
10.8
2.3
0.9
l.M
10.9
12.1
7.7
13.9
2.6
1.0
1.6
17.1
34.1
12.9
16.2
9.7
9.3
3.1
l.M
1.8
From Douglas and Waller, 1966.
90
14-161
-------
Air Act. However, the children in areas with lower concentrations actually
probably experienced little change in exposure while those in higher polluted
areas probably experienced much higher levels previously.
Further study of this population at 20 years of age indicated that in
these now young adults, cigarette smoking had the greatest effect on respi-
ratory 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 dis-
appeared by age 20, unless there was a history of lower respiratory illness
before age 2. However, no information is provided in the report to indicate
the concentration of pollution to which the children were exposed after 1957
when they were 11 years old. Nevertheless, various reviewers have con-
sistently accepted this as a valid study although they have disagreed somewhat
regarding the specific S02 and particulate levels associated with the observed
effects.
A final survey, when the study population was 25 years old, confirmed the
go
observation made 5 years earlier. At this time, Kiernan et al. 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.
14-162
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The lasting impact of respiratory illness during the early years of life
93 94
was confirmed by Burrows et al. ' These investigators observed more than
2600 adults over 20 years of age and found that histories of pediatric
respiratory illness were associated with the current prevalence of respiratory
symptoms, obstructive airway disease, and ventilatory impairment. The authors
concluded that childhood respiratory illnesses cause the adult lung to be
unusually susceptible to the adverse effects of a variety of bronchial irri-
tants and infectious agents.
95
Taussig also produced evidence that effects of respiratory illnesses in
childhood persist into later years. This investigator concluded from studies
of children that a past history of croup or bronchiolitis, whether or not
asthma was present, was associated with an increased prevalence of abnor-
malities in lung function. The predominant alterations were found in those
tests believed to evaluate small airway function (V 25; V. V). In
uiaX 1 SO
addition, these high risk children showed exercise-induced bronchospasm that
also was independent of an allergic history.
The association between air pollution and lower respiratory tract illness
96
was observed also by Lunn et al. These investigators studied respiratory
illness in 5- and 6-year-old schoolchildren living in four areas of Sheffield,
England. Air pollution concentrations showed a gradient in 1964 across four
3
study areas for mean 24-hour smoke (BS) concentrations from 97 ug/m to 301
ug/m and the same gradient for mean 24-hour SCK concentrations from 123 ug/m
to 275 ug/m . The following year, the concentrations of smoke were about 20
percent lower and SCL about 10 percent higher, but the gradient was preserved
for each pollutant. In high-pollution areas, the 24-hour mean smoke concen-
tration exceeded 500 ug/m3 30 to 45 times in 1964 and 8 to 15 times in 1965.
14-163
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SOp exceeded 500 ug/m3 11 to 32 times in 1964 and 5 to 23 times in 1965.
Information on respiratory symptoms and illness was obtained by questionnaires
completed by the parents, by physical examination, and by tests of pulmonary
function (FEVQ ?5 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. Positive associations were found between air pollution concen-
trations and both upper and lower respiratory illness. Lower respiratory
illness was 33 to 56 percent more frequent in the higher pollution areas than
in the low-pollution area (p <0.005).
97
In a second report, Lunn et al. 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 24-hour mean smoke (BS) concentrations of 230 to 300 ug/m
and 24-hour mean SOp concentrations of 181-275 ug/m than in children exposed
3 3
to smoke (BS) at 97 ug/m and SOp 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, the concentrations of smoke (BS) were only
about one-half of those measured in 1964, and SOp 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 pre-
valence 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
14-164
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results were similar.) Also, the 9-year-old children had less respiratory
illness than the 11-year-old group seen previously. 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
96 97
quality. It should be noted that these Lunn et al. ' findings have been
widely accepted245'248>301>307'308'312 as being valid, and, on the basis of
changes observed between the two surveys, the NAS report on particulate matter
concluded that levels of effect were 100 ug/m3 BS and 120 ug/m3 SO 307
Hammer et al. and French et al. reported on two studies, conducted
as part of the EPA CHESS Program which investigated the occurrence of lower
respiratory disease (LRD) in United States children less than 12 years of age
New York City. ' In the two studies, data were obtained from questionnaires
asking mothers to recall how many times each of their children under age 12
had had pneumonia, croup, or bronchitis during the previous 3 years. Data
were gathered also on related hospitalizations and physician visits. Validation
studies of the questionnarie yielded highly significant correlations between
the illnesses reported on the questionnaire and confirmatory hospital and
257
physician records.
214
Hammer et al. reported on a study of historical acute lower respiratory
disease in children aged 1 to 12 years surveyed retrospectively by questionnaire
among parents in four New York metropolitan communities representing different
exposures to sulfur dioxide, particulate matter and suspended sulfates.
Morbidity patterns were similar with regard to age for blacks and whites, but
pneumonia was more frequent and bronchitis and other chest infections were
less frequent among blacks than whites in each community. Rates of "any lower
respiratory disease" (a combined category), croup, bronchitis, and "other"
14-165
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chest infections were significantly higher among black and white children
residing in the communities with exposure to higher pollution. Pneumonia and
hospitalization were significantly higher only among white children 1n the low
exposure community but the absolute rates were low for both conditions in all
communities. Differences in family size and composition, crowding, parental
cigarette smoking or indoor air pollution due to gas stoves or gas space
heaters could not explain the morbidity excesses in the high exposure communities
Significant differences in LRD in the previous 3 years were found for all ages
(1-12) after adjusting for sex and education of head of household. Estimates
of the average annual pollutant concentrations associated with excess childhood
respiratory morbidity in this study were 160 to 260 ug/m of sulfur dioxide,
3 3
82 to 96 ug/m of total suspended particulates, and 13 to 14 ug/m of suspended
sulfates as measured by the New York City Department of Air Resources (NYC
7QC
DAR). As reported by French et al., there was an increased relative risk
of acute lower respiratory disease in all family members in the high pollution
areas, especially for those with 3 or more years residence in the areas, and
after adjusting for parents' smoking habits.
French et al. conducted a similar study in the children (ages 1-12) in
212
the families studied by Chapman et al. in the four Utah communities. The
prevalence rates of reported past lower respiratory diseases (LRD) were similar
for those residing in the communities less than 3 years. For those with three
or more years of residence, the rates were similar for the three low pollution
communities Magna's prevalence rates, in those with the 3+ years residence,
were significantly higher: age-, sex-, and SES-adjusted attack rates for one
or more LRDs were 38.2 in Magna vs. 26.5 to 29.0 in the other three areas;
age-, sex-, and SES-adjusted attack rates for two or more LRDs were 23.4 in
14-166
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Magna vs 14.6 to 17.2 in the other three areas. Again, local monitoring
indicated similar TSP averages for the four areas (about 70 ug/m3), but higher
SCL readings in Magna (107 mg/m or more).
Some of the comments discussed for other EPA CHESS Program studies (see
also Appendix A) may also apply to the above studies by Hammer et al214 and
French, to the extent that similar methodological tools or procedures were
used as in the other studies. Especially applicable, then, are questions
raised concerning: (1) air quality measurements obtained by "CHESS" monitor-
ing in the study locations at the time immediately proceeding and during the
collection of health effects data and (2) the estimation of historical exposures
for the study populations from limited past local air monitoring data. Caution
must, therefore, similarly be applied in regard to full acceptance of the
published "CHESS" air pollution values for these studies. As judged by IR,
the local values (shown above) are more accurate, and they have been used to
estimate exposures. Since these studies ' are in children, prior exposures
are likely similar to those presented.
Another retrospective survey conducted by Hammer ' regarding the
frequency of lower respiratory illness in children was undertaken in 1971 in
the south east, using similar questionnaire sampling as employed in the above
New York studies. ' 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 with low S02 exposures. 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
14-167
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pneumonia and croup among blacks and more lower respiratory disease,
bronchitis and croup among whites in Birmingham than in Charlotte, as shown in
Table 14-38. 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 assumed that cigarette-smoking for children under age 13 in
the South was minimal, equally distributed, and did not affect their results.
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 did not differ significantly between communities. Therefore, the
results were taken to be indicative of associations between increased lower
respiratory disease rates in children and exposure to moderately elevated
particulate matter 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.
214 257
The above Hammer ' study, peer-reviewed and published as a Harvard
University doctoral dissertation, would appear to provide important and mean-
ingful findings demonstrating significant respiratory effects in children
associated with elevated particulate matter air concentrations in the presence
of low levels of SO,,, suspended sulfates, and suspended nitrates. The response
rates were excellent in both communities, though significantly lower in Charlotte
(88 percent) than in Birmingham (95 percent) and significantly lower for
Blacks (84 percent) than for Whites (89 percent) within Charlotte. The small
differences in response rates in absolute terms, however, appear unlikely to
14-168
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TABLE 14-38. FOUR-YEAR REPORTED RATES OF ONE OR MORE EPISODES
OF LR& AMONG"WHITE AND BLACK CHILDREN, BY COMMUNITY EXPOSURE
SOUTHEASTERN U.S. 1971
Adjusted age-specific rates, (%) ,C7
Type of LRO
*ny LRO
Croup
Bronchitis
Pneumonia
Hospltallratlon
Pollution
Exposure
Charlotte
Birmingham
Charlotte
Bi rmingham
Charlotte
Birmingham
Charlotte
Birmingham
Charlotte
Birmingham
1-4
35.0
38.9
17.5
16.3
23.1
28.7
9.0
10.3
5.5
5.8
White
age
5-B
29.9
36.3
14.2
16.3
20.4
26.2
6.3
8.5
2.7
6.1
9-12
22.0
26.4
9.3
12.2
14.9
18.6
5.2
6.3
0.9
2.4
1-4
27.8
24.0
10.8
8.6
13.7
10.6
14.0
15.1
4.0
5.7
Black
age
5-8
16.4
20.6
7.0
7.9
7.8
7.9
8.3
13.7
1.8
2.9
A1r Pollution Levels - 1971^
(annual averages In pg/m )
9-12
12.7
15.9
4.7
5.9
6.3
6.9
8.9
10.2
1.3
2.5
City Year
Charlotte 1971
Birmingham 1971
1960-1971 avg.
Charlotte 93
Birmingham 155
TSPa RSP
74 40. 7b
133 57. 2C
TSP
(74-112)f 8
(133-169) 10
,,d ,Md
J 3 j™
9.6 1.7
11.8 2.5
SS
(4-10) 17
(9-16) 15
S02
16.3"
12.1
so,
(13-20)
(6 <25)
?Values obtained from trend lines.
°TSP x .55.
-------
have affected the overall study results in view of excellent internal consistency
in lower respiratory disease morbidity patterns among blacks and whites within
both study communities, with morbidity patterns being similar 1n relation to
age, sex, parental education, and history of asthma in each of the communities.
The fact that many of the most likely potential confounding or covarying
factors were adequately controlled for in terms of the particular multivariate
age-, sex-, race-, and socioeconomic level - specific statistical analyses
employed is another strength of the study. In addition, smoking does not
appear to be a credible factor accounting for the observed results, especially
those for the children in the 1 to 4 and 5 to 8 year old age groups. Lastly,
the 1960-71, 1964-71, and 1968-71 air quality estimated shown in Table 14-39
respectively index lifetime exposures for the 9-12, 5-8, and 1-4 year old
children constituting the present study populations. Thus, if those air
quality data are accurate and adequately representative of the respective
study population exposures, it would seem to be possible to define a relatively
narrow range of annual average TSP concentrations likely associated with the
childhood respiratory disease effects observed in the study.
In regard to further critical assessment of the Hammer ' study, it
should be noted that it was not specifically discussed in the Congressional
Investigative Report, which evaluated other EPA CHESS Program studies com-
pleted earlier. On the other hand, the present Hammer study appears to have
avoided well most all of the methodological shortcomings of the types noted
for various other specific CHESS Program studies in the IR review. Only in
a recently published review by Holland et al has there appeared any specific
critical comments regarding the study, and those were directed to an earlier
unpublished draft report on the study. Referring to the draft report, Holland
et al301 noted:
14-170
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I
»—•
••J
Total
Suspended
Particulates
TABLE 14-39. ESTIMATED3 POLLUTANT EXPOSURE LEVELS IN CHARLOTTE, NORTH CAROLINA..,
(INTERMEDIATE EXPOSURE) AND BIRMINGHAM, ALABAMA (HIGH EXPOSURE): 1960-1971liJ>
Estimated Pollutant Concentrations, ug/m
Pollutant
Community
1960-63
Average
1964-67
Average
1968-71
Average
1960-71
Average
Charlotte
Birmingham
107
168
93
159
79 93(74-112)°
139 155(133-169)
Sulfur
Dioxide
Suspended
Sul fates
Suspended
Nitrates
Charlotte
Birmingham
Charlotte
Birmingham
Charlotte
Birmingham
17
<25
6
10
2
2
16
11
9
11
2
3
17
13
10
14
1
3
17(13-20)
15(6-<25)
8(4-10)
10(9-16)
2(1-3)
2(2-3)
aAll values obtained from reference 257 and based on both measured and estimated values. Twenty- four hour integrated
estimates of concentrations were measured expressed in micrograms per cubic meter. For each year, the average of
all daily estimates was computed. For periods of several years, the average of the individual years is tabulated.
For the period 1960 to 1971, the average for the 12-year period is shown together with the range of the 12 indi-
vidual years.
Range in parentheses
-------
Rates of illnesses in the two cities were compared in three age groups
and by race after adjusting for sex and education of head of household. The
rates were higher in Birmingham except for blacks (sic) 1-4 years of age.
However, in another analysis, consistent differences were only found for
whites (sic). Although parental smoking was considered, 1t was not Included
in the analyses. No discussion was given of the validity of the data or
consistency of results in different sectors of the cities, as had been pro-
vided by Love et al. In light of the results of the prospective study (ie. by
Love et al),* this retrospective study, with its Inherently less reliable
data,requires more detailed analysis than is provided in the draft paper
before the observed effects can reasonably be ascribed to differences in
levels of total suspended particulates (HV).
Reference to the Love et al prospective study concerns a different CHESS
Program study of acute respiratory disease during fall, winter and spring of
1970-71 and 1971-72 in preschool and schoolchildren in Birmingham and Charlotte
a study which failed to demonstrate higher acute respiratory disease rates in
Birmingham and, for which, internal inconsistencies existed with regard to
social class, race, and smoking.
All told, the above Holland et al comments do not seem to provide any
compelling reasons for rejecting the findings or conclusions contained in the
later, more thorough and complete, published analyses ' of the Hammer
study, judged by prominent American epidemiologists and statisticians (on
Hammer's doctoral committee) to be methodologically sound and appropriately
interpreted. Thus, for example, the failure to find higher rates of respiratory
disease for Blacks age 1-4 in Birmingham, does not negate the finding of other
statistically significant, internally consistent, and biologically plausible
Increases in respiratory disease rates in Birmingham for other Black age
groups and all White age groups. Nor are the Hammer findings negated by the
failure of the Love et al prospective study to find analogous effects at a
*Editors' insertion.
14-172
-------
later time when available air quality data indicates that lower TSP and SOp
levels existed in both study communities along with smaller intercommunity
differences than at the time of the Hammer study. Also, perhaps acre Importantly,
the -Love et al study used markedly different data collection procedures (telephone
survey versus questionnaires in the Hammer study, etc.) and health endpoint
neasurements.
257
Also in his later report, Hammer does demonstrates the validity of the
data and the consistency of results (see above). In addition, Hammer
demonstrated that parental smoking was not important in his findings, which
confirms the findings of other epidemiological studies.338'339'340
Two key issues that remain and must be considered before accepting the
specific quantitative dose-effect relationships implied by Hammers' published
analyses ' are: (1) the representativeness of the reported air quality
data as reflections of the respective exposures of the different study popu-
lations; and (2) the validity and accuracy of Hammers' published quantitative
estimates for air levels of TSP, SO-, and other pollutants in Birmingham and
Charlotte during the 1960-71 period (as shown in Table 14-38 and 14-39).
With regard to the first issue, it should be noted that annual average
TSP and S0? estimates for years before 1964 are based on data obtained from a
single monitoring site in Charlotte and Birmingham each, and the published
estimates for those years (1960-64) shown in Table 14-39 are thusly likely to
be the most tenuous in reflecting actual exposures in comparison to data
obtained with multiple monitoring sites in later years. The estimates listed
in Table 14-39 for 1964-1968 are derived from results obtained via multiple
county, NASN, or other Federal monitoring sites situated as depicted in Figures
14-5 and 14-6- The estimates listed in Table 14-38 and 14-39 for 1968-71 are
14-173
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IIHUINCHAM.AIAIAUA
8 I 1 )
U-l I I I
c^T s.«
n A •• '•«
• A
J. II
N.I]
SITE lOIHTiriCATION
>• • HOI MAI STUDY
«L A BASH
C CME»
J. _• JIFFtRSON
COUNTY
Figure 14-5 Locations of air monitoring stations in Birmingham Alabama from u»h K
in Hammer study were obtained. mingnam. Alabama, from which air quality data employed
-------
CHARIOTTI. NOR1H CAHOtlN*
Nl
o
CHtSS
MtCKKNIURC COUNTY
Figure 14-6 Locations of air monitoring stations in Charlotte, N. C. from
which air quality data employed in Hammer study were obtaineo.
14-175
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also derived from the same multiple county, NASN, and other Federal monitoring
sites dispersed at points shown in Figures 14-3 and 14-4 so as, in general, to
cluster around major air pollution emission point sources within Cjiarlotte and
Birmingham metropolitan areas.
Additional "CHESS" monitoring sites were set up in late 1969 at locations
indicated in Figures 14-3 and 14-4, with one site (o) being situated in each
of three residential neighborhoods (sectors) in each city and generally further
distant from any of the high emission point sources than the other monitoring
sites; the CHESS sites were also within 1% to 2 miles of the residences of
each of the study population families living in the respective sectors and
were situated, except for one, at approximately six feet off the ground on
flat, relatively open terrain. Thus such sites would appear to be likely to
yield data well representative of exposures of the various study populations,
exposures likely to be less than the air levels of pollutants monitored at the
other sites closer to known pollution sources: and, consistent with this,
"CHESS" estimates of TSP and S02 levels for 1969-71 are distinctly
lower than the estimates based on the other monitoring data for the same
period. Thus, the available "non-CHESS" monitoring data shown in Table 14-39
for TSP and SO,, levels would seem to clearly represent the maximum estimates
of the highest possible annual average (arithmetic mean) exposure levels
likely to be associated with the respiratory disease effects demonstrated by
the Hammer study.113'257
Turning to the second issue noted above, that concerning the validity and
accuracy of the Hammer study air quality measurements, it should be noted that
the Investigative Report concluded that the TSP measurements obtained for
other CHESS Program studies by means of procedures yielding the CHESS estimates
14-176
-------
alluded to above were among the most consistent and reliable of the CHESS air
quality estimates obtained and likely errored toward underestimation of actual
TSP levels by, at most, 10 to 30 percent. Increasing the reported113'257
Hammer study CHESS estimates by 30 percent, to allow for the naxiwum likely
error associated with them, results in their approaching analogous estimates
from the other monitoring networks more closely, but still remaining distinctly
lower (being about 80-90 ug/m for Charlotte sectors and 110-120 ug/m3 for
Birmingham sectors). As for the S02 air quality data, the IR107 concluded
that errors in SOp measurements in other CHESS studies may have resulted in
underestimations of S02 levels by 50 to 100 percent or more, which means that
published Hammer study S02 levels (being similar to the other monitoring
estimates) might, theoretically, range up to still very low levels of 25 to 35
ug/m . On the hand, as discussed in the IR the sensitivity of the SOp
analytical methods employed in "CHESS" monitoring is such that 50^ values
under 25 to 50 ug/m cannot be considered to be significantly different from
zero. In other words, regardless of the precise S02 values actually present,
there appears to be no question that they were equally low (nearly zero) in
both Charlotte and Birmingham.
14.5.4 Pulmonary Function Studies
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 biological 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.
14-177
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74-77
Studies in the Netherlands reported by van der Lende and colleagues
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^ Q 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 pol-
lution concentrations. The highest 24-hour values for SOp during the time of
the surveys in the high-pollution area were 160 and 300 ug/m , respectively.
in 1969 and 1972; the highest 24-hour smoke values were 40 and 100 ug/m .
Again, neither pollutant can be implicated individually. The investigators
considered other possible causes of the improved pulmonary function but con-
cluded that the most plausible was the effect of reduced air pollution.
Expected decreases were seen in a rural area. The authors explored possible
sources of bias in the study but were unable to explain their results on that
basis. A third survey of this population, conducted in 1977, found that,
under the improved air quality condition, expected decreases in pulmonary
function values in the aging population was observed. This strengthens the
possibility that the former pollution concentrations were related causally to
4
the pulmonary status.
33
Becklake et al. 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 that were associated with
TSP levels. In the three areas studied, ambient S02 was reported to be 15,
123, and 59, and annual mean high-volume TSP values were 84, 95, and 131
3
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. ) discriminant analysis was utilized to control for smoking, after which
differences in health variables were not significant.
14-178
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Hanfreda et al. studied pulmonary function in one rural and one urban
population (25 to 54 years old) residing in the Winnepeg area of Canada in
order to determine the effect of any urban factor. Pulmonary function was
assessed by single breath N2 tests and by force vital capacity using a dry
rolling Seal Spirometer. Tests were repeated until three gave results within
10 percent of each other or a maximum of five determinations was reached.
Annual mean concentrations of SCL were about 15 ug/m3 (0.005 ppm) in both
areas, although the authors stated that subjects in the urban area may have
been exposed part of the time to the 30 ug/m (0.01 ppm) that is measured in
the more polluted part of Winnipeg. Annual mean TSP concentrations were
reported to be no more than 56 pg/m in either study area, although those in
Winnipeg were 73 to 78 ug/m . The study results indicated that total lung
capacity, vital capacity on expiration, residual volume, and closing volume in
men and women were very significantly related to height, age, and smoking
status (p < 0.05). However, there were no differences associated with the
place of residence. Thus an urban factor was not apparent in a low-pollution
urban area.
218 264
Kagawa et al. ' investigated the effects of photochemical air pol-
lution (oxidants, ozone, hydrocarbons, NO, N02, SOp, suspended particulate
matter), temperature, and humidity on respiratory functions of Tokyo school-
children. Ventilatory function was measured weekly for 29 weeks, June-December
1972, in 21 schoolchildren and again from November 1972-March 1973. Of seven
measures of respiratory function, maximum expiratory flow rate showed the
highest correlation (p <0.05) with the greatest number of environmental vari-
ables. Among environmental variables, temperature significantly affected a
number of respiratory functions, being positively correlated with Rflw in
14-179
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particular. Partial correlations showed, however, that regardless of
temperature, ozone, sulfur dioxide, and N02 alone also played significant
roles in affecting individual respiratory functions.
ft7
Zapletal et aT. studied pulmonary function in 111 healthy 10- to
11-year-old children who had lived for at least 5 years in highly polluted
areas of Czechoslovakia. Only 19 (17 percent) of the children demonstrated
baseline abnormalities in FEV,. They were studied further; 6 of the 19 showed
significant reductions in maximal flow rates at low volumes. The investigators
concluded the FEV, and flow abnormalities might be related to air pollution.
Air concentrations of S0« and TSP were in excess of 240 ug/m (daily averages)
on more than 7 days a month during winter.
Holland et a!.101'102 and Bennett et al.103 reported the results of
studies of pulmonary function in schoolchildren, aged 5, 11, and 14 years,
living in two urban and two rural areas of Kent, England. Peak expiratory
flow rate (PEFR) was measured with a Wright Peak Flow Meter. Approximately
10,000 children were included in the study populations. Mean smoke concen-
trations in the two urban areas for the period from November 1966 to March
1967 were 69 and 50 ug/m (BS). Smoke measurements were available from only
one of the rural areas, and these averaged 34 ug/m . The other rural area was
said to be at least as clean. Mean peak expiratory flow rates, adjusted for
differences in age, height, and weight as well as for a history of bronchitis
or pneumonia, social class, and the number of siblings in the family showed
significant area differences. In the highest area (Rochester), the lowest
levels of PEFR were found to be independent of parents' social class, family
size, and past history of respiratory illness. The four factors operate
independently and additively. Differences between other areas did not corre-
spond to differences in air pollution concentrations. Thus, mean values of BS
14-180
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3 3
of 70 ug/m in winter (123 ug/m TSP) were associated with reduced PEFR, but
30 to 50 ug/m BS were not. Smoking in the home and other pollution were not
considered in this study. Also details on instrument calibration and number
of trials for each child were not given.
112
Col ley and Reid reported results of respiratory symptoms and lung
function (PEFR) in approximately 10,000 children ages 6-10 in different parts
of England. They examined relationships with S02 specifically. Mean values
were found in the different areas from 33 ug/m to 150 ug/m3 of S02 (converted
lead peroxide sulfation rates). Smoke levels were not provided. The biggest
gradient they found was between respiratory symptoms and social class by area;
the biggest differences occurred in social classes IV and V. They found an
association of lower respiratory tract infections with the air pollution
gradients, but no association for upper respiratory tract infections.
Differences were not explained by domestic circumstances (persons per dwelling,
rooms per dwelling, crowding). (The trends followed similar trends in the
248
frequency of killing and disabling bronchitis among adults in the same areas. )
Turning to American studies on morbidity effects associated with long-term
195
exposures, Ferris conducted a carefully executed study of absence rates and
pulmonary function in first and second grade schoolchildren in seven schools
in areas of Berlin, N. H. with different concentrations of air pollution.
2
Pollution measurements included sulfation rates in ug of S03/100 cm /day and
o
average dustfall in tons/mile /30 days. Indications were that SO^ was about
four times more concentrated in the area of highest than lowest pollution (619
i 246 vs. 130 ± 101 ug of S03/100 cm2/day) and that particulates were nearly
five times more concentrated in the area of highest pollution (62 ± 16 vs. 13
± 7 tons/miIe2/30 days). Maximum particulate and S02 levels did not occur in
14-181
-------
the same area. In spite of the differences in pollution, school absences for
respiratory illnesses were not significantly different between schools; nor
was their any relationship between social class and absence rates. Pulmonary
function tests (peak flow with Wright Peak Flow Meter and forced vital capacity
and 1-second forced expiratory volume from a Stead-Wells spirometer) during
the winter (January) showed no significant relationship to school. However,
such measurements taken in summer significantly related to particulate air
pollution, as shown by individual comparison T-tests following an overall
analysis of variance (ANOVA) comparing results obtained with children from
different schools in high, medium, and low pollution areas.
Holland et al. (1979)301 evaluated the Ferris195 Berlin study results as
follows:
The children in the school in the most polluted area tended to have
lower peak expiratory flow rates (both sexes), forced vital capacity
and forced expiratory volume (girls only) than in one or two schools
from areas with intermediate levels of dustfall. However, no differences
were found between children in the most and least polluted areas.
The method of carrying out individual t tests between so many schools
is an unwise statistical practice: the analysis of variance is more
appropriate as it indicates to what extent the variation between all
the schools could have occurred by chance, given the hypothesis that
there were no real differences. Since the result of the analysis of
variance was not reported it is probable that no significant differences
between the schools could be found.
Of course exactly the opposite inference should be drawn from the one
stated by Holland et al. on the basis of the above information; that is,
one must assure that the individual t-test comparisons between shcools would
not have beers carried out unless significant overall differences were first
obtained by means of the ANOVA in keeping with standard statistical procedures
associated with ANOVA usage. It is difficult to understand how Holland et
301 195
al. missed information clearly stated in the Ferris publication confirming
that, in fact, this was done (as quoted below):
14-182
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The results of the tests of pulmonary function were tested for
significant differences among the schools by a one-way analysis of
variance. If significant difference was noted, a two-tailed t test
was done (table 12). Pulmonary function in pupils of School A was
significantly lower than that in pupils of several other schools,
particularly in the June 1967 study.
Furthermore, use of one-tailed t-test may have been more appropriate In this
case, to test the hypothesis that air pollution was causing the observed
health effects differences and may have identified even more statistically
significant differences due to particulate pollution.
Mostardi and Leonard compared measurements of pulmonary function (VC,
FEV1, MMF, and V02max) in 42 volunteer male high school students from a pol-
luted area with similar measurements for 50 male students from a rural area.
The subjects in this 1973 study had all participated in a 1970 study in which
measurements were limited to VC and FEVyc- Air pollution concentrations in
both study areas declined somewhat between 1970 and 1973 but results of the
two studies were similar. In 1970 the group in the polluted area had a mean
VC (3.27 ± SE 0.07) lower than the group in the cleaner area (3.54 ± SE 0.10)
p <0.05. In 1970, means were higher (4.65 ± SE 0.11 for the polluted area and
5.04 ± SE 0.10 for the rural pollution area) but the difference remained (p
<0.01). The mean FEV 75 in 1970 also was lower in the polluted area (2.57 ±
SE 0.10) than in the low-pollution area (2.90 ±SE 0.08, p <0.01) but the mean
FEV, values in 1973 (4.09 ± 0.09 and 4.20 ± 0.08) were not significantly
2
different. Annual mean S02 concentrations measured as mg S02/100 cm /day by
the lead peroxide candle method ranged in the high pollution area from 1.014
in 1970 to 1.020 in 1972 (81.1 to 81.6 ug/m3) and in the low pollution area
from 0.763 to 0.36 (61 to 28.8 ug/m ). Comparable data were not collected in
1973. Annual mean suspended particulate matter concentrations ranged in the
14-183
-------
high pollution area from 77 to 110 ug/m , and in the low-pollution area from
71 to 83 ug/m . The investigators suggested that the differences in test
pesults may have related to the differences in pollution. The Inclusion of
blacks did not affect the results, although smoking may have. SES (apart from
race) may have also had some effect. The area in which the study was done is
heavily industrialized and the differences in the measured pollution levels
may have been adequate indices of difference in risk experienced in the high
pollution area.
pep
Mostardi and Martell reported on 173 and 161 students, respectively,
from the same urban and rural areas. They tested FVC and FEV jr on subjects
residing in the areas for 4 or more years. The groups were analyzed separately
by sex and males were analyzed separately by whether or not they smoked ciga-
rettes. The two groups were comparable in anthropometric characteristics.
Higher values for pulmonary function were reported in the rural area for all
males, females, and smoking males. While a higher proportion of smokers were
found in the urban area (12 percent versus 6 percent in the rural area), the
authors stated that this did not influence their results. They did not analyze
by race in this study, because they found that the lung function differences
persisted in their previous study after exclusion of the three black students
in the urban area.
Pulmonary function was also studied in Cincinnati schoolchildren in
215
1967-1968 by Shy et al. . 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
14-184
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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 corresponding differences
for suspended sulfates, suspended nitrates, and SOp ranged from 0.1 to 1.1,
0.1 to 0.8, and 0.6 to 10.4, respectively. Thus, the Industrial valley had
Bore TSP than the non-industrial valley, but its levels of SS, SN, and S02
exceeded those in the non-industrial valley by very small margins. Arithmetic
averages over the 7 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. SOp for the 7-month average ranged from 39 to 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 75) on a Stead-Wells
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 computations. Height, sex, and race were
used to make adjusted FEV ,r 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 socio-
economic data. The educational attainment of fathers was similar for corresponding
schools in the industrial and non-industrial valleys.
215
The Shy et al. 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 con-
sistently had lower FEV 75 values, and a pollution effect was seen among
blacks during only one of three study periods. The absolute differences in
average FEV 75 were roughly 40-120 ml (< 10 percent) in most cases. A
14-185
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multivariate 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 75 values. They concluded from
this analysis that suspended sulfates had the strongest association with
FEV 75. These studies support the notion that FEV 75 was 3 to 10 percent less
among white second graders in the industrial valley than among those in the
non-industrial valley.
215
In 1970 to 1971, a ventilatory function study was conducted by Shy et al.
in New York as part of the EPA CHESS Program. It included children ages 5 to
13 who attended schools situated within 1.5 miles of air monitors. Riverhead,
Bronx, and Queens were represented by three schools each. Only white children
were included in the analysis. Unfortunately, the electronic spirometer used
to assess pulmonary function exhibited drift (<350 ml). This could bias the
study results only if one community was systematically studied with a spirometer
with extreme drift or if the drift varied in phase with the rotation of spirometers
through communities. The variability of the observations is increased by
random distribution of drift, since the community effects (60 ml or less) are
much smaller than the drift. However, during testing periods, the instruments
were calibrated against a Stead-Wells volume spirometer. They also were
tested for reproducibility by obtaining six or seven successive FEV 75 measurements
with trained subjects and comparing them with the results obtained with the
Stead-Wells spirometer connected in series. Percent differences in pulmonary
function ranged from -7.0 to +6.6, about the same as the accuracy of any
spirometer.
14-186
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Families of children studied in Riverhead, Queens, and Bronx, were similar
in regard to age distribution and parental smoking habits. Income and educa-
tional attainment decreased in the order Queens, Riverhead, and Bronx. No
comparison of children's smoking habits is reported, although this aay have
been crucial in interpreting the results in view of statistically significant
differences in pulmonary function being found only for older children.1
Male FEV 75 values, adjusted for height and age, from Riverhead (the low
pollution community) were intermediate between Queens and Bronx (the two
higher pollution communities) for three of four test periods. For females,
the Riverhead values exceeded Bronx and Queens values in each test period, but
the differences usually were less than 50 ml. Riverhead height-adjusted
FEV 75 values were largest during one of four test periods for young males and
females, and during three of four for older males and females. The average
differences were inconsistent. However, the analyses for individual test
periods do show statistically significant differences for older males and
215
females. Shy et al. speculate that lack of differences in 5- to 8-year
olds may be due to improved air quality in years since the early childhood
period of the older subjects studied. As noted above, local monitoring levels
were judged accurate, and were used to assess area differences in this
study.
Chapman et al.213 performed an EPA CHESS Program survey of the ventilatory
function of 7997 black and white elementary schoolchildren in Charlotte, North
Carolina and Birmingham, Alabama, during the 1971-1972 school year. These
cities had been selected for study because they exhibited a gradient of exposure
to suspended particulates, and had low levels of other pollutants. Birmingham
had an average RSP of 45 g/m3 compared with 33.4 in Charlotte. The ventilatory
14-187
-------
function test employed was the three-quarter second forced expiratory volume
(FEVQ 75). Two instruments were utilized in each area sequentially (a hot
wire anerometer in the first two surveys and a dry-seal spirometer thereafter).
In all eight age-, sex-, and race-specific subgroups, nean age- and
height-adjusted FEV 7& readings were consistently lower in the more polluted
city, Birmingham. This finding strongly indicated that exposure to particulate
pollution had exerted a deleterious effect on the FEV« -,,- of children in
Birmingham. The results may be consistent with either of two alternate hypotheses:
first, that exposure to TSP (high RSP and suspended sulfates) from the beginning
of life onward promotes impairments in FEV 75 in later childhood; or second,
that such particulate exposure for the past several years promotes such impairments
The authors assumed, possibly wrongly, that children ages 12 and under do
not smoke appreciably nor differently in the two areas. See Appendix A for
more discussion of this point.
Intercity differences in mean FEVQ 75 were smallest in fall, greater in
winter, and greatest in spring. Intercity differences in TSP, RSP, suspended
sulfates, and suspended nitrates parallelled this pattern. Because ventilatory
function testing was performed on only three occasions, and the first two used
a different instrument than used in the third, it was not possible to test the
seasonal differences in FEV ,,. as a function of changes in particulate concen-
trations. Sulfur dioxide and suspended nitrates were present in low
concentrations in both cities, both during the year of study and throughout
the lives of the children under study. Thus, it was unlikely that either of
these pollutants had exerted important deleterious effects on FEV0 75 in
either city. Beyond this point, it was not possible to determine which specific
particulate fraction or fractions had exerted the strongest effects of FEVQ 7r.
14-188
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14.5.5 Studies Combining Respiratory Disease Symptoms with Pulmonary Function
34
Neri et al. compared the prevalence of chronic bronchitis and results
from respiratory function tests in Ottawa and in Sudbury, a Canadian smelter
town. The authors reported that the smelting operation in Sudbury emitted
large quantities of S02 at the time of the study, but that they were far lower
than quantities emitted in former years. The operation shut down when 24-hour
•ean concentrations of SOp reached 850 ug/m (0.3 ppm) or the TSP reached 500
ug/m . Twenty-two shutdowns occurred during the 2-year study period. Three-
year mean values for high-volume TSP and SOp were 93.0 ug/m and 52.1 ug/m ,
•} O
respectively in Sudbury. In Ottawa, there were 45.8 ug/m and 90.5 ug/m ,
respectively.
In Ottawa, the prevalence of chronic respiratory disease and reduced
pulmonary function values were associated with smoking and age but showed no
relationship to duration of residence. However, in Sudbury, length of residence
was associated with increased rates of chronic respiratory illness, and living
in Sudbury for any period of time was associated with reduced pulmonary function
In Sudbury, smoking, occupation, and age were associated with the prevalence
of chronic respiratory illness and impaired pulmonary function. After adjusting
for smoking, age, and occupation, residence in Sudbury was associated with
excess respiratory disease and diminished ventilatory function. Neri et al.
found that the mean ratio of FVC to FEV for 3280 Ottawa residents in 1969 to
1971 was higher than the mean for 2208 Sudbury residents in 1972-73. The
difference was significant for both males and females and held true even after
considering age and smoking habits (p <0.001). The prevalence of chronic
bronchitis also was higher in Sudbury males (p M3.03), but no difference was
found for females. Holland et al.301 discussed the effects of the short-term
high exposures 1n Sudbury, but did not negate the study.
14-189
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Cohen et al. made a comparison of respiratory symptoms and pulmonary
function tests in two similar groups of nearly 2000 nonsmoking adults each.
They found no indication that either increased symptoms of chronic lung disease
or impairment of lung function as reflected by spirometry or flow volume loops
was caused by a twofold difference in peak values of oxidant air pollution, or
differences between 78 and 124 ug/m annual average TSP (annual mean S02
3
concentrations were about 43 ug/m ).
179
Ramaciotti et al. determined rates for the occurrence of bronchitis
symptoms in 1182 men in Geneva in relation to the ambient SO^ concentration at
the site of residence, the number of cigarettes smoked per day, and age.
Because the prevalence of chronic bronchitis among non-smokers was very low,
these were excluded from the study. Information on illness symptoms and
demographic factors was collected by means of the BMRC questionnaire and the
aerometric data were collected by the Institut d1Hygiene, Geneva. The study
covered the period 1972 to 1976 and found 98 cases classified as chronic
bronchitis, 477 classified as having intermediate symptoms, and 637 subjects
were asymptomatic. Regression analysis (Linder-Berchtold method) was used to
determine associations. The adjusted incidence of chronic bronchitis within
the group increased from 2 percent to approximately 20 percent as the consump-
tion of cigarettes increased from 1 to 50 per day; from 2 percent to about 16
percent as age increased from 18 to 65 years; and from 4 percent to about 12
percent as annual mean SCL pollution levels increased from 10 to 60 ug/m .
Similar adjusted rates showed no significant slopes for the group with less
severe symptoms (intermediate group). Peak respiratory flow (PFR) decreased
from 500 to 470 liters/min on the average as cigarette consumption increased
from 1 to 50 cigarettes per day; from 530 to 40 liters/min as age increased
14-190
-------
from 18 to 65 years; and from 500 to 475 liters/min as annual S0? pollution
levels increased from 20 to 65 pg/m . Similar relationships were observed in
the intermediate group. The levels of S02 smoke and NOp observed 1n the study
were positively associated with the prevalence of chronic bronchitis.
A series of studies, reported on from the early 60s to the »id-70s,
have been conducted by Ferris, Anderson, and others. The Initial study Involved
comparison of three areas within a pulp-mill town in northern New Hampshire.
41 47
In the original prevalence study, ' no association was found between question-
naire-determined symptoms and lung function tests in the three areas with
differing pollution levels after standardizing for cigarette smoking. The
47
authors discuss why residence is a limited indicator for exposure. The
study was extended to compare Berlin, New Hampshire, with the cleaner city of
Chilliwack, British Columbia in Canada. 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 conclude
that this difference is 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
248
pollution. Ethnic differences could have been a confounding factor. The
S02 level in Berlin, NH, in 1961, may also be in doubt since it is based on a
312
2 month period at a single site.
The Berlin, New Hampshire, population was followed up in 1967 and again
in 1973.42'45 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
-------
TABLE 14-40. POLLUTION LEVELS, BERLIN, NEW HAMPSHIRE,
DURING THREE STUDY PERIODS
1961
1966-1967
% decline
1961-1966/67
1973
Total dustfall
gm/m2/30-day
18.4
14.3
22%
--
—
TSP (HV)
ug/m3
180
-131
28%
--
80
Sulfation
(lead peroxide)
mg S03/100 cmVday
0.731
0.469
36%
—
0.901
Sulfation*
converted to
S02 pg/m3
55
37
28%
--
66
*Assuming all sulfur in the form of S0?.
During the 1961 to 1967 period, standardized respiratory symptoms 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.
The authors conclude that either the air pollution change was not associated
with a change in respiratory health or that the study was not sensitive enough
to detect an effect. However, the type of cigarette smoking may have changed.
Internal migration may have been an additional factor. For these various
reasons, these studies are difficult to interpret.247t312,314b
16ft
Bouheys et al. used the NHLI questionnaire to obtain information on
the prevalence of respiratory symptoms in study subjects 7 years old or more
in an industrial urban and a rural community in Connecticut in 1973. Annual
mean TSP concentrations had been 88 to 152 pg/m in the urban area during the
314b
14-192
-------
previous 7 years, but similar data were not available for the rural area. In
1973, the year of the study, S02 annual concentration was 13.5 ±1.7 and 10.9
±1.6 ug/m , respectively, for the urban and the rural area, both low. Annual
mean-TSP concentrations were 63.1 ±3.7 and 39.5 ±4.2 for the urban and rural
areas, also relatively low. Means were based on approximately 1 measurement
per week. Results, adjusted for sex, race, age, smoking, occupation, and
previous residence of the bronchitic symptom of "usual cough and phlegm"
showed significant decreasing gradient from lifetime urban to lifetime rural
among non-smokers but not among smokers. Shortness of breath also showed an
association with residence that was most pronounced among non-smoking women
(12.8 percent lifetime rural and 19.2 percent lifetime urban). However,
asthma occurred more frequently among the rural residents. Inconsistencies
with indoor exposures were present in the data as well.
go
Irwig et al. studied relationships between air pollution and respiratory
disease in British schoolchildren. Information on 1816 children was collected
by self-administered questionnaires. Positive responses to questions concerning
the occurrence and frequency of respiratory symptoms were associated with results
of pulmonary function testing (PEFR) and the data analyzed by a regression
method specially designed to handle quanta! data. The air pollution levels
used were the mean smoke and SCL for November, 1973. Both pollutants were
found to be significantly associated with a history of colds going to chest
(p <0.05). Over the range of smoke levels in the analysis (10 to 130 ug/m ),
it was predicted by the equation that for each increment of 10 ug/m of smoke
(ignoring S02) 0.77 percent more of the population would have colds to the
chest. The authors report that similar results were obtained with S02, ignoring
smoke, but the measured concentrations of S02 (H202 method) were not reported.
14-193
-------
They did conclude that the analysis suggests that dimunition of smoke or SC^
from 130 to 10 ug/m would result in a decline in prevalence of colds going to
chest of as much as 49 percent in the highest risk group, and at least 12
percent in the lowest risk group.
99
Kerrebijn et al. collected data from fourth and fifth grade students on
the relationships between respiratory symptoms or pulmonary function tests and
the concentrations of pollution in areas in which they lived. Data on respiratory
illness and social and domestic circumstances of the family were obtained by
means of a self-administered questionnaire. Pulmonary function measurements
for the approximate 2400 children were made over the period of April 2 to June
8, 1973 to correspond with the period of low viral infections and few high air
pollution peak concentrations. At the time of examination, height and weight
were recorded; peak expiratory flow rate was measured in standing position
with a Wright Peak flow Meter (highest of five readings recorded), forced
vital capacity and forced expiratory volume in 0.75 second were measured in
the sitting position with Lode D-53 watersealed spirometers (the highest of
three values recorded) and the maximum expiratory flow at 50 percent vital
capacity and at 25 percent vital capacity were measured in the standing
position with a Monaghan M402 pulmonary analyzer connected to a rapid recorder.
The Peak Flow Meters were calibrated once a day over their full range with a
Godart calibration set and with standard flows. All measurements were
corrected to standard flows. The Monaghan instruments also were calibrated at
their peak flow reading with the Godart set.
Children living in the high pollution area showed a higher prevalence of
cough during the day or at night. Ventilatory function tests showed no
differences between the high and low pollution areas. Depending on the
14-194
-------
criteria used to define chronic respiratory disease, prevalence in the high
pollution area was 1.3 to 1.6 times that in the low pollution area. Annual
nean concentration of SOp 1n the low pollution area was 50 ug/m as a result
of a change in fuel from oil to gas that began only 3 years earlier. Prior to
the change the annual mean S02 concentration had been equal to that 1n the
high pollution area or 150 ug/m or higher. Particulate measured as standard
smoke (BS) was low in all areas, usually below 30 ug/m3 for annual means.
Biersteker and van Leeuwen ' reported on pulmonary function measure-
ments and bronchitis histories in 935 elementary schoolchildren living in two
areas of Rotterdam with differing air pollution levels. In a new suburb, the
3 3
winter median for smoke (BS) was 40 ug/m ; that for SOp was 120 ug/m (0.04
ppm). Concentrations of smoke and SO^ in older downtown districts were about
50 percent higher. After adjustments for height, no differences in peak
expiratory flow rates were found for boys or girls. A history of bronchitis
was more common in the more polluted area; however, the differences in socio-
economic levels were not controlled and may have been be a factor in the
difference seen.
The results of the studies discussed above are summarized in Table l4-40a.
It can be seen there that various studies have demonstrated pulmonary function
deficits (as assessed by lung function tests) or chronic respiratory disease
rates to be associated with TSP and S02 air levels of approximately 100-200
ug/m . Still others (mainly EPA CHESS studies) have been reported as indicating
that such effects may occur at somewhat lower levels; however, questions have
been raised regarding the interpretation of these study results as discussed
1n the 19^6 Investigative Report (see also Appendix A). These include concerns
regarding some of the air quality measurements reported for TSP, S02, and
suspended sulfate (SS) levels, the specific nature of which may lead to
14-195
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TABLE 14-40a
SUMMARY OF LONG-TERM EXPOSURE STUDIES OF PULMONARY FUNCTION
DEFICITS AND CHRONIC RESPIRATORY DISEASE
Type of Study
Reference
Effects observed
Annual average pollutant levels
at which effect occurred
TSP (|jg/ma) S02
UD
Cross-sectional and
long (2 areas)
Cross-sectional
(2 areas)
(children)
van der Lende74 77
Improvement in lung function
accompanying an improvement in
air quality
100 BS
(24-hr avg.)
(200 TSP)
300
(24-hr avg.)
Cross-sectional
(3 areas)
Cross-sectional
(4 areas)
Cross-sectional
(2 areas)
(children)
Goldberg et al.109
House et al.108
Kerrebi jn et al . "
Increased chronic respiratory
disease
Increased chronic respiratory
disease
Increased cough, no decreased
pulmonary function*
78-82
70
(15 SS)
low (<30 BS)
(<80 TSP)
69-160
107
150
*(low area > 3 years
ago same, now lower)
Yoshida et al.176
Increased asthma
110-120
Cross-sectional and
long (2 areas)
Sawicki and
Lawrence (1977)181
Increased previous CB and
asthma. Increased persistence,
males 31-50. Increased incidence,
females, some ages.
169
114
Cross-sectional
(3 areas) children
Rudnick182
Increased respiratory symptoms 150-227 BS
in boys. Increased Rh. in girls (240-340 TSP)
180-148
Cross-sectional and
retro- long (4 areas)
(children)
Cross-sectional
(2 areas) (children)
Cross-sectional
(3 areas) (children)
Nelson et al.114
Hammer113'257
Shy et al.215
Increased LRD (« residence)
Increased LRD
Decreased adjusted FEV0>75 in
children > 8 years
70
133
(SS=14)
72-82
107
<25
69-160
-------
TABLE 14-40a (continued).
Annual average pollutant levels
at which effect occurred
Type of Study
Cross-sectional
(2 areas) (children)
Cross-sectional
(2 areas) (children)
Cross-sectional and
Reference
Shy et al.215
Chapman et al . 213
Neri et al.34 35
Effects observed
Decreased adjusted FEV0>75
Decreased adjusted FEV0<75
Decreased FEV../FVC and increased
CB L
TSP (ug/nr3)
96-114
45 RSP
93 with peaks
S02 (ug/m3)
(= and low)
( = S02 & low)
with higher average
in lower AP areas
I
!-•
to
-------
reinterpretation of those findings suggesting that reported health effects may
be associated with somewhat higher TSP or SO^ levels (i.e., >100 to 150
»3>.
14-198
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14.6 CHAPTER SUMMARY AND CONCLUSIONS
14.6.1 Overview Summary of Chapter Contents -
In the preceding sections of this chapter, an extensive array of information
was discussed concerning: (1) methodological considerations that must be
taken into account in evaluating community health epidemiology studies (Section
14.1); (2) critical assessment of practical applications of air quality
measurement techniques employed in the collection of sulfur oxides and particulate
matter data utilized in related community health studies (Section 14.2); (3)
critical review of such studies on mortality effects associated with acute and
chronic exposures to sulfur oxides and particulates (Section 14.3); (4)
critical review of studies of morbidity associated with acute exposures to the
same pollutants (Section 14.4); and (5) critical assessment of morbidity
effects associated with chronic exposures to sulfur oxides and particulate
matter.
Through the discussion in Section 4.1, it was seen that numerous methodo-
logical factors, including covarying or confounding variables, can potentially
affect the results and interpretation of community health studies. It was
also seen, through material summarized in Section 14.2, that a number of
sources of errors have been identified as having affected sulfur oxides and
particulate matter air quality measurements obtained in both the United Kingdom
and the United States and used in British and American epidemiology studies
which provide the bulk of the information reviewed in this chapter. It was
further noted that while such errors in air measurements can at times be
fairly large, they also often act to introduce both positive and negative
biases into air quality data sets that tend to cancel each other out, especially
when considering data grouped or averaged over long time periods (monthly;
14-199
-------
annually) from the same sites or across several geographic areas classed as
"low" or "high" pollution areas. At other times, however, it also became
clear that certain measurement errors were such as to introduce either
consistently negative or positive bias into particular British or American
sulfur oxides or particulate matter data sets used in various community
epidemiology studies providing information on quantitative air pollution/health
effects relationships. It was further noted that such biases due to air
quality measurement errors must be taken into account in evaluating such
epidemiology studies -- not for the purpose of discrediting such studies but
rather to understand better the error limits likely associated with the reported
quantitative findings derived from them and to thereby allow for more accurate
interpretation of overall patterns of pertinent results.
Turning to the critical assessments of pertinent community health mortality
and morbidity studies contained in Sections 4.3, 4.4 and 4.5, results of many
of the better known and often cited quantitative studies discussed in this
chapter are summarized in Tables 14-41 and 14-42. More specifically, Table 14-42
summarized chronic exposure study results. If the results of all the various
studies summarized were accepted as being valid, then certain conclusions
might be drawn regarding air levels of sulfur oxides and particulate levels
associated with mortality or morbidity effects, as discussed in the next
several chapter overview subsections.
14-200
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TABLE 14-41 SUMMARY TABLE - ACUTE EXPOSURE EFFECTS
fSJ
O
Type of Study
Mortality (episodic)
British
Dutch
Japanese
USA
(Non-episodic)
Reference
Table 14-1
Table 14-2
Table 14-2
Table 14-2
Martin and Bradley11
Martin6
Glasser and
Greenburg222
24- hour average pollutant levels
at which effects appear
Effects observed
Excess deaths
Excess deaths
Excess deaths
Excess deaths
Increases in daily mortality
Increases in daily mortality
above the 15 moving average
Increases in daily mortality
TSP (pg/mj)
546*
300-500
285
570 (5 CoH)
500*
500*
350-450**
S02 (pg/m3)
994
500
1800
400-532
(1 hr max: 2288)
300
400
524
Morbidity
Martin16
Lawther et al. 53
Greenberg et al.196
Lawther et al . 52
Stebbings and
Hayes190
Increases in hospital admissions 500*
for cardiac or respiratory illness
Worsening of health status among
195 bronchitics
Increased cardio- respiratory
ER visits
Increased clinical condition
in CB patients
Increased symptoms in chronic
bronchitis (CB) patients
344* (250 BS)
357** (260 BS)
529* (400 BS)
344* (250-350 BS)
200 (60 RSP)
(12SS) 8 SN)
400
300-500
715
450
300
100
-------
TABLE 14-41 (continued).
Type of Study Reference
Cohen et al.55
McCarroll et al.163
Cassell et al.208 209
Stebbings and
Fogleman et al.216
24- hour average pollutant levels
at which effects appear
Effects observed
Increased AS attacks
Increased ARI daily
inc/prev
Increased ARI average
daily inc/prev
Decreased FEV0>75 (children)
TSP (Mg/m3)
150 (20SS)
160* (1.2 COM)
205* (2 COM)
700
S02 (Mg/mJ)
200
372
452
300
Converted from BS (British Smoke).
-------
TABLE 14-42 SUMMARY TABLE - CHRONIC EXPOSURE EFFECTS
Type of Study
Reference
Annual average pollutant levels
at which effect occurred
Effects observed
TSP
S0
Mortality (geog.)
Winkelstein188
Increased mortality
125-140
not significant
Zeidberg and
colleagues16-18
Increased mortality
55-60
30
Morbidity
Longitudinal and
cross-sectional
Ferris
et al.41 42
47
Higher rate of respiratory
symptoms; and decreased lung
function
180
55
fo
o
Cross-sectional
(2 areas)
Sawicki (1972)31
More chronic bronchitis,
asthmatic disease in smokers;
reduced FEV%
250*
125
Cross-sectional
study of school-
children in 4 areas
Lunn et al.96 97
Increased frequency of res-
piratory symptoms; decreased
lung function in 5-year olds
260*
190
Follow-up of school-
children in 4 areas
Douglas and Waller90
Increased lower respiratory
tract infection
197* (130 BS)
130
Cross-sectional study
of children in 4 areas
Hammer et al.214
Increased incidence of lower
respiratory diseases
85-110
175-250
Cross-sectional study
of high school
children in 2 areas
Mostardi and
colleagues177 258
Lower FVC, FEV0i75 and maximal
oxygen consumption
77-109
96-100
Cross-sectional
(multiple areas)
Lambert and Reid28
Increased respiratory symptoms
160* (100 BS)
100-150
Cross-sectional
(3 areas)
Goldberg et al.109 Increased CRD
78-82
69-160
-------
TABLE 14-42 (continued)
Type of
Study Reference Effects observed
Annual average pollutant levels
at which effect occurred
TSP (|jg/m3) S02 ((jg/m3)
Cross-sectional
(4 areas)
House et al.108
Increased CRD
70 (15SS)
100-150
Cross-sectional
and Long (2 areas)
Sawicki and
Lawrence (1977)181
Increased Prev CB and AS
Increased persistance, Males
31-50; Increased incidence,
Females, some ages
169+
114-130
Cross-sectional
(3 areas)
Rudnick182
Increased respiratory symptoms
in boys. Increased Rh in girls
221-316*
(150-227 BS)
Cross-sectional
2 areas (children)
Shy et al.215
Chapman et al.213
Decreased adjusted FEV>75
96-114 (45 RSP)
108-148
l-f
1
o
Cross-sectional and
retro- long in 4 areas
(children)
Cross-sectional
2 areas
Cross-sectional
3 areas (children)
Nelson et al.114
Hammer113 257
Shy et al.215
Increased LRD
Increased LRD
Decreased adjusted FEV<75 in
children > 8 years
70
133
(SS=14)
78-82
107
<25
69-160
(= and low)
Converted from BS (British Smoke).
**Converted from CoH.
-------
14.6.1.1 Health Effects of Acute Exposure to SCL and Particulate Matter
Studies providing evidence of acute health effects of sulfur oxide and
particulate matter are summarized in Table 14-41. Overall, various British,
Dutch, Japanese and American episodic mortality studies appear to suggest that
•ortality effects can occur at or above 300-500 ug/m3 S02- The three non-episodic
mortality studies listed in the table suggest that mortality effects can be
seen when TSP levels reach 500 to 600 ug/m and S02 concentrations reach 300
to 500 ug/m . These three studies summarize a relatively small body of data
from two winters in London and five winters in New York City. The stated
effect levels may be conservative, however, since examination of the detailed
evidence from these studies presented in Section 14.3 suggests the possibility
of an exposure-response relationship at lower levels of these pollutants.
More complex time series studies of daily mortality have also found associations
between mortality and these pollutants at lower levels. The size of the
estimated effects has proved to be sensitive to model specification and choice
of other adjustment variables. Although the possibility of mortality effects
of TSP and SOp levels below those cited in Table 14-41 cannot be excluded, it
is unlikely that this question can be resolved in the near future by observational
studies. Thus, the minimum air levels at which acute mortality increases
might be projected to be seen would be 300-500 ug/m for both TSP and SO^,
based on the studies summarized in Table 14-41.
Numerous studies reporting morbidity effects associated with acute exposures
are also listed in Table 14-41. Worsening of symptoms in bronchitis patients
an£ increased hospital admissions in Britain were reported to occur at TSP and
SO. levels of 300 or 350 to 500 ug/m3 or more. A United States study, however,
found exacerbation of symptoms among bronchitics at 200 ug/m TSP and 100
jjg/m SO, and asthmatics were reported to show increased attacks at 150 ug/m
14- 205
-------
TSP and 200 (jg/m SOp. Also, spirometry tests were reported to show decreases
in lung function at 700 ug/m TSP and 300 ug/m SOp. However, van der Lende
saw improvement in lung function among adults when pollution levels were
3 3
reduced from 245 ug/m (TSP) and 300 ug/m (S02). Acute upper and/or lower
respiratory illness also has been reported to occur at levels as low as at 160
ug/m TSP (24-hour averages). Overall, then, the summarized studies suggest
that (1) very severe morbidity effects, e.g., worsening of symptoms in bronchitic
patients, clearly occur at TSP and SOp levels of approximately 300 or 350 to
500 ug/m , and (2) less severe but significant morbidity effects may occur
o
with acute exposure at levels of approximately 150-300 ug/m . These studies r
do not, however, provide a basis for separately estimating the health effects
of SOp and particulates. Since these two forms of pollution have important
common sources, their levels tend to usually vary together over time.
14.6.1.2 Health Effects of Chronic Exposure to SO- and Particulate Matter
Mortality and morbidity studies that have been reported as demonstrating
associations between mortality, illnesses, or decrements in pulmonary function
with annual average levels of particulate matter of SOp are summarized in
Table 14-42. As seen in that table, the two mortality studies suggest that
o
mortality effects can occur at annual levels of 125 to 140 ug/m or less of
TSP and SOp. In the morbidity studies, lower respiratory disease, chronic
bronchitis, and reduced pulmonary function results were reported that are
indicative of morbidity effects likely clearly occurring at annual average TSP
o
or SOp levels of 150 to 250 ug/m or more. Other study results summarized in
the table suggest an association of various morbidity effects with concentrations
3
in excess of about 70 to 80 ug/m TSP and SOp concentration in excess of 96 to
107 ug/m . As with studies of acute effects, many of these studies could be
14-206
-------
further interpreted not only as demonstrating that health effects are
exposure-related but also that they increase as these pollutants increase over
the entire range of exposures studied and no clear "no effect" level can be
determined on the basis of presently available information. Also, in general,
these studies cannot be used to distinguish between the effects of sulfur
oxides and particulates. In several studies, however, TSP effects were reported
to occur in the presence of low or non-significant levels of $Q 188«212»213»215»257
14.6.1.3 Health Effects of Atmospheric Sulfates
Conversion to sulfate compounds, including sulfuric acid, has been proposed
as a major pathway by which sulfur dioxide and possible other sulfur compounds
may exert toxic effects. However, only a few community health studies have
attempted to measure and assess health effects associated with suspended
190
sulfates (SS). Stebbings and Hays, for example, reported increased symptoms
in patients with 24-hour averages of 12 ug/m3 SS (200 TSP, 60 RSP, 8 SN, 100
212
S02). Also, Chapman et al. reported increased chronic respiratory disease
prevalence rates in a high pollution community with an annual average of 15
3 257
ug/m SS (70 TSP and 107 SO^)- Hammer further reported increased lower
respiratory disease prevalence rates in a high pollution community with an
annual average of 14 ug/m SS (133 TSP and SOp >17). Thus, suspended sulfate
levels of 12 ug/m (daily) or more and 15 ug/m (annually) might be interpreted
as being important based on those results.
14.6.1.4 Respirable Particulates Effects
As discussed in Chapter 11, particles below 15 ug/m MMAD are important.
Respirable suspended particulates (RSP) £3um, have been measured in only a few
American epidemiology studies, e.g., those by Hammer, ' Stebbings and
Hayes,190 and Shy and Chapman et al.213'215 The latter study was reported as
14-207
-------
demonstrating decreased adjusted FEV ,,. in children in an area with higher
pollution with RSP of 45 ug/m3 (96 to 114 ug/m TSP and S02 very low). Thus
o
RSP of 45+ |jg/m may be important.
14.6.2 METHODOLOGICAL FACTORS IMPACTING INTERPRETATION OF RESULTS
If it were assumed that all of the results summarized in Tables 14-41 and
14-42 were derived from methodologically sound studies and were universally
accepted as valid, then the above summary of their results could be accepted
as a reasonable representation of the likely atmospheric particulate and
sulfur oxides levels found to be associated with mortality and morbidity
effects. However, the matter of the methodological soundness and validity of
various studies has been a matter of considerable controversy and discussion
during the past decade. Such controversy has derived, in large part, from the
fact that certain additional risk factors can often be as important as the air
pollution variables studied in affecting human health. For example, in earlier
discussions (Sections 14.1, 14.3, 14.4), it has been strongly emphasized that
smoking is one such factor, as are occupational exposures. Furthermore, age
and sex co-variables can also be critical in the evaluation of health effects.
Race or ethnic group characteristics likely fall into this category as well.
In addition, numerous social variables may be highly critical in terms of
their existing direct effects on human health, as well as how they may modify
the health effects of environmental pollutants. Such social factors include
social economic status (income, education, and occupational levels and associated
social class status), migration, and household characteristics. Finally,
meterological variables such as sudden temperature changes or shifts in humidity
levels may also be critical co-variables which, along with air pollutants,
might affect health in a deleterious manner. Parental smoking and other
14- 208
-------
sources of indoor pollutants may also be critical. Other less-well defined
social/ environmental variables, such as a greater degree of crowding
in housing conditions, too, may represent a set of "urban factors" differen-
tially acting to affect health in comparison to "rural" conditions.
Studies of the episodic effect of pollutants reviewed above usually
considered meterological variables and age as important possible co-variables;
but many essentially ignored other variables as being relatively unimportant.
Studies of urban vs. rural differences in health effects, similarly, have
often not attempted to assess the nature of possible contributing factors
other than the relative differences in concentrations of air pollutants; and
some have demonstrated urban-rural differences in health measurements that are
independent of or unrelated to air pollutant concentrations. Only relatively
few have been successful in providing reasonably good analyses of results tha*
take such possible confounding urban-rural differences into account.
For studies of geographical comparison, investigators generally have
attempted to achieve as much homogeneity among populations in different study
areas as possible. In situations where this is difficult, many have tried to
record measurements of the confounding and co-variables such that they can be
adjusted for in statistical analyses. In these studies, for instance, it is
usually considered satisfactory to either have equal sex ratios and 10-15 year
age groupings, or otherwise, to analyze results by sex and age. Essentially
no one would claim that it is necessary to examine age groups defined by one
or two year age intervals.
In studies of adults, results have either been analyzed by taking
smoking and pollutant levels into account separately, so that one can determine
any additive effects of smoking and air pollution; or study groups that have
14-209
-------
very similar smoking habits but different pollutant exposures have been compared
On the other hand, in longitudinal studies, it has been necessary to also
measure changes in smoking habits in regard to number of cigarettes, and
whether they are low in tar/nicotine. Many longitudinal changes «ay be associ-
ated with changes in smoking habits (Ferris et al.; Fletcher et al.).
Social class, as mentioned before, may affect reports of health outcomes
or the actual health outcomes themselves, and this has often been controlled
for in one form or another, e.g., either through selection of similar social
groups or via statistical analyses techniques. Some geographical studies have
ignored social class as well as other factors (e.g., Burn and Pemberton),
which makes them difficult to evaluate. Controlling for social class in
British terms, however, may in effect also adequately control for occupational
differences, although not occupational exposures. Studies elsewhere more
often used education or income to control for socioeconomic factors, because
such variables are highly correlated with overall socioeconomic status and
related factors. For example, smoking and migration are highly correlated
with social class in many countries. Social class is also correlated with
household characteristics, such as the number in a family, the number of rooms
per house, and crowding (number of people per room). Exposure to parental
smoking and/or sources of indoor pollution may or may not be critical, as the
relevance of those exposures remain to be more clearly established. Ethnic
group differences, in some ways similar to social class differences, may also
be related to physiologic differences, as in regard to pulmonary functions.
It has usually been easier either to exclude all but one ethnic group/race
from a given study or to analyze results for them separately (Mostardi et al.;
Chapman et al.; Hammer et al.; French et al.; Bouhuys et al.). Failure to do
so may have confounded and confused the results derived from certain other
studies.
14- 210
-------
Also, some investigations studied only one sex within a specific occu-
pation group in order to minimize occupational and social class differences
(for example, British Ministry of Pensions, Burn and Pemberton, Gervois,
Ipse"n, Bouhuys et a!., Lambert and Reid, Holland et al., Deane et al., Fletcher
et al.)- This may not always have been sufficient, however, 1n that urban/rural
differences, economic differences, or activity differences may have still
existed and affected health. Even so, this approach is generally considered
to be an acceptable way to control for occupational and social class differ-
ences. Differential specific occupational exposure conditions, however, are
almost never considered in such epidemiological studies.
Some studies have focussed on children only, generally including children
too young to have started smoking as a means of eliminating this as a possible
important confounding factor. Many such pediatric studies also consider
parental factors (including social class), as well as race, age, sex, and
urban/rural differences. Occasionally, past history of illness was also
considered. Studies of children also gain the advantage of being able to
better quantitate life-time air pollution exposure histories.
In addition to the above considerations, many studies have recognized
that certain factors, such as education (or social class), may affect health
endpoint reporting levels, and therefore attempted to control for them.
Generally, controlling for or adjusting for any similar (highly correlated)
factor across study groups has been considered sufficient to help alleviate or
minimize possible differences attributable to reporting artifacts.
Different migration (self-selective residence) patterns, also, may have
been Important in some studies, especially those of geographical comparisons
or of a longitudinal nature (e.g., the Winklestein, Ferris, Petrilli, Hammer
et al., French et al., and Neri studies). Migration patterns and self-selection
14-211
-------
In regard to evaluating other (less well-designed) studies, it should be
noted that some studies exist which indicate that possible confounding variables
are not always as important as they were originally thought to be. For example,
follow-up studies on an adult cohort previously studied as children by Douglas
and Waller did not confirm original social class differences between the
groups to be of much significance in accounting for health findings for the
groups later in life. Also, Manfreda did not find "urban" characteristics to
be relevant in explaining his study results, and other studies have shown that
household/familial factors are not necessarily important in all cases in
accounting for observed results. Therefore, care must also be taken not to
over-emphasize the relative importance of potential confounding or covarying
factors not ruled out as possible alternative explanations for the results of
a given study. In other words, being overly critical where information is
lacking to support the likelihood of a specific confounding factor or co-variable
affecting the pattern of results obtained in a study at a particular time
represents as much of a disservice in trying to achieve an objective, balanced
appraisal of study results under discussion as would any countervailing lack
of reasonable regard for the potential importance of such factors.
It must also be recognized that no single study alone, no matter how
well-designed or conducted in and of itself completely establishes what comes
to be accepted as a "scientific fact" defining either a relationship between
two or more variables studied or a lack thereof. Rather, excellence in the
design and conduction of a given study, internal consistency and biological
plausibility of its results, and their consistency with other known results or
information all help to heighten confidence in the likely existence of relation-
ships indicated by that study's results. Even greater certainty is attributed
14-213
-------
to the probable existence of such relationships if further independent studies,
regardless of particular individual flaws, yield results consistent with such
relationships. Thus, consistency in the overall pattern of results indicative
erf particular relationships or the overall "weight of the evidence" from more
than one study are crucial in establishing given relationships as "scientific
facts" or in determining the degree of certainty ascribed to them.
14.6.3 Quantitative Dose-Response Relationships Defined by Community Health
Studies
In order to elucidate dose-response relationships established by commun-
ity health epidemiology studies of the type reviewed above, numerous attempts
besides the present one have been made to examine both negative and positive
information concerning such studies. This has usually been done to determine
which are sufficiently sound methodologically to allow for reasonable conclu-
sions to be drawn from them in evaluating the overall meaning of their results
individually and collectively. Such attempts include critical reviews and
O/IC
commentaries written by Rail (1974) , Higgins et al. (1974) , Goldsmith
and Friberg (1977), 247 Ferris (1978), 314a and Waller (1978). 314b They also
include the following evaluative documents appearing in 1978: an American
Society (ATS) review of Health Effects of Air Pollution (Shy et al. ,
251
1978); a National Research Council /National Academy of Sciejice CNRC/NAS)
document on Airborne Parti cles/^ by Higgins and Ferriv(1978) and an NRC/NAS
document on Sulfur Oxides^ by Speizer and Ferris (1978) More recent such
reviews and commentary appearing in 1979 include: the 1979 World Health
Organization (WHO) document, Environmental Health (8): Sulfur Oxides
\\9
and Suspended Particulate Matter; a report by Holland et al. (1979)
written for the American Iron and Steel Institute and appearing in the
14-214
-------
American Journal of Epidemiology; and a reply to that report in the same
journal by Shy (1979). Some of the more salient points of these reviews
and commentaries are concisely highlighted below.
As will quickly become apparent through the course of the discussion
below, there are certain studies that many reviews consistently rate as being
methodologically sound and their results valid. Also, when those study results
are viewed together, collectively, fairly consistent patterns of quantitative
relationships emerge regarding exposures to sulfur oxides and particulate
matter associated with the occurence of various types of health effects,
including (1) mortality and-morbidity effects associated with acute exposures
to fairly high ranges of air concentrations of those substances and (2) mor-
bidity effects associated with chronic exposures to lower atmospheric levels
of the same agents. Given the general concensus that appears to exist regarding
the validity of these studies, then, there seems to exist very good support
for placing considerable confidence in the overall patterns of quantitative
relationships defined by their findings.
In regard to other reasonably well-designed studies, but for which less
of a concensus exists regarding their likely validity, several interesting
points emerge from the subsequent discussion. First, it becomes apparent
that, beyond some small modicum of agreement among the reviews concerning
problems associated with certain studies, the various reviews often differ
considerably in regard to their assessments of the methodological soundness or
validity of any given individual study. This derives mainly from different
reviewers emphasizing or citing different possible confounding or covarying
factors as potentially being important in affecting the results of a given
study — at least in their respective subjective opinions. Secondly, it is
14-215
-------
also notable that very rarely, if ever, have any of the reviewers presented
actual data or other information, e.g., new or additional statistical analyses
of study results, to support their speculations as to what factors might
represent reasonable alternative explanations, besides the air pollution
variables studied, for the observed study results. Lastly, despite whatever
real or imagined flaws might be associated with the particular individual
studies, a surprisingly great degree of consistency exists both between most
of their results and, also, in comparison with the findings of the other
studies alluded to above as being widely recognized as being valid. In some
cases, however, the results of some of the supposedly "flawed" studies point
toward still lower levels of sulfur oxides and particulate matter being asso-
ciated with significant mortality or morbidity effects. Thus, whereas not as
much confidence can yet be placed in such findings as those from the more
universally accepted studies, it is still not appropriate scientifically to
completely disregard or ignore them. This is especially true in view of the
fact that, all too often, relationships indicated to exist by "suggestive"
evidence derived from numerous "flawed" studies are later confirmed by more
carefully designed and conducted "definitive" studies.
14.6.3.1 Review Articles and Commentary (1974-1978)--Turning to discussion of
the different reviews and commentaries listed above, Rail published a review
in 1974 on the health effects of sulfur oxides and particulate matter that
examined the then existing scientific information. Rail's 1974 summary of
studies showing pertinent dose-effects relationships is presented in Table
14-43. In addition, Rail drew attention to the then current WHO evaluation
shown in Table 14-44. In summarizing his evaluation, Rail stated that
14-216
-------
TABLE 14-43.
SUMMARY OF DOSE-RESPONSE RELATIONSHIPS FOR EFFECTS
OF PARTICLES AND S02 AND HEALTH*
Averaging time
for pollution
measurements Place
Particles,
pg/m3
S02
ug/m3
Effect
24 hr
24 hr
24 hr
Weekly mean
24 hr
Winter mean
Annual
London
London
London
London
New York
Britain
Britain
Britain
Britain
Britain
Buffalo
Berlin, N.H.
2000 1144 Mortality
750 700 Mortality
300 600 Deterioration of patients
200 400 Prevalence or incidence of
h respiratory illnesses
6 1500 Mortality
100-200 100-200 Incapacity for work from
bronchitis
70 90 Lower respiratory infections
in children
100 100 Upper and lower respiratory
infections in children
100 100 Bronchities prevalence
100, 100 Prevalence of symptoms
100a 300^ Respiratory mortality
180 731 Increased respiratory symptoms
Decreased pulmonary function
a"01d" results, leading to original standards.
In coefficient of haze units (COHS).
cAs ug S02/100 cm /day.
*
From Rail (1974)
14-217
-------
TABLE 14-44. EXPECTED HEALTH EFFECTS OF AIR POLLUTION
ON SELECTED POPULATION*
Effect Pollutant
Excess mortality and hospital 500 500
admissions (24 hr mean)
Worsening of patients with 250 500-250
pulmonary disease (24 hr
mean)
Respiratory symptoms (annual 100 100
arithmetic mean)
Visibility and/or annoyance 80 80
(annual geometric mean)
World Health Organization
(WHO) data
*
From Rail (1974)
14-218
-------
Disease and death seldom, if ever, result from pollution alone. They
are the outcome of many factors, both individual and environmental,
acting together. Acute episodes of high air pollution have clearly
resulted in mortality and morbidity. In addition to these acute
episodes, pollutants can attain daily levels which have been shown to
have serious consequences to city dwellers. There 1s a large and
increasing body of evidence that significant health effects are pro-
duced by long-term exposures to air pollutants. It 1s not possible to
state a concentration below which such health effects will not occur.
245
Rail (1974) elaborated further on the above points in his review, as
follows:
Health effects may range from discomfort through physiological
deviations from the norm, prevalence of symptoms, appearance of
illness, lost working time, and premature retirement to complete
incapacity and death. In practice, it is better to consider these
indices in the reverse order, starting with death, serious illness,
and significant disability, about which there can be little argument,
and to proceed thence to physiological deviations and minor disorders,
the significance of which may be open to question. Disease and
death seldom, if ever, result from pollution alone. They are the
outcome of many factors, both individual and environmental, acting
together. Any epidemiological study of the effects of air pollution
must allow adequately for these other factors. Indeed, the quality
of such studies often depends on the success with which such allowance
has been achieved. At the other end of the range of health effects,
the implication of minor symptoms and small deviations from some
physiological or biochemical norm between persons living in polluted
and nonpolluted neighborhoods may be imperfectly known. Until it
can be shown that such effects predispose to disease, disability,
or reduced expectation of life, the weight that should be given to
them in setting standards will remain a matter for personal judgment.
Acute episodes of high pollution have clearly resulted in
mortality and morbidity. Often the effects of high pollutant concen-
trations in these episodes have been combined with other environmental
features such as low temperatures or epidemic diseases (influenza)
which many in themselves have serious or fatal consequences. This
has sometimes made it difficult to determine to what extent pollution
and temperature extremes are responsible for the effects. Nevertheless,
there is now no longer any doubt that high levels of pollution
sustained for periods of days can kill. Those aged 45 and over with
chronic diseases, particularly of the lungs or heart, seem to be
predominantly affected.
14-219
-------
In addition to these acute episodes, pollutants can attain
daily levels which have been shown to have serious consequences to
city dwellers. For many years in London, daily deaths and illnesses
were clearly related to daily levels of smoke and SOp. Comparable
observations have been made in New York City, Philadelphia, and
Chicago. In the New York - New Jersey Metropolitan area, an analysis
of daily mortality for the years 1962-66 showed that deaths were
1.5% below expectation at the lowest S02 Concentrations and 2% above
expectation at concentrations of 500 ug/m and above. A similar
though weaker relationship was found in Philadelphia but not in
Chicago.
The implication of daily levels of SOp and particulates has
been studied in particularly vulnerable groups, such as patients
with chronic bronchitis and emphysema. Deterioration in their
respiratory well being has resulted from a daily concentration of
SOp of about 500 ug/m which is not much above the 24-hr primary
standard. A few studies have even suggested that deterioration in
particularly vulnerable groups may occur with daily concentrations
which are below this standard. Confirmation of this is urgently
needed."
245
In reference to chronic exposure effects Rail (1974) concluded:
There is a large and increasing body of evidence that signifi-
cant health effects are produced by long-term exposures to air
pollutants. Acute respiratory infections in children, chronic
respiratory diseases in adults, and decreased levels of ventilatory
lung function in both children and adults have been found to be
related to concentrations of SOp and particulates, after apparently
sufficient allowance has been made for such confounding variable as
smoking and socioeconomic circumstances.
It is not possible to state a concentration below which such
health effects will not occur. In many studies the proportion of
persons affected increases from the lowest to highest categories of
pollution. Had even lower categories of pollution been used in the
analyses, even lower critical levels might have been suggested.
Thus, as in the case of daily mortality, the concept of no-effect
level may be a chimera. A reasonable conclusion from these studies
would however be that health effects have been found when annual
levels of particulates or SOp exceed 100 ug/m .
The essential points of these conclusions stated by Rail in 1974 have been
consistently echoed in virtually all of the other major reviews appearing
throughout the remainder of the decade, with few notable exceptions (e.g., the
"Holland Report" ) discussed later. Also, a fairly high degree of consistency
14-220
-------
or consensus among the reviewers can be seen as to what their published opinions
indicate to be reasonable quantitative estimates of sulfur oxides and particulate
matter air concentrations associated with the occurrence of human nortality or
morbidity effects, this overall consistency emerging despite differences in
opinion regarding the strengths or weaknesses of any given individual studies.
248
For example, in another 1974 review, by Higgins, there was provided a
dose response table as presented below (Table 14-45). In the conclusion of
that report, Higgins states, "Although these are rather inadequate data, it
would perhaps be reasonable to conclude that average annual levels of particulates
3
and S02 should both be under 100 ug/m . It should further be noted that,
although not necessarily crucially used in arriving at that conclusion or
listed in Table 14-45, several additional studies were considered by Higgins
to be positive as well: that is, the McCarroll et al., Cassell et al., and
Lebowitz et al. studies; several of Lawther's studies; the Speicer studies,
the Shephard studies, and the Becker study. Higgins also pointed out the
relevance of the Ciocco and Thompson follow-up study, which indicated the
major influence of episodic conditions on the elderly and infirmed. Higgins
248
(1974) went on in his review, however, to speculate that the Fletcher et
al. and Angel et al. studies, showing decreases in signs and symptoms potentially
associated with decreases in air pollution, might be more related to decreases
in tar in British cigarettes (if so, this would presumably also affect many
later studies in Great Britain, including the Waller et al. and Lawther et al.
studies, the Emerson study, etc.). The influence of ethnic differences, he
suggested, might have affected results from certain other studies such as
those by Ferris and Anderson; and usual inter-city differences were suggested
14-221
-------
TABLE 14-45. PARTICULATE AND SULFUR DIOXIDE LEVELS AND EFFECTS ON HEALTH*
Averaging time
for pollution
measurements
24 hours
Winter
Annual
Place
London
New York
Chicago
Britain
Britain
Britain
Buffalo
Parti culates
ug/m cons
2000
1000
250
200
6
Not
specified
200
70
100
100
S00 levels
3 ?
|jg/m mg/100 cm -30 days
1000
500
500
250
1500
700
200
90
100
0.30
Effect
Mortality
Mortality
Exacerbations of
bronchitis
Increased absence from
work
Mortality
Exacerbations of
bronchitis
Correlation of
pollutants with
bronchitis incidence
Lower respiratory
infections in children
Bronchitis prevalence
Respiratory mortality
Reference
Scott, (1959)332 „
Gore and Shaddick (1958)° „
Burgress and Shaddick (1959)
Martin (1964)° 7
Waller et al. (1969)'
KQ
Angel et al. (1965)b*
McCarrol and Bradley.Qgee)331
Carnow et al. (1968)1™
Ministry of Pensions
and National-Insur-
ance (1965)
on
Douglas and Waller (1966)™
Lambert and Reid (1970)28
Winkelste1n..st fL, (1967
and 1968)J J>1
*Adapted from Higgins (1974)248 review.
-------
as perhaps influencing certain studies such as those by Prindle. The lack of
both smoking and social status analyses were also noted as potentially affecting
interpretation of still other studies, such as the one by Burn and Pemberton.
248
Higgins also cited the Winklestein and Kantor results on smoking for
White females in areas of Buffalo previously studied by Winkelstein in collecting
data for evaluating air pollution - mortality relationships; the later smoking
data appeared to ameliorate criticism regarding the lack of smoking information
in the earlier Winklestein studies. Higgins went on to discuss studies showing
positive associations with air pollution after occupation was controlled for;
such as: Fairbairn and Reid, Cornwall and Raffle, Holland et al., Deane et
al., Holland and Reid. Other studies, Holland et al., Colley and Holland,
Colley and Reid, in which smoking, residence, family size, past history of
illness, and occupation were controlled, were also discussed in terms of the
relevance of these factors in producing chronic lung diseases and SO ASP
health effects. Certain other studies by Toyama, Watanabe, and Lunn were
noted as showing that declines in disease symptoms or improvements in lung
function might be related to declines in air pollution. Some difficulties
were noted, however, as complicating the determination of precise levels of
SO or particulate matter assoicated with the various changes observed.
247
The Goldsmith and Friberg (1977) review, although not summarizing
specific estimates of dose-response relationships, did emphasize the positive
findings of certain critical studies deemed to be adequate scientifically, as
part of an overall review of health effects of air pollution in a book chapter.
«
Where appropriate, pollutant levels were indicated. For example, in evaluating
Lawther's53 studies, Goldsmith and Friberg (1977) stated:
14-223
-------
When two winters (1959-60 and 1964-65) were compared in terms
of the association of exacerbations with SOp, the general impression
was of slightly reduced and less consistent effect during the latter
period. The mean BS concentrations had then decreased from a mean
of 342 ug/m ...to 129... while SCL had decreased only from 296 to
264 ug/m3.
They also further stated in their 1977 review that:
... even during the winter period of 1967-68, when the daily
data were treated statistically, a significant correlation (5%
level) was found with both smoke and S0?, with mean BS concentrations
of only 68 ug/rn (sd=48)3and 204 ug/ni tsd=100) of SO" (Note that
the BS level,of 68 ug/m would be approximately equivalent of
130-140 ug/nT TSP.)
Certain studies were also considered by Goldsmith and Friberg (1977) to
be "representative" of the effects of the SO /TPS pollutant complexes on
/\
emplysema, chronic bronchitis, and asthma, including the following: the
studies of the Royal College of General Practitioners, Buck and Brown, Toyama;
Nose; Takahashi; Yoshida; Comstock; Deane: Holland; Deane; Carnow; Spizer;
McCarroll et a!.; Cassell et al.; Lebowitz et al.; Winklestein; and Ishikawa.
Representative studies of the effects of SO /TSP on asthma were: the studies
f\
of Tokyo, Yokohama asthma, Zeidberg et al., Sim and Pattle, Peranio, and
several EPA studies. Additional studies thought to be worthwhile and pertinent
were those of Martin, Schimmel, Buechley, Lawther et al., Goldsmith, Fletcher,
Holland, Douglas and Waller, Lunn, Holland et al., Colley and Reid, Zaplatel.
314a
A more recent (1978) review by Ferris provides both a dose-response
table (14-46) and summary statements about his evaluation of the health
effects of exposure to levels of sulfur oxides and particulate matter. He
states:
14-224
-------
TABLE 14-46. SUMMARY OF EFFECTS OF SULFUR DIOXIDE AND PARTICULATES
ON HUMAN HEALTH - LONG TERM EFFECTS*
S°23
ug/m
250
130
120
120
98
23
425-50
55
37
66
Suspended
participates
(ppm) ug/m
(0.095) 250a
(0.05) 240a
(0.046) 180a
(0.046) 230a
(0.037)b 93
(0.009) 110
(0.162. -0.019) 195-85
(0.021)b 180
(0.014)b 131
(0.025)b 80
Effects Reference
Increased phlegm 274
production
Increased respira- 181
tory disease
Increased respira- 96,97
tory illness and
decreased pulmonary
function
Increased lower 90
respiratory
illness
Decreased FVC, 177,258
FEV0.75C
Decreased 212
FEV0.75C
Increased lower 214
respiratory _
disease morbidity
Increased respiratory 43
symptoms, decreased
pulmonary function
No effect 43
No effect 46
a 89
Corrected from original data to TSP equivalents.
SO- equivalent calculated from lead peroxide data.
See text for discussion of results.
Adapted from Ferris (1978)
14-22ST
-------
There is not much information with respect to the short term
effects. A study by Cohen et al. on asthmatics indicates an effect
at a level below present 24 hour standards for SOp and particulates;
van der Lende noted small reversible changes in pulmonary function.
The other study where effects have been noted is either above or
close to the present standard, one showed no effect at levels considerably
above the standards. More information is available on the long term
effects, and it appears that the present annual averages for SOp and
particulates are reasonable. More information is still needed with
respect to an effect, if any, of higher SOp levels associated with
low levels of particulates. Information snould also be obtained to
develop the standard for fine particles, and in due course to try to
make a better chemical characterization of the fine and coarse
particles. The health effects of a considerable fluctuation above a
mean also need a evaluation.
For the sake of clarity, it should be noted that the 24-hr standards referred
to by Ferris for SOp and particulates are 365 and 260 ug/m , repectively;
the present annual average standards for SOp and particulates referred to,
3 3
respectively are: 80 ug/m and 75 ug/m (annual geometric mean).
314a 43
Ferris also opined that his studies may demonstrate certain levels
at which no effects appear to occur. In addition, the Emerson study was
noted as possibly yielding information on "no effects" levels. Despite minor
criticisms, the Chapman et al. study and the Mostardi et al. studies were also
considered sufficiently satisfactory to include in the dose-response summary
314a
of the review. However, the van der Lende et al. studies, the Cohen et
al. study and the Lawther study were apparently not considered sufficiently
adequate to include in the table, whereas the studies of Goldstein and Block,
Dohan et al. (Ipsen et al.) were considered to be inadequate.
In the same 1978 issue of JAPCA containing the above Ferris review3143
Waller discussed the Ferris review. There, Waller commented on the Lawther
report, and also stated that British smoke is not more important than
total suspended particulates. He, too, felt that the Cohen study was weak in
some respects and that the Emerson study was weak, but not a study demonstrating
14-226
-------
"negative" findings or a "no-effect" level. He pointed out other results
published by van der Lende in 1975, which confirmed a later decline in function
with age. In regard to the Ferris et al. 1973 follow-up study, Waller opined
that the air pollution measurements were often sporadic and Inappropriate and
that there may have been a change in smoking habits vis-a-vis filters and/or
low tar/nicotine cigarettes. In addition, Waller apparently generally felt
that many of the other studies that Ferris utilized in arriving at his
dose-response estimates were not necessarily appropriate or adequate.
14.6.3.2 Major Evaluative Documents (1978)--In regard to the series of major
pCl
evaluative documents appearing in 1978, the ATS document by Shy et al.
pointed out several studies considered to be critical in establishing
associations between air pollution and health effects. Besides many of the
295 248 314a
above-mentioned studies alluded to by Rail , Higgins and Ferris, the
Toyama and Watanabe studies, which showed an increase in peak expoloratory
flow rate with declining air pollution, were noted in the ATS report as being
pertinent and important. The relevance of the WHO conclusions regarding SO™
a^~
&&particulate health effects (see below) was also noted and endorsed in the
ATS document.
In another 1978 document, the NRC/NAS review on Airborne Particles
prepared by a study group chaired by Ian Higgins, Higgins and Ferris formulated
a dose-response table (14-47), utilizing those studies they felt to be adequate
and critical. Studies by Schimmel and bv) Emerson were considered indicative
of negative levels. Also, changes in funciton from an early study of Lunn's
to. a later one were used by Higgins and Ferris to estimate SOp and particulate
levels below which they thought health effects were not occurring. Certain
positive studies, such as those of Shephard's, although not discounted, were
not utilized in the Higgins and Ferris dose-response table.
14-227
-------
TABLE 14-47. NRC/NATIONAL ACADEMY OF SCIENCES*
HEALTH EFFECTS AND DOSE/RESPONSE RELATIONSHIPS FOR PARTICULATES AND SULFUR DIOXIDE
oq
Averaging time
for pollution
measurements
24 hour
Weekly Mean
6 Winter Months
Annual
*
A»J~«.»~..J *«~K UD
Place
London
New York City
Chicago
New York City
Birmingham
New York City
London
Britain
Britain
Buffalo
Berlin
P/UAC A{ _**_...**» n
Particles,
rng/m3
2.00
0.75
0.50
6 COHSa (5)d
3 COHS
Not Stated
0.145 (+?)
0.18-0.22
2.5 COHS
0.20
0.20 (>.l)d
0.07
0.10
0.10
0.08
0.18
1 •*•*+ 4 *•! A*> DAnn«+
S°23
ntg/m
1.04
0.71
0.50(4)d
0.50
0.70
0.70
0.286
0.026
0.52
0.40
0.20 (>.l)d
0.09
0.10
0.12
0.45*
0.73C
307
Effect
Mortality
Mortality
Exacerbation of bronchitis
Mortality
Morbidity
Exacerbations of bronchitis
Increased prevalence of respiratory
symptoms
Increase prevalence of respiratory
symptoms
Mortality
Increased prevalence or incidence of
respiratory illnesses
Bronchitis sickness absence from work
Lower respiratory infection in children
Bronchitis prevalence
Respiratory symptoms and lung function
in children
Mortality
Decreased lung function
References
(Gore et al.8)g
Burgess1et al.
Lawther1J ,,
Lawther et al.
Greenberg et al.,-.
Greenberg et al.
Carnow et al.174
212
Chapman et a1.?14
(Hammer et al. )
Hammer et al.257
Glasser222
69
Angel et al. »74
(Fletcher et al. )
CO
Min. Pensions
90
Douglas and Wallar
Lambert andQBeid^
Lunn et al. >3'
Winklestein et,al.21'188
Ferris et al.
^Coefficient of Haze Units.
mg S0,/cm /SO.days.
>g S0,/100 cm^/day.
aas stated in text
-------
In summarizing the dose-responses relationships defined by the findings
included in their dose-response table (14-47), Higgins and Ferris stated that
the table:
provides estimated concentrations of particulates and sulfur
dioxide that may affect health. To reiterate, these two pollutants
nay not be the most important. They serve only as indices of other,
perhaps more important, pollutants. In London, mortality has clearly
resulted when 24-hr smoke concentrations have exceeded 1.0 mg/m and
sulfur dioxide concentrations have reached 0.750 mg/m (0.288 ppm).
These peaks used to occur in London during average annual background
concentrations of 0.3 to 0.4 mg/m of smoke and 0.25 to 0.30 mg/m
(0.1-0.12 ppm) sulfur dioxide. Such concentrations are now fortunately
only of historical interest. They should certainly not be tolerated.
,In London, 24-hr concentrations of ~0.5 mg/m of smoke and 0.4
mg/m (0.15 ppm) of sulfur dioxide exacerbated bronchitis. With the
present lower concentrations, such exacerbations are infrequent.
Some correlation stilKexisted when the average annual concentration
of smoke was 0.06 mg/m and of sulfur dioxide was 1.70 mg/m (0.654
ppm). Since then, pollution has declined further in London but it
is not clear if exacerbations still occur with increases in pollution.
In Britain, sick leave attributed to bronchitis appeared to
correlate linearly with winter smoke and sulfur dioxide concentrations
over 0.1 mg/m (0.038 ppm). It would be very interesting to know if
similar correlations can still be demonstrated at the present lower
pollutant concentrations.
It should be clarified that the above noted levels of0.06 mg/m and 0.1 mg/m
for smoke concentrations would be approximately equivalent to 120 and 200
ug/m3 TSP.
Turning to findings for American cities, Higgins and Ferris noted that:
In New York City, 24-hr coefficient of haze units (CoHs) of 5
or more and sulfur dioxide of 2.0 mg/m (0.769 ppm) have resulted in
deaths; 3 CoHs and 0.7 mg/m (0.269 ppm) sulfur dioxide have caused
illness. Studies of daily mortality in relation to pollution suggest
that-excess deaths may occur when sulfur dioxide is as low as 0.35
mg/m (0.013 ppm). In Chicago, exacerbations of bronchitis were3
associated with daily sulfur dioxide concentrations of 0.75 mg/m
(0.288 ppm), probably in the presence of high concentrations of
particulates.*
In Buffalo, mortality from respiratory illness appeared to
increase progressively from the lowest to the highest pollutant
concentrations. The lowest level of smoke was <0.08 mg/m and of
sulfation, 0.045 mg/cm /day. A number of other British studies
suggest that average annual concentrations of particul|te^^and
sulfur dioxide should both be held to under 0.100 mg/m .
14-221
-------
In final summary, Higgins and Fern's stated:
There is good evidence that exceptional episodes of pollution
(>1.0 mg/m [0.385 ppm] sulfur dioxide and particulates) caused
illness and death. There is also a good deal.of evidence that
sustained lower levels of pollution >0.1 mg/m (0.039 ppm) of sulfur **
dioxide and particulates for a number of years affect health adversely.
Pollution predominantly affects those who are already suffering from
disease, particularly of the heart or lungs; however, evidence,
especially from studies of children, suggests that pollution can
initiate disease as well as exacerbate it. Particulate pollution,
especially from sulfur compounds, probably plays a considerable role
in the development and progression of bronchitis and emphysema.
There have also been suggestions that it plays a role in lung cancer;
however, this is much more debatable.
308
In another 1978 NRC/NAS report, on Sulfur Oxides, Speizer and Ferris
(308) developed graphs (figures 14-5 A and B) to depict estimates of dose
reponse relationships. In the process, they had to accept certain studies,
despite their minor limitations. On the other hand, certain studies were
excluded in the judgment of the authors because of questions raised about the
adequacy of those studies. Thus, the studies by Greenburg et al., Goldstein
and Block, and Chiaromonte on acute effects in asthmatics have been deemed
unacceptable. The works of Buechley and of Schimmel were utilized to demonstrate
negative short-term effects below 300^g/m . Martin's study of short term
3 1
mortality, showing mortality effects at 277Jxg/m SOp and 417yw.g/m BS and
morbidity effects at 340 and 515p.g/m , respectively, of S02 and British
smoke, although discussed as valid, were not included in the plotting of acute
*Particulate levels expressed as 3 or 5 CoHs units are approximately equivalent
to 350 or 550 ug/m TSP, respectively.
**TSP and S02 levels of 0.100 mg/m3 = 100 ug/nT
14-230
-------
300
n 200
O
v>
100
\
VI
V*J
| L2J
100 200
24-hr TSP, ug/m3
300
300
FIGURE 14-5 A. Acute dose-response relationships
from selected studies.*
ui
5
o
X
5
CM
3
Z
Z
O
CO
200
100
fj NUMBERS REFER TO SPECIFIC STUDY
O INDICATES NO EFFECTS [j[]
0 100 200 300
TSP ANNUAL 24-hr GEOMETRIC MEAN, ug/m3
FIGURE 14-5 B. Chronic dose-response relation-
ships from selected studies.*
1.
2.
3.
4.
Lawther et al.
53
van de Lende.at al
Cohen et?al.
Emerson
*Speizer, Ferris, et al.; NRC/NAS
308
74
6.
7.
8.
9.
10.
11.
12.
13.
14.
Fletcher et al.274 ,01
1 Hi
Sawicki andQLawrence
Lunn et al. '97
Douglas and Waller
Ferris et al..::
Ferris et al.
Mostardi and Mattel!
Hammer et al. *
f 1 ?
Chapman et al.
-------
dose-response estimates shown in Figure 14-5A. The work of Stebbings et al.
in the Pittsburgh episode was excluded because of a lack of prior baseline
308
information. Overall, Speizer and Ferris concluded that short term exposure
effects occur above 300 micrograms/cubic meter of both S02 and TSP, although
the data used by them to plot dose-response relationships likely demonstrate
some effects at 200 - 230 pg/m .
308
In terms of chronic effects, Speizer and Ferris excluded the work of
Mostardi and Leonard because of small sample size and lack of sufficient
smoking information, even though a later study of a similar group showed that
smoking was not a significant factor. (Mostardi's study showed effects at
levels of S02 96-100 pg/m3 and levels of TSP of 77-109 ug/m3). Overall, it
308
was concluded, for chronic exposures, that annual mean 24-hour exposures
o
somewhat above the current S02 primary standard (75 jjg/m ) are associated with
increased morbidity.
In regard to possible effects of suspended sulfates, results of studies
by Winklestein did not appear to be sufficiently clearly presented to allow
conclusions to be drawn. Also, other studies from the EPA CHESS Program were
not considered, e.g. Chapman et al., and Hammer et al.. Thus, Speizer and
308
Ferris did not feel that they could draw meaningful conclusions about the
effects of suspended sulfates.
The World Health Organization in 1979 published a report on Environmental
Health Criteria for Sulfur Dioxides and Suspended Particulate Matter. They
formulated dose response relations for short term exposures (Table 14-48), for
long term exposures (Table 14-49), and have published tables on the expected
effects of air pollutants on health in selected segments of the population in
terms of both short term exposures and long term exposures (Tables 14-50 and
14-51). The tables themselves provide indication of the studies that the
14-232
-------
TABLE 14-48. EXPOSURE-EFFECT RELATIONSHIPS OF SULFUR DIOXIDE, SMOKE; AND TOTAL
SUSPENDED PARTICULATES: EFFECTS OF SHORT-TERM EXPOSURES*
Concentration
24-h mean
values
Sulfur dioxide Smoke
Total
suspended
particulates
Effects
>1000
>1000
710
500
750
500
500
500
250
300
200e
140
150L
London, 1952. Very large increase
in mortality to about 3 times normal,
during 5-day fog. Pollution figures
represent means for whole area:
maximum (central site) sulfur dioxide
3700 ug/m , smoke 4500 ug/m
(Ministry of Health, UKt 1954)
London, 1958-59. Increases in daily
mortality up to about 1.25 times
expected value (Lawther, 1963; Martin
& Bradley, 1960).
London, 1958-60. Increases in daily
mortality (as above) and increases in
hospital admissions, becoming evident
when pollution levels shown were
exceeded (magnitude increasing steadily
with pollution) (Martin, 1964).
New York 1962-66. Mortality correlated
with pollution: 2% excess at level
shown (Buechley, 1973).
London, 1954-68. Increases in
illness score by diary technique
among bronchitic patients seen above
pollution levels shown (means for
whole area) (Lawther et al., 1970).
Vlaardingen, Netherlands, 1969-72.
Temporary decrease in ventilatory
function (Van der Lende et al., 1975).
Cumberland, WV, USA. Increased
asthma attack rate among small
group of patients, when pollu-
tion levels shown were exceeded
(Cohen et al., 1972).
*From WHO 1979 Criteria Document for Sulfur Oxides and Particulate Matter.
method.
312
High volume sampling method.
Other measurements by Organization for Economic Cooperation and Development or
British daily smoke/sulfur dioxide methods (Ministry of Technology, UK, 1966)
Organization for Economic Cooperation and Development, 1965).
14-233
-------
TABLE 14-49. EXPOSURE-EFFECT RELATIONSHIPS OF SULFUR DIOXIDE, SMOKE, AND TOTAL
SUSPENDED PARTICULATES: EFFECTS OF LONG-TERM EXPOSURES*
-Concentration
24-h mean
values (ug/m3)
Sulfur dioxide Smoke
Total
suspended
particulates
Effects
200
200
150
125
1401
60-140C
1801
170
1401
100-200°
Sheffield, England. Increased
respiratory illnesses in children
(Lunn et al., 1967, 1970)
Berlin, NH, USA. Increased respiratory
symptoms, decreased respiratory func-
tion in adults (Ferris et al., 1973)
England & Wales. Increased respiratory
symptoms in children (Colley & Reid,
1970).
Cracow, Poland. Increased respiratory
symptoms in adults (Sawicki, 1972).
Great Britain. Increased lower respira-
tory tract illnesses in children (Douglas
& Waller, 1966).
Tokyo. Increased respiratory symptoms
in adults (Suzuki & Hitosugi, unpublished
data, 1970).
*From WHO 1979 Criteria Document for Sulfur Oxides and Particulate Matter.312
Automatic conductimetric method.
High volume sampler (2-month mean, possible underestimation of annual mean).
cLight-scattering method, results not directly comparable with others.
Estimates based on observations after end of study; probable underestimation
of exposures in early years of study.
Other measurements by Organization for Economic Cooperation and Development or
British daily smoke/sulfur dioxide methods (Ministry of Technology, UK, 1966;
Organization for Economic Cooperation and Development, 1965).
14-234
-------
TABLE 14-50. EXPECTED EFFECTS OF AIR POLLUTANTS ON HEALTH IN SELECTED
SEGMENTS OF THE POPULATION: EFFECTS OF SHORT-TERM EXPOSURES**
24-h mean concentration (ug/m )
Expected effects Sulfur dioxide Smoke
Excess mortality among the elderly 500 500
or the chronically sick
Worsening of the condition of patients 250 250
with existing respiratory disease
Concentrations of sulfur dioxide and smoke as measured by OECD or British
daily smoke/sulfur dioxide method (Ministry of Technology, UK, 1966;
Organization for Economic Cooperation and Development, 1965). These
values may have to be adjusted in terms of measurements made by other
procedures. 212
*From WHO 1979 Criteria Document for Sulfur Oxides and Particulate Matter.
14-235
-------
TABLE 14-51. EXPECTED EFFECTS OF AIR POLLUTANTS ON HEALTH IN SELECTED
SEGMENTS OF THE POPULATION: EFFECTS OF LONG-TERM EXPOSURES3*
Annual mean concentration (pg/m )
Expected effects Sulfur dioxide Smoke
Increased respiratory symptoms 100 100
among samples of the general
population (adults and children)
and increased frequencies of
respiratory illnesses among
children
Concentrations of sulfur dioxide and smoke as measured by OECD or British
daily smoke/sulfur dioxide method (Ministry of Technology, UK, 1966;
Organization for Economic Cooperation and Development, 1965). These values
may have to be adjusted in terms of measurements made by other procedures.,?
*From WHO 1979 Criteria Document for Sulfur Oxides and Particulate Matter.
14-236
-------
TABLE 14-52. GUIDELINES FOR EXPOSURE LIMITS CONSISTENT
WITH THE PROTECTION OF PUBLIC HEALTH8'*
Concentration (ug/m )
Expected effects Sulfur dioxide Smoke
24-h mean 100-150 100-150
Annual arithmetic mean 40-60 40-60
aVa1ues for sulfur dioxide and smoke as measured by OECD or British daily
smoke/sulfur dioxide method (Ministry of Technology, UK, 1966; Organization
for Economic Cooperation and Development, 1965). Adjustments may be necessary
where measurements are made by other methods. For example, smoke concentrations
of 100-150 pg/m convert to approximately 200-300 po/m TSP and smoke levels
of 40-60-jug/m convert to approximately 80-120 ug/m TSP.
*From -31*
14-237
-------
the WHO felt were relevant in these dose response determinations. In addition,
312
the guidelines arrived at by the WHO for protection of public health are
shown in Figure 14-52.
•J-l O
The WHO report also comments on several additional studies which they
felt were positive; the study published by Watanabe in 1966, show that 20%
increase in mortality at 200 |jg/m3 S02 and 1000 ug/m3 of TSP (24 hours). The
Yoshida study showed effects with weekly S02 above 140 pg/m (no TSP or &S). A
study by Toyama et al. published in 1966 shows prevalence of respiratory
symptoms in males (ages 40 to 59) adjusted for age and smoking in areas with
S0? concentrations of less than 30 pg/m and TSP less than 106-341 pg/m .
Tani (1975) reported a study around a pulp mill (compared to a controlled
area) which showed a consistent increase with prevalence of bronchitis with
2 3
sulfation rates of 1.2gm/100cm per day (approximately 48-96 pg/m SO^)- In
their report, WHO points out that they think that the Cohen et al. study of
asthma was positive. They also commented that the Lambert and Reid study did
control for social status as well as smoking, such that one can assume that
there were not likely to be further confounding factors in that study. In
regard to the Ferris study in 1962, the report questions the air pollution
measures and indicates they were also limited to S0? reading in the 1973
survey. The WHO report also questions the health index used by Lawther et al.
in their series of studies extending from 1954 to 1968. In regard to the
Waller report of 1971, they felt that discrimination between effects of pollution
•3-10
and those of adverse weather was poor. The WHO report presented further
information on sensory and reflex function resulting from short-term exposures
to H2$04, and S02 and exposures of H,,SO. and S02 combined. The review indicates
that a physiological response occurs at short-term H^SO. concentrations of
14-238
-------
g
from 400 to 730 ug/m and short-term SO- concentration of from 600 to 2800
ug/m . When concentrations of fr^SO^ and SO^ are combined, however, the same
effects occur for H2$04 at concentrations ranging from 150 to 600- ug/m3 and
S6p at concentrations ranging from 250 to 1200 ug/m .
Other recent evaluations of dose-response relationships 1n a review by
304
Ware et al. are summarized in Tables 14-53 and 14-54. Many of the same
studies accepted by WHO and others in earlier reviews are taken by Ware et al.
(1980) to be valid and to demonstrate health effects of the levels listed in
the two tables. Certain other findings were also thought to indicate a possible
lack of effect at the levels studies, including specifically Emerson's, possibly
Ipsen's, and possibly SchimmeVs results. Ware et al. also discussed
Bennett's interpretation of the Waller and the Lawther data concerning the
decline of symptoms in bronchitis with declining air pollution, without however
They
clarifying the bases of that interpretation. / also considered certain
studies of acute asthma (Derrick, Goldstein et al., Glasser et al.) as being
essentially negative. They did not think that the initial Stebbings studies
of the 1975 Pittsburgh episode could be utilized, since pre-episodic lung
function data were not obtained as a comparison baseline. However, a later
Stebbings article in which post-episodic function was examined and "sensitive"
individuals were examined did not seem to be considered. They also did not
Sawicki
appear to consider the later study of / , although earlier studies were
included in their dose response table, and the study by Hammer in the Southeastern
United States was not mentioned. The Cohen et al. study of asthma was considered
weak, for unclearly specified reasons. Morbidity during episodes was examined,
but not included in the table (Shrenk, Ministry of Pensions and Health, Fry)
and a few other studies were examined. Overall, though, despite some of the
14-239
-------
TABLE 14-53. SUMMARY OF EVIDENCE FOR HEALTH EFFECTS OF ACUTE EXPOSURE TO S02 AND PARTICULATES
i
ro
Type of study Reference
Mortality Martin
and Bradley
Martin16
Glasser and
222
Greenburg
Morbidity Martin16
Lawt ber-
et al.
74
Van der Lende
24- hour average
pollutant levels at
Effects observed which effects appear
Increases in daily total
mortality above the 15
moving average
Increases in hospital
admissions for cardiac
or respiratory illness
Worsening of health status
among 195 bronchi tics
Improvement in lung function
accompanying an improvement
in air quality
500 ug/m3 (TSP)
300 ug/m (S02)
500 ug/m3 (TSP)
400 ug/m3 (S02)
580 ug/m3 (TSP)
780 ug/m3 (S02)
500 ug/m3 (TSP)
400 ug/m3 (S02)
312 ug/m3 (TSP)
500 ug/ni (S02)
245 ug/m3 (TSP)
300 ug/m3 (S02)
-------
TABLE 14-52. GUIDELINES FOR EXPOSURE LIMITS CONSISTENT
WITH THE PROTECTION OF PUBLIC HEALTH8'*
Concentration (pg/m )
Expected effects Sulfur dioxide Smoke
24-h mean 100-150 100-150
Annual arithmetic mean 40-60 40-60
aVa1ues for sulfur dioxide and smoke as measured by OECD or British daily
smoke/sulfur dioxide method (Ministry of Technology, UK, 1966; Organization
for Economic Cooperation and Development, 1965). Adjustments may be necessary
where measurements are made by other methods. For example, smoko concentration;
.^-100-150 pg/m convert te-appTOTTmiPEe^-gaQ^^nn |ig/m-TSP and-smoke levels—
&f 40-OO.aj'q/m—convert to appruximaLely 80-120 py/m
*From WHO l
14-237
-------
the WHO felt were relevant in these dose response determinations. In addition,
312
the guidelines arrived at by the WHO for protection of public health are
shown in Figure 14-52.
OT O
The WHO report also comments on several additional studies which they
felt were positive; the study published by Watanabe in 1966, show that 20%
3 3
increase in mortality at 200 ug/m S02 and 1000 ug/m of TSP (24 hours). The
3
Yoshida study showed effects with weekly S02 above 140 |jg/m (no TSP or &S). A
study by Toyama et al. published in 1966 shows prevalence of respiratory
symptoms in males (ages 40 to 59) adjusted for age and smoking in areas with
3 3
SOp concentrations of less than 30 ug/m and TSP less than 106-341 ug/m .
Tani (1975) reported a study around a pulp mill (compared to a controlled
area) which showed a consistent increase with prevalence of bronchitis with
2 3
sulfation rates of 1.2gm/100cm per day (approximately 48-96 ug/m SOp). In
their report, WHO points out that they think that the Cohen et al. study of
asthma was positive. They also commented that the Lambert and Reid study did
control for social status as well as smoking, such that one can assume that
there were not likely to be further confounding factors in that study. In
regard to the Ferris study in 1962, the report questions the air pollution
measures and indicates they were also limited to S0? reading in the 1973
survey. The WHO report also questions the health index used by Lawther et al.
in their series of studies extending from 1954 to 1968. In regard to the
Waller report of 1971, they felt that discrimination between effects of pollution
312
and those of adverse weather was poor. The WHO report presented further
information on sensory and reflex function resulting from short-term exposures
to HpSO^, and SO,, and exposures of H,,S04 and SO^ combined. The review indicates
that a physiological response occurs at short-term HpSO. concentrations of
14-238
-------
from 400 to 730 ug/m and short-term SO- concentration of from 600 to 2800
ug/m . When concentrations of H2$04 and S02 are combined, however, the same
effects occur for H2$04 at concentrations ranging from 150 to 600- ug/m3 and
S02 at concentrations ranging from 250 to 1200 ug/m .
Other recent evaluations of dose-response relationships 1n a review by
304
Ware et al. are summarized in Tables 14-53 and 14-54. Many of the same
studies accepted by WHO and others in earlier reviews are taken by Ware et al.
(1980) to be valid and to demonstrate health effects of the levels listed in
the two tables. Certain other findings were also thought to indicate a possible
lack of effect at the levels studies, including specifically Emerson's, possibly
O f\/(
Ipsen's, and possibly Schimmel's results. Ware et al. also discussed
Bennett's interpretation of the Waller and the Lawther data concerning the
decline of symptoms in bronchitis with declining air pollution, without however
They
clarifying the bases of that interpretation. / also considered certain
studies of acute asthma (Derrick, Goldstein et al., Glasser et al.) as being
essentially negative. They did not think that the initial Stebbings studies
of the 1975 Pittsburgh episode could be utilized, since pre-episodic lung
function data were not obtained as a comparison baseline. However, a later
Stebbings article in which post-episodic function was examined and "sensitive"
individuals were examined did not seem to be considered. They also did not
Stwicki
appear to consider the later study of / , although earlier studies were
included in their dose response table, and the study by Hammer in the Southeastern
United States was not mentioned. The Cohen et al. study of asthma was considered
weak, for unclearly specified reasons. Morbidity during episodes was examined,
but not included in the table (Shrenk, Ministry of Pensions and Health, Fry)
and a few other studies were examined. Overall, though, despite some of the
14-239
-------
TABLE 14-53. SUMMARY OF EVIDENCE FOR HEALTH EFFECTS OF ACUTE EXPOSURE TO S0? AND PARTICULATES
ro
Type of study Reference
Mortality Martin ....
and Bradley
Martin16
Glasser and
222
Greenburg
Morbidity Martin16
Lawther,
et al.
74
Van der Lende
24- hour average
pollutant levels at
Effects observed which effects appear
Increases in daily total
mortality above the 15
moving average
Increases in hospital
admissions for cardiac
or respiratory illness
Worsening of health status
among 195 bronchi tics
Improvement in lung function
accompanying an improvement
in air quality
500 ug/m3 (TSP)
300 ug/nT (S02)
500 |jg/m3 (TSP)
400 ug/m3 (S0£)
580 ug/m3 (TSP)
780 ug/m3 (S02)
500 ug/m3 (TSP)
400 ug/m3 (S02)
312 ug/m3 (TSP)
500 ug/rn (S02)
245 ug/m3 (TSP)
300 ug/m3 (S02)
-------
TABLE 14-54. SUMMARY OF EVIDENCE FOR HEALTH EFFECTS OF CHRONIC
EXPOSURE TO S02 AND PARTICULATE MATTER
I
f\3
-pi
Type of study Reference
Longitudinal Ferris. ,_ ,.- ...
j 4 42 4o 4/
and et al . ' ' '
Cross-Sectional
Cross-Sectional Sawicki
(2 areas)
nc n~j
Cross-Sectional Lunn et al. '
study of school
children in
4 areas
Fol low-Up of Douglagnand
school children Waller
in 4 areas
214
Cross-Sectional Hammer et al.
study of
children in
4 areas
Cross-Sectional Mostardi and fi7
study of high colleagues '
school
children in
2 areas
Annual
Effects observed at
Higher rate of respiratory
symptoms; and decreased
lung function
More chronic bronchitis, asthmatic
disease in smokers; reduced FEV%
Increased frequency of respiratory
symptoms; decreased lung function
in five-year-olds
Increased lower respiratory tract
infection
Increased incidence of lower
respiratory diseases
Lower FVC, FeVnyc and maximal
oxygen consumption
average pollutant levels
which effects occurred
180 ug/m3 (TSP)
55 ug/m (S02)
250 ug/m3, (TSP)
125 ug/nT (S02)
260 ug/m3 (TSP)
190 ug/m (S02)
230 ug/m3, (TSP)
130 ug/rn (S02)
85-110 ug/«3 (TSP)
175-250 ug/"T (S02)
77-109 ug/m3 (TSP)
96-100 ug/n» (S02)
-------
above nuances of their evaluation that might differ from some of the
evaluations contained in earlier reviews, their assessment appeared to agree
fairly well with those of others regarding studies accepted as being valid and
their interpretation.
One additional recently appearing review remains to be discussed, the
report by Holland et al. published in November, 1979. That published
review was based on a more extensive report commissioned by certain American
industrial interest groups (the American Iron and Steel Institute and member
steel companies) to be written for the purpose of reappraising epidemiologic
and other scientific evidence bearing on criteria underlying United States
National Ambient Air Quality Standards (NAAQS) for particulate matter.
More specifically, the following was stated at the outset of the 1979
301
publication by Holland and colleagues:
The aim of this review is to consider available epidemiologic evi-
dence on the health effects of particulate pollution, and to examine,
in the light of this evidence, criteria for setting standards for
levels of suspended particulate matter in the atmosphere.
Elaborating further on their intent, Holland et al. ' opened the final dis-
cussion of their "Conclusions" with the following statements:
Our purpose in this report, in which for ease of comparison we have
followed the format of the Criteria Document, has been to assess
the epidemiologic evidence for the effects of suspended particulates
in the presence of other air pollutants on various aspects of health,
and to critically analyze the basis for setting standards for levels
of suspended particulate.
Close examination and critical assessment of the Holland et al. (1979)
published review reveals that one of its most outstanding features is notable
divergence of certain of their evaluations and conclusions from scientific
appraisals of the same subject matter by other equally prominent and know-
ledgeable international experts. This not only includes divergence from
14-242
-------
evaluations and conclusions contained in reviews by Rail, Higgins, Goldsmith
and Friberg, and Ferris published in the 1974 to 1978 period, but also marked
divergence on certain key points from the more recent appraisals contained in
the ATS, NRC/NAS, atid WHO documents published within the past two years (1978-79)
One point of partial agreement between Holland et al.301 and the pub-
lished views of other experts concerns levels of sulfur oxides and particulate
matter capable of inducing mortality. Holland and colleagues concluded that
increases in deaths were discernable when smoke exceeded something
in the range of 500-800 ug/m (as 24-hour averages by smoke (BS) or
equivalent method) together with sulfur dioxide of more than 700-
1000 ug/m (24-hour average).
This can be compared with roughly comparable conclusions by some other
evaluators and the levels of 500 ug/m for both BS and S0? concluded by
312
WHO to be associated with acute mortality effects. However, the studies
of McCarroll and of Greenberg et al. in New York were the only ones outside
of Britain considered by Holland et al., Dutch, Japanese, and other U.S.
studies suggesting possible mortality effects at particulate levels below
500 ug/m were largely ignored by Holland et al .
Similarly, in their summary table for studies of acute morbidity related
to short term pollution exposure Holland et al. ignore all but British
studies and accept only a few of those as being valid. Holland et al., further
did not mention acute or chronic pulmonary function changes in discussing
the basis for their conclusions to the effect that the evidence reviewed by
them "does not substantiate any level of air pollution below 250 ug/m , smoke
(BS) as a 24-hour average, as having a harmful effect on health." Holland
et al. also stated: "There is no scientifically acceptable evidence...
which can implicate a level at which mortality is associated with long term
14-243
-------
exposure to SO /TSP." This is in contrast to several other reviews citing
certain studies as showing such effects. In addition, it is asserted by
Holland et al. (1979) that no scientifically valid epidemiology studies
exist by which to establish associations between health effects and long-
term (annual average) exposures to sulfur oxides or particulate matter.
This is, of course, at variance with all of the published expert views
summarized above. Importantly, it should be noted that Holland et al.
did not exclude all studies on the basis of scientific merit, but excluded
many as somehow simply being irrelevant (e.g., Neri eft al.) or completely
ignored others yielding results not supporting their conclusions. Further-
more, they failed to discuss or note many countervailing opinions existing
in the literature, eg., those expressed in the reviews by Rail, Goldsmith
and Friberg, Shy et al., Higgins, Ferris, NAS, and WHO discussed above.
Figure 14-8 illustrates some of the striking differences between evaluations
of various key studies by Holland et al. in comparison to those by WHO
312
(1979) or other reviews such as the present EPA (1980) assessment.
301
In view of the divergence of various Holland Report evaluations and
conclusions from those of other published expert reviews, it is not surprising
that the Report has not been universally well received or accepted as a
scientifically objective or accurate reappraisal of the evidence regarding
the health effects of particulate pollution. Thus, for example, commentary
critical of the appraisal by Holland et al. appeared in the next issue of
the publishing journal. In that commentary on the Holland et al. review,
Shy states that Holland Report comments fall into three categories:
14-244
-------
1000
•w
900
700
too
o
u.
400
JOO
200
100
| OSAKA (19621? I
IPA (mOirj'vP*-
X
1 ^HOLLAND, ET AL (1976) | j
_^
^©HOLLAND. ET AL (1979)
mtf'/ tf°
~~ EPA (1980)0' C' —
-ACUTE MORTALITY
ROTTERDAM (1960 •)•
EPA (1980)/
LONDON (19S"0-66f£J" ^
ACUTE MORBIDITY *
^HOLLAND. ET AL (1979) —
X
X
,^y
/
D WHO (1979) __
ACUTE MORTALITY
LONDON C1KMCU* O MARTIN. ET AL. (1960*4, - LONDON
_ LONDON B NETHERLANDS (1969-721
NEW YORK CITYH (1964-65) /
(1960-70) LJ '
© GLASSER & GREENBURG (1971) - NYC
C APLING. ET AL, WALLER (1977-78) LONDON
• OTHER STUDIES
ACUTE MORBIDITY _
Q LAWTHER (1970) - LONDON 1950-1975
B VAN DER LENDE (1975) - NETHERLANDS
CHRONIC MORBIDITY ^~ - ~! C COHEN. ET AL (19721 WEST VIRGINIA
WEST ^ SHEFF IE -ai963^^HOLLAND. ET AL (1979) | OTHER STUDIES
— VIRGINIA n ^ _ ~~ ' —
(1969) ^ WHO • FRANCE (1973)
(1979) 1
I
I
UK (1946-66) A WHO (1979) (
CHICAGO (19721 y CRACOW (1968-73)
-T- — | v (
TOKYO (1970)T 1 1 I
* ! 1
BERLIN, NH (1967-73)^ WHO (1979) j
I |
|r SOUTHEAST U.S.A. (196&71) J ]
CHRONIC MORBIDITY
A LUNN, ET AL (1967. 1970) • SHEFFIELD. UK
A DOUGLAS* WALLER (1966) -UK
/\ FERRIS, ET AL (1973. 1976) - BERLIN. NH
y SAWICKI (1972) - CRACOW. POLAND —
Y OTHER STUDIES
(III
100
200
300
400
500
600
700
too
900
1000
TOTAL SUSPENDED PAHTICULATES.
Figure 14-8.
Comparison of interpretations-of studies evaluated by Holland
et al. (1979), U1 WHO (l§^)3no or other reviews such as those
in the NRC/NAS documents ' and the present chapter. Aside
from the British studies noted for London and Sheffield.and the
1960-64 New Youk City mortality study, Holland et al. either
ignored the other studies shown or evaluated them as being in-
valid based on methodological flaws or reinterpretation of their
findings. "OTHER STUDIES" not specifically identified in the
above key include those reported by: Gervois et al.-,.-Ta-France
(1973); Martinlb D London £1958-60); Mostardi et al. '*" V
Chicago (1972); Hammer11"5'"7 V Southeast USA (1969-71);
Suzuki and-bitosugi V Tokyo (1970). The dashed lines depict
HO (1979) conclusions regarding SOp and particulate levels
associated with acute (24-hr) mortality, acute morbidity, and
chronic (annual) morbidity.
14-245
-------
1) a low level of criticism of negative studies; 2) a high level of
criticism of roost positive studies; 3) a polemical, often broad-brushed
criticism of EPA Studies.
31 ^
In regard to the negative studies, Shy further notes: "the possibility of
systematic measurement errors or of confounding, that may have biased the
results toward the null hypothesis of no effect, is not addressed..." Shy
also states that it appears that Holland et al. rejected positive studies
if there were any possible confounder, even if they lacked evidence that the
potential confounder was indeed differentially distributed between exposed and
referent populations. Shy provides a table (Table 14-55) listing comments
by Holland et al. regarding certain studies, as well as his own rebuttal
remarks, and questions whether the Holland et al. group adequately addressed
the concepts of sensitive populations groups, appropriate margins of safety,
or other considerations relevant to a determination of health effects criteria
in their discussion of dose-response relationships.
It should also be noted that the Holland Report, while in press, was
submitted for consideration by international experts of the WHO Task Group on
Environmental Health Criteria for Sulfur Oxides and Particulate Matter as
they neared finalization of the WHO (1979) document "Environmental Health
•3-1 p
Criteria (and) Sulfur Oxides and Suspended Particulate Matter." That
group of international experts individually reviewed the Holland Report and
provided comments on it to the WHO. Those comments, together with others
received from international organizations such as the International Iron and
Steel Institute, were then considered by the Chairman of the Task Group
14-246
-------
TABLE 14-55. EP1DEMIOLOGIC STUDIES SUGGESTING AN EFFECT OF PARTICULATE AIR
POLLUTION AT CONCENTRATIONS AT OR NEAR THE U.S. AMBIENT AIR QUALIJX,STANDARD
AND COfWENTS BY SHY313 ON THE REVIEWS OF THEM BY HOLLAND ET AL.301
Author and
location of $tudy
Findings
Comments
321
Lindeberg
Oslo, Norway
Average deaths per week
during 1958 - 1965
winters were signifi-
cantly correlated with
levels
smoke
of S00 but not
Winkelstein et al.
Buffalo, New York
188
Geographic association
between mortality from
chronic respiratory
disease among 50 - 69-
year-old men and partic-
ulate levels over the
range of380 to more than
135 ug/m annual average
(HV).
Van der Lende et al. Comparison of lung func-
Netherlands
tion between 1969 and
1972 revealed improved
function 1n the residents
of a polluted area that
experienced improved air
quality over the 4-year
interval. No similar
functional change occur-
red in residents of a
cleaner rural area.
Holland et al. state that there
may be confounding with long-
term trends 1n air pollution
levels and with influenza
epidemics. However, no evidence
1s presented showing a correla-
tion of Influenza epidemics with
air pollution levels, nor are
data presented on the long term
air pollution trends.
Holland et al. state that these
results were not adequately
standardized for age, social
class, ethnicity, occupation,
nobility or smoking habits.
These limitations are Inherent
1n mortality-based geographic
studies. However, the authors
did stratify on age and social
class, and there Is no positive
evidence that other risk factors
were correlated with the distri-
bution of particulate levels.
Air quality changed from 160 3
ug/m (smoke, BS) to 40 ug/m
during the 1969 - 72 interval.
Holland et al. state that firm
conclusions cannot be drawn "in
the absence of direct evidence
on changes in lung function in
random samples of urban popula-
tions." This scientific purism
would tend to cause rejection
of the results of most air
pollution epidemiologic data.
14 - 247
-------
TABLE 14-55. EPIDEMIOLOGIC STUDIES SUGGESTING AN EFFECT OF PARTICULATE AIR
POLLUTION AT CONCENTRATIONS AT OR NEAR THE U.S. AMBIENT AIR OUALUX, STANDARD
AND COMMENTS BY SHY313 ON THE REVIEWS OF THEM BY HOLLAND ET AL.301
Author and
location of study
Findings
Comments
Gervois et al.
Two towns in France
Levy et al.70
Hamilton, Ohio
Ferris et al.
Berlin, N.H.
46
An association was
reported between employee
sickness absence records,
adjusted for temperature,
and day-to-day variations
in smoke and SOp. Highest
daily values for each were
200 ug/m , with 3-month
means of 53 ug/n (smoke,
BS) and 37
A significant correlation
was found for weekly
hospital admission for
respiratory infections
and an index of air
quality over a 12-month
period. Effect was
adjusted for temperature.
An improvement in respira-
tory symptoms and pulmo-
nary function was noted
in the same persons
examined in 1961 and 1967,
and these changes were
accompanied by a decline
in particulates from 180
Mg/m, (HV) in 1961 to 131
pg/m5 (HV) in 1967. A
later follow-up study in
1973 showed a further
decline in particulates
by 1973 to 80 um/mj (HV).
even while S0? levels
increased. Tne latter
decline was not accom-
panied by a change in
pulmonary function or
respiratory symptoms.
Holland et al. claim that "the
seasonal distribution of respira-
tory infections could have had
some confounding effect." Adjust-
ment for temperature would remove
some of the seasonal effect, but
no evidence was provided that
season was correlated with air
pollution levels.
Holland et al. feel that there
nay be confounding of seasonal
respiratory disease frequency
and air pollution. Again, no
evidence for actual confounding
is presented, and temperature
adjustment provides at least a
partial control for seasonal
effects.
The orginal investigators
interpret these results to
indicate that all the benefit
occurred from the reduction in
particulates, and that the gase-
ous sulfur compounds did not
have an effect at these levels.
Holland et al. state that data
from different years are not
comparable. However, the
original investigators speci-
fically addressed this issue
and failed to find evidence
for lack of comparability.
14 - 248
-------
TABLE 14-55. EPIDEMIOLOGIC STUDIES SUGGESTING AN EFFECT OF PARTICULATE AIR
POLLUTION AT CONCENTRATIONS AT OR NEAR THE U.S. AMBIENT AIR QUALUX,STANDARD
AND COMMENTS BY SHY313 ON THE REVIEWS OF THEM BY HOLLAND ET AL.301
Author arrd
location of study
Findings
Comments
28
Lambert and Reid
England
Sawicki181
Cracow, Poland
A gradient of respiratory
symptom prevalence corre-
sponded with the pollu-
tion gradient. Data were
derived from a self-
administered questionnaire
sent to a national proba-
bility sample. Prevalence
ratios are adjusted for
smoking and age.
Prevalence of chronic
respiratory disease was
significantly greater in
residents of a high air
pollution area (annual
average particulates, 170
ug/m (smoke, BS) vs.
those in a low pollution
area (annual avg.: 90
u/m ). Data were strati-
fied for smoking and age.
Holland et al. for unexplained
reasons discount the correspond-
ence of the symptom and air
pollution gradients. Particu-
late levels range frorruless than
100 ug/m to 200+ ug/m (smoke,
BS).
Holland et al. state that
differences are not adjusted
for occupational and social
class, but they fail to provide
evidence that these factors are
confounding variables in this
study. The reviewers admit that
the strong differences are
unlikely to be explained away by
one confounding factor, but the
use of these data is discounted
in their final assessment.
Holland etal
and Bennett et
Kent, England
al.
Within urban areas, air
pollution levels were
associated with lung
function of children
ages 5-14 years. Effects
were adjusted for social
class, family size and
previous history of
bronchitis. Smoke levels
(BS)3were less than 100
ug/m in both urban areas.
Holland et al. (1) reject the
association with air pollution
because the lung function effect
was "inconsistent" across the mix
of urban and rural study areas.
However, urban-rural differences
are to be expected, and, within
the urban stratum, the air pollu-
tion effect could not be accounted
for by other risk factors.
14 - 249
-------
TABLE 14-55. EPIDEMIOLOGIC STUDIES SUGGESTING AN EFFECT OF PARTICULATE AIR
POLLUTION AT CONCENTRATIONS AT OR NEAR THE U.S. AMBIENT AIR QUALIJX,STANDARD
,313
AND COMMENTS BY SHYJAJ ON THE REVIEWS OF THEM BY HOLLAND ET AL.
301
Author and
location of study
Findings
Comments
Tessier et al.
Bordeaux, France
98
Irwig et al.
10 areas of England
An association was found
between absenteeism due
to respiratory disease
among schoolchildren ages
6-11 years and short-term
levels in air pollution
less than 100 ug/m
(smoke level by method
similar to BS).
Investigators reported a
statistically significant
relationship between the
frequency of chest colds
during 1972-1973 and air
pollution measurements
taken in November, 1973,
after allowing for
differences in the
distribution of age,
sex and social class.
Socioeconomic and other factors
were not Included in the analysis
However, these risk factors are
unlikely to be determinants of
temporal variations in disease
frequency among the same group
of children. Likewise, there
is no evidence for an effect
of meteorologic factors and
temporal variations in absen-
teeism, as Holland et al.
allege.
Holland et al. state that the
effect of smoking in the home
was not considered but offer
no evidence that this factor
was a confounder. Reviewers
state that a second report
from this study indicated no
relationship with air pollution
but they fail to provide details
on this study.
14-250
-------
Meeting, the Rapporteur, and members of the WHO Secretariat; and, it was
determined that the Task Group experts' opinions of the Holland Report con-
tents were such that the Task Group's views, as expressed in the now published
312
1979 WHO document, remained unaltered. See Appendix 3C for further information
regarding this matter.
One other important consideration should be noted in regard to the recently
301
published Holland Report. That concerns the fact that Holland and colleagues
apparently failed to apply the same standards of review to the British air
quality measurement data (critically appraised in Chapter 3 of this document
and summarized earlier in this chapter) and study designs employed by British
epidemiologists in evaluating quantitative air pollution/health effects relationships
of the type assessed in their report. This possible flaw in their appraisal,
especially in view of their dismissal of results of various American or other
studies on the basis of criticisms of errors in their pertinent methodologies
and aerometry data need to be further evaluated (together with other points
noted above) since it may raise questions regarding their review and its
conclusions. Full judgement by the scientific community regarding such questions
remains to be more completely formulated and voiced; pertinent comments on
views expressed in the Holland Report are, therefore, invited as input in
order to assist in the evaluation of its potential usefulness as it might bear
on the present review of health criteria for sulfur oxides and particulate
matter.
14-251
-------
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4. Sugden, F. G. Local authority problems in an industrial area. Royal
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Soc. Health J. 79:10-24, 1959.
10. Scott, J. A. The London fog of December, 1962. Med. Off. 109: 250-252,
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Minist. Health Public Health Lab. Serv. 19:56-72, 1960.
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292. Weill, H., M. M. Ziskind, V. Derbes, R. Lewis, R. J. M. Horton, and
R. 0. McCaldin. Further observations on New Orleans asthma. Arch.
Environ. Health 8:184, 1964.
293. Carroll, R. E. Epidemiology of New Orleans epidemic asthma. Am. J.
Public Health 58:1677, 1968.
294. Phelps, H. W. Follow-up studies in Tokyo-Yokohama respiratory disease.
Arch. Environ. Health 10:143, 1965.
295. Meyer, G. W. Environmental respiratory disease (Tokyo-Yokohama Asthma):
The case for allergy. In: Clinical Implications of Air Pollution
Research. A. J. Finkel and W. C. Duel, ed., Publishing Sciences Group,
Inc., Acton, MA, 1976.
296. Glasser, M., L. Greenburg, and F. Field. Mortality and morbidity during
a period of high levels of air pollution. New York, Nov. 23-25, 1965.
Arch. Environ. Health 15:684, 1967.
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297. Chiaramonte, L. T., J. R. Bongiorno, R. Brown, and M. E. Laano. Air
pollution and obstructive respiratory disease in children. NY State
J. Med. 70:394, 1970.
298. Rao, M., P. Steiner, Q. Qazi, R. Padre, J. E. Allen, and M. Steiner.
Relationship of air pollution to attack rate of asthma 1n children.
J. Asthma Res. 11:23, 1973.
299. Ball, D. J., R. Hume. The relative importance of vehicular and domestic
emissions of dark smoke in Greater London in the mid-1970s, the signi-
ficance of smoke shade measurements, and an explanation of the relation-
ship of smoke shade to gravimetric measurements of particulate. Atmos.
Environ. 11:1065-1073, 1977.
300. 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.
301. Holland, W. W., A. E. Bennett, I. R. Cameron, C. du V. Florey,
S. R. Leeder, R. S. F. Schilling, A. V. Swan, and R. E. Waller.
Health Effects of Particulate Pollution: Re-appraising the Evidence.
Am. J. Epidemic!. 110(5):525-659, 1979.
302. Brasser, L. J., P. E. Joosting, and D. von Zuilen. Sulfur Dioxide -
To What Level is it Acceptable? Research Institute for Public
Health Engineering, Delft, Netherlands, Report G-300, July 1967.
303. Joosting, P. E. Air Pollution Permissibility Standards Approached
from the Hygienic Viewpoint. Ingenieur, 79(50):A739-A747, 1967.
304. Ware, J., F. Speizer, et al. Assessment of the Health Effects of
Sulfur Oxides and Particulate Matter: Analysis of the Exposure-
Response Relationship. Research Triangle Park, NC, U.S. Environ-
mental Protection Agency, in press, 1980.
305. Winkelstein, W. Utility or futility of ordinary mortality statistics
in the study of air pollution effects. Proceedings of the Sixth
Berkeley Symposium on Mathematical Statistics and Probability, 1970.
pp. 539-554.
306. French, J. G. , G. Lowrimore, W. C. Nelson, J. F. Finklea, T. English,
and M. Hertz. The effect of sulfur dioxide and suspended sulfates
on acute respiratory disease. Arch. Environ. Health 27:129-133, 1973.
307. National Research Council. Airborne Particles. National Academy of
Sciences. Washington, DC, 1978, Chapter 9, Epidemiological Studies on
the Effects of Airborne Particles on Human Health. I. T. T. Higgins and
B. G. Ferris, Jr.. pp. 243-288.
308. National Research Council. Sulfur oxides. National Academy of Sciences
Washington, DC, 1978, Chapter 7. Epidemiological Studies of Health
Effects. F. E. Speizer and B. G. Ferris, Jr.. pp. 180-209.
14-274
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309. HAS. Proceedings of the Conference on Health Effects of Air Pollutants,
prepared for the Committee on Public Works, U.S. Senate, Committee Print,
Serial no. 93-15, U.S. Government Printing Office, Washington, DC, 1978.
310. WHO. Air Quality Criteria and Guides for Urban Air Pollutants. Re-
port of a WHO Expert Committee. WHO Technical Report Series no. 506,
Geneve, 1972a.
311. WHO. Health Hazards of the Human Environment, Geneva, 1972b.
312. WHO. Environmental Health Criteria (8): Sulfur Oxides and Suspended
Particulate Matter. WHO, Geneva, 1979.
313. Shy, C. M. Epidemiologic Evidence and the United States Air Quality
Standards. Am. J. Epidemiol. 110:661-671, 1979.
314a. Ferris, B. G. , Jr. Health Effects of Exposures to Low Levels of
Regulated Air Pollutants: A Critical Review. JAPCA 28:482-497, 1978.
314b. Waller, R. E. Discussion of 314a. I. T. T. Higgins, R. E. Waller,
R. S. Chapman, and J. R. Goldsmith. JAPCA 28:883-892, 1978.
315. Biersteker, K. Polluted Air Causes, Epidemiological Significance, and
Prevention of Atmospheric Pollution. Assen, Netherlands, Van Gorcum
and Co., pp. 21-23 (in Dutch), 1966.
316. Watanabe, H. Health effects of air pollution in Osaka City. J.
Osaka Life Hyg. Assoc. 10:147-157(in Japanese), 1966.
317. Toyama, T., H. Kanyo, K. Makamura, J. Kagawa, S. Yakura, S. Adachi,
N. Yamoto, F. Iriyama, F. Kumagaya, S. Osawa, and T. Nakamura. Study
on the prevalence of respiratory symptoms in a rural area (Kashima,
Ibaragi Pref.) in Japan. J. Jpn. Soc. Air Pollut. 7:24-35 (in
Japanese), 1966.
318. Tani, S. Epidemiological Study on Chronic Bronchitis. Japan. J.
Public Health 22:431-438 (in Japanese), 1975.
319. Yoshii, M. , J. Nonoyama, H. Oshima, H. Yamagiwa, and S. Taked. Chronic
pharyngitis in air-polluted districts of Yo KKAICHI in Japan. Mie
Med. J. 19:17-27, 1969.
320. Becker, W. H., F. J. Schilling, and M. P. Ferma. The effect on health
of the 1966 Eastern seaboard air pollution episode. Arch. Environ.
Health. 16:414, 1968.
321. Lindeberg, W. Correlations between air pollutant concentrations and
death rates in Oslo. In: Air Pollution in Norway. III. Oslo,
Norway, Smoke Damage Council, 1968.
14-275
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322. Tessier, J. P., J. G. Faugere, P. Coudray et al. Essai de correlation
entre les donnees de la pollution atmospherique a Bordeaux et les
absences scolaires des infants pour cause bronchorespiratoire.
Bronchopneumologie 26:30-45, 1976.
323. College of General Practitioners, Brit. Med. J. 11:973 , 1961.
324. Nose, Y. Jjr Proceedings of the First International Clean Air Con-
ference, Nat. Soc. Clean Air, London, England, p. 209, 1960.
325. Takahashi, H. Chest Dis. 8:1687, 1964. (In Japanese)
326. Bell, A., and J. L. Sullivan. Air Pollution by Metallurgical In-
dustries. New South Wales Dept. of Public Health, Sydney,
Australia, 1963.
327. Shephard, R. J. , M. L. Thomson, G. C. Carey, and J. J. Phair. Field
testing of pulmonary dynamics. J. Appl. Physiol. 13:189-193, 1958.
328. Shephard, R. J., M. E. Turner, G. C. R. Carey, and J. J. Phair.
Correlation of pulmonary function and domestic microenvironment. J.
Appl. Physiol. 15:70-76, 1960.
329. Cornwall, C. J. , and P. A. B. Raffle. Bronchitis—Sickness Absence
in London Transport. Brit. J. Ind. Med. 18:24-32, 1961.
330. Toyama, T. Arch. Environ. Health 8:153, 1964.
331. McCarroll, J. R. , and W. H. Bradley. Excess mortality as an indicator
of health effects of air pollution. Am. J. Pub. Health 56:1933, 1966.
332. Scott, J. A. Fog and atmospheric pollution in London, winter 1958-1959
Med. Officer (London) 102:191, 1959.
333. Scott, J. A. Fog and deaths in London, December 1952. Pub. Health
Rep. 68:474-479, 1953.
334. Colley, J. R. T., and W. W. Holland. Social and Environmental Factors
in Respiratory Disease. Arch Environ. Hlth. 14:157, 1967.
335. Howard, P. The Changing Face of Chronic Bronchitis and Airway
Obstruction. Br. Med. J. 2:89, 1974.
336. Spicer, W. S., P. B. Storey, W. K. C. Morgan, H. D. Kerr, and
N. E. Standiford. Am. Rev. Resp. Dis. 86:705-712, 1962.
337. Spicer, W. S. Arch. Environ. Hlth. 14:185-188, 1967.
338. Lebowitz, M. D., and B. Burrows. Respiratory Symptoms Related to
Smoking Habits In Family Members. Chest Vol. 69:48-50, 1976.
14-276
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Changes to References for Chapter 14 - PM/SO
Certain Chapter 14 reference numbers represent studies deleted from earlier
drafts of Chapter 14 or designate studies now to be deleted in keeping with
changes in text noted earlier in Chapter 14 corrigenda comments. Thus, the
following Chapter 14 reference numbers should be disregarded: 98; 108-111;
113-117; 120-124; 190; 212-214; 314; 342.
References for studies cited in Chapter 14 but not listed in the original
reference list, as noted in earlier corrigenda comments or text errata listings,
are as follows:
342. Melia, R. J. W. , C. duV. Florey, and A. V. Swan. The effect of atmo-
spheric smoke and sulfur dioxide on respiratory illness among British
schoolchildren: A preliminary report. Paper given at the Vllth Inter-
national Scientific Meeting of the International Epidemiological Association,
Puerto Rico, 1977.
343. Lawrence, W. W. Of acceptable risk, science and determination of safety.
Los Altos, William Kaufman, 1976.
344. Warren Spring Laboratory. The Investigation of Atmospheric Pollution
1958-1966. Thirty-second report. Her Majesty's Stationary Office, London,
1967.
345. Warren Spring Laboratory. National Survey of Smoke and Sulfur Dioxide,
Instruction Manual. Warren Spring Laboratory, Stevenage, England, 1966.
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339. Cederlof, R., and J. Colley. Epidemiologies! Investigations on Environ-
mental Tobacco Smoke. JJK R. Rylander, ed. Environmental Tobacco
Smoke. Effects on the Non-smoker. U. of Geneva. 1974. pp. 47-49.
(Scand. J. Resp. Dis., Suppl. 91, 1974.)
340. Schilling, R. S. F. , A. D. Letai, S. L. Hui, G. J. Beck, J. B. Schoenberg,
and A. Bouhuys. Lung Function, Respiratory Disease, and Smoking In
Families. Amer. J. Epidemiol. 106:274-283, 1977.
341. Riggan, W. B., J. B. Van Bruggen, L. E. Truppi, and M. B. Hertz. Daily
Mortality Models: Air Pollution Episodes, Paper given at the VHIth
International Scientific Meeting of the International Epidemiological
Association, Puerto Rico, 1977.
14-277
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APPENDIX 14-A
CONGRESSIONAL INVESTIGATIVE REPORT (1976)
COMMENTARY ON U.S. EPA CHESS PROGRAM
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APPENDIX A
Congressional Investigative Report (1976) Commentary
on U.S. EPA CHESS Program
As first discussed on p. 14-93 of this chapter, the various epidemologic
studies carried out under the EPA CHESS Program (Community Health and Environ-
mental Surveillance System) have engendered a great deal of controversy. Most
controversial was a 1974 Monograph reporting on certain of these studies and
entitled: "Health Consequences of Sulfur Oxides: A Report from CHESS, 1970-1971".
Subcommittees of the House Committee on Science and Technology 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 Health and Environmental Surveillance
System (CHESS): An Investigative Report." This report, referenced throughout
this 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 of April 2, 1980, 45 FR 21702.
Because of the controversy surrounding CHESS, all references in this
document to CHESS have been very carefully considered. An effort was made to
discuss only those studies which have undergone scientific peer review and
have been published in the open literature apart from, or in addition to,
official EPA publications. Further, in this chapter (14), each study has been
assessed on its own merits, considering pertinent published criticisms and
qualifications. Many such qualifications concern errors in aerometric measure-
ments, and these have been discussed at length in Chapter 3. Other qualifications
-------
concern the analysis of CHESS data and the conduct of epidemiology generally;
these are
discussed as appropriate throughout this chapter and further below.
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
epidemiologic studies in context, however, the following passage from Section
VI A of the IR (1976) is presented. Following that passage, critiques from
the IR (1976) which specifically address studies cited in this chapter are
reproduced. Finally, a review of CHESS air quality analysis procedures and
results is presented, based on Sections V and VI of the IR (1976).
Section VI A of the IR (1976) opens with the following passage:
A. GENERAL PROBLEMS OF EPIDEMIOLOGIC INVESTIGATIONS OF POLLUTION EFFECTS
Before discussing health effects problems specific to CHESS, some discussion
of general difficulties inherent to pollution epidemiology may be helpful.
Exposure to suspect pollutants is not controlled in population studies.
Indeed with current technologies, it is not possible to be sure that the
correct pollutant is even being measured. Combinations of pollutants may be
more harmful than any single pollutant, and the number ot studies needed to
investigate such synergisms (interactions) increases rapidly with the number
of pollutants under consideration. The analysis of synergisms is often impractical
since sites with the needed configurations of pollutants are seldom at hand.
Not only is exposure uncontrolled, it is often difficult to measure.
Even when aerometric measurements are valid, special meteorologic conditions
or personal habits may cause a given subject to experience pollution levels
very different from those measured at a nearby fixed monitoring station.
These problems are exacerbated in long term studies during which the quality
of aerometric data has been variable and individuals have changed jobs and
residences. Aerometric methods for measuring hourly or daily pollution levels
are often less reliable than required for studies associating pollution levels
with short-term health effects.
The health measurements are often subjective responses to a questionnaire
or interview. An individual may give one answer on a self-administered
questionnaire and another to a friendly interviewer. Other factors, such as
the public announcement of a pollution alert, can also influence subjective
health measurements. Some health measurements, such as pulmonary function
tests or blood analyses, are less influenced by poorly defined conditions
surrounding the measurements and are said to be objective. However, even
objective endpoints respond to uncontrolled events like an undetected
influenza epidemic or high pollen count.
-------
Whether the health measurement is subjective or objective, the response
is often affected by factors (covariates) associated with the subject studied
and unrelated to pollutant exposure. Whether the individual smokes or is
subjected to cigarette smoke at home or work is a covariate of dominant
importance in pollution studies. Educational attainment may affect responses
to questions about phlegm or pneumonia. Occupation, age, sex, race, immunity
to influenza, allergy, access to air-conditioning and countless other covariates
complicate the interpretation of epidemiologic data. Epidemiologists treat
covariates in two ways. They try to choose study populations which have
similar covariate characteristics so that health differences between such
populations can be ascribed to pollution effects. Alternatively, they make
mathematical adjustments to nullify the effects of covariate imbalances. Both
strategies have weaknesses, and neither works if the investigator is unaware
of an important covariate or has failed to measure it.
The epidemiologist has little control over the subjects studied. He
cannot assign them at random to reside in polluted communities of interest.
Thus, a clean town may contain many asthmatics because asthmatics have wisely
chosen to live there rather than in a more polluted community. This fundamental
problem of self-selection must qualify any conclusions obtained from non-
randomized population studies: it may be possible to demonstrate temporal or
spatial associations between health and pollution measurements, but a causal
relationship cannot be inferred on the basis of a single epidemiologic study.
Students of pollution counter these weaknesses in several ways. One
strategy is to replicate an epidemiologic study in a variety of circumstances
and serially in time. If a consistent association between pollution and
health measurement is observed, it is held to be reliable since covariate
imbalances and problems of self-selection are unlikely to affect all sites and
to persist over time. Clinical studies, in which healthy volunteers are
subjected to controlled pollution exposures, and toxicological studies, in
which animals are subjected to various combinations and doses of pollutants,
complement information obtained from epidemiologic studies. This body of
information from clinical and toxicological studies and from several epidemiolgic
studies may substantiate an interesting association suggested by the health
and pollution measurements of a single epidemiologic study.
In addition to these general issues, several questions directly pertinent
to the CHESS health measurements were examined, namely:
(1) Was the health measurement a reliable and meaningful indicator of
public health?
(2) Was the statistical analysis sound and impartial?
(3) Were the methods used to ascribe specific health effects to specific
pollutants and to establish dose-response relationships logically compelling?
The following critiques from Appendix A, Part B, of the IR {1976) may be
helpful in assessing studies cited in this chapter.
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No.l, "Prevalence of chronic respiratory disease symptoms in adults:
212
1970 survey of Salt Lake Basin Communities." Reported by Chapman et al.
APPENDIX A
!•*
A RECAPITULATION OF THE AEROMETRIC AND METEOROLOGICAL,
FINDINGS or 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 is
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 been appropriate to have mentioned that only es-
timated long-term data were available and indicated their degree of
uncertainty in the discussion and summary.
(85)
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86
Further, we find many errors on Page 2-37, Table 2.1.A.14. It seems
that 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 than that which can be obtamed from Table 2.1.4,
i.e.:
SS=0.065(TSP) + 1.93
S02 exposures were derived by multiplying the yearly smelter
Emission of S03 by the ratio of the 1971 measured annual average
S02 concentration to the 1971 SOa 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
rate (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 seen in Figure 2.1.17. The
lowest value, which occured 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
emeltcr stack plume would not be blowing toward the town, such an
annual average would result in short-period concentrations many times
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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 Magnawould 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 wnen peo-
ple are generally indoors and perhaps in bed. When temperatures 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.
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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
accompanied 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 SO2 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 have 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 says "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
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89
between concentrations and temperature are true, the report does
not explain how the percentages of days were obtained. The 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
how 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 high 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 columnj
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.
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No. 7, "Prevalence of chronic respiratory disease symptoms in military
212
recruits: Chicago induction center." Report by Chapman et al.
92
ties where certain health effects were observed, the source of the
suspended sulfftte is inadequately determined. The study findings are
much too incomplete to call for the stringent control of suspended
julfates as has been done on page 3-51.
7. Prevalence of Chronic Respiratory Disease Symptoms in Military
Recruits: Chicago Induction Center (Paragraph 4-ty
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 nz/m3), suspended particulates (103 to 155 Mg/m') and
suspended sulfates (14 ^ig/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 Mg/ms, whereas the 217 Mg/m' is an average
value for five suburban communities for the. 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 pther year. It averaged 183 ^g/m!. The 14 Mg/m1 concentration for
sulfates 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 the 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.
(Page 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 didxide 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)
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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 Volunteer Fam-
ilies: Chicago Nursery School Study, 1969-1970
On page 4-41, in Table 4.3.1, it is not clear where the sulfur dioxide
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 include1
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.
(Page 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, 1944-1971
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." (Last paragraph on page) "The
observed annual ratios of suspended sulfate to dustfall for New York
City were used to estimate the suspended sulfate levels in Queens and
Bronx."
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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 al.
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
bis 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 1# 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 particulate
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 John 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 Mg/m' and sulfate exposures ranging from
9-24 jig/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 60 Mg/ms (accompanied by annual average suspended
sulfate levels of about 14 ng/nr and annual arithmetic mean total
suspended particulate levels of about 60 to 105 ng/ms) 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. I\ is not reasonable to infer that
lower pollution levels axe responsible for the observed health effects.
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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
214 212
Hammer et al, and Chapman et al.
11. Prospective Surveys of Acuie 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, i
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 yg/nr (accompanied
by elevated annual average levels of total suspended particulate of
97 to 123 Mg/m* and annual average suspended sulfate levels of
10 to 15 Mg/nr). 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 Mg/ni', 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 Mg/m' (accompanied by annual average total sus-
pended particulate levels of 63 to 104 Mg/m3 and annual average sus-
pended sulfate levels of 13 to 14 Mg/ms). i'he 51 to 63 ^g/'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/mS 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.
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No. 12, "Aggravation of Asthma by Air Pollutants: 1970-1971 New York
Studies." Reports by Finklea et al.
It. 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 penod 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
eulfate levels of 12 /*g/m» on cooler days (Tmln equal to 30 to 50 )
and 7.3 Mg/m' on warmer days (Tinln 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
ng/m1 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.
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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 u different curve is plotted for the low community Figure 5.6.2,
(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 wee"k 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'20tn 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 5.6).
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 /ig/ni5. There seemed to be good evidence of a threshold effect
between 6 and 10 Mg/rna, with a greater morbidity excess on wanner
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 sulfate 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 lort-, and a period of low values was not followed by a rise as shown
in the Figure. Further, the low values shown, which are about 25
Mg/m1, or .01 ppm or less, are quite low for the New York metro-
politan area. Average weekly low values two or three times this value
would generally be expected for a comparable period.
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No. 14, "Ventilatory Function in School Children: 1970-1971 New York
?i ^
Studies." Report by May et al.
14. Ventilatory Function in School Children: 1970-1971 New York
Studies (Paragraph 6.6).
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, ana 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 Mg/m3
(accompanied by suspended particulate levels of about 75 to 200
fig/m8) and suspended sulfate levels of about 5 to 25 /jg/m1 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 ng/m* for sulfur dioxide and 5 /jg/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.
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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 Mg/ro*) io 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 jig/m8, in the polluted lower middle white
community, but previous average exposure was estimated to be 10.7
to 12.1 Mg/m!, based on the National Air Surveillance Network station.
The average suspended sulfate level in the clean white sectors was 8.3
Mg/m8, 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 us/in* in polluted sec-
tors and 61 to 92 Mg/ni* in 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.
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SUMMARY ASSESSMENT OF CHESS POPULATION STUDIES
The 1976 Investigative Report (IR) on page 76 states:
No formal methods are used to link specific pollutants with
specific health effects in the CRD, LRD, ventilation, and ARD studies.
If a demonstrated health difference between communities cannot be
explained in terms of imbalances in known covarieates, it is generally
ascribed to pollution. It is not possible to know which specific
pollutants, if any, or what concentrations of any suspect pollutants,
were responsible for the health effects. The health effects data
provide at most a rough guide for making general judgments about
probable health effects in other communities with similar pollutant
sources, meteorology and population composition.
The methodology used in the panel studies (asthma and cardio-
pulmonary) attempts to disentangle the effects of the several pollutants.
The multiple regression and relative risk calculations are interpreted
as implicating...
...these formal methods do not provide logically compelling
evidence that SS, or indeed any of the measured pollutants is of
dominant importance. The remarks are meant to aid in the assessment
of the validity of the conclusions presented in the Monograph and to
assist researchers performing similar studies and encountering
similar difficulties. This endeavor was greatly assisted by hindsight.
Other specific criticism of the 1974 CHESS studies have been that:
1. Since ARD incidence has not been related to smoking habits consistently
all of the results must be suspect. The results from studies of ARD
have been inconsistent and the reason is not clear.
2. Since increases in some adverse effects, e.g., LRD have not always
been consistent with the indicated pollution gradient shown by multiple
study communities the data are not valid.
3. Because the arbitrary scores developed to indicate LRD severity or
ARD severity seem sometimes not to represent a consistent gradient, the
entire system is suspect. An accurate gradient may not be expressed by
an increasing numerical score, though the lowest scores represent less
severe illness than do the highest.
4. Because consideration was not always given to exogenous smoking and
thus secondary exposure, or because ethnic or religious factors were
not considered in the analyses, the results are suspect.
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5. Panel study comments:
a. Many relevant factors, including medication (steroids), humidity,
exercise, daily temperature changes, nitrogen dioxide levels, and
exposure to smokers at home or work were not evaluated.
b. The overreporting of asthma attacks on weekends would tend to
invalidate results. Higher reported rates of asthma attacks occur
on weekends when pollution levels generally are somewhat lower.
c. The underreporting of attacks as the length of subject participation
grew longer.
d. Reporting of attacks on heavy consecutive days suggests a lack of
association with pollution. In many individuals the occurrence of
an asthma attack can be triggered by many stimuli.
e. Daily measurements of air pollution are so poor that they cannot
be correlated with daily changes in symptom aggravation.
f. Failure to consider such factors as pollen density, indoor pollutant
concentrations, location where episodes began, and medication taken
by study subjects, cases doubt on the validity of the data collected.
Comments for the future contained in the IR (1976) on page 16 included:
"The overall impression left with the review groups was a general
awareness of many of the problems we found in the air quality health
effects research area.
Specifically, questions such as the following must be resolved for
future epidemiological studies:
(1) How do CRD questionnaire responses change on serial administration
in an area with unchanging pollution patterns?
(2) What is the sensitivity of the self-administered CRD questionnaire
compared with its use in an interview?
(3) What is the nature of the statistical dependence of-ARD *
attack rates, and what formal statistical methods are appropriate to the analysis
of relative attack rates?
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(4) What can be done to tighten the eligibility requirements
for asthma and cardiopulmonary panels?
(5) How can the statistical analysis of asthma and cardiopulmonary
panels be improved?
(6) What combination of CHESS health measurements is most
appropriate to long-term serial surveillance?
(7) What combination of CHESS health measurements is appropriate
to intensive studies of specific pollution hazards?"
It is apparent from previous comments in this chapter and this section
that the Investigative Reports' comments (IR, 1976) apply to all past related
epidemiologic studies. Yet, even the Committee indicated that the health
effects were there. Some sense can be made from previous findings as well
as for planning future studies.
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Section IV of the 1976 Congressional
Investigative Report (IR) concerning
CHESS air quality measurements is as
follows:
IV. CHESS AEROMETRIC MEASUREMENTS
A. INTRODUCTION
As pointed put in the introduction, the attainment of precise, reli-
able, reproducible, and real time air quality measurements in the field
(e.g., SO: and particulates) was a critical element of the CHESS pro-
gram. This chapter provides a critical review of the aerometric
measurement aspects of CHESS.
However, before reporting on this review two facts about CHESS
aerornetry should be mentioned. First, the methods used in CHESS,
especially in 1970-71, were probably as good as any available. Second,
quality control procedures were slowly introduced into the CHESS
program. EPA cannot be criticised, and is not criticised in this report,
for using the best available methods. However, EPA can be criticized
for not pursuing a vigorous program of quality control throughout
CHESS. The review reported here showed that CHESS did not
employ well-established quality control measures. The quality control
prop-am described in Appendix A of the Monograph was not carried
out. A thorough quality control program would have discovered, for
example, the temperature effects on the method used to measure SO:
(described below). It would also hnve placed bounds on the validity
of the data and precluded ovcrinterpretations.
In the design and implementation of any measurement sj'stem, the
single most important consideration is the end user of the data pro-
duced by that measurement system. In the simplest of all measure-
ment processes, an individual scientist conducting his own research,
both measures the parameters of interest and uses the resultant data
to draw conclusions about his experiment. In such a process the
individual involved has at his disposal all of the information contained
in the data, especially that concerned with the limitations of the data
and the constraints under which they should be used. In this type
of situation, few formal qualifications of the recorded data ore neces-
sary since those'qualifications are implicit in the mind of the scientist.
In larger programs however, the measurement process and the
utilization process are quite often compartmentalized such that one
group of scientists is responsible for the collection, quality assessment
and storage of the measurement data, and a second, usually nonrelated,
group of scientists is responsible for the synthesis of all pertinent
information into a final set of conclusions. In this type of systems
research, the determination of the fundamental quality 01 the measure-
ment data and transmittauce of that quality assessment are the single
most important qualifier in the process of going from observation to
understanding.
The CHESS program, as designed and implemented by the Envi-
ronmental Protection Agency, is a classic example of the large sys-
tems approach to research. The epidemiological measurements
were designed, conducted, and stored by one group of scientists; the
(25)
77-530—78 3
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26
fccromctric measurements were designed, conducted and stored by a
second group of scientists. The desired end product, a correlation of
health effects with atmospheric pollution was then derived from these
two independent sets of data accumulated in a large data storage net-
work. It is important to reemphasize here that in such a research
program it is incumbent upon the measurement personnel to transmit
to the data user all of the information containea in the resultant data,
especially that relative to accuracy and precision. In order to under-
stand the problems encountered in a large research program such as
CHESS, it is necessary to understand the types of measurements that
were made.
The assessment of atmospheric pollution exposure received by a
defined population can be derived from one of two broad classes of
measurement. The first is a measurement that yields an "index" of
pollution. The second is a measurement that yields quantitative in-
formation about a specific pollutant as it is found in the atmosphere.
A pollution index is a measure of the relative level of pollution which
contains little or DO information as to the specific chemical or physical
properties of that pollution.* These indices can be useful in assessing
short-term trends of atmospheric quality in well-defined and limited
geographic regions. They cannot be used to deduce information about
the source or chemical nature of the material being measured. They
also cannot be used to assess long-term trends of pollution burden
since gradual changes in pollution sources will distort the quan-
titative aspect of the index. Most importantly, they cannot be used to
correlate atmospheric pollutant levels among diverse geographic
areas. Here again, the difference in chemical and physical makeup of
the pollutants being measured distort the quantitative aspect of the
index.
An example of a measurement thnt gives a pollution index is the
dustfall observations as applied in CHESS. In this method, an open
topped cylinder called a dustfall bucket is used to collect any pnr-
ticulate matter that falls out,of the atmosphere. This collection is
carried out over a long time period, usually one month; and the total
dry weight of material collected is used to estimate pnrticulate burden
of the atmosphere during that time period. A detailed description of
this process is given later in this Chapter. This measurement falls in
the index class because nil solid material, regardless of its derivation
or chemical nature, is included in the final quantitative result.
The second class of pollution measurement is that which contains
information both on the specific species of pollutants and on the
atmospheric concentrations of those pollutants. In this tvpe or
measurement the sigruil that is measured is derived from a process or
Rroperty which is specific to the pollutant of interest and which corre-
ites directly with the concentration of that pollutcnt in the atmos-
phere. An example of this type of method is the West-Gaeke proce-
dure for the measurement of atmospheric sulfur dioxide. In this pro-
cedure, air is bubbled through an absorbing solution at a known rate.
The solution is specific for the r.bsorplion of SO2 from the air. After a
known duration of sampling, the quantity of SO; which was absorbed
from the air is quantitatively determined by the formation of a
• N.B. This Imlct 1« not the kind of "nlr qmlity Inrtri" oflrn uwl pnpnlvly fin ridlo broadcast* rtr 1
to »drlv clllims of Ihr rclid*. urfjunlitv of * city. 6ucb popular air quiLty Indicti *rr ujually »m»«l at
by combioint raeuuiemeouof Mrcral poUuUnU.
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27
colored chcmicnl complex of S02. If carefully carried out, the procedure
pives an accurate value for the S02 concentration. The procedure is
described in detail later in this Chapter.
Measurements such as the West-Gneke procedure, which are
specific and quantitative, can be used to compare atmospheric
pollutant burdens across diverse geographic areas and through long
time periods. They can also be used to assess short-term variations in
pollutant levels provided that sufficient sensitivity exists in the
method to obtain a meaningful signal for the short time period used.
In conducting a program such as CHESS, vrhere an attempt is made
to relate health effects to pollution burdens, only those measurements
that fall in the second class, specific and quantitative, can properly
be used to assess the relation between health effects and pollutant
burden.
In this chapter, an attempt will be made to evaluate the method-
ology used to measure aerometric parameters and to assess the
validity of the resultant data. The review will encompass procedures
used in the field situation, the quality control exercised over the proce-
dures, and the data storage and retrieval network. Conclusions will
be drawn as to the adequacy of the measured pollution levels to assess
exposures received by specific CHESS population groups.
B. REVIEW or CHEMICAL AND PHYSICAL METHODS
1. THE WEST-GAEKE METHOD FOR THE MEASUREMENT OF AMBIENT SOj
a. Description, of the Method
The West-Gacke colorimetric procedure for S05 determination is
the designated Reference Method (Federal Register, S6, No. 84, 61CS,
April 30, 1971).* Atmospheric SO2 is collected bv bubbling air through
a solution of potassium tetrachloromercurate (TCM). The product of
the reaction between S02 and TCM is the nonvolatile dichloro-
sulfitomercurate that is then determined quantitatively bv reaction
with formaldehyde and pararosanilino hydrochloride, followed by
photometric measurement of the resulting intensely colored para-
rosaniline methyl sulfonic acid.
b. Description of the Field Apparatus and Sample Collection
Outside air is drawn through a sample line at the rate of 200 nil
rnin"1, then through a 6-inch long glass bubbler stem (tip diameter
of 0.025 in.) immersed in 35 ml (50 ml after January, 1974) of
0.1 M TCM solution contained in a 32 mm diameter by 164 mm long
potypropylene sample container. The exhaust air passed through a
glass wool moisture trap, then through ft hypodermic needle used as a
critical orifice to control the flow, tlirough another moisture trap, and
finally through a vacuum pump. A sample consisted of a 24-hour
collection. Collected samples were stoppered, and mailed to EPA/
RTP for analysis.
e. Validity as a Laboratory Procedure
A collaborative study by McKcc et al. (H. C. McKee, R. E.
Guilder?, and O. Saenz, Southwest Research Institute, S'WRI Project
21-2811, EPA contract CPA 70^10) indicates that "the method can-
•AUercaUlr M« CFR Title 40, Fart SO. Apr?ndu A.
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28
not detect a difference smaller than 10 percent between two observa-
tions by the same analyst in the range of 0 to 1000 ^g m~5 A difference
of 20 percent or less may be detected above '^DO^g m~3, and a difference
of less than 50 percent may be detected above lOO^g m~V For
analyses conducted by different laboratories on the some sample, "the
method cannot detect a difference of less than 20 percent between
single-replicate observations of two laboratories in the range of 0 to
1000 Mg m~3- At a level of 100 /jg m~3, a difference of less than 100
percent is not detectable." The National Primary Ambient Air
Quality Standard for S02 is: For 24 hour average, 365 ^g/m*. For annual
average, 80 jig/m3. Thus if the standard is met, most values will be
around or below 80 Mg/m3, no more than one will be above 365 Mg/EQ3.
Regarding the lower limit of detection, the authors cited aoove
propose a value of 25 Mg ni~3 as a practical figure. "A single determina-
tion less than this value is not significantly different from zero"
(Instrumentation for Environmental Monitoring, Air-SO,, Instru-
mentation, Lawrence Berkeley Laboratories, March 1972).
It is therefore evident that a single analysis is of little use, con-
sidering that the expected concentrations of SO2 will usually be less
than the ambient air quality standard of 80 ^g m~3. Results should
be regarded as valid only in terms of the mean of multiple determina-
tions, and only when the analytical method has been followed
rigorously by experienced analysts.
2. TOTAL SUSPENDED PARTICULATES
Total suspended particulates (TSP) were measured using the EPA
Reference Method as specified in the Federal Register (86 (84):
8191-8194, April 30, 1971$).
Total suspended particulates (TSP) were measured by drawing air
through a prcwieghed 8 x 10 inch glass fiber filter for a period of 24
hours. The apparatus used for this procedure was the standard High
Volume Sampler. At the end of the 24 hour time period, the filter was
reweighed, and the TSP computed on the basis of total air flow. The
ail- flow rate was approximately 60 ft'min""1 at the start, and must be
not Ie?s than 40 ft3uiin~l at the end for the measurement to be accept-
able. The average air flow rate was computed on the basis of a straight-
line interpolation between beginning and ending flow rates.
The National Primary Ambient Air Quality Standard for TSP is:
For 24 hour average, 260 pg/m*. For annual geometric mean, 75 ji£/m3.
8. SUSPENDED SULFATE
Suspended sulfate was analyzed, during the CHESS program, using
portions of the TSP samples. From the beginning of CHESS to
September 1971 the turbidimetric method of analysis was used; then
the turbidimetric method was dropped in favor of the methylthymol
blue method, which was used throughout the remainder of the CILESS
program.
The turbidimetric method consists of the water extraction of soluble
sulfates on the TSP filter, the addition of a barium chloride prepara-
tion to the extract, and measurement of the resultant turbidity (from
sco CFR Title 40, Part M, Appendix B.
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the formation of insoluble barium sulfntc) with a spcctrophotometcrT>r
colorimeter. Accuracy of the method is affected by the kind and con-
centration of other ions present, as well as pH, conductance, tempera-
ture, and bnrium concentration in the test solution.
The methyl thymol blue method also utilizes the wafer extraction of
soluble sulfates from the TSP. The filter extract is then passed through
nn ion-exchange bed to remove interfering ions, and barium chloride
is added under slightly acid conditions, forming barium sulfatc. Then
the test mixture is made alkaline and methyfthymol blue is added,
which forms a chclate with the excess barium. The uncomplexed
methythymol blue is equivalent to the amount of sulfatc present, and
is measured spectrophotometrically. The metbylthymol blue procedure
is automated (Technicon Autoanalyzer) in all steps following water
extraction of the TSP, end this part of the procedure is reproducible
within a ranee of 2 percent. Error in the determination of sulfate occurs
predominant!}- in the steps preceding the methyl thymol blue method.
4. DUSTFALL BTJCKET, TAPE SAMPLER, CASCADE IMPACTOR,
AND CYCLONE SAMPLER
In addition to TSP measurements using the Hi-Vol sampler, four
other means of estimating particulate concentrations were used at
various times. The}' are the duslfall bucket, the tape sampler, the
co.scade impactor, and the cyclone sampler.
(a) The name "dustfall bucket" is adequately descriptive. It is
basically an open-topped cylinder, with some protection against wind
and rain loss, that is left out in the open, close to the ground or on a
rooftop, for a month. At the end of that time the dry matter collected is
weighed, and sometimes analyzed for trace metals. The dustfall bucket
method is very crude and misses almost completely the very significant
part of the aerosol, including the respirable aerosol, that does not settle
rapidly. It must be considered here, however, because dustfall measure-
ments were extrapolated to obtain estimates of suspended sulfates
and sulfur dioxide in Mew York City during the period 1949-5S
((Table 5.2.1, CHESS Monograph), and intermittently in Chicago
(Table 4.1.A.3), CHESS Monograph). Dustfall measurements were
used as the basis for these extrapolations because there was no other
basis for such estimates, but it must be remembered that the relation-
ship between suspended sulfates and dustfall is unknown, and that
between sulfur dioxide and dustfall is another step removed from
reality.
(6) Coefficient of Haze (COH) is determined by the automatically
operating tape sampler. It is determined by measuring the optical
density of an aerosol deposited on n filter tape. The aerosol deposit
is obtained by drawing air at a given flow rate through white filter
paper tape for a known period of time. If one could assume that the
composition and physical characteristics of the aerosol in a given
location did not change with time—that only atmospheric loadings
would change—then the COH would give a fairly good approximation
of the variations of particulate loading and visibility.
However, this assumption is seldom justified, and even at a given
location the COH only roughly approximates the true particulate
loading. The COH method is worthless, or nearly so, for comparisons
between areas with dissimilar aerosols. For example, the aerosols
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30
collected at the Utah sites are primarily the light-colored alumir.o-
silicate dust, whereas the aerosol collected within the inner core of
large cities has a predominantly sooty chnracter. For a given par-
ticulate lending the Utah aerosol will often have as little as one-tenth
the optical density of the urban aerosol.
(c) The cascade impactor operates on the principle that particles
in an air stream will tend to follow a straight line when the air stream
is deflected, and thus can be impacted on a surface in their path.
The cascade unpactor consists of a series of parallel plates separated
by precisely determined spaces. Alternate plates contain a certain
number of "holes of a size that is decreased as one goes through the
scries of plates from entrance to exit. Alternating with the plates
containing the calibrated holes are plates without holes. These may
be coated with R medium for the trapping of impinged particles. Air
is drawn through the apparatus at a known rate, and tho particles are
collected in decreasing size fractious related to the decreasing size of
the holes in the plates.
(d) The cyclone sampler is a device for the collection of the re=pi-
rable size fraction of an atmospheric particulute loading. It operates
on the principle that the inertia of individual particles will tend to
keep the particles moving in a straight line when the air stream in
which they are carried is deflected. By this means the larger size
particles are removed by impaction and settling, while the respirable
particles are carried along with the air stream and are subsequently
collected on a filter.
C. FINDINGS AND EVALUATIONS OF MEASUREMENTS AND DATA
REDUCTION
It is important to preface this evaluation of the CHESS air moni-
toring program with a statement of the following facts. The inves-
tigative team looked backward at the program through a window in
time with all of the subsequent knowledge built up during that time.
More than ten years have passed since the initial planning of the
CHESS program and more than six years have passed since the first
data were collected. During that time there has been a vast improve-
ment in the understanding of the methods used for pollution moni-
toring. Many of the procedures used in CHESS have subsequently
been found to contain serious errors. These problems were often
uncovered as a direct result of research and quality control programs
ongoing within EPA. It would thus be unjustified to lay criticism on
the principal? in the CHESS program for using state of the .irt meas-
urement technology.
On the other hand, some serious oversights in scientific judgement
did occur. In the area of pollutant monitoring, these oversights could
have been completely avoided had proper attention been paid to even
rudimentary quality control procedures. Throughout the program,
much more emphasis was placed on the uninterrupted collection of
data than was placed on the systematic evaluation of data quality.
The fiHd investigation stage of this review identified numerous prob-
lems that resulted in the propagation of unnecessarily large errors in
the aeromctric data. These unevalu.itcd errors persist even today in
the data as it is stored in the CHESS computer system. They could
have been avoided or easily discovered and quantified hnd "a well-
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31
designed quality control procedure been applied to the CHESS aero-
metric monitoring program. This statement is contrary to the state-
ment of the quality control procedures in appendix A of the 1974
CHESS Monograph. Appendix A \vns not a manual provided to
CHESS data gatherers, but was written lont: after the data in the
1974 Monograph were collected. However, during the field investi-
gation of the CHESS monitoring contractors, it was found that the
quality control procedures as described in Appendix A of the CHESS
Monograph were routinely disregarded. In fact, for the first two years
of the program, virtually no EPA-direclcd quality control program
was implemented at any of the New York, Salt Lake City or Los
Angeles CHESS monitoring sites. Problems that were found in this
time period were observed and documented by contractor personnel
and it was mainly through their personal professional conduct that
any of the field problems were corrected. Reasons for this rather
TOSS oversight on proper data management can only be conjecture,
nit it did appear that inadequate staffing of the monitoring group,
coupled with the intense pressure to get "the monitoring stations on
line and producing data, led to the situation described.
In fairness (regarding the time perspective mentioned earlier) the
problem of inadequate quality control on many large EPA programs
eventually was recognized internally and in 1074 a Quality Control
Branch was established in the Quality Assurance and Environmental
Monitoring Laboratory. This brunch was given the authority to im-
plement proper quality control procedures on all large atmospheric
monitoring programs. Since the formation of this group, there has
been a significant and steady improvement iu quality assurance as
applied to air monitoring methods and data.
In this section, major emphasis will be placed on review and evalu-
ation of the analytical methodology used in the CHESS program to
assess population exposures to sulfur oxides and total suspended
participates. Conclusions will be general to all data taken at "official"
CHESS monitoring sites, regardless of location. Where local differ-
ences in procedures or rcsultont data did occur, these will be described
separately. Health studies, as described in the 1974 CHESS Mono-
graph, that used aerometric data derived from non-CHESS monitor-
ing sites will be reviewed separately.
1. EULKUR DIOXIDE
Atmospheric levels of S03 were determined using the EPA Ref-
erence Method, better known as the \Vest-Gacke or Pararosanaline
method. The specific details of this method are described in the
procedures section of this chapter (Part B.I.). However, a few im-
portant aspects of this method will bo reiterated. This reference
method is basically a laboratory method adapted for field use. It is
a "wet chemical" procedure relying on a gas-liquid phase chemical
reaction between S02 and sodiuVa tetrachloromercuratc (TCM). To
accomplish this reaction, the SOj as a gas phase pollutant, mu~t be
quantitatively absorbed into the liquid reuctnnt solution. This is
accomplished" by bubbling ambient air through the solution at u
controlled flow rate, thus, its description as a "bubbler method."
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In an attempt to stnndardize the methodology nmi to eliminate
problems associated with intcrlaborutory errors, a CHESS policy was
instituted whereby nil air sampling equipment was assemble;! nml
tested at the central EPA research laboratory und then shipped to
the contractors for field use. Also, bubbler tubes were prefillod with
the appropriate absorber solution, shipped to the contractor for their
daily monitoring use, and shipped back to the central laboratory for
chemical analysis. It was this long distance shipment of the chemical
solutions that led to the first of a scries of field-use problems with the
procedure. These problem areas will be summarized below with an
attempt to evaluate their net effect on the resultant CHESS S02 tlritu.
Following this summary of individual problem areas, nn assessment
of the overall S02 data quality will be given.
a. Spillage of Peagenl During Shipment
The first field data were obtained in New York City nr,d the Salt
Lake area (Utah) in November, 1970. By mid-1971, field personnel
nt the Utah site reported to their CHESS field engineers that sevpre-
spillnge was occurring during shipment. Many bubbler tubes were
arriving partially filled with reagent and some were completely empty.
At the Salt Lake area an attempt was made to refill with solution
from extra tubes those tubes that were low. However, due to insuffi-
cient reagent, this was only partially successful. This problem was
not officially recognized until October, 1972, at which time p.n internnl
EPA/CHESS memo was written outlining tho problem and suggesting
corrective action. The magnitude of the problem can be best n-ses=ed
bv quoting from the memo. "The present rcngent tubes for SO; and
Js'Oj leak during shipment. . . . The S0: leakage rate (was found to
be) 18% of the total volume, 50% of the time. ... It follows there-
fore, that the resultant pollution data are unreliable." Recommenda-
tions were made in this memo as to possible corrective measures. These
recommendations were not instituted until March, 1973.
During the subsequent years, many attempts were made to correct
this leakage problem. However, none were wholly successful and ns
late as January 1975, another EPA memo described losses of solution
in SO; bubblers during shipment and suggesting appropriate corrective
action.
The effects of the reagent spillage problem on the SO- data can
be only grossly estimated. Certainly, ninny samples were totally lo-t.
These lost samples were not the major problem. Of more signilirancr
was the undetermined amount of daily SOj data that were in error
due to the loss of sample by spillage and yet included in the network
system.
If the reagent was partially lost during shipment to the ?nmplin2
site and used as received, fin increased concentration of TCM-SOj
complex would occur relative to normal sampling. This potential
positive bias would be corrected by for the analvtical procet'ure u
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33
According .tt> the EPA Memo of October, 1972, onr> half of oil SOj
datn taken between November, 1970 and March, 1973 are likely to
have been biased low by nn average of 17%. This problem was cor-
rected after April, 1973.
b. Time Delay of the Reagent—S0< Complex
The Reference Method as originally described in the Federal
Register, was to be conducted at 20° C. There was a known error in
the method associated with tune delay between sampling and analy-is
which was dependent on temperatures. This error was derived from
the spontaneous decomposition over time of the TCM-SOj complex
as a function of temperature. The magnitude of the error anu its
exact dependence on temperature was not known but a brief study
was conducted to determine its magnitude by scientists of the CHESS
monitoring group in November, 1971. As a result of this study, a
correction factor of +1.5% per day was arithmetically applied to nil
CHESS SO; data to compensate for the time delay between sampling
nnd analysis.
A more recent and comprehensive study has been carried out within
the Quality Control Branch, Environmental Monitoring Laboratory
at EPA on the effect of temperature on "The Stability of SOi Samples
Collected by the Federal Reference Method." This study indicated a
much more severe problem than was estimated by the original CHESS
study. The evaluation was carried out over the range of 35 to 278
MS/m3 SO2 concentration. The following findings were presented in
the report:
Over a normal range of temperature, the rate of decav of the
TMOSO2 complex increases five-fold for every 10°C increase
in temperature, respectively.
The rate of decay is independent of SO: concentration.
At 20, 30, 40, nnd 50° C the following SOj losses were observed:
0.9, 5, 25, and 74% loss per day, respectively.
This study makes abundantly clear a second and even more severe
error associated with the SOj measurements conducted by CHESS.
During the summer months, when the S0: absorber solutions were
subjected to high and unknown temperatures between field sampling
nnd laboratory analysis, significant degradation of the samples did
occur. Estimates of time delay between sampling and analysis range
from 7 to 14 davs. Estimates of summer temperature exposures range
from 25 to 40° C being most severe for the Utah CHESS sites. Thus,
CHESS SO; data can be estimated to be negatively biased, mainly
during the summer months. It would normally be difficult or impossible
to estimate the magnitude of the bias except to say that it is probably
large. However, simultaneous S0: measurements were taken by the
New York City Department of Air Resources and by the Utah State
Division of Health. These results were obtained by aa independent
method not susceptable to the temperature related error. A consistent
pattern emerged when side by side data are compared. From May to
October, the CHESS S0: data were lo\v with the largest error occurring
in the middle three summer months. The magnitude of the error varied
from month to month and year to year, but the CHESS data were
consistently low and represented only n portion of the true ambient SOj
conceutration.
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34
c. Concentration Dependence, oj Sampling Kfethod
The SOj reference method was subjected to a collaborative study
program in 1973. Four participating laboratories tested the 24-hour
•version of the Federal Reference Method. A previously unknown source
of error wns documented that npplics to the CHESS SO: data. It wr.s
found that the 24-hour sampling method does have i\ concentration
dependent bin1; which become^ significant nt the high eonr.pntm-
tion levels (200Mg/m5). Observed values tend to be lower than the
expected (known) S02 concentration levels. This error source will yield
n negative bias on the dnily CHESS S0: data when they exceed 200
Mg/ins and on nil monthly and yearly average datn.
d. Low flow correction
The determination of atmospheric S02 concentration was dependent
on, among other factors, the accurate measurement of nir that, passed
through the TCM solution. This flow wns controlled bv a critical flow
orifice in the form of a standard hypodermic needle. In practice, the
air flow through the sampling system wns measured at the start and
end of each 24-hour sampling period. Tins was done to detect low
flow due to needle blockage. The Federal Register Method (Rpference
Method) calls for an air flow of 200±20 ml/min. In field operation, the
CHESS procedure substantially broadened these tolerances. Replace-
ment needles were installed if the initial air flow was greater than
220 ml/min which is consistent with the Reference Method; however.
needles were not replaced nor were samples voided until the measured
flow dropped below 100 inl'min. Integrated flows were calculated by
assuming a linear decrease in flow between the start and end of the
24-hour sampling period. If, however, the needle was partially blocked
near either the beginning or the end of the sampling period, the
linear flow correction would be in error. Using the Reference Method
flow tolerance, only small errors would be introduced by this correction
•(less than 10%). Using the CHESS procedure, however, errors as
large as 50% could be introduced ond not detected. These errors
would be random (either positive or negative) depending on when dur-
ing the sampling period the needle blockage occurred? Thus a larse
random error component wns added to the SO2 daily data but this
component was somewhat damped statistically in the monthly or
yearly averages.
The modification of flow tok>rancc by the CHESS ncrometric
group is a procedure that would not have withstood the critical review
of a competent quality assurance program.
«. Bubbler train leakage
The West-Gaeke method, as described in the Federal RegUter,
employs a vacuum bubbler train. That i?, the sampled air i< drawn
through the bubbler train by a vacuum pump rather than being
pushed through by a positive pressure pump. There are many ad-
vantages to the vacuum procedure, most important is that the air
does not come in contact with any internal pump mechanism. However,
there is a modest pressure differential between the atmosphere and the
internal bubbler; thus nil fittings and joints must be gas tight. The
bubbler train used in the CHESS program had two points where frequent
air leak problems were encountered. One was around the rubber
stoppers for the bubbler tube and moisture trap and the other was the
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35
rubber tubing used to hold the class assembly pieces together. Field
operators reported consistent problems with lenknge in the routine field
use of the bubbler train. In a severe leak situation, the samples were
voided due to out of tolerance (Low) flow rntes. There were many
cases however, where small leaks occurred but the fmnl flow was
within specifications so the sample was included ns valid. In cases
where the leaks formed around the rubber stoppers, no significant
error would be introduced except due to the linear flow correction as
applied to instantaneously developing leaks. This error is similar in
nnturc to that discussed in the flow section. In the case of leeks up-
stream of the bubbler train, room air inslcnd of outside air is drawn
through reagent. In normal situations, it hns ber-n observed that room
nir is significantly less polluted than outside air. (See page C-C.
CHESS Monograph—comparison of school air to outside nir). This
effect may not ue as large for the small buildings used to house CHESS
stations, but a somewhat decreased pollutant level would undoubtedly
be sampled. The absolute magnitude of this error cannot be fidcquntrly
assessed but it can be stated that the error would be in a negative
direction, that is, again to underestimate SO2 levels.
2. GENERAL ASSESSMENT OF CHESS SOj nATA
The SOj data, accumulated at "official" CHESS sites, followed a
remarkably uniform trend as the prosrom progressed. The method
Used was the EPA Reference Method wliich is specific for the chemical
specie^, SO:. Thus, regional chanses in pollutant mix, i.e., the propor-
tion of other pollutant species relative to SO:, hod minimal effort on
the SO: data. However, the sum effect of the errors detailed in this
section did have a profound effect ou both the accuracy find the preci-
sion of the data.
Under normal circumstances, n. retrospective evaluation of a
monitoring effort that occurred a number of year; in thr pa-t and
whirh had been terminated, could yield only the broadest of estimates
of data quality. Fortunntelv for this review, two geographically
different locations with six different monitoiing sites were involved
in the collection of simultaneous SOj data. Further, the groups re-
sponsible for the two data sets were managed independently and the
methodology used was also independent. This fortunate circumstance
enabled the reviewers to acquire n quantitative understanding of
absolute differences among data sets ns well as correlations with renvl aridiTietiicly and in
Salt Lake City they were quantified cond'ictiomctriedlly. Neither
muthoil is ns specific for SOj as H the R-fcrcncc Method, that is,
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36
pollutants that are in a significant ronmntrntion, relative to S0:
and that also oxidize to form nn acidic compound will be interpreted
as SOj. For tin"? reason, when the NYC Department of Air Resources
initially brought to the attention of the CHESS Aerometric team the
large (fiscrepancy between their respective dnta, the discrepancy wai
dismissed as method bin< on the part of (he Now York method. An
EPA memo dated November 3, 1971 described n limited study into the
Reference Method. The conclusion reached was "On the basis of
(this study) ... I feel there is no sound bi^is for discrediting the
•EES (Environmental Exposure System) methodology."
No further attempt was made to uncover the cixr.'-e of the discrep-
ancy in S03 data. Had the CHESS EES team obtained and compared
the Salt Lake Bnsin data, especially thnt from Magnu site, ft disturbing
similarity would have been immediately apparent. This data confirmed
in detail the discrepancies observed in New York. It is important that
the Magna site data were confirmatory since it \vns in a region of
sincle source pollution, that from the nenrby copper smelter. In this
site very low levels of other pollutants existed relative to SO:, thus
the peroxide method win capable of giving rensonablv reliable esti-
mates of the S0: concentration. Of equal importance the general pol-
lutant mix was very different between this rurnl smelter site and the
urban area of New York City. Despite these differences the compari-
son of side bv Fide Federal-State data indicate the same discrepancies
in both trends and absolute concp.nlrafionv The following conclusions
as to SO; data validity can thus be reasonably drawn from the review
of methodological errors and the comparison of existing side by side
data.
From November 1970 until December 1971 the S0: data generated
from CHESS sites using {lie modified Reference method were bia-pd
low by 50 to 100 percent in the High Exposure sites when compared
with existing State S0: data. Tims, the 1971 annual average SO;
exposure estimates of eOpg/m3 as reported for Muslin in the CHESS
monograph (page 2-24) arc more likely in the vicinity of 100 nz'
Al-o, the same phenomenon occurred in New York and the reported
values arc also m ciinihi:- error.
A confirming fact is that during cool months njtcr 1971 SOj dnta
correlated well both in trends and ubsolut" corporations between
State and Federal analyses. It thus seems likely that the State data
were reasonably accurate throughout that time'pcriod. However, one
consideration' must be applied here: namely, that due to tlir Jiflrrcr.cr
between the independent methods an error bar of at leant one hundred
percent must be applied to the da'a ami rrpHcltli/ correct data cannot be
drawn from these obwnations. In other words where (wo or more
independent observations are in disagreement by a significant amount
it cannot be said by inference nlon? thr.t one data >--et is more correct
than the other. It is reasonable to t\ssumc, however, from our review
of nil State and Federal data in (he time period of 1970 through 1971,
that the Federal SO: d.ita ft- collected in the CHESS program were
substantially low mid went through an abrupt upward tran-:ition in
concentration in December 1971 nt all CHESS sites ami Federal data
taken before that (ime may reasonably be c.xpcctcd to have a Ian:?,
unknown negative bias.
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In November 1971, the CIIESS monthly mean SO: data underwent
nn abrupt change in tlic po-itive direction. The cau-c of thi- change i<
not apparent. However, the result was profound. From tlmt time until
the conclusion of tlic CHESS program in July of 1975, the fall-winter
data were in very good agreement with other existing data end very
likely pave reliable estimates of fc>O: exposures.
Throughout the entire program, the CIIESS SO: data had nn
associated negative bias during the summer months, becoming mo-t
severe during the ho!te:-t periods of July and August. This error
usually reached fx niaximurn of CO to SO pel cent imdcrci-timation oT
exposures nud was variable. A- a result, even though wintertime
monthly S0; averages appear valid from 1072-1975, annual average-;
of the snmc datu ure biasrd low due to the inclusion of the summer
errors. The best estimate of error in the annual average data 1972-
1075 is approximately minus 15-20 percent relative.
The individual daily SO: levels, when compared to city or State
data or to replicate CIIESS measurements taken after 1C73 had ?-o
large a random error component that they ore not useful to a--e~s
daily SO2 exposure (as attempted in the asthma panels). The random
errors associated with the daily values were much larger than the
differences observed over lime.
Due to inherent methodological errors, the following may be con-
sidered as minimum differences between High and Ix>w SO: exposures
which mrty be considered "real." These are b:i«ed on EPA's collab-
orative study of the reference method and used a 95 percent confidence
interval.
Below 100 jig/m' SO;, ft difference of at least 50 yg,m3 is
necessary to be statistically significant.
Between 100 and 300 ^g/in3 S0:, a difference of at least 60 ^g/m:
is nccc>«ary to be significant.
Below 25 /jg/m3, a single determination is not significantly
different from zero.
3. TOTAL SUSPENDED PARTICVLATE
The Hcfer'-nce Method for the determination of total suspended
participate mutter (TSP) is probably the simplest and mo^t reliable
method used by CHESS. It has been well studied and most error
sources are known. However, it is a method that measures an arbitrary
and poorlv defined portion of the total atmospheric pnrticulatc burden
and the portion measured has unknown relevance to the human respir-
uble portion. The si?.c fraction measured is somewhat dependent on the
design of tlic shelter used for Hi-Volume sampler. The design and di-
mensions of the Reference Method shelter arc specified in the Federal
Register, thus the portion of TSP that is collected by the method
is generally uniform. Best estimates of particle size range included
in the Reference Method are from 0.05 to CO pin diameter. Above
60 ttm diameter, the particle fall velocity is too great to navigate the
bend nround the roof of the shelter. Below 0.05 ^m the collection
efficiency of the glass fiber filter used in the method diminishes.
A collaborative study was conducted on the Reference Method
using 12 different groups sampling ambient r.ir at a common location.
The results of this study indicate tlic method is capable of reproducible
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38
measurements with les? than 5 percent error nt the 95 percent con-
fidence level. Also, the minimum detectable amount of TSP is approxi-
mately 2 jjg/m' (or a 24-hour sampling period. This *f.nsitivity is
more ihan sufficient for most 24-hour fSP measurements.
Tlie TSP measurement method, as used in CHESS, had one notable
difference from the laboratory procedure which was collaboratively
studied. The weighing procedure to determine TSP was performed at
EPA/RTP laboratory not by the CHESS contractors on site. This
necessitated the shipment of individual filter samples through the
mail and the subsequent storages of the samples at EPA. During
laboratory reorganizations nt RTP, periods ns long as 6 months
elapsed between actual field sampling and laboratory analysis.
The following is a summary of individual errors and an assessment
of overall TSP data quality.
Loss of partifulate matter before weighing
In the TSP methodology there were field-related procedures that
resulted in partial loss of participate matter from the Hi-Volume
filter samples. Due to the exposed location of the Hi-Vol TSP samplers,
wind and cold sometimes made it very difficult to remove the filter
paper from the apparatus without lor.ing pnrt of the sample. No
estimate has been made of loss due to this problem; it would, of course
bias the reported results only in the direction of lo\ver-than-actual
atmospheric loadings. This was not a constant problem among CHESS
sites. It was noted by field operators us bcinj a particularly severe
problem in the Salt Luke City urea during the winter months.
Two other error sources have been identified in the determination
of TSP, both of which would also produce a low-side bias: (1) the
shaking-off of particles from the filter during transit from the field
site to EPA/RTP, und (2) the evaporation of organic substances. In nn
attempt to quantify the mass loss during transit, David Ilinton, EPA/
RTP, made a comparison of filters collected in Utah, before and after
mailing from Salt Lake City to RTP (22). He found that there was a
overtime 4 percent loss. Carl Broadhcad, of the Utah Division of
Heult.li, conducted u similar comparison; however, he noted nn
apparent loss of approximately 25%. This difference may, in part, be
due to the time of year the studies were conducted, During the dry
summer months in the Salt Lake City area, much cf the TSP lending
is due to windborn crustal material (sand). This material is much more
easily lost in sample handling that is the finer anthropogenic particu-
late material.
A final error source, one more difficult to assess, derives from wind
velocity versus collection efficiency. On days with relatively high wind
(>15 mph), the Hi-Vol sampler is more susceptible to the inclusion
of large diameter participate material. To compound this problem,
the design of the shelter makes the magnitude of the error dependent
on the wind direction relative to the orientation of the shelter. The
main result of this problem is that two side by side Hi-Vol samplers,
oriented 00 degrees relative to each other, will produce dissimilar
measurements with the discrepancy increasing as the daily wind
velocity increases.
The "overall effect of the summed errors with the Ili-Vol TSP
measurement is a slight negative bins. This bias may be ns smalPns
10% or may be ns large as" 30%. Side by side data from New York
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39
nnd Sr.lt Luke indicate that this assessment is reasonable. Those
datu filso indicate tlint the TSP data were by far the best quality
data tak^n in the CHESS monitoring program. Differences measured
between High and Low sites urc probably reasonable estimates of
the differences of TSP exposures ^s received by populations within
these areas. Some local source variations undoubtedly did occur, but
average annual exposures worn reasonable.
In any overall assessment of the CHESS TSP data it should be
noted that nil of the sources of errors mentioned previously related
almost exclusively to the loss of large participate matter and mnst
likely that matter is a-^ociated with crustal weathering. This material
is outside of the normal human rcspirable size fraction and by com-
?osition, it would be unlikely to be associated with aggravated health.
has, loss of that portion of the total material may not have di-
minished the quality of data for heulth effects studies. It mav in fact
have rendered that data a closer estimate of the resniruble TSP
exposure to which the CHESS population groups were subjected.
It has been suggested by some environmental scientists that when-
ever Hi-Vol measurements are made for health related studies, the
filter pads should be "shaken out" much like a housewife does when
shaking crumbs from a used tablecloth. The resultant TSP exposure
estimates derived from such a procedure would then more closely
relate to the human rcspirable size fraction of the total atmospheric
particulate burden. Although never actually implemented, this
suggestion indicates the general level of dissatisfaction with the TSP
Hi-Vol measurement method.
4. TOTAL SUSPENDED SULFATE
The determination of atmospheric sulfate concentrations, its
carried out in the CHESS program, was a methodological extension
of the Hi-Vol TSP method. Thus, all errors r.ssociated^with the TSP
method also affect the sulfale method. Sub^amples w.-re cut from the
exposed Hi-Vol filters and were analyzed for totr.l \vater soluble sulfate.
Methods available for sulfate analysis at th? time of CHESS deter-
mined all water-soluble sulfatcs as a class rather than distinguishing
them by chemical species. Two different methods were available for
total sulfate ond both were used in CHESS. From November 1970
until September 1971, the manual turbidimetric method was em-
ployed. From September 1971 until Julv 1975, the methj-lthymol
blue (MTB) method was used. The methods are somewhat similar
and are described in detail above.
The turbidimetric method is subject to interferences, many of them
being other common pollutants. In arcus like the Salt Luke Basin
where the pollutants are dominated by a single source, the procedure
may be adequate. However, in urban areas like Cincinnati or New
York City, where the pollutant mix is derived from many independent
sources and is variable even within the city, the method is capable of
only the crudest estimates of sulfate levels. It should not be thought
of as an accurate measurement of atmospheric sulfate. Especially,
small differences between High and Ix>w exposure commmiitio*, such
ns were reported in the Cincinnati Study in the CHESS Monograph
(page 6-5) cannot be identified n.s real differences. When a realistic eTror
estimate is applied to the reported sulfate concentrations, the differ-
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40
encc becomes statistically insignificant. Any correlation of CHEF'S
hc.ilth effects with sulfntc levels where the sulf;;tc data were obluined
using the turbidimctric method muM be carefully qualified.
The MTI3 method is b;\-ically u better measurement method becnu-e
most of the neromctrir interferences luivc been eliminated by its
revised methodology. The t\vo remaining interfcrents, phosphate nnd
barium, nrc not normnlly found in atmospheric con<.cntra!ion> high
enough to cause inordinate problems. However, problems os§orinted
with the sampling aspect of the melliod have been documented ond
do impact on the "general CHESS sulfatr data c;unlity.
First, problems associated with sidfnte blanks (the level of sulfnlo
on tlie (liter pad ns manufactured) were reported to be high nnd
variable. In the 1071-1073 time period, problems of variable blank*
within the EPA NASN program were documented. Tl.c general
blank level was equivalent to an atmospheric sulfalc concentration
of 1-2/ig/ni'. However, the majur problem VMS variability of the
blank among manufactured lots of the filters. The blank level ofr^n
varied by more than 100 percent among lots so that routine ond
continuous blank assessment should have been mandatory.
No evidence of routine sulfate blank determination was found in
the CHESS monitoring program until 1974. From that time period
on, adequate blank assessment and correction were applied to the data.
From 1971 until 1974 however, the blank contribution to the CHESS
sulfate data was not adequately assessed and consequently a. po.-itive
nnd highly variable bias of unknown magnitude wr.s included in the
data.
Second, adsorption of atmospheric S0: onto the fiberglass filter
material followed by spontaneous oxidation of the S0: to sullats had
been well documented. A 19GG publication by R. E. Lee nnd
J. Wagman provided results of their invc>tigation of the problem. The
conversion was clearly documented v.ilh severe eticcts (Icmor.stratrd
on four-hour samples. The conversion did appear to he an uctive-site
catalytic conversion that decreased in magnitude ofler an initial
saturation of sites. Thus, 24-hour samples were much les? affected
by this problem thnn were those taken for shorter time intervals.
Even so, the paper by Lee and Wr.gman, presented data in which
routinely 0.5 to 1 ^m3 oMhe measured sulfate was derived Jrom
SOj conversion products. The maximum conversion presented was
2.1pg;m3 derived from SO;; this constituted a 10 percent positive
bias of the sulfate data. A more realistic overage bias is likely in the
5 percent range. However, there is clear evidence that in regions of
high levels of SO:, relative to sulfatc, the positive measurement bias
becomes much more severe. Tin's is probably the caie in the Salt
Lake Basin orea.
The third nnd most devastating problem associated with the
CHESS sulfate data occurred when the laboratory analysis of sulfates
was contracted to an outside firm. During this time period (October
1972-June 1974) the reported sulfate data underwent a sudden and
sustained decrease in apparent «tino-.phcric sulfalc level. Upon
investigation it was determined that tlm laboratory nno'.vsis of' all
sulfate data from nil CHESS sites were biased low by approximately
50 percent. Tho reason for this negative bias was nnd still i? not
completely clear, but the continued dissemination cf poor dnhi was
clearly due to inadequate quality controls. An imcriiu EPA report
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41
on n retrospective quality assurance evaluation of CHESi Sulfntc
Data states:
A quality control protocol was designed for CHESS chemical an.Myfis but ha*
not been implemented ns per the contract .... The quality control protocol
•hould be implemented immediately.
In n scries of following studios the roognitude of the ofTcctcil data
and of the error were documented and nn attompt was made to correct
and therefore recover the data. This type of procedure is difficult fit
best nnd impossible in most crises. The validity of this data corre< tion
was again assessed by the EPA Quality Assurance Branch. Their
finding was:
The basic question . . . is — How dow one make bad data good"1 Whatever is
tried will be attacked for a multitude of (ju-tihablc) reason;,. Using the c\i-nr.g
data set for relative pollution level ass«?ment will be acceptable, but statement-,
concerning absolute levels will not be. It would not be RISC to submit tbe-:e
dnt.i to the NADB,1 but rather answer all requests for these data internally.
Their statement gives a reasonable assessment of the CHESS
sulfate data between 1972 and 1974. The assessment of other year
CHESS sulfate data is more difficult. No comparative sulfate duta
exists from the local agencies as it did for S03 and TSP. Based on
the intrinsic capabilities of the methods, nnd the error assessment of
the field use procedures, it can generally be stated that:
1. From 11)70 to September 1971 the sulfate data were obtained
using the turbidimetric method. It should be used only as a sulfate
level indicator. Due to interferences, there will be severe problems if
an attempt is made to correlate sulfate levels in one part of the country
with sulfate levels in another.
2. From October 1971 until October 1972, the data are subject to
the following considerations:
a. The data are likely biased in the positive direction from
1-2 pg/m'. This bias ma}' be more Revere in ureas of high S0:
concentration relative to sulfate.
b. The random error component of the measurement is probably
in the order of ±25% at an atmospheric concentration of
10 fig/m3
3. From October 1972 until June 1974, all CHESS sulfate data were
biased negatively bv approximately 50% on an r.nnual average bn-i =
due to improper laboratory analysis by the contractor. These data
should be used only on an adjusted annual average basis to establish
local trends within site locations. The unknown cause of the bins
prohibits use of the data in shorter time structure (i.e., day, week,
month) increments.
4. From July 1974 until July 1975, CHESS sulfate data underwent
a marked improvement nnd was somewhat better than that collected
in the 1971-1972 era. The positive bias of the data is probably
similar to that of the earlier period but the random error component
was improved due to improved sulfate blanks on the TSP filters.
D. THE CHAMP AIR MONITORING PROGRAM
1. INTRODUCTION
Early in the execution of the CHESS prop-am iu 19G9, a number of
start members in the air quality measurements organization of EPA
' Nitlooil Atromttrlc Do to Bank.
77-590—70 - 1
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42
decided it was desirable, indeed imperative, to improve the efficiency
find accuracy of short-term air Quality duta monitoring coverage.
EPA coined the term CHAMP (Community Health Air_Monitoring
Program) for this concept of a second generation automatic system of
nir monitoring stations. Seven prototype stations were operated in
California from January, 1972 to February 1974. The manpower
ceiling placed on EPA resulted in a decision to contract for the devel-
opment, installation, and operation of the CHAMP system. A con-
tract for the development of the CHAMP system was awarded in
February, 1973. The developmental monitoring system was to contain
the newest technology in monitoring instrumcntotion. Accurate
measurement of all critical air and liquid flows in the system was
incorporated to enhance the accuracy of the system. The development
continued to mid 1974 when the first station systems were installed
in the Los Angeles area for field evaluation.
2. BTSTEM DESCRIPTION
The CHAMP air quality measurement system assembles the avail-
able discrete pollutant measurement devices and associated meteor-
ological instruments into a complete svstem in an air-conditioned
portable building. EPA specified the pollutants to be measured and
selected the instruments with the advice of the CHAMP contractor.
All data are recorded digitally in a mini-computer integral to each
Rvstem. The data are checked and stored on tape nt each CHAMP
site for transmittal to the EPA/RTP Laboratory nt Durham, North
Carolina. SO; and NOj, nnd TSP measurements" are also taken peri-
odically using older CHESS-type bubblers and Hi-Vol sampler
instruments described previously for backup and validation of the
CHAMP instruments. These bubbler and filter samples are sent to
the contractor's chemical laboratory in California for analysis.
All the CHAMP systems measure ozone, total gaseous sulphur
NO/N02, TSP./RSP combinations, temperature, wind direction and
velocity, and humidity. Selected systems also incorporate CO nnd hv-
drocarbon sampling. The CHAMP system while automatic in principle,
requires periodic calibration and servicing by an operator to maintain
a high duty factor and an acceptable quality of data (less than 15%
error band). The operator repairs and adjusts instruments as required,
checks for failures, and does periodic calibrations and data verifica-
tions. A quality assurance specialist continually spot-monitors the
CHAMP sites carrying-out calibration and quality checks.
It should be noted that the instrumentation of the CHAMP
stations is not completely uniform. Some stations do not have wind and
pressure instruments; not all have CO and hydrocarbon instruments.
The manner in which meteorological data from the CHAMP stations
is being analyzed and used has not been investigated. This is a subject
of interest depending on the future of the CHAMP program.
CHAMP stations were visited in Thousand Oaks, California, nnd
Salt Lake City, Mugnn. nnd Kenrns, Utah. The kind of meteorological
instruments in u«e appeared to be appropriate nnd they appear to b
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43
There nrc at present 18 CHAMP stations on line at locations se-
lected by EPA; six in the Los Angles Basin, three in Birmingham,
Alabama, four in New York City,'four in the Salt Lake Valley, and
one at the EPA Health Effects Research Laboratory at Research
Triangle Park, North Carolina.
8. FINDINGS REGARDING THE CHAMP PROGBAM
As in the CHESS program, all the instruments incorporated in the
CHAMP station were developed by the manufacturer for laboratory
use. In fact, some non-commercial instruments were selected by EPA
to try to use the most advanced technology. The CHESS experience
has demonstrated the need for validation in field use and the con-
tractor appears to be attempting to do this.
There was apparently some attempt to standardize on one instru-
ment manufacturer for ease of maintenance, etc. Bcndix ozone and
NOE instruments were employed. Flame photometric measurement
was selected for S03 EPA apparently was interested in a pulsed
flouresccnce device but the equipment cost was too high for the budget.
The present instrument actually measures total gaseous sulphur and
it is assumed that this is SOj. (The onlv other likely gaseous sulfur
compound H2S, does not seem to be widely present.) The rest of the
measurements appear to be well-validated. The backup measurement
with bubbler methods have validated N02, to the extent possible.
The TSP/Hi-Vol measurements were apparently validated at the
beginning of the CHAMP program. However, because of the non-
linear calibration character of the flame photometric instrument in
the low concentration ranges of interest from 0 to 50 jig/M3, calibra-
tion and range setting by the operator still results in 5% to 159c
range of uncertainty in the total sulphur readings. Further, while the
"U'cst-Gacke bubblers used to check CHAMP S02 are stored at 70°
F at the sites, they are shipped to the contractor's facilities for analysis
without temperature control and are subject to the unpredictable
temperature dependent decay of solutions prior to analysis. Thus, the
SO; validation in the CHAMP sj'stem may be in greater error than
EPA expects.
The execution of the CHAMP program has yielded validation
and quality control of field measurements better than CHESS. How-
ever, there arc clearly numerous unresolved problems with the opera-
tion which have led to delays in validating the data bank and which
require high level attention for resolution ocfore reliable quantitative
aeromelric dnta can be obtained.
The data processing was 2,900 data-days behind at the time of this
investigation and no date agreed on for total backlog elimination.
Drift of zero selling and data span of instruments have invalidated
pnrt of the earlier analyses. The data are only about GO percent
machine validated. Field operator problems have arisen possibly due,
in part, to a lack of standardized operating procedures. Successful
operation of the CHAMP system requires well-trained instrument
technicians, and peoplo of tlus high level of skill have not beeu em-
ployed in the past. Because of such circumstances, the S0: data
obtained through 1975 have been lost and apparently are uot
recoverable.
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Some months npo EPA fouml that Mfrnificnnl data were lost in
Irnusmitting over leased lines lo the RTF Inhorntory. Thus, the
primary data source is the datu tapes from the CHAMP site computer
which are mailed to RTF.
The CHAMP contract is up for renewal in November 197C and the
bids are beins solicited competitively. It is believed that nt this time
competitive bidding could be n destabilizing step iu this program nnd
could delay the achievement of reliable routine d:;ta gathering another
year. On the other hnnd there nre obvious advantages to open com-
petitive bidding. When system development is more nearly complete,
it would certainly be appropriate for competitive bidding to be
adopted. The competition should include quality control considera-
tions. Unfortunately, the EPA quality n-surnncc group was not
consulted on the renewal request for proposal, although that group did
participate in evaluating proposals received.
4. SUMMARY
CHAMP appears to be an improvement in real time field measure-
ment of air pollutants in comparison with CHESS. However, the
system is still not completely validated and may not be ready for
routine use for 6 to 12 months. Data should not be stored in an ac-
cessible data bank until it is validated.
The present best estimate of expected accuracy is ±15 to 20^o on
the CHAMP measurements. However, this will be a significant im-
provement over previous CHESS oerometric network mesuremcnt
systems when and if it is realized.
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Section V of the 1976 Congressional
Investigative Report (IR) concerning
CHESS air quality analyses procedures
and results is as follows;
V. REVIEW OF CHESS AIR QUALITY ANALYSIS
PROCEDURES AND RESULTS
A. INTRODUCTION
This chopter presents the results of the investigative team's critical
review of the utilization of neromctric data in the analysis and data
modeling presented in the CHESS Monograph. The citations to
pages, fipures and paragraph numbers nre to the 1974 CHESS Mono-
prnph. The findings nre highlighted in terms of examples wherein
it appears that estimates have been extended beyond the range of
credibility, model* hnve been misused, or miscellaneous errors of
vnrious types have occurred which lend lo misinterpretation or over-
interpretation of data or results of analyses.
B. USE OF ESTIMATED DATA
A serious weakness in the CHESS study was acknowledged in the
Inst paragraph on page 7-9, which refers to the Salt Lake Basin stud}-
nnd the Rocky Mountain stud}'. It is in part:
Severn! factors should be remembered when interpreting the results of the
lower respiratory disease atudiei ... a majority of the pollution exposure
data in both studies were estimated from emissions data.
This statement applies to one of the most important And contro-
versial paragraphs in the CHESS report, also on page 7-9, which
follows:
It is interesting to note th.it larcer increases in total lower respiratory disease
nnd two nf its component* were observed in the High pollution community of
the Salt Lake Basin study thr\n in the corresponding communities in the Rocky
Mountain studv. Also, the mcnn annual suspended sulfate concentration was
higher in the High pollution community in the Salt Lake Basin study than in
the Rocky Mountain study; the opposite was true for sulfur dioxide. This suggests
that increases in lower respiratory disease frequency are probably associated
with suspended sulfatej rather than sulfur dioxide.
The paragraph summarizes the argument that exposure to sus-
Eended sulfates over a period of years produces significant adverse
ealtb effects.
Analysis of the background material leading to the conclusion
shows that it is derived from an interpretation of the relationship of
four numbers all of which are estimated values. The sulfur dioxide
values' are estimated from smelter emissions and the sulfate values
nre estimated from estimates of sulfur dioxide in one case and esti-
mates of suspended pnrticulate based on smelter emissions in the
other, assuming no difference in the ratio of sulfate to suspended
particulate in the communities, Kellog" Idaho; Helena-East Helena
nnd Anaconda, Montana; and Magna, Utah.
The "High pollution community"of the Salt Lake Basin" is Mngna,
Utah. It is less clear what is meant by the words "than in the Rocky
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46
Mountain study". However, this parngraph refers to the preceding
pnrngrapb of the CUESb report, which spooks of concentrations, "us
Tow as 7.2 ng/m' in the Rocky Mountain Study".
From this it cnn be concluded that reference is being made to con-
centrations of sulfates in Anaconda, Monlnnn.
A comparison is being made, therefore, between average sulfur
dioxide concentrntions nnd average sulfute concentrations in Mnpnn.
aud Anaconda. The period of the records being compared covers the
yenrs 196S-1S70.
From the preceding paragraph the values being compared may be
obtained. They nre os follows:
(Th> conccntutiofl v»lu«i iri |ivtn in microi'imt per cubic m»l«r. written it *\J-n'-\
Sulfur
Mifni [[[ ?? li 0
Anicondi [[[ 177 ~i.l
Because of the methods used for making estimates, the nb-oUifc
values of these concentrations arc questionable. The next four section-
discuss these estimates.
1. ESTIMATED SULFUR DIOXIDE COXCEXTIIATIOX, 92 fiG/M* (MACNA)
The concentration value 92 ^g/m5 for Mairnn can be obtained from
Table 2.1.A.14 or Table 2.1. A. 10. It is bused on the following (siimaU'
1970 ........................ „ ........................... 64
lyes
Average go
Thesp estimates of annual sulfur dioxide exposures wero derived l,v
multiplying the yciirly smelter emission for sulfur dioxide by the ratio
of the 1971 measured tinmml average sulfur dioxide cou'centrution
(61.8 Aicr/m3) to the same year's sulfur dioxide emission rn.te (103 tons'
day). The last chapter established that these data could be oft' by
100 percent, probably on the low side.
61.8/193 =.320 (Mg/mJ)/(tons/dny)
The emission rates used were ns follows (page 2-37):l
Year:
1970
1909
19CS
Tanil
ti-
(SO,)
T.I
"OO
2S1
In order to obtain the estimated sulfur dioxide concentrations, it
must be first assumed that the meteorological conditions for each of
the years 19CS, 1909 nnd 1970, were identical to those conditions in
1 Tlir:c ralci of fmlwion »re off hy t factor of two. Tons of sulfur, no- 'ons of sulfur •Jit>\idi>. art li>t»'l
Th*;r ralurs corrccinl ihnulJ h» 52.'. 6H m-| V>2 Innn.M^v. llowcvfr. this d"r? not chin:.' t">c vinnivci of
tulfur dloxl't*- concriurniions. which "Irjwnrt on .1 mi" l^'.«rcn rnfi^ur*'!! I'd conctMuradons »nd I'-Tl
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47
1971. There was no pro-cntaiion, in tlie Monograph of the u«c of
climntolopicul data to show that 1071 was i-iinilar to the other vonrs,
an average ycnr, or a generally representnlivc year. Even If the
mctcorologinil condition* for nil four years had be'cn identicn), there
H still a problem because the yenr 197-1, on which the estimates ore
based is not n normal year for smelter operations. Emi^ions were
zero, or practically zero for two weeks dining July, and nearly zero
for FIN weeks in July nnd August. Therefore, the emi?sion,'coiicentrn-
tion ratio is deficient in showing the effects of the summer sermon,
•when wind direction frequencies from the smelter to Mnpm might
hnvc been less thnn during the remoinder of the year. This sug^e^
tlmt the average concentration of sulfur dioxide in Mngnn is likely to
have been slightly over-estimated, but it supports rather than changes
the conclusion that nveragc concentrations of sulfur dioxide nre Ic-^
in Magna than in Anaconda. Primarily this estimate is criticized
because it is not supported by clhnatologicul information.
Also it should be realized that the method used for estimating the
annual average concentration can result in nn incorrect estimate if
there is a significant background of sulfur dioxide from a source or
sources other than the smelter. Multiplying the emission rnte of the
smelter by a factor assumes that all individual observational values
that make up the annual average can be multiplied by this same factor,
when actually only those values totr.lly resulting "from the smelfr
emissions would be effected. The Salt Lake City airport wind ro^c
(Figure 2.1.2) is probably not representative "for estimating the
percentage of time that Mngna is downwind from the smelter because
the smelter stack is at the base of the Oquirrh mountain range.
However, the frequency of west northwest and northwest winds at
the airport suegest that Magna. is only downwind about 5C,'0
of the time. Allowing for the effect of calm and variable winds, it
seems unlikely that Mogna would be under the influence of the
smelter more than 10% of the time. It follows then, sulfur dioxide
values for only these hours would be affected. On the other hand,
if the smelter is the only significant source of sulfur dioxide, a* inny
be the case, then multiplying individual observation values of zero
concentration would yield only zero, and the procedure for estimating
yields a true result, assuming no change in meteorological or emission
conditions. Since the sulfur dioxide background in Magna is not
known, the error that could be produced by background concentra-
tions cannot be determined. Probably most of the sulfur dioxide
does come from the smelter, so this source of error is not significant.
2. ESTIMATED SULFUn DIOXIDE CONCENTRATION, 177 Mg/m' (ANACONDA)
A paragraph in the right hand column of page 3-12 explains how the
averaze concentration of 177 jijr/m1 for sulfur dioxide was estimated
for Anaconda for the period 19GS-70 using sulfation plate data and
emission rates. However, the explanation is incomplete, because it
requires the 1971 emission rate of tho smelter, which has been omitted
from the Monograph. Thus, the validity of the entire procedure is im-
possible to verify. Table 3.1.2., wbich lists the emission rate? by year
begins with the year 1970. The ratio of 0.343±.233 (jig,ms)/(ton day)
was obtained by a very dubious procedure. To begin with, sulfiition
plate data are'of somewhat uncertain nature. The document "Air
-------
48
Quality Criteria for Sulfur Oxides", U.S. Department of Health, Educa-
tion and Welfare, Public Health Service, National Air Pollution Con-
trol Administration, Washington, D.C., January, 1969, pp 24-25
snys th.H sulfation "candles" (and plates) give only "an empirical
estimate of the average concentration". It also says "results are influ-
enced by wind movement and humidity" and that "the lead peroxide
candle provides intelligence on the oxidiznble sulfur compounds in
the atmosphere which seldom can be directly related to iulfur
dioxide".
The CHESS Monograph paragraphs refer to sulfotion plate data for
19C5. The sulfntion plate is a variation of the lead peroxide candle.
Developmental work on the plate was reported in the following
reference: Huey, N.A. "The Lend Peroxide Estimation of Sulfur
Dioxide Pollution" J. Air Pollution Control Association, Vol. 18,
pp 010-611, Sept. 19CS. Consequently it is unlikely that sulfatiou
plates were in use in Anuconda in 1965.*
In order to determine sulfur dioxide from a lead peroxide candle or
plate nn empirical relationship must be used. For example, in the
Helena Valley, Montana, Area Environmental Study, (EPA, Office
of Air Programs, Research Triangle Park, North Carolina, January
1972) the sulfation values were converted to sulfur dioxide values by
means of the relationship: 1 mg S0} per 100 cm* per day is equivalent
to 0.035 ppin ?O2. In the history of the use of lead peroxide devices,
there has not been general agreement as to what ratio should be
used, nnd a belief prevails that sulfation condle or plate data ore
conservative, i.e., that sulfur dioxide concentrations arc sometimes
higher than indicated. Further, more information is needed concerning
the location of the station, or stations, in the Anaconda area, where
the sulfation data were obtained. In order to validate the Anaconda
sulfur dioxide data further work needs to be done.
In 1965 the annual average concentration of sulfur dioxide was
reported to be SO jig/in3 with an emi*sion rate of 609 tons/day. Since
the 1971 emission rate is omitted from the report it cannot be compared
with the corresponding concentration of 2SG jig/m1. Assuming that
the 1971 emission rate is also on the order of COO-700 tons/day, then
there seems to be too great a dilTerence between the 80 Mg;m5 con-
centration and the 2S6 jig/m1 concentration. (Center paragraph, right
hand side, page 3-12.)J
The ratio 0.343±.253 has n Inrge error factor. The range is from
.090 to .597. If the low value is multiplied by the emissions for the
years 196S-1970, the following concentrations are obtained:
IToru per diy]
Table 31.? New Ttlu»
Ycu (SOi) Montint
IOT1 Omitted
l-.i MS *.<
15f* ... 117 (tj
11167 " 148 44'J
NOTE.—The nmiuion n( the 1771 »mi«Jon rite? m>Lu It Impossible to check tU« effect o( us>n( the
new T&lue for 1971 on the esiirotleJ emiuon rtlei.
•Tli» rhunlrnl rcartlon for "rnnill«" ind "plntcs" li tbt .
tArrorrtlnt 10 Inlormalion rrcfutly rrrrivrd from ihft Mnniint sine O'pirincil of Dtl'.lb»nd EnTiron-
mtnlal Sclrnr'i, the emlulon rates lined lor tb« Antcondt imeller are low.
-------
49
Y«lr
IJ70 _
1959
IK!
SO] (miuioni onccitilt'Oii
(tent fw t»i) Ul"1')
_ |J5
. . Ml,
_ . |67
$7
The average of these values is 46 :g.'ms (MAGNA)
The 15 Mg/m3 estimate is a double estimate since the sulfur dioxide
concentration data on which it is based is also estimated. The sulfate
value seems to be an average for the years 196S-1970. It i.s obtained
by using the following regression equation, which is found on page
2—39
Magna-SS=O.C9(SOj)-i-G.66
This equation is based on 1971 condition*:.
It is of interest to note that with a zero concentration of sulfur
dioxide there would still be 6.66 pg/m3 of sulfate, or approximately
half the average annual value reported on 1971, which was 12.4 yirTn1
Further, 44%'of the 15 Mg/m3 of interest for the years 10GS-1970 is
\inrelatcd to sulfur dioxide concentration^. The Figures 2.4.2 and
2.4.4 suggest some lack of complete con-elation between sulfur dioxide
and sulfate concentrations.
During the strike with zero sulfur dioxide concentrations, there
still is an appreciable amount of suspended sulfate. Also, a peak
value of sulfate occurred during the third week that docs not corre-
spond with sulfur dioxide value behavior during the same period.
Similarly, the very large rise in sulfur dioxide that peaked in the
ninth week hardly shows in the sulfate values. Consequently, the
regression equation can be questioned because the reason for the
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50
sulfate values is not understood. What is the physical source of the
sulfates?
Since the sulfur dioxide concentrations used in the regression equa-
tion are themselves estimated, uncertainties in the sulfur dioxide
estimates are compounded in the sulfate estimates. Further, *ince the
source of a considerable amount of the sulfate seems to be not associ-
ated with the sulfur dioxide, it is not clear what effect the strike period
has on the estimates.
The CHESS report lists the suspended sulfate concentration as
12.4 jjg/ni5 in 1971 and this is the basis for the estimate of 15 pg.'m'
for the 196S-1970 period. Observations of sulfate in Magna area
subsequent to 1971 support the argument that average annual con-
centrations are in the neighborhood of 15 yg/m3, or that they are sig-
nificantly higher than reported for Annconda.
On page 2-79, in Table 2.4.1, it may be noted that suspended sulfate
values for the High communitv do not follow the sulfur dioxide con-
centrations, particularly for tfie Spring and Summer. Tlu's raises a
3uestion about using sulfur dioxide as an indicator of sulfatc, cs was
one with the regression equation on page 2-39. (Median values for
the High community are: Sulfur dioxide, Spring 64, Summer 9, whereas
for suspended sulfate they are 8 and 7, respectively.)
Wind blowing from the smelter stack to Magna would generally
cross a portion of the Great Salt Lake and, therefore, might carry
more moisture, thereby facilitating the conversion of sulfur dioxide
to sulfate. Perhaps this mechanism helps to account for the high
sulfate concentrations observed in Magna.
4. ESTIMATED SUSPENDED SULFATE CONCENTRATION, 7.2 Jlg/mS
(ANACONDA)
The 7.2 Mg/m1 suspended sulfate value can be obtained from
Table 3.1.7, page 3-12, by taking an average of sulfate values for
three years, as Follows:
Year: •*/">'
1970 8.9
1969 7.6
1968 5. 1
Average 7. 2
These sulfate values are estimates, based on estimates of total sus-
pended particulate and an estimate of the ratio of suspended sulfate
concentration to total suspended particulate concentration, based on
results from East Helena and Helena, Montana, and Magna, Utah.
The same procedure was used for Kellogg, Idaho.
On page 3-11, in an attempt to explain how the suspended sulfate
estimates were made for Kellogg, it i> stated that "Data observed for
Magna during the period January 1971-June 1972 indicated an average
ratio of suspended sulfate concentration to total suspended piu-
ticulute of 0.159." Following this is the reference number "22," re-
ferring to National Air Pollution Control Administration Publication
No. AP-61, "Characteristics of Particulote Patterns 1957-1960."
This publication presents graphs of suspended particulate concentra-
tions for various cities over a ton year period. In it, suspended sulfates
are not mentioned, the time penod is wrong, and there are no data
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51
for Mag-na; therefore, it must be concluded that the reference is an
error.
An obvious reference for this paper would have been tH/> paper bv
Marvin B. Hertz, et al., "Human Exposure to Air Pollution in Saft
Lake Communities, 1940-1971," however, it is not referenced. Perhaps
this was tho reference intended. Even so, the ratio 0.159 caunot be
obtained from the Hertz paper.
In the Hertz paper, page 2-11, Table 2.1.2, which giro CHESS
1971 Annual Averages lor Magna, the suspended sulfate concentra-
tion is 0.6 M?/rns and the total suspended particulate concentration
is 53.9, which gives a ratio of 0.178. In Tables 2.1.5 and 2.1.A.16, the
following concentrations are given: TSP, 66 Mg/m1, SS, 12.4 it%!m3.
Here the ratio is 0.188. Other ratios can be determined for various
time periods from Tables 2.1.A.4 and 2.1.A.5, but none of the^e is
0.159.
Note (page 3-11) that the unexplained ratio 0.159 for Magna is
used with the 0.063 ratio for East Helena to obtain the ratio 0.111
plus or minus 0.057 that is used to estimate suspended sulfate con-
centrations for Kellogg, and the 0.11 plus or minus 0.06 ratio for
Anaconda (page 3-13).
(Pages 3-8 and 3-9) Particulate emissions for East Helena are given
in two tables on pages that face each other. The headings of the second
column in Table 3.1.4 should be "Emissions, Tons/year," not "Emis-
sions, Tons/day."
On page 3-7 it is stated that estimates of stack emissions for both
particulate and sulfur dioxide for East Helena for the years 1941-1070
were provided by Asarco. Presumably the data in "Table 3.1.3 are
Asarco data. The source of the data in Tnble 3.1.4 is not stated.
The Office of Air Programs Publication No. AP-91, Helena Valley,
Montana, Area Environmental Pollution Study, give* more informa-
tion about the industrial complex at East Helena. This study was
conducted during the period June. .10.69 through June 1970. The
table below is from this study.
[MISSIONS FROM CAST HELENA INDUSTRIAl COMPLEX
|Tom f»r tfjy|
[Million:
Comptnyandoptntion JOi production firUulitei production
KtduCKJ Normal Hjiimom Rrtucid Nofnul Minmum
Awco:
Sintering
Subtotal ...__ __—.
Antcondi:
Miuillintout.4 —
Subtotil
AmtrlonChtmct: Pi|m«nt production.
Tolil
114 C
I 4
C)
193 0
13.0
C)
1) 0
C)
206.0
315 6
U 6
(i)
330 2
13.0
0)
13 0
C)
143 2
355 1
Z3 2
(i)
17! 3
13.0
C)
13 0
C)
191.3
0.1
C)
(*)
.3
o
1.0
1.0
C)
1.3
0.5
<')
(i)
.5
P)
1.0
1.0
0)
1.5
6.54-
(')
C)
.SJ-
o
1.0
1.0
<')
1.5 +
I Tht ouUidi llcujj* of conctntritei conl-ibuttt I iiinficint but undfttimintd I mount of pirliculclti.
1 Cmiiiioni ftfso ocrur during thf ill; cr-.*'6
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52
It may be noted that ASARCO is only one of several purticu-
late sources for the East Helena area. Fuming and other sh>g
processing activities of the Anaconda Co. ore estimated to produce
1.0 tons per day of participates, resulting in a normal total of 1.0tons
per day, not a rate in the neighborhood of 0.3 tons per day as Table
3.1.3 suggests. Further, the total normal sulfur dioxide cmf^ion
rate in the preceding table is 343.2 tons per day, a considerably
higher rate than is given in Table 3.1.2. (i.e., 1969: 221 tons/day;
1970: 239 tons/day).
On page 3-7, right hand side, is given an explanation of how the
data in Table 3.1.4 were used to ootain a ratio of total suspended
participate concentration to tons of participate emitted per any for
East Helena. However, after giving this explanation, the eUimntPs
of TSP in Table 3.1.5, that were used to make the suspended sulfatc
estimates were not obtained by means of this ratio. They seem to
have been obtained from the particulate emission data in Table 3.1.3,
using the factor 3S3.22 (^g/m')/(tons/dny). The derivation of this
factor is not explained. Tin: ratio thnt is explained never seems to
have been used. The suspended sulfate estimates are obtained by
multiplying the total suspended particulate concentrations by the
factor 0.063, which is explained on page 3-8.
Both observed and estimated suspended participate concentrations
are given in Table 3.1.4 and 3.1.5. It may be noted that the estimated
TSP values are used to estimate the suspended sulfate concentrations
and not the observed values for the years 1966 through Ift69. In
1966, the observed value was 87 ng/m3, whereas the estimated value
is 114.2 >ig/m'. No explanation is given for rejecting the observed
values.
Data for Magna during the period January 1971-June 1972 indi-
cated an average ratio of suspended sulfate concentration to total
suspended particulate of 0.159. The available data for East Helena
indicated a suspended sulfate to total suspended particulate ratio
of 0.063±0.022 jig/m3. For Kellogg, the assumption has been made.
that the ratio of suspended sulfate to total suspended paniculate
is the average of these values, or 0.111 ±0.057. For Anaconda, this
value was rounded to 0.11 ±0.00. It is multiplied by the estimated
concentrations of total suspended particulate listed in Table 3.1.7,
to obtain the suspended sulfate values for enrh year.
The following table has been prepared from the Helena Valley
study, June through October 1969.
Slilion
1
2
3
4 .
Avtrije
Loctlion
Dffrtti
]4
|05
11?
274
i
Milts
0 1
2 i
4
4 5
Mfticulitt
1D8
74
19
62
76
lulfile
3 S
3 7
4.4
2.9
3.4
Rltio
0 T32
.C5
.Ot9
.C-7
.OiD
I With rtiprct Id Iht imtller itjck.
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53
The data from station1; I and 3, the stations nearest the stack, were
used to obtain a ratio range (6.037, pages 3-8), but for some curious
reason the available ratios from the Helena Valley study were not
used. The average ratio for stations 1 and 3 is 0.051.
The ratio chosen for Enit Helena, 0.063 plus or minus OU22 Gig/m1)/
Gig/m3), is not significantly different from that which might have been
obtained had more use baen made of the Helena Valley study, but
there is no basis for the assumption that the ratio of suspended sulfate
to suspended particulate is similar in Magna, East Heleat, Helena,
and Anaconda.
The dubious nature of using suspended particulate concentrations
to estimate suspended sulfate can be seen by comparing Figures 2.4.3
and 2.4.4. In the Low Exposure Community, the sulfate level remains
low and nearly constant wlu'le the suspended particulate concentra-
tions fluctuate.
In the High Exposure Community, the highest concentration of
suspended particulate occurred on the fourth week whereas the peak
suliate value occurred on the third week. On the fourth week, sulfate
levels dropped. A corresponding drop in the sulfate levels does not
occur until the fifth week. Only during the last seven or eight weeks
do suspended particulate and suspended sulfate concentrations
fluctuate together. There may be some situations where suspended
5articulate and suspended sulfate concentrations are well correlated.
ustification for assuming correlation in the Salt Lake Basin and the
Rocky Mountain communities is inadequately supported by scientific
evidence presented in the CHESS Monograph.
Further, the 7.2 Mg/m3 suspended sulfate estimate for Anaconda is
based on an estimate that comes from another estimate of suspended
particulnte values based on rates of emission from the smelter. During
the period 1961-1962, the annual total suspended particulate concen-
tration was found to be 84.5 Mg/m'. In 1971, the average suspended
particulate level was observed to be 52 »jg/m3. By comparing the
observed total suspended particulate concentration with the por-
ticulate emitted from the Anaconda plant, a ratio of 9.1±2.3 (Mg/m3)/
(ton/dnv) was determined. This rntio was multiplied by the particu-
lnte emission for Anaconda shown in Table 3.1.3 to estimate the total
suspended particulate concentrations for the years 1940-1970. This
ratio cannot be actually obtained from the data presented in the report
because particulate emissions for the year 1971 are not given, i.e.,
they ore not listed in Table 3.1.3.
The basis for this ratio Is unfounded since there are sources for the
suspended particulate other than the smelter emissions.
Although there are no actual sulfate observations from the Ana-
conda area included in the CHESS report there are some actual
observations of suspended sulfate versus total suspended particulate
available for the year 1971, that were obtained from the Montana
State Department of Health and Environmental Sciences. These
suggest that annual average suspended sulfate levels in Anaconda are
in the neighborhood of 4 or 5 jig/m3, even less &m tne estimated
value (7.2 Mg/m3).
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64
There are also pronounced seasonal effects, with much higher values
in winter than in summer. The months of February ana April had
values of 7 and 9 Mg/m1 whereas the months of July and August have
values of less than 1 ug/m5. Local heating emissions and relative humid-
ity may be significant factors determining the measured concentra-
tion as well as the smelter emissions.
6. ESTIMATES OF SUSPENDED PARTICULATE, SALT LAKE BAEI.V BTUDY
On page 2-23 it is stated that "the number of sulfric acid plants
utilizing sulfur recovered from emissions have increased from one in
1940 to seven in 1971, and that air pollution control device? in the
form of baghouses, scrubbers, cvcloues, and mist eliminators have
been installed. Such changes in the smelter operations would greatly
effect the ratio of suspended particulate to tons of copper produced.
Therefore, aside from the fact that there would be differences from
year to year because of meteorology, the procedure described in the
first paragraph, right band column, pngc 2-24, for estimating sus-
pended particulate from copper production in tons for 1971, is highly
questionable.
$. ESTIMATES IN THE CH1GACO AND NEW TORK STUDIES
In the Chicago and New York studies suspended sulfate concen-
trations were estimated from suspended particulate concentrations.
In Chicago, the estimates were used to fill in data for some years when
no data were available. In the New York study measured values for
suspended sulfates for 1956-1970 were available from the Manhattan
121st Street station, and these values were used as citywide values.
The observed annual ratios of suspended sulfate to dustfall for New
York City were used to estimate the suspended sulfate levels in Queens
and Bronx. In Table 5.3.1 suspended sulfate levels for the Low Com-
munity (Riverhead) are listed as about 10 jig/m1 for the years 1961
through 1970. The basis for this estimate is not given, although it was
probably determined from the 1971 concentration, which was 10.2
fg/m3.
In summary, it appears that some values, on which are based
important conclusions that sulfates may be harmful to health, are
estimated values.
C. USE OF MATHEMATICAL DISPERSION MODELS
The dispersion model shown in Figure 2.1.16 is incorrectly applied.
It was used in the Salt Lake Bnsin study to determine sulfur dioxide
contours around the smelter source and to show that annual exposure
estimates obtained from the ratio of 1971 observed nir quality to
1971 emissions were not unreasonably high or low. First, the contours
arc incorrect because the model used does not take into account the
elevation of the terrain and the wind direction frequencies for the
Salt Lake City airport, which were used are different from those
affecting the smelter plume, which originates at the base of the
Oquirrh Mountains. Second, n dispersion model is based on numerous
assumptions and applied in this way might be off by a factor of two,
or more. It does not make sense to use a model to check observations.
-------
55
The usual npplicntion is to ,opply observational data to calibrnte,
or verify, a model. A model such as the one used might have been
applied to show some sort of relative distribution of concentrations
across the Salt Luke Volley, however, it should not hav£ been used
to justify estimates of concentrations over the period^940-1970.
(See Tables 2.1.A.14 and 2.1.A.16). Further, during this review of the
CHESS report it wns discovered that smelter emissions used for the
model estimates were tons of sulfur, not tons of sulfur dioxide. There-
fore, the model estimate is only half what it should have b^£pn Doub-
ling the emission rate and reducing the wind direction frequency
somewhat with respect to Magna might result in an estimated con-
centration near that measured, which was 61 Mg/™3.
Apparently the dispersion model wns run only once and then the
ratio between the emission at the smelter for 1971 and the calculated
concentration was applied to emission values for the other years in
order to obtnin the other listed concentrations in the column headed
"Diffusion Model". No nccount is taken of the fact that meteorological
conditions, or perhaps stack conditions, were not the same for all
yenrs. More information should have been included in this report on
exactly whnt meteorological data were used in the model. The model
requires the use of the STAR program, which is obtained from the
National Climate Center. Frequently the results of running this
program ore based on data for the year 1904, which is the only ycnr
when wind directions were punclW on data cards to the nearest 10
degrees each hour rather than each 3-hours. Therefore, the model is
likely to have incorporated meteorological data for some year other
than 1971, the year of the emission data. No attempts is made to
show that the year for period) of the meteorological data is average,
good or bod. Similarly there is no attempt to show that 1971 was an
average yenr, yet all of the estimates are based on this assumption.
Considering how the model estimates for the yenrs 1940-1970 were
obtained it is misleading to include them in the table, and they serve
little purpose since the ratio for the year 1970 is repented throughout.
On page 2-43, bottom of right hand column, trie following state-
ments appear: "Estimates of sulfur dioxide, total suspended partic-
ulates, and suspended sulfate concentrations in the High exposure
community for 1940-1970 and the Intermediate II exposure com-
munity for 1950-1970 were obtained by a mathematical dispersion
model, which utilized emissions from the industrial source nnd exten-
sive local meteorological diUa, and by observed relationships among
pollutants. Observed suspended pnrticulate, suspended sulfate, and
sulfur dioxide concentrations for 1970-1971 were used to calibrate the
models used to estimate exposure levels for previous yenrs." Tlu's is an
overstatement. The estimates were obtained from simple rntios and
the application of ft regression equation. See page 2-39. The model
was pnJy applied once to demonstrate that annual exposure estimates
obtained from a ratio were not unreasonably high or low.
In the Chicago study, another attempt was made to apply a dis-
persion model (Figure 4.1.10). This model pives a false picture of
pollution conditions that prevailed in the study area because it is
based only on pollution sources within the city limits of Chicago,
omitting effects of adjoining large industrial sources in Indiana and of
some suburban communities to the southwest of the Loop area, which
have considerable air pollution.
-------
56
Mnps recently published by the Chicago Deportment of Environ-
ment Control, for the years 1970 and 1975 clearly show that pollution
concentrations are not simply Concentric around the urban core fts
the model indicates.
On page 4-8, it is stated Measured data from the City netwprk,
from which the exposure estimates were made, were best supported
by the Mitre model. It is not clear why a greater use was not made of
the available actual measurements instead of the model estimates.
Also, it is not sufficiently clear why the model happens to be for the
year 1968.
-------
SUMMARY ASSESSMENT—METEOROLOGY AND POLLUTION MEASURES
The Investigative Report (1976, 99-102) cited the following
problems with the environmental measures:
1. superficial and perfunctory treatment of meteorological
information;
2. insufficient exploration of possible relationships between
meteorological conditions and asthma attack rates;
3. failure to consider peak and episode concentrations;
4. use of a single monitoring station to determine the exposure of
a community;
5. failure to establish similarity of exposure and stress factors
between communitites in the same study, excluding the exposure
to specific pollutants;
6. impreciseness of monitoring station locations;
7. inexact locations of residences of individuals studied.
-------
APPENDIX 14-B
ANALYSIS OF TEMPERATURE
EFFECTS ON MORTALITY
(Appendix materials to be inserted)
-------
APPENDIX 14-C
WHO TASK GROUP ON ENVIRONMENTAL
HEALTH CRITERIA FOR SULFUR OXIDES
AND SUSPENDED PARTICULATE MATTER
AND
TASK GROUP CONSIDERATION OF
HOLLAND REPORT
-------
WHO TASK GROUP ON ENVIRONMENTAL
HEALTH CRITERIA FOR SULFUR OXIDES
AND SUSPENDED PAR TICULA TE MA TTER
i O
I
Participants
Members"
Professor K. Biersteker, Medical Research Division, Municipal Health Department,
Rotterdam, Netherlands (Vice-Chairman).
Professor K. A. BuStueva, Department of Community Hygiene, Central Institute for
Advanced Medical Training, Moscow, USSR
Dr P. Camner, Department of Environmental Hygiene, The Karolinska Institute,
Stockholm, Sweden
Professor L. Friberg, Department of Environmental Hygiene, The Karolinska Institute,
Stockholm, Sweden (Chairman)
Mrs M. Fugas, Laboratory for Environmental Hygiene, Institute for Medical Research
and Occupational Health, Zagreb, Yugoslavia
Dr R. 1. M. Horton, Health Effects Research Laboratory, US Environmental Protection
Agency, Research Triangle Park, NC, USA
Professor S. Maziarka, National Institute of Hygiene, Warsaw, Poland
Dr B. Piinz, State Institute for Protection of Air Quality and Land Usage, Essen, Federal
Republic of Germany
Dr H. P. Ribeiro, Laboratory of Pulmonary Function, Santa Casa de Misericordia de Sao
Paulo, Sao Paulo, Brazil
Dr T. Suzuki, Institute of Public Health, Tokyo, Japan
Mr G. Verduyn, Institut d'Hygiene et d*Epidemiologie, Brussels, Belgium
Mr R. E. Waller, Medical Research Council, Air Pollution Unit, St Bartholomew's Hospital
Medical College, London, England (Rapporteur)
Mr D. A. Williams, Surveillance Division, Air Pollution Control Directorate, Environment
Canada, Ottawa, Ontario, Canada
Representative* of other Organizations
Mr J. Janczak, Environment and Housing Division, United Nations Economic Commission
for Europe, Geneva, Switzerland
Mr D. Larrf, Division of Geophysics, Global Pollution and Health, United Nations
Environmental Programme, Nairobi, Kenya
Dr D. Djordevic, Occupational Safety and Health Branch, International Labour Organisa-
tion, Geneva, Switzerland
Mr G. W, Kronebach, Technical Supporting Services Branch, World Meteorological
Organization, Geneva, Switzerland
Dr A. Berlin, Health Protection Directorate, Commission of the European Communities,
Luxembourg
Mr J. A. Bromley, Environmental Directorate, Organization for Economic Co-operation
and Development, Paris, France
Secretariat
Professor B. G. Ferris, Jr, Department of Physiology, Harvard University School of
Public Health, Boston, MA, USA (Temporary Adviser)
Dr Y. Hasegawa, Medical Officer, Control of Environmental Pollution and Hazards,
World Health Organization, Geneva, Switzerland (Secretary)
Dr H. W. de Koning, Scientist, Control of Environmental Pollution and Hazards, World
Health Organization, Geneva, Switzerland
Dr B. Marschall, Medical Officer, Occupational Health, World Health Organization,
Geneva, Switzerland
Dr R. Masironi, Scientist, Cardiovascular Diseases, World Health Organization, Geneva,
Switzerland
Dr S. I. Muravieva, Institute of Industrial Hygiene and Occupational Diseases, Academy
of Medical Sciences of the USSR, Moscow, USSR (Temporary Adviser)
Dr V. B. Vouk, Chief, Control of Enviromental Pollution and Hazards, World Health
Organization, Geneva, Switzerland
* Unable to attend:
Professor M. H. Wahdan, High Institute of Public Health, University of Alexandria,
Alexandria, Egypt
-------
o
I
ro
ENVIRONMENTAL HEALTH CRITERIA FOR SULFUR
OXIDES AND SUSPENDED PAR TICULA TE MA TTER
A WHO Task Group on Environmental Health Criteria for Sulfur Oxides
and Suspended Particulate Matter met in Geneva from 6 to 12 January 1976.
The meeting was opened by Dr B. H. Dieterich, Director, Division of Environ-
mental Health, who welcomed the participants and the representatives of
other international organizations on behalf of the Director-General. Dr
Dieterich briefly outlined the history and purpose of the WHO Environmental
Health Criteria Programme and the progress made in its implementation,
thanks to the active collaboration of WHO Member States and the support of
the United Nations Environment Programme (UNEP).
The Task Group reviewed and revised the second draft criteria document
and made an evaluation of the health risks from exposure to these substances.
The first and second drafts were prepared by Professor B. G. Ferris, Jr,
Harvard University School of Public Health, USA. The comments on which the
second draft was based were received from the national focal points collabora-
ting in the WHO Environmental Health Criteria Programme in Belgium,
Bulgaria, Canada, Czechoslovakia, the Federal Republic of Germany, Greece,
Japan, New Zealand, Poland, Sweden, USA, USSR and from the Food and
Agriculture Organization of the United Nations (FAO), the United Nations
Eduational Scientific and Cultural Organization (UNESCO), the United Nations
Industrial Development Organization (UNIDO), the World Meteorological
Organization (WMO), the International Atomic Energy Agency (IAEA), and the
Commission of European Communities (CEC). Comments were also received
from Professor H. Antweiler and Dr B. Prinz (Federal Republic of Germany),
Professor K. Biersteker and Dr R. van der Lende (Netherlands), Professor F.
Sawicki (Poland), and Professor W. W. Holland and Professor P. J. Lawther
(United Kingdom).
The collaboration of these national institutions, international organiza-
tions and individual experts is gratefully acknowledged. The Secretariat also
wishes to thank Professor B. G. Ferris,-Jr and Mr R.'E. Waller for their in-
valuable assistance in the final stages of the preparation of the document.
In view of the substantial amendments made to the document (particularly
within sections 2 to 5) since the meeting of the Task Group, a revised version
was circulated to all members in February 1978. At the same time, copies of
a newly-produced review of the health effects of particulate pollution (Holland
et al., in press), that had been submitted for consideration, were distributed
to the members. Comments were sought on the draft of the criteria docu-
ment itself, and on any amendments or additions considered necessary in
light of the new report. These comments, together with others received from
the International Petroleum Industry Environmental Conservation Association,
and the International Iron and Steel Institute, were then considered by "a
small group consisting of the Chairman of the Task Group meeting, the
Rapporteur and some members of the Secretariat^ The alterations suggested
(mainly within section 9) were circulated again to the original members of
the Task Group prior to publication.
The document has been based, primarily, on original publications listed in
the reference section. However, several recent reviews of health aspects of sulfur
oxides and suspended particulate matter have also been used including those
by Katz (1969), Committee on the Challenges of Modern Society (1971),
Organization for Economic Cooperation and Development (1965), Rail (1974),
Task Group on Lung Dynamics (1966), Task Group on Metal Accumulation
(1973), US Department of Health, Education and Welfare (1969a), US
Environmental Protection Agency (1974), World Health Organization (1976a),
and World Meteorological Organization (1974).
The purpose of this document is to review and evaluate available informa-
tion on the biological effects of sulfur oxides and suspended particulate
matter including suspended sulfates and sulfuric acid aerosols, and to provide
a scientific basis for decisions aimed at the protection of human health from
the adverse consequences of exposure to these substances in both occupational
and general environments. Although there are various routes of exposure,
such as inhalation, ingestion (World Health Organization, 1971, 1974) and
contact with skin, attention in this report has been concentrated upon the
effects of inhalation of these substances, since this is the most important
route of exposure. The discussion has also been limited to sulfur dioxide,
sulfur trioxide, sulfate ions, and particulate matter primarily resulting from
the combustion of fossil fuels. The sulfate ion has been considered in the
variety of forms in which it occurs in the atmosphere, e.g., sulfuric acid and
various sulfate salts.
The vast literature on these pollutants has been carefully evaluated and
selected according to its validity and relevance for assessing human exposure,
for understanding the mechanisms of the biological action of the pollutants
and for establishing environmental health criteria, i.e.,exposure-efTect/response
relationships in man. Environmental considerations haw been limited to
elucidating the pathways leading from the natural and man-made sources of
these substances to the sites of toxic action in the human organism. The non-
human targets (plants, animals, ecosystems) have not been considered unless
the effects of their contamination were judged to be of direct relevance to
human health. For similar reasons, much of the published information on the
effects of these pollutants on experimental animals has not been included.
Details concerning the WHO Environmental Health Criteria Programme
-------
GLOSSARY
AaDO.: Alveolar-arterial difference or gradient of the partial pressure of
oxygen. An overall measure of the efficiency of the lung as a gas ex-
changer. In healthy subjects, the gradient is 5 to 15 m Hg (torr).
A/PR/8 virus: A type of virus capable of causing influenza in laboratory
animals; also, A/PR/8/34.
Abscission: The process whereby leaves, leaflets, fruits, or other plant
parts become detached from the plant.
Absorption coefficient: A quantity which characterizes the attenuation with
distance of a beam of electromagnetic radiation (like light) in a substance
Absorption spectrum: The spectrum that results after any radiation has
passed through an absorbing substance.
Abstraction: Removal of some constituent of a substance or molecule.
Acetaldehyde: CH..CHO; an intermediate in yeast fermentation of car-
bohydrate anil in alcohol metabolism; also called acetic aldehyde,
etha1dehyde, ethana1.
Acetate rayon: A staple or filament fiber made by extrusion of cellulose
acetate. It is saponified by dilute alkali whereas viscose rayon remains
unchanged.
Acetylcholine: A naturally-occurring substance in the body which can
cause constriction of the bronchi in the lungs.
Acid: A substance that can donate hydrogen ions.
Acid dyes: A large group of synthetic coal tar-derived dyes which
produce bright shades in a wide color range. Low cost and ease
of application are features which make them the most widely used
dyes for wool. Also used on nylon. The term acid dye is derived
from their precipitation in an acid bath.
Acid mucopolysaccharide: A class of compounds composed of protein
and polysaccharide. Mucopolysaccharides comprise much of the
substance of connective tissue.
Acid phosphatase: An enzyme (EC 3.1.3.2) which catalyzes the disassociation
of phosphate (PO.) from a wide range of monoesters of orthophosphoric
acid. Acid phosphatase is active in an acidic pH range.
Acid rain: Rain having a pH less than 5.6, the minimum expected from
atmospheric CO..
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Acrolein: CH2=CHCHO; a volatile, flammable, oily liquid, giving off
irritant vapor. Strong irritant of skin and mucuous membranes. Also
called acrylic aldehyde, 2-propenal.
Acrylics (plastics): Plastics which are made from acrylic acid and are
light in weight, have great breakage resistance, and a lack of
odor and taste. Not resistant to scratching, burns, hot water,
alcohol or cleaning fluids. Examples include Lucite and Plexiglass.
Acrylics are thermoplastics and are softened by heat and hardened
Into definite shapes by cooling.
Acrylic fiber: The generic name of man-made fibers derived from acrylic
resins (minimum of 85 percent acrylonitrite units).
Actinic: A term applied to wavelengths of light too small to affect
one's sense of sight, such as ultraviolet.
Actinomycetes: Members of the genus Actinomyces; nonmotile, nonspore-
forming, anaerobic bacteria, including both soil-dwelling saprophytes
and disease-producing parasites.
Activation energy: The energy required to bring about a chemical reaction.
Acute respiratory disease: Respiratory infection, usually with rapid
onset and of short duration.
Acute toxicity: Any poisonous effect produced by a single short-term
exposure, that results in severe biological harm or death.
Acyl: Any organic radical or group that remains intact when an organic
acid forms an ester.
Adenoma: An ordinarily benign neoplasm (tumor) of epithelial tissue;
usually well circumscribed, tending to compress adjacent tissue rather
than infiltrating or invading.
Adenosine monophosphate (AMP): A nucleotide found amoung the hydrolysis
products of all nucleic acids; also called adenylic acid.
Adenosine triphosphatase (ATPase): An enzyme (EC 3.6.1.3) in muscle
and elsewhere that catalyzes the release of the high-energy, ter-
minal phosphate group of adenosine triphosphate.
Adrenalectomy: Removal of an adrenal gland. This gland is located near
or upon the kidney and is the site of origin of a number of hormones.
Adsorption: Adhesion of a thin layer of molecules to a liquid or solid sur-
face.
Advection: Horizontal flow of air at the surface or aloft; one of the
means by which heat 1s transferred from one region of the earth
to another.
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Aerodynamic diameter: Expression of aerodynamic behavior of an irregularly
shaped particle in terms of the diameter of a sphere of unit density
having identical aerodynamic behavior to the particle in question.
Aerosol: Solid particles or liquid droplets which are dispersed or sus-
pended in a gas.
Agglutination: The process by which suspended bacteria, cells or similar
particles adhere and form into clumps.
Airborne pathogen: A disease-causing microorganism which travels in the
air or on particles in the air.
Air pollutant: A substance present in the ambient atmosphere, resulting
from the activity of man or from natural processes, which may cause
damage to human health or welfare, the natural environment, or
materials or objects.
Airway conductance: Inverse of airway resistance.
Airway resistance (Rflw)' The pressure difference between the alveoli
and the mouth required to produce an air flow of 1 liter per second.
Alanine aminotransferase: An enzyme (EC 2.6.1.2) transferring amino
groups from L-alanine to 2-ketoglutarate. Also known as alanine
transaminase.
Albumin: A type of simple, water-soluble protein widely distributed
throughout animal tissues and fluids, particularly serum.
0
ii
Aldehyde: An organic compound characterized by the group -C-H.
Aldolase: An enzyme (EC 4.1.2.7) involved in metabolism of fructose
which catalyzes the formation of two 3-carbon intermediates in the
major pathway of carbohydrate metabolism.
Algal bloom: Sudden spurt in growth of algae which can affect water
quality adversely.
Alkali: A salt of sodium or potassium capable of neutralizing acids.
Alkaline phosphatase: A phosphatase (EC 3.1.3.1) with an optimum pH of
8.6, present ubiquitously.
Allergen: A material that, as a result of coming into contact with appro-
priate tissues of an animal body, induces a state of sensitivity result-
Ing in various reactions; generally associated with idiosyncratic
hypersensitivities.
Alpha-hydroxybutyrate dehydrogenase: An enzyme (EC 1.1.1.30), present
mainly in mitochondria, which catalyzes the conversion of hydro-
xybutyrate to acetoacetate in intermediate biochemical pathways.
G-3
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Alpha rhythm: A rhythmic pulsation obtained in brain waves exhibited
in the sleeping state of an individual.
Alveolar capillary membrane: Finest portion of alveolar capillaries,
where gas transfer to and from blood takes place.
Alveolar macrophages (AM): Large, mononuclear, phagocytic cells found
on the alveolar surface, responsible for the sterility of the lung.
Alveolar oxygen partial pressure (PA02): Partial pressure of oxygen in the
air contained in the air sacs of the lungs.
Alveolar septa: The tissue between two adjacent pulmonary alveoli, con-
sisting of a close-meshed capillary network covered on both surfaces
by thin alveolar epithelial cells.
Alveolus: An air cell; a terminal, sac-like dilation in the lung. Gas
exchange (O-XCCL) occurs here.
Ambient: The atmosphere to which the general population may be exposed.
Construed here not to include atmospheric conditions indoors, or in
the workplace.
Amine: A substance that may be derived from ammonia (NH,) by the re-
placement of one, two or three of the hydrogen (H) atoms by hydro-
carbons or other radicals (primary, secondary or tertiary amines,
respectively).
Ami no acids: Molecules consisting of a carboxyl group, a basic ami no
group, and a residue group attached to a central carbon atom. Serve
as the building blocks of proteins.
p-Aminohippuric acid (PAH): A compound used to determine renal plasma
flow.
Aminotriazole: A systemic herbicide, C.H^N., used in areas other than
croplands, that also possesses some antithyroid activity; also called
amitrole.
Ammonification: Decomposition with production of ammonia or ammonium
compounds, esp. by the action of bacteria on nitrogenous organic
matter.
Ammonium: Anion (NH.) or radical (NH.) derived from ammonia by combination
with hydrogen. Present in rainwater, soils and many commercial ferti-
lizers.
Amnestic: Pertains to immunologic memory: upon receiving a second
dose of antigen, the host "remembers" the first dose and responds
faster to the challenge.
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Anaerobic: Living, active or occurring in the absence of free oxygen.
Anaerobic bacteria: A type of microscopic organism which can live in
an environment not containing free oxygen.
Anaphylactic dyspneic attack: Difficulty in breathing associated with
a systemic allergic response.
Anaphylaxis: A term commonly used to denote the immediate, transient
kind of immunological (allergic) reaction characterized by contraction
of smooth muscle and dilation of capillaries due to release of pharmacologically
active substances.
Angiosperm: A plant having seeds enclosed in an ovary; a flowering plant.
Angina pectoris: Severe constricting pain in the chest which may be
caused by depletion of oxygen delivery to the heart muscle; usually
caused by coronary disease.
o _o
Angstrom A: A unit (10 cm) used in the measurement of the wavelength
of light.
Anhydride: A compound resulting from removal of water from two molecules
of a carboxylic (-COOH) acid. Also, may refer to those substances
(anhydrous) which do not contain water in chemical combination.
Anion: A negatively charged atom or radical.
Anorexia: Diminished appetite; aversion to food.
Anoxic: Without or deprived of oxygen.
Anthraquinone: A yellow crystalline ketone, ^.HgO^ derived from
anthracene and used in the manufacture of dyes.
Anthropogenic: Of, relating to or influenced by man. An anthropogenic
source of pollution is one caused by man's actions.
Antibody: Any body or substance evoked by the stimulus of an antigen
and which reacts specifically with antigen in some demonstrable way.
Antigen: A material such as a foreign protein that, as a result of
coming in contact with appropriate tissues of an animal, after a latent
period, induces a state of sensitivity and/or the production of antibody.
Antistatic agent: A chemical compound applied to fabrics to reduce or
eliminate accumulation of static electricity.
Arachidonic acid: Long-chain fatty-acid which serves as a precursor
of prostaglandins.
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Area source: In air pollution, any small individual fuel combustion
or other pollutant source; also, all such sources grouped over a
specific area.
Aromatic: Belonging to that series of carbon-hydrogen compounds in
which the carbon atoms form closed rings containing unsaturated
bonds (as in benzene).
Arterial partial pressure of oxygen (PaCL): Portion of total pressure of
dissolved gases in arterial blood as measured directly from arterial
blood.
Arterialized partial pressure of oxygen: The portion of total pressure
of dissolved gases in arterial blood attributed to oxygen, as
measured from non-arterial (e.g., ear-prick) blood.
Arteriosclerosis: Commonly called hardening of the arteries. A condition
that exists when the walls of the blood vessels thicken and become
infiltrated with excessive amounts of minerals and fatty materials.
Artifact: A spurious measurement produced by the sampling or analysis
process.
Ascorbic acid: Vitamin C, a strong reducing agent with antioxidant proper-
ties.
Aspartate transaminase: Also known as aspartate aminotransferase
(EC 2.6.1.1). An enzyme catalyzing the transfer of an amine group
from glutamic acid to oxaloacetic, forming aspartic acid in the
process. Serum level of the enzyme is increased in myocardial in-
farction and in diseases involving destruction of liver cells.
Asphyxia: Impaired exchange of oxygen and carbon dioxide, excess of
carbon dioxide and/or lack of oxygen, usually caused by ventilatory
problems.
Asthma: A term currently used in the context of bronchial asthma in
which there is widespread narrowing of the airways of the lung.
It may be aggravated by inhalation of pollutants and lead to
"wheezing" and shortness of breath.
Asymptomatic: Presenting no subjective evidence of disease.
Atmosphere: The body of air surrounding the earth. Also, a measure of
pressure (atm.) equal to the pressure of air at sea level, 14.7 pounds
per square inch.
Atmospheric deposition: Removal of pollutants from the atmosphere onto
land, vegetation, water bodies or other objects, by absorption,
sedimentation, Brownian diffusion, impaction, or precipitation in rain.
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Atomic absorption spectrometry: A measurement method based on the
absorption of radiant energy by gaseous ground-state atoms. The
amount of absorption depends on the population of the ground state
which is related to the concentration of the sample being analyzed.
Atropine: A poisonous white crystalline alkaloid, C,7H?^NOV from
belladonna and related plants, used to relieve Spasms ind to dilate
the pupil of the eye.
Autocorrelation: Statistical interdependence of variables being analyzed;
produces problems, for example, when observations may be related
to previous measurements or other conditions.
Autoimmune disease: A condition in which antibodies are produced against
the subject's own tissues.
Autologous: A term referring to cellular elements, such as red blood cells
and alveolar macrophage, from the same organism; also, something
natually and normally ocurring in some part of the body.
Autotrophic: A term applied to those microorganisms which are able to
maintain life without an exogenous organic supply of energy, or which
only need carbon dioxide or carbonates and simple inorganic nitrogen.
Autotrophic bacteria: A class of microorganisms which require only
carbon dioxide or carbonates and a simple inorganic nitrogen com-
pound for carrying on life processes.
Auxin: An organic substance that causes lengthening of the stem when
applied in low concentrations to shoots of growing plants.
Awn: One of the slender bristles that terminate the glumes of the
spikelet in some cereals and other grasses.
Azo dye: Dyes in which the azo group is the chromophore and joins
benzene or napthalene rings.
Background measurement: A measurement of pollutants in ambient air due
to natural sources; usually taken in remote areas.
Bactericidal activity: The process of killing bacteria.
Barre: Bars or stripes in a fabric, caused by uneven weaving, irregular
yarn or uneven dye distribution.
Basal cell: One of the innermost cells of the deeper epidermis of the
skin.
Benzenethiol: A compound of benzene and a hydrosulfide group.
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Beta (b)-lipoprotein: A biochemical complex or compound containing both
lipid and protein and characterized by having a large molecular
weight, rich in cholesterol. Found in certain fractions of human
plasma.
Bilateral renal sclerosis: A hardening of both kidneys of chronic
Inflammatory origin.
Biomass: That part of a given habitat consisting of living matter.
Biosphere: The part of the earth's crust, waters and atmosphere where
living organisms can subsist.
Biphasic: Having two distinct successive stages.
Bleb: A collection of fluid beneath the skin; usually smaller than
bullae or blisters.
Blood urea: The chief end product of nitrogen metabolism in mammals,
excreted in human urine in the amount of about 32 grams (1 02.)
a day.
Bloom: A greenish-gray appearance imparted to silk and pile fabrics
either by nature of the weave or by the finish; also, the creamy
white color observed on some good cottons.
Blue-green algae: A group of simple plants which are the only N--fixing
organisms which photosynthesize as do higher plants.
Brightener: A compound such as a dye, which adheres to fabrics in order
to provide better brightness or whiteness by converting ultraviolet
radiation to visible light. Sometimes called optical bleach or
whitening agent. The dyes used are of the florescent type.
Broad bean: The large flat edible seed of an Old World upright vetch
(Vicia faba), or the plant itself, widely grown for its seeds and
for fodder.
Bronchi: The first subdivisions of the trachea which conduct air to
and from the bronchioles of the lungs.
Bronchiole: One of the finer subdivisions of the bronchial (trachea)
tubes, less than 1 mm in diameter, and having no cartilage in
its wall.
Bronchiolitis: Inflammation of the smallest bronchial tubes.
Bronchiolitis fibrosa obliterans syndrome: Obstruction of the bronchioles
by fibrous granulation arising from an ulcerated mucosa; the condition
may follow inhalation of irritant gases.
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Bronchitis: Inflammation of the mucous membrane of the bronchial tubes.
It may aggravate an existing asthmatic condition.
Bronchoconstrictor: An agent that causes a reduction in the caliber
(diameter) of a bronchial tube.
Bronchodilator: An agent which causes an increase in the caliber (diameter)
of a bronchus or bronchial tube.
Bronchopneumonia: Acute inflammation of the walls of the smaller bronchial
tubes, with irregular area of consolidation due to spread of the in-
flammation into peribronchiolar alveoli and the alveolar ducts.
Brownian diffusion: Diffusion by random movement of particles suspended
in liquid or gas, resulting from the impact of molecules of the
fluid surrounding the particles.
Buffer: A substance in solution capable of neutralizing both acids
and bases and thereby maintaining the original pH of the solution.
Buffering capacity: Ability of a body of water and its watershed to
neutralize introduced acid.
Butanol: A four-carbon, straight-chain alcohol, C.hLOH, also known as
butyl alcohol. * 3
Butylated hydroxytoluene (BHT): A crystalline phenolic antioxidant.
Butylated hydroxyanisol (BHA): An antioxidant.
14
C labeling: Use of a radioactive form of carbon as a tracer, often
in metabolic studies.
14
C-proline: An amino acid which has been labeled with radioactive carbon.
Calcareous: Resembling or consisting of calcium carbonate (lime), or
growing on limestone or lime-containing soils.
Calorie: Amount of heat required to raise temperature of 1 gram of
water at 15°C by 1 degree.
Cannula: A tube that is inserted into a body cavity, or other tube
or vessel, usually to remove fluid.
Capillary: The smallest type of vessel; resembles a hair. Usually
in reference to a blood or lymphatic capillary vessel.
Carbachol: A chemical compound (carbamoylcholine chloride, C-H.-CIN-OO that
produces a constriction of the bronchi; a parasympathetic stimulant
used in veterinary medicine and topically in glaucoma.
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Carbon monoxide: An odorless, colorless, toxic gas with a strong affinity
for hemoglobin and cytochrome; it reduces oxygen absorption capacity,
transport and utilization.
Carboxyhemoglobin: A fairly stable union of carbon monoxide with hemo-
globin which interferes with the normal transfer of carbon dioxide
and oxygen during circulation of blood. Increasing levels of
Carboxyhemoglobin result in various degrees of asphyxiation, In-
cluding death.
Carcinogen: Any agent producing or playing a stimulatory role in the
formation of a malignancy.
Carcinoma: Malignant new growth made up of epithelial cells tending to
infiltrate the surrounding tissues and giving rise to metastases.
Cardiac output: The volume of blood passing through the heart per unit
time.
Cardiovascular: Relating to the heart and the blood vessels or the
circulation.
Carotene: Lipid-soluble yellow-to-orange-red pigments universally
present the photosynthetic tissues of higher plants, algae, and the
photosynthetic bacteria.
Cascade impactor: A device for measuring the size distribution of particulates
and/or aerosols, consisting of a series of plates with orifices of
graduated size which separate the sample into a number of fractions
of decreasing aerodynamic diameter.
Catabolism: Destructive metabolism involving the release of energy and
resulting in breakdown of complex materials in the organism.
Catalase: An enzyme (EC 1.11.1.6) catalyzing the decomposition of hydrogen
peroxide to water and oxygen.
Catalysis: A modification of the rate of a chemical reaction by some
material which is unchanged at the end of the reaction.
Catalytic converter: An air pollution abatement device that removes
organic contaminants by oxidizing them into carbon dioxide and
water.
Catecholamine: A pyrocatechol with an alkalamine side chain, functioning
as a hormone or neurotransmitter, such as epinephrine, morepinephrine,
or dopamine.
Cathepsins: Enzymes which have the ability to hydrolyze certain proteins
and peptides; occur in cellular structures known as lysosomes.
Cation: A positively charged ion.
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Cellular permeability: Ability of gases to enter and leave cells; a
sensitive indicator of injury to deep-lung cells.
Cellulose: The basic substance which is contained in all vegetable
fibers and in certain man-made fibers. It is a carbohydrate and
constitutes the major substance in plant life. Used to make cellulose
acetate and rayon.
Cellulose acetate: Commonly refers to fibers or fabrics in which the
cellulose is only partially acetylated with acetate groups. An
ester made by reacting cellulose with acetic anhydride with SO.
as a catalyst.
Cellulose rayon: A regenerated cellulose which is chemically the same
as cellulose except for physical differences in molecular weight
and crystal!inity.
Cellulose triacetate: A cellulose fiber which is completely acetylated.
Fabrics of triacetate have higher heat resistance than acetate and
may be safely ironed at higher temperature. Such fabrics have improved
ease-of-care characteristics because after heat treatment during
manufacture, a change in the crystalline structure of the fiber
occurs.
Cellulosics: Cotton, viscose rayon and other fibers made of natural fiber
raw materials.
Celsius scale: The thermometric scale in which freezing point of water
is 0 and boiling point is 100.
Central hepatic necrosis: The pathologic death of one or more cells,
or of a portion of the liver, involving the cells adjacent to the
central veins.
Central nervous system (CNS): The brain and the spinal cord.
Centroacinar area: The center portion of a grape-shaped gland.
Cerebellum: The large posterior brain mass lying above the pons and
medulla and beneath the posterior portion of the cerebrum.
Cerebral cortex: The layer of gray matter covering the entire surface
of the cerebral hemisphere of mammals.
Chain reaction: A reaction that stimulates its own repetition.
ChaJlenge: Exposure of a test organism to a virus, bacteria, or other
stress-causing agent, used in conjunction with exposure to a pollutant
of interest, to explore possible susceptibility brought on by the
pollutant.
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Chamber study: Research conducted using a closed vessel in which pollutants
are reacted or substances exposed to pollutants.
Chemiluminescence: A measurement technique in which radiation is pro-
duced as a result of chemical reaction.
Chemotactic: Relating to attraction or repulsion of living protoplasm
by chemical stimuli.
Chlorophyll: A group of closely related green photosynthetic pigments
occurring in leaves, bacteria, and organisms.
Chloroplast: A plant cell inclusion body containing chlorophyll.
Chlorosis: Discoloration of normally green plant parts that can be
caused by disease, lack of nutrients, or various air pollutants,
resulting in the failure of chlorophyll to develop.
Cholesterol: A steroid alcohol C-yH.gOH; the most abundant steroid in
animal cells and body fluids.
Cholinesterase (CHE): One (EC 3.1.1.8) of a family of enzymes capable
of catalyzing the hydrolysis of acylcholines.
Chondrosarcoma: A malignant neoplasm derived from cartilage cells,
occurring most frequently near the ends of long bones.
Chromatid: Each of the two strands formed by longitudinal duplication
of a chromosome that becomes visible during an early stage of cell
division.
Chromophore: A chemical group that produces color in a molecule by absorbing
near ultraviolet or visible radiation when bonded to a nonabsorb-
ing, saturated residue which possesses no unshared, nonbonding valence
electrons.
Chromosome: One of the bodies (46 in man) in the cell nucleus that is the
bearer and carrier of genetic information.
Chronic respiratory disease (CRD): A persistent or long-lasting intermittent
disease of the respiratory tract.
Cilia: Motile, often hairlike extensions of a cell surface.
Ciliary action: Movements of cilia in the upper respiratory tract, which
move mucus and foreign material upward.
Ciliogenesis: The formation of cilia.
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Citric acid (Krebs) cycle: A major biochemical pathway in cells, in-
volving terminal oxidation of fatty acids and carbohydrates. It
yields a major portion of energy needed for essential body functions
and is the major source of C02. It couples the glycolytic breakdown
of sugar in the cytoplasm witn those reactions producing ATP 1n the
mitochondria. It also serves to regulate the synthesis of a number
of compounds required by a cell.
Clara cell: A nonciliated mammalian cell.
Closing volume (CV): The lung volume at which the flow from the lower
parts of the lungs becomes severely reduced or stops during expiration,
presumably because of airway closure.
Codon: A sequence of three nucleotides which encodes information re-
quired to direct the synthesis of one or more ami no acids.
Coefficient of haze (COH): A measurement of visibility Interference in the
atmosphere.
Cohort: A group of subjects included in a test or experiment; usually
characterized by age, class or other characteristic.
Collagen: The major protein of the white fibers of connective tissue,
cartilage, and bond. Comprises over half the protein of the mammal.
Collisional deactivation: Reduction in energy of excited molecules
caused by collision with other molecules or other objects such
as the walls of a container.
Colorimetric: A chemical analysis method relying on measurement of the
degree of color produced in a solution by reaction with the pollutant
of interest.
Community exposure: A situation in which people in a sizeable area are
subjected to ambient pollutant concentrations.
Compliance: A measure of the change in volume of an internal organ (e.g.
lung, bladder) produced by a unit of pressure.
Complement: Thermolabile substance present in serum that is destructive
to certain bacteria and other cells which have been sensitized by
specific complement-fixing antibody.
Compound: A substance with Us own distinct properties, formed by the
chemical combination of two or more elements in fixed proportion.
Concanavalin-A: One of two crystalline globulins occurring in the jack
bean; a potent hemagglutinin.
Conifer: A plant, generally evergreen, needle-leafed, bearing naked seeds
singly or in cones.
G-13
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Converter: See catalytic converter.
Coordination number: The number of bonds formed by the central atom in
a complex.
Copolymer: The product of the process of polymerization in which two or
more monomeric substances are mixed prior to polymerization. Nylon is
a copolymer.
Coproporphyrin: One of two porphyrin compounds found normally in feces
as a decomposition product of bilirubin (a bile pigment). Porphyrin
is a widely-distributed pigment consisting of four pyrrole nuclei
joined in a ring.
Cordage: A general term which includes banding, cable, cord, rope, string,
and twine made from fibers. Synthetic fibers used in making cordage
include nylon and dacron.
Corrosion: Destruction or deterioration of a material because of reaction
with its environment.
Corticosterone: A steroid obtained from the adrenal cortex. It induces
some deposition of glycogen in the liver, sodium conservation, and
potassium excretion.
Cosmopolitan: In the biological sciences, a term denoting worldwide
distribution.
Coulometric: Chemical analysis performed by determining the amount of a
substance released in electrolysis by measuring the number of
coulombs used.
Coumarin: A toxic white crystalline lactone (CgM-CO found in plants.
Coupler: A chemical used to combine two others in a reaction, e.g. to
produce the azo dye in the Griess-Saltzman method for N0«.
Crevice corrosion: Localized corrosion occurring within crevices on metal
surfaces exposed to corrosives.
Crosslink: To connect, by an atom or molecule, parallel chains in a complex
chemical molecule, such as a polymer.
Cryogenic trap: A pollutant sampling method in which a gaseous pollutant
is condensed out of sampled air by cooling (e.g. traps in one method
for nitrosamines are maintained below -79 C, using solvents maintained
at their freezing points).
Cuboidal: Resembling a cube in shape.
Cultivar: An organism produced by parents belonging to different species
or to different strains of the same species, originating and persist-
ing under cultivation.
G-14
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Cuticle: A thin outer layer, such as the thin continuous fatty film
on the surface of many higher plants.
Cyanosis: A dark bluish or purplish coloration of the skin and mucous
membrane due to deficient oxygenation of the blood.
Cyclic GMP: Guanosine B'-phosphoric acid.
Cytochrome: A class of hemoprotein whose principal biological function
is electron and/or hydrogen transport.
Cytology: The anatomy, physiology, pathology and chemistry of the cell.
Cytoplasm: The substance of a cell exclusive of the nucleus.
Dacron: The trade name for polyester fibers made by E.I. du Pont de Nemours
and Co., Inc., made from dimethyl terephthalate and ethylene glycol.
Dark adaptation: The process by which the eye adjusts under reduced
illumination and the sensitivity of the eye to light is greatly in-
creased.
Dark respiration: Metabolic activity of plants at night; consuming oxygen
to use stored sugars and releasing carbon dioxide.
Deciduous plants: Plants which drop their leaves at the end of the grow-
ing season.
Degradation (textiles): The decomposition of fabric or its components
or characteristics (color, strength, elasticity) by means of light,
heat, or air pollution.
Denitrification: A bacterial process occurring in soils, or water, in
which nitrate is used as the terminal electron acceptor and is re-
duced primarily to N-. It is essentially an anaerobic process; it
can occur in the presence of low levels of oxygen only if the micro-
organisms are metabolizing in an anoxic microzone.
De novo: Over again.
Deoxyribonucleic acid (DMA): A nucleic acid considered to be the carrier
of genetic information coded in the sequence of purine and pyrimidine
bases (organic bases). It has the form of a double-stranded helix
of a linear polymer.
Depauperate: Falling short of natural development or size.
Derivative spectrophotometer: An instrument with an increased capability
for detecting overlapping spectral lines and bands and also for
suppressing instrumentally scattered light.
6-15
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Desorb: To release a substance which has been taken into another substance
or held on its surface; the opposite of absorption or adsorption.
Desquamation: The shedding of the outer layer of any surface.
Detection limit: A level below which an element or chemical compound
cannot be reliably detected by the method or measurement being used for
analysis.
Detritus: Loose material that results directly from disintegration.
DeVarda alloy: An alloy of 50 percent Cu, 45 percent Al, 5 percent Zn.
Diastolic blood pressure: The blood pressure as measured during the period
of filling the cavities of the heart with blood.
Diazonium salt: A+ch§mical compound (usually colored) of the general
structure ArN?Cl , where Ar refers to an aromatic group.
Diazotizer: A chemical which, when reacted with amines (RNhL, for example),
produces a diazonium salt (usually a colored compound).
Dichotomous sampler: An air-sampling device which separates particulates
into two fractions by particle size.
Differentiation: The process by which a cell, such as a fertilized egg,
divides into specialized cells, such as the embryonic types that
eventually develop into an entire organism.
Diffusion: The process by which molecules or other particles intermingle
as a result of their random thermal motion.
Diffusing capacity: Rate at which gases move to or from the blood.
Dimer: A compound formed by the union of two like radicals or
molecules.
Dimerize: Formation of dimers.
1,6-diphosphofructose aldolase: An enzyme (EC 4.1.1.13) cleaving fructose
1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde-
3-phosphate.
D-2,3-diphosphoglycerate: A salt or ester of 2,3-diphosphoglyceric acid,
a major component of certain mammalian erythrocytes involved in the
release of Op from HbO™. Also a postulated intermediate in the bio-
chemical patnway involving the conversion of 3- to 2-phosphoglyceric
acid.
Diplococcus pneumoniae: A species of spherical-shaped bacteria belonging
to the genus Streptococcus. May be a causal agent in pneumonia.
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Direct dye: A dye with an affinity for most fibers; used mainly when
color resistance to washing is not important.
Disperse dyes: Also known as acetate dyes; these dyes were developed
for use on acetate fabrics, and are now also used on synthetic
fibers.
Distal: Far from some reference point such as median line of the body, point
of attachment or origin.
Diurnal: Having a repeating pattern or cycle 24 hours long.
Dl_co: The diffusing capacity of the lungs for carbon monoxide. The ability
of the lungs to transfer carbon monoxide from the alveolar air into the
pulmonary capillary blood.
Dorsal hyphosis: Abnormal curvative of the spine; hunch-back.
Dose: The quantity of a substance to be taken all at one time or in
fractional amounts within a given period; also the total amount of a
pollutant delivered or concentration per unit time times time.
Dose-response curve: A curve on a graph based on responses occurring
in a system as a result of a series of stimuli intensities or doses.
Dry deposition: The processes by which matter is transferred to ground
from the atmosphere, other than precipitation; includes surface ab-
sorption of gases and sedimentation, Brownian diffusion and impaction
of particles.
Dyeing: A process of coloring fibers, yarns, or fabrics with either
natural or synthetic dyes.
Dynamic calibration: Testing of a monitoring system using a continuous
sample stream of known concentration.
Dynamic compliance (C,. ): Volume change per unit of transpulmonary
pressure minus tneypressure of pulmonary resistance during airflow.
Dynel: A trademark for a modacrylic staple fiber spun from a copolymer
of acrylonitrile and vinyl chloride. It has high strength, quick-
drying properties, and resistance to alkalies and acids.
Dyspepsia: Indigestion, upset stomach.
Dyspnea: Shortness of breath; difficulty or distress in breathing; rapid
breathing.
Ecosystem: The interacting system of a biological community and its
environment.
Eddy: A current of water or air running contrary to the main current.
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Edema: Pressure of excess fluid in cells, intercellular tissue or cavities
of the body.
Elastomer: A synthetic rubber product which has the physical properties
of natural rubber.
Electrocardiogram: The graphic record of the electrical currents that
initiate the heart's contraction.
Electrode: One of the two extremities of an electric circuit.
Electrolyte: A non-metallic electric conductor in which current, is carried
by the movement of ions; also a substance which displays these qualities
when dissolved in water or another solvent.
Electronegativity: Measure of affinity for negative charges or electrons.
Electron microscopy: A technique which utilizes a focused beam of electrons
to produce a high-resolution image of minute objects such as particu-
late matter, bacteria, viruses, and DNA.
Electronic excitation energy: Energy associated in the transition of
electrons from their normal low-energy orbitals or orbitals of higher
energy.
Electrophilic: Having an affinity for electrons.
Electrophoresis: A technique by which compounds can be separated from a
complex mixture by their attraction to the positive or negative
pole of an applied electric potential.
Eluant: A liquid used in the process of elution.
Elute: To perform an elution.
Elution: Separation of one material from another by washing or by dissolving
one in a solvent in which the other is not soluble.
Elutriate: To separate a coarse, insoluble powder from a finer one by
suspending them in water and pouring off the finer powder from the
upper part of the fluid.
Emission spectrometry: A rapid analytical technique based on measurement
of the characteristic radiation emitted by thermally or electrically
excited atoms or ions.
Emphysema: An anatomic alteration of the lung, characterized by abnormal
enlargement of air spaces distal to the terminal bronchioles, due
to dilation or destructive changes in the alveolar walls.
Emphysematous lesions: A wound or injury to the lung as a result of
emphysema.
G-18
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Empirical modeling: Characterization and description of a phenomena
based on experience or observation.
Encephalitis: Inflammation of the brain.
Endoplasmic reticulum: An elaborate membrane structure extending from the
nuclear membrane or eucaryotic cells to the cytoplasmic membrane.
Endothelium: A layer of flat cells lining especially blood and lymphatic
vessels.
Entropy: A measure of disorder or randomness in a system. Low entropy
is associated with highly ordered systems.
Enzyme: Any of numerous proteins produced by living cells which catalyze
biological reactions.
Enzyme Commission (EC): The International Commission on Enzymes, established
in 1956, developed a scheme of classification and nomenclature under
which each enzyme is assigned an EC number which identifies it by
function.
Eosinophils: Leukocytes (white blood cells) which stain readily with the
dye, eosin.
Epidemiology: A study of the distribution and determinants of disease
in human population groups.
Epidermis: The outermost living layer of cells of any organism.
Epididymal fat pads: The fatty tissue located near the epididymis. The
epididymis is the first convoluted portion of the excretory duct
of the testis.
Epiphyte: A plant growing on another plant but obtaining food from the
atmosphere.
Epithelial: Relating to epithelium, the membranous cellular layer which
covers free surfaces or lines tubes or cavities of an animal body,
which encloses, protects, secretes, excretes and/or assimilates.
Erosion corrosion: Acceleration or increase in rate of deterioration
or attack on a metal because of relative movement between a corrosive
fluid and the metal surface. Characterized by grooves, gullies, or
waves in the metal surface.
Erythrocyte: A mature red blood cell.
Escherichia coli: A short, gram-negative, rod-shaped bacteria common
to the human intestinal tract. A frequent cause of infections in
the urogem'tal tract.
G-19
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Esophageal: Relating to the portion of the digestive tract between the
pharynx and the stomach.
Estrus: That portion or phase of the sexual cycle of female animals
characterized by willingness to permit coitus.
Estrus cycle: The series of physiologic uterine, ovarian and other
changes that occur in higher animals.
Etiolation: Paleness and/or altered development resulting from the
absence of light.
Etiology: The causes of a disease or condition; also, the study of
causes.
Eucaryotic: Pertaining to those cells having a well-defined nucleus
surrounded by a double-layered membrane.
Euthrophication: Elevation of the level of nutrients in a body of water,
which can contribute to accelerated plant growth and filling.
Excited state: A state of higher electronic energy than the ground state,
usually a less stable one.
Expiratory (maximum) flow rate: The maximum rate at which air can be
expelled from the lungs.
Exposure level: Concentration of a contaminant to which an individual
or a population is exposed.
Extinction coefficient: A measure of the space rate of diminution, or
extinction, of any transmitted light, thus, it is the attenuation
coefficient applied to visible radiation.
Extramedullary hematopoiesis: The process of formation and development
of the various types of blood cells and other formed elements not
including that occurring in bone marrow.
Extravasate: To exclude from or pass out of a vessel into the tissues;
applies to urine, lymph, blood and similar fluids.
Far ultraviolet: Radiation in the range of wavelengths from 100 to 190
nanometers.
Federal Reference Method (FRM): For NO-, the EPA-approved analyzers based
on the gas-phase chemiluminescent measurement principle and associated
calibration procedures; regulatory specifications prescribed in Title
40, Code of Federal Regulations, Part 50, Appendix F.
Fenestrae: Anatomical aperatures often closed by a membrane.
Fiber: A fine, threadlike piece, as of cotton, jute, or asbestos.
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Fiber-reactive dye: A water-soluble dyestuff which reacts chemically
with the cellulose in fibers under alkaline conditions; the dye
contains two chlorine atoms which combine with the hydroxyl groups of
the cellulose.
Fibrin: A white insoluble elastic filamentous protein derived from fibrino-
gen by the action of thrombin, especially in the clotting of blood.
Fibroadenoma: A benign neoplasm derived from glandular epithelium, in-
volving proliferating fibroblasts, cells found in connective tissue.
Fibroblast: An elongated cell with cytoplasmic processes present in
connective tissue, capable of forming collagen fibers.
Fibrosis: The formation of fibrous tissue, usually as a reparative or
reactive process and not as a normal constituent of an organ or
tissue.
Flocculation: Separation of material from a solution or suspension •
reaction with a flocculant to create fluffy masses containing * -„
material to be removed.
Fly ash: Fine, solid particles of noncombustible ash carried out of a
bed of solid fuel by a draft.
Folded-path optical system: A long (e.g. 8-22 m) chamber with multiple
mirrors at the ends which can be used to reflect an infrared beam through
an ambient air sample many times; a spectrometer can be used with such
a system to detect trace pollutants at very low levels.
Forced expiratory flow (FEF): The rate at which air can be expelled from
the lungs; see expiratory flow rate.
Forced expiratory volume (FEV): The maximum volume of air that can be
expired in a specific time interval when starting from maximal
inspiration.
Forced vital capacity (FVC): The greatest volume of air th-t can be
exhaled from the lungs under forced conditions after ; /,'xvi'jm
inspiration.
Fractional threshold concentration: The portion of the concentration
at which an event or a response begins to occur, expressed as a
fraction.
Free radical: Any of a variety of highly-reactive atoms or molecules
characterized by having an unpaired electron.
Fritted bubbler: A porous glass device used in air pollutant sampling
systems to introduce small bubbles into solution.
-------
Functional residual capacity: The volume of gas remaining in the lungs
at the end of a normal expiration. It is the sum of expiratory
reserve volume and residual volume.
Gas exchange: Movement of oxygen from the alveoli into the pulmonary
capillary blood as carbon dioxide enters the alveoli from the blood.
Gas chromatography (GC): A method of separating and analyzing mixtures
of chemical substances. A flow of gas causes the components of a
mixture to migrate differentially from a narrow starting zone in a
special porous, insoluble sorptive medium. The pattern formed by
zones of separated pigments and of colorless substances in this
process is called a chromatogram, and can be analyzed to obtain the
concentration of identified pollutants.
Gas-liquid chromatography: A method of separating and analyzing volatile
organic compounds, in which a sample is vaporized and swept through
a column filled with solid support material covered with a nonvolatile
liquid. Components of the sample can be identified and their con-
centrations determined by analysis of the characteristics of their
retention in the column, since compounds have varying degrees of
solubility in the liquid medium.
Gastric juice: A thin watery digestive fluid secreted by glands in the
mucous membrane of the stomach.
Gastroenteritis: Inflammation of the mucous membrane of stomach and
intestine.
Genotype: The type of genes possessed by an organism.
Geometric mean: An estimate of the average of a distribution. Specifically,
the nth root of the product of n observations.
Geometric standard deviation: A measure of variability of a distribution.
It is the antilogarithm of the standard deviation of the logarithms
of the observations.
Globulins (a, b, q): A family of proteins precipitated from plasma (or
serum) by half-saturation with ammonium sulfate, or separable by
electrophoresis. The main groups are the a, b, q fractions, differ-
ing with respect to associated lipids and carbohydrates and in their
content of antibodies (immunoglobulins).
Glomular nephrotic syndrome: Dysfunction of the kidneys characterized
by excessive protein loss in the urine, accumulation of body fluids
and alteration in albumin/globulin ratio.
Glucose: A sugar which is a principal source of energy for man and other
organisms.
Glucose-6-phosphate dehydrogenase: An enzyme (EC 1.1.1.49) catalyzing
the dehydrogenation of glucose-6-phosphate to 6-phosphogluconolactone.
G-22
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Glutamic-oxaloacetic transaminase (SCOT): An enzyme (EC 2.6.1.1) whose
serum level increases in myocardial infarction and in diseases in-
volving destruction of liver cells. Also known as aspartate
aminotransferase.
Glutamic-pyruvic transaminase (SGPT): Now known as alanine aminotransferase
(EC 2.6.1.2), the serum levels of this enzyme are used in liver function
tests.
Glutathione (GSH): A tripeptide composed of glycine, cystine, and glutamic
acid.
Glutathione peroxidase: An enzyme (EC 1.11.1) which catalyzes the destruction
of hydroperoxides formed from fatty acids and other substances.
Protects tissues from oxidative damage. It is a selenium-containing
protein.
Glutathione reductase: The enzyme (EC 1.6.4.2) which reduces the oxidized
form of glutathione.
Glycolytic pathway: The biochemical pathway by which glucose is con-
verted to lactic acid in various tissues, yielding energy as a
result.
Glycoside: A type of chemical compound formed from the condensation of
a sugar with another chemical radical via a hemiacetal linkage.
Goblet cells: Epithelial cells that have been distended with mucin and when
this is discharged as mucus, a goblet-shaped shell remains.
Golgi apparatus: A membrane system involved with secretory functions
and transport in a cell. Also known as a dictyosome.
Grana: The lamellar stacks of chlorophyll-containing material in plant
chloroplasts.
Griege carpet: A carpet in its unfinished state, i.e. before it has
been scoured and dyed. The term also is used for woven fabrics
in the unbleached and unfinished state.
Ground state: The state of minimum electronic energy of a molecule or
atom.
Guanylate cyclase (GC): An enzyme (EC 4.6.2.1) catalyzing the trans-
formation of guanosine triphosphate to guanosine 3':5'-cyclic phosphate.
H-Thymidine: Ihymine deoxyribonucleoside: One of the four major nucleosides
in DMA. H-thymidine has been uniformly labeled with tritium, a radio-
active form of hydrogen.
Haze: Fine dust, smoke or fine vapor reducing transparency of air.
G-23
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Hemagglutination: The agglutination of red blood cells. Can be used as
as a measurement of antibody concentration.
Hematocrit: The percentage of the volume of a blood sample occupied by
cells.
Hematology: The medical specialty that pertains to the blood and blood-
forming tissues.
Hemochromatosis: A disease characterized by pigmentation of the skin
possibly due to inherited excessive absorption of iron.
Hemoglobin (Hb): The red, respiratory protein of the red blood cells,
hemoglobin transports oxygen from the lungs to the tissues as oxy-
hemoglobin (HbO«) and returns carbon dioxide to the lungs as hemoglobin
carbamate, completing the respiratory cycle.
Hemolysis: Alteration or destruction of red blood cells, causing hemoglobin
to be released into the medium in which the cells are suspended.
Hepatectomy: Complete removal of the liver in an experimental animal.
Hepatic: Relating to the liver.
Hepatocyte: A liver cell.
Heterogeneous process: A chemical reaction involving reactants of more
than one phase or state, such as one in which gases are absorbed into
aerosol droplets, where the reaction takes place.
Heterologous: A term referring to donor and recipient cellular elements
from different organisms, such as red blood cells from sheep and
alveolar macrophage from rabbits.
Hexose monophosphate shunt: Also called the phosphogluconate oxidative
pathway of glucose metabolism which affords a total combustion of
glucose independent of the citric acid cycle. It is the important
generator of NADPH necessary for synthesis of fatty acids and the
operation of various enzymes. It serves as a source of ribose and
4- and 7-carbon sugars.
High-volume sampler (Hi-vol): Device for taking a sample of the particulate
content of a large amount of-air, by drawinq air through a fiber filter
at a typical rate of 2,000 m 724 hr (1.38 m /min), or as high as 2,880
mV24 hr (2 in /min).
Histamine: An amine derived from the amino acid, histidine. It is a
powerful stimulant of gastric secretion and a constrictor of bronchial
smooth muscle. It is a vasodilator and causes a fall in blood
pressure.
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Homogenate: Commonly refers to tissue ground into a creamy consistency
in which the cell structure is disintegrated.
Host defense mechanism: Inherent means by which a biologic organism
protects itself against infection, such as antibody formation,
macrophage action, ciliary action, etc.
Host resistance: The resistance exhibited by an organism, such as man,
to an infecting agent, such as a virus or bacteria.
Humoral: Relating to the extracellular fluids of the body, blood and
lymph.
Hybrid: An organism descended from parents belonging to different
varieties or species.
Hydrocarbons: A vast family of compounds containing carbon and hydrogen
in various combinations; found especially in fossil fuels. Some
contribute to photochemical smog.
Hydrolysis: Decomposition involving splitting of a bond and addition
of the H and OH parts of water to the two sides of the split bond.
Hydrometeor: A product of the condensation of atmospheric water vapor (e.g.
fog, rain, hail, snow).
Hydroxyproline: An amino acid found among the hydrolysis products of
collagen.
Hygroscopic: Pertaining to a marked ability to accelerate the condensation
of water vapor.
Hyperplasia: Increase in the number of cells in a tissue or organ ex-
cluding tumor formation.
Hyperplastic: Relating to hyperplasia; an increase in the number of
cells.
Hypertrophy: Increase in the size of a tissue element, excluding tumor
formation.
Hypertension: Abnormally elevated blood pressure.
Hypolimnia: Portions of a lake below the thermocline, in which water
is stagnant and uniform in temperature.
Hypoxia: A lower than normal amount of oxygen in the air, blood or tissues
G-25
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Immunoglobulin (Ig): A class of structurally related proteins consist-
ing of two pairs of polypeptide chains. Antibodies are Ig's and
all Ig's probably function as antibodies.
Immunoglobulin A (IgA): A type of antibody which comprises approximately
10 to 15 percent of the total amount of antibodies present in normal
serum.
Immunoglobulin G (IgG): A type of antibody which comprises approximately
80 percent of the total amount of antibodies present in normal serum.
Subfractions of IgG are fractions G,, and Sy-
Immunoglobulin M (IgM): A type of antibody which comprises approximately
5 to 10 percent of the total amount of antibodies present in normal
serum.
Impaction: An impinging or striking of one object against another; also,
the force transmitted by this act.
Impactor: An instrument which collects samples of suspended particulates
by directing a stream of the suspension against a surface, or into a
liquid or a void.
Index of proliferation: Ratio of promonocytes to polymorphic monocytes
in the blood.
Infarction: Sudden insufficiency of arterial or venous blood supply
due to emboli, thrombi, or pressure.
Infectivity model: A testing system in which the susceptibility of
animals to airborne infectious agents with and without exposure to air
pollutants is investigated to produce information related to the
possible effects of the pollutant on man.
Inflorescence: The arrangement and development of flowers on an axis;
also, a flower cluster or a single flower.
Influenza A-Aaiwan Virus: An infectious viral disease, believed to
have originated in Taiwan, characterized by sudden onset, chills,
fevers, headache, and cough.
Infrared: Light invisible to the human eye, bgtween the wavelengths
of 7x10 and 10 m (7000 and 10,000,000 A).
Infrared laser: A device that utilizes the natural oscillations of atoms
or molecules to generate coherent electromagnetic radiation in the
infrared region of the spectrum.
Infrared spectrometer: An instrument for measuring the relative amounts
of radiant energy in the infrared region of the spectrum as a function
of wavelength.
G-26
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Ingestion: To take in for digestion.
In situ: In the natural or original position.
Instrumental averaging time: The time over which a single sample or
measurement is taken, resulting in a measurement which 1s an average
of the actual concentrations over that period.
Insult: An injury or trauma.
Intercostal: Between the ribs, especially of a leaf.
Interferant: A substance which a measurement method cannot distinguish
completely from the one being measured, which therefore can cause some
degree of false response or error.
Interferon: A macromolecular substance produced in response to infection
with active or inactivated virus, capable of inducing a state of
resistance.
Intergranular corrosion: A type of corrosion which takes place at and
adjacent to grain boundaries, with relatively little corrosion of
the grains.
Interstitial edema: An accumulation of an excessive amount of fluids
in a space within tissues.
Interstitial pneumonia: A chronic inflammation of the interstitial tissue
of the lung, resulting in compression of air cells.
Intraluminal mucus: Mucus that collects within any tubule.
Intraperitoneal injection: An injection of material into the serous
sac that lines the abdominal cavity.
In utero: Within the womb; not yet born.
In vitro: Refers to experiments conducted outside the living organism.
In vivo: Refers to experiments conducted within the living organism.
Irradiation: Exposure to any form of radiation.
Ischemia: Local anemia due to mechanical obstruction (mainly arterial
narrowing) of the blood supply.
Isoenzymes: Also called isozymes. One of a group of enzymes that are
very similar in catalytic properties, but may be differentiated by
variations in physical properties, such as isoelectric point or
electrophoretic mobility. Lactic acid dehydrogenase is an example
of an enzyme having many isomeric forms.
G-27
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Isopleth: A line on a map or chart connecting points of equal value.
Jacobs-Hochheiser method: The original Federal Reference Method for NOp,
currently unacceptable for air pollution work.
Klebsiella pneumoniae: A species of rod-shaped bacteria found in soil,
water, and in the intestinal tract of man and other animals. Certain
types may be causative agents in pneumonia.
Kyphosis: An abnormal curvature of the spine, with convexity backward.
Lactate: A salt or ester of lactic acid.
Lactic acid (lactate) dehydrogenase (LDH): An enzyme (EC 1.1.1.27) with
many isomeric forms which catalyzes the oxidation of lactate to
pyruvate via transfer of H to NAD. Isomeric forms of LDH in the
blood are indicators of heart damage.
Lamellar bodies: Arranged in plates or scales. One of the characteristics
of Type II alveolar cells.
Lavage fluid: Any fluid used to wash out hollow organs, such as the lung.
Lecithin: Any of several waxy hygroscopic phosphatides that are widely
distributed in animals and plants; they form colloidal solutions in
water and have emulsifying, wetting and hygroscopic properties.
Legume: A plant with root nodules containing nitrogen fixing bacteria.
Lesion: A wound, injury or other more or less circumscribed pathologic
change in the tissues.
Leukocyte: Any of the white blood cells.
Lewis base: A base, defined in the Lewis acid-base concept, is a sub-
stance that can donate an electron pair.
Lichens: Perennial plants which are a combination of two plants, an alga
and a fungus, growing together in an association so intimate that they
appear as one.
Ligand: Those molecules or anions attached to the central atom in a
complex.
Light-fastness: The ability of a dye to maintain its original color under
natural or indoor light.
Linolenic acid: An unsaturated fatty acid essential in nutrition.
Lipase: An enzyme that accelerates the hydrolysis or synthesis of fats
or the breakdown of lipoproteins.
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Lipids: A heterogeneous group of substances which occur widely in bio-
logical materials. They are characterized as a group by their
extractability in nonpolar organic solvents.
Lipofuscin: Brown pigment granules representing 1ipid-containing residues
of lysosomal digestion. Proposed to be an end product of lipid
oxidation which accumulates in tissue.
Lipoprotein: Complex or protein containing lipid and protein.
Loading rate: The amount of a nutrient available to a unit area of body
of water over a given period of time.
Locomotor activity. Movement of an organism from one place to another
of its own volition.
Long-pathlength infrared absorption: A measurement technique in which a
system of mirrors in a chamber is used to direct an infrared beam
through a sample of air for a long distance (up to 2 km); the amount
of Infrared absorbed is measured to obtain the concentrations of
pollutants present.
Lung compliance (C,): The volume change produced by an increase in a
unit change in pressure across the lung, i.e., between the pleural
surface and the mouth.
Lycra: A spandex textile fiber created by E. I. du Pont de Nemours & Co.,
Inc., with excellent tensile strength, a long flex life and high
resistance to abrasion and heat degradation. Used in brassieres,
foundation garments, surgical hosiery, swim suits and military and
industrial uses.
Lymphocytes: White blood cells formed in lymphoid tissue throughout the
body, they comprise about 22 to 28 percent of the total number of
leukocytes in the circulating blood and function in immunity.
Lymphocytogram: The ratio, in the blood, of lymphocyte with narrow
cytoplasm to those with broad cytoplasm.
Lysosomes: Organelles found in cells of higher organisms that contain
high concentrations of degradative enzymes and are known to destroy
foreign substances that cells engulf by pinocytosis and phyocytosis.
Believed to be a major site where proteins are broken down.
Lysozymes: Lytic enzymes destructive to cell walls of certain bacteria.
Present in some body fluids, including tears and serum.
Macaca speciosa: A species of monkeys used in research.
Macrophage: Any large, ameboid, phagocytic cell having a nucleus without
many lobes, regardless of origin.
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Malaise: A feeling of general discomfort or uneasiness, often the first
indication of an infection or disease.
Malate dehydrogenase: An enzyme (EC 1.1.1.37) with at least six Isomeric
forms that catalyze the dehydrogenation of malate to oxaloacetate
or its decarboxylation (removal of a CO- group) to pyruvate. Malate,
oxaloacetate, and pyruvate are intermediate components of biochemical
pathways.
Mannitol: An alcohol derived from reduction of the sugar, fructose.
Used in renal' function testing to measure glomerular (capillary)
filtration.
Manometer: An instrument for the measurement of pressure of gases or
vapors.
Mass median diameter (MMD): Geometric median size of a distribution of
particles based on weight.
Mass spectrometry (MS): A procedure for identifying the various kinds of
particles present in a given substance, by ionizing the particles
and subjecting a beam of the ionized particles to an electric or
magnetic field such that the field deflects the particles in angles
directly proportional to the masses of the particles.
Maximum flow (V ): Maximum rate or expiration, usually expressed at
50 or 25 percent of vital capacity.
Maximum mid-expiratory flow rate (MMFR): The mean rate of expiratory gas
flow between 25 and 75 percent of the forced expiratory vital capacity.
Mean (arithmetic): The sum of observations divided by sample size.
Median: A value in a collection of data values which is exceeded in
magnitude by one-half the entries in the collection.
Mesoscale: Of or relating to meteorological phenomena from 1 to 100
kilometers in horizontal extent.
Messenger RNA: A type of RNA which conveys genetic information encoded
in the DMA to direct protein synthesis.
Metaplasia: The abnormal transformation of an adult, fully differentiated
tissue of one kind into a differentiated tissue of another kind.
Metaproterenol: A bronchodilator used for the treatment of bronchial
asthma.
Metastases: The shifting of a disease from one part of the body to another;
the appearance of neoplasms in parts of the body remote from the seat
of the primary tumor.
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Meteorology: The science that deals with the atmosphere and its phenomena.
Methemoglobin: £+form of hemoglobin in which the normal reduced state
of iron (Fe ) has been oxidized to Fe . It contains oxygen in
firm union with ferric (Fe ) iron and is not capable of exchanging
oxygen in normal respiratory processes.
Methimazole: An anti-thyroid drug similar in action to propylthiouracil.
Methyltransferase: Any enzyme transferring methyl groups from one compound
to another.
Microcoulometric: Capable of measuring millionths of coulombs used in
electrolysis of a substance, to determine the amount of a substance
in a sample.
Microflora: A small or strictly localized plant.
Micron: One-millionth of a meter.
Microphage: A small phagocyte; a polymorphonuclear leukocyte that is
phagocytic.
Millimolar: One-thousandth of a molar solution. A solution of one-
thousandth of a mole (in grams) per liter.
Minute volume: The minute volume of breathing; a product of tidal volume
times the respiratory frequency in one minute.
Mitochondria: Organelles of the cell cytoplasm which contain enzymes
active in the conservation of energy obtained in the aerobic part
of the breakdown of carbohydrates and fats, in a process called
respiration.
Mobile sources: Automobiles, trucks and other pollution sources which are
not fixed in one location.
Modacrylic fiber: A manufactured fiber in which the fiber-forming sub-
stance is any long chain synthetic polymer composed of less than 85
percent but at least 35 percent by weight of acrylonitrite units.
Moeity: One of two or more parts into which something is divided.
Mole: The mass, in grams, numerically equal to the molecular weight of
a substance.
Molecular correlation spectrometry: A spectrophotometric technique which
is used to identify unknown absorbing materials and measure their
concentrations by using preset wavelengths.
Molecular weight: The weight of one molecule of a substance obtained
by adding the gram-atomic weights of each of the individual atoms
in the substance.
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Monocyte: A relatively large mononuclear leukocyte, normally constituting
3 to 7 percent of the leukocytes of the circulating blood.
Mordant: A substance which acts to bind dyes to a textile fiber of fabric.
Morphological: Relating to the form and structure of an organism or any
of its parts.
Moving average: A procedure involving taking averages over a specific
period prior to and including a year in question, so that successive
averaging periods overlap; e.g. a three-year moving average would
include data from 1967 through 1969 for the 1969 average and from
1968 through 1970 for 1970.
Mucociliary clearance: Removal of materials from the upper respiratory
tract via ciliary action.
Mucociliary transport: The process by which mucus is transported, by
ciliary action, from the lungs.
Mucosa: The mucous membrane; it consists of epithelium, lamina propria
and, in the digestive tract, a layer of smooth muscle.
Mucous membrane: A membrane secreting mucus which lines passages and
cavities communicating with the exterior of the body.
Murine: Relating to mice.
Mutagen: A substance capable of causing, within an organism, biological
changes that affect potential offspring through genetic mutation.
Mutagenic: Having the power to cause mutations. A mutation is a change
in the character of a gene (a sequence of base pairs in DNA) that
is perpetuated in subsequent divisions of the cell in which it occurs.
Myocardial infarction: Infarction of any area of the heart muscle usually
as a result of occlusion of a coronary artery.
Nares: The nostrils.
Nasopharyngeal: Relating to the nasal cavity and the pharynx (throat).
National Air Surveillance Network (NASN): Network of monitoring stations
for sampling air to determine extent of air pollution; established
jointly by federal and state governments.
Near ultraviolet: Radiation of the wavelengths 2000-4000 Angstroms.
Necrosis: Death of cells that can discolor areas of a plant or kill
the entire plant.
Necrotic: Pertaining to the pathologic death of one or more cells, or
of a portion of tissue or organ, resulting from irreversible damage.
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Neonate: A newborn.
Neoplasm: An abnormal tissue that grows more rapidly than normal; synonymous
with tumor.
Neoplasia: The pathologic process that results in the formation and
growth of a tumor.
Neutrophil: A mature white blood cell formed in bone marrow and released
Into the circulating blood, where it normally accounts for 54 to 65
percent of the total number of leukocytes.
Ninhydrin: An organic reagent used to identify amino acids.
Nitramine: A compound consisting of a nitrogen attached to the nitrogen
of amine.
Nitrate: A salt or ester of nitric acid (N03~).
Nitrification: The principal natural source of nitrate in which ammonium
(NH.+) ions are oxidized to nitrites by specialized microorganisms.
Othlr organisms oxidize nitrites to nitrates.
Nitrite: A salt or ester of nitrous acid (NCL~).
Nitrocellulose: Any of several esters of nitric acid formed by its action
on cellulose, used in explosives, plastics, varnishes and rayon;
also called cellulose nitrate.
Nitrogen cycle: Refers to the complex pathways by which nitrogen-containing
compounds are moved from the atmosphere into organic life, into the
soil, and back to the atmosphere.
Nitrogen fixation: The metabolic assimilation of atmospheric nitrogen by
soil microorganisms, which becomes available for plant use when the
microorganisms die; also, industrial conversion of free nitrogen into
combined forms used in production of fertilizers and other products.
Nitrogen oxide: A compound composed of only nitrogen and oxygen. Components
of photochemical smog.
Nitrosamine: A compound consisting of a nitrosyl group connected to the
nitrogen of an amine.
Nitrosation: Addition of a nitrosyl group.
N-Nitroso compounds: Compounds carrying the functional nitrosyl group.
Nitrosyl: A group composed of one oxygen and one nitrogen atom (-N=0).
Nitrosylhemoglobin (NOHb): The red, respiratory protein of erythrocytes
to which a nitrosyl group is attached.
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N/P Ratio: Ratio of nitrogen to phosphorous dissolved in lake water,
Important due to its effect on plant growth.
Nucleolus: A small spherical mass of material within the substance of the
nucleus of a cell.
Nucleophilic: Having an affinity for atomic nuclei; electron-donating.
Nucleoside: A compound that consists of a purine or pyrimidine base com-
bined with deoxyribose or ribose and found in RNA and DNA.
S'-Nucleotidase: An enzyme (EC 3.1.3.5) which hydrolyzes nucleoside 5'-
phosphates into phosphoric acid (H^PO.) and nucleosides.
Nucleotide: A compound consisting of a sugar (ribose or deoxyribose),
a base (a purine or a pyrimidine), and a phosphate; a basic structural
unit of RNA and DNA.
Nylon: A generic name chosen by E. I. du Pont de Nemours & Co., Inc.
for a group of protein-like chemical products classed as synthetic
linear polymers; two main types are Nylon 6 and Nylon 66.
Occlusion: A point which an opening is closed or obstructed.
Olefin: An open-chain hydrocarbon having at least one double bond.
Olfactory: Relating to the sense of smell.
Olfactory epithelium: The inner lining of the nose and mouth which contains
neural tissue sensitive to smell.
Oligotrophic: A body of water deficient in plant nutrients; also generally
having abundant dissolved oxygen and no marked stratification.
Oribitals: Areas of high electron density in an atom or molecule.
Orion: An acrylic fiber produced by E. I. du Pont de Nemours and Co., Inc.,
based on a polymer of acrylonitrite; used extensively for outdoor
uses, it is resistant to chemicals and withstands high temperatures.
Osteogenic osteosarcoma: The most common and malignant of bone sarcomas
(tumors). It arises from bone-forming cells and affects chiefly
the ends of long bones.
Ovarian primordial follicle: A spheroidal cell aggregation in the ovary
in which the primordial oocyte (immature female sex cell) is surrounded
by a single layer of flattened follicular cells.
Oxidant: A chemical compound which has the ability to remove electrons
from another chemical species, thereby oxidizing it; also, a substance
containing oxygen which reacts in air to produce a new substance, or
one formed by the action of sunlight on oxides of nitrogen and hydro-
carbons.
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Oxidation: An ion or molecule undergoes oxidation by donating electrons.
Oxidative deamination: Removal of the NHL group from an ami no compound
by reaction with oxygen. *•
Oxidative phosphorylation: The mitochondria! process by which "high-
energy" phosphate bonds form from the energy released as a result of
the oxidation of various substrates. Principally occurs in the tri-
carboxylic acid pathway.
Oxyhemoglobin: Hemoglobin in combination with oxygen. It is the form
of hemoglobin present in arterial blood.
Ozone layer: A layer of the stratosphere from 20 to 50 km above the
earth's surface characterized by high ozone content produced by ultra-
violet radiation.
Ozone scavenging: Removal of 0, from ambient air or plumes by reaction with
NO, producing NO- and 0-.
Paired electrons: Electrons having opposite intrinsic spins about their
own axes.
Parenchyma: The essential and distinctive tissue of an organ or an ab-
normal growth, as distinguished from its supportive framework.
Parenchymal: Referring to the distinguishing or specific cells of a
gland or organ.
Partial pressure: The pressure exerted by a single component in a mixture
of gases.
Particulates: Fine liquid or solid particles such as dust, smoke, mist,
fumes or smog, found in the air or in emissions.
Pascal: A unit of pressure in the International System of Units. One
pascal is equal to 7.4 x 10 torr. The pascal is equivalent to one
newton per square meter.
Pathogen: Any virus, microorganism, or other substance causing disease.
Pathophysiological: Derangement of function seen in disease; alteration
in function as distinguished from structural defects.
Peptide bond: The bond formed when two amino acids react with each other.
Percent!les: The percentage of all observations exceeding or preceding
some point; thus, 90th percentile is a level below which will fall 90
percent of the observations.
Perfusate: A liquid, solution or colloidal suspension that has been passed
over a special surface or through an appropriate structure.
G-35
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Perfusion: Artificial passage of fluid through blood vessels.
Permanent-press fabrics: Fabrics in which applied resins contribute to the
easy care and appearance of the fabric and to the crease and seam
flat-
ness by reacting with the cellulose on pressing after garment
manufacture.
Permeation tube: A tube which is selectively porous to specific gases.
Peroxidation: Refers to the process by which certain organic compounds
are converted to peroxides.
Peroxyacetyl nitrate (PAN): Pollutant created by action of sunlight on
hydrocarbons and NO in the air; an ingredient of photochemical smog.
pH: A measure of the acidity or alkalinity of a material, liquid, or solid.
pH is represented on a scale of 0 to 14 with 7 being a neutral state,
0 most acid, and 14 most alkaline.
Phagocytosis: Ingestion, by cells such as macrophages, of other cells,
bacteria, foreign particles, etc.; the cell membrane engulfs solid or
liquid particles which are drawn into the cytoplasm and digested.
Phenotype: The observable characteristics of an organism, resulting from
the interaction between an individual genetic structure and the
environment in which development takes place.
Phenylthiourea: A crystalline compound, CyHgN^S, that is bitter or tasteless
depending on a single dominant gene in the tester.
Phlegm: Viscid mucus secreted in abnormal quantity in the respiratory passages
Phosphatase: Any of a group of enzymes that liberate inorganic phosphate
from phosphoric esters (E.G. sub-subclass 3.1.3).
Phosphocreatine kinase: An enzyme (EC 2.7.3.2) catalyzing the formation of
creatine and ATP, its breakdown is a source of energy in the contraction
of muscle; also called creatine phosphate.
Phospholipid: A molecule consisting of lipid and phosphoric acid group(s).
An example is lecithin. Serves as an important structural factor
in biological membranes.
Photochemical oxidants: Primary ozone, NOp, PAN with lesser amounts of
other compounds formed as products of atmospheric reactions involving
organic pollutants, nitrogen oxides, oxygen, and sunlight.
Photochemical smog: Air pollution caused by chemical reaction of various
airborne chemicals in sunlight.
Photodissociation: The process by which a chemical compound breaks down into
simpler components under the influence of sunlight or other radiant energy.
G-36
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Photolysis: Decomposition upon irradiation by sunlight.
Photomultiplier tube: An electron multiplier in which electrons released
by photoelectric emission are multiplied in successive stages by
dynodes that produce secondary emissions.
Photon: A quantum of electromagnetic energy.
Photostationary: A substance or reaction which reaches and maintains a
steady state in the presence of light.
Photosynthesis: The process in which green parts of plants, when exposed to
light under suitable conditions of temperature and water supply, produce
carbohydrates using atmospheric carbon dioxide and releasing oxygen.
Phytotoxic: Poisonous to plants.
Phytoplankton: Minute aquatic plant life.
Pi n bonds: Bonds in which electron density is not symmetrical about a
line joining the bonded atoms.
Pinocytotic: Refers to the cellular process (pinocytosis) in which the cyto-
plasmic membrane forms invaginations in the form of narrow channels
leading into the cell. Liquids can flow into these channels and the
membrane pinches off pockets that are incorporated into the cytoplasm
and digested.
Pitting: A form of extremely localized corrosion that results in holes in
the metal. One of the most destructive forms of corrosion.
Pituary: A stalk-like gland near the base of the brain which is attached
to the hypothalmus. The anterior portion is a major repository for
for hormones that control growth, stimulate other glands, and regulate
the reproductive cycle.
Placenta: The organ in the uterus that provides metabolic interchange between
the fetus and mother.
Plasmid: Replicating unit, other than a nucleus gene, that contains
nucleoprotein and is involved in various aspects of metabolism in
organisms; also called paragenes.
Plasmolysis: The dissolution of cellular components, or the shrinking
of plant cells by osmotic loss of cytoplasmic water.
Plastic: A plastic is one of a large group of organic compounds synthesized
from cellulose, hydrocarbons, proteins or resins and capable of being
cast, extruded, or molded into various shapes.
Plasticizer: A chemical added to plastics to soften, increase malleability
or to make more readily deformable.
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Platelet (blood): An irregularly-shaped disk with no definite nucleus;
about one-third to one-half the size of an erythrocyte and containing
no hemoglobin. Platelets are more, numerous than leukocytes, numbering
from 200,000 to 300,000 per cu. mm. of blood.
Plethysmograph: A device for measuring and recording changes 1n volume of
a part, organ or the whole body; a body plethysmograph 1s a chamber
apparatus surrounding the entire body.
Pleura: The serous membrane enveloping the lungs and lining the walls of
the chest cavity.
Plume: Emission from a flue or chimney, usually distributed stream-like
downwind of the source, which can be distinguished from the surrounding
air by appearance or chemical characteristics.
Pneumonia (interstitial): A chronic inflammation of the interstitial tissue
of the lung, resulting in compression of the air cells. An acute, infec-
tious disease.
Pneumonocytes: A nonspecific term sometimes used in referring to types of
cells characteristic of the respiratory part of the lung.
Podzol: Any of a group of zonal soils that develop in a moist climate,
especially under coniferous or mixed forest.
Point source: A single stationary location of pollutant discharge.
Polarography: A method of quantitative or qualitative analysis based on
current-voltage curves obtained by electrolysis of a solution with
steadily increasing voltage.
Pollution gradient: A series of exposure situations in which pollutant con-
centrations range from high to low.
Polyacrylonitrile: A polymer made by reacting ethylene oxide and hydrocyanic
acid. Dyne! and Orion are examples.
Polyamides: Polymerization products of chemical compounds which contain
amino (-NH.) and carboxyl (-COOH) groups. Condensation reactions
between the groups.form amides (-CONH-). Nylon is an example of
a polyamide.
Polycarbonate: Any of various tough transparent thermoplastics characterized
by high impact strength and high softening temperature.
Polycythemia: An increase above the normal in the number of red cells in the
blood.
Polyester fiber: A man-made or manufactured fiber in which the fiber-
forming substance is any long-chain synthetic polymer composed of
at least 85 percent by weight of an ester of a dihydric alcohol and
terephthalic acid. Dacron is an example.
G-38
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Polymer: A large molecule produced by linking together many like molecules.
Polymerization: _ In fiber manufacture, converting a chemical monomer (simple
molecule) into a fiber-forming material by joining many like molecules
into a stable, long-chain structure.
Polymorphic monocyte: Type of leukocyte with a multi-lobed nucleus.
Polymorphonuclear leukocytes: Cells which represent a secondary non-
specific cellular defense mechanism. They are transported to the lungs
from the bloodstream when the burden handled by the alveolar macrophages
is too large.
Polysaccharides: Polymers made up of sugars. An example is glycogen which
consists of repeating units of glucose.
Polystyrene: A thermoplastic plastic which may be transparent, opaque,
or translucent. It is light in weight, tasteless and odorless, it
also is resistant to ordinary chemicals.
Polyurethane: Any of various polymers that contain NHCOO linkages and are
used especially in flexible and rigid foams, elastomers and resins.
Pores of Kohn: Also known as interalveolar pores; pores between air cells.
Assumed to be pathways for collateral ventilation.
Precipitation: Any of the various forms of water particles that fall from
the atmosphere to the ground, rain, snow, etc.
Precursor: A substance from which another substance is formed; specifically,
one of the anthropogenic or natural emissions or atmospheric constituents
which reacts under sunlight to form secondary pollutants comprising
photochemical smog.
Probe: In air pollution sampling, the tube or other conduit extending
into the atmosphere to be sampled, through which the sample passes
to treatment, storage and/or analytical equipment.
Proline: An amino acid, CgHgNO^, that can be synthesized from glutamate
by animals.
Promonocyte: An immature monocyte not normally seen in the circulating
blood.
Proteinuria: The presence of more than 0.3 gm of urinary protein in a
24-hour urine collection.
Pulmonary: Relating to the lungs.
Pulmonary edema: An accumulation of excessive amounts of fluid in the lungs.
G-39
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Pulmonary lumen: The spaces in the interior of the tubular elements of
the lung (bronchioles and alveolar ducts).
Pulmonary resistance: Sum of airway resistance and viscous tissue resistance.
Purine bases: Organic bases which are constituents of DMA and RNA, Including
adenine and guanine.
Purulent: Containing or forming pus.
Pyrimidine bases: Organic bases found in DNA and RNA. Cytosine and
thymine occur in DNA and cytosine and uracil are found in RNA.
QRS: Graphical representation on the electrocardiogram of a complex of three
distinct waves which represent the beginning of ventricular contraction.
Rainout: Removal of particles and/or gases from the atmosphere by their
involvement in cloud formation (particles act as condensation nuclei,
gases are absorbed by cloud droplets), with subsequent precipitation.
Rayleigh scattering: Coherent scattering in which the intensity of the
light of wavelength g, scattered in any direction making an angle
with the incident direction, is.directly proportional to 1 + cos r
and inversely proportional to g .
Reactive dyes: Dyes which react chemically with cellulose in fibers under
alkaline conditions. Also called fiber reactive or chemically
reactive dyes.
Reduction: Acceptance of electrons by an ion or molecule.
Reference method (RM): For NO-, an EPA-approved gas-phase chemiluminescent
analyzer and associated calibration techniques; regulatory specifications
are described in Title 40, Code of Federal Regulations, Part 50,
Appendix F. Formerly, Federal Reference Method.
Residual capacity: The volume of air remaining in the lungs after a maximum
expiratory effort; same as residual volume.
Residual volume (RV): The volume of air remaining in the lungs after a
maximal expiration. RV = TLC - VC
Resin: Any of various solid or semi-solid amorphous natural organic sub-
stances, usually derived from plant secretions, which are soluble in
organic solvents but not in water; also any of many synthetic substances
with similar properties used in finishing fabrics, for permanent press
shrinkage control or water repellency.
Ribosomal RNA: The most abundant RNA in a cell and an integral constituent
of ribosomes.
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Ribosomes: Discrete units of RNA and protein which are instrumental in the
synthesis of proteins in a cell. Aggregates are called polysomes.
Runoff: Water from precipitation, irrigation or other sources that flows
over the ground surface to streams.
Sclerosis: Pathological hardening of tissue, especially from overgrowth
of fibrous tissue or increase in interstitial tissue.
Selective leaching: The removal of one element from a solid alloy by
corrosion processes.
Septa: A thin wall dividing two cavities or masses of softer tissue.
Seromucoid: Pertaining to a mixture of watery and mucinous material such
as that of certain glands.
Serum antiprotease: A substance, present in serum, that Inhibits the activity
of proteinases (enzymes which destroy proteins).
Sigma (s) bonds: Bonds in which electron density is symmetrical about a
line joining the bonded atoms.
Silo-filler's disease: Pulmonary lesion produced by oxides of nitrogen
produced by fresh silage.
Single breath nitrogen elimination rate: Percentage rise in nitrogen fraction
per unit of volume expired.
Single breath nitrogen technique: A procedure in which a vital capacity
inspiration of 100 percent oxygen is followed by examination of nitrogen
in the vital capacity expirate.
Singlet state: The highly-reactive energy state of an atom in which certain
electrons have unpaired spins.
Sink: A reactant with or absorber of a substance.
Sodium arsenite: Na-AsO-, used with sodium hydroxide in the absorbing solu-
tion of a 24-hour integrated manual method for NO-.
Sodium dithionite: A strong reducing agent (a supplier of electrons).
Sodium metabisulfite: Na^Oj, used in absorbing solutions of N02 analysis
methods.
Sorb: To take up and hold by absorption or adsorption.
G-41
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Sorbent: A substance that takes up and holds another by absorption or
adsorption.
Sorbitol dehydrogenase: An enzyme that interconverts the sugars, sorbitol
and fructose.
Sorption: The process of being sorbed.
Spandex: A manufactured fiber in which the fiber forming substance is a
long chain synthetic elastomer composed of at least 85 percent of a
segmented polyurethane.
Spectrometer: An instrument used to measure radiation spectra or to deter-
mine wavelengths of the various radiations.
Spectrophotometry: A technique in which visible, UV, or infrared radiation
is passed through a substance or solution and the intensity of light
transmitted at various wavelengths is measured to determine the spectrum
of light absorbed.
Spectroscopy: Use of the spectrometer to determine concentrations of an
air pollutant.
Spermatocytes: A cell destined to give rise to spermatozoa (sperm).
Sphingomyelins: A group of phospholipids found in brain, spinal cord, kidney
and egg yolk.
Sphygomenometer: An apparatus, consisting of a cuff and a pressure gauge,
which is used to measure blood pressure.
Spirometry: Also called pneometry. Testing the air capacity of the lungs
with a pneometer.
Spleen: A large vascular organ located on the upper left side of the abdominal
cavity. It is a blood-forming organ in early life. It is a storage
organ for red corpuscles and because of the large number of macrophages,
acts as a blood filter.
Sputum: Expectorated matter, especially mucus or mucopurulent matter expec-
torated in diseases of the air passages.
Squamous: Scale-like, scaly.
Standard deviation: Measure of the dispersion of values about a mean
value. It is calculated as the positive square root of the average of
the squares of the individual deviations from the mean.
Standard temperature and pressure: 0°C, 760 mm mercury.
Staphylococcus aureus: A spherically-shaped, infectious species of bacteria
found especially on nasal mucous membrane and skin.
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Static lung compliance (c.stat): Measure of lung's elastic recoil (volume
change resulting from cRange in pressure) with no or insignificant air-
flow.
Steady state exposure: Exposure to air pollutants whose concentration
remains constant for a period of time.
Steroids: A large family of chemical substances comprising many hormones and
vitamins and having large ring structures.
Stilbene: An aromatic hydrocarbon C...H.. used as a phosphor and in making
dyes. ^ ^
Stoichiometric factor: Used to express the conversion efficiency of a non-
quantitative reaction, such as the reaction of NO- with azo dyes in air
monitoring methods.
Stoma: A minute opening or pore (plural is stomata).
Stratosphere: That region of the atmosphere extending from 11 km above the
surface of the earth to 50 km. At 50 km above the earth temperature
rises to a maximum of 0 C.
Streptococcus pyogenes: A species of bacteria found in the human mouth,
throat and respiratory tract and in inflammatory exudates, blood stream,
and lesions in human diseases. It causes formation of pus or even fatal
septicemias.
Stress corrosion cracking: Cracking caused by simultaneous presence of
tensile stress and a specific corrosive medium. The metal or alloy is
virtually unattached over most of its surface, while fine cracks progress
through it.
Strong interactions: Forces or bond energies holding molecules together.
Thermal energy will not disrupt the formed bonds.
Sublobular hepatic necrosis: The pathologic death of one or more cells, or
of a portion of the liver, beneath one or more lobes.
Succession: The progressive natural development of vegetation towards
a climax, during which one community is gradually replaced by others.
Succinate: A salt of succinic acid involved in energy production in the
citric acid cycle.
Sulfadiazine: One of a group of sulfa drugs. Highly effective against
pneumococcal, staphlococcal, and streptococcal infections.
Sulfamethazine: An antibacterial agent of the sulfonamide group, active
against homolytic streptococci, staphytococci, pneumococci and meningococci
Sulfam'limide: A crystalline sulfonamide (CgHgN^S), the amide of sulfanilic
acid and parent compound of most sulfa arugs.
G-43
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Sulfhydryl group: A chemical radical consisting of sulfur and hydrogen
which confers reducing potential to the chemical compound to which it is
attached (-SH).
Sulfur dioxide (S0?): Colorless gas with pungent odor released primarily from
burning of fossil fuels, such as coal, containing sulfur.
Sulfur dyes: Used only on vegetable fibers, such as cottons. They are
Insoluble in water and must be converted chemically in order to be
soluble. They are resistant (fast) to alkalies and washing and fairly
fast to sunlight.
Supernatant: The clear or partially clear liquid layer which separates
from the homogenate upon centrifugation or standing.
Surfactant: A substance capable of altering the physi ©chemical nature of
surfaces, such as one used to reduce surface tension of a liquid.
Symbiotic: A close association between two organisms of different species in
which at least one of the two benefits.
Synergistic: A relationship in which the combined action or effect of two
or more components is greater than that of the components acting separately.
Systolic: Relating to the rhythmical contraction of the heart.
Tachypnea: Very rapid breathing.
Terragram (Tg): One million metric tons, 10 grams.
Teratogenesis: The disturbed growth processes resulting in a deformed
fetus.
Teratogenic: Causing or relating to abnormal development of the fetus.
Threshold: The level at which a physiological or psychological effect begins
to be produced.
Thylakoid: A membranous lamella of protein and lipid in plant chloroplasts
where the photochemical reactions of photosynthesis take place.
Thymidine: A nucleoside (<-in^l4N2^5^ t^iat 1S comPose^ of thymine and
deoxyribose; occurs as a strQctural part of DMA.
Tidal volume (V,): The volume of air that is inspired or expired in a single
breath during regular breathing.
Titer: The standard of strength of a volumetric test solution. For example,
the titration of a volume of antibody-containing serum with another
volume containing virus.
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Tocopherol: a-d-tocopherol is one form of Vitamin E prepared synthetically.
The a form exhibits the most biological activity. It is an antioxidant
and retards rancidity of fats.
Torr: A unit of pressure sufficient to support a 1 mm column of mercury;
760 torr = 1 atmosphere.
Total lung capacity (TLC): The sum of all the compartments of the lung, or
the volume of air in the lungs at maximum inspiration.
Total suspended particulates (TSP): Solid and liquid particles present in
the atmosphere.
Trachea: Commonly known as the windpipe, a cartilaginous air tube extending
from the larnyx (voice box) into the thorax (chest) where it divides,
serving as the entrance to each of the lungs.
Transaminase: Ami notransf erase; an enzyme transferring an ami no group from
an a-amino acid to the carbonyl carbon atom of an a-keto acid.
Transmissivity (UV): The percent of ultraviolet radiation passing through a
a medium.
Transmittance: The fraction of the radiant energy entering an absorbing
layer which reaches the layer's further boundary.
Transpiration: The process of the loss of water vapor from plants.
Triethanolamine: An amine, (HOChLCfrOgN, used in the absorbing solution
of one analytical method for NO,.
Troposphere: That portion of the atmosphere in which temperature decreases
rapidly with altitude, clouds form, and mixing of air masses by convection
takes place. Generally extends to about 7 to 10 miles above the earth's
surface.
Type 1 epithelial cells: Squamous cells which provide a continuous lining
to the alveolar surface.
Type I pneumonocytes: Pulmonary surface epithelial cells.
Type II pneumonocytes: Great alveolar cells.
Ultraviolet: Light invisible0to the human eye of wavelengths between 4x10
and Sxio"9 m (4000 to BOA).
Urea- formaldehyde resin: A compound composed of urea and formaldehyde in
an arrangement that conveys thermosetting properties.
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Urobilinogen: One of the products of destruction of blood cells; found in
the liver, intestines and urine.
Uterus: The womb; the hollow muscular organ in which the impregnated ovum
(egg) develops into the fetus.
Vacuole: A minute space in any tissue.
Vagal: Refers to the vagus nerve. This mixed nerve arises near the medulla
oblongata and passes down from the cranial cavity to supply the larynx,
lungs, heart, esophagus, stomach, and most of the abdominal viscera.
Valence: The number of electrons capable of being bonded or donated by
an atom during bonding.
Van Slyke reactions: Reaction of primary amines, including amino acids,
with nitrous acid, yielding molecular nitrogen.
Variance: A measure of dispersion or variation of a sample from its
expected value; it is usually calculated as the square root a sum of
squared deviations about a mean divided by the sample size.
Vat dyes: Dyes which have a high degree of resistance to fading by light,
NO and washing. Widely used on cotton and viscose rayon. Colors are
brilliant and of almost any shade. The name was originally derived
from their application in a vat.
Venezuelan equine encephalomyelitis: A form of equine encephalomyelitis
found in parts of South America, Panama, Trinidad, and the United States,
and caused by a virus. Fever, diarrhea, and depression are common. In
man, there is fever and severe headache after an incubation period of 2
to 5 days.
Ventilatory volume (Vp): The volume of gas exchanged between the lungs and
the atmosphere tnat occurs in breathing.
Villus: A projection from the surface, especially of a mucous membrane.
Vinyl chloride: A gaseous chemical suspected of causing at least one type
of cancer. It is used primarily in the manufacture of polyvinyl
chloride, a plastic.
Viscose rayon: Filaments of regenerated cellulose coagulated from a solution
of cellulose xanthate. Raw materials can be cotton 1 inters or chips
of spruce, pine, or hemlock.
o
Visible region: Light between the wavelengths of 4000-8000 A.
Visual range: The distance at which an object can be distinguished from
background.
Vital capacity: The greatest volume of air that can be exhaled from the
lungs after a maximum inspiration.
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Vitamin E: Any of several fat-soluble vitamins (tocopherols), essential
in nutrition of various vertibrates.
Washout: The capture of gases and particles by falling raindrops.
Weak interactions: Forces, electrostatic in nature, which bind atoms and/or
molecules to each other. Thermal energy will disrupt the Interaction.
Also called van der Waal's forces.
Wet deposition: The process by which atmospheric substances are returned
to earth in the form of rain or other precipitation.
Wheat germ lipase: An enzyme, obtained from wheat germ, which is capable
of cleaving a fatty acid from a neutral fat; a lipolytic enzyme.
X-ray fluorescence spectrometry: A nondestructive technique which utilizes
the principle that every element emits characteristic x-ray emissions
when excited by high-energy radiation.
Zeolites: Hydrous silicates analogous to feldspars, occurring in lavas
and various soils.
Zooplankton: Minute animal life floating or swimming weakly in a body of water.
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